pediatric pulmonology

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PEDIATRIC PULMONOLOGYTHE REQUISITES IN PEDIATRICS ISBN 0-323-01909-9Copyright © 2005, Mosby, Inc.

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Library of Congress Cataloging-in-Publication Data

Pediatric pulmonology : the requisites in pediatrics / [edited by] Howard Panitch.p. ; cm.

ISBN 0-323-01909-91. Lungs—Diseases. 2. Children—Diseases. 3. Pediatric respiratory diseases.

I. Panitch, Howard.[DNLM: 1. Lung Diseases—Child. WS 280 P3668 2005]

RJ431.P395 2005618.92′24--dc22

2004052406

Acquisitions Editor: Anne LenehanDevelopmental Editor: Patrick M.N. StoneProject Manager: Mary StermelMarketing Manager: Theresa Dudas

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NOTICE

Knowledge and best practice in this field are constantly changing. As new researchand experience broaden our knowledge, changes in practice, treatment and drugtherapy may become necessary or appropriate. Readers are advised to check themost current information provided (i) on procedures featured or (ii) by the manu-facturer of each product to be administered, to verify the recommended dose orformula, the method and duration of administration, and contraindications. It is theresponsibility of the practitioner, relying on their own experience and knowledgeof the patient, to make diagnoses, to determine dosages and the best treatment foreach individual patient, and to take all appropriate safety precautions. To the fullestextent of the law, neither the Publisher nor the Editor assumes any liability for anyinjury and/or damage to persons or property arising out or related to any use of thematerial contained in this book.

The Publisher

To future caregivers of children with respiratory disease, and to our patients,who teach and inspire by their bravery and determination.

Julian L. Allen, M.D.Professor of PediatricsUniversity of Pennsylvania School of MedicineChief, Division of Pulmonary Medicine

and Cystic Fibrosis CenterRobert Gerard Morse Chair in

Pulmonary MedicineThe Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania

Raanan Arens, M.D.Associate Professor of PediatricsDivision of Pulmonary MedicineThe Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania

Anita Bhandari, M.D.Assistant Professor of PediatricsDivision of Pulmonary MedicineThe Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania

Michael R. Bye, M.D.Professor of Clinical PediatricsColumbia University College of Physicians and SurgeonsActing Director, Pediatric Pulmonary MedicineMorgan Stanley Children's Hospital of

New York PresbyterianNew York, New York

Col. Charles W. Callahan, D.O.Chief, Department of Pediatrics—Pediatric

PulmonologyTripler Army Medical CenterHonolulu, HawaiiProfessor of PediatricsUniformed University of the Health SciencesBethesda, Maryland

Russell G. Clayton, Sr., D.O.Assistant Professor of PediatricsDivision of Pulmonary MedicineThe Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania

Oscar H. Mayer, M.D.Clinical Associate in PediatricsDivision of Pulmonary MedicineThe Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania

Joshua P. Needleman, M.D.Assistant Professor of PediatricsAlbert Einstein College of MedicineSection of Pediatric Respiratory MedicineThe Children's Hospital at MontefioreBronx, New York

Brian P. O’Sullivan, M.D.Associate Professor of PediatricsUniversity of Massachusetts Medical SchoolUMass Memorial Health CareWorcester, Massachusetts

Howard Panitch, M.D.Attending PulmonologistDirector of Clinical ServicesDivision of Pulmonary MedicineThe Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania

Anand C. Patel, M.D.Fellow, Pediatric PulmonologyDepartment of PediatricsDivision of Allergy and Pulmonary MedicineSt. Louis Children's Hospital/Washington University

School of MedicineSt. Louis, Missouri

Contributors

vii

viii CONTRIBUTORS

Clement L. Ren, M.D.Associate Professor of PediatricsUniversity of RochesterChief, Division of Pediatric PulmonologyGolisano Children’s Hospital at StrongRochester, New York

Gail L. Rodgers, M.D.Associate Professor of PediatricsSection of Infectious DiseasesDrexel University College of MedicineAttending PhysicianSt. Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania

Carlos Sabogal, M.D.Pediatric PulmonologistNemours Children's ClinicOrlando, Florida

Thomas F. Scanlin, M.D.Professor of PediatricsUniversity of Pennsylvania School of MedicineDirector, Cystic Fibrosis CenterDivision of Pulmonary MedicineThe Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania

Daniel V. Schidlow, M.D.Professor and ChairDepartment of PediatricsDrexel University College of MedicineChief Medical and Academic OfficerSt. Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania

Jonathan Steinfeld, M.D.Assistant Professor of PediatricsDepartment of PediatricsDrexel University School of MedicineSt. Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania

Isaac Talmaciu, M.D.Pediatric Pulmonary and Allergy AssociatesPlantation, Florida

Haviva Veler, M.D.Pulmonary FellowDivision of Pulmonary MedicineThe Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania

Judith A. Voynow, M.D.Associate Professor of PediatricsDivision of Pediatric PulmonologyDuke University Medical CenterDurham, North Carolina

Daniel J. Weiner, M.D.Assistant ProfessorDepartment of PediatricsUniversity of Pennsylvania School of MedicineAttending Physician, Division of Pulmonary MedicineMedical Director, Pulmonary Function LaboratoryThe Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania

As I review the fourth volume of The Requisites inPediatrics, entitled Pediatric Pulmonology, two thoughtscome to mind. First, a certain momentum is building aseach new volume is published, adding substance andreality to the conceptual framework for this series.Recall that the goal of this series was to ask leading pedi-atric subspecialists to edit a book that would include theessential fund of pediatric knowledge in their subspe-cialty area. Each volume was to review the commonpediatric conditions information that would guide pri-mary care providers, resident physicians, nurse practi-tioners and students in the care of their patients. Theeditor and authors were asked to include informationabout appropriate referral to the specialist and to outlinethe laboratory testing that should be performed prior tothe referral to assist the specialist in her or his search forthe difficult diagnosis.

My second thought after reading PediatricPulmonology, edited by Howard Panitch, is how wellthis volume adheres to the vision for this series. The edi-tor and authors have created a rare book, one that isboth concise and thorough. Filled with radiographicimages, tables, pathologic pictures and numerous illus-trations, the information is accessible and practical.

There are 15 chapters in this volume, beginning with “Assessment and Approach to Common Problems” by Dr. Needleman and ending with “Viral Infections of theRespiratory Tract” by Dr. Bye. In between there arenumerous examples of the combination of medical writ-ing that is both “concise and thorough.” For example,Chapter 2, “Noisy Breathing in Infants and Children” byDr. Mayer is excellent. A common complaint in pediatrics,Dr. Mayer makes the important point that “with a focused

history and physical examination one should be able tocome very close to a diagnosis before any evaluations areperformed.” He takes the reader through the logicalapproach to these patients.

Dr. Aren’s Chapter 5, “Sleep-Disordered Breathing inChildren” is a valuable contribution. He offers an excel-lent review of this important topic, particularly obstruc-tive sleep apnea syndrome (OSAS) in children.

Another example of concise and thorough writing is theoutstanding review of “Respiratory Failure in Children,”Chapter 14, by Dr. Weiner. After reviewing normal respi-ratory physiology and the definition of hypoxia, he takesthe reader to an understanding of respiratory failure andits causes and management. Non-traditional therapies tomanage respiratory failure, such as prone positioning,negative pressure ventilation, high-frequency oscillatoryventilation, and liquid ventilation, are discussed.

After reviewing the newest volume in the Requisitesin Pediatrics series, I congratulate Dr. Panitch and theauthors for their wonderful contributions. We hope youenjoy Pediatric Pulmonology.

Louis M. Bell, M.D.Patrick S. Pasquariello, Jr. Chair in General Pediatrics

Professor of PediatricsUniversity of Pennsylvania School of Medicine

Chief, Division of General PediatricsAttending Physician, General Pediatrics

and Infectious DiseasesThe Children’s Hospital of Philadelphia

Philadelphia, Pennsylvania

Foreword

ix

Pediatric pulmonology was recognized as a subspecialtyof the American Board of Pediatrics less than two decadesago. Pediatric pulmonologists, however, have been caringfor children with lung disease in the United States andaround the world for much longer. Most pediatric pul-monary centers grew out of the teams of health careproviders assembled to treat children with cystic fibrosis.A multidisciplinary approach was developed both todeliver care and also to study the pathophysiology of thedisorder. Similar approaches have been developed to treatother pulmonary disorders like asthma, bronchopul-monary dysplasia, sleep-disordered breathing, and chronicrespiratory failure. While such specialized teams, consist-ing of physicians, nurse specialists, nutritionists, socialworkers, physiotherapists, and other medical subspecial-ists have become indispensable for delivering care to chil-dren with chronic and complex respiratory disorders, thegeneralist remains at the forefront of diagnosis and man-agement of children with respiratory disorders. Illnessesaffecting the lung remain among the most common rea-sons for parents to seek medical care for their children.

Today, pediatric pulmonologists care for childrenwith a variety of diseases that can be shared with othersubspecialists: asthma with allergists, sleep disorders withneurologists, pneumonia with infectious disease special-ists, respiratory failure with critical care physicians, to

name a few. Pediatric Pulmonology combines respiratoryembryology, physiology, and molecular biology in itsapproach to understanding and managing diseases, com-plementing those of other disciplines. It is that uniqueprocess that is highlighted in this volume.

Pediatric Pulmonology: The Requisites in Pediatricsis designed to provide students, residents, general practi-tioners and other non-physician health care providerswith such an approach to a variety of respiratory disor-ders. The content emphasizes an orderly approach to thediagnosis and management of common respiratory condi-tions affecting infants, children, and adolescents.Whenever possible, disease manifestations are explainedin terms of pathophysiologic alterations, which in turnare discussed in light of known underlying basic defects.Authors of each chapter endeavored to present practicalinformation about their respective topics, including clin-ical pearls and indications for referral to a specialist.

Working with each of the authors on their chaptershas been both a joy and a great learning experience. Ihope the reader will experience the same enjoyment andsense of enlightenment in reading this work, and comeaway with a solid understanding of the requisites in pedi-atric pulmonology.

Howard Panitch, M.D.

Preface

xi

I have many people to thank for completing this project. To begin, Drs. Louis Bell and Julian Allen gave me theopportunity to undertake and to fashion the contents ofthis volume. Thank you both for your guidance and wordsof encouragement. To the chapter authors, my friends andmembers of my “academic family tree,” I am indebted toyou for your enthusiasm and your willingness to put upwith my innumerable queries and suggestions. Your loveof the topics you wrote, and of your commitment both tocaring for children with respiratory disease and to teach-ing others how to do so, shines through. I am indebted toKathleen Sullivan, M.D., Ph.D., who helped to identifyradiographic studies of patients with immunodeficiencies,and Avrum Pollock, M.D., who magnanimously providedpublication-quality radiographs seen in several chapters.

Their contributions added critical visual reinforcements tothe authors’ texts, and were invaluable. To KimberleyCox, Patrick Stone, Anne Lenehan, and others at Elsevier,thank you for keeping us on track and moving forward.This book would never have been completed withoutyour gentle guidance. Thanks also to my mentors, Julesand Dan, who taught me that caring for one child can helpthe individual, but sharing wisdom and experience withothers has a far greater effect on the health and welfare ofour patients. You inspire by example, and I have beenblessed to have you as my teachers. And finally, to Mary,Oren, and Becky, who put up with my preoccupationswith this project on countless nights, weekends and vaca-tions, thank you for your tolerance and patience. You arethe loves of my life.

Acknowledgments

xiii

1

CHAPTER

1 Assessment andApproach to CommonProblemsJOSHUA P. NEEDLEMAN, M.D.

Investigative Techniques

History and Physical Examination

Laboratory Evaluation

Pulmonary Function Testing

Diagnostic Imaging

Bronchoscopy

Common Problems in Pediatric Pulmonary Medicine

Cough




Diagnostic Imaging

Bronchoscopy

Wheezing




Diagnostic Imaging

Bronchoscopy

Recurrent Pneumonia




Diagnostic Imaging

Bronchoscopy

Exercise Limitation


Cardiology Evaluation


Chronic Stridor


Diagnostic Imaging

Bronchoscopy

Polysomnography

Respiratory complaints are the most common reasonfor children to have sick visits and consultation with aphysician. Recurrent or chronic respiratory problems

are responsible for missed school, emergency room vis-its and hospitalizations in overwhelming numbers.Asthma alone is responsible for more than 10 millionmissed school days in the United States1–3. There is alarge set of disease states and clinical problems that pres-ent with a limited variety of respiratory signs and symp-toms. The challenge for the clinician is to isolate thepathophysiologic cause of the symptom and follow thatpath to diagnosis and eventual therapy. The object ofthis chapter will be to review the basic tools available tothe clinician in the approach to common problems inpediatric pulmonology and the application of these toolsto the most common clinical situations.

INVESTIGATIVE TECHNIQUES


The history and physical examination continue to bethe keystones of diagnosis and assessment of progress inrespiratory disease. A careful respiratory history mayrequire more than 30 minutes but is essential in deter-mining the initial approach. In addition to the standardmedical history that focuses on timing, duration andcharacterization of symptoms, there are aspects to thehistory of a chronic or recurrent respiratory problemthat require extra emphasis.• Variation with time of day. Do the symptoms vary

between day and night? Are there certain times of thenight that the symptoms are significantly worse? Somesymptoms, such as those resulting from post-nasal dripor gastroesophageal reflux, are worse immediatelyupon lying down for bed due to positioning; others,related to airway inflammation, are worse in themiddle of the night and early morning. Symptomsthat are stress-induced or habitual will often keep the patient awake but will not awaken a sleepingpatient.

• Seasonal variation. This is often quite helpful,especially with pre-school children in establishingexacerbating factors such as viral infection orpotential allergens. It can help when planning acourse of therapy with the family to have an idea ifthe symptoms are likely to be easier to controlduring the summer months or if they continueunabated.

• Medication use and delivery devices. In addition to thetypes of medications used and the clinical responseobserved, it is important to take careful note ofexactly what type of delivery device is used forinhaled medications and to have the patientdemonstrate his or her technique. Poor response totherapy is often a result of poor aerosol delivery andnot incorrect therapy prescribed. If the patient uses anebulizer, nebulizations should be supervised andgiven through a mouthpiece whenever possible.Patients with metered dose inhalers should all havespacers that are age-appropriate and they mustdemonstrate good technique in their use.

• Exercise and activity limitations. Many children withchronic or recurring respiratory problems havebecome acclimated to their disease states and willnot report difficulty with activity or exercise unlesspressed. Questions regarding the exact nature ofexercise or gym class activity, the patient’s level ofparticipation, and after-school activities can yieldvaluable clues to the level of limitation.

• Clarification of terminology. Families will often useterms such as “wheezing,” “croupy cough,” and“distress” with a variety of meanings. It is obviouslyessential to be sure that the family and the clinicianare communicating effectively4.The physical examination of the child with a persistent

respiratory problem can also be time-consuming andrequire extra attention in certain areas. As young childrenare frequently anxious in medical settings, time and careare essential to acquiring accurate data. “Slapping a stetho-scope” on the chest of a screaming toddler will, unfortu-nately, yield little useful information. As with the history,there are certain aspects worthy of extra emphasis.• Observation. Observing the young child, whose shirt

has been removed, from across the room yieldsinsight into the baseline pattern of breathing. Theinspiratory to expiratory ratio that is prolonged inobstructive disease, the presence or absence ofretractions, the natural respiratory rate, and level ofdistress can all be determined this way.

• Auscultation. Carefully listening to all lung fields isessential to characterize abnormal breath sounds.Attention to variations in character of breath soundsacross all lung fields, with notation of asymmetry, iscritical. Auscultation of the chest at different lungvolumes is important in order to comprehend the

pathology. After listening to tidal breathing, thepatient must be encouraged to take deep inspirationsand forced exhalations to reveal pathology inobstructed or partially collapsed airways. Smallchildren who cannot comply with the forcedexhalation maneuver should have the time-honored“squeeze the wheeze” technique applied. In thisprocedure, the clinician places his or her hands onthe back and front of the chest with the stethoscopeheld in between the fingers. The chest iscompressed, firmly yet gently, during exhalation toassist the patient in making a larger exhalation at ahigher flow rate. Another result of this maneuver isthat the subsequent inhalation will often be larger,and so a better assessment of inspiratory sounds canalso be made.

• Digital clubbing. An often overlooked finding, thepresence of clubbing can lead the clinician towards thediagnosis of a group of serious conditions (Table 1-1),and aid in following progress of patients with chronicchest disease.


There are some basic laboratory tests that can behelpful in the initial approach to respiratory disease.Although there is no routine panel of tests for evaluationof respiratory problems, the history and physical exami-nation will guide the clinician in effective use of the clin-ical laboratory. Some commonly utilized tests deserveextra discussion.

2 PEDIATRIC PULMONOLOGY: THE REQUISITES IN PEDIATRICS

Table 1-1 Causes of Digital Clubbing

Conditions with chronic lung infectionCystic fibrosisBronchiectasisCiliary dyskinesiaLung abscess or empyema

Pulmonary conditions associated with hypoxemiaInterstitial lung diseasePulmonary fibrosisBronchopulmonary dysplasiaHypoventilation syndromes

CongenitalSevere obstructive sleep apnea

Pulmonary hypertensionPulmonary malignancyCardiac conditions

Congenital cyanotic heart diseaseBacterial endocarditis

Gastrointestinal conditionsLiver diseaseInflammatory bowel disease

ThyrotoxicosisFamilial (benign)

• Quantitative sweat chloride. This is a non-invasive,inexpensive, highly sensitive diagnostic test for cysticfibrosis (CF). A sweat test by pilocarpine iontophoresisshould be performed at an accredited CF center asexperience with proper collection technique andquality control is important. The sweat test shouldbe considered in the evaluation of any patient withsymptoms consistent with possible CF, or history ofa sibling with CF.

• Sputum culture. Often overlooked in pediatrics, thesputum culture can be helpful in children who are oldenough to expectorate their secretions successfully.Unusual isolates, such as Pseudomonas, shouldprompt further evaluation for underlying airwaydisease or immunodeficiency.

• Arterial blood gas determination. A measure ofoxygen exchange and efficiency of ventilation, anarterial blood gas can prove valuable in evaluatingpotential hypoventilation syndromes, anxietydisorders, or potential shunting conditions. Asarterial puncture is painful, it should be performedsparingly and with the use of topical anestheticcream and intradermal lidocaine whenever possible.Transcutaneous pulse oximetry can provide a goodmeasure of oxygen saturation and, therefore, anestimate of oxygen tension that can suffice for manypatients. In addition, a venous bicarbonate level canprovide an estimate of the degree of compensationfor chronic hypoventilation in some patients.

• Allergy testing. RAST tests are available for specificallergens including fungi, dust mites and food proteins.These may be helpful in some patients, who reportspecific symptoms at certain times. Referral for skintesting is also an option for patients who appear tohave a large allergic component to their symptoms.

• Immunoglobulin levels. Total IgE may be elevated inallergic problems and is part of the screeningevaluation for allergic bronchopulmonary aspergillosis(ABPA). Quantitative immune globulins, includingIgG subclasses, are part of the evaluation forimmunodeficiency.


Pulmonary function testing includes a wide variety ofprocedures that aid in defining the underlying respira-tory physiology and pathophysiology. Pulmonary func-tion testing is useful in diagnosis of pulmonary disease,evaluating potential therapies, and monitoring progressof therapy. An understanding of the basic pulmonaryfunction tests will lead to utilizing them effectively.• Spirometry. The most commonly used pulmonary

function test, spirometry consists of measures offorced expiratory flows. Spirometry can be used todetect obstructive lung disease and to estimate

whether the site of the obstruction is in the large or small airways. It can also be used to evaluateresponse to therapy, administration ofbronchodilators (Figure 1-1). Many spirometers areportable, making them useful in diverse locations.With some instruction and patience, reliable data canbe obtained from children as young as 5 or 6 years.Recently, children as young as 3 years of age havebeen shown to be able to perform spirometryreproducibly with careful coaching.

• Measurements of lung volumes. While spirometrymeasures air forced out of the lungs, the actual sizeof the lungs cannot be determined withoutmeasuring the air remaining at the end of exhalation.The measurement of lung volumes allows thediagnosis of restrictive lung disease and air trappingfrom obstructive lung disease to be made.

Assessment and Approach to Common Problems 3

0

Flow

20.5 2.01.51.0

Volume

Baseline

Post-bronchodilator

Tidal F–V loop

Partial inspiratoryflow–volume curve

0.50.0

1

2

23

22

21

3

4

Figure 1-1 Spirometry performed by a 7-year-old boy withasthma. Flow is graphed on the ordinate and volume on theabscissa. Expiratory flow is above the baseline, while inspiratoryflow is below it. Expired volumes progress left to right from thevital capacity to residual volume. The flow–volume loops areshown before and following bronchodilator administration(smaller and larger curves, respectively). The smaller loop repre-sents a tidal volume breath. The baseline spirometry revealsmarked airflow obstruction reflected in a concavity of theflow–volume loop towards the volume axis. There is an almostcomplete reversal of obstruction following the bronchodilator,with a significant increase in flow at all lung volumes. It is of notethat the patient was asymptomatic and had a normal physicalexamination at baseline.

Lung volumes are measured by either gas dilutionmethods or in a plethysmographic box. Bothtechniques require equipment usually found only inpulmonary function laboratories and can be done incooperative children as young as 7–8 years of age.

• Bronchial provocation. Bronchial provocation testsare used to provoke airway reactivity and aid in thediagnosis of asthma. Pulmonary function is measuredat baseline and then at increasing doses of an inhaledbronchoconstrictor while lung function is measuredserially. A reduction in pulmonary function of 20% orgreater from baseline in response to the provocativeagent is considered a positive sign of airway reactivity.Agents commonly used include methacholine,histamine, hypertonic saline and dry cold air.

• Exercise testing. As exercise limitation is a commoncomplaint, exercise testing can be a valuable tool. Ina formal exercise test, the subject performs spirometryand then exercises maximally on either a stationarybicycle or a treadmill. Oxygen consumption, carbondioxide production, heart rate, oxygen saturation andblood pressure are all measured. Following exercise,spirometry is again measured serially for 20 minutes.Utilizing this test, the cause of the exercise limitationcan be pinpointed. If there is a significant decline inlung function, for example, a diagnosis of exercise-induced asthma can be established. Non-pulmonarycauses of exercise intolerance can be diagnosed as well.

Diagnostic Imaging

There are several important diagnostic imaging modal-ities available to the clinician in the initial approach torespiratory disease5. Diagnostic imaging can frequentlyestablish a diagnosis, but is often just as useful to excludeunusual diagnoses and to allow the clinical impression to lead therapy. The most commonly used tests arereviewed below.• Chest radiographs. Still the staple of evaluation of

respiratory disease, the plain chest film is useful inexcluding pneumonia, pneumothorax and thoracictumors among other causes of symptoms. In additionto the presence of large lesions and infiltrations, thechest radiograph can demonstrate signs ofinflammation and airflow obstruction such asperibronchial cuffing and hyperinflation. The plainfilm can demonstrate interstitial lung disease as well,which will lead the clinician to consider otherpossibilities.

• Fluoroscopy. Fluoroscopic evaluation of the airwaycan be useful in the diagnosis of large airwaycollapse. Although less sensitive than bronchoscopy,it is fast, does not require sedation and can be pairedwith an esophagram6. Fluoroscopy is also useful indetecting abnormal diaphragm function.

• Esophagram. A useful test for structural evaluationof the upper gastrointestinal tract in patients withgastroesophageal reflux, it is also helpful in thediagnosis of vascular anomalies that cause airwaycompression including vascular rings and slings.

• Computed tomography (CT scan). The CT scanprovides a more detailed picture of the lungs withhigher resolution than the standard chest radiograph.It is useful in the diagnosis of parenchymal problemssuch as interstitial lung disease, pneumonia andabscesses. The CT scan can also evaluate airwaylesions including bronchiectasis, and pleural diseaseas well (Figure 1-2).

• Magnetic resonance imaging and angiography(MRI/MRA). While the CT scan provides a detailedimage of the airways and lung parenchyma, MRI andMRA scans can provide the most detailed informationabout vascular structures in the chest. This can beuseful in the evaluation of possible vascular anomaliesthat are compromising the airways.

Bronchoscopy

Visualization of the laryngeal structures, trachea andbronchi is useful in the evaluation of many respiratorysymptoms7. When done while the patient is comfort-able, sedated and breathing spontaneously, flexiblebronchoscopy can yield valuable information about thestructure of the airway and its function. In addition, flex-ible bronchoscopy affords the clinician the opportunityto sample distal airway secretions in the form of bron-choalveolar lavage fluid. Lavage fluid can be processedfor cultures and for evidence of chronic aspiration orbleeding.

COMMON PROBLEMS IN PEDIATRICPULMONARY MEDICINE

Cough

Cough is one of the most common symptoms forwhich patients present to their doctors8. The impact ofcough on the quality of life for the patient and family can-not be overemphasized. In addition to discomfort and lossof sleep, a child with a chronic cough provokes worry andanxiety on the part of the entire family. While pursuingthe diagnosis and appropriate treatment, the clinicianmust also be sensitive to the family’s concerns and addressthem directly. This discussion will focus on the chroniccough, usually defined as a cough present for more than6–8 weeks.

History and Physical ExaminationThe potential etiologies for a chronic cough are

numerous (Table 1-2), and a careful history and physical


examination is the first step to narrowing the focus.Characterization of the cough, its timing and severity isimportant9. However, the quality of the cough (dry, wet,barky) often proves to be unhelpful, as patients may per-ceive the cough differently from a trained clinician. It iscommon, for example, for the parent of a child with sinusi-tis to say that the cough has “gone to his chest” despite theabsence of any thoracic findings on examination.

The timing of the cough can be helpful in narrowingdiagnostic options. Irritative coughs from post-nasal drip,sinusitis, or gastroesophageal reflux are often worseimmediately upon lying down for sleep. Nocturnal coughis a major feature of asthma and often occurs in the mid-dle of the night or early morning10. Cough followingexercise or activity can also suggest an asthma compo-nent. The presence of any nocturnal symptoms wouldargue strongly against habit (psychogenic) cough11.

The physical examination can prove helpful if posi-tive findings are revealed, such as wheezing on forcedexhalation suggesting asthma, or the presence of post-nasal drip in the hypopharynx. The presence of digitalclubbing or nasal polyps would certainly raise the suspi-cion of CF. In many cases, however, the physical exami-nation will prove to be unremarkable and leave theclinician with the list of diagnostic possibilities unaltered.

Laboratory EvaluationA sweat test is the most commonly indicated test in

the evaluation of the child with chronic cough. It shouldbe considered in any child in whom the cause of thecough is not readily determined. As CF can present in avariety of ways, with variable severity, the sweat testshould not be withheld because the patient is well-appearing12. Other laboratory tests that may be helpfulin selected patients are allergy panels if there appears


Figure 1-2 CT scan with contrast revealing obstruction of the left main bronchus and completecollapse of the left lung in a 9-year-old boy. The lumen of the left main bronchus can be seen justdistal to the main carina in the left upper panel (arrow). As images are taken more caudally, thelumen of the airway disappears. The left lung is smaller than the right, suggesting central airwayobstruction with atelectasis, and not a diffuse infiltrative process, as the cause of these findings. Thepatient had aspirated chewing gum while sleeping.


Table 1-2 Causes of Chronic Cough in Childrenwith Some Typical Features

Upper respiratory tract irritationPost-nasal drip/rhinitis Nasal congestion

Throat clearingComplain of “tickle” in throatWorse on lying down

Sinusitis HeadachesHalitosisWorse on lying down

Gastroesophageal reflux After feeds (especially infants)Worse on lying down

Swallowing dysfunction Cough when eating or drinkingInfectious or postinfectious

Respiratory syncytial Infants, seasonalvirus (RSV)

Chlamydia Infants, history of eye dischargePertussis May have missed immunizationTuberculosis Positive purified protein

derivative (PPD)Intrathoracic airway

Tracheomalacia Airway collapse onfluoroscopy/bronchoscopy

Bronchomalacia Diagnosis by bronchoscopyForeign body Sudden onset with choking

episodeCharacteristic radiographic

findingsAsthma Responds to bronchodilators

Worse with exercise or upperrespiratory infections (URIs)

Gastroesophageal refluxConditions with chronic

infectionCystic fibrosis Abnormal chest radiograph

Gastrointestinal symptoms/poor growth

Primary ciliary dyskinesia SinusitisOtitis

Bronchiectasis Purulent sputum, abnormal radiograph

Immunodeficiency Recurrent infectionsMedication-induced

ACE inhibitors Dry coughPreservatives in inhaled Temporal association

medicationsHabit cough Not present while sleeping

to be an environmental or seasonal component, and animmunodeficiency investigation if a history of otherinfections is present.

Pulmonary Function TestingThe presence, on spirometry, of airflow obstruction

that responds to bronchodilator inhalation confirms thepresence of asthma in the child with a chronic cough. Ifinitial spirometry is normal and the etiology of the coughis still in doubt, bronchial provocation may be indicatedto further evaluate the possibility of asthma as a factor.

Diagnostic ImagingA chest radiograph is often helpful in the evaluation

of the child with chronic cough. Frequently unremark-able, it helps alleviate familial concerns, often unspoken,of tuberculosis or tumor as a cause of the symptoms. Aradiograph that looks surprisingly “dirty” could suggestchronic inflammation or recurrent aspiration. If sinusitis isan etiologic possibility, a sinus CT scan is the modality ofchoice for making the diagnosis.

BronchoscopyAlthough infrequently indicated, when used judi-

ciously bronchoscopy can add a great deal to the evalu-ation. It is the ideal method for diagnosis of large airwaycollapse and for sampling lower airway fluid for culture.The identification of lipid-laden macrophages providescircumstantial evidence that chronic aspiration may beplaying a role in the symptoms.

When pursuing the cause and treatment of chroniccough in a child it is important to take the symptoms seri-ously and to be cognizant of their impact on the child andfamily. Evaluation of therapy is complicated by the factthat available treatments for post-nasal drip and gastro-esophageal reflux are often only partially effective and thatoften a significant placebo effect exists. The clinician needsto remember, as well, that many patients can have morethan one cause of cough at given times: the patient withasthma can develop sinusitis, for example. Patience in theevaluation and careful attention to the patient’s complaintsand reports will lead to a satisfactory conclusion.

Wheezing

A wheeze on auscultation is a musical, continuoussound that reflects increased airway narrowing at somepoint in the respiratory system. Although historicallyconsidered a sign of intrapulmonary disease, it hasrecently been shown that wheezing can occur withextrapulmonary obstruction as well13. The most com-mon cause of wheezing is asthma, but careful considera-tion of alternative diagnoses will reveal additionalproblems as well (Table 1-3).

History and Physical ExaminationThe history is important with regard to timing and

seasonal variation. Careful attention to diurnal variationin symptoms will help narrow the focus and allow theisolation of possible environmental factors. As previ-ously stated, clarification of terminology can be critical,yet difficult; the word wheeze may have a differentmeaning to the patient versus the clinician.

The physical examination is vital if there are ausculta-tory findings. The clinician should try to provoke find-ings with forced exhalation maneuvers if they areabsent. Wheezing can be categorized by phase of respi-ration (expiratory, inspiratory, or both) and by quality

of tone. A heterophonous wheeze, such as that heard inasthma or bronchiolitis, is diffuse and changes in toneand pitch as the stethoscope is moved across the chest.A homophonous wheeze, such as that heard in tracheo-malacia or bronchomalacia, is uniform in tone and pitchthroughout the thorax, although it may differ in ampli-tude regionally.

As in every evaluation, the presence of digital club-bing should raise suspicion that CF or some otherchronic suppurative lung disease is present.

Laboratory EvaluationThe laboratory evaluation of the child with recurrent

or chronic wheeze is usually limited and guided by sus-picions raised on the physical examination. The mostcommonly ordered test is the sweat test to exclude CF.Additionally, allergy testing may be helpful in somecases. If ABPA is suspected then the appropriate serol-ogy can be obtained.

Pulmonary Function TestingWhenever possible, pulmonary function should be

obtained in children who are being evaluated for recur-rent or chronic wheezing. The major constraint toobtaining spirometry is often the child’s age. Infant pul-monary function testing exists but is still not available tomost clinicians. All other children will have their evalua-tion enhanced by the presence of spirometry and addi-tional lung function tests as indicated.

The demonstration of reversible airflow obstructionon spirometry is an important component in the establish-ment of a diagnosis of asthma. If there is no obstruction

documented, bronchial provocation may be considerednext. Lung volumes are helpful in excluding restrictivedisease. The patient with a great deal of distress, loudwheezing and non-obstructed pulmonary function testson exhalation may have vocal cord dysfunction.

Diagnostic ImagingThe chest radiograph may reveal infiltration, collapse,

or differential hyperinflation suggestive of a foreign body.Additional studies include an esophagram with fluo-roscopy to look for large airway impingement or col-lapse, and a CT scan if the plain film suggests interstitialdisease or bronchiectasis.

BronchoscopyWhen used judiciously the flexible bronchoscope can

yield a wealth of information in the evaluation of chronicwheezing7. The larynx can be examined carefully andvocal motion assessed. Adduction of the vocal cords dur-ing inspiration in the awake or lightly sedated patient willconfirm the diagnosis of vocal cord dysfunction (VCD).The trachea and bronchi can be assessed for malacia.Bronchoalveolar fluid can be sampled for signs of infectionor aspiration.

Recurrent Pneumonia

The child with a history of more than one episode ofpneumonia may require further evaluation. A singleepisode of pneumonia is usually not a cause for concernin a child, but more that one episode in a year, or threeduring childhood, should provoke further evaluation14.


Table 1-3 Causes of Recurrent or Chronic Wheezing in Children

Features Findings on Evaluation

Asthma Worse with exercise or respiratory infections Reversible obstruction on pulmonary function testsResponds to bronchodilators Heterophonous wheezeResponds to steroids Positive broncho-provocation

Tracheomalacia Worse with activity Homophonous wheezePoor response to bronchodilators Airway collapse on fluoroscopyPoor response to steroids Collapsible trachea on bronchoscopy

Bronchomalacia Worse with activity Homophonous wheezePoor response to bronchodilators Collapsible bronchus on bronchoscopyPoor response to steroids

Foreign body Sudden onset in history Differential breath soundsDifferential hyperinflation or collapse

on radiographHeart failure/pulmonary edema Poor response to albuterol Hepatomegaly

Poor growth Responds to diuresisBronchiolitis Infant—viral infection Positive viral studiesVocal cord dysfunction Poor response to all therapies Pulmonary function tests: normal or with abnormal

Severe distress reported inspiratory loopLaryngoscopy: vocal cord adduction during inspiration

Cystic fibrosis Poor growth, gastrointestinal symptoms Positive sweat testRecurrent pneumonias

Some studies have suggested that an underlying illnesswill be found as frequently as 80% of the time in thesepatients15 (Table 1-4).

History and Physical ExaminationThe history is important to narrow the focus of the

evaluation. Careful questioning for signs associated withasthma is important. Extrapulmonary symptoms areimportant to elicit, as they will suggest underlying dis-eases such as CF or immunodeficiency.

In addition to a careful respiratory examination, thephysical examination should also look for extrapulmonaryclues, such as digital clubbing, nasal polyps, or chronicpurulent rhinorrhea, suggesting an underlying disease.

Laboratory EvaluationA sweat test is, as previously noted, the test of choice

for ruling out CF and should be considered in everyevaluation of a child with recurrent pneumonia, especiallywhen the area of involvement occurs in different loca-tions. An immunodeficiency evaluation may be indicatedas well.

Pulmonary Function TestingPulmonary function testing is helpful in the diagnosis

of asthma, a common cause of recurrent radiographicfindings in children. In addition, children with CF andother causes of bronchiectasis often have obstructivedefects on their pulmonary function tests.

Diagnostic ImagingEssential to the initial evaluation is the comparison of

all radiographs obtained. Recurrent infiltrates or atelec-tasis in the same area suggest the possibility of an

anatomic malformation, airway anomaly, or retained foreign body. This will guide the evaluation towardsscrutiny of the airways, mediastinal structures, and lungparenchyma. Recurrent or persistent right middle lobeinfiltration is common in children with asthma. Rightupper lobe pneumonia with atelectasis is a frequent presenting finding in infants with CF.

CT scans can be valuable in the diagnosis of bronchiec-tasis and other parenchymal diseases. Congenital anomaliessuch as sequestrations or congenital cystic adenomatoidmalformations that can become infected repeatedly canalso be demonstrated on a CT scan with intravenous con-trast. Swallowing studies and an esophagram may be indi-cated if dysphagia or reflux and aspiration are suspected.

BronchoscopyBronchoscopy can be helpful in the diagnosis of

retained foreign body, airway anomalies and in samplingbronchoalveolar fluid for microbiology studies16. Mucosalbiopsies can also be taken to evaluate the cilia by electronmicroscopy. The lavage fluid, in addition to being culturedto detect possible infection, should be evaluated for hemo-siderin-laden macrophages, as in the case of pulmonaryhemosiderosis, and lipid-laden macrophages, which can beseen in large numbers in aspiration syndromes.

Exercise Limitation

A common complaint in the school-aged and adoles-cent patient is a limitation of activity or exercise. The ini-tial challenge to the clinician is to determine whether


Table 1-4 Causes of Recurrent Radiographic Infiltration in Children

Asthma Often right middle lobeMay be atelectasis that is diagnosed as pneumonia

Cystic fibrosis Sweat test positivePrimary ciliary dyskinesia Chronic otitis, chronic purulent rhinitis, sinusitisBronchiectasis (idiopathic) Seen on CT scanCongenital pulmonary anomalies

Cystic adenomatoid malformationPulmonary sequestrationBronchogenic cyst

Airway anomalies Evaluated by bronchoscopyTracheomalaciaBronchomalaciaAirway compression syndromes

Immunodeficiency Usually other infections as well and poor growthAspiration syndromes Suggested by history, upper gastrointestinal and swallowing studies

Tracheo-esophageal fistulaDysphagiaGastroesophageal reflux

Pulmonary hemosiderosis Associated with anemiaNeuromuscular disease Weak cough

the symptoms represent pathology or merely poor con-ditioning or effort. The purpose of the initial evaluationis to localize the cause of the limitation to pulmonary dis-ease, cardiac disease, musculoskeletal weakness, poorconditioning, or psychogenic causes17 (Table 1-5).

History and Physical ExaminationThe history of the complaint will, as always, guide the

course of the initial evaluation. Key features to establishin the history include:• Timing of the problem with regard to exercise: does

it happen at the start of exercise or after a period ofintense exercise? Exercise-induced asthma usuallymanifests itself at the beginning of exercise, althoughit can also occur at the end of an exercise period. Itis less likely to occur after a warm-up period, andusually self-resolves after 30–60 minutes18.

• Past history of exercise. Has the patient beensedentary or athletic in the past? Is this a newproblem or a long-standing one? If poor conditioningis a factor, it will often appear after a long hiatusfrom physical activity.

• Associated respiratory symptoms. The presence ofcough, chest tightness or wheeze suggest that theproblem is exercised-induced asthma.

• History of loss of consciousness or palpitations. Thesymptoms suggest a cardiac dysrhythmia and shouldprompt a cardiology evaluation.The physical examination when performed at rest is

often normal. All physical findings should be pursued, of

course, but the patient may need to be stressed and exer-cised in order to produce both symptoms and physicalfindings.

Cardiology EvaluationWhen suggested by the history and initial evaluation,

a cardiac evaluation is indicated. This can include anelectrocardiogram (ECG), an echocardiogram, a Holtermonitor, and a stress test. The stress ECG can, ideally, becombined with measures of metabolism and pulmonaryfunction in the cardiopulmonary exercise test.

Pulmonary Function TestingBasic pulmonary function testing including spirome-

try with a bronchodilator challenge is often sufficient toestablish a provisional diagnosis. If the patient demon-strates reversible airflow obstruction, it is likely thatasthma is the cause of the exercise complaints and a trialof asthma therapy can be initiated.

If the initial pulmonary function testing is normaland the clinician suspects that the problem is asthmathen two possible courses of action can follow: thepatient can be given a therapeutic trial of asthma ther-apy or the evaluation can proceed with cardiopul-monary exercise testing. Cardiopulmonary exercisetesting is indicated when the cause of the patient’sexercise limitation is undetermined or the role of aknown condition, such as asthma, in the patient’ssymptoms is unclear. Many patients who have asthmathat is well controlled will also have poor conditioningand attribute their exercise symptoms to asthmainstead of their lack of conditioning. These patientswill often inappropriately limit their activity or increasetheir asthma therapy. Cardiopulmonary exercise test-ing can help tailor appropriate exercise regimens andprograms for asthma control.

The role of exercise and play in a child’s developmentand health should not be under-emphasized. Any limita-tion of a child or adolescent’s activity level should bepursued and addressed. Careful attention to this aspectof the respiratory evaluation will have a large impact onthe quality of life of many patients.

Chronic Stridor

Stridor, the harsh, coarse, grating sound with crowingquality, is indicative of extrathoracic airflow obstruc-tion19. Stridor can be inspiratory or inspiratory and expi-ratory. Biphasic stridor implies a fixed airflow obstructionwhile a sound present only during inspiration is morelikely to be from a dynamic extrathoracic lesion. Whilethere are a number of possible causes of chronic stridor ininfants and children (Table 1-6 and Chapter 2), a carefulhistory and physical examination will differentiate thechildren who need aggressive evaluation from those whomerely need observation.


Table 1-5 Common Causes of Exercise Limitation inChildren

Poor conditioning ObesitySedentary lifestyle

Respiratory disease Exercise-induced asthmaRestrictive lung diseasePulmonary fibrosisChronic obstructive lung diseases

Cystic fibrosisBronchiectasisEmphysema

Bronchopulmonary dysplasiaCardiac disease Cardiomyopathy

Heart failurePulmonary hypertension

Neuromuscular disease Skeletal muscle weaknessRespiratory muscle weakness

Systemic, chronic illness Sickle cell diseaseChronic metabolic acidosisDiabetes mellitus

Functional or psychogenic Vocal cord dysfunctionAnxiety reactionPoor effort

History and Physical ExaminationSpecific issues to elucidate in the history include:

• Timing of onset. Has this problem been there sincebirth, such as laryngomalacia or a congenital stenosis,or did it arise after a traumatic event? Is there a historyof choking or coughing preceding the developmentof stridor? Is there a history of behaviors, such aseating nuts or mouthing small objects, that wouldsuggest a risk of possible foreign body aspiration20,21?

• Relationship to feeding. Both gastroesophageal refluxand primary aspiration can present with stridor22,23,with timing of the respiratory noise during or soonafter a meal.

• Effect of position and sleep state on stridor.Laryngomalacia is often better when the infant is inthe prone position, is often worse with excitementor activity and is better with sleep. Hypopharyngealhypotonia is often worse during sleep.

• Observations of respiratory distress or apnea. Thiscan be critical in deciding which child should beobserved and which needs an aggressive evaluation.Many children are noisy but are comfortable and aregrowing. Any report of poor growth, cessation ofrespiration, distress, or cyanosis would, obviously,require an in-depth evaluation.When performing the physical examination, attention

should be paid to the quality of the stridor and its phase.Stridor can be classified as inspiratory or biphasic. Someauthors refer to the homophonous wheeze of intratho-racic, central airway obstruction as expiratory stridor.The stridor of laryngomalacia has softer, blowing qualitythan the harsh stridor of a fixed obstruction such as subglottic stenosis.

Diagnostic ImagingInitial evaluation can begin with radiographs of the

chest and soft tissues of the neck. This is helpful in caseswith radio-opaque foreign bodies or retropharyngealswelling. Some cases of subglottic narrowing will beapparent on the soft tissue neck films.

An esophagram is often the next study when consid-ering the possibility of vascular compression of the airway24. In some situations CT scan reconstructions ofthe airway can provide information not obtained duringbronchoscopy.

BronchoscopyDirect visualization of the airway is most often the key

to diagnosis25. Ideally the patient will be comfortable andbreathing spontaneously, allowing a dynamic evaluationof the respiratory system in motion. The airway should beevaluated completely from the opening of the nares tothe trachea and bronchi. The presence of laryngomalaciadoes not exclude the possibility of pathology below thevocal cords, mandating a complete evaluation.

PolysomnographyAlthough not necessary for diagnosis, physiologic

recordings of breathing patterns and oxygenation can behelpful in grading the severity of the airflow obstructionand in decision-making regarding intervention. Thenoisy breather who does not have hypoventilation oroxyhemoglobin desaturation is more likely to be onewho can be watched carefully without intervention.

In summary, a wide variety of clinical entities presentwith a limited number of respiratory complaints. Thechallenge for the clinician is to determine the underlyingpathophysiology and direct the evaluation and therapyappropriately. A careful history and physical examina-tion will direct the clinician to a focused evaluation andthe appropriate approach in the majority of cases.


MAJOR POINTS

1. A large number of clinical problems present witha limited variety of signs and symptoms.

2. A careful respiratory history will narrow thedifferential diagnosis and guide the evaluation.

3. The sweat test is the best test to rule out CF. Non-invasive and inexpensive, it should beconsidered in any patient with symptomsconsistent with CF.

4. Pulmonary function testing can aid in thediagnosis and management of chronic respiratoryconditions, providing information not obtainablethrough history or physical examination.

5. Flexible bronchoscopy, when used judiciously, canyield a great deal of information, especially withsuspected central airway lesions.

�

�

Table 1-6 Causes of Chronic Stridor in Infants andChildren

Nasal pharyngeal Often associated with malformations dysmorphism or syndrome

Hypopharyngeal hypotonia Worse with sleepLaryngomalacia Improved with sleep, prone positionLaryngeal web, cysts Usually biphasicVocal cord paralysis History of weak crySubglottic stenosis Often history of intubation,

usually biphasicSubglottic hemangioma Can be associated with other

hemangiomasVascular malformation Positive barium swallowForeign body aspiration History can be positiveEsophageal foreign body May have findings on chest

radiographGastroesophageal reflux Can worsen laryngomalacia or

cause laryngospasmHypocalcemia Can cause tetany of vocal cords

REFERENCES

1. Taylor WR, Newacheck PW. Impact of childhood asthmaon health. Pediatrics 90:657–662, 1992.

2. vonMutius E. The burden of childhood asthma. Arch DisChild 82(Suppl II):ii2–ii5, 2000.

3. Maier WC, Arrighi HM, Morray B, Llewllyn C, Redding GJ.The impact of asthma and asthma-like illness in Seattleschool children. J Clin Epidemiol 51:557–568, 1998.

4. Elphick HE, Sherlock P, Foxall G, Simpson EJ, Shiell NA,Primhak RA, Everard ML. Survey of respiratory sounds ininfants. Arch Dis Child 84:35–39, 2001.

5. Harty MP, Kramer SS. Recent advances in pediatric pul-monary imaging. Curr Opin Pediatr 10:227–235, 1998.

6. Callahan CW. Primary tracheomalacia and gastroesophagealreflux in infants with cough. Clin Pediatr 37:725–732, 1998.

7. Schellhase DE, Fawcett DD, Shutze GE, Lensing SY, Tryka AF.Clinical utility of flexible bronchoscopy and bronchoalveolarlavage in young children with recurrent wheezing. J Pediatr132:321–328, 1998.

8. Irwin RS, Madison JM. The diagnosis and treatment ofcough. N Engl J Med 343:1715–1721,2000.

9. Schidlow DV. Cough in children. J Asthma 33:81–87, 1996.

10. Martin RJ, Banks-Schlegel S. Chronobiology of asthma. AmJ Respir Crit Care Med 158:1002–1007, 1998.

11. Lokshin B, Lindren S, Weinberger M, Koviach J. Outcomeof habit cough in children treated with a brief session ofsuggestion therapy. Ann Allergy 67:579–582, 1991.

12. Rosenstein BJ. What is a cystic fibrosis diagnosis? Clin ChestMed 19:423–441, 1998.

13. Newman KB, Mason UG, Schmaling KB. Clinical features ofvocal cord dysfunction. Am J Respir Crit Care Med 152:1382–1386, 1995.

14. Owayed AF, Campbell DM, Wang EEL. Underlying causesof recurrent pneumonia in children. Arch Pediatr AdolescMed 154:190–194, 2000.

15. Lodh R, Puranik M, Natch UC, Kabra SK. Recurrent pneu-monia in children: clinical profile and underlying causes.Acta Pediatr 91:1170–1173, 2002.

16. Khan FW, Jones JM. Diagnosing bacterial respiratory infection by bronchoalveolar lavage. J Infect Dis 155:862–869,1987.

17. Wasserman K, Hansen JE, Sue DY, Casaburi R. Patho-physiology of disorders limiting exercise. In: Principles ofexercise testing, pp 95–114. Baltimore: Lippincott Williamsand Wilkins, 1999.

18. McFadden ER, Gilbert IA. Exercised-induced asthma. N EnglJ Med 330:1362–1367, 1994.

19. Friedman EM, Vastola AP, McGill TJ, Healy GB. Chronicpediatric stridor: etiology and outcome. Laryngoscope100:227–280, 1990.

20. Virgilis D, Weinberger JM, Fisher D, Goldberg S, Picard E,Kerem E. Vocal cord paralysis secondary to impacted foreign bodies in young children. Pediatrics 107:e101,2001.

21. Chan YL, Chang SS, Kao KL, Liao HC, Liaw SJ, Chiu TF, et al. Button battery ingestion: an analysis of 25 cases.Chang Gung Med J 25:169–174, 2002.

22. Sheikh S, Allen E, Shell R, Hruschak J, Iram D, Castile R, et al. Chronic aspiration without gastroesophageal refluxas a cause of chronic respiratory symptoms in neurologi-cally normal infants. Chest 120:1190–1195, 2001.

23. Bibi H, Khvolis E, Shoseyov D, Ohaly M, Dor DB, London D,et al. The prevalence of gastroesophageal reflux in children with tracheomalacia and laryngomalacia. Chest119:409–413, 2001.

24. Bove T, Demanet H, Casimir G, Viart P, Goldstein JP,Devaert FE. Tracheobronchial compression of vascular origin. Review of experience in infants and children. J Cardiovasc Surg 42:663–666, 2001.

25. Wood RE. The emerging role of flexible bronchoscopy inpediatrics. Clin Chest Med 22:311–317, 2001.


12

CHAPTER

2 Noisy Breathing inInfants and ChildrenOSCAR H. MAYER, M.D.

History

Physical Examination

Differential Diagnosis of Noisy Breathing

Extrathoracic

Nose/Nasopharynx

Oropharynx

Hypopharynx

Larynx

Glottis

Subglottis/Extrathoracic Trachea

Intrathoracic Airway

Trachea: Extrinsic Compression

Trachea: Intramural Airway Lesions

Intraluminal Airway Lesions

Bronchi/Bronchioles

Evaluation

Conclusion

Evaluating a child with noisy breathing can be chal-lenging due to the wide range of potential causes of thenoise. Obtaining a comprehensive history and physicalexamination is a critically important first step in assessingthe child with noisy breathing, and often the diagnosis isevident afterwards and before any testing is performed.

Noisy breathing occurs as a result of turbulent airflow;therefore, airflow is necessary to produce noisy breath-ing. For example, a patient in status asthmaticus whoseairflow is poor because of severe airway obstruction mayonly demonstrate very mild or even no wheezing. Clearlyin this situation, a physical examination that includes achest evaluation that is “clear to auscultation” would be apoor prognostic sign. The converse also holds, whereimproving aeration in a patient with an obstructive air-way disease leads to more audible adventitious breathsounds, suggesting improvement rather than worsening.Therefore it is important to place findings from the phys-ical examination within the proper paradigm.

HISTORY

It is helpful first to determine whether a condition isacute, chronic, or recurrent. If a condition is acute, itssymptoms are present for less than 3 weeks. Acutesymptoms can accompany a new episode of noisybreathing with no prior occurrence, or they may ariseduring a chronic or recurrent process as an exacerba-tion, as with asthma. Chronic conditions are present forover a month with baseline symptoms that never fullyresolve or remit without therapy, such as with asthma.Recurrent conditions last through at least one treatmentcourse and/or 2 weeks, but after treatment the symp-toms completely resolve without the need for chronicintervention. Recurrent symptoms come back again afterinitial resolution of symptoms, but the intervening periodbetween exacerbations should be free of symptoms. Onoccasion chronic or recurrent conditions will come tolight during an acute exacerbation of symptoms. Initialonset of symptoms is also important to determine. Thosethat arise at birth or within the first 3–4 months of lifeoften are associated with congenital lesions. Those thatappear later are typically acquired.

After determining whether something is acute,chronic, or recurrent, one should then localize the lesionto the extra- or intrathoracic airway. This can often beaccomplished by asking the patient or caregiver whetherthe noise occurs primarily during inspiration or expira-tion. Typically, inspiratory sounds are extrathoracic andexpiratory sounds are intrathoracic. Noises that occur dur-ing both inspiration and exhalation, or biphasic sounds,usually represent a fixed intrathoracic or extrathoracic air-way lesion. Less commonly, biphasic sounds can arisefrom two separate lesions, one residing in the intratho-racic and the other in the extrathoracic airway.

Response to previous therapies can yield importantclues to the cause of a disorder. Resolution of symptoms

Noisy Breathing in Infants and Children 13

after bronchodilator use, even if relief is partial or short-lived, reflects some component of reversibility of airwayobstruction, which is a major component of asthma.Similarly, improvement with inhaled or systemic anti-inflammatory therapy would also be consistent withasthma or another inflammatory disease. The conditionsor time of day when the symptoms are worst also pro-vide important diagnostic clues. Asthma symptoms areoften triggered by exercise, or environmental conditionssuch as hot or cold temperature or humid or dry air.Increased activity can also worsen symptoms in patientswith dynamic obstruction such as laryngomalacia andthose with fixed airway obstruction. Nocturnal symp-toms are commonly seen with upper airway obstructionparticularly from airway hypotonia or adenotonsillarhypertrophy. Patients with increased upper airwaysecretions from allergic rhinitis or sinusitis will demon-strate symptoms that are most prominent during thenighttime when they are recumbent.

An environmental history to evaluate home and com-munity conditions is also important. Unrepaired waterdamage and excessive humidification can favor moldand dust mite growth that can increase symptoms inpatients with allergic rhinitis or asthma. Patients wholive in rural areas and in river basins can be exposed toa variety of endemic fungi to which they may develop asensitivity.

Past medical history and previous medical interven-tions uncover pre-existing conditions and risk factors foracquired problems. Premature birth with the develop-ment of bronchopulmonary dysplasia, and prolongedinvasive mechanical ventilation, can cause lung parenchy-mal and airway damage with airway smooth musclehypertonia and hypersensitivity. Prior airway interven-tions, such as intubation for any period, can cause upperairway obstruction ranging from acute post-extubationinflammation and edema to fixed changes such as granu-lation tissue formation and subglottic stenosis. Many priorviral lower airway infections, such as those from respira-tory syncytial, influenza, and parainfluenza viruses, canresult in episodes of recurrent wheezing.

A thorough review of systems can pick up coincidentconditions that may impact the respiratory systemincluding those within the cardiac, gastrointestinal, andimmune systems.

In performing a comprehensive history, one can sig-nificantly narrow the differential diagnosis before movingon to a physical examination and diagnostic testing.

PHYSICAL EXAMINATION

Observation should be the first and is perhaps themost important component of a physical examination.

How comfortably is the patient breathing? How well isthe patient compensating for any difficulty that he or shemay have? Is the chest wall motion symmetric? Is thereevidence of asynchronous motion between the chestwall and abdomen (thoracoabdominal asynchrony)?

Common signs of respiratory difficulty that are evi-dent on observation include alterations in respiratoryrate and size of breath, accessory muscle use, and pres-ence of retractions. The patient will adjust minute venti-lation (the product of respiratory rate and tidal volume)in the most energy-efficient way, by increasing eitherdepth of each breath, respiratory rate, or both, to satisfythe metabolic demands for oxygen and to remove thecarbon dioxide produced during metabolic processes.However, the principal change in pattern will be anincrease in the respiratory rate if the tidal volume is limitedby a process that increases airway resistance or lowersrespiratory system compliance (makes the lungs stiffer).This is evident in the tachypnea that is commonly seen inrespiratory disease.

Accessory muscle use during inspiration (scalene andsternocleidomastoid muscles) and exhalation (rectusabdominus and lateral oblique muscles) is often seenwith respiratory disease. Any process that stiffens thelungs (decreases compliance) or increases airway resist-ance will be reflected by retractions. In such cases, theincreased negative intrathoracic pressure needed to pro-duce inward airflow during inspiration causes intercostal,suprasternal, supraclavicular or sternal retractions. Inobstructive airways disease there is commonly somecomponent of air trapping after exhalation, whichcauses lung hyperinflation. This places the diaphragm ina more horizontal orientation at the end of exhalation,and at the onset of inspiration diaphragm contractionwill be more in the horizontal plane and will causeinward motion of the inferior border of the ribcage withsubcostal retractions (Figures 2-1, 2-2).

In perfectly healthy patients abdominal motionslightly leads chest wall motion through both inspirationand expiration, although this may be difficult to appre-ciate on physical examination. Asynchronous thoraco-abdominal motion (Figure 2-3) occurs when pulmonarymechanics are abnormal. Thoracoabdominal asynchronyis especially prominent in infants and young childrenwhose chest walls are not stiff enough to withstand theincreased intrathoracic pressure generated to overcomeobstruction or low lung compliance.

If there are differential mechanics between the twosides of the chest, such as a unilateral increase in airwaysresistance resulting from a retained bronchial foreignbody, there will be more airflow to the unaffected lungcompared with the lung with the obstruction. This willcause asymmetric chest wall excursion between the twosides of the chest, with greater excursion occurring on

the unaffected side. Similarly, unilateral diaphragm paralysisor paresis will cause diminished excursion of the affectedside as well as a paradoxical upward inspiratory move-ment of the affected hemi-diaphragm, and the umbilicus

will swing to the affected side during inspiration asabdominal contents are drawn into the thoracic cavity(“belly dancer’s” sign).

On auscultation one can evaluate other aspects ofbreathing not evident on inspection. During what phaseof respiration is the sound heard? What are the charac-teristics of the sound? Is it continuous (wheeze if duringexpiration or stridor if during inspiration) or is it discon-tinuous (crackles)? Is the sound the loudest in one placeor is it heard equally throughout the chest? At whatpoint during a phase of respiration is the sound heard?

The phase of respiration in which the sound is heardis important since inspiratory sounds typically representan extrathoracic obstruction, while expiratory soundsindicate an intrathoracic obstruction. Sounds heard inboth inspiration and expiration are either from two sep-arate lesions or the result of a “fixed” lesion, with theobstruction present during both inspiration and expira-tion. Sounds heard during only one phase of breathingare “dynamic” lesions, as the degree of obstructionvaries with the respiratory phase.

Dynamic lesions exist because they accentuate airwaycaliber changes that normally occur as a result of phasicpressure differences across the airway wall. Duringinspiration intrapleural pressure becomes more nega-tive, creating a pressure gradient from atmospheric pres-sure at the mouth to subatmospheric pressure in thealveoli. This gradient causes air to flow into the lungs.Pressure gradients, however, also develop across the air-way wall especially during forceful inspiration (Figure 2-4).Thus, the transmural pressure in the extrathoracic air-way (intraluminal pressure minus atmospheric pressure)favors narrowing of the airway during inspiration whilethe transmural pressure of the intrathoracic airway(intraluminal pressure minus pleural pressure) favors its


A C

B D

Figure 2-1 Subcostal retractions. In the normal situation (A) thediaphragm will contract inward and downward causing outwardribcage motion (B). In a patient with hyperinflation (C), thediaphragm will be in a more horizontal position and will causeprimarily diaphragm contraction in the transverse plane andinward motion of the inferior rib cage (D).

Figure 2-2 Six-month-old infant with laryngomalacia withmarked lower costal and sternal retractions.

A C

DB

Figure 2-3 Thoracoabdominal motion. From end expiration (A) normal inspiration occurs with outward motion of the thoraxand abdomen (B). Thoracoabdominal asynchrony can occur withoutward abdominal and inward thoracic motion (C) or with outward thoracic and inward abdominal motion (D).


expansion (Figure 2-4). Outward traction on the intra-parenchymal airways by the expanding alveoli contributesto inspiratory dilation of the intrathoracic airways.

During exhalation, intrathoracic pressure becomespositive and creates a pressure gradient from high pres-sure in the alveoli to atmospheric pressure at the mouth(Figure 2-5). The positive pressure gradient results fromthe sum pressure of the elastic recoil of the lungs and chestwall, and any expiratory muscle activity. Airway resist-ance causes the airway pressure gradually to decrease asair travels proximally from smaller to larger airways.A point within the thorax exists where the intraluminalairway pressure will be equal to the intrathoracic pres-sure (Figure 2-5). This point is called the equal pressure

point and from that point to the thoracic inlet there is agradient favoring airway collapse. Under normal circum-stances, however, the equal pressure point occurs in thelarger, more central airways that contain large amountsof cartilage in their walls to resist collapse. If, however,the central airway is collapsible (malacic) or if the equalpressure point moves to more distal airways because ofincreased peripheral airway resistance and a more rapiddissipation of pressure during exhalation, significantintrathoracic airway collapse can occur. In the extratho-racic airway, however, the intraluminal pressure will begreater than the surrounding atmospheric pressure favor-ing dilation of the extrathoracic airway (Figure 2-5).

After establishing the phase of respiration in whichthe sound is heard, the character of the sound is impor-tant to distinguish. Is the sound continuous or is it inter-mittent through inspiration, expiration, or both?Narrowing of the airway lumen causes turbulent airflowand produces continuous sounds. Such sounds can beheard in both phases of respiration, with “wheezing”used to describe an expiratory sound and “stridor” aninspiratory sound. The sound produced by wheezing isusually musical and that of stridor a “crowing” harshnoise; however, the stridor produced by laryngomalaciacan be vibratory. Both wheezes and stridor can be of vari-able and multiple pitches. Intermittent sounds or cracklestypically represent intraluminal obstruction of smallerairways either from narrowing or debris in the lumen,such as mucus or fluid. Crackles can occur during bothinspiration and expiration. Crackles represent move-ment of air through an air–liquid interface, such as withair movement through airways secretions and equa-lization of airway pressure1. They also can be produced by sudden opening of closed airways1. Some havedescribed crackles as sounding like crumpling Cellophaneor separating Velcro.

The symmetry of the sound through the respiratorytract is important. Sounds that differ regionally in termsof pitch and composition of tones when heard through-out the respiratory tract (heterophonous sounds) arefrom multiple peripheral sites of obstruction. However,sounds that are symmetric in quality, or homophonous,represent a more central process.

The timing of the sounds within each phase of the res-piratory cycle can help determine the severity of theobstruction. Since the caliber of the intrathoracic air-ways progressively narrows during exhalation, turbulentairflow and adventitious sounds will be produced earlierin airways with severe narrowing, whatever the cause.The earlier in the respiratory cycle the onset of thewheezing is, the more severe the airway obstruction.Abnormal breath sounds in milder obstructive airwaydisease will occur later in exhalation due to the greateramount of airway narrowing needed to cause turbulentairflow.

�20

�12 �10 �8 �4 �2

�20

�20

�20

�20

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0

0

Figure 2-4 Forceful inspiration. Diaphragm contraction pro-duces negative intrathoracic pressures and creates a gradient ofdecreasing pressure from the airway opening to the alveoli. Thenegative pressure in the airway creates pressure gradients favoringdilation of the intrathoracic airway and narrowing of the extratho-racic airway in regions that may be prone to collapse. The differ-ence between the intrathoracic pressure (−20 cm H2O) and theintra-alveolar pressure (−12 cm H2O) is due to the inward elasticrecoil of the lung. The numbers in the image reflect hypotheticalpressures in cm H2O.

�40

�48 �44 �42 �40 �36 �24 �16 �8

�40

�40�40

�40�40

0

0

Figure 2-5 Forceful exhalation. The passive recoil of the lung isaugmented by expiratory muscle activity to produce positiveintrathoracic pressure and a gradient of decreasing pressures fromalveoli to the airway opening. The gradient across the intrathoracicairway will maintain airway patency until the pressure in the air-way is equal to the intrathoracic pressure, the equal pressure point(EPP). From the EPP to the thoracic inlet there is a gradient favor-ing airway narrowing. In contrast, in the extrathoracic airway thepressure gradient will favor dilation of the airway. The numbers inthe image reflect hypothetical pressures in cm H2O.


Two separate areas of obstruction, such as the smallairways in asthma and central airway in tracheomalacia,enhance each other’s degree of obstruction by creatinggreater net resistance than either lesion would alone.This can occur both with extrathoracic obstruction duringinspiration (Figure 2-6) and with intrathoracic obstructionduring exhalation (Figure 2-7). When both peripheraland central airway obstruction coexist, the higher pleu-ral pressure needed to overcome peripheral resistance

during exhalation will also compress the central airwayand so will worsen the central airway obstruction.This is particularly likely in patients with collapsibleairways, such as those with tracheomalacia and bron-chomalacia. The converse also holds in that treating onesite of airway obstruction can help to reduce the severityof another.

Since all respiratory noises require adequate flow toproduce them, the most accurate physical examinationof the respiratory system will occur when flow isincreased to the point of flow limitation. Ideally, to reachthis point the patient should inhale deeply to approxi-mate total lung capacity and exhale forcefully to residualvolume. To the extent the patient is unable to do this,the accuracy of the physical examination of the respira-tory system decreases. With proper coaching during aphysical examination, most cooperative children abovethe toddler age group can inhale and exhale deeply andforcefully. In infants and younger children, expiratoryflow can be augmented by manually compressing thechest at the onset of expiration.

DIFFERENTIAL DIAGNOSIS OF NOISYBREATHING

With the information gleaned from a comprehensivehistory and physical examination, one can then create amore focused location-based differential diagnosis(Tables 2-1, 2-2). Causes of noisy breathing at each sitecan also be separated into acute and chronic problems.

Extrathoracic

The extrathoracic airway can be divided from proxi-mal to distal into the nose, nasopharynx, oropharynx,hypopharynx, larynx/glottis, subglottis, and extratho-racic trachea (Table 2-1).

Nose/NasopharynxAcuteNasal inflammation with turbinate edema and

increased secretions can cause noisy breathing, espe-cially in infants who are obligate nose-breathers. Becausethese conditions can cycle between different levels ofseverity within a short period of time, the character andloudness of the sounds produced can be quite variable.Retained foreign bodies are another important source ofnasal obstruction and always need to be considered,especially in children of toddler age.

ChronicStatic conditions that cause noisy breathing result

from fixed obstruction to nasal airflow. These includeadenoidal enlargement (Figure 2-8) and less commonlynasal polyps. Uncommon congenital conditions include

Rest

R1

R1 �2�4�8�12

�20

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Inspiration

R1 R2�4�14�18�22

�30

�30

Inspiration

R1(b) �R1(c)

A

B C

Figure 2-6 Extrathoracic airway resistances in series. Withupper airway obstruction (R1) (A) the negative intraluminal pres-sure during forceful inspiration will favor further airway narrowingin that airway segment (B). With added extrathoracic airwayobstruction (R2) closer to the airway opening, the pressure neededto overcome the higher airway resistance will increase (becomemore negative) and the initial site of obstruction (R1) will narrowfurther (C).

Rest

Expiration

R1

EPP

R1�28 �24 �20

�20

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�30�30

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Expiration

R1R2 �16

R1(b) �R1(c)

�28�24

A

B C

Figure 2-7 Intrathoracic airway resistances in series. With anintrathoracic obstruction (R1) (A) the positive intrathoracic pres-sure during forceful expiration will favor airway narrowing pastthe equal pressure point (EPP) (B). With increased intrathoracicairway obstruction (R2), the pressure needed to overcome thehigher airway resistance will increase (more positive) and the ini-tial site of obstruction (R1) will narrow further (C). The extratho-racic airway will not narrow, and there will be a pressure gradientfavoring dilation.

Table 2-1 Differential Diagnosis of Noisy Breathing from Extrathoracic Airway Obstruction

Location Acute Chronic

Nose/nasopharynx Nasal inflammation Adenoidal enlargementNasal turbinate edema Nasal polypsNasal secretions Asthma

Allergic rhinitis Allergic rhinitisUpper respiratory infection Cystic fibrosisMaxillary sinusitis Choanal stenosis

Foreign bodies Midface/maxillary hypoplasiaTreacher–Collins syndromeApert syndrome

Oropharynx Infectious Adenotonsillar hypertrophyPeritonsillar abscess MacroglossiaRetropharyngeal abscess Down syndromePalatine tonsillitis Beckwith–Wiedemann syndrome

MicrognathiaPierre–Robin syndromeMoebius syndrome

Hypopharynx Acute nose/nasopharyngeal/ Hypopharyngeal hypotoniaoropharyngeal obstruction Down syndrome

Static encephalopathyMoebius syndromeTrigeminal, glossopharyngeal or vagus nerve injury

GlossoptosisObesityNeoplasia

LymphomaLymphangioma

Larynx Epiglottitis LaryngomalaciaHaemophilus influenzae type B Primary/congenitalHaemophilus species (other than type B) SecondaryStaphylococcus aureus Chronic inflammationGroup A Streptococcus Papillomatosis

Laryngotracheobronchitis (croup) Human papillomavirusParainfluenza types 1 and 3 HemangiomaRespiratory syncytial virus Laryngeal granulomaInfluenza Congenital

Foreign bodies Laryngeal cystLarge Laryngeal webIrregular edges Laryngocele

LaryngospasmGlottis Vocal cord paralysis/paresis Vocal cord dysfunction (paradoxic motion)

Endotracheal intubation Brainstem compressionTrauma Structural

Vocal cord overuse injury Chiari malformationInflammation Dandy–Walker cystPolyps Mass effect

NeoplasiaHemorrhage

Nerve injuryVagus nerveGlossopharyngeal nerveRecurrent laryngeal nerve

PapillomatosisSubglottis/ Endotracheal/tracheal intubation Subglottic stenosis

extrathoracic trachea Laryngotracheobronchitis (croup) Congenital Parainfluenza types 1 and 3 Complete tracheal ringsRespiratory syncytial virus MaldevelopmentInfluenza Secondary

Bacterial tracheitis Endotracheal/tracheal intubationStaphylococcus aureus PapillomatosisHaemophilus influenzaeStreptococcus species


Table 2-2 Differential Diagnosis of Noisy Breathing from Intrathoracic Airway Obstruction

Location Acute Chronic

Trachea Extrinsic compression Uncommon Cardiovascular

Vascular anomaly (Table 2-3)Pulmonary artery

Main/lobar bronchus compression (except right upper lobe bronchus)Cardiac

Left main bronchus compressionRecurrent laryngeal nerve compression (cardiovocal syndrome)

Anterior mediastinal massesLymphomaThymomaTeratoma

Middle mediastinumLymphomaLymphadenopathy

TuberculosisMycoses

HistoplasmosisBlastomycosisCoccidiomycosis

SarcoidosisPosterior mediastinum

Neurogenic tumorsEsophageal duplication cystBronchogenic cyst

Intramural lesions Uncommon TracheomalaciaPrimary (congenital)

Cartilaginous defect: Campbell–Williams syndromeMuscular defect: Mounier–Kuhn syndrome s/p Tracheoesophageal fistula repairExternal compression

Secondary (acquired)Chronic inflammation

Recurrent infectionsGastroesophageal refluxRecurrent aspiration

Prolonged positive pressure ventilationExternal compression

Complete tracheal cartilaginous ringsIntraluminal lesions Foreign bodies Tracheal granulomas

Irregularly shaped Artificial airway and “deep suctioning”Elongated Hemangioma

Bacterial tracheitis PapillomatosisChronic tracheostomy Tracheal web

tube usagePseudomonas

aeruginosaSerratia marcescens

Bronchi/bronchioles Viral bronchiolitis AsthmaRespiratory syncytial virus Bronchopulmonary dysplasiaParainfluenza virus BronchomalaciaInfluenza virus Prolonged positive pressure ventilationAdenovirus Chronic inflammation

Pneumonia Carcinoid Viral AdenomaMycoplasma

Foreign bodySmall size

Tumor

choanal stenosis and midface hypoplasia, and nasaltumors. Nasal obstruction, however, may not be as clini-cally evident as infants get older and are no longer obligatenose-breathers. Older infants and children with severeobstruction bypass the nasal obstruction by breathingthrough their mouths chronically.

OropharynxAcutePeritonsillar and retropharyngeal abscesses, and pala-

tine tonsillitis are important to consider in patientspresenting with a “muffled” voice, often described asa “hot-potato” voice. Children with tonsillitis may havefever and can be ill-appearing, but their constitutional ill-ness usually is not as severe as that seen in children witha peritonsillar or retropharyngeal abscess.

ChronicPersistent sounds of similar character with a muffled

or hyponasal voice can be heard in children with severeadenotonsillar hypertrophy. Sonorous or striduloussounds during inspiration occur when the oral airway isnarrowed from macroglossia or micrognathia.

When nasal and oral obstructions are both present,they represent a set of resistances in series. As such, thepressure drop across the nasal obstruction can accentuate

the magnitude of the oral obstruction. Conversely,“unloading the nasal airway” by use of decongestantscan also markedly improve symptoms resulting fromoropharyngeal obstruction.

Nasopharyngeal and oropharyngeal lesions often willpresent first during sleep, as the tone in the supportmusculature of the pharynx decreases and the airwaycollapses during inspiration, producing snoring and per-haps obstructive apnea.

HypopharynxAcuteHypopharyngeal obstruction can occur in patients

with an otherwise normal hypopharynx when anotherobstruction occurs more proximally in the airway, asdescribed above. This process causes a dynamic hypopha-ryngeal obstruction and produces a rattling striduloussound or snore. Anything that causes acute nasopharyn-geal or oropharyngeal obstruction can also cause noisybreathing from the hypopharynx due to airway collapseduring inspiration.

ChronicHypopharyngeal obstruction can be prominent in

patients with intrinsic airway hypotonia. Hypopharyngealhypotonia is a common source of obstruction in patients


Figure 2-8 Lateral neck radiograph demonstrating adenoidal enlargement with nasopharyngealnarrowing (between arrows) in a 5-year-old child with snoring at night. (Courtesy of Raanan Arens, M.D.)

with a variety of central nervous system abnormalities,including both cerebral and cranial nerve abnormalities.This hypotonia causes hypopharyngeal narrowing orcollapse under a normal pressure gradient across thehypopharyngeal wall. Hypopharyngeal narrowing is accen-tuated during periods of decreased airway muscle tone,such as when the child is sedated or asleep. Furthermore,tone falls to its nadir during the stage of rapid eye move-ment (REM) sleep. As a result, children with hypopharyn-geal hypotonia can develop sleep hypoventilation orobstructive apnea requiring therapy with non-invasive pos-itive pressure, a nasopharyngeal airway, or tracheostomytube. Hypopharyngeal collapse is also made worse withthe addition of a second site of extrathoracic obstruction,such as nasal obstruction (Figure 2-6).

The obstruction caused by glossoptosis, or prolapse ofthe tongue into the posterior pharynx, is often hard to dis-tinguish from the obstruction from hypopharyngeal hypo-tonia. Turning the head to the side to move the tongue outof the posterior pharynx can relieve the glossal obstructionpresent in glossoptosis. A jaw thrust can decrease thesound from hypopharyngeal hypotonia by putting tensionon the pharynx and can also elevate the tongue. Extrinsiccompression of the hypopharynx from the increased softtissue mass in obesity or neoplasia can cause a fixedobstruction that will produce biphasic sounds.

LarynxAcuteEpiglottitis (Figure 2-9) occurs most commonly from

an infection with Haemophilus influenzae type B, andless commonly due to other Haemophilus species,

Staphylococcus aureus and group A Streptococcus. Withmodern immunization practice for Haemophilusinfluenzae type B, epiglottitis is now very rare. The typicalpresentation includes a “muffled” voice, significant respi-ratory distress or respiratory failure, and generalizedtoxicity. Epiglottitis is a true medical emergency and air-way stabilization is of utmost importance. Maintainingthe child in a calm state can minimize his or her work ofbreathing and prevent or delay the onset of respiratoryfailure. Epiglottitis may be confused with other disorderssuch as retropharyngeal abscess or laryngotracheobron-chitis (croup), but patients with epiglottitis are moretoxic-appearing, they have dysphagia and drool, and theyoften sit in a tripod posture to help maintain an openairway.

Croup is caused by a viral infection (parainfluenza types1 and 3, respiratory syncytial virus (RSV), or influenza)that leads to laryngeal and subglottic edema and markedsubglottic narrowing. It usually responds promptly toadrenergic agonists and steroids, which help to reducethe airway swelling. Croup may be discriminated fromepiglottitis by the presence of a viral prodrome.

Where foreign bodies lodge in the airway depends ontheir size and contour. Large and round or asymmetricforeign bodies typically lodge in the larynx or posteriorpharynx (Figure 2-10) because they have difficulty passinginto the esophagus or between the vocal cords and intothe trachea. As with any fixed obstruction, the patientwith a laryngeal foreign body will produce biphasicsounds with a more prominent inspiratory component.Smaller foreign bodies may pass between the vocal cordsand lodge in the distal trachea at the carina (Figure 2-11)or in the bronchi (Figure 2-12). Broad and flat foreignbodies often lodge in the esophagus (Figure 2-13) and cancause biphasic sounds if they are large enough to causecompression or displacement of the adjacent airway.

Acute obstruction with stridor can occur from laryn-gospasm during anaphylaxis. In such situations, life-threatening respiratory distress requiring immediateairway stabilization can also occur.

ChronicLaryngomalacia is the most common cause of stridor in

infants2. It presents as a rattling, vibratory or high-pitchedinspiratory sound that is made louder with exertion andcrying but is usually absent during restful breathing andsleep. The noise results from prolapse of laryngeal tissuesinto the airway during inspiration. Laryngomalacia isproposed to occur because of delayed maturation ofthe laryngeal cartilage and muscle3, which results in inad-equate support of the laryngeal tissue. It can also occurin children with gastroesophageal reflux (GER), perhapsdue to upper airway hypotonia2 similar to the loweresophageal sphincter hypotonia that often occurs in GER.

Laryngoscopic findings include arytenoid cartilageprolapse during inspiration and curling of the epiglottis


OPE

H

T

Figure 2-9 Lateral neck radiograph showing epiglottitis(E) with a positive “thumb sign” (below arrows) in a 2-year-oldchild. OP, oropharynx; H, hyoid bone; T, trachea. (Courtesy of IanJacobs, M.D.)

into an omega shape. Primary (congenital) laryngomala-cia usually presents shortly after birth and can worsenduring the first year of life as a result of the infant’sincreased activity and respiratory effort. It often com-pletely resolves by the end of the first or second year oflife. In rare cases when obstruction is severe enough tocause respiratory embarrassment or growth failure, sur-gery (“epiglottoplasty”) is performed to remove redun-dant tissue that prolapses into the airway. Even lesscommonly, a tracheostomy may be required to bypassthe laryngeal obstruction. Secondary laryngomalacia canoccur after any chronic inflammatory process thatcauses weakening of the laryngeal tissue, such as recur-rent aspiration or prolonged endotracheal intubation.

Papillomas from human papillomavirus infection cancause biphasic sounds when the masses grow on thevocal cords and narrow the glottic opening. If the papil-lomas grow large enough the airway narrowing cancause respiratory difficulty. Although papillomas canoccur throughout the respiratory tract, they are mostcommon in the upper airway due to exposure during thebirthing process.

Airway hemangiomas can displace the laryngeal struc-tures causing inspiratory and expiratory sounds, depend-ing on the size of the lesion. They should be consideredin any child who also has a cutaneous hemangioma andstridor or wheezing.

Patients receiving aggressive oropharyngeal “deep”suctioning may develop granulomas where the suctioncatheter contacts the airway, such as at the epiglottis orglottis. These lesions would cause biphasic sounds ofvariable severity, depending on the size of the lesion.

Other less common causes of laryngeal obstructioninclude congenital lesions such as laryngeal cyst, laryn-geal web and laryngocele. Each would likely cause abiphasic noise because of its fixed nature and position inthe airway.

GlottisAcuteThe vocal cords can cause airway obstruction and a

variety of different abnormal sounds. Changes in voicewill be most clear in children who are beyond infancyand have clear vocal characteristics. Infants with dys-functional vocal cords can present with a weak or absentcry. Paralyzed vocal cords can be fully abducted, inwhich case no abnormal sounds will be present duringquiet inspiration, or in a paramedian or median (fullyadducted) position. The closer to the median positionthe vocal cords are fixed, the more audible the soundswill be during relaxed breathing, due to the narrowingof the airway opening. During forced inspiration (e.g.,crying), even fully abducted paralyzed cords can causestridor as the structures are passively drawn togetherwhen transmural pressure across the glottis becomesnegative. Vocal cord paresis can occur after traumatic or


Figure 2-10 Anteroposterior neck radiograph which showsaspiration of a small bell (between arrows) that lodged in the pos-terior pharynx. (Courtesy of Ian Jacobs, M.D.)

Figure 2-11 Lateral chest radiograph demonstrating trachealaspiration of a small whistle, with positioning just above thecarina. (Courtesy of Ian Jacobs, M.D.)

prolonged endotracheal intubation due to direct injuryto or inflammation of the vocal cords.

Vocal cord inflammation from overuse during repeti-tive periods of loud speaking, often referred to as “laryn-gitis,” can occur in vocalizing children of any age.Multiple episodes can cause polyps to develop on thevocal cords. Therapy involves vocal cord rest.

ChronicVocal cord dysfunction (paradoxical vocal cord

motion) is disordered movement of the vocal cords thatcauses vocal cord adduction, as opposed to abduction,during inspiration. The chief complaint is often mistakenas “wheezing.” Patients often are unsuccessfully treatedwith bronchodilator and anti-inflammatory therapy and

diagnosed as having “refractory” asthma. With a goodhistory, however, the findings can usually be isolated toinspiration and to the suprasternal region (glottis). Thesymptoms can sometimes be reproduced during a phys-ical examination or lung function testing with hyperven-tilation or exertion. Spirometry when symptoms arepresent discloses limitation of inspiratory peak flow, butexpiratory flows are normal, indicating a variableextrathoracic obstruction. The noise is usually accompa-nied by acute respiratory distress during periods of phys-ical or emotional stress and reverses with calmingtechniques and speech therapy.

Brainstem compression from an intracranial mass orstructural abnormality or injury at the locus of the vagus


AFigure 2-12 Anteroposterior (A) and lateral (B) chest radiographs demonstrating right mainbronchus aspiration of a button. (Courtesy of Ian Jacobs, M.D.) (Continued)


BFigure 2-12 Cont’d

and glossopharyngeal nerves can cause vocal cord pare-sis or paralysis with stridor and/or a hoarse voice.Excessive neck traction during delivery or previous car-diac or mediastinal surgery can cause recurrent laryngealnerve injury and ipsilateral vocal cord paresis or paraly-sis. Compression of the left recurrent laryngeal nervefrom enlarged pulmonary arteries will cause left vocalcord paralysis (cardiovocal syndrome, see below).

Since the infection from human papillomavirus canoccur at any point along the airway, glottic involvementis certainly possible.

Subglottis/Extrathoracic TracheaAcuteEndotracheal intubation in and of itself can cause

mucosal inflammation. If the inflammation is moderateto severe, acute respiratory distress and stridor can bequite prominent after extubation. This occurs most sig-nificantly at the level of the cricoid cartilage because themucosal inflammation and edema can only extend intothe center of the tracheal lumen. Direct trauma to theglottis itself and to the mucosa above and below thecricoid cartilage can further contribute to the acute air-way obstruction post-extubation. Resolution can occur

spontaneously over time if the patient’s ventilatory sta-tus remains adequate. Steroids or adrenergic agents canbe used to reduce the mucosal swelling, accelerate reso-lution, and avoid the need for reintubation. Placing apatient on a helium and oxygen mixture can stabilize orimprove respiratory status until the inflammation in theairway resolves.

Croup and bacterial tracheitis cause narrowing in theimmediate subglottic area, and may additionally involvethe distal trachea and bronchi. Patients with either con-dition can present with stridor and/or a “barking” cough.Because of the airway narrowing patients often presentwith markedly increased work of breathing to overcomethe increased airways resistance. Infectious croup, orlaryngotracheobronchitis, is caused by a viral infection(parainfluenza types 1 and 3, RSV, or influenza) leading toglottic and subglottic edema and marked laryngeal andsubglottic narrowing, with further inflammation poss-ible throughout much of the respiratory tract. It usuallyresponds to adrenergic agonists and steroids, whichreduce the swelling. Some patients have positive, calm-ing responses when exposed to cool and/or humidifiedair; however, there is no conclusive evidence of the effi-cacy of either intervention.

Patients with bacterial tracheitis (usually resultingfrom infection with Staphylococcus aureus) begin theirillness with similar respiratory complaints to those whopresent with croup. Several days into the illness, how-ever, they develop new onset of fever and respiratorydistress returns. These children are usually more ill-appearing with high fever and do not respond to stan-dard croup therapy since the infection is of bacterialorigin, and is one with a large purulent component.Treatment requires aggressive airway clearance, antibi-otic therapy and airway stabilization, preferably in a con-trolled intensive care or operating room environment.

Any lesion that causes glottic narrowing producesincreased airways resistance and alteration in the flowpatterns in the affected airways. Airflow is laminar inperipheral airways, with the flow vectors all directed inthe same direction. In this setting, airways resistance isdirectly proportional to the flow rate. However, in thetrachea, where flow is turbulent, with vectors in multi-ple directions, the resistance is related to the square ofthe flow rate. Therefore, when a child with croup orbacterial tracheitis tries to inhale rapidly because of anx-iety or air hunger, resistance across the narrowed airwaysegment will rise dramatically and make it more difficultto inspire effectively. Thus, anxiety worsens the child’sdyspnea and leads to further clinical deterioration. Forthis reason, patient calming is an important interventionthat can often cause substantial relief of symptoms.

Since the infection from human papillomavirus canoccur at any point along the airway, tracheal involve-ment is certainly possible.

ChronicAs a fixed airway obstruction, subglottic stenosis

(Figure 2-14) causes both inspiratory and expiratorysounds. It can present as a congenital lesion with abnor-mal tracheal formation such as with complete trachealrings in the extrathoracic trachea. Though it is oftenassociated with other congenital midline lesions and vas-cular abnormalities, it can occur as an isolated lesion. Itcan also occur after endotracheal tube placement of anyduration with the sequence of mucosal irritation, inflam-mation, fibrosis, scarring, and narrowing. Tracheostomyplacement is a temporizing solution to bypass theobstruction and to allow the patient to breathe with lesseffort. With growth subglottic stenosis can resolve spon-taneously or become easier to repair. When subglotticstenosis does not improve spontaneously, several surgi-cal approaches are available to increase airway diameter.An anterior cricoid split, in which the anterior subglottictrachea is incised down to the mucosa, can enlarge theairway enough in cases of mild subglottic stenosis to


A BFigure 2-13 Anteroposterior (A) and lateral (B) chest radiographs of a patient who swallowed acoin and the typical positioning in the esophagus. Note that on the anteroposterior radiograph, theface of a coin lodged in the esophagus will be seen, whereas a coin lodged in the airway will appear“on edge” as it lines up between the vocal cords. (Courtesy of Ian Jacobs, M.D.)

avoid tracheostomy placement. When the stenosis is moresevere, a staged laryngotracheoplasty may be needed to increase tracheal diameter to a caliber that allows adequate ventilation. During laryngotracheoplasty, thestenotic section of trachea is incised longitudinally andcartilage grafts, the number depending on the severity,are inserted to increase the tracheal diameter.

Intrathoracic Airway

The intrathoracic airway starts as the trachea passesthrough the thoracic inlet and includes a portion of thetrachea, the main bronchi, smaller bronchi, and bron-chioles (Table 2-2). Dynamic and fixed obstruction ofintrathoracic airways produces expiratory sounds; how-ever, fixed obstruction can also produce inspiratorysounds. The amplitude of the sound can increase throughexhalation due to the progressive narrowing of the intratho-racic airway through exhalation (Figure 2-5). The oppo-site circumstance occurs during inspiration (Figure 2-4).

Obstruction can result from extrinsic compression, anintrinsic defect of the airway wall, or an intraluminalprocess.

Trachea: Extrinsic CompressionAcuteThe common lesions causing tracheal compression

are chronic processes. Extrinsic compression may becompletely asymptomatic when the patient is well butbecomes clinically apparent during acute respiratory dif-ficulty, as in a respiratory tract infection. Clues to anextrinsic compression include atypical physical findingson examination of a patient with “acute” wheezing, suchas homophonous biphasic wheezing, that would be asso-ciated more with a fixed central airway obstruction thanwith an acute respiratory infection.

ChronicThe numerous etiologies of tracheal compression can

be divided into two broad groups: cardiovascular andnon-pulsatile fixed compression. Because these lesionsare fixed obstructions, they cause biphasic sounds withmore prominent expiratory sounds. Computed tomog-raphy (CT) and magnetic resonance imaging (MRI)


A BFigure 2-14 Subglottic stenosis on laryngoscopy (A) and on anteroposterior neck radiograph (B)with the functional airway outlined by arrows. (Courtesy of Howard Panitch, M.D. (A) and IanJacobs, M.D. (B).)

are useful in differentiating the different mediastinalmasses.

Vascular rings (Table 2-3) cause a fixed but pulsatilecompression of the trachea in a variety of ways dependingon the specific defect. Children with these abnormalitiespresent with chronic coughing and can have promi-nent inspiratory sounds and homophonous wheezing.

Table 2-3 Common Types of Vascular Abnormalities4

Lesion Relative Prevalence

Double aortic arch 43%Anomalous innominate artery 15%Right aortic arch with aberrant 11%

subclavian arteryRight aortic arch with left ligamentum 11%

arteriosumPulmonary artery sling 7%Other 13%

In many series, the most common vascular anomaly isthe double aortic arch, followed by anomalous innomi-nate artery, right aortic arch with an aberrant left sub-clavian artery or with mirror image branching and a leftligamentum arteriosum, and pulmonary artery sling4.Although tracheal and bronchial compression may notbe visible on the chest radiograph, vascular anomaliesoften are associated with a right descending aorta,which should be visible directly along the spine or indi-rectly as a medially displaced trachea. A barium esopha-gram is helpful in confirming compression (Figure 2-15),but a CT scan or MRI study (Figure 2-16) is often neces-sary to identify the course of the vessels with more cer-tainty. Some institutions are able to performthree-dimensional reconstruction of the trachea and vas-cular structures allowing for even easier understandingof the anatomy (Figure 2-17).

Because complete vascular rings with vessels or rem-nants of vessels encircle both the trachea and esopha-gus, the biphasic sounds are made worse withswallowing as the bolus in the esophagus compressesthe trachea within the ring. Dysphagia will also be aprominent symptom if the ring is tight, as solids andeven liquids may not pass easily beyond the esophagealobstruction. A double aortic arch encircles the tracheaand esophagus proximal to the carina (Figures 2-15, 2-16)and may cause marked bilateral tracheal compression(Figure 2-18), compromising airway clearance from the

distal airways. In such situations recurrent pneumonia oratelectasis can occur. Between 70% and 90% of doubleaortic arches have a right descending aorta4.

The anomalous innominate artery leaves the aorticarch more distally than normal and courses across theanterior portion of the proximal trachea slightly to theright of midline (Figure 2-19). It can present with ahomophonous wheeze or stridor, especially in infants.About 95% of patients with congenital heart disease have


A BFigure 2-15 A barium esophagram demonstrating a double aortic arch, represented as bilateralcompression in anteroposterior (A) and posterior compression in lateral (B) images of the esophagus.

Figure 2-16 Right aortic arch (A) passing posterior to and com-pressing the esophagus (E) and trachea (T) on a CT scan of the chest.

an anomalous innominate artery4. Although it is involvedin 20% of cases of infant stridor and apnea4, it usually isnot severe enough to require surgical correction.Additionally, an anomalous innominate artery can beasymptomatic and discovered incidentally on bron-choscopy when the airway compression is mild. Onecan diagnose an anomalous innominate artery by usingthe bronchoscope to press on the right anterolateral pul-satile compression while palpating the right brachial orradial pulse5. The pulse will diminish or be absent if thecompression is from an anomalous innominate artery5.

The right aortic arch with mirror image branchingcauses left anterolateral compression, opposite to that ofanomalous innominate artery. A left descending aortawith a ligamentum arteriosum forms a complete vascularring and may present similarly to a double aortic arch. Inapproximately 90% of cases this type of ring is associatedwith congenital heart disease4.

In patients with a right aortic arch with an aberrantleft subclavian artery, the left common carotid arteryarises from the ascending aorta and also causes left antero-lateral compression just above the carina. As with theright aortic arch with mirror image branching, a com-plete vascular ring is formed if there is a left descending


A BFigure 2-17 3-Dimensional MRI reconstruction of the double aortic arch (A) and with the tracheaand esophagus (B). D Ao, double aortic arch; A Ao, ascending aorta; R Arch, right aortic arch; L Arch, left aortic arch; LSCA, left subclavian artery; RSCA, right subclavian artery; RCA, right carotidartery; LCA, left carotid artery; T, trachea; E, esophagus. (Courtesy of Paul Weinberg, M.D., reprintedwith permission from: Aortic arch abnormalities, in Moss and Adams’ Heart disease in infants, chil-dren and adolescents, 6th edition, p 724, 2001.)

Figure 2-18 Bronchoscopic view of double aortic arch withanterior tracheal compression. The compression causes wideningand invagination of the posterior muscular wall of the trachea.

aorta and a ligamentum arteriosum. Because the com-pression caused is not as severe as that of a double aor-tic arch, the right aortic arch with an aberrant leftsubclavian or with mirror image branching causes lesssevere respiratory symptoms.

A pulmonary sling results when the left pulmonaryartery arises not from the main pulmonary artery butfrom the right pulmonary artery instead. The left pul-monary artery then courses between the trachea andesophagus just above the carina and can cause rightbronchial compression and a focal homophonouswheeze. This lesion is associated with complete trachealrings (Figure 2-20), congenital heart disease, as well asother congenital anomalies, and an overall poor progno-sis. It is unique in that it causes an anterior compression

of the esophagus and a posterior compression of the tra-chea. This can clearly be seen on the lateral view of abarium esophagram.

Large vessel dilation can cause compression of the dis-tal trachea or central bronchi and a fixed obstruction.The right and left main pulmonary arteries may be dilatedin situations of increased flow, owing to a left to rightshunt from atrioseptal or ventriculoseptal defects, apatent ductus arteriosus, or partially corrected congenitalheart disease, such as a Stage 2 Norwood repair of leftventricular hypoplasia. Main pulmonary artery dilationcan also occur with peripheral branch pulmonic stenosisand conditions causing pulmonary hypertension.

The left main bronchus can be compressed by the leftpulmonary artery, and the bronchus intermedius can be


A BFigure 2-19 Anomalous innominate artery compression of the trachea on bronchoscopy(A) and on airway fluoroscopy (B). (Courtesy of Howard Panitch, M.D. (A) and Ian Jacobs, M.D. (B).)

compressed by the right pulmonary artery. The rightupper lobe bronchus is free from potential compression,because it is positioned superior to the correspondingpulmonary artery branch. Vascular compression cancause a focal, homophonous wheeze, but if the obstruc-tion is large enough there may also be a history of recur-rent lobar pneumonia or chronic atelectasis dependingon the location and extent of the compression. Pressureon the recurrent laryngeal nerve from an enlarged pul-monary artery medially displacing the aorta can result inleft vocal cord paralysis with stridor (the cardiovocalsyndrome).

Left ventricular dysfunction and left atrial enlarge-ment can also cause left main bronchus compressionfrom below and clinical findings similar to those seenwith left pulmonary artery compression.

Anterior mediastinal masses, such as lymphoma, ter-atoma, and thymic masses, cause a fixed compression onthe proximal trachea and are difficult to differentiatefrom vascular abnormalities without CT or MRI scans ordirect visualization during bronchoscopy.

In the middle mediastinum, the high concentration ofperitracheal and perihilar lymph nodes can be the focusof lymphoma or lymphadenopathy from any of a numberof sources and may cause a central wheeze and an inspi-ratory sound. Other non-infectious etiologies of lym-phadenopathy, such as sarcoidosis, can cause clinicallysignificant wheeze or stridor if the lymph node is largeenough to displace the trachea or compress the mainbronchus.

Although lymphadenopathy secondary to infectionmore commonly presents without remarkable auscultatoryfindings, airway compression can occur. Tuberculosisshould be at the top of an infectious disease differential

of lymphadenopathy, but other chronic respiratoryinfections need to be considered as well. Chief amongthese in North America are regional endemic mycoticdisease from histoplasmosis in the Midwestern states,blastomycosis in the South Central and Midwesternstates, and coccidiomycosis in the Southwestern states.

Posterior mediastinal masses such as neurogenictumors and esophageal duplication or bronchogenic cystsare rarely symptomatic unless they are large. Symptomaticlesions usually lie adjacent to the main carina and causemain bronchus compression.

Masses that cause extrinsic compression tend to pres-ent as chronic processes. They may remain subclinicalwith slow growth, but can present as acute processes witha lower respiratory tract infection. One should stronglyconsider chest radiography in any child with a homopho-nous wheeze of unclear etiology, since the physical findingpoints to a problem involving the central airways.

Trachea: Intramural Airway LesionsAcuteIntramural lesions tend to be chronic, but acute respi-

ratory changes with infection or other abnormality maycause acute worsening of tracheal intramural lesions.

ChronicTracheomalacia is the most common intrinsic airway

lesion and causes a dynamic airway obstruction. It wors-ens with the increased transmural pressure gradientscreated during forceful exhalation, such as with crying,agitation, or increased exertion. The patient withintrathoracic tracheomalacia produces a homophonouswheeze that is made louder with vigorous exhalation. Itcan be made worse after bronchodilator therapy due totracheal smooth muscle relaxation, which makes thetrachea more compliant or collapsible.

In contrast, increasing tracheal smooth muscle tonereduces compliance, making the trachea more rigid andless collapsible. Tracheal smooth muscle stimulationcauses the posterior tracheal muscle to shorten and pullsthe posterior edges of the tracheal cartilage together.Both of these make the trachea less compliant and there-fore less susceptible to collapse when exposed to hightransmural pressure gradients6.

The rigidity of the trachea is primarily due to the pres-ence of the C-shaped tracheal cartilage “rings.” The pos-terior tracheal muscle then spans the two posterior endsof the tracheal cartilage (Figure 2-21). Tracheomalaciacan result from a muscular or cartilaginous defect, or inassociation with tracheoesophageal fistula or trachealcompression from vessels or other lesions. It can alsoarise from a defect in the tracheal smooth muscle or itsmechanics.

Secondary or acquired tracheomalacia can also occurafter chronic inflammation, from infections or chemicaldamage as occurs in gastroesophageal reflux withchronic aspiration, or after exposure to positive pressure


Figure 2-20 Bronchoscopic view of complete tracheal ringsdemonstrating the absence of the posterior membrane and thetypical “U”-shaped tracheal cartilage.


Medial compressionLateral compression

Expiration

Rest

Normal

A B C

Figure 2-21 The effect of distortion and tracheal col-lapsibility. In the normal trachea (A) during expiration,there is a small amount of invagination of the posteriormembrane (trachealis muscle) and narrowing of the tra-cheal lumen. Both lateral (B) and medial (C) compres-sion of the trachea cause distortion of the trachea andbroadening of the posterior membrane at rest and morenarrowing of the tracheal lumen during expiration.

in a premature infant. All of these can weaken the carti-lage and disrupt the interaction between cartilage andairway smooth muscle.

In some instances, the collapsibility of the trachea canbe related to an increased muscle-to-cartilage ratiowithin the tracheal wall5. An altered ratio can result fromabnormal formation (i.e., in tracheoesophageal fistula),or from external distortion. For example, anterior pres-sure on the cartilage can cause the posterior tips to sep-arate and the posterior tracheal membrane to broaden(Figure 2-18). The smooth muscle would then comprisea greater percentage of the tracheal circumference.Tracheal compliance would increase and the trachealmembrane would be prone to invaginate with changesin transmural pressure (Figure 2-21).

Following removal of a mass compressing the trachea,tracheomalacia can persist and the distortion of the tra-chea (increased muscle-to-cartilage ratio) or abnormalcartilage mechanics may not resolve completely. Priorrepair to the tracheal wall, such as after a tracheo-esophageal fistula repair or tracheostomy decannulation,may leave a residual distortion or defect in the conti-nuity of the tracheal wall. Furthermore, a tracheo-esophageal fistula in and of itself can be associated withan increased muscle-to-cartilage ratio and increasedtracheal compliance (Figure 2-21) even after repair. Bothsituations can adversely affect tracheal mechanics andcause tracheomalacia.

Complete tracheal rings, where the posterior mem-brane is absent (Figure 2-20), cause airway narrowingand a fixed obstruction with sounds that are most promi-nent during exhalation. Although uncommon, they areoften associated with pulmonary arterial sling, trachealbronchus, and pulmonary hypoplasia.

The intramural airway lesions also are primarily chronicprocesses; however, as with any airway obstruction,

they are made worse during respiratory tract infections.As is often the case with tracheomalacia, the homopho-nous wheeze may only be evident with increased effort of breathing associated with agitation or withmore distal small airway obstruction. In these situations,the increased positive intrathoracic pressure generatedduring exhalation will favor compression of a malacictrachea.

Intraluminal Airway LesionsAcuteIntraluminal lesions typically cause biphasic sounds

or just expiratory sounds if less severe.Tracheal foreign bodies (Figure 2-11) are uncommon,

for anything that is able to pass between the vocal cordsis substantially smaller than the tracheal caliber andtherefore should lodge in a bronchus. Irregularly shapedor elongated foreign bodies, however, can rotate andbecome trapped in the trachea with the long axis in theanteroposterior plane (Figure 2-22). As with the rest ofthe intrathoracic airway, tracheal foreign bodies usuallypresent with biphasic noisy breath sounds, more promi-nent during expiration because of dynamic narrowing ofthe intrathoracic airway.

Tracheitis or tracheal aspiration of upper airwaysecretions is associated with a low-pitched wheeze witha rattling character. Bacterial colonization of the tracheais common in patients with an artificial airway, and onoccasion the colonizing bacteria can increase in numberand cause a tracheitis. The tracheitis that occurs inpatients with an artificial airway is typically caused byGram-negative organisms (e.g., Pseudomonas aerugi-nosa, Serratia marcescens) and is not associated withthe same generalized toxicity as that caused byStaphylococcus aureus in otherwise healthy childrenwithout an artificial airway. This tracheitis is associatedwith an increase in tracheal secretions and clinically

significant respiratory difficulty, often with coarsewheezing and crackles and oxyhemoglobin desaturation.

ChronicTracheal granulomas are a common cause of intralu-

minal obstruction, especially in patients who are sub-jected to “deep” tracheal suctioning. The AmericanThoracic Society recommends endotracheal or trachealtube suctioning only to within 0.5 cm of the distal tip ofthe airway7. The points of trauma from deep suctioningusually occur at the carina or in the right main bronchus(Figure 2-23), and can cause unilateral crackles, biphasicwheezes, and decreased breath sounds if large enough.Segmental and/or lobar atelectasis can also occur due tocomplete obstruction or to compromised airway clear-ance distal to the obstruction.

Patients with an artificial airway for any duration maydevelop granulation tissue at the tip of the tube from theartificial airway rubbing against and/or injuring thenative airway wall. These lesions lie within the mid-trachea at the typical positioning of the distal tip of the artificial airway. Auscultatory findings are typicallysymmetric, homophonous and biphasic.

Patients with cutaneous hemangiomas and wheezingor stridor should be evaluated closely for airway heman-giomas using direct visualization by flexible or rigidbronchoscopy. These lesions typically present in infancyand many lesions regress spontaneously within the firstdecade; however, symptomatic lesions may require ther-apy with local steroid injection, laser cautery, Interferon-α,or other sclerosing agents to bring about regression.

Other less common intraluminal tracheal lesionsinclude tracheal papillomas from infection with humanpapillomavirus, and tracheal web, which is most likely topresent in the newborn period.

Bronchi/BronchiolesAcuteViral bronchiolitis can present similarly to an asthma

exacerbation with coarse heterophonous wheezing, buttypically there is a viral prodrome, prominent airwaysecretions and occasionally crackles. Viral culture ordirect fluorescent antigen testing for common respira-tory viruses, will help distinguish viral bronchiolitis fromasthma. Therapy for bronchiolitis is supportive with sup-plemental oxygen, fluid therapy and bronchodilator andanti-inflammatory drug administration, based on patientresponse. There are antiviral medications that can beused to limit the course of the disease caused by manyviral pathogens. Their efficacy is limited unless they areinitiated early in the course of disease, and they are notwidely used. There is a use for antiviral agents in sub-jects who have not had leukocyte engraftment afterbone marrow transplant, since untreated viral bronchi-olitis is almost universally fatal in such patients.

Bacterial pneumonia usually presents as focal cracklesthat can be localized to a particular lobe or lung region.Viral or Mycoplasma pneumonia, however, often pres-ents with diffuse crackles. The inflammatory reactionthat accompanies pneumonia can also cause airway walledema and wheezing. This occurs most commonly in


Figure 2-22 Pumpkin seed lodged in the distal trachea at thecarina.

Figure 2-23 Granuloma formation in the right main bronchusof a child with a tracheostomy tube and a history of “deep” tra-cheal suctioning past the end of the tracheostomy tube.

patients with viral pneumonia. It is also important toassess for lung regions in which there is decreased aera-tion or tubular breath sounds, representing enhancedtransmission of larger airway sounds through a consoli-dated region of lung.

Small foreign bodies that enter the trachea commonlybecome wedged in one of the main bronchi as opposedto the trachea due to the typically small caliber of foreignbodies that are able to pass between the vocal cords. Inadults, foreign bodies more commonly wedge in theright main bronchus because of the less acute angle ittakes from the trachea compared with the left mainbronchus. This predilection does not exist in children,however, and foreign bodies are found in either mainbronchus with near equal frequency.

ChronicAsthma is a disease of small airway obstruction, and

though by definition it is a chronic disease it frequentlypresents with acute exacerbations and is a commoncause of acute onset of wheezing. The hallmark of asthmais recurrent heterophonous wheezing, airway obstruc-tion that is reversible with bronchodilator therapy, andairway smooth muscle reactivity to an exposure. Airwayobstruction in asthma results from bronchoconstriction,inflammation, mucosal edema and increased mucus secre-tion. Usually, the wheeze in asthmatic children respondsto bronchodilator therapy. With a more severe exacerba-tion, mucosal edema and mucus in the airways can causewheezing that is less sensitive to bronchodilator therapy.Mucus in the airway can cause a deeper-soundingwheeze as well as crackles due to opening and closing ofairways throughout the respiratory cycle. Both wheezingand crackles can occur during an asthma exacerbation.

Bronchopulmonary dysplasia (BPD) is associated withobstructive lung disease primarily in small airways. BPDis seen most commonly in prematurely born infants whorequired mechanical ventilation in the newborn period,a prolonged (>1 month) use of supplemental oxygen,and who have persistent clinical findings at 1 month ofage. BPD has clinical similarities to asthma, includingincreased airway smooth muscle tone, frequentlydemonstrable bronchodilator responsiveness, and het-erophonous wheezes during acute illnesses.

If there is a diffuse process, such as bronchomalaciaor airway wall edema from inflammation or cardiac fail-ure, homophonous wheezing will be present, reflectingcentral airway disease.

Prolonged positive pressure ventilation in prematureinfants can lead to bronchomalacia, and produce ahomophonous wheeze. Secondary bronchomalacia fromchronic regional inflammation or infection will be asym-metrically distributed and cause a localized homopho-nous wheeze. As with tracheomalacia, the wheezingmay worsen after a bronchodilator treatment since the

airway will be more compliant due to smooth musclerelaxation.

EVALUATION

Diagnosing a respiratory abnormality can often beaccomplished with a comprehensive history and physi-cal examination; however, additional studies can behelpful in confirming or further elucidating the diagno-sis. Chest radiography should be performed in anypatient with asymmetric wheezing or air entry, espe-cially if it is new in onset. Children with a symmetric res-piratory examination, especially those with a history ofasthma, do not necessarily need a chest radiograph.Because the chest radiograph only shows one plane at atime, it may miss more complicated, inhomogeneous orearly disease with small areas of airway damage, such asbronchiectasis, or parenchymal damage, such as areas ofsubsegmental atelectasis or necrosis. With chest radio-graphy one can evaluate the aortic arch and descendingaorta, cardiothymic silhouette, mass lesions, pulmonaryparenchyma and vessels, and large airway position.

Chest CT gives a clearer view of the pulmonaryparenchyma and delineates healthy from diseased lung,as well as mediastinal structures and other relationshipsto more central and larger airways. When airway com-pression is a concern, a CT scan can often document airway narrowing and clearly show the compressingmass. Three-dimensional reconstruction from a CT scanor MR image can more clearly show the mediastinalstructures and their interrelationships, especially withvascular abnormalities.

Using a barium esophagram one can evaluate for vas-cular compression, gastroesophageal reflux, and forabdominal anatomic abnormalities. A barium esopha-gram will demonstrate compression of the esophagusresulting from a fixed intrathoracic lesion such as a vascular abnormality or a mediastinal lesion.

A video feeding study can be used to evaluate swal-lowing function for a variety of textures and consisten-cies of food and liquids. This is helpful in assessing foraspiration, which can cause recurrent lower airwayinfection and inflammation. Non-contrast fluoroscopycan also give a dynamic view of the central airway toevaluate for dynamic tracheal narrowing non-invasively.When direct endoscopic airway visualization is not avail-able, airway fluoroscopy is a reasonable alternative eval-uation. It must be remembered, however, that evennormal infants can narrow their airways by up to 50%during crying, so that fluoroscopic presence of luminalnarrowing may not be abnormal.

Direct visualization of the central airway using flexi-ble bronchoscopy under conscious sedation is the best


method to show how the airways behave under dynamicconditions. Bronchoalveolar lavage using flexible bron-choscopy provides a sample for culture of pathogens,especially in subjects with persistent lower respiratorysymptoms. In addition, a lavage specimen can be sent forcytologic analysis to evaluate for lipid-laden macrophages,an indication of recurrent aspiration, or for a preponder-ance of neutrophils or lymphocytes that also would indi-cate chronic inflammation.

Rigid bronchoscopy is performed under general anes-thesia and is less helpful for evaluating dynamic conditions.For foreign body removal, however, rigid bronchoscopyis preferable since the working channel is larger to allowfor better instrumentation. Furthermore, rigid bron-choscopy is the safer technique for foreign body removal,since it is performed under general anesthesia and with acontrolled airway in place through which assisted venti-lation can be delivered.

Pulmonary function testing is helpful in evaluating res-piratory system mechanics, determining the severity of aparticular disorder, and assessing its change with inter-ventions, such as after bronchodilator, anti-inflammatoryor antibiotic administration. Spirometry is a useful initialtest in which patients perform a maximal expiratoryflow volume maneuver (MEFVM). It provides an accu-rate measure of airway mechanics and obstructive air-way disease. Obstructive lung disease is usually present

when the ratio of forced expiratory volume in the first second of exhalation (FEV1) to forced vital capacity (FVC)is below 0.8. Post-bronchodilator increase in FEV1 ofgreater than 12%7 is a statistically significant change anddefines reversible airway obstruction, one of the centralcomponents of asthma.

Examination of the flow–volume curve can also helpto diagnose airway obstruction (Figure 2-24). Normalspirometry (Figure 2-24a) involves a rapid increase inexpiratory flow at the onset of expiration with a gradualdeceleration of flow through lower lung volumes, and amore gradual increase in flow during inspiration withpeak inspiratory flow occurring midway through inspi-ration. A rapid decrease in expiratory flow after reachingpeak flow (i.e., a “concave” expiratory flow–volumecurve) is diagnostic of peripheral intrathoracic airwayobstruction (Figure 2-24b). A truncated inspiratoryflow?volume curve, where peak flow is low and the loopis flattened, together with a normal expiratory flow–volume curve (Figure 2-24c), is diagnostic for a variableextrathoracic obstruction such as a supraglottic tumoror vocal cord paralysis. Conversely, expiratory peak flowlimitation, with a normal inspiratory flow–volume loop(Figure 2-24e), represents a variable intrathoracicobstruction seen in large intrathoracic airway obstruc-tion. Truncation of both inspiratory and expiratory peakflows (Figure 2-24d) is diagnostic of a fixed obstruction.


VolumeExp

Insp

Flo

w

VolumeExp

Insp

Flo

w A B C

ED

Figure 2-24 Representative flow–volume curves: (A) normal; (B) intrathoracic peripheral airwayobstruction; (C) variable extrathoracic airway obstruction; (D) fixed airway obstruction; and (E) vari-able intrathoracic central airway obstruction. By convention, flow is represented on the y-axis, vol-ume on the x-axis, expiration as an upward deflection, and inspiration as a downward deflection.

These measurements require that the subject willfullybe able to take a deep breath and exhale with maximaleffort for at least 6 seconds8, a task which is challengingfor children 6 years and under and impossible for tod-dlers and infants to perform. Some have suggested adapt-ing the American Thoracic Society end-of-test criterionfor spirometry to the capabilities of younger children, butno criteria have been widely accepted yet. Similar mea-surements can be performed in sedated infants and tod-dlers using equipment that applies positive pressure tothe mouth to inflate the lungs and external compressionto the chest and abdomen to forcefully deflate the lungs.

There are a variety of laboratory studies that can behelpful in evaluating for an infectious cause of noisybreathing. In the fall, winter and early spring months,viral antigen testing from the nasal secretions for com-mon viral pathogens (RSV, parainfluenza types 1 and 3,influenza, and adenovirus) is diagnostic in the acute set-ting. Bacterial serologic antigen testing for Mycoplasmaand pertussis is widely offered. PPD (purified proteinderivative) intradermal testing for tuberculosis exposureand or infection is an important part of the evaluationfor any chronic pneumonia, parenchymal lesion, or lym-phadenopathy. A positive test must be reported to localpublic health authorities for infection control and toinsure that definitive therapy is initiated.

If recurrent wheezing is associated with chronic orrecurrent sinusitis and otitis, a deficiency of the immunesystem may be present. Quantitation of the amount ofcirculating immunoglobulins (IgG, IgA, IgM and IgE) willdetect deficiencies or excess of antibodies. IgM and IgGdeficiencies can cause clinically significant disease.Although IgA deficiency is the most common immuno-deficiency, it rarely causes clinically significant disease.An elevated IgE level is associated with many chronicinflammatory conditions such as asthma and atopy.

Sweat chloride testing is a definitive test for cysticfibrosis and is an important part of any evaluation ofchronic respiratory disease that is not responsive to stan-dard asthma therapy or is associated with failure tothrive, chronic diarrhea, or nasal polyps. Testing shouldbe performed in a recognized Cystic Fibrosis Center,which is experienced in the proper collection and ana-lytic techniques in order to maximize the accuracy ofthe results.

CONCLUSION

Evaluating the child with noisy breathing can bedaunting because of the wide range of presentations andetiologies. With a focused history and physical examina-tion, however, one should be able to diagnose most ofthe causes of noisy breathing and reserve testing for con-firmation or refinement of the diagnosis.


MAJOR POINTS

1. Although there is a wide range of etiologies of noisybreathing, with a focused history and physicalexamination one should be able to come very closeto a diagnosis before any evaluations are performed.

2. By history, be able to discriminate between acute,recurrent and chronic processes and whether thenoisy breathing is occurring during inspiration,expiration or both.

3. On the physical examination determine whetherthe noisy breathing is focused in the intrathoracicor extrathoracic airway and describe the quality ofthe sound (wheeze, stridor, or crackle).

4. Use evaluations judiciously to augment, but not toreplace, a thorough history and physicalexamination.

5. Reassess the diagnosis after initial therapy toevaluate the response.

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REFERENCES

1. Pasterkamp H. The history and physical examination. InChernick V, Boat T, editors: Kendig’s disorders of the respi-ratory tract in children, 6th edition, pp 85–106. Philadelphia:WB Saunders, 1998.

2. Mancuso R. Stridor in neonates. In Isaacson G, editor: Pediatricotolaryngology. Pediatr Clin North Am 43:1339–1356, 1996.

3. Clements B. Congenital malformations of the lungs andupper airway. In Taussig L, editor: Pediatric respiratorymedicine, pp 1106–1136. Philadelphia: Mosby, 1999.

4. Valletta E, Pregarz M, Bergamo-Andreis I, et al.Tracheoesophageal compression due to congenital vascularanomalies (vascular rings). Pediatr Pulmonol 24:93–105, 1996.

5. Holinger L, Green C, Benjamin B, et al. Tracheobronchialtree. In Holinger L, Lusk R, Green C, editors: Pediatriclaryngology and bronchoesophagology, pp 187–213.Philadelphia: Lippincott-Raven, 1997.

6. Panitch H, Keklikian E, Motley R, et al. Effect of alteringsmooth muscle tone on maximal expiratory flows in patientswith tracheomalacia. Pediatr Pulmonol 9:170–176, 1990.

7. American Thoracic Society. Care of the child with a chronictracheostomy. Am J Respir Crit Care Med 161:297–308, 2000.

8. American Thoracic Society. Standardization of spirometry.Am J Respir Crit Care Med 152:1107–1136, 1994.

OTHER RESOURCES

Chernick V, Boat TF, editors. Kendig’s disorders of the respiratorytract in children, 6th edition. Philadelphia: W. Saunders, 1998.

Taussig LM, LI Landau, editors. Pediatric respiratory medicine.Philadelphia: Mosby, 1999.

West JB. Respiratory physiology: the essentials, 6th edition.Philadelphia: Lippincott, Williams and Wilkins, 2000.

35

CHAPTER

3 CongenitalMalformations of theLung and the AirwayANITA BHANDARI, M.D.

Embryology of the Lung

Laryngeal and Tracheal Malformations

Laryngeal Atresia and Web

Congenital High Airway Obstruction Syndrome

Tracheal Agenesis

Tracheal Stenosis

Tracheomalacia

Tracheoesophageal Fistula

Abnormalities of the Lung

Pulmonary Agenesis

Pulmonary Hypoplasia

Congenital Lobar Emphysema

Bronchogenic Cysts

Congential Cystic Adenomatoid Malformation

Pulmonary Sequestration

Vascular Rings

Pulmonary Lymphangiectasis

Congenital malformations of the lung are a part of thedifferential diagnosis of lung masses on the chest radi-ograph in infants and children. Though usually easy tospot, differentiation is a challenge, and may require fur-ther diagnostic testing.

EMBRYOLOGY OF THE LUNG

Lung development is divided into five stages (Table 3-1).The lung develops as a ventral outpouching of the prim-itive gut during the embryonic period (stage 1, day 26 today 52). Over this period, the trachea appears first as arespiratory diverticulum. Its distal end then divides intothe two main bronchi. These elongate into the mes-enchyme and form lobar and segmental bronchi. In thepseudoglandular stage (stage 2, day 52 to 16 weeks) thebranching continues such that by the end of this stage allthe airway branching is complete and conducting air-ways and the terminal bronchioles are now completely

formed. During this phase of development the arteriescan be seen running alongside the conducting airways.Within the canalicular stage (stage 3, 16 weeks to 28weeks) the respiratory bronchioles are formed. Theseend in primitive alveoli called saccules and the lungdevelops a vascular bed that is closely associated withrespiratory bronchioles. During the saccular stage (stage4, 28 weeks to 36 weeks), as the pulmonary capillariesproliferate, close contact between the airspaces and theblood supply develops. As the epithelium thins, a rich vas-cular supply is established and gas exchange is now poss-ible. During this stage elastic fibers that are responsible forfurther alveolar growth are also laid down. In the alveolarstage (stage 5, 36 weeks to 2–8 years), secondary septationof the alveoli occurs thereby increasing the surface area forgas exchange. A knowledge of the stages of airway and pul-monary parenchymal development is crucial to an under-standing why various congenital malformations occur, andhow they may affect lung physiology.

LARYNGEAL AND TRACHEALMALFORMATIONS

Laryngeal Atresia and Web

Laryngeal atresia occurs as a result of failure ofrecanalization of the larynx around 10 weeks of gesta-tion and is usually associated with a normally developedlung, although lung hyperplasia has been reported(Figure 3-1). Cases of partial recanalization may result inthe formation of a laryngeal web.

The typical clinical presentation of laryngeal atresia isdevelopment of respiratory distress immediately afterbirth. The baby has a voiceless cry and no air movementdespite respiratory effort. If pulmonary hyperplasia ispresent, hydrops fetalis can occur, presumably fromcompression of the vena cava by the massively enlarged


Table 3-1 The Stages of Lung Development

Stages of Lung Development Gestational Age

Stage 1 Embryonic stage Day 26 to day 52Stage 2 Pseudoglandular stage Day 52 to 16 weeksStage 3 Canalicular stage 16 weeks to 28 weeksStage 4 Saccular stage 28 weeks to 36 weeksStage 5 Alveolar stage 36 weeks to postnatal

A

lungs (see the section on CHAOS, below). The infantwith a laryngeal web will present with stridor and aweak cry at birth. If the web causes severe airway nar-rowing, respiratory distress can develop soon after birth.

DiagnosisDiagnosis is confirmed by direct visualization in both

cases. In the case of laryngeal atresia, a fibrous mem-brane occluding the lumen of the larynx can be visual-ized on laryngoscopy. Laryngeal webs are mostcommonly located in the glottic area and are anteriorlyplaced, revealing a concave posterior glottic opening onlaryngoscopy.

TreatmentTreatment of laryngeal atresia involves tracheostomy

placement to bypass the obstruction. Once the child islarge enough (usually 10 kg or more), laryngeal recon-struction can be undertaken. Treatment involves exci-sion of the web in cases of partial occlusion, and shouldbe curative.

PrognosisThe outcome of patients with laryngeal atresia will

depend in part on the presence of other associatedanomalies. Patients with partial recanalization do betterthan those with complete occlusion of the laryngeal lumen.The rapidity with which the airway is established at birthwill also impact long-term prognosis. Reconstructive sur-gery in some cases may allow development of speech.

Congenital High Airway ObstructionSyndrome

Congenital high airway obstruction syndrome(CHAOS) is a syndrome of prenatally diagnosed com-plete or near-complete upper airway obstruction.Airway obstruction is usually caused by laryngeal atresia,a laryngeal web, or severe subglottic stenosis. Prenatalsonographic findings include bilateral enlarged lungs,dilated airways and flattened diaphragms with associatednon-immune hydrops or fetal ascites. Ex utero intra-partum therapy (EXIT), which involves tracheostomyplacement during delivery while the infant is still sup-ported by the placenta, and positive pressure ventila-tion, has been tried with some success in these cases1.

Tracheal Agenesis

Tracheal agenesis is a rare congenital abnormality ofthe airway that is incompatible with life. It is thought tooccur because of a malformation of the laryngotrachealgroove. Thus, this lesion occurs early in the embryonicstage of lung development. There is usually an incompletepresence or complete absence of a trachea below thecricoid cartilage or the larynx with or without main-stembronchi. There is also an associated tracheoesophageal fis-tula in 80% of these cases. Clinically, patients have respi-ratory distress at birth, and usually die soon after birth.

TreatmentReconstructive surgery has been attempted with poor

results.

PrognosisTracheal agenesis carries a poor prognosis and is uni-

formly fatal.

Tracheal Stenosis

Congenital stenosis of trachea most commonly occursas a result of the presence of tracheal webs causing nar-rowing of the airway. These webs are typically fibrous innature and occur most commonly in the subglottic region.

Figure 3-1 (A) Lateral neck radiograph of an infant with laryngealatresia. Note the abrupt cessation of the air column at the level ofthe larynx (arrow). (B) Serial CT images of the same patient, pro-gressing caudally from just above the lesion. Note the disappear-ance of the air column in images 6 through 10, with itsreappearance and placement of a tracheostomy tube in the lasttwo panels. (Images courtesy of Avrum Pollock, M.D., FRCPC.)

(Continued)

Clinically, patients present shortly after birth with respi-ratory difficulty and stridor suggesting an upper airwaylesion.

DiagnosisA plain chest and neck radiograph can suggest airway

narrowing. Bronchoscopy is definitive and reveals nar-rowing of the airway on direct visualization. In situationswhere the stenosis is too small to permit the entry of abronchoscope, a tracheogram with water-soluble con-trast can be used to confirm diagnosis and define theextent of the narrowing (Figure 3-2).

TreatmentConservative management is preferred, since the tra-

cheal lumen may widen enough with time to alleviaterespiratory distress. Intraluminal stenting and high doses

of intralesional steroids as well as inhaled steroids havebeen tried. Tracheostomy may be necessary if the patientpresents in acute respiratory distress.

Tracheomalacia

Tracheomalacia is the commonest tracheal abnormal-ity. It may be congenital or acquired. Acquired tracheo-malacia can occur secondary to extrinsic compressionby, for example, a vascular ring. The intrathoracic tra-cheal lumen dilates during normal inspiration and nar-rows during normal expiration. In patients withintrathoracic tracheomalacia, this normal expiratoryprocess will be exaggerated because of lack of trachealsupport, resulting in pronounced narrowing during


A BFigure 3-2 (A) Tracheobronchogram with water-soluble contrast medium (Omnipaque) in a 3-month-old infant with distal tracheal stenosis. Note that the caliber of the distal trachea is smallerthan that of the left main bronchus. The bronchoscope, which has a diameter of 3.6 mm, can beseen at the top of the airway for a size reference. (B) Bronchoscopic view of the trachea. The tra-cheal lumen was too small to allow the bronchoscope to be advanced through it. In this patient, thestenosis was associated with a series of complete tracheal rings. The posterior tracheal membrane(pars trachealis) that normally spans the ends of the C-shaped cartilages, is absent. (Images courtesyof Howard B. Panitch, M.D.)

exhalation. For similar reasons, patients with extratho-racic tracheomalacia will experience airway narrowingduring inspiration. This condition can present withsymptoms of persistent wheeze, cough, stridor, dyspneaor tachypnea. Symptoms typically worsen with high-air-flow activities, e.g., during feeding or crying. In contrast,symptoms will improve during sleep. They may alsoworsen with intercurrent upper respiratory infections.

DiagnosisThe diagnosis is generally made based on clinical history

and presence of stridor (extrathoracic tracheomalacia) or ahomophonous wheeze (intrathoracic tracheomalacia) onclinical examination. The presence of an easily collapsibletracheal wall can be confirmed by flexible bronchoscopy.Airway fluoroscopy, demonstrating a narrowing of thetracheal air column, has also been used as a diagnostic test(Figure 3-3). Symptoms usually improve with age andresolve spontaneously by 12 months of life.

Differential Diagnosis1. Vascular rings, especially double aortic arch and

right aberrant subclavian artery, may causesymptoms of tracheal compression and should beruled out. A normal upper gastrointestinal seriesrules out most significant vascular rings but willmiss an anterior tracheal compression by an

anomalous innominate artery. Presence of apulsatile mass on bronchoscopic examinationsuggests the presence of a vascular ring.

2. Tracheal webs and congenital tracheal stenosis alsocause narrowing of the tracheal lumen. On clinicalexamination, the noise will often be bi-phasic.These lesions can be ruled out by directvisualization during bronchoscopy.

TreatmentIf symptoms are mild, anticipatory guidance is ade-

quate. In cases of severe tracheomalacia, infants and chil-dren may have life-threatening episodes of airway collapse.In such situations, prolonged treatment with continuouspositive airway pressure (CPAP) via tracheostomy may berequired. The application of CPAP can improve forcedexpiratory flows by acting as an intraluminal stent or byincreasing lung volume (or both). When measured, therehas been no increase in the forced vital capacity (FVC)detected with institution of CPAP, but there is a decreasein inspiratory capacity (IC) suggesting an increase in func-tional residual capacity (FRC). Together, these mecha-nisms help prevent airway collapse especially duringforced expiratory maneuvers such as crying2–4.

Bronchoconstrictors, such as bethanechol and metha-choline, cause an increase in airway smooth muscle tone

Congenital Malformations of the Lung and the Airway 39

A BFigure 3-3 (A) Chest fluoroscopy in the lateral position during inspiration, demonstrating a tra-cheal air column of normal caliber (arrows). (B) Expiratory view of same patient, showing markednarrowing of the intrathoracic airway (arrows), consistent with intrathoracic tracheomalacia. Careshould be taken to avoid the patient crying during the examination, since the airway caliber can nar-row by as much as 50% in normal babies under such conditions. (Images courtesy of Avrum Pollock,M.D., FRCPC.)


A B

EDC

which in turn stiffens the trachea. This intervention hasbeen shown to improve expiratory flow in patients withtracheomalacia when the narrowed trachea is the majorsite of obstruction5.

The surgical approach to treatment of tracheomalaciaincludes placement of a tracheostomy tube, which iflong enough, can preserve the airway lumen by stentingthe trachea. Aortopexy has also been used successfullyin patients with distal tracheomalacia. Suspension of theaorta to the anterior chest wall can relieve vascular com-pression as well as preventing anterior tracheal wall col-lapse. A marked improvement in clinical symptoms aswell as evidence of relief of tracheal obstruction hasbeen documented on infant pulmonary functions, con-trolled ventilation CT scans and MRI postoperatively.

Since tracheomalacia may result in poor airway clear-ance, intercurrent infections need to be treated withaggressive airway clearance maneuvers. Occasionally,antibiotics may be required, especially if the patient hasa history of recurrent pneumonia and bronchitis.

PrognosisThe prognosis is excellent for infants with isolated

tracheomalacia. In most cases, symptoms resolve spon-taneously by 12 months of age. Tracheomalacia associ-ated with vascular compression or tracheoesophagealfistula, however, may persist for years. In patients withsevere tracheomalacia requiring tracheostomy andmechanical ventilation, the course is usually prolongedand resolution of tracheomalacia takes months to years.

Tracheoesophageal Fistula

Tracheoesophageal fistula (TEF) results from the fail-ure of the digestive and the respiratory tracts to separatefrom each other during the embryonic stage of develop-ment. Four different types of TEF have been recognized.The commonest type involves the esophagus ending in ablind proximal pouch while the distal esophageal rem-nant communicates with the trachea. This type accountsfor 85% of all TEFs (Figure 3-4). The distal and the prox-imal esophageal pouches may be attached by a fibrousband and the distance between the distal pouch and theproximal pouch is variable. The fistula runs from the dis-tal esophageal segment to the posterior wall of the tra-chea and enters the airway typically just above the carinaor the proximal part of either one of the main-stembronchi.

Esophageal atresia with the TEF originating from theproximal esophageal pouch is uncommon (Figure 3-4E).Here, the fistula opens either in the mid-portion of thetrachea or close to the carina depending upon the lengthof the proximal esophageal pouch.

Three to six percent of all TEFs occur as an H-type fis-tula, where both the esophagus and the trachea maintainpatent lumens throughout their lengths, but there exists

a fistula between the trachea and the esophagus (Figure 3-4C). The fistula usually runs upwards from the esophagus towards the middle of the trachea andappears as an opening in the posterior tracheal wall. Theepithelium lining the fistula is usually esophageal. Thetracheal epithelium in patients with TEF reveals multipleareas of squamous metaplasia with loss of ciliated epithe-lium. There is also often a greater proportion of muscleto cartilage in the tracheal wall at the site of the fistula,resulting in an area of tracheomalacia. Together, thesefactors result in poor airway clearance, thus contributingto recurrent bronchitis and pneumonia.

Esophageal atresia with both the proximal and thedistal esophageal pouch communicating with the tra-chea occurs rarely (Figure 3-4D). Approximately 10% ofesophageal atresia is not associated with any TEF.

Clinical FeaturesAbout 30% of the cases of TEF with esophageal atresia

are complicated by hydramnios and 50% of the patientsmay have associated cardiovascular, renal, gastrointestinal,and central nervous system abnormalities6,7. Infants with

Figure 3-4 The common (A, B) and less common (C, D, E) com-binations of esophageal atresia (EA) and tracheoesophageal fistula(TEF). (From Blickman H, editor: The requisites: pediatric radiol-ogy, 2nd edition, p 93. Philadelphia: Mosby, 1998.)

esophageal atresia usually present with copious oral secre-tions and, when attempted, there is a failure to pass anorogastric tube. There may be recurrent vomiting and/orrespiratory distress. Recurrent aspiration of oral secretionsoccurs because of pooling of secretions in the proximalblind pouch. Patients may present with a history of recur-rent bronchitis and pneumonia. There may be history ofintermittent choking with food and symptoms are usuallyworse with ingestion of fluids rather than solids.

Clinical presentation of an H-type fistula is usuallymore subtle, consisting of cough in association withingestion of formula or food. Affected patients are usually

full-term infants and patients may not be diagnosed untiladulthood.

DiagnosisThe plain chest radiograph can disclose aspiration

pneumonia or chronic scarring from recurrent episodes ofaspiration pneumonia. There will be an associated gaslessabdomen in cases of TEF with proximal esophageal atresiawhereas esophageal atresia with a distal TEF is associatedwith presence of gas in the abdomen (Figure 3-5).

A fistulous opening between the trachea and theesophagus can often be demonstrated by bronchoscopicexamination. Esophagoscopy can also reveal an orifice.


AFigure 3-5 (A) Anteroposterior and lateral chest radiographs of a newborn with esophageal atre-sia and distal TEF. The proximal pouch can be seen as a lucency that abruptly ends on both views(arrows). Presence of gas in the abdomen suggests that the distal esophageal segment must be inconnection with the airway. (B) Anteroposterior and lateral chest radiographs of the same infantafter an attempt to pass an orogastric tube. The tube loops back upon itself in the proximal fistula,demonstrating the pouch. (Images courtesy of Avrum Pollock, M.D., FRCPC.) (Continued)

If methylene blue dye instillation through one orifice isrecovered from another, especially when the distalesophagus is occluded with a Foley catheter, the diag-nosis is confirmed.

Continuous imaging and videotaping with a contrastmedium swallow helps differentiate between filling of thetrachea via a fistulous opening and tracheal filling seen inoverflow aspiration. Instillation of contrast medium underpressure via a feeding tube (Figure 3-6) can demonstratea fistula too small to be identified endoscopically. Thecombination of this technique with bronchoscopy willdetect >90% of cases of TEF.

Differential Diagnosis1. A vascular ring that includes both the airway

and esophagus, such as a double aortic arch orright aberrant subclavian artery, may causetracheomalacia and gastroesophageal reflux

disease (GERD) symptoms because of compressionof the esophagus and the trachea. An uppergastrointestinal series with contrast helps rule out a vascular ring or sling.

2. Cystic fibrosis should be considered when patientspresent with recurrent pneumonia and failure tothrive. A negative sweat test will rule out cysticfibrosis in most cases.

3. Immunodeficiency should be considered inpatients presenting with recurrent pneumonia.

ManagementSurgical repair is the treatment of choice and opera-

tive mortality is low. Surgical repair may be carried outas a primary repair or as a staged procedure in prematureinfants or infants with other associated anomalies.Prompt diagnosis and operative management are crucialto minimize development of chronic pulmonary disease.




Figure 3-6 Upper gastrointestinal series with barium instillationvia a tube demonstrates an H-type TEF with filling of both theesophagus and the airway. Placement of the tube beyond the fistula, with retrograde filling, allows for differentiation betweenthe fistula and possible aspiration of contrast material into the air-way during swallowing. (Image courtesy of Avrum Pollock, M.D.,FRCPC.)

PrognosisRecurrence of TEF after surgical repair occurs in

4–10% of cases. Postoperative strictures at the site of theanastomosis are common6,8,9. Persistent tracheomalaciaat the fistula site occurs frequently as well. It has beenreported that 60% of affected children, after successfulsurgical repair, have persistent GERD symptoms untillate adulthood10. Recurrent bouts of pneumonia andbronchitis are seen in about half of these patients post-operatively11. The rate of postoperative complications islower in patients with H-type fistula compared withpatients with associated esophageal atresia.

Without surgery, TEF with esophageal atresia is fatal;however, patients with H-type fistula may survive manyyears without surgery. When promptly diagnosed 95% ofterm infants with TEF survive. Survival rates in prema-ture babies with moderate pneumonia or congenitalabnormalities are lower.

ABNORMALITIES OF THE LUNG

Pulmonary Agenesis

Pulmonary agenesis is characterized by underdevel-opment of lung. In cases of pulmonary agenesis there isno development of the bronchial tree or pulmonary tis-sue12, whereas in pulmonary aplasia there may be a rudi-mentary pouch with no pulmonary tissue. Both theseentities may be associated with other congenital abnor-malities. Pulmonary agenesis and aplasia both occur dur-ing the embryonic stage of lung development12–14.Agenesis can affect either a single lobe, an entire lung or

both lungs. The unaffected lobes or lung usually demon-strate compensatory hypertrophy. Agenesis of the rightlung is more likely to be associated with other congenitalabnormalities than is agenesis of the left lung.

Patients are usually symptomatic and present withtachypnea, respiratory difficulty or recurrent pulmonaryinfections. As the patient gets older, the chest examina-tion can reveal an abnormal chest contour because oflack of lung growth on the affected side. The hemithoraxthat lacks the lung may be filled with the hypertrophiedcontralateral lung that herniates over to the affected side.The mediastinal structures may also shift to fill the emptyhemithorax. There are decreased breath sounds on theaffected side, though often there may not be completeabsence of breath sounds because of air movement in theherniated lung that is filling the empty hemithorax.

DiagnosisThe chest radiograph shows approximation of the

ribs, elevation of the diaphragm and presence of a uni-form dense opacity on the affected side (Figure 3-7).There is deviation of the mediastinal structures towardsthe affected side12,15.

On bronchoscopic examination, there is absence ofbronchi (agenesis) or presence of a rudimentary pouchon the affected side (aplasia). Bronchography can out-line the tracheobronchial tree and confirm findings seenon bronchoscopy. Angiography has been used todemonstrate absence of pulmonary vasculature14. ChestCT is useful in showing absence of lung parenchyma andthe tracheobronchial tree.

Differential Diagnosis1. Pneumonia presents as a large opacity on a plain

chest radiograph. However, close approximation ofribs and an elevated hemidiaphragm, or deviationof trachea and the mediastinal structures, all reflectloss of volume on the side of the opacification andtherefore are suggestive of lung agenesis. Incontrast, acute pneumonia is not associated withipsilateral volume loss.

2. Atelectasis may be difficult to distinguish frompulmonary agenesis radiographically. Bronchoscopywill demonstrate both main bronchi, and probablyalso reveal a central airway obstruction leading tothe atelectasis.

TreatmentIntervention is aimed at supportive care. If respiratory

insufficiency is present, tracheostomy tube placementwill facilitate chronic mechanical ventilation. Aggressiveairway clearance is recommended for adequate pulmonarytoilet. If there is an isolated lobar agenesis, resection ofthe abnormal lobe may be helpful16.

PrognosisOutcome depends on the extent of agenesis and

the presence of associated congenital malformations.

Right-sided agenesis causes a greater degree of medi-astinal shift. Because of the shift, the risk for spillage ofthe contents of the right bronchial pouch into the leftlung will be increased and can lead to recurrent lunginfections13,17.

Pulmonary Hypoplasia

Hypoplastic lungs are small, have a decreased alveolarnumber, lower DNA content, and a decreased number ofairway generations. Reduction in airway number, whenpresent, suggests an injury before 16 weeks gestation.Isolated lung hypoplasia is unusual but is more likely tooccur as a secondary event. A number of clinical condi-tions result in pulmonary hypoplasia. For example, con-genital neuromuscular diseases that result in decreasedfetal movements and decreased expansion of the chestand the lungs in utero will lead to pulmonary hypoplasia.Renal and congenital genitourinary diseases can lead tooligohydramnios, which is also associated with adecreased alveolar number. A space-occupying lesion inthe chest cavity, such as diaphragmatic hernia or pleuraleffusion (as in hydrops), can also impair lung growth andresult in lung hypoplasia. Abnormal pulmonary artery

formation or congenital heart disease can lead toimpaired pulmonary perfusion and decreased lunggrowth. An abnormal bronchus can also interfere withlung development and lead to pulmonary hypoplasia.

Since there are many causes of pulmonary hypoplasia,clinical features will depend on the underlying cause ofthe hypoplasia. The spectrum of clinical presentation iswide and depends on the severity of associated lesionsand the degree of hypoplasia. Thus patients may be com-pletely asymptomatic or may present with significantrespiratory distress.

DiagnosisThe chest radiograph or CT scan shows poorly aerated

lungs or findings of the associated abnormality respon-sible for the hypoplasia, such as pleural effusion ordiaphragmatic hernia. The main pulmonary arteries mayalso appear small.

TreatmentThe mainstay of care is supportive; therapy depends

upon the degree of hypoplasia and associated anomalies,if any. Some children with pulmonary hypoplasia mayrequire supplemental oxygen only initially whereas oth-ers require chronic mechanical ventilation to maintainadequate gas exchange.


A B

AA

LA

MPA

ERMP

Figure 3-7 (A) Anteroposterior chest radiograph of a newborn infant with right-sided pulmonaryaplasia. The right hemithorax is uniformly opacified. Endoscopic evaluation demonstrated a rudi-mentary bronchial bud on the right, with a normal left main bronchus. (B) Chest CT scan of thesame patient. The rudimentary right main bronchus can be seen as well as a normal-sized left main pulmonary artery. The right main pulmonary artery is absent. AA, aortic arch; E, esophagus; MPA,main pulmonary artery; LPA, left pulmonary artery; RMB, right main bronchial bud. (Images cour-tesy of Avrum Pollock, MD, FRCPC.)


Table 3-2 Causes of Bronchial Obstruction

Intrinsic Extrinsic

Hypoplastic/dysplastic Patent ductus arteriosusbronchial cartilage Pulmonary artery sling

Inspissated mucus plugs Pulmonary stenosisBronchial stenosis/ atresia Tetralogy of Fallot with absent Bronchial granulations pulmonary valve

Bronchogenic cystMediastinal teratomaNeuroblastomaMediastinal lymphadenopathyEsophageal duplication cystAccessory diaphragm

Figure 3-8 Newborn infant with congenital lobar emphysemainvolving the left upper lobe. Although the area is hyperlucent,lung markings can still be identified within the lesion. The overdis-tended left upper lobe crosses the midline (thin arrows), com-presses the left lower lobe and lingula (thick arrows), and causes aright-ward shift of the mediastinal structures. (Image courtesy ofAvrum Pollock, M.D., FRCPC, and Howard Panitch, M.D.)

PrognosisOutcome depends upon the cause of hypoplasia and

presence of other associated anomalies.

Congenital Lobar Emphysema

Congenital lobar emphysema (CLE) makes up 14% ofall bronchopulmonary malformations. The emphysema-tous lobes are commonly left-sided and usually occur inthe upper lobes. This malformation is most often charac-terized by overdistension of the affected lobe and the alve-oli are otherwise normal anatomically. Occasionally, theremay be a reduced number of alveoli within the lobe. Thepathogenesis of CLE is thought to be secondary to anobstruction of the bronchus leading to secondary hyper-inflation. This obstruction of the airway may be the resultof an intrinsic lesion or extrinsic compression (Table 3-2).Intrinsic lesions result either from abnormal characteris-tics of the bronchial wall or intraluminal causes. Extrinsiclesions cause compression of the airway by vascular ormass structures. Vascular compression can result fromabnormal structures (e.g., rings, slings) or from enlargedvessels associated with left-to-right shunts.

Clinical presentation depends on the degree of lobaroverdistension and resultant compression and impair-ment of ventilation of normal areas of lung. Symptomscan range from mild tachypnea in the neonatal period tosignificant respiratory distress, wheezing and cough.Early presentation with significant respiratory distress inthe neonatal period can occur because of progressive airtrapping and shift of mediastinal structures, often requir-ing emergency surgical intervention. About 50% ofpatients are diagnosed by 1 month of age13. Rarely, CLEmay escape early diagnosis and present with recurrentrespiratory infections in an older child. Physical exami-nation reveals asymmetric chest wall prominence on theside of the lesion, and mediastinal shift away from theaffected side. On auscultation, breath sounds are

decreased on the affected side and the ipsilateralhemithorax may be hyper-resonant on percussion.Associated congenital cardiovascular abnormalities canfurther complicate the clinical picture.

DiagnosisAn area of hyperlucent lung with lung markings

throughout the lesion is characteristic on the chest radi-ograph (Figure 3-8). Shortly after birth, the lesion may beopacified because of abnormal drainage of fetal lungfluid. CT scan of the chest with contrast can reveal anarea of bronchial narrowing and air trapping. MRI canexclude abnormal vasculature or the presence of a vas-cular ring causing bronchial compression.

Differential Diagnosis1. Polyalveolar lobe is considered to be a distinct

entity where there is a true increase in the numberof alveoli instead of increased distension of theterminal alveolar spaces. The pathogenesis ofpolyalveolar lobe is poorly understood.

2. Swyer-James-Mcleod syndrome. This syndromeoccurs as a result of obliterative bronchiolitis,where both terminal airways and their attendantblood vessels become irreversibly scarred andobliterated. As a result, there is decreasedpulmonary blood flow to the affected areas. Thedecreased pulmonary blood flow in turn causeshyperlucency of the affected region. Here, theaffected lung is hyperlucent but smaller comparedwith the normal lung (Figure 3-9). In contrast, inCLE the affected lung is hyperlucent and largerthan the unaffected lung.

ManagementSurgical excision of the affected lobe is recom-

mended. Elective resection before respiratory distressoccurs is safe and associated with low mortality. Surgicalintervention may be needed urgently if the patient pres-ents with significant respiratory distress.

PrognosisUntreated, patients may do well. However, in such sit-

uations acute respiratory infection can worsen theobstruction, resulting in enlargement of the emphyse-matous lobe and creation of life-threatening respiratorydistress. For those patients who undergo excision of theemphysematous lobe, the prognosis is good. Long-termfollow-up after lobectomy reveals compensatory lunggrowth18–20. Although some other investigators reportevidence of obstructive lung disease on pulmonary func-tion tests on follow-up21,22 most patients are asympto-matic postoperatively.

Bronchogenic Cysts

Bronchogenic cysts occur as a result of abnormal bud-ding of the bronchial tissue. This abnormal budding may

occur either in early or late gestation. If the abnormalbud separates from the embryonic bronchial tissue early,it results in formation of central (mediastinal) bron-chogenic cysts whereas tissue separation later in gesta-tion results in formation of peripheral (pulmonary) cysts.Bronchogenic cysts can be multilocular or unilocular.Histologically, they are thin-walled cysts lined withcuboidal epithelium or secretory ciliated epithelium.The cyst can contain mucus glands, smooth muscle, elas-tic tissue and cartilage. Gastric or respiratory epitheliummay also be found in the cyst depending upon the timeof development. The cyst fluid is usually thin, clear ormucoid; recurrent hemorrhage results in thick, dark-brown cyst contents. There is typically no communica-tion between the cyst and the tracheobronchial tree, buton occasion one may occur.

Bronchogenic cysts usually are found in the medi-astinum, and are typically located subcarinally in para-esophageal, paratracheal, and hilar regions (Figure 3-10).Intrapulmonary cysts are uncommon and are usually foundin the lower lobes. A case of intraluminal tracheal cyst,which presented with tachypnea and stridor in a 7-month-old otherwise healthy baby has recently been reported23.


A BFigure 3-9 (A) Posteroanterior chest radiograph of Swyer-James-Mcleod syndrome in a 13-year-old.Note that the right lung is both hyperlucent and smaller, compared with the left lung. (B) CT scanof the same patient, again demonstrating the smaller hyperlucent right lung. The vascular markingsare diminished in the right lung, giving it its hyperlucent appearance. (Images courtesy of AvrumPollock, M.D., FRCPC.)


A

Figure 3-10 (A) Anteroposterior and lateral chest radiographs of an infant with a bronchogeniccyst (arrows). (B) The lesion’s position in the mediastinum is confirmed by CT scan (arrows). It isof uniform density and is without loculations. (Images courtesy of Avrum Pollock, M.D., FRCPC, andRichard Markowitz, M.D.)

B

Clinically, small cysts are mostly asymptomatic andpresent as an incidental radiographic finding in adult-hood. If the cyst is large enough or positioned in such away as to cause compression and distortion of the tra-cheobronchial tree, however, the infant will present

with severe respiratory distress. This compressionresults in a check-valve type mechanism, causingenlargement of the cyst and further impairment of gasexchange as the offending mass lesion increases in size.Such acute enlargement of the cyst is commonly seen

in infancy; as children get older, enlargement of the cyst is less common. In older children, a bronchogeniccyst can present with signs of infection, cough, fever,hemoptysis or recurrent attacks of pneumonia24.

DiagnosisChest radiography is the most useful modality for

diagnosing a cyst25. The radiographic appearance of abronchogenic cyst usually is of a round or oval structureof uniform density located peripherally. Mediastinalcysts are located more centrally and may be difficult tovisualize on a plain chest radiograph. An air–fluid levelmay be visualized in an infected bronchogenic cyst. CTscan with contrast allows identification of the cyst andits differentiation from mediastinal structures. MRI canalso be helpful, although it does not add much more tothe information provided by a CT scan. Occasionallyesophagoscopy and bronchoscopy have been used todelineate cysts that may be poorly visualized by othermodalities26,27.

Differential Diagnosis1. Encapsulated empyema can be confused with

an infected bronchogenic cyst, since theradiological appearance is similar on a plain chest radiograph. Anatomic location of the lesionwill help distinguish between the two if the cyst is subcarinal. A thoracic CT scan with contrast can also help differentiate between the twoentities.

2. Post-infectious pneumatoceles after staphylococcalpneumonia may be mistaken for an air-filled cyst.These commonly resolve spontaneously whereasan air-filled bronchogenic cyst is unlikely to resolvespontaneously.

3. Loculated pneumothorax is also important todifferentiate from an air-filled bronchogenic cyst; theimportant distinguishing point for a pneumothoraxis the presence of a compressed lung, which may be seen as a hilar shadow on a plain chestradiograph.

TreatmentExcision of the cyst, whether mediastinal or pulmonary,

is recommended. Intrapulmonary lesions may require segmental or lobar excision. Excision is preferentially performed electively, before compression of normal struc-tures results in significant respiratory distress and the needfor emergency excision.

PrognosisIn general, outcome is good following surgery.

Patients who present with significant air trapping showgradual improvement following surgical excision.Residual bronchomalacia and tracheomalacia can lead topersistent symptoms. Without surgery, mortality rate insymptomatic patients is 100%.

Congenital Cystic AdenomatoidMalformation

Congenital cystic adenomatoid malformation (CCAM)occurs secondary to the cystic adenomatous overgrowthof terminal bronchioles, which results in the secondaryinhibition of alveolar growth28,29. These cysts communi-cate with each other and also with the tracheobronchialtree. Grossly, a CCAM appears as a firm mass withoutnormal lobar configuration. It mostly affects one lobe,although no lobar predilection is known (Figure 3-11).Occasionally, it can affect an entire lung. Histologically,there is an interspersion of adenomatous areas and cysts.Two types of cysts have been described, the first ofwhich is characterized by cuboidal respiratory epithe-lium lining the cyst with no elastic tissue or smooth mus-cle in the cyst wall28,30–33. In the second type of cyst, thelining contains primarily pseudostratified columnarepithelium with papillary projections into the cyst lumenand large amounts of elastic tissue as well as some smoothmuscle present in the cyst wall. However, there is com-plete lack of cartilage. The adenomatous areas consist oftubular structures similar to terminal bronchioles but withcomplete absence of mature alveoli, suggesting develop-mental arrest in the second (pseudoglandular) stage oflung development.

There is no known race or gender predilection forCCAM but there is a known association with maternalpolyhydramnios. Polyhydramnios is thought to occur asa result of compression of the esophagus by the masslesion, causing impairment in fetal swallowing and fluidaccumulation in the amniotic sac. Compression of theheart by the lesion can also result in hydrops. Normallung surrounding the CCAM is commonly compressed,atelectatic, and hypoplastic. Polyhydramnios is alsothought to occur because of impaired fluid absorptionfrom this atelectatic normal lung surrounding the CCAM.

There are three types of CCAM as described by Stockeret al.28:Type I: Characterized by presence of large cystic

spaces interspersed with large alveolar spaces withfew or no adenomatous components. This accountsfor 50% of all cases of CCAM.

Type II: Characterized by mixed cystic andadenomatoid components. It is the subtype mostcommonly associated with other congenitalabnormalities.

Type III: Characterized by entirely adenomatousstructures with no cystic lesions.

Clinical PresentationPatients with CCAM typically present with tachypnea

or respiratory distress soon after birth or in infancy. Theremay be a history of maternal hydramnios complicating



A

Figure 3-11 CT scout film (A) and axial images (B) of a congenital cystic adenomatoid malforma-tion (CCAM) in a 6-week-old infant. A large multicystic structure involves much of the right upperlobe. The right lower lobe is spared, and there was no evidence of a feeding systemic vessel. Thelargest cyst was estimated to measure 1.5–1.8 cm. (Images courtesy of Avrum Pollock, M.D.,FRCPC.)

the pregnancy. Stillbirth and premature birth are com-monly associated with CCAM. The presence of micro-cystic lesions as identified on prenatal ultrasonographyhas been reported to be associated with hydrops andstillbirth, whereas the presence of macrocystic lesionsprenatally is associated with a more stable clinical con-dition after birth34–36.

Since the cysts in CCAM communicate with the tra-cheobronchial tree, the lesions can rapidly enlarge afterbirth and cause significant respiratory distress. Mostcases present by early infancy, but others with smallerareas of involvement can present with recurrent

pneumonia in the same lobe during adolescence oradulthood. CCAM is associated with other congenitalpulmonary defects such as pulmonary hypoplasia andalso cardiovascular and genitourinary anomalies. Rarely,it is diagnosed as an incidental finding on a chest radi-ograph in adulthood.

DiagnosisRadiographic findings vary depending upon the size

of the cyst. Typically the chest radiograph shows a mul-ticystic lesion. Lesions may also be solid-appearing orpresent as a single cystic lesion. The surrounding normallung may be compressed and atelectatic with evidence

B


Figure 3-12 Anteroposterior view of the chest and abdomen ofa newborn with right-sided congenital diaphragmatic hernia. Thebowel has entered the right hemithorax and appears like a multi-cystic mass. The mediastinum is displaced to the left. (Image cour-tesy of Avrum Pollock, M.D., FRCPC, and Howard Panitch, M.D.)

of mediastinal shift. A barium swallow with contrast willhelp differentiate between a congenital diaphragmatichernia and a CCAM. Ultrasonography can distinguishcystic versus solid lesions in the thorax. Prenatal ultra-sonography can reveal the presence of microcystic ormacrocystic lesions, thus aiding in predicting outcomein the perinatal period.

Chest CT scan with contrast can differentiatebetween the different types of CCAM based on the dif-ferent sizes of the cysts visible on the examination, espe-cially type III lesions37,38.

Differential Diagnosis1. Diaphragmatic hernia: Loops of bowel migrate

through the diaphragmatic defect into the chestcavity and can be confused with a multicysticCCAM (Figure 3-12). An upper gastrointestinalseries with contrast or a barium enema can helpdifferentiate between the two entities.

2. Post-infectious pneumatoceles: Pneumatoceles thatform after acute infection are frequently seenfollowing staphylococcal pneumonia. These canpresent as numerous small air-filled cysts on achest radiograph.

3. Bronchogenic cyst: In some cases an air-filled cystmay be difficult to differentiate from a CCAMthough, typically, bronchogenic cysts appear asopaque dense shadows.

4. Mesenchymal hamartomas are lesionscharacterized by nodules and cysts. The cysts arelined by respiratory epithelium with an underlyinglayer of mesenchymal cells, while the nodules aremade of primitive mesenchymal cells. Theselesions usually enlarge with time and may bebilateral, unlike CCAMs which are rarely bilateralor progressive. The radiographic appearance maybe very similar to that of a CCAM.

TreatmentSurgical resection is the treatment of choice. Since

most patients present in the neonatal period with respi-ratory distress, excision is done urgently in most cases.Observation and stabilization of the patient is notadvised since expansion of the lesion can occur, furtherworsening the respiratory status of the patient. Electiveexcision is recommended even in asymptomatic casesbecause of the reported potential for malignant transfor-mation39. Once the diagnosis is suspected, early inter-vention is recommended since excision allowsdecompression of the compressed normal lung sur-rounding the CCAM, thus maximizing the potentialgrowth of normal lung tissue.

PrognosisAs noted above, the presence of microcystic lesions

on prenatal ultrasonography has been reported to resultin a poorer prognosis and is usually associated with

hydrops and stillbirth. In contrast, the presence ofmacrocystic lesions prenatally portends a better progno-sis with a more stable clinical condition after birth34–36.

CCAM type I carries the best prognosis. Patients withCCAM type II have the worst prognosis since the lesionis most likely to undergo a malignant change and to beassociated with other congenital abnormalities.

Long-term prognosis following resection of the CCAMis good, with evidence of compensatory lung growth onfollow-up pulmonary lung function testing40,41.

Pulmonary Sequestration

Pulmonary sequestration is defined as a mass of non-functioning lung tissue that has a systemic vascular sup-ply but usually no connection with the tracheobronchial

tree. Sequestrations are classified as either intralobar orextralobar (Table 3-3). Intralobar sequestrations occurwithin the borders of the pleural membrane surroundingthe normal lung, while extralobar sequestrations existoutside of the lung tissue surrounded by the pleura.Extralobar sequestrations are usually invested with theirown pleural membrane. Extralobar sequestration isthought to occur later in gestation compared with anintralobar sequestration31. Intralobar sequestrations arefar more common than the extralobar type, althoughboth types of sequestrations are uncommon. Both typesoccur twice as frequently on the left side compared withthe right. Ninety-eight percent of all intralobar seques-trations occur in the lower lobes. Extralobar sequestra-tions are also thought to occur more commonly in thelower lobes, although they may occasionally occur in theupper lobes. Intra-abdominal extralobar lung sequestra-tions have also been reported.

Intralobar sequestrations are clearly distinguishablefrom the surrounding normal lung on gross pathologicexamination; their texture is variable depending onwhether or not there is any air in the sequestration.Grossly, extralobar sequestrations are gray or dark brownand firm to the touch. Histologically, the extralobarsequestration has embryonic lung tissue with evidence ofa single or multiple cysts, while intralobar sequestrationscharacteristically demonstrate areas of bronchiectasis andcysts, the walls of which may contain cartilage, muscle,bronchial glands, and alveolar structures.

Clinical PresentationPatients with intralobar sequestration rarely present

in infancy. About one third present before 10 years ofage and 15% of sequestrations are found incidentally ona chest radiograph taken for another reason. The mostcommon clinical presentation is one of recurrent pneu-monia. Patients typically present with fever, cough, andchest pain. In occasional patients, hemoptysis may be

present. Congestive cardiac failure, cyanosis, and digitalclubbing may be present in patients who have a signifi-cant systemic arterial-to-pulmonary arterial shunt.

Extralobar sequestrations are usually diagnosed in theneonatal period in infants with other congenital abnor-malities. Much less commonly, these lesions can presentwith respiratory distress in an otherwise normal newborn.Infection of the sequestered lobe can occur, especially ifthere is a communication with the gastrointestinal tract.

DiagnosisSequestrations are usually first detected on a plain

chest radiograph. They appear as a solid mass or cysticstructure on the plain film. It is difficult to differentiateextralobar from an intralobar sequestration on a plainchest radiograph, but an extralobar sequestration ismore often seen as a solid lesion whereas an intralobarsequestration more often appears as a cystic lesion.

Definitive diagnosis of a sequestration is made bydemonstration of a systemic vessel leading to the mass. Achest CT scan with contrast can reveal the presence of thesystemic feeding vessel to the sequestration (Figure 3-13).Although a CT scan is less invasive, it is also a less reliableprocedure than an angiogram in identifying the vessel37.

Since a pulmonary angiogram or an aortogram candelineate both small and large vessels feeding thesequestration, it has the best success rate in making thedefinitive diagnosis of a sequestration25,31,37,42–44.

MRI is much less invasive than an angiogram or aor-togram and has a good success rate, especially when thefeeding vessels are large and arise directly from theaorta45. However, 15% of smaller vessels may be missedduring imaging with CT or MRI.

Differential Diagnosis1. Post-infectious pneumatoceles: Air-filled pulmonary

sequestrations may be confused with post-infectiouspneumatoceles. Sequestration is more likely to persiston serial imaging studies, while post-infectious


Table 3-3 Characteristics of Pulmonary Sequestration

Characteristics Extralobar Intralobar

Incidence Rare UncommonGender Male > female Male = femalePleural covering Separate from the lung Same as the lungArterial supply Systemic Pulmonary artery/systemicVenous drainage Systemic Pulmonary vein/systemicCommunication with tracheobronchial tree A small patent opening may be present Does not communicate with the

airwayAssociated anomalies 50% (30% associated with diaphragmatic hernia) IsolatedAge at presentation Usually neonatal Adolescent/young adultClinical features Respiratory difficulty Recurrent lung infections


A BFigure 3-13 Contrast-enhanced CT scans of a pulmonary sequestration in the left lower lobe of a5-week-old infant. (A) The lesion has arterial feeders from the aorta (arrow) and peripheral cysticcomponents are present. (B) There is a large draining vein emptying into the left inferior pulmonaryvein (arrow). (Images courtesy of Avrum Pollock, M.D., FRCPC.)

pneumatoceles regress over time. The presence ofa feeding vessel originating from the systemicblood supply to the lesion confirms asequestration.

2. Diaphragmatic hernia: The loops of bowel in thechest cavity may be confused with an air-filledsequestration. An upper gastrointestinal series withcontrast or a barium enema can help differentiatebetween the two entities. Extralobar sequestrations,however, are often associated with diaphragmatichernias.

3. CCAM should be ruled out in cases of air-filledsequestration, although CCAM is usually multicysticand only rarely appears as a unilocular cyst.

4. Bronchogenic cyst: A bronchogenic cyst may bedifficult to distinguish from a sequestration; again,presence of systemic blood supply confirms asequestration. A thoracic CT scan may also reveal astalk connecting a bronchogenic cyst with thetracheobronchial tree.

5. Pulmonary arteriovenous malformation (AVM): A pulmonary AVM also appears as a solid structurewith systemic arterialization; however, the clinicalmanifestations of AVM are distinct from that of apulmonary sequestration. Patients with pulmonaryAVM typically present with dyspnea, exerciseintolerance, cyanosis, clubbing, and an

unremarkable cardiac examination. Polycythemia,with a hematocrit of 60–80%, and low arterialoxygen saturation occur because of anintrapulmonary right-to-left shunt. A bruit may bepresent over the lesion. Since it is a vascularabnormality, a pulmonary AVM may appear as apulsatile lesion on fluoroscopy and it can decreasein size during a Valsalva maneuver.

TreatmentExcision of the sequestration is recommended in all

cases. In cases of extralobar sequestration, the lesionmay be removed completely since the pleural coveringis separate from the rest of the lung. A lobectomy maybe required for removal of an intralobar sequestration,since the sequestered lobe shares the same pleural cov-ering as the rest of the normal lung43.

PrognosisThe prognosis is excellent if there are no associated

abnormalities. Risk of bleeding from accidental severing ofthe systemic artery is the commonest cause of intraopera-tive mortality7. If pulmonary sequestration is left untreated,there is a risk of recurrent serious infection.

Vascular Rings

Vascular rings usually occur as anomalies of the aorticarch. Although many variations from normal develop-


A B C

FED

Figure 3-14 Various anomalies of the aortic arch andpulmonary artery. (A) Normal left arch. (B) Double aor-tic arch. (C) Right aortic arch with aberrant subclavianartery. (D) Right aortic arch with mirror-image branch-ing and left ductus arteriosus. (E) Left aortic arch withaberrant right subclavian artery with left ductus arterio-sus. (F) Left pulmonary artery arising from right pul-monary artery (pulmonary artery sling). A, aorta; LC, leftcommon carotid artery; L Ductus, left ductus arteriosus;LPA, left pulmonary artery; LS, left subclavian artery; LArch, left aortic arch; PT, pulmonary arterial trunk; RC,right common carotid artery; RPA, right pulmonaryartery; RS, right subclavian artery; R Arch, right aorticarch. (From Valletta EA, et al. Pediatr Pulmonol24:93–105,1997, with permission.)

Table 3-4 Vascular Rings producing Tracheal andEsophageal Compression

Tracheal Esophageal Type of Vascular Ring Compression Compression

Double aortic arch + +Right aortic arch with ductus + +

arteriosusLeft aortic arch with ductus + +

arteriosusAnomalous innominate artery + −Aberrant subclavian artery − +

ment of the arch have been reported, only a few distinctpatterns produce tracheal and esophageal compression(Table 3-4). The double aortic arch is the most commonvascular ring. In this condition, both the fourth branchialarch and dorsal aortic root persist on both sides, so thata tight ring of vascular structures is formed around thetrachea and esophagus (Figures 3-14).

A right-sided aortic arch with persistent left ductusarteriosus or ligamentum arteriosum from the descend-ing aorta also results in the formation of a complete vas-cular ring. In this situation, persistence of the rightfourth branchial vessel results in compression of the tra-chea anteriorly. The persistent left ductus or ligamen-tum, which now runs behind the esophagus, results inthe formation of a circular ring around the trachea andesophagus producing symptoms of both tracheal andesophageal compression.

An anomalous innominate artery does not representa vascular ring, but it produces direct anterior pressureon the tracheal wall. In this situation, the origin of theinnominate artery arises to the left of its normal posi-tion. It must traverse the anterior trachea to reach its

destination, and in so doing can produce tracheal com-pression. The aberrant right subclavian artery does notcross over the trachea and so does not produce any res-piratory symptoms. It does, however, cause constric-tion of the posterior esophageal wall as it coursesbehind the esophagus and can produce dysphagia. Apulmonary artery sling is the least common of all vascu-lar rings. Here the left pulmonary artery arises from theright pulmonary artery. In order to reach the left lung,it must cross over the right main bronchus, the left mainbronchus, and the esophagus. In so doing, it can causecompression of one or more of these structures. It usu-ally does not cause any esophageal compression.

Clinically, patients with a double aortic arch anomalyand right aortic arch with ligamentum arteriosum pres-ent early, from 2 to 9 months of age. Earlier presentationcorrelates with a greater degree of compression of thetrachea or esophagus. Thus, presenting symptomsinclude respiratory distress, tachypnea, stridor orcyanosis. Because the esophagus is included in the ring,feeding intolerance or dysphagia is often present.Symptoms worsen with an intercurrent infection, duringfeeds, and with crying. Flexion of the neck can alsoworsen respiratory symptoms.

The presence of the vascular ring typically causescompression of the tracheoesophageal complex result-ing in obstruction to airflow especially during exhala-tion. Esophageal distension from feeding and swallowingcan further compress the trachea and exacerbate its nar-rowing17. Thus, double aortic arch, right-sided aorticarch with persistent left ductus arteriosus from thedescending aorta, and left aortic arch with right persist-ent ductus arteriosus from the descending aorta presentearly. In contrast, children with anomalous innominateartery present later, and patients with right aberrant sub-clavian artery may be completely asymptomatic, or haveonly dysphagia. A syndrome of reflex apnea has been

described especially in patients with double aortic archand anomalous innominate artery46. This is thought to bea reflex respiratory arrest initiated by irritation of thearea of tracheal compression by a bolus of food or pool-ing of secretions47.

DiagnosisPlain chest films may show well-aerated or even

hyperinflated lungs, pneumonia or scattered atelectasis.If present, a right-sided aortic arch can be detected on aplain chest radiograph. Other clues on an anteroposte-rior film include a midline trachea and disappearance ofthe air shadow of the distal trachea and main carinabecause of the overlying vascular ring. The lateral chestradiograph shows narrowing or anterior buckling of thetrachea just above the carina (Figure 3-15).

The contrast esophagogram (barium swallow) is tra-ditionally the most helpful study to detect a vascularring. A normal esophagogram effectively rules out a vas-cular ring of a magnitude significant enough to causerespiratory compromise. An anterior indentation of the

esophagus is pathognomonic for a pulmonary arterysling, and a double lateral indentation of the esophagusand trachea at the same level is typical of a double aor-tic arch (Figure 3-16). The aberrant subclavian appearsas a fixed posterior esophageal indentation. The anom-alous innominate artery cannot be detected by the con-trast esophagogram.

Bronchoscopy demonstrates a posterolateral pul-satile mass in cases of double aortic arch (Figure 3-17).A right anterolateral pulsatile compression approxi-mately 2 cm proximal to the main carina is typical for an anomalous innominate artery. Here, the diagnosis is confirmed by compressing the vessel with the bron-choscope and noting the disappearance of the rightradial artery pulse. Angiography helps define vascularanatomy, especially small vessels that may not be readilyseen on an aortogram. Thoracic CT with contrast andMRI, however, have become the diagnostic imagingmodalities of choice for vascular rings (Figure 3-18).They are less invasive than an angiogram and allow


A BFigure 3-15 (A) Anteroposterior chest radiograph of an infant with a vascular ring (double aor-tic arch). The trachea is deviated to the right by the right-sided aortic arch, so that it is positioned inthe midline. There is loss of definition of the distal tracheal air column and main carina because ofthe overlying vascular ring. (B) Lateral chest radiograph demonstrates anterior buckling of the trachealair column resulting from the vascular ring. (Images courtesy of Avrum Pollock, M.D., FRCPC.)


Figure 3-16 Anteroposterior view of a barium esophagogram,demonstrating bilateral lateral indentations of the esophagus at thesame level, typical of a double aortic arch. (Image courtesy ofAvrum Pollock, M.D., FRCPC.)

Figure 3-17 Endoscopic image of a double aortic arch. The maincarina cannot be visualized clearly because of the pulsatile com-pressions of the anterior tracheal walls. There is also invaginationof the posterior membrane, further narrowing the airway lumen.(Image courtesy of Howard Panitch, M.D.)

good visualization of the airways and the esophagus. Aligamentum arteriosum and the atretic part of the aorticarch will not be well visualized, but can be inferred. Bothmodalities can be used to provide three-dimensionalreconstruction of the airway.

Differential DiagnosisLesions that produce wheezing along with dysphagia

include:1. Mediastinal tumors, if they compress the

tracheoesophageal complex. These can be ruledout by a plain chest radiograph or CT scan.

2. Retained foreign bodies produce symptoms oftracheal obstruction. The plain chest radiographmay demonstrate an area of atelectasis or unilateralhyperlucent lung that fails to empty on a lateraldecubitus film. Bronchoscopy confirms thediagnosis in the absence of a significant chokinghistory and when the chest radiograph is normal.

3. TEF without esophageal atresia may also producesimilar clinical symptoms. A barium swallow canshow a fistulous tract or presence of barium in theairway in case of a TEF. In contrast, fixedindentations on the barium esophagogram pointtowards a vascular ring.

4. Tracheal stenosis should also be considered as acause of bi-phasic central airway noise. ThoracicCT scan with three-dimensional reconstruction candefine the stenosis. Direct visualization with a flexiblebronchoscope confirms the diagnosis of stenosis.Non-invasive studies to confirm this diagnosisinclude radiographs of the chest and lateral neck.

5. Tracheomalacia without vascular compression canpresent in a similar manner. Direct visualization of theairway is often necessary to distinguish this dynamiccause of airway obstruction from other fixed lesions.

ManagementSurgical ligation and takedown of the ring is standard.

In cases of a double aortic arch the division of the smallerarch, which is usually the anterior one, is performed andprovides relief of symptoms. In cases involving a right aor-tic arch with ligamentum arteriosum, the ligamentum isdivided and that provides relief of symptoms. In patientswith anomalous innominate artery, surgery may be neces-sary in 10% of cases.

PrognosisThe mortality and morbidity with surgical inter-

vention is low. Relief of symptoms following surgery isusually immediate. The most commonly seen postopera-tive problem results from residual tracheomalacia, especially following surgery for double aortic arch.Tracheomalacia frequently persists for months to yearsafter surgery.

In untreated cases death may occur suddenly becauseof airway compression or sepsis.

Pulmonary Lymphangiectasis

Pulmonary lymphangiectasis is a rare conditioninvolving congenital dilatation of pulmonary lymphatics.


A B

C

Figure 3-18 Three images of a double aortic arch obtained byMRI. The right arch is the larger of the two, and the ring encirclesboth the trachea and esophagus. (Images courtesy of AvrumPollock, M.D., FRCPC.)

It is seen more commonly in males than females, and itis usually lethal. Familial occurrence has been reported.Three different types of pulmonary lymphangiectasishave been recognized:1. Generalized lymphangiectasia. This is the rarest

type of lymphangiectasis. Both pulmonary andintestinal involvement as well as hemihypertrophyhave been reported with this form. Involvement oflungs may also be seen as part of a syndrome ofgeneralized angiomatosis predominantly involvingthe bones.

2. Lymphangiectasia in association with congenitalheart disease occurs when pulmonary venousobstruction causes obstruction of lymph flow. Themost commonly associated congenital heart diseaseis total anomalous pulmonary venous return(TAPVR). An association with hypoplastic left heart

syndrome, atrioventricular canal, and other septaldefects has also been reported.

3. Lymphangiectasia can occur as an isolated pulmonaryabnormality where there is no associated heartabnormality.

The lungs in this case are bulky and the subpleural sur-face has a dense network of lymphatic vessels. On histo-logic examination, the lung parenchyma is riddled withdilated lymphatic vessels and increased connective tissuein the perivascular, interlobular, and sub-pleural areas.Other congenital defects such as urogenital malformations,facial anomalies, and asplenia have also been reported tooccur in association with pulmonary lymphangiectasis.

Most patients with isolated pulmonary lymphangiec-tasis present soon after birth with severe respiratory dis-tress and usually do not survive for more than 2 weeks.Those with associated congenital heart disease present

somewhat later. Here, respiratory difficulty is thought tobe secondary to decreased compliance of the lung, andblood gas analysis reveals low oxygen content and car-bon dioxide retention supporting hypoventilation.

Pulmonary involvement is usually less severe in patientswith systemic lymphangiectasis and angiomatosis, andlong-term survival has been reported in these patients.

DiagnosisThe chest radiograph demonstrates a non-specific retic-

ular pattern with small areas of atelectasis or areas ofpatchy infiltration (Figure 3-19). Lung biopsy is diagnostic.

Differential DiagnosisDisorders that present early in life and cause promi-

nence of the interstitium on the chest radiograph mustbe considered.1. Meconium aspiration syndrome is usually seen in

term or post-term infants who have undergoneextreme perinatal stress. Infants have a history offetal hypoxia, and pulmonary hypertension withpersistence of the fetal circulation is common.Meconium is passed before delivery, staining theamniotic fluid. Often, thick meconium is alsoaspirated, adding to respiratory compromise.

2. Hyaline membrane disease or neonatal respiratorydistress syndrome is usually seen in prematureinfants and is the result of surfactant deficiency.The infant demonstrates respiratory distress andthe chest radiograph has a typical “ground-glass”appearance with low lung volumes, reflecting thelow compliance of the lungs. Respiratory distresstypically resolves or improves over the first week of life.

3. Neonatal pneumonia: The clinical picture is verysimilar and the chest radiograph findings are non-specific.

4. Veno-occlusive disease can also cause prominenceof the pulmonary interstitium and respiratorycompromise. Obstructed veins can occasionally bedetected by echocardiogram, but a cardiaccatheterization is diagnostic.

DiagnosisLung biopsy is diagnostic.

ManagementSevere cases are uniformly fatal. Atrial septostomy has

been tried in cases with pulmonary venous obstruction.No specific treatment is known.


A BFigure 3-19 (A) Anteroposterior chest radiograph of an infant with Noonan syndrome and lym-phangiectasis. There is a fine reticular pattern present in both lungs. (B) Chest CT image of the samepatient. In addition to intraparenchymal linear densities related to abnormal lymphatics, bilateraldependent atelectasis is present. There is a pleural effusion in the right hemithorax (arrows).Analysis of the fluid was consistent with a chylous effusion. (Images courtesy of Avrum Pollock,M.D., FRCPC, and Howard Panitch, M.D.)

REFERENCES

1. Lim FY, Crombleholme TM, Hedrick HL, Flake AW,Johnson MP, Howell LJ, Adzick NS. Congenital high airwayobstruction syndrome: natural history and management. J Pediatr Surg 38:940–945, 2003.

2. Davis S, Jones M, Kisling J, Angelicchio C, Tepper RS.Effect of continuous positive airway pressure on forcedexpiratory flows in infants with tracheomalacia. Am JRespir Crit Care Med 158:148–152, 1998.

3. Panitch HB, Allen JL, Alpert BE, Schidlow DV. Effects ofCPAP on lung mechanics in infants with acquired tracheo-bronchomalacia. Am J Respir Crit Care Med 150:1341–1346,1994.

4. Zinman R. Tracheal stenting improves airway mechanics ininfants with tracheobronchomalacia. Pediatr Pulmonol19:275–281,1995.

5. Panitch HB, Keklikian EN, Motley RA, Wolfson MR,Schidlow DV. Effect of altering smooth muscle tone onmaximal expiratory flows in patients with tracheomalacia.Pediatr Pulmonol 9:170–176, 1990.

6. Ein SH, Freidberg J. Esophageal atresia and tracheo-esophageal fistula. Review and update. Otolaryngol ClinNorth Am 14:219–249, 1981.

7. Lierl M. Congenital abnormalities. In: Pediatric respiratorydisease, diagnosis and treatment, 1st edition, pp 457–498.Philadelphia: WB Saunders, 1993.

8. Daum R. Postoperative complications following operationfor oesophageal atresia and tracheo-oesophageal fistula.Prog Pediatr Surg 1:209–237, 1970.

9. Hicks LM, Mansfield PB. Esophageal atresia and tracheo-esophageal fistula. Review of thirteen years’ experience. J Thorac Cardiovasc Surg 81:358–363, 1981.

10. Orringer MB, Kirsh MM, Sloan H. Long-term esophagealfunction following repair of esophageal atresia. Ann Surg186:436–443, 1977.

11. Holder TM, Ashcraft KW. Developments in the care ofpatients with esophageal atresia and tracheoesophageal fistula. Surg Clin North Am 61:1051–1061, 1981

12. Booth JB, Berry CL. Unilateral pulmonary agenesis. ArchDis Child 42:361–374, 1967.

13. Keslar P, Newman B, Oh KS. Radiographic manifestationsof anomalies of the lung. Radiol Clin North Am 29:255–270, 1991.

14. Markowitz RI, Frederick W, Rosenfield NS, Seashore JH,Duray PH. Single, mediastinal, unilobar lung: a rare form ofsubtotal pulmonary agenesis. Pediatr Radiol 17:269–272,1987.

15. Maltz DL, Nadas AS. Agenesis of the lung. Presentation ofeight new cases and review of the literature. Pediatrics42:175–188, 1968.

16. Eraklis AJ, Griscom NT, McGovern JB. Bronchogenic cystsof the mediastinum in infancy. N Engl J Med 281:1150–1155, 1969.

17. Krummel TM. Congenital malformations of the lung. In:Disorders of the respiratory tract in children, 6th edition,pp 287–316. Philadelphia: WB Saunders, 1998.

18. Frenckner B, Freyschuss U. Pulmonary function afterlobectomy for congenital lobar emphysema and congenitalcystic adenomatoid malformation. A follow-up study.Scand J Thorac Cardiovasc Surg 16:293–298, 1982.

19. McBride JT, Wohl ME, Strieder DJ, Jackson AC, Morton JR,Zwerdling RG, Griscom NT, Treves S, Williams AJ, Schuster S.Lung growth and airway function after lobectomy ininfancy for congenital lobar emphysema. J Clin Invest 66:962–970, 1980.

20. Tapper D, Schuster S, McBride J, Eraklis A, Wohl ME,Williams A, Reid L. Polyalveolar lobe: anatomic and physi-ologic parameters and their relationship to congenitallobar emphysema. J Pediatr Surg 15:931–937, 1980.

21. De Muth GR, Sloan H. Congenital lobar emphysema: longterm effects and sequelae in treated cases. Surgery 59:601–607, 1966.

22. Eigen H, Lemen RJ, Waring WW. Congenital lobar emphysema: long-term evaluation of surgically and conser-vatively treated children. Am Rev Respir Dis 113:823–831,1976.

23. Stewart B, Cochran A, Iglesia K, Speights VO, Ruff T.Unusual case of stridor and wheeze in an infant: trachealbronchogenic cyst. Pediatr Pulmonol 34:320–323, 2002.

24. Ribet ME, Copin MC, Gosselin BH. Bronchogenic cysts ofthe lung. Ann Thorac Surg 61:1636–1640, 1996.

25. Bailey PV, Tracy T Jr, Connors RH, deMello D, Lewis JE,Weber TR. Congenital bronchopulmonary malformations.Diagnostic and therapeutic considerations. J ThoracCardiovasc Surg 99:597–602, 1990.

26. Di Lorenzo M, Collin PP, Vaillancourt R, Duranceau A.Bronchogenic cysts. J Pediatr Surg 24:988–991, 1989.

27. Koval JC, Joseph SG, Schaefer PS, Tenholder MF. Fiberopticbronchoscopy combined with selective bronchography. Asimplified technique. Chest 91:776–778, 1987.


MAJOR POINTS

1. Congenital abnormalities form an important groupof disorders that cause respiratory problems ininfants and children.

2. Though easy to spot on a radiograph, they are hardto differentiate without further testing.

3. Abnormalities that affect airway number resultfrom defects that occur within the first 16 weeksof gestation.

4. Lung sequestration and CCAM occur mostcommonly in the lower lobes.

5. Congenital lobar emphysema occurs mostcommonly in the upper lobes.

6. Congenital abnormalities of the lung are frequentlyassociated with other extra-pulmonary congenitalabnormalities.

�

�

28. Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatoid malformation of the lung. Classification andmorphologic spectrum. Hum Pathol 8:155–171, 1977.

29. Walker J, Cudmore RE. Respiratory problems and cysticadenomatoid malformation of lung. Arch Dis Child 65:649–650, 1990.

30. Kwittken J, Reiner L. Congenital cystic adenomatoid mal-formation of the lung. Pediatrics 30:759–768, 1962.

31. Silverman FN. Caffey’s pediatric diagnosis, 8th edition, pp1135–1153. Chicago: Year Book Medical Publishers, 1985.

32. Wesenberg RL. The newborn chest, pp 187–198.Hagerstown: Harper and Row, 1973.

33. Wolf SA, Hertzler JH, Philippart AI. Cystic adenomatoiddysplasia of the lung. J Pediatr Surg 15:925–930, 1980.

34. Adzick NS, Harrison MR, Glick PL, Golbus MS, AndersonRL, Mahony BS, Callen PW, Hirsch JH, Luthy DA, Filly RA,et al. Fetal cystic adenomatoid malformation: prenatal diag-nosis and natural history. J Pediatr Surg 20:483–488, 1985.

35. Adzick NS, Harrison MR. Management of the fetus with acystic adenomatoid malformation. World J Surg 17:342–349,1993.

36. Duncombe GJ, Dickinson JE, Kikiros CS. Prenatal diagnosisand management of congenital cystic adenomatoid malfor-mation of the lung. Am J Obstet Gynecol 187:950–954, 2002.

37. Haddon MJ, Bowen A. Bronchopulmonary and neurentericforms of foregut anomalies. Imaging for diagnosis and man-agement. Radiol Clin North Am 29:241–254, 1999.

38. Shamji FM, Sachs HJ, Perkins DG. Cystic disease of thelungs. Surg Clin North Am 68:581–620, 1988.

39. Ueda K, Gruppo R, Unger F, Martin L, Bove K.Rhabdomyosarcoma of lung arising in congenital cysticadenomatoid malformation. Cancer 40:383–388, 1977.

40. Bolande RB, Schneider AF, Boggs JD. Infantile lobar emphy-sema. AMA Arch Pathol 61:289–294, 1956.

41. Franken EA Jr, Buehl I. Infantile lobar emphysema. Report of two cases with unusual roentgenographic mani-festation. Am J Roentgenol Radium Ther Nucl Med 98:354–357, 1966.

42. Hoeffel JC, Bernard C. Pulmonary sequestration of theupper lobe in children. Radiology 160:513–514, 1986.

43. Piccione W Jr, Burt ME. Pulmonary sequestration in theneonate. Chest 97:244–246, 1990.

44. Savic B, Birtel FJ, Tholen W, Funke HD, Knoche R. Lungsequestration: report of seven cases and review of 540 published cases. Thorax 34:96–101, 1979.

45. Naidich DP, Rumancik WM, Lefleur RS, Estioko MR, BrownSM. Intralobar pulmonary sequestration: MR evaluation. J Comput Assist Tomogr 11:531–533, 1987.

46. Ardito JM, Ossoff RH, Tucker GF Jr, DeLeon SY. Innominateartery compression of the trachea in infants with reflexapnea. Ann Otol Rhinol Laryngol 89:401–405, 1980.

47. Fearon B, Shortreed R. Tracheobronchial compression bycongenital cardiovascular anomalies in children: syndromeof apnea. Ann Otol Rhinol Laryngol 72:949–969, 1963.


60

CHAPTER

4 BronchopulmonaryDysplasia (ChronicLung Disease ofInfancy)CARLOS SABOGAL, M.D.

ISAAC TALMACIU, M.D.

Definition

Incidence

Pathogenesis

Oxygen Toxicity

Positive-Pressure Ventilation

Glucocorticoids

Inflammation and Infection

Nutrition

Vascular Hypothesis

Clinical Manifestations

History



Radiology

Laboratory Tests

Pathology

Treatment

Oxygen Therapy

Diuretic Therapy

Inhaled Bronchodilators

Anti-inflammatory Therapy

Nutrition

Prevention of Intercurrent Viral Infections

Long-Term Prognosis

Prevention

The terms bronchopulmonary dysplasia (BPD) andchronic lung disease of infancy (CLDI) are often used syn-onymously to describe the chronic respiratory disordersprimarily associated with premature birth and its therapy.BPD was initially described in 1967 by Northway et al.1 asa condition seen in premature infants with severe respi-ratory distress syndrome of the newborn (RDS) treatedwith mechanical ventilation and supplemental oxygenwho subsequently developed clinical, radiologic, andpathologic alterations.

Since the 1960s, there have been many advances in thetreatment of neonatal respiratory diseases. These develop-

ments have changed the pattern of BPD presentation andprognosis. Extremely premature infants with severe lungdisease now survive more frequently than when BPD wasoriginally described. New definitions and name changeshave come up over time, and now the condition is alsoknown as CLDI. In general, the diagnosis of BPD is welldefined and is based on clearly distinct criteria. In con-trast, CLDI remains a more vague expression that encom-passes any long-term pulmonary complication associatedwith preterm birth and, in some cases, with full-terminfants whose course was complicated by perinatal infec-tions, congenital heart disease, aspiration, or other pul-monary insults. This chapter will predominantly focus on BPD.

DEFINITION

The initial definition of BPD used by Northway et al.1

consisted of a radiologic description in prematureinfants who had required prolonged mechanical ventila-tion. Their description included four successive radi-ographic stages: (1) RDS (1–3 days of life); (2) opacificationof both lungs (4–10 days); (3) small rounded bilateral radiolucencies (10–20 days); and (4) enlarged areas ofradiolucency together with strands of radiodensity (>30 days).

Bancalari et al.2 proposed a different definition of BPDwhich included respiratory failure in the neonatal periodrequiring assisted ventilation for at least 3 days, followedby persistent respiratory symptoms and oxygen depend-ence by 28 days of life, in addition to the characteristicradiographic changes described previously.

Over time, with the improved survival of very prema-ture infants, it was noted that many infants who had res-piratory symptoms and oxygen dependence at 28 daysof life had minimal pulmonary problems and hadbeen weaned to ambient air by the time they were being

discharged from the hospital. Shennan et al.3 generated anew definition that took into account a history ofmechanical ventilation in premature infants whoremained oxygen-dependent and had radiographic abnor-malities at 36 weeks postconceptional age (PCA), ratherthan at 28 days of life.

More recently, a workshop organized by the NationalInstitute of Child Health and Human Development, theNational Heart, Lung and Blood Institute, and the Officeof Rare Diseases agreed to retain the name of BPD inorder to distinguish this condition clearly from other causesof chronic lung disease of later life4. It also proposed anew severity-oriented definition of BPD (Table 4-1).Common criteria for all groups include persistent symp-toms of respiratory disease and treatment with supplemen-tal oxygen for at least 28 days. Radiographic abnormalitieswere felt to be non-contributory to the resolution of thisnewer definition. Other diagnostic criteria differ forpreterm infants less than 32 weeks gestational age (GA)and for those with a GA of 32 weeks and more. For theformer group, BPD is defined as: (a) mild, if the infantis breathing room air at 36 weeks PCA, (b) moderate,if the infant is breathing <30% O2 at 36 weeks PCA, or(c) severe, if the infant requires ≥30% O2 or positive-pressure ventilation at 36 weeks PCA. For the lattergroup, BPD severity is based on the oxygen requirementat 56 days of life in a manner similar to that previouslyexplained. Since these newer definitions rely greatlyon the persistence of a supplemental oxygen require-ment at specific ages, they are limited as they do not provide a precise target for either arterial partial

pressure of oxygen (PaO2) or oxygen saturation (SpO2).According to the workshop summary, extensive valida-tion is needed to determine whether this BPD definitionis superior to prior ones.

INCIDENCE

The incidence of infants who develop BPD is closelyrelated to birthweight and gestational age, as well as thedefinition of BPD used. There is also variability in theincidence of BPD depending on the reporting institu-tion, since there are no consistent criteria for oxygensupplementation among different neonatal intensivecare units. For example, in 1998 the reported incidenceof BPD in treated infants with RDS weighing more than1000 g at Stanford University Medical Center was 18%,and in treated infants weighing less than 1000 g it was78%5. In the Midlands region of England, for infants bornat <32 weeks gestation and requiring mechanical venti-lation, the rate of BPD remained constant at approxi-mately 40–45% during the 1990s6.

BPD becomes a more frequent complication as gesta-tional age and birthweight decrease (Table 4-2). Thenewer definition in which infants are assessed at 36weeks PCA has undoubtedly decreased the percentageof infants diagnosed with BPD, but the increased num-ber of survivors has counterbalanced this so that thenumber of patients with BPD has remained relativelyconstant, with an estimated 3000–7000 new cases eachyear in the United States.

Bronchopulmonary Dysplasia (Chronic Lung Disease of Infancy) 61

Table 4-1 Definition of Bronchopulmonary Dysplasia: Diagnostic Criteria

(From Jobe AH, Bancalari E. NICHD/NHLBI/ORD workshop summary on bronchopulmonary dysplasia. Am J Respir Crit Care Med, 163:1723, 2001.)Abbreviations: NCPAP, nasal continuous positive airway pressure; PMA, postmenstrual age; PPV, positive-pressure ventilation.aA physiologic test confirming the oxygen requirement at the assessment time point remains to be defined. This assessment may include a pulseoximetry saturation range.

The incidence of BPD appears to be higher in whiteand male infants7. Others have reported a higher incidenceof atopic disorders in families of infants with BPD. Onestudy found that a family history of asthma is associatedwith increased severity of BPD.

PATHOGENESIS

Multiple factors contribute to the pathogenesis ofBPD, and most likely act additively or synergistically tocause lung injury. In the pre-surfactant era, “old” or“classic” BPD seemed to be caused primarily by oxidant-and ventilation-mediated damage to the immature lung4.Advances in neonatal care have led to changes in the riskfactors and pathogenesis of “new” BPD, as well as theextent and type of pulmonary damage encountered.

Oxygen Toxicity

Elevated concentrations of oxygen cause the releaseof oxygen radical species that can directly injureendothelial and epithelial cells. Endothelial cells are par-ticularly vulnerable to injury, which leads to increasedmicrovascular permeability and development of acutepulmonary edema. Protein leak from edema inhibits thesurface-tension-lowering properties of surfactant, thusexacerbating the underlying surfactant deficiency.This acute phase of alveolar damage is followed by amarked proliferative reaction7. Long-term exposure tohigh concentrations of oxygen causes recruitment andactivation of lung neutrophils and macrophages, necro-sis of type I pneumocytes, hyperplasia of type II cells,and marked proliferation of fibroblasts in the lung inter-stitium. Since premature infants have lower levels ofantioxidant enzymes such as catalase, peroxidase, andsuperoxide dismutase, they are much more vulnerableto oxygen toxicity.


Barotrauma and volutrauma secondary to stretchingof the immature lung were strongly associated with thepathogenesis of the “old” BPD. The pathologic lesions ofBPD are found even when premature animals areexposed to mechanical ventilation without simultaneousexposure to high levels of supplemental oxygen.

In the presence of low lung compliance, the highlycompliant tracheobronchial tree is preferentially dis-tended, leading to distortion of the distal airways. As aresult of cyclic bronchiolar stretching, there is terminalairway ischemia and necrosis, followed by pulmonaryinterstitial emphysema and air leaks that complicate theclinical picture in many patients with BPD8. This is asso-ciated with maldistribution of ventilation, which resultsin some areas of the lung being overdistended andothers poorly ventilated.

It appears that lung stretch (volutrauma) is the realoffender for the damage caused by positive-pressure ven-tilation. Studies have shown that the newborn lung cantolerate high levels of positive pressure without signifi-cant damage if lung stretch is prevented.

With progress in neonatal care that includes antenatalsteroids, surfactant treatment, and less aggressive venti-lation strategies, the pattern and pathogenesis of BPDhas changed. Presently, large premature infants rarelydevelop BPD, whereas it is a common complication ininfants weighing <1 kg who do not appear to have severelung disease soon after birth. The “new” BPD may be pri-marily an arrest of lung development9, resulting in alveolarsimplification and “dysmorphic” vascular growth.

Both prenatal and postnatal risk factors probably con-tribute to the aberration in lung development seen inBPD. Infants dying of BPD have fewer and larger alveoliwith less striking fibrosis and inflammation than in thepast10. The lungs at 24–28 weeks of gestation are in thelate canalicular stage or in the early saccular stage. Atthis time, lung volume and surface area increase consid-erably secondary to septation and alveolarization.Parallel increases in vascular growth are closely syn-chronized with alveolarization, but the molecular signalsthat link distal airspace growth with angiogenesis havenot been completely identified.

Research has focused on understanding the regula-tion of septation and alveolarization. In experimentalmodels, hyperoxia, hypoxia, glucocorticoid treatment,and poor nutrition decrease septation.

Glucocorticoids

The effects of glucocorticoids on the preterm lung are complex because they can interfere with alveo-larization while at the same time they induce both thesurfactant system and structural maturation by thinning


Table 4-2 Percent of Surviving Infants with BPD inDifferent Birthweight Groups

O2 DependenceO2 Dependence at 36 Weeks PMAat 28 Days for Infant Born

Birthweight (g) Postnatal Age35 <32 weeks36

<750 90–100% 54%750–999 50–70% 33%1000–1249 30–60% 20%1250–1499 6–40% 10%

(From Fernandez-Nievas F, Chernick V. Bronchopulmonary dysplasia. ClinPediatr 41:77, 2002.)

the mesenchyme. Their effects depend on timing duringdevelopment, dose and other factors. The glucocorticoid-induced inhibition of alveolarization can be blocked innewborn rats with retinoic acid.

Inflammation and Infection

It is known that inflammation is essential to the devel-opment of BPD. Multiple proinflammatory and chemotac-tic factors are found in the lungs of ventilated prematureinfants, and are present in higher concentrations in infantswho go on to develop BPD. Overexpression of cytokinessuch as tumor necrosis factor-α (TNF-α), pulmonarytransforming growth factor-β (TGF-β), interleukins (IL)-6and 11 results in lungs with fewer and larger alveoli.Infants exposed to prenatal infection or colonizationwith Ureaplasma urealyticum have proinflammatorycytokines in their lungs at the time of delivery and are ata higher risk of developing BPD11. Studies in infantsexposed to chorioamnionitis have shown that there is adiminished incidence of RDS but increased risk forBPD12. Apparently, preterm lungs exposed to inflamma-tory mediators seem to mature faster but at the sametime are more sensitive to exposure to other noxiousagents, such as oxygen and mechanical ventilation.

Neutrophils are important in initiating and perpetuat-ing the inflammatory response. The appearance of gran-ulocytes in alveolar washes correlates with pulmonaryedema and early lung injury. Proteases, such as elastase,produced by activated neutrophils in the lungs, may con-tribute to the progression to lung damage.

Nutrition

Animal models have shown that alveolar developmentis negatively affected by reducing food to the mother andto the progeny. Early nutrition provided to preterminfants may lack important factors that are needed forlung growth, repair and protection against injury.

Vitamin A and E deficiency have been found to lead tohypoplastic alveolar regions. Some studies have shownthat administration of parenteral vitamin A may reducethe incidence and severity of BPD13,14.

Vascular Hypothesis

Recently, a vascular hypothesis for the developmentof BPD has been proposed. Studies have shown that thelungs of deceased BPD infants have reduced vascularendothelial growth factor (VEGF) mRNA and proteinexpression, as well as reduced numbers of VEGF recep-tors15. Tracheal VEGF levels are lower in infants withBPD than in premature infants without BPD16. VEGF isa potent endothelial-cell-specific mitogen and survival factorthat stimulates angiogenesis, and its impaired signalingmay contribute to the vascular pathology of BPD. It hasbeen speculated that inhibition of vascular growth itselfmay directly impair alveolarization, as angiogenesis maybe necessary for alveolarization during normal lungdevelopment.

In summary, very early preterm birth, together withexposure to positive-pressure ventilation and supple-mental oxygen, interferes with normal signaling for lungdevelopment, specifically for alveolarization, vasculardevelopment, or both. Antenatal and/or early postnatalinflammation appears to aggravate the adverse effects onlung development (Figure 4-1).

CLINICAL MANIFESTATIONS

History

The usual history of BPD is that of a premature infantwho develops RDS and associated hyaline membranedisease (HMD). These infants are generally intubated andplaced on mechanical ventilation. Before the introduc-tion of surfactant, these infants required long periods of


Figure 4-1 Pathogenesis of the new BPD in verylow birthweight infants. (From Jobe AJ. The newBPD: an arrest of lung development. Pediatr Res46:641–643, 1999.)

high positive pressures and oxygen concentrations inorder to be adequately ventilated and oxygenated. Thesefactors were the main risk factors for the “old” BPD.

Since the beginning of the 1990s, routine administra-tion of surfactant has meant that infants with RDSimprove significantly and can be weaned to minimal ven-tilatory pressures and low concentrations of oxygen.This period, which may be referred to as a “honeymoonperiod,” usually lasts from several days to a few weeks.Older premature babies usually do not go on to developchronic pulmonary complications.

Another group of infants, usually younger and smallerpremature babies (extremely very low birthweight orEVLBW; birthweight <1000 g) or those with a more con-voluted clinical course, are likely to develop complica-tions in the neonatal intensive care unit including apnea,viral or bacterial infections such as pneumonia and/orsepsis, persistence of the ductus arteriosus (PDA) orreopening of a previously closed ductus with secondaryheart failure, among other problems. These complicationsaffect the clinical course of preterm infants with second-ary deterioration of their respiratory status. Consequently,many of these babies require longer periods of ventilatorysupport and oxygen supplementation that produce fur-ther damage to their immature pulmonary architectureand favor the development of BPD13,17. This descriptionapplies to the “new” BPD, the type commonly seennowadays in the post-surfactant era.

Infants with BPD can have multiple problems due toprimary and secondary factors. The most common pul-monary complications seen in these infants includeatelectasis interspersed with areas of emphysema.Pulmonary interstitial emphysema and other air leaks,including pneumothorax and pneumomediastinum, maydevelop in relation to increased pulmonary stiffness.Increased airway collapsibility, especially tracheomala-cia and bronchomalacia, aggravates airway narrowingand is seen more commonly in these infants comparedwith those who do not require positive-pressure ventila-tion in the neonatal period. Pneumonias, which can beviral, bacterial or fungal, may occasionally be associatedwith secondary sepsis.

In some infants with BPD, right-sided heart failure andpulmonary hypertension become significant problems.All these factors aggravate oxygenation and ventilation,mainly due to ventilation–perfusion mismatch. Verysevere cases can also present with aortopulmonary anas-tomoses due to chronic hypoxemia14.

Once these babies are discharged from the neonatalintensive care unit they continue to have a higher inci-dence of pulmonary and non-pulmonary complications.Exacerbations of respiratory symptoms are common ininfants with BPD. Potentially the most serious exacer-bating factor is viral infection. Viruses such as respira-tory syncytial virus (RSV), influenza and adenovirus

can be particularly devastating, leading to hospitalization,respiratory failure and further damage to the pulmonaryparenchyma. Recurrent wheezing episodes are com-mon. There are reports of a higher incidence of suddeninfant death syndrome (SIDS) and apparent life-threateningevents (ALTE) among infants with BPD18.

Non-pulmonary complications found in infants withBPD include gastroesophageal reflux (GER), aspiration,and failure-to-thrive (FTT). GER is common in these infantsand may present with obvious vomiting and spitting up,poor feeding, and irritability. It may also cause anemia,hematemesis, esophageal stricture, laryngospasm, stridor,chronic nasal discharge, apnea and ALTE.

FTT may occur as a consequence of behavioral feed-ing problems, swallowing disorders, GER, chronic orintermittent hypoxemia, heart failure, and elevatedmetabolic rates. Feeding problems include oral aversion,given that many of these infants remain intubated andreceive orogastric or nasogastric feedings for prolongedperiods of time due to their underlying prematurity andassociated diseases. Resting metabolic expenditure, esti-mated through measurements of oxygen consumptionand indirect calorimetry, appears to be higher in infantswith BPD than in age-matched full-term healthy controls.It is important to note that increased work of breathingonly partially accounts for this finding and other mecha-nisms may act to elevate the metabolic expenditure ofBPD infants.19

Heart failure is common in infants with BPD.Exacerbations caused by cardiac failure may present in asimilar way to those caused by infection. Poor feeding,tachypnea, increased oxygen requirements, and inap-propriate weight gain may be present. Hepatomegaly istypical of right-sided heart failure. Cyanotic spells aresometimes seen in these babies due to different reasons,such as tracheobronchomalacia, GER, apnea, or cardio-vascular problems.

Neurodevelopmental problems are also found amonginfants with BPD. Developmental delay affects primarilymotor, speech, and feeding maturity and appears to beworse in infants treated with dexamethasone, asrecently stated by the American Academy of Pediatrics(AAP) Neonatal Committee20. Hearing abnormalitieshave also been found to be more prevalent amonginfants with BPD. A recent study showed that at 8–12months of corrected age, 22.1% of infants with BPD hadpersistent conductive hearing loss compared with 7.7%of non-BPD control infants with a similar gestationalage21. Other conditions seen in infants with BPD includehernias and retinopathy of prematurity.


The initial physical examination shows a preterm new-born with RDS: tachypneic with nasal flaring, intercostal


retractions, grunting, and irregular respirations with fre-quent apneas and cyanosis, requiring immediate ventila-tory assistance. At this point, the auscultatory findingsmay include coarse breath sounds with crackles andpoor air exchange. The infant’s clinical status usuallyimproves after intubation and surfactant administration.

This initial respiratory distress improves with theabove-mentioned treatment. After this period, the lungauscultation usually normalizes or some crackles can beheard due to pulmonary edema. Cardiovascular auscul-tation can reveal a continuous murmur from a PDA.Bounding pulses and wide systolic–diastolic pressure dif-ferential are typical findings of a PDA. This PDA canmake pulmonary edema worse and at the same time putthe baby at higher risk of developing heart failure13. Thetime that the infant stays intubated is variable, usuallylonger for younger premature babies and those withassociated medical complications.

After extubation, many infants persist with tachypnea,intercostal retractions and hypoxemia. On lung ausculta-tion, rhonchi and “Velcro-type” dry crackles are common.Wheezing may be heard during acute respiratory exac-erbations, usually triggered by viral infections. Infantswith moderate-to-severe BPD usually require oxygensupplementation to keep them normoxemic.

As mentioned previously, pulmonary hypertensionand cor pulmonale can be seen in severe cases of BPD.These babies can present with signs of hypoxemia, pul-monary edema, and right ventricular failure. Physical signsinclude an increased loudness of the second heart soundespecially over the pulmonary valve area, hepatomegaly,and fluid retention.

As mentioned before, FTT is seen in some patientswith BPD. Weight, length and, in severe cases, head cir-cumference, fall below the 5th percentile for age, evenwhen age is corrected for prematurity. With adequatenutritional support, most infants exhibit catch-up duringthe first 2 years of life.


BPD produces inflammation and secondary scarringof the lungs affecting its structure and therefore its phys-iology. Performing pulmonary function testing allowsthe clinician to characterize these changes and followtheir progression over time.

Lung mechanics during tidal breathing have beenextensively studied in infants with BPD, usually usingsedation with chloral hydrate. Respiratory system com-pliance is low in the first months of life, a reflection oflung stiffness, whereas resistance is high, an indicationof airway obstruction. Both compliance and resistanceapproach the range of normalcy by 2 years of age22.

Lung volumes measured by helium dilution or nitrogenwashout may underestimate functional residual capacity

(FRC) and are reported to be low in the first 6 months ofage, progressing to normal values by 12 months. Lungvolumes measured by plethysmography are higher thannormal, suggesting air trapping. The ratio of residual vol-ume to total lung capacity (RV/TLC) remains significantlyincreased at 1 year of age in infants with severe BPD9, andhyperinflation continues to be a common finding in ado-lescents with a history of BPD. Partial forced expiratoryflow–volume curves obtained by the chest squeeze tech-nique in infants with BPD are clearly abnormal with expi-ratory flow limitation, as reflected by low values for maximalflow at FRC (V

•

maxFRC) (Figure 4-2)23. This expiratory flowlimitation does not improve as fast as other parameters,with decreased values still common by 2 years of age22.

Airway hyperreactivity, as defined by increasedresponsiveness to a bronchoconstrictor challenge or


EXP

0

Volume (ml)

VmaxFRC•

Flo

w (

ml/s

ec)

0Volume (ml)

VmaxFRC•F

low

(m

l/sec

)

A

BFigure 4-2 Partial expiratory flow–volume curves. The smallerinner curve represents tidal breathing, and the larger curve repre-sents maximal expiratory flow generated by the rapid compressiontechnique. Maximal expiratory flow at functional residual capacity(V

•

maxFRC) is indicated by the dashed line. The difference betweentidal breathing and maximal expiratory flow represents expiratoryflow reserve. (A) Normal control infant has a convex to linear max-imal expiratory flow–volume curve, with large expiratory flowreserve. (B) Infant with BPD has a concave flow–volume curve,with decreased expiratory flow reserve and V

•

maxFRC, comparedwith A. (From Tepper RS, Morgan WJ, Cota K, et al. Expiratory flowlimitation in infants with bronchopulmonary dysplasia. J Pediatr109:1040–1046, 1986.)

bronchodilator therapy, is frequently found in BPD infants.Bronchial hyperreactivity may be caused by airway inflam-mation, altered neurogenic responses, altered maturationalresponses of airway smooth muscle, and genetic factors.Increased airway reactivity persists in older children andadolescents with a history of BPD.

Radiology

When Northway described the first cases of BPD heclearly showed four different radiological stages thatevolved over time1. This sequence is no longer seen,mainly due to the use of early surfactant therapy andimprovement in ventilatory management.

The first stage is still seen and is characterized by areticular, granular pattern with ground-glass appearance,associated with air bronchograms and decreased lungvolumes. This stage is classically observed in the acutephase of HMD. The second stage was characterized bydense non-specific parenchymal opacification, indistin-guishable from pulmonary edema and/or pulmonaryhemorrhage. The third stage, rarely seen nowadays, wascalled the “bubble-like pattern”, characterized by cystic-like lesions more noticeable in the upper lobes. Stagefour was characterized by hyperlucency in both baseswith increased radiopacity in the upper lobes. This laststage is reserved today for infants with severe BPD and,fortunately, is rarely seen2 (Figure 4-3).

It is more common now to see stage I and, after sur-factant administration, clearance of the chest radiograph(Figure 4-4). After some time with mechanical ventilatorysupport or oxygen supplementation, some radiographicfindings start to appear, characteristically as a hazyappearance of both lungs13 (Figure 4-5).

Several radiographic classifications have been pro-posed since the introduction of surfactant. TheWeinstein score is one of these, which establishes six


Figure 4-3 Chest radiograph characteristic of stage IV BPD thatshows hyperlucency in both bases with strands of radiodensity inthe upper lung fields. (From Bancalari E, et al. In Fanaroff AA,Martin RJ, editors: Neonatal-perinatal medicine: diseases of thefetus and infant. St. Louis: Mosby, 1997.)

A BFigure 4-4 Chest radiographs of an infant with HMD, with ground-glass appearance before (A)and marked improvement after (B) administration of exogenous surfactant. (From Taussig LM,Landau LI. Pediatric respiratory medicine. St. Louis: Mosby, 1999.)

different grades of radiographic abnormalities in BPD24.The most benign is grade 1, characterized by faint, notwell-defined opacities, which give a hazy appearance tothe lung. The most severe is grade 6, characterized bycystic and opaque areas giving the lung a “bubble-like”appearance. In between these grades, gradual appear-ance of more dense opacities with cystic changes is pro-gressively appreciated.

There are some conditions that can radiographicallymimic BPD and should be considered in the differentialdiagnosis. The most important are: surfactant proteindeficiency (more commonly seen in term babies withRDS with a protracted course), Wilson-Mikity syndrome(rarely seen these days), pneumonia, congenital heartdisease, pulmonary lymphangiectasis, interstitial lungdisease, and aspiration syndromes14 (Box 4-1).

Studies using high-resolution computed tomographyhave become a useful auxiliary test. They can providemore detailed information of the actual airway size and

wall thickness, and show hyperinflation caused by gastrapping. At the same time, they reveal the structure ofthe pulmonary interstitium and provide information onthe degree of edema and/or fibrosis affecting the lungs4.

Other radiology tests frequently ordered in infantswith BPD are gastrointestinal studies, especially in babieswho have frequent vomiting, FTT, apnea, cyanotic spells,or ALTEs. An upper gastrointestinal series with bariumcontrast assesses the swallowing mechanism, as well asthe anatomy of the esophagus, stomach, and the upperportion of the intestine. It is helpful in the evaluation ofswallowing dysfunction, GER, and anatomic abnormali-ties such as H-type tracheoesophageal fistula and intes-tinal malrotation. GER nuclear scans can be useful in thediagnosis of GER and aspiration secondary to this condi-tion. More detailed information regarding possible swal-lowing dysfunction is obtained with video swallowingstudies performed fluoroscopically in the presence of aspeech therapist.

Laboratory Tests (Box 4-2)

Arterial Blood Gases (ABGs)Full ABG measurement is most likely to be indicated

during the early phase of severe BPD with respiratoryfailure or during an acute exacerbation. In the earlyphase, the infant with RDS has respiratory acidosis with


Figure 4-5 Chest radiograph of an infant with “new” BPD.Haziness in both lung fields is noted.

Box 4-1 Some Differential Diagnosesof BPD

PneumoniaCongenital heart disease with pulmonary edemaSurfactant protein deficiencyWilson-Mikity syndromePulmonary lymphangiectasiaInterstitial lung diseaseAspiration

Box 4-2 Radiology and Laboratory Testsin BPD

RadiologyAcute: Hyaline membrane disease (HMD)Chronic (“old” BPD): four stages

HMDDense parenchymal opacificationBubble like patternHyperlucency of bases with radiopacity of the apices

Chronic (“new” BPD): Bilateral haziness ofboth lungs

Chest CT scan: Evaluates airway and interstitiumLaboratory tests

Arterial blood gas (ABG) and electrolytes:Early: Respiratory acidosis, hypoxemiaChronic: Metabolic alkalosis with ↓ Na+, ↓ K+,

↓ Cl− with use of diureticsElectrocardiogram (ECG)

Hypertrophies (i.e., RVH)Rhythm disturbances

EchocardiogramCongenital heart diseasePDAPulmonary hypertensionOther acquired systemic-pulmonary anastomoses

CO2 retention and hypoxemia, which improve with sur-factant administration, oxygen supplementation andventilatory support. In the infant with established BPD,ABGs may demonstrate CO2 retention and compensatorymetabolic alkalosis with elevated serum bicarbonate(HCO3

−). In some children, a primary metabolic alkalosismay be present as well, with pH in the normal or slightlyalkalotic range. This might result from the use of diuret-ics, or the presence of heart failure with a low cardiacoutput state and hyperaldosteronemia. In both cases, themetabolic alkalosis occurs because of volume contrac-tion and depletion of potassium and chloride.

ElectrolytesElectrolyte disturbances are usually caused by the use

of diuretics such as furosemide and, to a lesser degree,thiazides. They produce hyponatremia, hypokalemia,and hypochloremia, as well as metabolic alkalosis withelevated serum bicarbonate. Potassium-sparing diureticsand potassium chloride supplements are used to preventhypokalemia and metabolic alkalosis. Loop diuretics alsocause hypercalciuria, which can lead to nephrocalci-nosis, increased bone resorption, osteopenia, and rickets.

Electrocardiogram (ECG)The ECG is a useful tool in the evaluation of associ-

ated cardiovascular disease. It provides informationabout ventricular hypertrophies, rhythm disturbancesand, indirectly, pulmonary hypertension (right ventricu-lar hypertrophy and pulmonary “p” wave).

EchocardiogramThis diagnostic test has become very useful and is

used almost routinely in premature babies to rule outcongenital cardiac disease or a PDA that will requireimmediate medical care. It is a non-invasive test that sup-plies information about the heart’s and great vessels’anatomy and function, and can provide evidence of pul-monary hypertension.

Pathology

The classical pathologic findings of BPD havechanged since the introduction of surfactant for prophy-laxis and treatment of RDS. In the pre-surfactant era, thepathologic findings in the lungs were more severe. Thelungs had an abnormal appearance with a darker colorand an irregular surface showing emphysematouschanges alternating with areas of atelectasis (Figure 4-6).Microscopically, the emphysematous areas were seen asdistended alveoli, alternating with atelectasis (Figure 4-7).Another finding was a diminished number of alveoli. Inthe large and small airways, there was evidence of inflam-mation with metaplasia and hyperplasia of the mucosa,associated with increased numbers of goblet cells andthickening of the basal membrane (Figure 4-8). In thepulmonary interstitium there was pulmonary edema,progressing to fibrosis in the most severe cases.

Pathologic findings also affected the pulmonary vas-culature. Pulmonary vessels presented with diminishedbranching, elastic degeneration, and hypertrophy of themuscular layer. Lymphatic vessels were usually dilatedand tortuous. In cases of pulmonary hypertension, therewas cardiomegaly with right ventricular hypertrophy(cor pulmonale).

In the post-surfactant era, there is less fibrosis andmore uniform inflation of the BPD lungs. The alveoli areenlarged and significantly fewer in number, indicatingan interference with septation and alveolarization.The airways, large and small, are usually free of epithelial


Figure 4-6 Macroscopic appearance of lungs with BPD showinguneven expansion. (From Bancalari E, et al. In Fanaroff AA, MartinRJ, editors: Neonatal-perinatal medicine: diseases of the fetus andinfant. St. Louis: Mosby, 1997.)

Figure 4-7 Low-magnification view showing areas of emphy-sema alternating with areas of partial collapse. (From Bancalari E,et al. In Fanaroff AA, Martin RJ, editors: Neonatal-perinatal medi-cine: diseases of the fetus and infant. St. Louis: Mosby, 1997.)

metaplasia and smooth muscle hypertrophy. In the inter-stitium, there is an increase in elastic tissue that is pro-portionate to the severity and duration of the respiratorydisease. Finally, a decrease in the pulmonary microvascu-lature is also noted. More information is needed about theprogression of lung injury in survivors of the “new” BPD4.

TREATMENT

In addition to chronic respiratory disease, infantswith BPD may have significant growth, nutritional, neu-rodevelopmental and cardiovascular problems. The fol-lowing discussion on clinical management is directedprimarily towards the outpatient care of infants andolder children with BPD (Box 4-3).

Oxygen Therapy

Patients with BPD have chronic alveolar hypoxia andhypoxemia secondary to ventilation–perfusion (V

•/Q

•)

mismatch. Over time, chronic hypoxemia leads toaltered lung vascular development and an increasedresponse to vasoactive agents that ultimately causes anirreversible increase in pulmonary vascular resistance.

If hypoxemia is left uncorrected, pulmonary hypertensionand cor pulmonale develop. Therefore, the risks of uncor-rected hypoxemia in patients with BPD are pulmonaryhypertension and right ventricular hypertrophy and failure,as well as slow somatic growth and developmental delay.


A

B

Figure 4-8 Microscopic appearance of airway metaplasia. (A)Photomicrograph showing normal ciliated respiratory epithe-lium. (Hematoxylin–eosin, ×240.) (B) Photomicrograph showingmature, keratinizing, stratified squamous epithelium that ismarkedly thickened from infant with BPD. (Hematoxylin–eosin,×100.) (From Taussig LM, Landau LI. Pediatric respiratory medi-cine. St. Louis: Mosby, 1999.)

Box 4-3 The Most Common TherapeuticModalities for Managementof BPD

Oxygen supplementation: if necessary to keepSpO2 ≥ 92–95%

Diuretics: furosemide, thiazides and/or potassium-sparing diuretics, for patients with recurrentpulmonary edema

Inhaled bronchodilators: β2-agonists indicated if clinicalevidence of reversible airway obstruction

Anti-inflammatory therapy: no definitive benefitsof inhaled corticosteroids at this time

Nutrition: maintain caloric intake at120–140 cal/kg/day

Prevention of intercurrent viral illnesses: RSVprophylaxis, influenza vaccine

Decreased oxygen supply may suppress appetite andincrease metabolic demands through neurohumoralstimulation.

Currently, supplemental oxygen is provided to chil-dren with BPD by nasal cannula in order to maintain arte-rial oxyhemoglobin saturation (SpO2) ≥ 92–95% asmeasured by pulse oximetry, when the infant is awake,asleep and during feeds. If there is clinical or echocar-diographic evidence of pulmonary hypertension, SpO2

should be kept at a minimum of 95–96% to prevent pro-gression of the condition. These therapeutic ranges arepartly based on clinical experience and partly on datafrom cardiac catheterization studies. Most of the declinein pulmonary vascular resistance with supplemental oxy-gen occurs with correction of hypoxemia; higher con-centrations of inspired oxygen generally do not causefurther improvement. Selected patients, however,respond better to higher SpO2 (≥ 95%), suggesting thathigher target oxygen saturations may improve clinicaloutcome in some infants25.

Pulse oximetry is used to measure oxygen saturationwhile the child is quiet and awake. Once oxygen has beenweaned to low-flow supplementation (1/8–1/16 liter perminute or less), this measurement should be done every2–4 weeks after the patient has been on ambient air for10 minutes, and if SpO2 is ≥ 92%, oxygen may be discon-tinued during wakefulness. At first, oxygen therapy isdiscontinued while the child is awake, since SpO2 tendsto be lower during sleep than wakefulness. SpO2 needs tobe assessed during sleep before complete discontinuationof supplemental oxygen. During the weaning process, itis important to ensure that the infant has normal SpO2

during feeding and activities; if not, the maintenancedose of oxygen may be too low, the infant may haveepisodic pulmonary hypertension with transient right-to-left shunting of blood, or other conditions previouslymentioned such as GER or airway malacia may exist.

If somatic growth rate slows down or stops in theweeks after discontinuation of oxygen therapy, this mayindicate significant intermittent hypoxemia, for whichoxygen supplementation should be restarted. If the needfor supplemental oxygen rises or fails to decrease duringthe first few months after discharge from the neonatalintensive care unit, coexisting conditions that mayworsen BPD should be excluded, including uncontrolledreactive airways disease, GER and aspiration, congenitalheart disease and airway anomalies.

Diuretic Therapy

The role of diuretics in the management of BPD hasbeen extensively reviewed. Although the exact mecha-nisms by which diuretic therapy improves pulmonaryfunction are incompletely understood, there are data tosupport the notion that the beneficial effects of diuretics

are probably a combination of diuresis and local pul-monary effects26.

Most infants with established BPD do not have a needfor diuretics. Short-term diuretic treatment may be ben-eficial for infants with established BPD and acute fluidoverload. Long-term diuretic therapy is used in infantswith more severe BPD, especially those with recurrentpulmonary edema whose pulmonary disease has demon-strated a favorable response to diuretics.

The most frequently used diuretic in the acute phaseis furosemide (1 mg/kg/dose IV or IM, or 1–2 mg/kg perdose PO). This drug causes an increase in pulmonarycompliance, as well as a fall in resistance and supple-mental oxygen requirement. For chronic care, the mostfrequently used diuretics are furosemide on alternatedays or thiazides in combination with spironolactone.Use of a thiazide–spironolactone combination has alsobeen shown to improve pulmonary compliance, withless striking decline in resistance and oxygen require-ment when compared with furosemide.

Extended diuretic therapy may produce two seriouscomplications. One includes electrolyte imbalance,volume contraction and metabolic alkalosis, which aretreated with supplementation with potassium chloride(KCl) and/or dose adjustments. Although sodiumchloride (NaCl) supplements are occasionally used tocorrect the hyponatremia caused by aggressive diuresis,this therapy seems counterproductive because it leadsto fluid retention. The other complication, seen withfurosemide, is hypercalciuria with secondary hyper-parathyroidism and nephrocalcinosis. The diagnosis ofnephrocalcinosis is established by finding echogenicareas during renal ultrasonography. Some clinicians pre-fer alternate-day therapy with furosemide since it is asso-ciated with sustained improvement in lung mechanicswithout causing alterations in serum electrolytes or highurinary calcium losses. Other practitioners favor thiazidediuretics over furosemide to help reduce urinary calciumlosses.

There is no standard weaning process for diuretic ther-apy. Most clinicians merely allow infants to “outgrow”their therapy and withdraw it when the dose has fallenbelow the accepted therapeutic range.

Inhaled Bronchodilators

Most infants with CLDI have intermittent wheezingand proof of expiratory airflow limitation on infantpulmonary function testing. Studies have shown thatβ-agonists produce short-term improvement in pul-monary mechanics in parameters such as respiratorysystem compliance and airway resistance. It is reason-able to treat infants with BPD who demonstrate clinicalevidence of reversible airway obstruction with inhaledβ2-agonists.


The use of β2-agonists may be associated with poten-tial complications, such as simultaneous induction ofpulmonary vasodilation. Prolonged therapy with highdoses of β2-agonists may increase pulmonary blood flowto underventilated lung units, thus aggravating V

•/Q

•mis-

match and hypoxemia. Secondly, β2-agonists mayincrease airway instability in infants with tracheomala-cia. Increased airway smooth muscle tone is necessary ininfants with tracheomalacia in order to maintain stabilityof the large airways. β2-agonists cause relaxation of thesmooth muscle, which may lead to increased collapsibil-ity of the affected airway. This occurrence could explainwhy inhaled bronchodilators have variable effects onpulmonary mechanics in infants with BPD. Therefore,effectiveness of β-adrenergic therapy for BPD infantsneeds to be carefully determined on an individual basis.Dysrhythmias and hypokalemia have also been reportedwith frequent administration of inhaled albuterol.

Atropine and ipratropium bromide have also beenstudied in infants with BPD. Short-term improvement inpulmonary function has been documented with bothmedications. There is weak evidence for synergy betweenβ-agonists and anticholinergic agents.

The appropriate dose and means of administration ofbronchodilators have not been determined. Depositionof medication into the lower airways depends on inspi-ratory flow rate, particle size, distance of the nebulizerfrom the face, and type of spacer and inhaler used. Itappears that in infants not mechanically ventilated, allmethods of delivery are fairly inefficient.

Anti-inflammatory Therapy

The rationale for the use of anti-inflammatory agentsin infants at risk for developing BPD is based on therecognition of the role of lung inflammation in thepathogenesis of BPD. Corticosteroids are the most care-fully studied anti-inflammatory agents in the preventionand treatment of BPD.

It has been shown that late administration of highdoses of systemic corticosteroids in infants at risk fordeveloping BPD reduces the duration of mechanical ven-tilation and temporarily improves lung mechanics.However, long-term benefits in terms of duration of oxy-gen therapy and length of hospitalization have not beendemonstrated. When steroids are administered earlier inthe course of RDS (as early as day 1 of life), total durationof mechanical ventilation and oxygen may be reduced,as well as the incidence of severe BPD, without a clearinfluence on mortality27.

The use of systemic corticosteroids in prematureinfants is associated with significant side effects such asadrenal suppression, gastrointestinal perforation, hyper-trophic cardiomyopathy, somatic growth failure,delayed development of the central nervous system,

higher rate of infections, systemic hypertension, hyper-glycemia, and bone demineralization. Long-term conse-quences of systemic corticosteroid use may includenegative effects on neurologic development and func-tion. Systemic glucocorticoids impair alveolar septationin animal models, leading to decreased lung surface area.

Because of the significant side effects associated withsystemic steroids, several investigators have looked atthe effects of inhaled corticosteroids (ICS) in infantswith impending BPD. One of the main problems withthis mode of treatment is the variability and difficulty inachieving drug deposition in the distal airways, espe-cially in the presence of airway obstruction. So far, theuse of ICS in infants at risk of BPD has produced someenhancement in lung mechanics and gas exchange, aswell as improvement in extubation rates, without modi-fying the incidence or severity of BPD, mortality or long-term outcome in the treated infants27. The beneficialeffects of ICS are slower and less striking than those ofsystemic corticosteroids. Likewise, the reported sideeffects of ICS are substantially milder, but includereversible hypertrophy of the tongue, adrenal suppres-sion, oral candidiasis and growth impairment.

The role of non-steroidal anti-inflammatory medica-tions in the prevention of BPD has been studied as well.Watterberg and Murphy28 determined that in prematurenewborns with RDS, cromolyn sodium did not decreasethe incidence or severity of BPD, defined as survival to30 days of life without oxygen dependence. However, amore recent study showed a decline in TNF-α and IL-8concentrations in lung lavages of infants after 7 days ofaerosolized cromolyn sodium therapy in infants ≤1000 gat birth28.

In established BPD, oral corticosteroids are used dur-ing respiratory exacerbations. ICS may be recommendedfor infants who have recurrent episodes of wheezingand respiratory distress responsive to bronchodilatorssuggestive of reactive airways disease (RAD), especially ifthere is a family history of asthma. The role of cromolynsodium in the treatment of established BPD has not beenadequately studied, but could be an alternative forinfants with mild RAD in order to avoid the use of ICS.

Nutrition

Altered growth, nutrition, and metabolism mayadversely affect the long-term outcome of infants withBPD. Infants with BPD are at risk for malnutrition, failureto thrive and delayed lung repair. Many of these infantshave GER, oral aversion, and increased energy expendi-ture. Oxygen consumption may be increased in propor-tion to the severity of pulmonary disease.

Since poor nutrition can compromise the developmentof new alveoli, it is crucial to provide these children withaggressive nutritional support. Nutritional interventions


aim to facilitate catch-up growth at a rate of at least20–30 g/day. Thus, caloric intake should be 120–140cal/kg/day. Commercial infant formulas with caloric den-sities higher than 20 cal/oz may be used to avoid exces-sive fluid intake and the risk of fluid overload. Furtherincreases in caloric density (up to 30 cal/oz) can beachieved by adding medium-chain triglycerides or glu-cose polymers to the infant’s formula. Older childrenwith inadequate caloric intake may be given high calorieformulas such as Pediasure or Nutren Jr. Maintenanceelemental iron (2 mg/kg/day) should be given to allinfants and iron-deficiency anemia should be treatedwith 5–6 mg/kg/day. Multivitamins should be given toinfants drinking less than 450 ml daily of formula and tobreast-fed infants.

Poor caloric intake is often behavioral due to adverseoral stimulation from prolonged endotracheal intubation,gavage feedings and frequent suctioning. Gastrostomytube placement may be indicated to provide adequatenourishment, while speech therapists work aggressivelyto resolve oral feeding problems. Fundoplication is oftenrequired with gastrostomy for GER that does not resolvewith medical management.

When an infant is not gaining weight appropriatelydespite an adequate caloric intake, coexisting conditionsthat may interfere with growth and lung healing shouldbe sought. The following should be considered:• Persistent hypoxemia because of early termination or

excessive reduction of supplemental oxygen, or pooradherence to a home oxygen therapy plan.

• Unrecognized intermittent hypoxemia (e.g.,obstructive sleep apnea).

• Inadequate oxygen delivery to tissues secondary toanemia.

• Gastroesophageal reflux.• Unsuspected cardiopulmonary abnormalities, such as

congenital heart disease, tracheomalacia, vascularring, and tracheoesophageal malformations.

• Recurrent aspiration due to swallowing dysfunction.

Prevention of Intercurrent Viral Infections

Infants with BPD have frequent respiratory exacerba-tions due to recurrent infections of the upper and lowerrespiratory tract. RSV is a frequent cause of respiratorycomplications during winter and early spring months inmost of the United States, although in some areas suchas South Florida RSV is isolated throughout the year.Other viral agents such as influenza A and B, parain-fluenza, and adenovirus have also been identified ascauses of acute respiratory distress in children with BPD.

In the absence of an effective RSV vaccine, alternativemethods of protection have been developed. In themid-1990s, RSV immunoglobulin (Respigam®) was intro-duced for infants at risk for severe lower respiratory

tract infection by RSV. RSV-IVIG was given as monthlyintravenous infusions (750 mg/kg or 15 ml/kg per dose)during the RSV season (November–March in theNorthern Hemisphere) and it was able to reduce thenumber of hospitalizations, number of hospital days, andduration of stay in intensive care units attributed to RSVinfections.

Towards the end of the 1990s, palivizumab, a human-ized monoclonal antibody against RSV, was developed.The use of palivizumab (Synagis®) as a monthly intra-muscular injection (15 mg/kg) during the RSV seasonresulted in a 35% reduction in RSV admissions and a42% reduction in hospital days due to RSV disease inthe treated group of infants with BPD. At this time,palivizumab has replaced RSV-IVIG for RSV prophylaxisand it is recommended that infants with BPD receiveit on a monthly basis during the RSV season in the first2 years of life.

Infants with BPD 6 months and older should receivethe influenza vaccine annually in the early fall months.Many clinicians recommend that parents, siblings andcaretakers of these infants also receive the influenzavaccine each year. Routine immunizations should be givento infants with BPD according to their chronological age,regardless of their gestational age. The ultimate effect ofprevention of RSV or influenza infections on the long-term prognosis of BPD has not been established, butshould be expected to favorably impact final outcome.

In order to decrease the frequency of respiratoryinfections in children with BPD, advice for their familiesshould include: avoidance of large day-care settings dur-ing the winter months, elimination of tobacco smokeexposure, deferral of elective surgical procedures tonon-respiratory virus months, and close monitoring forearly signs of infection.

LONG-TERM PROGNOSIS

Many of the studies that refer to long-term prognosisin infants with BPD preceded the introduction of surfac-tant replacement therapy. These reports do not includethe EVLBW infants and, at the same time, do not reflectthe impact of recent therapeutic approaches that arecommonly used these days30.

Infants who develop BPD are more prone to viral res-piratory infections, particularly in the first 2 years of life.These respiratory infections can be severe and canprogress to respiratory failure because of poor respiratoryreserve.

As mentioned previously, one of the most detrimentalrespiratory infections seen in these babies is RSV. Thisvirus can not only produce acute disease but can also leadto recurrent inflammation of the airways that can persistfor years increasing the likelihood of developing asthma31.


Reactive airway disease is more common in children withBPD, and presents with recurrent episodes of wheezingand cough, many times in association with respiratoryinfections.

An interesting study compared pulmonary function at7 years of age in children with BPD, former prematurechildren who did not have BPD and full-term children. It showed that children with BPD had significantlyreduced airflows, particularly forced expiratory volumein 1 second (FEV1), and forced expiratory flow between25% and 75% of the vital capacity (FEF25%–75%). Lungvolume measurements showed an elevated residualvolume/total lung capacity (RV/TLC) ratio, indicative ofair trapping. When bronchodilator responsiveness wasevaluated in these groups, children who had BPD hadpositive responses twice as often as controls. These dif-ferences remained significant even after adjustment forbirthweight and gestational age32.

Children with BPD may also have neurodevelopmen-tal sequelae, with problems such as cerebral palsy,impaired vision and hearing, speech delay and learningdisabilities. They may also exhibit impaired growth, mal-nutrition, higher infant mortality rate, and SIDS8.

Further studies are necessary to determine the long-term outcome of children with the “new BPD”, whichwould include very small premature infants treated withantenatal steroids and surfactant replacement.

PREVENTION

As discussed in the section on the pathogenesis of BPD,there are many factors that play a role in the etiology ofBPD. The early recognition of these risk factors shouldbe the main focus of prevention.

The most important risk factor for BPD is prematurity.The younger the infant in terms of gestational age, themore likely he or she is to develop BPD. The main effortshould be to prolong the pregnancy as much as possiblein cases of preterm labor, cooperating as much as poss-ible with the obstetricians. The use of antenatal steroidseffectively reduces the incidence and severity of HMDand reduces the risk of severe BPD. However, thisapproach has not effectively changed the incidence ofthe new forms of BPD13.

We know that proinflammatory cytokines are likelymediators in the pathogenesis of BPD. These cytokinesmay be induced by many different conditions, one ofwhich is antenatal exposure to infection (chorioam-nionitis)33. Emphasis should be given to early recogni-tion and treatment of these intrauterine infections,especially in mothers at risk of preterm labor.

Since Northway’s original description of BPD, it wasrecognized that higher ventilatory pressures and oxygenconcentrations lead to more severe forms of BPD.

Over time, multiple studies have evaluated differentmodes of ventilation and types of ventilators. Strategiessuch as patient-triggered ventilation, permissive hyper-capnia and low tidal volume ventilation have not affectedthe incidence of BPD, even though some patients havebeen ventilated for shorter periods of time. The efficacyof high-frequency ventilation in preventing BPD stillremains controversial. In contrast, use of continuouspositive airway pressure (CPAP) immediately after deliv-ery may offer some protection. In one recent study, thegroup of infants treated in this manner required less sur-factant therapy and had a lower incidence of BPD34. Itmust also be remembered that high concentrations andprolonged use of oxygen supplementation inhibit alveolardevelopment.

The use of surfactant replacement therapy in infantswith HMD has improved the respiratory course and sur-vival of infants with BPD. It has also changed the courseof “classical” BPD, allowing the survival of EVLBW infants.At the same time, the use of surfactant has facilitated lessaggressive ventilatory strategies in these infants, makingbarotrauma infrequent these days13,17. Interestingly, sur-factant replacement has not decreased the overall inci-dence of BPD, probably because of the increased survivalof EVLBW infants.

Premature infants may require fluid restriction sincethey are more prone to develop pulmonary edema.Aggressive treatment of a PDA is necessary since its pres-ence can produce pulmonary edema, heart failure anddiminished lung compliance. These may translate intolonger courses of ventilatory support and oxygen therapy,leading to worse BPD.

Postnatal infections, specifically pneumonias andsepsis, also provoke inflammation in the lungs andworsen the underlying condition. These postnatal infec-tions should be prevented with measures such as generalhygiene, isolation, and immunizations. Prophylaxis forcertain viral respiratory infections such as RSV andinfluenza is extremely important as discussed previously.

Adequate nutrition is fundamental in prematureinfants, essentially for two reasons. It provides enoughcalories to match the increased metabolic needs of BPDinfants, and assures satisfactory somatic and pulmonarygrowth. It also provides important substrates for theantioxidant mechanisms to protect the lungs againstoxidative injury. One of these nutrients is vitamin A,which preserves airway epithelium and promotes alveo-lar septation, reducing the risk of BPD. Other importantantioxidant agents are vitamin E and sulfur-containingamino acids such as glutathione13.

Postnatal use of systemic steroids, specifically dexa-methasone, is no longer recommended as a routine anti-inflammatory therapy due to adverse neurologicoutcomes in infants treated with them. Postnatal sys-temic corticosteroids to aid in weaning an infant from


mechanical ventilation should be reserved for the mostsevere cases that remain oxygen- and ventilator-depend-ent for prolonged periods of time, and their use shouldbe considered experimental18.

In summary, BPD describes the chronic respiratorydisorders primarily associated with premature birth andits therapy. Its definition, risk factors, radiologic, andpathologic features have evolved over time, mainlyrelated to advances in the care of premature neonates.Its clinical features involve not only the respiratory sys-tem but other structures such as the cardiovascular, gas-trointestinal and central nervous systems. Its treatmentmay include oxygen supplementation, diuretics, inhaledbronchodilators and anti-inflammatory medications. Assomatic growth is associated with lung development inthe first years of life, ensuring adequate nutrition is vitalfor the resolution of BPD. Prophylaxis against viral infec-tions such as influenza and RSV is very important as well.BPD is unlikely to disappear until preterm delivery ofEVLBW infants is prevented. A better understanding ofthe risk factors for BPD needs to be reached in order forphysicians to be able to prevent them or, at least, moresuccessfully treat them.

Acknowledgments

The authors thank Dr. Eduardo Bancalari for his criticalreview of this chapter, and Dr. Alexander Auais for hisassistance with word- and image-processing technology.


MAJOR POINTS

1. Key Aspects in Pathogenesis“Old” BPD: – Prematurity

– Oxygen toxicity– Positive-pressure ventilation:

barotrauma/volutrauma“New” BPD: – Prematurity

– Glucocorticoids: antenatal/postnatal

– Inflammation/infection: chorioamnionitis

– Nutrition– Fluid balance: PDA

2. Key Clinical FindingsRespiratory: – Cough

– Tachypnea and increasedrespiratory effort

– Wheezing– Crackles– Hypoxemia– Recurrent respiratory infections– ALTE/SIDS

Gastrointestinal: – GER– Aspiration– Poor feeding– FTT

Cardiovascular: – Heart failure– Hepatomegaly– Pulmonary hypertension– Cor pulmonale

Neurologic: – Developmental delay– Retinopathy of prematurity

3. Key Pathologic FindingsPulmonary parenchyma and airways:

– Decreased alveolarization– Alternating areas of emphysema

and atelectasis– Airway metaplasia– Pulmonary edema

Pulmonary vasculature:– Decreased branching– Elastic degeneration– Hypertrophy of muscular layer

4. Key TreatmentSee Box 4-3

5. Key Preventive StrategiesPrenatal: – Prolongation of gestation

– Use of antenatal steroids– Early recognition and treatment

of intrauterine infectionsPostnatal: – Surfactant replacement

– Gentle ventilatory strategies– Fluid restriction/aggressive

management of PDA– Adequate nutrition�

�

REFERENCES

1. Northway WH Jr., Rosan RD, Porter DY. Pulmonary diseasefollowing respiratory therapy of hyaline membrane disease:bronchopulmonary dysplasia. N Engl J Med 276:357–368,1967.

2. Bancalari E, Abdenour GE, Feller R, et al. Bronchopulmonarydysplasia: clinical presentation. J Pediatr 95:819–823, 1979.

3. Shennan AT, Dunn MS, Ohlsson A, et al. Abnormal pulmonaryoutcomes in premature infants: prediction from oxygenrequirement in neonatal period. Pediatrics 82:527–532, 1988.

4. Jobe AH, Bancalari E. NICHD/NHLBI/ORF workshop sum-mary: bronchopulmonary dysplasia. Am J Respir Crit CareMed 163:1723–1729, 2001.

5. Northway WH Jr. Bronchopulmonary dysplasia: thirty-three years later. Pediatr Pulmonol Suppl 23:5–7, 2001.

6. Field T. Trent Neonatal Survey 1999 Annual Report.University of Leicester, 2000.

MAJOR POINTS—Cont’d�

�


7. Avery ME, Tooley WH, Keller MPH, et al. Is chronic lungdisease in low birthweight infants preventable? A survey ofeight centers. Pediatrics 79:26, 1987.

8. Abman SH, Groothuis JR. Pathophysiology and treatmentof bronchopulmonary dysplasia: current issues. Pediatr ClinNorth Am 41:277–315, 1994.

9. Jacob SV, Coates AL, Lands LC, et al. Long-term sequelae ofsevere bronchopulmonary dysplasia. J Pediatr 133:193–200,1998.

10. Husain NA, Siddiqui NH, Stocker JR. Pathology of arrestedacinar development in postsurfactant bronchopulmonarydysplasia. Hum Pathol 29:710–717, 1998.

11. Yoon BH, Romero R, Jun JK, et al. Microbial invasion of theamniotic cavity with Ureaplasma urealyticum is associ-ated with a robust host response in fetal, amniotic andmaternal compartments. Am J Obstet Gynecol 179:1254–1260, 1998.

12. Watterberg K, Demers L, Scott S, et al. Chorioamnionitisand early lung inflammation in infants in whom bron-chopulmonary dysplasia develops. Pediatrics 97:210–215,1996.

13. Bancalari E. Changes in pathogenesis and prevention ofchronic lung disease of prematurity. Am J Perinatol 18:1–9,2001.

14. Fanaroff A, Martin R, editors. Neonatal–perinatal medicine,6th edition. St. Louis: Mosby, 1997.

15. Bhatt AJ, Pryhuber GS, Huyck H, et al. Disrupted pul-monary vasculature and decreased vascular endothelialgrowth factor, Flt-1, and TIE-2 in human infants dying withbronchopulmonary dysplasia. Am J Respir Crit Care Med164:1971–1980, 2001.

16. Lassus P, Turanlahti M, Heikkilä P, et al. Pulmonary vascu-lar endothelial growth factor and Flt-1 in fetuses, in acuteand chronic lung disease, and in persistent pulmonaryhypertension of the newborn. Am J Respir Crit Care Med164:1981–1987, 2001.

17. Bancalari E, Del Moral T. Bronchopulmonary dysplasia andsurfactant. Biol Neonate 80 (Suppl 1):7–13, 2001.

18. Taussig LM, Landau LI, editors. Pediatric respiratory medi-cine, 1st edition. St. Louis: Mosby, 1999.

19. Kurzner SI, Garg M, Bautista DB, et al. Growth failure inbronchopulmonary dysplasia: elevated metabolic rates andpulmonary mechanics. J Pediatr 112:73–80, 1988.

20. American Academy of Pediatrics, Committee on Fetus andNewborn. Postnatal corticosteroids to treat or prevent

chronic lung disease in preterm infants. Pediatrics109:330–338, 2002.

21. Gray PH, Sarkar S, Young J, et al. Conductive hearing lossin preterm infants with bronchopulmonary dysplasia.J Paediatr Child Health 37:278–282, 2001.

22. Baraldi E, Filippone M, Trevisanuto D, et al. Pulmonary function until two years of life in infants with bronchopul-monary function. Am J Respir Crit Care Med 155:149–155,1997.

23. Tepper RS, Morgan WJ, Cota, K, et al. Expiratory flow limitation in infants with bronchopulmonary dysplasia. J Pediatr 109:1040–1046, 1986.

24. Weinstein RM, Peters ME, Sadek M, et al. A new radi-ographic scoring system for bronchopulmonary dysplasia.Pediatr Pulmonol 18:284–289, 1994.

25. Abman SH, Wolfe RR, Accurso FJ, et al. Pulmonary vascularresponse to oxygen in infants with severe BPD. Pediatrics75:80–84, 1985.

26. Rush MG, Hazinski TA. Current therapy of bronchopul-monary dysplasia. Clin Perinatol 19:563–590, 1992.

27. Bancalari E. Corticosteroids and neonatal chronic lungdisease. Eur J Pediatr 157 (Suppl 1):S31–S37, 1998.

28. Watterberg KL, Murphy S. Failure of cromolyn sodium toreduce the incidence of bronchopulmonary dysplasia: apilot study. The Neonatal Cromolyn Study Group. Pediatrics91:803–806, 1993.

29. Viscardi RM, Hasday JD, Gumpper KF, et al. Cromolynsodium prophylaxis inhibits pulmonary proinflammatorycytokines in infants at high risk for bronchopulmonarydysplasia. Am J Respir Crit Care Med 156:1523–1529, 1997.

30. Fernandez-Nievas F, Chernick V. Bronchopulmonary dys-plasia: an update for the pediatrician. Clin Pediatr41:77–85, 2002.

31. Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytialvirus in early life and risk of wheeze and allergy by age 13 years. Lancet 354:541–545, 1999.

32. Gross S, Ianuzzi D, Kveselis D, et al. Effect of preterm birthon pulmonary function at school age: a prospective con-trolled study. J Pediatr 133:188–192, 1998.

33. Jobe A, Ikegami M. Prevention of bronchopulmonary dys-plasia. Curr Opin Pediatr 13:124–129, 2001.

34. Van Marter LJ, Allred EN, Pagano M, et al. Do clinical markersof barotrauma and oxygen toxicity explain interhospitalvariation in rates of chronic lung disease? Pediatrics105:1194–1201, 2000.

76

CHAPTER

5 Sleep-DisorderedBreathing in ChildrenRAANAN ARENS, M.D.

Obstructive Sleep Apnea Syndrome

Terminology

Epidemiology

Clinical Features

Nocturnal Symptoms

Daytime Symptoms


Physiologic Consequences of OSAS

Hypoxemia

Hypercarbia

Sleep and Sleep States

Movements/Arousals

High-risk Groups for Developing OSAS

Obesity

Down Syndrome

Post-adenotonsillectomy

Complications

Neurobehavioral and Neurocognitive Manifestations

Cardiovascular Complications

Growth Impairment

Evaluation

Polysomnography

Screening Studies

Treatment

Outcome

Sleep-Disordered Breathing in Premature Infants and

Infants

Apnea of Prematurity

Apnea of Infancy

Central Hypoventilation and Sleep

Congenital Central Hypoventilation Syndrome

Obstructive and Restrictive Lung Diseases and Sleep

Obstructive Lung Diseases

Bronchopulmonary Dysplasia

Asthma

Cystic Fibrosis

Restrictive Lung Diseases

Chest Wall Deformities

Ventilatory Muscle Weakness

Treatment

Supportive Therapy

Supplemental Oxygen During Sleep

Non-invasive Positive-Pressure Ventilation

Summary

Sleep may bring deleterious effects to children withunderlying respiratory abnormalities. The term “sleep-disordered” breathing refers to a group of respiratorydisorders that are exacerbated during sleep. Importantphysiologic changes occur during sleep compared towakefulness including reduced upper airway dilatormuscle activity, reduced functional residual capacity(FRC), reduced chemoreceptor sensitivity, and alteredarousal threshold during sleep stages. These changes canaffect upper airway stability, ventilatory drive, and chestwall mechanics, and lead to immediate significant abnor-malities in gas exchange and sleep architecture as wellas to long-term consequences on the cardiovascular sys-tem and cognitive function.

The most prominent sleep-related breathing disorder inchildren is obstructive sleep apnea syndrome (OSAS),which affects up to 2% of normal children1,2. Other respi-ratory disorders exacerbated by sleep include: centralapnea, hypoventilation, obstructive lung diseases, andrestrictive lung diseases. This chapter will discuss the diag-nosis and management and the clinical implications ofthese disorders in children with special emphasis on OSAS.

OBSTRUCTIVE SLEEP APNEA SYNDROME

Obstructive sleep apnea syndrome (OSAS) in children isdefined as a breathing disorder characterized by recurrentevents of partial or complete upper airway obstruction

during sleep that result in disruption of normal ventila-tion and sleep patterns3. OSAS is most frequently diag-nosed in normal children between ages 2 and 6 yearswith adenotonsillar hypertrophy and is sometimesreferred to as primary OSAS. “Secondary OSAS” refers toother medical conditions associated with and causingOSAS. Children with secondary OSAS often have cranio-facial anomalies and or neurologic disorders affectingupper airway shape, configuration, and collapsibilityduring sleep. OSAS in this group may present at any timefrom early infancy throughout childhood.

OSAS has a range of clinical presentations and may bemanifested in mild through severe forms. Knowledgeand recognition of childhood OSAS has a tremendousimpact on child health care since, if untreated, OSAS mayhave profound neurobehavioral and cardiopulmonaryconsequences affecting a child’s health and lifestyle.

OSAS is not a new disorder. Children with adenoton-sillar hypertrophy associated with loud snoring, breath-ing pauses, and awakenings from sleep were noted in thenineteenth century by W. Hill and W. Osler. However, notuntil the mid-1960s with the development of polysomnog-raphy recording was there an understanding of the rela-tionship between obstructive events during sleep anddaytime symptoms in adults. About the same time severalreports recognized the association between adenotonsillarhypertrophy and cor pulmonale in children. However, thefirst detailed description of 8 children (age 5–14 years)with adenotonsillar hypertrophy and OSAS who werediagnosed by means of nocturnal polysomnography was

published by Guilleminault et al. only in 19764. Sincethat report and with the increasing awareness aboutOSAS among physicians, numerous studies have beenpublished, clearly distinguishing OSAS in children fromOSAS in adults with respect to etiology and clinical man-ifestations (Table 5-1).

Terminology

Obstructive apnea: Absence of oronasal air flow in thepresence of continued respiratory effort lastinglonger than 2 respiratory cycle times. Obstructiveapnea usually but not always is associated withhypoxemia (Figure 5-1).

Hypopnea: A 50% or greater decrease in the amplitudeof the oronasal airflow signal often accompanied byhypoxemia or arousal. Some investigators haveattempted to subtype hypopnea into obstructive andnon-obstructive forms. Obstructive hypopnea isdefined as a reduction in airflow without reductionin effort. On the other hand, non-obstructivehypopnea is associated with a reduction in bothairflow and respiratory effort by 50% (Figure 5-2).

Central apnea: Cessation of oronasal airflow andrespiratory effort lasting for longer than 2 respiratorycycle times. American Thoracic Society consensussuggests central apnea lasting longer than 20seconds in children is abnormal (Figure 5-3).

Obstructive hypoventilation: Partial airway obstructionleading to a peak end-tidal CO2 (PETCO2) >55 mmHg

Sleep-Disordered Breathing in Children 77

Table 5-1 Comparison of OSAS in Children and Adults

Children Adults

Population characteristicsEstimated prevalence 2% 1–3%Common age at presentation 2–6 years 30–60 yearsGender Male~Female Male > FemaleWeight Normal, decreased, increased OverweightMajor cause Adenotonsillar hypertrophy Obesity, narrow pharyngeal airwayAssociated disorders Craniofacial anomalies, neurologic disorders Obesity, hypertension, postmenopausePolysomnography findingsGas exchange abnormalities Always AlwaysDuration of obstructive apneas Any duration is abnormal Events >10 seconds are abnormalAbnormal AI >1 >5Abnormal AHI >5 >20Sleep architecture Often normal Always alteredMovement/arousal Occasional AlwaysComplicationsNeurobehavioral Excessive daytime sleepiness (EDS), hyperactivity Severe EDS, cognitive impairment

Poor school performanceCardiopulmonary Pulmonary hypertension, cor pulmonale Systemic hypertension, arrythmiasTreatment of choice Adenotonsillectomy CPAP, weight reduction

96%

EEG C4-A1

EEG O1-A2

Chin EMG

FLOW

Effort chest

Effort abdomen

Effort sum

PETCO2SpO2

EOG leftEOG right

91%

19 sec

Figure 5-1 A 30 second polysomnography tracing showing an obstructive apnea lasting 19 sec-onds ending with arterial oxygen desaturation to 91% (arrow). Paradoxical effort continues despitea cessation of flow seen on the oronasal flow and PETCO2 channels.

96%

EEG C4-A1

EEG O1-A2

Chin EMG

EKG

FLOW

Effort chest

Effortabdomen

PETCO2SpO2

EOG left

EOG right

91%

Decreased flow from baseline

Figure 5-2 A 30 second polysomnography tracing showing an hypopnea followed by arterialoxygen desaturation. Note a 50% reduction in the oronasal flow (arrows) as well as paradoxicalbreathing and a significant reduction in the chest and abdomen effort channels (arrows).

or PETCO2 > 45 mmHg for more than 60% of totalsleep time (TST), or PETCO2 > 55 mmHg for morethan 10% of TST (in the absence of lung disease).

Non-obstructive hypoventilation: Decreased minuteventilation associated with an increased PETCO2 dueto either a reduction in respiratory drive (central),chemoreceptor function, muscle weakness(neuromuscular), or decreased minute ventilationsecondary to a reduction in chest wall movement(restrictive).

Apnea index (AI): Number of obstructive and/orcentral apneic events per hour of sleep.

Hypopnea index (HI): Number of hypopneas per hourof sleep.

Apnea/hypopnea index (AHI): The summation ofapnea index and hypopnea index.

Primary snoring: Also known as habitual snoring,primary snoring is characterized by snoring duringsleep without apnea, hypoventilation, hypoxemia, orexcessive arousals.

Upper airway resistance syndrome: A respiratorydisorder of sleep associated with snoring causingexcessive daytime sleepiness due to arousals andsleep fragmentation5.

Epidemiology

There are no large-scale studies in children assessingthe prevalence of OSAS. In pre-school children the inci-dence of OSAS is estimated to be 2%1,2, whereas primary

snoring is more common and is estimated to occur in6–9% of school-aged children6. OSAS occurs in childrenof all ages, including neonates. Underlying conditionssuch as craniofacial anomalies affecting the structure ofthe upper airway as seen in Pierre–Robin syndrome maymanifest symptoms of obstruction early in the neonatalperiod, while later onset of symptoms may be found inobese children and therefore present in older age.However, the peak incidence of OSAS occurs between 2and 6 years of age and parallels the prominent growth ofthe nasopharyngeal lymphoid tissue during these years.Recent data suggest that OSAS may be more common inchildren with a family history of OSAS, in African-American children, and in children with chronic upperand lower respiratory diseases2,7. It is not certain if gen-der predisposes to OSAS during childhood.

Clinical Features

Although most cases of OSAS in children are second-ary to enlarged tonsils and adenoids, many other medicalconditions may lead to OSAS. Some of the more com-mon reported conditions associated with OSAS duringchildhood are listed in Table 5-2. Clinical features ofOSAS in children can be divided into nocturnal and day-time signs and symptoms (Table 5-3).

The main physiologic disturbance involves repetitiveobstructive apneas and hypopneas (partial obstructions)leading to hypoxemia, hypercapnia, acidosis, and sleepfragmentation. The short- and long-term neurologic,


EEG C4-A1

EEG O1-A2

EOG left

EOG right

Chin EMG

FLOW

Effort chest

Effort abdomen

Effort sum

PETCO2SpO2

RESP: A central event after an arousal

Figure 5-3 A 30 second polysomnography tracing showing a central apnea, following a sigh.Note the absence of oronasal flow and effort.

cardiovascular, and systemic complications found inchildren with OSAS are dependent on the severity andduration of these physiologic aberrations.

Nocturnal SymptomsBreathing During SleepSnoring and difficulty breathing during sleep are the

most common complaints of parents of children withOSAS, with reports of such symptoms in more than 96%of cases8,9. With the exception of young infants, childrenwith OSAS often snore loudly and continuously. In theolder child, snoring is often a low-frequency sound pro-duced by the vibration of the soft palate and tonsillar pil-lars. However, in a young child (<4 years), the snoringsound may have a high-pitched quality if oversized ade-noids and tonsils impede movement of the soft palate.Some children do not snore but have other forms ofnoisy breathing such as grunting, snorting, or gasping.

Furthermore, infants may not produce sufficient flow toproduce an easily audible snoring noise. Parents oftendescribe episodes of retractions with increased respira-tory effort. At times, absence of respiratory noise despitecontinued vigorous breathing may be noted. Theseepisodes may be terminated by gasping, movement, orfrequent awakenings. The abnormal breathing patternduring sleep may be frightening to parents, resulting inincreased vigilance on the part of the family and the per-ceived need to intervene in order to improve breathing.

When possible, observation of the child during sleep isrecommended. Snoring and labored breathing should benoted. This is manifest by visible supraclavicular, supraster-nal, and subcostal retractions. Paradoxical rib cage move-ment has been described as a marker of increased work ofbreathing. In the presence of a complete or partial upperairway obstruction, inspiratory downward motion of thediaphragm will expand the abdominal wall; however, thesudden increase in negative intrathoracic pressure willcause a paradoxical inward movement of the highly com-pliant rib cage of the young child.

Children with OSAS are found to have both completeand partial upper airway obstruction causing significant


Table 5-2 Medical Conditions Associated withOSAS in Children

Craniofacial syndromesMidfacial hypoplasia

Apert syndromeCrouzon syndromePfeiffer syndromeTreacher–Collins syndrome

Macroglossia/glossoptosisDown syndromeBeckwith–Wiedemann syndromePierre–Robin sequence

OtherAchondroplasiaHallerman–Streiff syndromeKlippel–Feil syndromeGoldenhaar syndromeMarfan syndrome

Neurologic disordersCerebral palsyMyasthenia gravisMoebius syndromeArnold–Chiari malformationMiscellaneous disordersObesityPrader–Willi syndromeHypothyroidismMucopolysaccharidosisSickle cell diseaseChoanal stenosisLaryngomalaciaAirway papillomatosisSubglottic stenosisFace and neck burnsPostoperativelyPost-adenotonsillectomy in children with secondary OSAS

and those younger than 2 yearsPost-pharyngeal flapPost-cleft lip repair

Table 5-3 Frequency of Signs and Symptoms in 23 Children with Obstructive Sleep ApneaSyndrome and in 46 Matched Controls

OSAS ControlSign/Symptom Group (%) Group (%) P Value

Difficulty breathing 96 2 0.001when asleep

Snoring 96 9 0.001Mouth-breathes 87 18 0.001

when awakeFrequent upper 83 28 0.001

respiratory tract infections

Stops breathing 78 5 0.001when asleep

Restless sleep 78 23 0.001Chronic rhinorrhea 61 11 0.001Sweating when 50 16 0.007

sleepingRecurrent middle 43 17 0.019

ear diseasesExcessive daytime 33 9 0.014

somnolencePoor appetite 30 9 0.019Frequent nausea/ 30 2 0.001

vomitingDifficulty swallowing 26 2 0.002Pathologic shyness/ 22 5 0.027

social withdrawalHearing problems 13 0 0.014

Modified from Brouillette et al.9

gas exchange abnormalities. Marcus et al.10 studied 50healthy children 1 to 17 years of age and found thatobstructive apneas were rare and were never longerthan 10 seconds, suggesting that obstructive sleep apneaof any length is abnormal in children. Partial obstructionevidenced by snoring appears to dominate the respira-tory pattern in children with OSAS11. Partial obstructionoccurs continuously or it can be interrupted by periodsof silence associated with vigorous respiratory effort(obstructive apnea). Variations in esophageal pressuresas low as −50 and −70 cm H2O accompanied by signifi-cant abrupt changes in oxygenation have been reported.Although partial obstruction may not result in hypox-emia or hypercarbia in some children, Brouillette et al.12

showed that prolonged partial airway obstruction isoften associated with more severe hypoxemia andhypercarbia than short events of obstructive apnea.Similar findings were noted by Rosen et al.12, who alsoreported the more frequent occurrences of partialobstruction compared with complete obstructive eventsin 36 children with OSAS.

Children with OSAS may have other abnormal breath-ing patterns in addition to obstructive apnea and evi-dence of partial obstruction during sleep. Central andmixed apneas (a central apnea followed by an obstruc-tive apnea) can coexist in these children and mayaccount for 17–34% of the total number of apneas, espe-cially in infants and in children with OSAS secondary tocraniofacial and neuromuscular syndromes.

In addition, a large number of children may presentwith increased work of breathing and multiple arousalsand sleep fragmentation, unassociated with gasexchange abnormalities. This condition is referred to asthe upper airway resistance syndrome (UARS)5,13. InUARS, subjects are noted to have multiple short arousalsleading to alteration in sleep architecture and impairedneurocognitive function5,14.

Sleep PatternsRestless sleep is also commonly reported in children

with OSAS. Children appear to be very fidgety during thenight, frequently changing sleep positions to those thatpromote airway patency, such as prone or sidewayspositions, and hyperextension of the neck15. Obese chil-dren with significant OSAS may prefer sleeping while sit-ting upright or at least propped upon pillows.

Nocturnal SweatingIn a study of 50 children with OSAS, nocturnal pro-

fuse sweating was noted in 96% of the children8. In acontrolled study of 23 children with OSAS and 46 con-trols16, 50% of those with OSAS had excessive sweatingcompared with 16% of the controls (P < 0.007). Nightsweating may be associated with the increased effortrequired to inspire against resistance over the course ofthe night. Increased calorie expenditure during sleephas also been demonstrated in children with OSAS17.

Nocturnal EnuresisNocturnal enuresis is a variable finding in children

with OSAS. Frank et al.18 reported that 33% of childrenolder than 4 years with OSAS had bed-wetting andWeider et al.19 reported a 76% improvement in noctur-nal enuresis after tonsillectomy and adenoidectomy.Guilleminault et al.4 reported that 6 of 8 children withsevere OSAS age 5–14 years had enuresis. In a secondstudy on 50 children, 18% presented with secondaryenuresis8. However, in perhaps the best controlledstudy, comparing 23 children with OSAS with 46matched controls, Brouillette et al.9 could not find a sig-nificant difference between the groups with respect tobed-wetting.

Polyuria has been reported in adults with OSAS.Adults with OSAS may make multiple trips to the bath-room during the night. In a recent study, 6 adults withpolyuria and severe OSAS were found to have anincreased level of atrial natriuretic peptide and cate-cholamines in the plasma. After initiation of continuouspositive airway pressure (CPAP) treatment and resolu-tion of apnea, these levels were significantly reducedand a 50% drop in nocturnal urine volume was noted20.It is not known if this mechanism applies to childrenwith OSAS.

Daytime SymptomsAlthough respiration in children with OSAS is typi-

cally unremarkable during wakefulness, some childrenwith severe OSAS may also experience difficulty breath-ing when awake, albeit this is less severe than whenasleep. These symptoms are most likely related to ade-noid and tonsillar hypertrophy. The most common com-plaints reported by parents of children with OSAS aremouth breathing, frequent upper respiratory tract infec-tions, recurrent ear infections, as well as hearing andspeech problems. Enlarged tonsils may cause difficultyswallowing. In addition, nausea and vomiting are com-monly reported in children with OSAS and tonsillarhypertrophy.

In contrast to reports in adults, excessive daytimesomnolence (EDS) is thought to be uncommon in chil-dren with OSAS. However, there has been considerablevariability in the reported frequency of this complicationin children. In uncontrolled studies, parents and teachersof school-aged children have observed EDS in between33% and 84% of children with OSAS8,14. However, in con-trolled studies the reported frequency of this complaintis considerably lower compared with that in adults withOSAS9.

School-aged children may complain of sleepiness,tiredness, and fatigue, but this may be difficult to distin-guish from the usual school-week behavior of averageadolescents. Abnormal daytime behavior includinghyperactivity and aggression has been reported in 31%to 42% of children with OSAS8,9,12, whereas pathologic


shyness and social withdrawal were reported in 22%9.Children with underlying genetic disorders, such asthose with trisomy 21 or inherited craniofacial malfor-mations, may have an additional impairment in intellec-tual performance above and beyond that imposed by the underlying syndrome8. Morning headaches werereported in 5 of the 8 patients originally described withOSAS by Guilleminault et al.4. In a second report on 50children with OSAS Guilleminault et al.8 found that 16%of the children had the same complaint. A typical featureof these headaches was that they tended to dissipatecompletely by late morning. It was hypothesized that thesignificant swings in intrathoracic pressure duringobstructive events could have altered cerebral blood flowand increased intracranial pressures. Moreover, increasedintracranial pressure during episodes of obstructiveapneas was reported by Pasterkamp et al.21, whodescribed a 16-year-old girl with OSAS, myelomeningo-cele, and Arnold–Chiari malformation. After tonsillec-tomy these elevations in intracranial pressuresdisappeared. Hypoxemia and hypercarbia duringobstructive episodes were considered the mechanismsfor pressure changes in this case.


The physical examination of the child with OSAS isvariable. In most cases children have only mildly to mod-erately enlarged tonsils and adenoids and do not neces-sarily demonstrate breathing difficulties during theexamination. Moreover, at times a significant amount oflymphoid tissue cannot be appreciated directly by theexaminer. Therefore, a normal physical examinationshould not exclude OSAS. Physical examination shouldinclude an assessment of the child’s growth pattern.Children with OSAS are frequently reported to havedelayed growth and weight gain17. Obesity, on the otherhand, may increase the risk for OSAS in others22.

The physical examination begins with a generalobservation of the patient. Mouth breathing and ade-noidal facies should be noted. Hyponasal voice is a clueto nasal obstruction and a muffled voice is suggestive oftonsillar enlargement. The lateral facial profile should beinspected for retrognathia, micrognathia, or midfacialhypoplasia. All can affect the nasopharyngeal andoropharyngeal passages and are key findings for diagno-sis. The nose is assessed for septal deviation, mucosalthickening, polyps, and patency of either vestibule withthe opposite naris occluded. The oral cavity should beobserved for tongue and soft palate size and appearance;a large tongue and/or a high-arched or elongated palatemay predispose to sleep-disordered breathing. Integrityof the hard palate should be evaluated. A bifid uvula maybe associated with submucosal cleft palate.

The size of the tonsils should be assessed. A scale from0 to a maximum of +4 when the tonsils meet the midlineis commonly used23. Some simply describe the tonsils’appearance as minimally visible, visible to the pillars, vis-ible beyond the pillars, or visible to the uvula. The nasalpassages as well as the oral cavity of children with cran-iofacial anomalies who have previously undergonerepair of these defects should be evaluated carefully inthe same manner, since these children may be at risk forrecurrent OSAS24,25.

The chest usually has a normal configuration althoughpectus excavatum has been reported in some cases. Thelungs are usually clear on auscultation. The cardiacexamination is usually normal; however, in advancedcases evidence of pulmonary hypertension manifested bya loud second pulmonary heart sound may be present.Systemic hypertension and clubbing have been reportedbut are uncommon. In children with possible secondaryOSAS and in young infants, a neurologic examination isrequired to exclude any neurologic impairment affectingmuscle tone that may contribute to OSAS.

When possible, observation of the child during sleepis recommended. Snoring and labored breathing shouldbe noted. Suprasternal retractions and paradoxical ribcage motion are commonly seen when more severehypopneas and obstructive apneas are present. Whencomplete obstructions are present, respiratory effort willnot be accompanied by breath sounds; however, termi-nation of these events may be associated with a gasp,movement, or an awakening.

Physiologic Consequences of OSAS

HypoxemiaHypoxemia, defined as arterial oxyhemoglobin satu-

ration (SpO2) below 92% or 90% is rare in normal infantsand children. Marcus et al.10 performed polysomnogra-phy on 50 healthy children aged between 1 and 17years. They found the mean SpO2 nadir to be 96 ± 2%,with a single child having a short desaturation to 89%during a central apnea event. Desaturations >4% frombaseline value during sleep were found more frequentlywith a mean rate of 0.3 ± 0.7/h. The maximal oxygendesaturation from peak to nadir value in these childrenwas 4 ± 2%.

Hypoxemia and repetitive significant oxygen desatu-ration are frequent in most children with OSAS. Stradlinget al.15 found that of 61 children referred for adenoton-sillectomy, 61% were noted to be hypoxemic duringsleep prior to surgery. Rosen et al.11 found significantoxygen desaturations to <85% in 19 of 20 childrenreferred for evaluation of OSAS with a relatively lowapnea index of 1.9 ± 3.2, suggesting that significant andsevere upper airway obstruction in children may not be


identified according to the apnea index alone or basedon the index as defined in adults. The same authorsshowed that hypopneas were mostly responsible for gasexchange abnormalities in this group as reported previ-ously by Brouillette et al.12.

It is not known how the degree and duration ofhypoxemia relate to the outcome of children with OSASwith respect to their neurologic or cardiopulmonary sta-tus, and what type of events have a reversible versus apermanent effect on these systems. Hypoxemia leadingto asphyxia and permanent neurologic disabilities hasbeen reported in children with OSAS12. Moreover,infants with apparent life-threatening events (ALTEs)have been reported to have OSAS at the time or soonafter these events26, suggesting an etiology for ALTE orsudden infant death in some infants.

HypercarbiaObstructive apnea and hypopnea are usually associ-

ated with hypoventilation and can be easily detected byan increase in end-tidal CO2 (PETCO2) by capnography inchildren with OSAS. In healthy children, PETCO2 is con-sidered a reliable estimate of arterial pCO2 and thus ofalveolar ventilation. In the past, values of PETCO2 > 45torr during sleep have been conventionally consideredabnormal. More recently, normal sleeping values forPETCO2 have been suggested for the pediatric age group.Based on data in 50 healthy infants and adolescents,hypoventilation may be described when: peak PETCO2> 53 torr, or PETCO2 > 50 torr more than 8% of sleeptime, or when duration of hypoventilation (PETCO2 > 45torr) exceeds more than 60% of total sleep time10.

In earlier reports, daytime hypercarbia in childrenwith OSAS was usually associated with cor pulmonaleand cardiorespiratory failure. However, these reports donot reflect current experience since cor pulmonale isnot a common complication today and daytime hyper-carbia is not frequently seen. However, hypercarbiaduring sleep in children with OSAS is at least as commonas hypoxemia, although the proportion of childrenwith nighttime hypercarbia and the degree of hyper-carbia is unknown. Brouillette et al.12, found hypercarbia(>45 torr) during sleep in 12 of 22 children with OSAS.Rosen et al.11 found hypercarbia (>50 torr), in 26 of36 (72%) children who were referred for evaluationof OSAS.

There are several groups who are at high risk for devel-oping hypercarbia and hypoventilation. Hypoventilationis the most common polysomnographic abnormalityin children with Down syndrome and OSAS, and wasreported in 81% of 16 children studied by Marcus et al.27.Obese children with OSAS were also found to develophypoventilation during sleep. Silvestri et al.28, who studied32 obese children, found hypercarbia in 75% of thechildren. Those who were morbidly obese with an ideal

body weight above 200% were at greatest risk for thedevelopment of this abnormality.

Sleep and Sleep StatesEffects of OSAS on sleep in children are poorly under-

stood. In adults, OSAS is known to cause sleep fragmen-tation and alterations in sleep architecture due tomultiple arousals. As a result, adults with OSAS have lessrapid eye movement (REM) sleep and slow wave sleep,and spend more time in light sleep of stages 1 and 216.These alterations in sleep architecture are responsiblefor the main side effect of OSAS in adults, which is EDS,reported in more than 90%29.

In children, however, few data exist to support thesefindings. Several studies have found that children withOSAS have normal amounts of slow wave sleep18,19,30,and absence of sleep fragmentation was reported inchildren with hypopneas and OSAS14. In contrast, sig-nificant alterations in sleep architecture were reportedby Guilleminault et al.4 in all 8 patients presentingwith severe OSAS. In these children, normal progressionto stages 3–4 non-REM sleep was delayed or pre-empteddue to the repetitive apneic events. In a second reporton 50 children with primary and secondary OSAS,Guilleminault et al.8 noted complete disappearance ofstage 3 non-REM sleep in 86% of children, a 22% reduc-tion in REM sleep and an increase in percent of stage 1non-REM sleep compared with controls. Moreover,movement time during sleep was higher in those withOSAS than in controls by as much as 100–250%8.

Movements/ArousalsMovement is a normal phenomenon during sleep.

However, increased motor activity is frequently reportedin subjects with OSAS. Movement may range from simpleleg jerks to gross movement of extremities and trunk.Movements are usually associated with arousals or withawakenings from sleep. In adults, movement/arousalswere found to correlate strongly with the apnea/hypopneaindex, and were normalized with the use of CPAP16.

Mograss et al.30 described three types of movement/arousals in children with OSAS in a sleep laboratory set-ting. They studied 15 children aged 2–11 years with amean respiratory disturbance index (RDI) of 7.5 ± 8.2,and classified movement/arousals as: spontaneous, res-piratory, and technician-induced. Of the total movement/arousals studied, spontaneous arousals were the mostcommon and accounted for 51%. Respiratory arousalswere found in 29.5% and technician-induced arousal in19.5%. Nearly all obstructive events were terminated bya movement/arousal and had the effect of re-establishingairway patency in these children. In addition, the respi-ratory movement/arousal index was directly related tothe RDI. However, these authors found that sleep stageswere not altered and were similar to those reported inage-matched children. They have speculated that since


movement/arousals were usually short (<3 seconds),children may experience fragmented sleep withoutaltering various sleep stages.

In a more recent study, McNamara et al.31 reported thata minority of the respiratory events in infants and childrenwith OSAS were terminated by an arousal, while theremaining events resolved spontaneously. Fifteen chil-dren (1–14 years), aroused to less than 40% of obstructiveevents and 20 infants (term to 21 weeks) aroused to only8% of the obstructive events. Therefore, these authorsconcluded that arousals are not an important mechanismof termination of obstructive events during sleep in chil-dren and are even less important in infants.

HIGH-RISK GROUPS FORDEVELOPING OSAS

As mentioned above OSAS is associated with manypediatric conditions aside from adenotonsillar hypertro-phy. These conditions mainly fall into the categories ofcraniofacial and neurologic disorders affecting upper air-way anatomy and patency during sleep (Table 5-2). Inaddition, other conditions may be associated with highrisk for OSAS and are discussed below.

ObesityObesity is a major risk factor in adults for developing

OSAS, and an increased neck collar size is strongly asso-ciated with OSAS in this group7. In contrast, the major-ity of children with OSAS are not obese, many havenormal weight, and failure to thrive is a common com-plication. However, there is evidence that obesity is arisk factor for the existence of OSAS in children.Guilleminault et al.8 reported that 10% of the 50 childrenwho were diagnosed with OSAS were obese, and a simi-lar finding was reported by Brouillette et al.12 who stud-ied 22 infants and children. A higher incidence of OSASwas reported when obese children were referred forevaluation of OSAS. Silvestri et al.28 found partial airwayobstruction in 66% and complete airway obstruction in59% of 32 obese children.

The above studies, however, were all performed onchildren who were referred for possible OSAS and there-fore the prevalence of sleep-disordered breathing mayhave been overestimated in this group. To evaluate moreprecisely the prevalence of OSAS in the general obesepopulation, Marcus et al.22 studied 22 obese childrenand adolescents age 10 ± 5 years with an ideal bodyweight of 184 ± 36% and with no history of sleep-disor-dered breathing. They found that 10 children (46%) hadabnormal polysomnography and in 6 children (27%)abnormalities were moderate to severe. Moreover, a pos-itive correlation between obesity and apnea index wasfound (r = 0.47, P < 0.05) as was an inverse relation

between obesity and oxygen saturation nadir (r = − 0.5,P < 0.01). Asymptomatic obese infants also have a higherincidence of obstructive apnea events compared withcontrols32, suggesting that OSAS is common in obesechildren of all ages.

Adenotonsillar hypertrophy is not always the causefor the development of OSAS in obese children22,28.Several other reasons may contribute to OSAS in thisgroup. Upper airway narrowing may result from deposi-tion of adipose tissue within the muscles and tissues sur-rounding the airway and increase pharyngeal resistance33.Moreover, obese subjects were shown to have decreasedchest wall compliance and displacement of the diaphragmwhile in the supine position. These physiologic alter-ations can result in decreased lung volumes and oxygenreserves during sleep and increase the risk for OSAS inthis group.

Down SyndromeDown syndrome (trisomy 21) is the most common

genetic cause of developmental disability and mentalretardation with an incidence of 1/660 live births.Obstructive sleep apnea is common in this group and isnoted in 30–60% of subjects27,34,35. Anatomic factorsrelated to the Down syndrome phenotype have beenattributed to the causation of OSAS in this group. Theseinclude midfacial and mandibular hypoplasia, enlargedtongue, adenoid and tonsillar hypertrophy, laryngotra-cheal anomalies, and obesity36. Reduced neuromusculartone has also been suspected of having a role in thedevelopment of OSAS in these subjects.

Post-adenotonsillectomyPostoperative respiratory compromise has been

reported to occur in 16–27% of children with OSAS.Particularly high-risk children include those youngerthan 3 years of age, those with severe OSAS, and thosewith additional complex medical conditions24,25. A post-operative polysomnogram 2–3 months following surgeryis recommended for patients with additional risk factorsfor OSAS, or those with a high apnea index, to ensurethat additional treatment is not required.

Complications

The cumulative effects of OSAS have adverse sequelaeon neurologic and cardiac function, and on growth.Complications may be mild and reversible or becomesevere and progressive in untreated children. The variouscomplications of childhood OSAS are the result of chronicnocturnal hypoxemia, acidosis, and sleep fragmentation.

Neurobehavioral and NeurocognitiveManifestationsNocturnal hypoxemia and sleep fragmentation are

considered the main causes for the neurobehavioral


sequelae of OSAS. In adults, EDS, decreased ability toperform everyday tasks, impairment in memory andattention, and reduction in general intellectual abilitieshave been reported16,29,37,38. Sleep fragmentation maylead to personality changes that are often first recog-nized by family members. These include irritability, anx-iety, aggression, and depression.

Excessive daytime sleepiness is less common in chil-dren with OSAS. However, there are some discrepanciesin the prevalence of EDS reported in children withOSAS. Guilleminault et al.8 reported EDS in 84% of50 children with OSAS, and in 70% of those cases symp-toms were noted by school teachers. However,Brouillette et al.9, in a controlled study, reported EDS in33% of 23 children, and Frank et al.18 reported EDS as asignificant problem in only 9% of the 32 children theystudied. Carroll et al.39 reported a similarly low rate ofEDS in a pediatric population. It is conceivable that feweror shorter arousals and a more preserved sleep architec-ture seen in children with OSAS compared with adultswith OSAS results in less daytime sleepiness18,30. It is alsopossible that since EDS is a subjective complaint, it isunderdiagnosed in young children who may take daytimenaps routinely. The multiple sleep latency test (MSLT), inwhich patients are studied during four or five 20-minutenaps after overnight polysomnography to determinehow quickly a patient falls asleep, affords an objectivemeasurement of sleepiness. Although widely used inadults, its applicability in children with OSAS has notbeen established; such studies could be useful to objec-tively assess prevalence and degree of EDS in childrenwith OSAS.

Brouillette et al.12 reported significant neurologicimpairment related to OSAS in 7 of 22 children with OSAS.In 5 children dysfunction was reversible with treatmentand included EDS, behavioral disturbances, and milddevelopmental delay. However, 2 children, of whomone had a metabolic disorder, presented with permanentneurologic dysfunction related to asphyxia occurring dur-ing obstructive events. Delays in referral and diagnosiswere noted in most of these children and were consideredthe cause for some of the above sequelae. In a secondstudy9, 33% of children with OSAS had EDS and pathologicshyness/social withdrawal was noted in 22%, rates whichwere significantly more common than in controls. Otherparental reports such as delays in development, morningheadaches, hyperactivity, and bizarre behavior were notobserved more frequently in these patients.

In another study Guilleminault et al.8 reported abnor-mal behavior in 42% of children in elementary school,kindergarten, and in day care centers. The most com-mon behavioral abnormality described was hyperactiv-ity; however, asocial behavior and disciplinary problemswere also noted. A small group of patients were reported

to have personality changes and bizarre withdrawnbehavior suggestive in 2 children of psychosis.

Learning difficulties such as delayed language develop-ment and inadequate school performance are commonlyreported, although only one report on neurocognitivefunction in children with OSAS has been published.Rhodes et al.40 studied 14 obese patients of whom 5 hadsevere OSAS. The OSAS children demonstrated signifi-cantly lower scores for learning, memory, and vocabu-lary tests. Moreover, severity of OSAS measured by anapnea/hypopnea index, was found to be significantlyand inversely correlated with the neurocognitive impair-ment. Recently, Gozal41 reported on the effects of ade-noid and tonsillar hyperplasia and sleep-disorderedbreathing on school performance. His study demon-strated that correction of these abnormalities resulted inimproved school performance among first- and second-grade students. These findings, although preliminary,may explain reports of lower school performance anddevelopmental delay in children with OSAS. However, itis still unknown whether the neurocognitive deficitsresult from chronic hypoxemia or sleep fragmentationand whether these deficits accumulate with time or arereversible. The extent to which recovery of functions ispossible may depend on the age of onset of OSAS, severity,and chronicity of the disorder. More studies of this typeare clearly required to define better the effect of OSASon neurobehavioral/cognitive function.

Cardiovascular ComplicationsIn adults with OSAS significant cardiovascular com-

plications contribute to morbidity and mortality. Thesecomplications are associated with acute and/or chroniceffects of hypoxemia, acidosis, and the hemodynamiceffect of obstructive apnea on the cardiovascular system.Acute cyclic changes in heart rate, blood pressure,intrathoracic pressures, and oxygen saturations mayinduce cardiac arrhythmia and various degrees of atri-oventricular blocks. Recent evidence suggests thatadults with OSAS are at an increased risk for ischemicheart disease and cerebral infarction42.

In contrast to adults with OSAS, systemic hypertensionis reported only anecdotally in children. However, pul-monary hypertension is the main cardiovascular complica-tion described in children with long-standing OSAS12,43,44.

In 1988 Tal et al.44 performed cardiac evaluations in27 children with OSAS between 9 months and 7.5 yearsof age. A radionuclide heart scan demonstrated a signifi-cant reduction in right ventricular ejection fraction in 10(37%) of the children and normalization of heart func-tion after adenotonsillectomy. A more recent study of 28children with OSAS has demonstrated hypertrophyinvolving both the right and the left ventricles and thatthe degree of left ventricular hypertrophy is related to


the degree of severity of OSAS45. In addition, cardiacarrythmias during obstructive events have been reportedby some investigators8,46,47.

Children with severe OSAS (SpO2 < 70%, apneaindex > 10/hour) should undergo cardiac evaluation priorto adenotonsillectomy. Preoperative and postoperativedeaths have been observed in this group. Therefore, acareful cardiac evaluation including physical examina-tion, electrocardiogram, chest radiograph, and echocar-diogram should be performed to evaluate for any signs ofcongestive heart failure or perioperative risks. If thesesigns or abnormal laboratory findings are present, admis-sion to an intensive care unit for preoperative stabiliza-tion is indicated.

Growth ImpairmentGrowth impairment is one of the unique features of

childhood OSAS. Early reports of children with severeOSAS almost always associated the two, especially whenanother complication such as cor pulmonale was present.Later reports in the 1980s found failure to thrive in 27–56%of the children with OSAS, while obesity in the samepopulation was reported in about 10% of children8,12.

Adenotonsillectomy in children with OSAS has a sig-nificant impact on growth. Brouillette et al.12 found thatrelief of airway obstruction resulted in catch-up growthin all 6 children studied with failure to thrive. Moreover,Lind and Lundell48 described a group of 14 childrenwith OSAS in whom height and weight velocity werenormal but significantly increased after adenotonsillec-tomy. These investigators hypothesized that abnormalrelease of growth hormone may alter growth in childrenwith OSAS.

Poor caloric intake may also result in inadequategrowth. Brouillette et al.9 reported the presence of poorappetite, difficulty swallowing, and nausea and vomitingmore frequently in children with OSAS compared withcontrols. Potsic et al.49 reported that 60% of children withOSAS were slow eaters and 37% had trouble swallowing.

Marcus et al.17 investigated the relation betweengrowth, caloric intake, and energy expenditure duringsleep before and after adenotonsillectomy in 14 childrenage 4 ± 1years with moderate OSAS. Diagnosis was basedupon an apnea index of 6 ± 3, oxygen desaturation to 85 ± 5%, and an increase in PETCO2 during sleep. Caloricintake prior to intervention in these children was normalat 91 ± 30 kcal/kg/day, and remained the same after ade-notonsillectomy with resolution of OSAS in all.However, energy expenditure during sleep droppedfrom 51 ± 6 kcal/kg/day prior to surgery to 46 ± 7kcal/kg/day after surgery (P < 0.005). This finding wasassociated with a significant increase in weight in allchildren. These findings suggest that poor growthdescribed in some children with OSAS may be secondaryto an increased energy expenditure and increased workof breathing during sleep.

Evaluation

PolysomnographyThe gold standard for diagnosing childhood OSAS is

polysomnography. This tool enables one to evaluate thebreathing quality of the child in addition to objectivelyquantifying gas exchange, number of apneas and hypop-neas, and sleep architecture during the night. Studiesshould be scored and interpreted using age-appropriatecriteria. The American Thoracic Society has published aconsensus statement outlining the requirements forpediatric polysomnography3.

Screening StudiesQuestionnaires, physical examination, lateral neck

radiographs (Figure 5-4), and nocturnal audiotapes havebeen shown to have a low sensitivity and specificity fordiagnosis3. Other screening tests, such as nocturnal video-taping, pulse oximetry, or nap polysomnograms, have lim-ited utility and have a high false-negative rate. Thus, theymay be useful for initial testing if polysomnography is notreadily available, but polysomnography is recommendedif the studies are negative or if the patient has othersignificant medical conditions.

If suspicion of cor pulmonale from severe or long-standing OSAS exists, cardiologic evaluation is indicated.An electrocardiogram may show evidence of right ven-tricular hypertrophy. Only after significant right ventric-ular hypertrophy has occurred will the chest radiographshow evidence of cardiomegaly. Echocardiography is amore sensitive technique and is indicated if moredetailed information is needed or if there is suspicion ofimpaired cardiac function, or if congestive heart failureis present.

Treatment

Adenotonsillectomy should lead to complete resolu-tion of clinical symptoms and polysomnographic abnor-malities in most children with OSAS. However, it isimportant to note that OSAS results from abnormalitiesin the size and function of the upper airway structure asa whole, rather than from the absolute size of the ade-noid and tonsils.

Additional treatment modalities are available for thosechildren who do not respond to adenotonsillectomy orthose in whom adenotonsillectomy is not indicated. Non-invasive ventilatory support in the form of CPAP is com-monly used and is well tolerated in infants and olderchildren50,51. However, behavioral techniques or admis-sion to the hospital to acclimate the child to the use of thismodality of treatment is necessary for it to be successful.

Uvulopharyngopalatoplasty has been successful inovercoming airway obstruction in children with oropha-ryngeal hypotonia, as in children with Down syndrome.More involved craniofacial surgery such as maxillary and


mandibular advancement is appropriate for some childrenwith craniofacial anomalies restricting the mid- and lower-face skeleton. Tracheostomy with or without ventilatorysupport should be considered as a short- or long-termtreatment for severe cases when other modalities of ther-apy have failed. A weight management program should beoffered to obese children with OSAS in conjunction withCPAP or non-invasive positive pressure ventilation (NPPV)therapy once evaluation and treatment for adenotonsillarhypertrophy has been completed.

The American Academy of Pediatrics has recentlypublished guidelines for the evaluation and managementof OSAS in children52. Recommendations include: (1) allchildren should be screened for snoring; (2) complexhigh-risk patients should be referred to a specialist; (3) patients with cardiorespiratory failure cannot awaitelective evaluation; (4) diagnostic evaluation, ideally withpolysomnography, is useful in discriminating betweenprimary snoring and OSAS; (5) adenotonsillectomy is thefirst line of treatment for most children, and CPAP is anoption for those who are not candidates for surgery or donot respond to surgery; (6) high-risk patients should bemonitored as inpatients postoperatively; and (7) patientsshould be re-evaluated postoperatively to determinewhether or not additional treatment is required.

Outcome

The natural history of children with OSAS is variable.The course is most affected by the etiology of airway

obstruction, degree of obstruction, and chronicity of thedisorder. The time elapsed from initial symptoms todiagnosis and management is a significant factor whenassessing the outcome of children with long-standingOSAS. Nowadays, when OSAS is more commonly recog-nized by physicians as well as parents, delays in diagno-sis are seen less often. It is difficult to predict the exactoutcome of each child with OSAS today. However, insevere cases, and if untreated, children can be expectedto progress, as in the past, to develop cor pulmonale andcongestive heart failure. Furthermore, they will encounterneurologic deficits that may extend to permanent braindamage due to asphyxia12.

Only one study has evaluated long-term outcome afterintervention. Guilleminault and colleagues53 re-evalu-ated adolescents who had been successfully treated withadenotonsillectomy during childhood. Thirteen percentof those evaluated had recurrence of OSAS. This studyleads to the hypothesis that children at risk for OSAS, dueto such factors as a small pharyngeal airway or decreasedupper airway neuromuscular tone, develop OSAS whenthey reach the age of maximal adenotonsillar hyperpla-sia. The adenotonsillar hypertrophy results in anincreased mechanical load on a marginal upper airway,thus precipitating OSAS.

It is important to mention that most complicationsdescribed in the pediatric literature, including cor pul-monale, neurobehavioral, and growth impairments werereversible once patients were treated and relieved ofairway obstruction. However, it is not known whether


A B

Figure 5-4 (A) Lateral neck radiograph of a 2-year-old girl with severe OSAS demonstrating complete occlusion of the nasopharyngeal airway space (white arrow). (B) Lateral neck radiographof a 4-year-old girl with mild OSAS demonstrating a narrowed nasopharyngeal airway space (NP). A, adenoid; SP, soft palate.

neurocognitive deficits will also reverse with treatment.The extent to which recovery of function is possiblemay depend on the age of onset of OSAS, severity, andchronicity of the disorder.

Some children may present with a mild form of OSASor upper airway resistance syndrome. These childrenmay have minimal findings by history, clinical examina-tion, and polysomnography. If there are no abnormali-ties in gas exchange during sleep, complications relatedto these changes are not expected. However, symptomsrelated to sleep fragmentation such as alteration in neu-robehavioral functions may persist and indicate need fortreatment. When no abnormal neurobehavioral symp-toms exist, close observation of the child and symptomsis sufficient, since children may experience spontaneousresolution in mild cases.

SLEEP-DISORDERED BREATHING INPREMATURE INFANTS AND IN INFANTS

Apnea of Prematurity

The association between prematurity and centralapnea is well known. It is particularly high in neonatesof 24–32 weeks’ gestational age. Apnea of prematurityoften resolves by 38 weeks postconceptual age butcould persist until 42 weeks. The close relationshipbetween age and both the incidence and severity ofapnea suggest that immaturity of the respiratory centeris a major underlying factor. Others have stressed thecausative role of various perinatal factors such asasphyxia, infection, hypoglycemia, thermal instability,seizures, and brain injury. In the majority of preterminfants, however, no clear etiology is found.

Apnea is more common during active sleep, when thereis loss of intercostal muscle tone, diminished postinspi-ratory breaking, reduced upper airway dilator muscleactivity, and decreased respiratory drive. Secondary tothese physiologic changes there is a 30% reduction inlung volumes, and a slight fall in PaO2. Both ventilatoryresponses to hypoxia and sensitivity to carbon dioxideare depressed more in active sleep than quiet sleep. Thepremature and newborn infant spends 80% of the timeasleep, most of which is in active sleep.

All infants considered to be at risk should be moni-tored continuously for heart rate and respiratory rateusing conventional monitoring devices. A pharmaco-logic approach is also available in the form of caffeine ortheophylline to increase respiratory drive. Caffeine hasmuch more stable plasma levels. The drugs may be usedon a trial basis for 2 weeks and then stopped, or theymay be continued until 52 weeks postconception.

Periodic breathing is another form of apnea consistingof very brief apneas of 5–10 seconds’ duration, followed

by breathing for 10–15 seconds before the next briefapnea. This pattern is common in premature infants andmay be accentuated by high altitude. Periodic breathingresponds well to supplemental oxygen and distendingairway pressures in the form of CPAP.

In addition, premature infants are predisposed toupper airway obstruction and oxygen desaturations dur-ing sleep due to poor airway stability and a highly com-pliant chest wall. Dransfield et al.54 found that of 76premature infants presenting clinically with apnea, 52(68%) of them had obstructive apnea and 24 (32%) hadcentral apnea only. Milner et al.55 found that half of theapneic episodes associated with periodic breathing in 8premature infants were the result of upper airwayobstruction and glottic closure. Spontaneous neck flex-ion was also found to cause upper airway obstruction inpremature infants and was suggested to play a role in thepathogenesis of apnea in some preterm infants56.

Apnea of Infancy

Periodic breathing and apnea during sleep are uncom-mon in normal term infants during the first few monthsof life. When prolonged apneas occur, especially if resus-citation is required, apnea of infancy may be diagnosed.Other possible causes of prolonged apnea include:gastroesophageal reflux, pharyngeal incoordination,convulsions, infection, heart disease, congenital centralhypoventilation syndrome, metabolic disorders, and braintumors.

Full-term neonates may also develop OSAS. Neonatesare obligate nose-breathers and may develop upper air-way obstruction whenever a mild nasal obstruction suchas a respiratory infection is present. Central nervous sys-tem immaturity, a highly compliant chest wall, andreduced airway stability all predispose newborn infantsto gas exchange abnormalities even during briefepisodes of OSAS. OSAS in early infancy can coexist withcentral apnea and sometimes can be mistaken for centralapnea. Guilleminault et al.57 found a peak incidence ofobstructive and mixed apnea to occur at 6 weeks ofage in 30 healthy infants. These events occur mostcommonly in non-REM sleep and progressively declineby 6 months to a non-significant amount57. Resolution ofthe events by 6 months may represent improved upperairway stability with growth.

Several reports describe the association betweenOSAS and apparent life-threatening event (ALTE) duringearly infancy. ALTE refers to an acute and unexpectedchange in an infant’s appearance or behavior that is fright-ening to the caregivers and causes them to seek medicalattention. Guilleminault et al.57 reported a higher numberof mixed and obstructive sleep apneas in childrenwho had ALTE. Moreover, a later report from the samegroup described 5 infants with ALTE who subsequently


developed severe OSAS. Polysomnography of the infantsat the time of the initial ALTE (3 weeks to 6 months old) demonstrated a high index of mixed and obstruc-tive apnea. These infants became progressively moresymptomatic by 6–10 months and improved only afteradenotonsillectomy58.

Similar finding have been observed in a few infantswho subsequently died of the sudden infant death syn-drome (SIDS) and who had polysomnography. When com-pared with age matched controls, these infants showeda higher number of mixed and obstructive events57,59.Kahn et al.59, in addition, found a lower number of sighsin these infants and postulated that abnormalities inperipheral chemoreceptor function may have led todeath in some of these children.

Upper airway obstruction and at times ALTE arereported in infants with severe gastroesophageal reflux.Gastroesophageal reflux may induce symptoms ininfants while awake or asleep. Symptoms usually occurafter meals in a sequence consisting of sudden cessationof breathing, rigidity and opisthotonic posture, plethoraand sudden cyanosis or pallor.

CENTRAL HYPOVENTILATION AND SLEEP

Central alveolar hypoventilation is defined as anincrease in PaCO2 due to a decrease in central nervoussystem ventilatory drive. Its hallmark is elevation of thePaCO2 on arterial blood gas sampling with a normal alveolar–arterial oxygen gradient [(A–a)DO2]. Patientswith central hypoventilation fail to ventilate adequatelyparticularly during sleep. Central hypoventilation can beprimary as in congenital central hypoventilation syndrome,or secondary to neurologic disorders such as: Arnold–Chiarimalformation, hypoxic-ischemic encephalopathy, Leigh’sencephalomyelopathy, brainstem and spinal cord tumors,and encephalitis. Other causes include inborn errors ofmetabolism, hypothyroidism, and drugs.

Congenital Central HypoventilationSyndrome

Congenital central hypoventilation syndrome (CCHS)is a congenital form of severe central hypoventilation ofundetermined etiology. Patients with CCHS usually pres-ent with cyanosis, respiratory failure, or occasionallyapnea at birth. Rarely, infants present later with ALTEsor cor pulmonale. It is quite possible that some cases ofsudden infant death syndrome are actually due to CCHS.

Patients with CCHS have intact voluntary control of ven-tilation but lack automatic control. Patients usually have adecreased tidal volume and respiratory rate during sleep60.Most patients breathe adequately during wakefulness;a subset requires ventilatory support 24 hours a day.

CCHS may be associated with other abnormalities,including Hirschsprung’s disease, autonomic dysfunc-tion, and neural crest tumors. The association of CCHSwith these disorders has led to the hypothesis that CCHSis due to a defect in neural crest migration. Physiologicstudies have shown that children with CCHS havedecreased or absent ventilatory chemosensitivity inresponse to progressive hypoxia and hypercapnia duringwakefulness and sleep.

The diagnosis of central hypoventilation is usually basedon a high suspicion, clinical findings, and polysomno-graphic findings of hypoventilation61. Evaluation for thecause of hypoventilation should include a cranial mag-netic resonance imaging examination. Other etiologiesinclude respiratory muscle weakness and metabolic dis-orders. The treatment of choice is chronic ventilatorysupport particularly during sleep, although, as men-tioned, a subset of children require ventilatory support24 hours a day. Various modalities of ventilation are usedto treat CCHS including NPPV, diaphragm pacing, andmechanical ventilation via tracheostomy.

OBSTRUCTIVE AND RESTRICTIVE LUNGDISEASES AND SLEEP

Obstructive Lung Diseases

Sleep-disordered breathing including hypoxemia,hypercarbia, and sleep fragmentation has been reportedin children with chronic obstructive lung diseases.Mechanisms that can exacerbate sleep-disorderedbreathing include effects of circadian rhythm on bron-choconstriction, hypoventilation during sleep, anddecreased mucociliary clearance during sleep. In addi-tion, cough may further disrupt normal sleep architec-ture by inducing arousals and awakenings.

Bronchopulmonary DysplasiaBronchopulmonary dysplasia (BPD) is a chronic lung

disease of infancy that follows acute lung injury in theneonatal period. BPD has been associated with degree ofprematurity, barotrauma, oxygen toxicity, and severityof lung inflammation during this period. Infants withBPD have altered lung mechanics with low lung volumesand low compliance in the early stages of the disease,and airway obstruction with air trapping at later stages.Most infants require extended mechanical ventilatorysupport, oxygen supplementation, diuretics, and bron-chodilator therapy. In addition, many of these childrenhave gastroesophageal reflux and swallowing difficultiesthat could further worsen their underlying lung disease.

Significant hypoxemia during sleep is common inBPD infants62,63. These infants have also been reported tohave an increased risk of SIDS and ALTE. The reason forthis predisposition is unclear but preventing hypoxemia


with oxygen supplementation can minimize it. A poss-ible explanation is that chronic hypoxemia and hyper-capnia may blunt the development of the normalchemoreceptor and arousal responses to chemical stimuli.Supporting this hypothesis is the study by Garg et al.64,who have shown diminished arousal responses to hypoxiain a stable group of BPD infants who did not require sup-plemental oxygen. Although 11 of 12 infants in this studyaroused, vigorous stimulation was needed for 2 of 3 of theinfants to recover from persistent apnea, bradycardia, andhypoxemia that developed following the challenge.

AsthmaAsthma and persistent wheezing predict sleep-disor-

dered breathing in children2. In this context, possiblemechanisms for sleep-disordered breathing includeincreased parasympathetic tone during sleep, circadianvariations in plasma levels of cortisol and histamine,reduced lung volumes, gastroesophageal reflux disease,increased airway inflammation and decreased airwayclearance, and, finally, abnormalities in chemoreceptorfunction that can adversely affect respiration duringsleep. Patients with life-threatening episodes of asthmahave been shown to have impaired peripheral chemore-ceptor function65 and impaired perception of respiratoryloads that could lead to a worsening of hypoxemia, aswell as abnormal arousal responses to respiratory stimuli.

Cystic FibrosisChildren with cystic fibrosis (CF) demonstrate abnor-

malities in gas exchange during sleep, particularly duringpulmonary exacerbation and with progression of theirlung disease. Allen et al.66 noted nocturnal hypoxemiaduring pulmonary exacerbation followed by resolutionwith treatment. Tepper et al.67 found that oxygen desat-uration in these subjects occurred particularly duringREM sleep. In another study of young adults with CF,those with severe disease were found to have significantlymore nocturnal hypoxemia, which could explain thedevelopment of cor pulmonale in some of these patients.

Alterations in gas exchange may disrupt normal sleeparchitecture in CF subjects. Spier et al.67 studied 10 CFadults with severe lung disease, under baseline condi-tions in the absence of pulmonary exacerbation. Theynoted low sleep efficiency, significant amount of awak-enings, and less time spent in REM stage when com-pared with healthy adults68.

Progressive deterioration of lung function in CFpatients may lead to significant hypoxemia and hyper-capnia, especially during sleep. Therefore, several stud-ies evaluated the use of NPPV versus low-flow oxygen onrespiration and sleep parameters in these subjects69,70.These studies noted that sleep architecture and arousalsremained unchanged during both NPPV and oxygentherapy. However, NPPV markedly improved alveolarventilation during all sleep states in comparison withlow-flow oxygen therapy.

Restrictive Lung Diseases

Chest Wall DeformitiesNot much literature exists on the effects of thoracic

deformities and respiratory compromise during sleep inchildren. Several disorders should be considered in thiscontext including idiopathic scoliosis, congenital scolio-sis, and congenital malformations involving the spineand chest wall leading to a small thorax.

Adults with severe kyphoscoliosis may experience res-piratory failure and cor pulmonale if untreated. Significanthypoventilation and oxyhemoglobin desaturations weredocumented in these subjects especially during REMsleep. Most children with idiopathic scoliosis are diag-nosed and treated early and therefore are not usually atrisk for developing sleep-disordered breathing and respi-ratory failure. However, in congenital forms of scoliosisand when the spinal angle exceeds 70°, sleep-disorderedbreathing may develop and should be evaluated.

Several chest wall deformities could lead to respira-tory insufficiency including congenital deficiency ofribs, thoracic dystrophy, and short limb dwarfism.Congenital diaphragmatic hernia, eventration ofdiaphragm, and abdominal wall defects such asomphalocele and prune belly syndrome, should also beconsidered in this context. Respiratory symptoms maybe mild to severe, even during wakefulness. Few data onbreathing during sleep exist in these patients, althoughit would be anticipated that desaturations and hypercap-nia would be worse during sleep. One group that hasbeen studied is children with achondroplasia. These chil-dren are prone to develop both central apnea due to asmall foramen magnum with potential brainstem com-pression, and obstructive sleep apnea due to mid-facialhypoplasia. In addition, short flare ribs lead to a small ribcage and significant restrictive lung disease. Mogayzel et al.71 noted that of 88 children with this disorder, 48%had sleep-disordered breathing, and 44% had at least oneepisode of desaturation to <90%.

Ventilatory Muscle WeaknessSleep disorders may occur in children with neuro-

muscular disorders associated with respiratory muscleweakness. Most studies of children and adolescents withventilatory muscle weakness have focused on patientswith Duchenne muscular dystrophy (DMD).

The disorder presents with proximal muscle weak-ness at 2–4 years of age. The patient usually becomesconfined to a wheelchair around 10–12 years of age,invariably dying prematurely before the age of 30 years.Respiratory muscle weakness evolves as the disease pro-gresses and this leads to more serious secondary problemssuch as scoliosis, thoracic mechanical abnormalities,widespread microatelectasis with reduced lung compli-ance, a weak cough with retained secretions, and venti-lation–perfusion imbalance. Lyager and coworkers72


reported that patients with DMD are at risk for respira-tory failure if vital capacity is less than 1.2 liters (orforced vital capacity <30% predicted). Hypercapnearesults when vital capacity falls below 55% of predictedvalues, and later becomes progressive. The risk of pul-monary morbidity and mortality from acute respiratoryfailure correlates with increasing hypercapnea.

The first significant blood–gas abnormality seen inolder children with DMD occurs during REM sleep asshort periods of hypercapnea and eventually hypox-emia73. These were observed in non-ambulatory patientswho complained of frequent awakenings and need forrepositioning in bed during sleep several years prior tothe study. Smith and coworkers74 described that inpatients with advanced DMD, nocturnal hypoventilationoften occurs with profound oxygen desaturations duringREM sleep despite normal wakeful ventilation. In a recentprospective study Phillips and coworkers75 reportedthat the age of onset of sleep-disordered breathing was16.5 years and the incidence was broadly spread acrossthe population above this age group.

Given the background of progressive neuromuscularweakness and consequent restrictive lung disease, patientswith DMD are potentially at risk for sleep hypopnea syn-drome. Early diagnosis and treatment of this syndrome isimportant and can prevent long-term complications76,77.

There have been fewer investigations in other formsof neuromuscular diseases such as spinal muscular atro-phy, nemaline myopathy, and myotonic dystrophy, doc-umenting nocturnal desaturation and apnea in thesechildren78,79. Affected individuals were chronicallysymptomatic with morning headaches and excessivesleepiness or acutely ill with respiratory failure and corpulmonale.

Treatment

Supportive TherapySupportive therapy is important for children with

obstructive or restrictive lung disease and chronic respi-ratory failure. Medical management should include,where appropriate, bronchodilators, steroids, diuretics,etc. Nutritional needs of these children should beaddressed and treated by experts. In patients with venti-latory muscle weakness, chest physical therapy andmodalities to enhance mucociliary clearance should beintroduced in order to prevent lung infections.

Supplemental Oxygen During SleepSupplemental oxygen should be prescribed when

nocturnal hypoxemia is present, although such guidelineshave not been developed for children. Supplemental oxy-gen has been demonstrated to improve growth in infantswith BPD who are hypoxemic. It has been suggestedthat SpO2 be maintained at >92–93% for BPD children aswell as for children with chronic lung diseases64.


MAJOR POINTS

1. Obstructive sleep apnea syndrome duringchildhood differs significantly from the disorder inadults in terms of pathophysiology and treatment.

2. Both anatomic and physiologic abnormalities aresuspected to play a significant role in the

�

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Supplemental oxygen is frequently prescribed forpatients with CF and nocturnal hypoxemia80, althoughlarge controlled studies are not available to show the effi-cacy of this treatment on morbidity or mortality.

Non-invasive Positive-Pressure VentilationNon-invasive positive-pressure ventilation (NPPV) has

become available in recent years to children with a widerange of disorders that lead to respiratory failure81. NPPVis being used for children with advanced obstructive lungdisease such as CF82, as well as restrictive lung disease dueto respiratory muscle weakness, such as DMD and spinalmuscular atrophy81,83. Moreover, nocturnal use of NPPVwas shown in the latter group to improve gas exchangefurther during spontaneous breathing while awake84 aswell as sleep architecture85. For DMD patients, NPPV hasbeen shown to improve quality of life, reduce number ofhospitalizations and improve mortality81,86.

Some children with ventilatory muscle weakness willeventually require a tracheostomy and positive-pressureventilatory support throughout the day and night. Sucha decision should be made after in-depth discussion withthe family and patient when appropriate, when signs ofdaytime hypoventilation develop and/or when such sup-port could enhance airway clearance.

SUMMARY

Sleep is an active process and has significant physio-logic impact on healthy children as well as on childrenwith underlying respiratory disorders. Significantadvancement in the field of pediatric sleep medicineoccurred since the first description by Guilleminault etal.4 of 8 children with OSAS. Although many questionsremain unanswered, especially in regard to the long-term effects of sleep-disordered breathing on the neu-rocognitive development of children, many otherquestions have been answered and are well docu-mented. For most sleep-related breathing disorders treat-ment is available today. This treatment can prevent mostknown complications if instituted early. An ever-grow-ing variety of diagnostic tools and technological solu-tions for the care of these children is available.

Continued

REFERENCES

1. Ali NJ, Pitson DJ, Stradling JR. Snoring, sleep disturbance,and behaviour in 4–5 year olds. Arch Dis Child 68:360–366, 1993.

2. Redline S, Tishler PV, Schluchter M, et al. Risk factors forsleep-disordered breathing in children. Associations withobesity, race, and respiratory problems. Am J Respir CritCare Med 159:1527–1532, 1999.

3. American Thoracic Society. Standards and indications forcardiopulmonary sleep studies in children. Am J Respir CritCare Med 153:866–878, 1996.

4. Guilleminault C, Eldridge FL, Simmons B, et al. Sleep apneain eight children. Pediatrics 58:23–30, 1976.

5. Guilleminault C, Pelayo R, Leger D, et al. Recognition ofsleep-disordered breathing in children. Pediatrics98:871–882, 1996.

6. Corbo GM, Fuciarelli F, Foresi A, et al. Snoring in children:association with respiratory symptoms and passive smok-ing. BMJ 299:1491–1494, 1989.

7. Redline S, Tishler PV, Hans MG, et al. Racial differences insleep-disordered breathing in African-Americans andCaucasians. Am J Respir Crit Care Med 155:186–192, 1997.

8. Guilleminault C, Korobkin R, Winkle R. A review of 50 chil-dren with obstructive sleep apnea syndrome. Lung159:275–287, 1981.

9. Brouillette R, Hanson D, David R, et al. A diagnosticapproach to suspected obstructive sleep apnea in children.J Pediatr 105:10–14, 1984.

10. Marcus CL, Omlin KJ, Basinki DJ, et al. Normal polysomno-graphic values for children and adolescents. Am Rev RespirDis 146:1235–1239, 1992.

11. Rosen CL, D’andrea L, Haddad GG. Adult criteria forobstructive sleep apnea do not identify children with

serious obstruction. Am Rev Respir Dis 146:1231–1234,1992.

12. Brouillette RT, Fernbach SK, Hunt CE. Obstructive sleepapnea in infants and children. J Pediatr 100:31–40, 1982.

13. Guilleminault C, Stoohs R, Clerk A, et al. A cause of excessivedaytime sleepiness. The upper airway resistance syndrome.Chest 104:781–787, 1993.

14. Guilleminault C, Winkle R, Korobkin R, et al. Children andnocturnal snoring: evaluation of the effects of sleep relatedrespiratory resistive load and daytime functioning. EurJ Pediatr 139:165–171, 1982.

15. Stradling JR, Thomas G, Warley AR, et al. Effect of adeno-tonsillectomy on nocturnal hypoxaemia, sleep distur-bance, and symptoms in snoring children. Lancet335:249–253, 1990.

16. Collard P, Dury M, Delguste P, et al. Movement arousalsand sleep-related disordered breathing in adults. Am J RespirCrit Care Med 154:454–459, 1996.

17. Marcus CL, Carroll JL, Koerner CB, et al. Determinants ofgrowth in children with the obstructive sleep apnea syn-drome. J Pediatr 125:556–562, 1994.

18. Frank Y, Kravath RE, Pollak CP, et al. Obstructive sleepapnea and its therapy: clinical and polysomnographic man-ifestations. Pediatrics 71:737–742, 1983.

19. Weider DJ, Sateia MJ, West RP. Nocturnal enuresis in chil-dren with upper airway obstruction. Otolaryngol HeadNeck Surg 105:427–432, 1991.

20. Baruzzi A, Riva R, Cirignotta F, et al. Atrial natriuretic pep-tide and catecholamines in obstructive sleep apnea syn-drome. Sleep 14:83–86, 1991.

21. Pasterkamp H, Cardoso ER, Booth FA. Obstructive sleepapnea leading to increased intracranial pressure in apatient with hydrocephalus and syringomyelia. Chest95:1064–1067, 1989.

22. Marcus CL, Curtis S, Koerner CB, et al. Evaluation of pul-monary function and polysomnography in obese childrenand adolescents. Pediatr Pulmonol 21:176–183, 1996.

23. Brodsky L. Modern assessment of tonsils and adenoids.Pediatr Clin North Am 36:1551–1569, 1989.

24. McColley SA, April MM, Carroll JL, et al. Respiratorycompromise after adenotonsillectomy in children withobstructive sleep apnea. Arch Otolaryngol Head Neck Surg118:940–943, 1992.

25. Rosen GM, Muckle RP, Mahowald MW, et al. Postoperativerespiratory compromise in children with obstructive sleepapnea syndrome: can it be anticipated? Pediatrics93:784–788, 1994.

26. Guilleminault C, Heldt G, Powell N, et al. Small upper air-way in near-miss sudden infant death syndrome infants andtheir families. Lancet 1:402–407, 1986.

27. Marcus CL, Keens TG, Bautista DB, et al. Obstructive sleepapnea in children with Down syndrome. Pediatrics88:132–139, 1991.

28. Silvestri JM, Weese-Mayer DE, Bass MT, et al.Polysomnography in obese children with a history of


MAJOR POINTS–Cont’d

pathophysiology of obstructive sleep apneasyndrome (OSAS) in children.

3. Long-standing obstructive sleep apnea syndromecan lead to significant end-organ injury andnegatively affect the cardiovascular system,neurocognitive function, and behavior of children.

4. Children with underlying craniofacial syndromesand neurologic disorders affecting their musculartone are at particular risk for obstructive sleepapnea syndrome.

5. The “gold standard” tool for diagnosis of childrenwith sleep-disordered breathing and particularlyfor obstructive sleep apnea is polysomnography.

6. Treatment for obstructive sleep apnea syndrome inmost cases is surgical (adenotonsillectomy) and is adefinite solution for the majority of children.

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sleep-associated breathing disorders. Pediatr Pulmonol16:124–129, 1993.

29. Partinen M, Guilleminault C. Daytime sleepiness and vas-cular morbidity at seven-year follow-up in obstructive sleepapnea patients. Chest 97:27–32, 1990.

30. Mograss MA, Ducharme FM, Brouillette RT. Movement/arousals. Description, classification, and relationship to sleepapnea in children. Am J Respir Crit Care Med 150:1690–1696,1994.

31. McNamara F, Issa FG, Sullivan CE. Arousal pattern followingcentral and obstructive breathing abnormalities in infantsand children. J Appl Physiol 81:2651–2657, 1996.

32. Kahn A, Mozin MJ, Rebuffat E, et al. Sleep pattern alterationsand brief airway obstructions in overweight infants. Sleep12:430–438, 1989.

33. Horner RL, Mohiaddin RH, Lowell DG, et al. Sites and sizesof fat deposits around the pharynx in obese patients withobstructive sleep apnoea and weight matched controls.Eur Respir J 2:613–622, 1989.

34. Southall DP, Stebbens VA, Mirza R, et al. Upper airwayobstruction with hypoxaemia and sleep disruption in Downsyndrome. Dev Med Child Neurol 29:734–742, 1987.

35. Stebbens VA, Dennis J, Samuels MP, et al. Sleep related upperairway obstruction in a cohort with Down’s syndrome. ArchDis Child 66:1333–1338, 1991.

36. Jacobs IN, Gray RF, Todd NW. Upper airway obstruction inchildren with Down syndrome. Arch Otolaryngol HeadNeck Surg 122:945–950, 1996.

37. Findley LJ, Barth JT, Powers DC, et al. Cognitive impair-ment in patients with obstructive sleep apnea and associ-ated hypoxemia. Chest 90:686–690, 1986.

38. Greenberg GD, Watson RK, Deptula D. Neuropsychologicaldysfunction in sleep apnea. Sleep 10:254–262, 1987.

39. Carroll JL, McColley SA, Marcus CL, et al. Inability of clini-cal history to distinguish primary snoring from obstructivesleep apnea syndrome in children. Chest 108:610–618,1995.

40. Rhodes SK, Shimoda KC, Waid LR, et al. Neurocognitivedeficits in morbidly obese children with obstructive sleepapnea. J Pediatr 127:741–744, 1995.

41. Gozal D. Sleep-disordered breathing and school perform-ance in children. Pediatrics 102:616–620, 1998.

42. Shahar E, Whitney CW, Redline S, et al. Sleep-disorderedbreathing and cardiovascular disease: cross-sectionalresults of the Sleep Heart Health Study. Am J Respir CritCare Med 163:19–25, 2001.

43. Perkin RM, Anas NG. Pulmonary hypertension in pediatricpatients. J Pediatr 105:511–522, 1984.

44. Tal A, Leiberman A, Margulis G, et al. Ventricular dysfunc-tion in children with obstructive sleep apnea: radionuclideassessment. Pediatr Pulmonol 4:139–143, 1988.

45. Amin RS, Kimball TR, Bean JA, et al. Left ventricular hyper-trophy and abnormal ventricular geometry in children andadolescents with obstructive sleep apnea. Am J Respir CritCare Med 165:1395–1399, 2002.

46. D’andrea L A, Rosen CL, Haddad GG. Severe hypoxemia inchildren with upper airway obstruction during sleep doesnot lead to significant changes in heart rate. PediatrPulmonol 16:362–369, 1993.

47. Aljadeff G, Gozal D, Schechtman VL, et al. Heart rate vari-ability in children with obstructive sleep apnea. Sleep20:151–157, 1997.

48. Lind MG, Lundell BP. Tonsillar hyperplasia in children.A cause of obstructive sleep apneas, CO2 retention, andretarded growth. Arch Otolaryngol 108:650–654, 1982.

49. Potsic WP, Pasquariello PS, Baranak CC, et al. Relief ofupper airway obstruction by adenotonsillectomy.Otolaryngol Head Neck Surg 94:476–480, 1986.

50. Marcus CL, Ward SL, Mallory GB, et al. Use of nasal contin-uous positive airway pressure as treatment of childhoodobstructive sleep apnea. J Pediatr 127:88–94, 1995.

51. Waters KA, Everett FM, Bruderer JW, et al. Obstructivesleep apnea: the use of nasal CPAP in 80 children. AmJ Respir Crit Care Med 152:780–785, 1995.

52. Clinical practice guideline: diagnosis and management ofchildhood obstructive sleep apnea syndrome. Pediatrics109:704–712, 2002.

53. Guilleminault C, Partinen M, Praud JP, et al. Morphometricfacial changes and obstructive sleep apnea in adolescents.J Pediatr 114:997–999, 1989.

54. Dransfield DA, Spitzer AR, Fox WW. Episodic airwayobstruction in premature infants. Am J Dis Child137:441–443, 1983.

55. Milner AD, Boon AW, Saunders RA, et al. Upper airwaysobstruction and apnoea in preterm babies. Arch Dis Child55:22–25, 1980.

56. Thach BT, Stark AR. Spontaneous neck flexion and airwayobstruction during apneic spells in preterm infants. J Pediatr94:275–281, 1979.

57. Guilleminault C, Ariagno R, Korobkin R, et al. Mixed andobstructive sleep apnea and near miss for sudden infantdeath syndrome. 1. Report of an infant with sudden death. 2.Comparison of near miss and normal control infants by age.Pediatrics 64:837–843, 882–891, 1979.

58. Guilleminault C, Souquet M, Ariagno RL, et al. Five cases ofnear-miss sudden infant death syndrome and developmentof obstructive sleep apnea syndrome. Pediatrics 73:71–78,1984.

59. Kahn A, Blum D, Rebuffat E, et al. Polysomnographic stud-ies of infants who subsequently died of sudden infant deathsyndrome. Pediatrics 82:721–727, 1988.

60. Fleming PJ, Cade D, Bryan MH, et al. Congenital centralhypoventilation and sleep state. Pediatrics 66:425–428, 1980.

61. Weese-Mayer DE, Silvestri JM, Menzies LJ, et al. Congenitalcentral hypoventilation syndrome: diagnosis, management,and long-term outcome in thirty-two children. J Pediatr120:381–387, 1992.

62. Garg M, Kurzner SI, Bautista DB, et al.1988 Clinically unsus-pected hypoxia during sleep and feeding in infants withbronchopulmonary dysplasia. Pediatrics 81:635–642, 1983.


63. Moyer-Mileur LJ, Nielson DW, Pfeffer KD, et al. Eliminatingsleep-associated hypoxemia improves growth in infantswith bronchopulmonary dysplasia. Pediatrics 98:779–783,1996.

64. Garg M, Kurzner SI, Bautista D, et al. Hypoxic arousalresponses in infants with bronchopulmonary dysplasia.Pediatrics 82:59–63, 1988.

65. Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivityand perception of dyspnea in patients with a historyof near-fatal asthma. N Engl J Med 330:1329–1334,1994.

66. Allen MB, Mellon AF, Simmonds EJ, et al. Changes in noc-turnal oximetry after treatment of exacerbations in cysticfibrosis. Arch Dis Child 69:197–201, 1993.

67. Tepper RS, Skatrud JB, Dempsey JA. Ventilation and oxy-genation changes during sleep in cystic fibrosis. Chest84:388–393, 1983.

68. Spier S, Rivlin J, Hughes D, et al. The effect of oxygen onsleep, blood gases, and ventilation in cystic fibrosis. AmRev Respir Dis 129:712–718, 1984.

69. Gozal D.1997 Nocturnal ventilatory support in patientswith cystic fibrosis: comparison with supplemental oxy-gen. Eur Respir J 10:1999–2003, 1983.

70. Milross MA, Piper AJ, Norman M, et al. Low-flow oxygenand bilevel ventilatory support: effects on ventilation dur-ing sleep in cystic fibrosis. Am J Respir Crit Care Med163:129–134, 2001.

71. Mogayzel PJ Jr., Carroll JL, Loughlin GM, et al. Sleep-disor-dered breathing in children with achondroplasia. J Pediatr132:667–671, 1998.

72. Lyager S, Steffensen B, Juhl B. Indicators of needfor mechanical ventilation in Duchenne muscular dystro-phy and spinal muscular atrophy. Chest 108:779–785,1995.

73. Redding GJ, Okamoto GA, Guthrie RD, et al. Sleep patternsin nonambulatory boys with Duchenne muscular dystro-phy. Arch Phys Med Rehabil 66:818–821, 1985.

74. Smith PE, Edwards RH, Calverley PM. Ventilationand breathing pattern during sleep in Duchenne musculardystrophy. Chest 96:1346–1351, 1989.

75. Phillips MF, Smith PE, Carroll N, et al. Nocturnal oxygena-tion and prognosis in Duchenne muscular dystrophy. Am JRespir Crit Care Med 160:198–202, 1999.

76. Barbe F, Quera-Salva MA, Mccann C, et al. Sleep-related res-piratory disturbances in patients with Duchenne musculardystrophy. Eur Respir J 7:1403–1408, 1994.

77. Barthlen GM. Nocturnal respiratory failure as an indicationof noninvasive ventilation in the patient with neuromuscu-lar disease. Respiration 64(Suppl 1):35–38, 1997.

78. Manni R, Cerveri I, Ottolini A, et al. Sleep related breathingpatterns in patients with spinal muscular atrophy. ItalJ Neurol Sci 14:565–569, 1993.

79 Labanowski M, Schmidt-Nowara W, Guilleminault C. Sleepand neuromuscular disease: frequency of sleep-disorderedbreathing in a neuromuscular disease clinic population.Neurology 47:1173–1180, 1996.

80. Zinman R, Corey M, Coates AL, et al. Nocturnal home oxy-gen in the treatment of hypoxemic cystic fibrosis patients.J Pediatr 114:368–377, 1989.

81. Padman R, Lawless S, Von Nessen S. Use of BiPAP by nasalmask in the treatment of respiratory insufficiency in pedi-atric patients: preliminary investigation. Pediatr Pulmonol17:119–123, 1994.

82. Granton JT, Shapiro C, Kesten S. Noninvasive nocturnalventilatory support in advanced lung disease from cysticfibrosis. Respir Care 47:675–681, 2002.

83. Bach JR, Wang TG. Noninvasive long-term ventilatory sup-port for individuals with spinal muscular atrophy and func-tional bulbar musculature. Arch Phys Med Rehabil76:213–217, 1995.

84. Hukins CA, Hillman DR. Daytime predictors of sleephypoventilation in Duchenne muscular dystrophy. Am JRespir Crit Care Med 161:166–170, 2000.

85. Barbe F, Quera-Salva MA, De Lattre J, et al. Long-term effectsof nasal intermittent positive-pressure ventilation on pul-monary function and sleep architecture in patients with neu-romuscular diseases. Chest 110:1179–1183, 1996.

86. Vianello A, Bevilacqua M, Salvador V, et al. Long-termnasal intermittent positive pressure ventilation in advancedDuchenne’s muscular dystrophy. Chest 105:445–448, 1994.


Etiology of Asthma

Pathophysiology of Asthma

Clinical Presentation


Differential Diagnosis

Classification of Asthma Severity

Therapy for Asthma

Pharmacologic Therapy

Controller Therapy

Inhaled Corticosteroids

Systemic Glucocorticoids

Cromolyn Sodium and Nedocromil

Leukotriene Modifiers

Methylxanthines

Long-Acting Beta-Agonists

Anti-immunoglobulin E

Acute Therapy

Short-Acting Beta-Agonists

Systemic Glucocorticoids

Non-Pharmacologic Therapy

Complicating Factors

In 63 AD, Aretaeus the Cappadocian wrote, “If fromrunning, gymnastic exercises, or any other work, thebreathing becomes difficult, it is called Asthma.” Almosttwo thousand years later, our scientific understanding ofasthma has grown, yet this entity is still defined usingsimilar clinical constructs. A working definition from the current guidelines for the diagnosis and treatment ofasthma states that asthma is a chronic inflammatory disease of the airways, and this inflammation causes an increase in (a) bronchial hyper-responsiveness to avariety of stimuli and (b) recurrent episodes of wheez-ing, breathlessness, chest tightness, and coughing usu-ally associated with widespread but variable (c) airflowobstruction that is often reversible. This definition pro-vides the basis for both diagnostic criteria and treatmentof the disorder1.

There is a wide variety of symptom expression andseverity in people with asthma, reflecting the heterogen-eous nature of the disease. It is unclear whether this het-erogeneity is due to extreme differences in phenotypicvariability or the possibility that what we call asthma mayrepresent a collection of similar airway diseases that wehave yet to appreciate. This variability can cause confu-sion in relation to the diagnosis, assessment, and treat-ment of the child with asthma. This confusion is amplifiedby “synonym” diagnoses such as reactive airways diseaseor wheezy bronchitis and by the assignment of “types”of asthma, such as “bronchial” asthma, cough-variantasthma, intrinsic or extrinsic asthma, and allergic or non-allergic asthma. While this expanded nomenclature mayserve the individual who evokes this terminology, thereis neither a physiologic basis nor broad acceptance ofthese terms. An individual who fulfills diagnostic criteriahas asthma, and the diagnosis should only be modifiedby classification of severity.

Asthma is the most common chronic disease in child-hood, affecting over 5 million children in the UnitedStates. It is one of the leading causes of emergency roomutilization and hospitalizations in children and adults,although the rate of hospitalization is higher in children.There is no racial, ethnic, or socioeconomic predisposi-tion to the development of asthma, but the rate of hospi-talization is higher among African-Americans and urbanlower-income groups. The rate of death from asthma hasincreased steadily over the last 10 years, despite a growingunderstanding of the disease and the initiation of aggres-sive disease management programs. Death from asthma inchildren occurs regardless of disease severity2.

ETIOLOGY OF ASTHMA

The prevalence of asthma has been increasing, particu-larly among children. The observance of this phenomenon

95

CHAPTER AsthmaHAVIVA VELER, M.D.RUSSELL G. CLAYTON, Sr., D.O.6

has led to much speculation and attempts to identify thereason behind the rising prevalence. Factors rangingfrom increased numbers of immunizations to increasedair pollution have been suggested, but subsequent analy-sis has failed to provide supporting evidence to implicatemost of these possibilities. However, a concept known asthe hygiene hypothesis has gained some support fromepidemiologic studies. This hypothesis is based on therelative decrease in microbial exposure in environmentsof modernized countries in relation to early immunedevelopment, and states that children with increasedmicrobial exposure are less likely to develop asthma3.

Observations of birth cohorts have suggested thatyoung children who have increased numbers of upperrespiratory and gastrointestinal infections are less likelyto develop asthma or allergic disease later in life. Similarstudies involving farm/non-farm cohorts demonstratedthat children exposed to relatively higher amounts ofbacterial endotoxin were less likely to develop asthma oratopic disease. In addition, children with animal contactfrom a young age seem to be less likely to develop asthma,possibly related to higher environmental levels of bacterialendotoxin associated with animals. While the evidencesupporting the hygiene hypothesis is compelling, thereare other studies that implicate certain viral infections,inhalant allergens, and ambient bacterial endotoxin aspossible causes for the development of asthma. At thistime, the reason or reasons for the increased prevalenceof asthma remains unclear.

There is also ambiguity shadowing the factors leadingto the development of asthma in the individual. In manycases asthma seems to be an inherited disease. Often theparents or siblings of children with asthma also have thedisease, or there is at least some family history of asthma4.However, the variability of presumed inheritance andthe heterogeneous expression of the disease suggest acomplex inheritance pattern that may involve severalgenes on several different chromosomes in variabledegrees of expression. Numerous genome-wide screenssearching for links to atopy and asthma have led to theidentification of possible active regions of almost everychromosome. Despite intense effort, however, fewgenes have been linked to asthma with any degree ofcertainty. Hence, there is presently no “genetic test” forasthma. Most of the chromosome regions identified areassociated with genes encoding for inflammatory media-tors or beta2-adrenergic receptors. While these discover-ies have yet to yield clinically relevant information, theirsum in time will probably yield important insight intothe genotypic and phenotypic variations of asthma.

Viruses have been implicated in the development ofasthma. Animal studies have provided the basis for directcausal evidence for this mechanism, while human clinicalstudies have been inferential at best. The strongest epi-demiologic evidence supporting a causal relationship be-tween viral infection and asthma comes from longitudinal

studies following children infected with the respiratorysyncytial virus (RSV). RSV is a common cause of bron-chiolitis in infants, and is also a common precipitant ofasthma exacerbations in all age groups. Infants hospital-ized with RSV bronchiolitis have been observed to be more likely to have recurrent wheezing episodes orasthma, but a direct cause and effect relationship has yetto be established. Since young children with asthma candevelop exacerbations from common respiratoryviruses, it is unclear as to whether those hospitalizedinfants may have asthma triggered by the RSV infection5.

Animal models likewise support the potential for theinduction of asthma as a result of exposure and sensiti-zation to common inhaled antigens. In these studies,subsequent sensitization to common indoor allergens(dust mite, mold, cat dander, dog dander, cockroach)resulted in clinical and histologic changes consistentwith asthma6. Data from human studies also suggest thatsensitized children exposed to common allergens havegreater asthma severity. However, the specific relation-ship between the development of allergen sensitivityand the development of asthma remains unclear.

In addition, other environmental exposures, specifi-cally particulate matter, have been linked to the develop-ment of asthma in children. Passive exposure to tobaccosmoke is most predictive of the subsequent developmentof asthma in children above all other environmental expo-sures. Epidemiologic studies have linked exposure totobacco in utero to the subsequent development ofasthma. Tobacco-exposed infants also have lower lungfunction that persists throughout life7. There also appearsto be a relationship between tobacco exposure and wors-ening asthma severity. While the precise mechanismsgoverning these relationships have not been fully uncov-ered, the effect of tobacco smoke on the development ofasthma and its severity is undeniable.

It is most likely that the development of asthma, as wellas the severity of the disease, is multi-factorial. The poten-tially complex interaction of the various factors may itselfexplain the heterogeneous nature of asthma. While mostindividuals with asthma experience the onset of symp-toms in childhood, the age of onset can vary from infancyto senescence. Similarly, asthma severity can worsen orlessen over time. These observations suggest that asthmaoccurs in individuals with some degree of genetic sus-ceptibility who are further influenced by various environ-mental exposures, and the severity is influenced bygenetics, environmental exposure, and the “life history”of the airways. Without a clearly identified etiology orgroup of causative factors, asthma prevention, identifica-tion of the pre-symptom individual with asthma, or pre-cise prediction of prognosis is impossible. However,insight into the natural history of asthma may providesome degree of accurate prognostication in children.

Consistent with the theme of heterogeneity, the natu-ral history of asthma in children is variable. This variability


has caused considerable controversy, particularly withregard to the infant and toddler with asthma. However,data from large epidemiologic studies continue to providegreater understanding of the natural history of asthma8.

Although asthma can present at any age, the peakages of presentation for males are during the first 3 yearsof life and then at school age. The peak ages for femalesare again during the first 3 years of life and then atpuberty or adolescence. It is not clear why the secondpeak occurs earlier in males. However, studies in respir-atory system development suggest that the average air-way caliber is smaller relative to body size in infant andpre-pubescent males than in females of the same age.After puberty, airway caliber is generally smaller infemales than in males9.

In population studies, nearly half of all infants and toddlers exhibit recurrent asthma symptoms. However,only a small percentage of these children have persistenceof symptoms or evidence of bronchial hyper-reactivitybeyond the sixth year of life. While it is impossible topredict which children will have persistent asthma,some general characteristics have been identified10.Children under 3 years of age who have evidence of atopy,who wheeze in between viral respiratory infections, orwhose parents have asthma, are more likely to have per-sistence of symptoms beyond age 6. In contrast, youngchildren who do not have these risk factors and wheezeonly with viral respiratory infections are less likely tohave asthma symptoms or bronchial hyper-reactivitylater in life. Overall, there is approximately a 50% likeli-hood that a young child with recurrent wheezing will goon to have asthma after age 6.

The high prevalence of asthma symptoms in thisyoungest age group and the potential marked differencein outcomes in preschool children and infants haveraised the question of whether or not children in this agegroup should be diagnosed with asthma or if differentterminology should be used. As there is no uniform agree-ment on this topic at present, the term asthma should beused for children who fit diagnostic criteria. In most casesthe child should receive therapy commensurate with thelevel of disease severity, and symptom occurrence shouldbe closely monitored over the first 3–6 years of life. If thechild is symptom-free for a period of time despite expo-sure to known triggers, an observed trial off therapy iswarranted.

Older children, adolescents, or adults with asthma mayenter a period of time when they do not seem to havesymptoms even when they are not taking controller med-ication. Although it appears that they no longer haveasthma, bronchial challenge testing reveals that they stillhave airway hyper-responsiveness. Little is known aboutthis remission period. It may last only a year or twobefore symptoms return, or it may continue for the restof the individual’s life. Children and adolescents with anestablished diagnosis of asthma who are in remission

should continue to have quick-relief medication avail-able and should be monitored at regular intervals in casethe asthma again becomes active.

For most children who have asthma, symptoms remainpresent indefinitely if not properly treated. With theexception of infants and toddlers, there is no evidencethat supports the notion that children “outgrow” asthma.To the contrary, longitudinal population studies confirmthe persistence of airway hyper-responsiveness intoadulthood. However, the severity of asthma can changein either direction. This may occur in response to therapyor with withdrawal of therapy, with a change in environ-ment, during periods of hormonal change, or for noidentifiable reason.

PATHOPHYSIOLOGY OF ASTHMA

The classic description of the pathology of asthmaincludes a mucosa that is thickened and infiltrated withinflammatory cells, presence of smooth muscle hyper-trophy, and alteration of the epithelium of the bronchiand bronchioles11. The airway caliber is smaller, and thelumen contains mucus mixed with debris. Neutrophilsand eosinophils may be abundant within the airways, andthe degradation of the latter gives rise to Charcot-ladencrystals. Mucus casts of smaller airways, referred to asCurschman’s spirals, are also present in extreme cases.This classic description arose mostly from post-mortemspecimens from individuals who succumbed to asthma.In contrast, biopsy specimens from airways of patientswith asthma have yielded a spectrum of pathologic find-ings, ranging from normal airway histology to that seen infatal asthma. However, consistent findings among thesespecimens include mucosal thickening with cellular infil-tration, disorganization of the epithelium, and submucosalalteration12.

This last observation, seen in some but not all patients,has given rise to a theory that asthma, over time, causesremodeling of the airway. Airway remodeling, while notyet a proven concept, is supported by longitudinal obser-vations of declining lung function in some children withasthma, along with a more rapid decline of lung functionin adults with asthma relative to the normal decline inhealthy non-smokers. This alteration is thought to occursecondary to prolonged exposure of airway tissue toinflammation, leading to destruction of normal airwaytissue and deposition of fibrin. It is important to notethat these changes have been observed in patients in allclasses of severity, including patients with mild and lessfrequent symptoms. It is unclear whether airway remod-eling (a) is preventable, (b) is reversible, and (c) poten-tially can occur in all patients with asthma or is limitedto a yet unspecified subset of patients.

A variety of chemical inflammatory mediators havealso been identified in the airways of patients with asthma.

Asthma 97

Interleukins, kinins, and leukotrienes have been isolatedin significantly elevated concentrations in specimensobtained by bronchial lavage. These findings, along withthe discovery of inflammatory cells, have given rise tothe idea that a complex cascade of pro-inflammatoryevents potentially takes place within the airways ofpatients with asthma. Despite intense research, no singlepredominant inflammatory pathway has been identified.Furthermore, it is difficult to discern which pathways areimportant in a given individual patient, reinforcing theconcept of asthma as a heterogeneous disease. Finally,since there is poor correlation between inflammatorymediators found in the lung and serum or urine markers,a laboratory test to confirm the diagnosis of asthma doesnot yet exist13.

Inflammation of the airway mucosa and constrictionof airway smooth muscle are the key pathophysiologicfeatures of asthma. Airway inflammation gives rise toepithelial irritation, excess mucus production and cellulardamage that in turn gives rise to cough. The inflammationalso causes mucosal swelling, leading to a narrowedairway lumen. The airway caliber is further reduced byairway smooth muscle constriction that is presumablytriggered by inflammatory mediators. Debris in the airwaycauses additional obstruction, and during exacerbationsof asthma the increased numbers of polymorphonuclearleukocytes increase the viscosity of airway secretions.The resultant airway obstruction causes increased resist-ance to airflow, particularly during expiration. As venti-lation continues through the narrowed bronchial tree,gas is trapped in the lung, and hyperinflation of the chestensues. The increase in residual volume must be balancedby a decrease in vital capacity, inspiratory capacity, andultimately tidal volume.

The patient with intrathoracic airway obstructionattempts to compensate by employing a prolonged andactive expiratory phase. To maintain minute ventilation, therespiratory rate increases, limiting the total expiratory time.If the obstruction is not relieved, the patient is maintainedin a constant state of respiratory compromise. The decreasein vital capacity limits the respiratory reserve available, sothat minute ventilation cannot increase in response toactivity. Progressive decrease in tidal volume and respira-tory muscle fatigue can lead to respiratory failure.

CLINICAL PRESENTATION

In the absence of laboratory tests or genetic markersfor asthma, the diagnosis of asthma is made with clinicalinformation (Table 6-1). A detailed history of the child’ssymptoms provides most, if not all, of the informationnecessary to make a diagnosis. The four common symp-toms of asthma are cough, wheeze, chest discomfort, andlabored breathing14. Some children may experience all

four symptoms, while others exhibit only one. A preciseinitial history will usually reveal that the patient hasexperienced more than one symptom, but there may notbe a clear temporal relationship between the symptoms.In any case, it is critical to establish a pattern of recur-rence or persistence of these symptoms to support adiagnosis of asthma. It is also important to investigatepatterns in the recurrences that suggest potential trig-gers, as these patterns support the characteristic of air-way hyper-responsiveness. Finally, the symptoms shoulddiminish or disappear when a bronchodilator or anti-inflammatory medication is administered to the child.

Cough occurs naturally as a defense mechanism inresponse to airway irritation. In asthma, it probablyreflects the hypersensitive state of the mucosa of inflamedairways. Cough is the most common symptom in childrenwith asthma, but it is also ubiquitous and non-specific inthe pediatric population. Therefore, it is important toestablish a chronic or recurrent pattern in order to decreasethe number of diagnostic possibilities. However, thereare qualitative and chronologic features of this symptomthat are more consistent with a diagnosis of asthma.

In most cases of asthma, the cough is described as“dry,” “tight,” or non-productive, particularly when thecough is episodic or in the early stages of an exacerbation.It is not unusual for the cough to become “wet,” “loose,”or productive as an asthma exacerbation evolves.However, a recurrent or persistent productive cough suggests alternative conditions, such as postnasal drip orcystic fibrosis. Parents may also use other descriptors, suchas a “deep,” “hacking,” or “chest” cough. These qualitiesare consistent with cough in asthma, but can suggest


Table 6-1 Diagnostic Findings in Asthma

Symptoms Signs Investigations

Cough Wheeze Pulmonary function testProlonged Retractions Chest radiograph“Deep, hacking” Prolonged Pulse oximetryAfter exertion expirationAfter exposure to trigger TachypneaDuring sleep

WheezeWith coldsWith exertionAfter exposure to trigger

Chest discomfortWith exertion

Labored breathingWith coldsWith exertionAfter exposure to trigger

Symptom should be recurrent, in response to a trigger, and reversible withasthma medications

alternative diagnoses as well. The cough is usually notparoxysmal, but children may have “coughing fits” duringasthma exacerbations.

The timing of the occurrence of cough is often helpful.In a child with asthma, a cough will start or increase infrequency or severity after exposure to a potential allergen(e.g., an animal, pollen, or mold) or irritant (e.g., smoke,fumes, or cold air). This can occur from within a few minutes to 12–24 hours after exposure. Further, the coughmay abate shortly after the child is removed from thestimulus or can continue or even worsen despite separa-tion of the child and the trigger. The duration and severityof the cough in this case is usually related to the severityof the asthma, but can also be a reflection of the degree ofunderlying airway inflammation. Cough may also occurafter several minutes of sustained exercise. In this case,the cough probably is a manifestation of airway irritationfrom cooler, drier air introduced into the airways as tidalvolume increases, rather than of the exercise itself.

Children with asthma will often manifest cough dur-ing sleep. However, it is important to be precise whenestablishing the chronology of the cough during sleep.Typically, children with asthma will cough several hoursinto sleep. In contrast, cough from gastroesophagealreflux tends to occur soon after lying down, as well asthroughout the night. Cough from postnasal drip alsooccurs soon after lying down, but also around the timeof waking. Usually the cough will not wake the child, butwill wake other members of the household. Therefore, itis helpful to question not only the parents but also thesiblings or other members of the household.

A wheeze is a continuous, musical sound that is pro-duced by turbulent flow that occurs in the bronchi. In asthma, this turbulence is produced by partial airwayobstruction, or narrowing, from mucosal inflammation,airway debris, and contraction of airway smooth muscle.During exhalation, lung volume decreases and intra-thoracic pressure increases, resulting in decreased airwaycaliber throughout the lung. Therefore, wheezing usu-ally occurs exclusively during the expiratory phase ofbreathing. However, airway narrowing present in somechildren may also result in wheezing during the inspira-tory phase as well. A continuous musical sound thatoccurs only during inhalation is usually termed stridorand reflects extrathoracic airflow obstruction.

A further clarification regarding the terminology ofwheezing is necessary. Wheezing can be polyphonic (orheterophonous) or it can be monophonic (or homopho-nous). Like a pipe organ, heterophonous sounds are pro-duced by forcing air through tubes of different calibers.Therefore, a heterophonous wheeze reflects gradations ofairway narrowing throughout the bronchial tree and is themore common type of wheeze heard in asthma. In contrast,a homophonous wheeze occurs when air is forced throughtubes with similar calibers. A homophonous wheeze, for

example, may occur from a partial obstruction in a fixedsegment of the intrathoracic airway, or if several bronchiapproximate a similar caliber. Although a homophonouswheeze usually suggests a condition other than asthma,it can occur in children with asthma, especially duringthe recovery phase of an exacerbation.

A reliable history of wheezing is difficult to obtain,particularly since children may make a variety of noisesduring breathing. Parents may interpret other noises as awheeze. On the other hand, the wheeze may be presentbut unappreciated without a stethoscope. Therefore,probing questions requiring detailed answers are requiredto validate a history of wheezing. Astute historians willassociate the wheeze with exhalation, or be able todescribe or mimic the sound. Parents or children may alsodescribe a “chest rattle” or perceived chest “congestion.”Older children and adolescents may also report that theyhear themselves wheeze, or that they can “feel” the wheezein their chest. Again, precise questioning and thoughtfulconsideration of the answers are required to establish atrue history of wheeze.

Once a history of wheeze has been elicited, the timingof the wheezing occurrences should be ascertained. Similarto cough, the wheeze in asthma should be recurrent andfollow exposure to an identifiable trigger. The perceptionof wheeze in children is usually episodic. Reports of a con-tinuous, ever-present wheeze suggest other causes of par-tial intrathoracic airflow obstruction. Wheezing may getlouder as airflow obstruction worsens, but it may alsobecome louder during times of increased tidal volume,such as during excitement or during or after periods ofexertion. Conversely, wheezing may become inaudible dur-ing sleep or as severely narrowed airways limit airflow.Wheezing from asthma should diminish to some extentafter bronchodilator or anti-inflammatory treatment. Ifthese therapies do not decrease wheezing when adminis-tered, alternative diagnoses should be considered.

Labored breathing can be a symptom by itself, but inthis context represents a category of “observed symp-toms” that are most often reported by a caregiver ininfants and younger children with asthma. Parents have asense of their child’s labored breathing but have difficultydescribing the observations that prompt that feeling. Anincreased respiratory rate is an early sign of respiratorycompromise, but in asthma this can occur gradually andtherefore be too subtle for the parent to notice until thebreathing rate is very high. Similarly, thoraco-abdominalasynchrony can occur in asthma, particularly in infantsand toddlers, but it is often unnoticed by an untrainedobserver unless there is serious respiratory compromise.Therefore, these representative observations of laboredbreathing in young children with asthma are usuallynoticed only during exacerbations, along with subcostaland intercostal retractions. Occasionally, an astute care-giver may notice a prolonged expiratory phase.

Asthma 99

Older children and adolescents with asthma maydescribe a vague sense of difficulty breathing duringinspiration, although some may articulate that they havedifficulty getting air out. In this age group, this symptomusually occurs during exacerbations or as part of a com-plaint of exercise intolerance. The latter situation is com-mon in patients with asthma, but can also occur withother conditions. Children with asthma should be ableto exercise for a few minutes before experiencing dysp-nea, unless their asthma is severe or they are in the midstof an exacerbation. Dyspnea within the first minute ofexertion is less likely due to asthma, and alternative etiologies should be considered. Also, the patient shouldbe able to distinguish between dyspnea and fatigue. In asthma, dyspnea may occur after a few minutes ofexercise, but fatigue should not be present unless theexertion continues in the face of impaired breathing.Alternative diagnoses should be sought if fatigue occursprior to or simultaneous with dyspnea during exertion.

Chest discomfort, or tightness, is sometimes mistakenas dyspnea, but is a separate and distinct symptom thatis characteristic of asthma. The precise physiologic basisfor this complaint is not known, although the sensationprobably reflects the hyperexpansion of the pleura orthoracic cage. Although the sensation is uncomfortable,it should be distinguished from chest pain, a symptomthat suggests other conditions.

Older children and adolescents with asthma presentwith chest tightness as a chief complaint or offer thissymptom without solicitation. However, even verbalpreschool children may articulate this symptom if askedin age-appropriate language. Like the other symptoms ofasthma, chest tightness can occur by itself or in associa-tion with other symptoms, and its historical occurrenceshould establish a pattern of recurrence and a temporalrelationship with potential triggers. Chest tightness canoccur at any time in patients with asthma, but most oftenit is experienced during exacerbations and with exercise.To be consistent with a diagnosis of asthma, both laboredbreathing and chest tightness should diminish with bron-chodilator or anti-inflammatory therapy. However, whenthese symptoms are associated with exertion, they mayalso resolve with rest.

A family history of asthma, particularly in the parents orsiblings, is not part of the diagnostic criteria for asthma.However, it is supportive of the diagnosis if present.A history of eczema or allergic rhinoconjunctivitis also issupportive of the diagnosis, since these conditions oftencoexist with asthma. The review of systems is importantin excluding alternative diagnoses and identifyingcomorbid conditions.

Unless the patient is experiencing an exacerbation,there may be no physical findings consistent with thediagnosis of asthma on presentation, even if symptomswere present within the previous 24 hours. Many of

the physical findings of asthma, such as tachypnea andsubcostal retractions, are non-specific and reflect pul-monary compromise in general. Other signs, such aswheeze and a prolonged expiratory phase, are more spe-cific to intrathoracic airway obstruction, but are notexclusive to asthma. Furthermore, wheezing may bemissed during quiet breathing, or if the patient is so com-promised that there is inadequate airflow to produce awheeze. To avoid missing a wheeze, the patient should beencouraged to take a slow deep breath in and thenexhale forcefully. In a young or uncooperative child, theexaminer can compress the thorax anteroposteriorly tomimic a forced exhalation. It is important to note that whilethere are physical findings that are supportive of a diagnosisof asthma, these findings do not confirm the diagnosis.However, an observed improvement in these findings bythe examiner after bronchodilator administration demon-strates reversibility of airflow obstruction, a key compo-nent of the diagnostic criteria. Findings on physicalexamination that are not consistent with a diagnosis ofasthma should lead to an investigation of alternative diag-noses or comorbid conditions.


Laboratory investigations of the patient with asthmamay support the diagnosis, but no investigation canindependently confirm the diagnosis of asthma. Bloodeosinophilia can be found in patients with asthma, but isneither a universal nor a specific finding. Some patientswith asthma may have an elevated serum immunoglobu-lin E (IgE), but this finding is also non-specific. Althoughpatients with asthma often have atopy, RAST or skin testing may be negative; alternatively, demonstration ofsensitivity does not confirm a diagnosis of asthma.

Chest radiographic findings also are non-specific.These include hyperinflation, peribronchial thickening,and atelectasis, but the study can be normal as well(Figure 6-1). Radiographic examination is useful to ruleout complications of asthma when suspected, such aspneumothorax, pneumomediastinum, or large areas ofatelectasis.

School-age children and adolescents who can executea forced expiratory maneuver can perform spirometry atbaseline and following bronchodilator administration15.While some patients with asthma will exhibit airflowobstruction at baseline, spirometry is within acceptedreference limits in most children with asthma unlessthey are in the midst of an exacerbation16. A significantincrease in flows following bronchodilator administra-tion demonstrates full or partial reversal of airflowobstruction, but this finding represents only one com-ponent of the diagnostic criteria (Figure 6-2). Moreover,some patients with asthma and airflow obstruction maynot demonstrate reversal of the obstruction with the


Asthma 101

BAFigure 6-1 (A) Posterior-anterior chest radiograph of an 11-year-old boy with asthma during anacute exacerbation. The interstitial markings are mildly increased. The cardiothymic silhouette isnormal. (B) Lateral view, demonstrating mild hyperinflation with flattening of the diaphragm and anincrease in the retrosternal air space. (Radiographs courtesy of Avrum Pollock, M.D.)

standard dose of bronchodilator used in pulmonaryfunction laboratories.

When airway hyper-responsiveness cannot be estab-lished by history in a patient suspected of having asthma,an airway provocation test can be performed17. This testuses a physical stimulus (exercise, inhaled cold air, orhypertonic saline) or pharmacologic stimulus (inhaledmethacholine or histamine) to assess airway sensitivity(Figure 6-3). After baseline spirometry is performed, thestimulus is applied and titrated either by accumulatedtime that the stimulus is applied (e.g., cold dry air) or byincreasing dose (e.g., methacholine). Spirometry is per-formed again after the stimulus, and a significantdecrease in flows indicates airway hyper-responsiveness.Usually a bronchodilator is administered after the lastspirometry to assess the reversibility of the airflowobstruction. Widely accepted standards exist for the per-formance and interpretation of commonly used provoca-tive tests.

Airway provocation tests are usually employed when some of the clinical diagnostic criteria are present,suggesting the diagnosis of asthma, but a degree of

uncertainty exists. Provocative tests provide two of thethree criteria for diagnosis: airway hyper-responsiveness(abnormal decrease in expiratory flow following expo-sure to the stimulus) and reversibility of airflow obstruc-tion (expiratory airflow returns to baseline, exceedsbaseline, or at least improves significantly when a bron-chodilator is administered following a decrease in airflowprovoked by a stimulus). Within a population suspectedof having asthma, the sensitivity and specificity ofprovocative testing are both above 90%. However, thishigh sensitivity and specificity is dependent on the properperformance of the test on an appropriate patient andcorrect interpretation of the results.

Patients without asthma who have allergic rhinitis, res-piratory infections, or other airway diseases (bronchopul-monary dysplasia, cystic fibrosis) may have “positive”provocative tests on either a transient or a recurrent basis.It is therefore important to use provocative testing as aconfirmatory test in patients with a history of chronic orrecurrent symptoms of asthma. It is impractical to useprovocative testing as a screening tool for asthma in theclinical setting because of the time and expense of the test

and the lack of information on the significance of the testin asymptomatic individuals.

What constitutes a significant decrease after provoca-tion or increase after bronchodilator administration variesaccording to the provocative stimulus or bronchodilatorused and the type of measurement employed. Accordingly,normal values and significant changes in airflow areoften determined by the testing laboratories based onaccepted standards and modified as needed to reflect theindividual laboratory testing conditions and experiencewith the local population. In general, a 15–20% declinein the forced expiratory volume in the first second(FEV1) is considered to be a significant decrease afterprovocation, while a 12–15% rise in FEV1 after bron-chodilator inhalation constitutes a significant increase.

Any form of lung function testing should be per-formed by trained and experienced personnel usinghigh-quality calibrated equipment. Testers should havedemonstrated proficiency working with the age groupbeing tested, and the testing laboratory should have doc-umented testing procedure, quality assurance, and infec-tion control practices that conform to accepted standards.Suboptimal testing, including poor performance by thepatient, yields results that have little diagnostic value.

Likewise, interpretation of test results should be per-formed by individuals with expertise in lung functiontest analysis. In particular, provocative testing should beadministered and interpreted by qualified personsbecause of added safety concerns inherent in the testand the complex nature of the data generated.

Some experts advocate the widespread use of peakexpiratory flow (PEF) monitoring. A variety of simple andinexpensive peak flow meters are available for measuringPEF, but values from one device are not interchangeablewith those of another. Proper use of a peak flow meterrequires a period of 1–2 weeks of twice-daily use andrecording of values to establish the patient’s “personalbest.” Both the absolute value and degree of diurnal variability are used to determine the presence of bron-chospasm or airway hyper-reactivity. A maximal effort ismandatory to obtain information that accurately reflectsthe underlying condition of the airways. This high degreeof effort dependence, and the fact that PEF measurementsare fairly insensitive to changes in small airway caliber(Figure 6-2), limit the usefulness of routine PEF monitor-ing. PEF monitoring is poorly reproducible in school chil-dren18, and several studies show that it adds little toprograms of asthma education that stress symptom


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Figure 6-2 Spirogram obtained from a16-year-old girl with severe persistentasthma during an acute exacerbation. Atbaseline (smaller curve) there is significantreduction in flows through small airways,reflected by a markedly decreased value forForced Expiratory Flows between 25 and75% of the vital capacity (FEF25-75%). Thereis a dramatic increase in forced expiratoryflows at all lung volumes after inhalation ofalbuterol and ipratropium (larger curve).Note that peak expiratory flows arenormal both before and after broncho-dilator administration, despite the obviousreversible small airway obstruction. The triangle represents reference values forgender and height.

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Figure 6-3 Methacholine challenge in a 6-year-old boy with exercise-related dyspnea. Spirometryis performed after which a methacholine aerosol is administered. Spirometry is repeated after eachdose of methacholine administered, and the dose is doubled until the forced expiratory volume inthe first second (FEV1) falls by 20% or a maximum dose of methacholine is administered. (A) TheFEV1 as a percent of the baseline value before and after each doubling dose of methacholine. The FEV1 began to fall at 1 mg methacholine, and fell below the targeted range with the 4 mg dose.The dose of methacholine causing a 20% drop in the FEV1 was calculated to be 3.9 mg.Bronchodilator administration returned the FEV1 to its pre-challenge level. (B) Progression from anormal, convex expiratory flow-volume loop at 0.03 mg, 0.125 mg and 1.0 mg methacholine, to aconcave shape at 2.0 and 4.0 mg methacholine, reflecting small airway obstruction. The curve shapereverted to normal after administration of albuterol (not shown).

recognition by patient or caregiver. The greatest utilityof PEF monitoring, then, is for the subset of patients whoare not sensitive enough to recognize chest tightness orshortness of breath when symptoms begin to escalate.Such patients might benefit from routine PEF testing toidentify early signs of an acute exacerbation in order toinitiate therapy early.

DIFFERENTIAL DIAGNOSIS

There are several conditions that mimic asthma byproducing similar chronic or recurrent symptoms, orexist as comorbid conditions. These conditions are pre-sented in Table 6-2. In most cases, there is little or norelief from bronchodilator administration, and pulmonaryfunction tests are in the normal range. However, in manycases patients may report a substantial subjective reliefafter bronchodilator use, and some conditions can beassociated with spirometric abnormalities.

Sinusitis and other rhinosinal diseases can result incough from postnasal drip19. However, these disordersby themselves are not associated with wheezing, chestdiscomfort, or difficulty breathing. The cough associatedwith postnasal drip is usually most prominent upon lyingdown, and again first thing in the morning, but is notassociated with cough during exertion. There is usually norelief after bronchodilator use, and spirometry is normal inpatients without lower airway disease. Symptoms of nasaldisease are usually elicited, and nasal and pharyngeal dis-charge and irritation can be found. Identifying rhinosinaldisease, however, does not rule out asthma. Indeed,untreated sinusitis or rhinitis can act as a symptom triggerin patients with asthma, complicating treatment.

Gastroesophageal reflux (GER) can also mimic asthma,causing cough, wheeze, chest discomfort, and a percep-tion of labored breathing20. These symptoms can resultfrom microaspiration of refluxate, or can also occur dueto afferent stimulation of the esophagus from stomachacid. Most patients with GER, when questioned, willcomplain of burning, dyspepsia, or other symptoms ofgastroesophageal reflux disease (GERD). However, some

patients may have “silent reflux” and deny overt symp-toms, and have no evidence of esophageal irritation onendoscopy. Respiratory symptoms from GER typicallyoccur after eating or upon lying down, but can alsooccur at random times. Furthermore, patients with GERmay report decreased symptoms with bronchodilatoruse, and may exhibit subtle abnormalities on spirometry.Consequently, it can be extremely difficult to differenti-ate asthma from GER. Diagnostic testing, such as gastricradionuclide scans or sustained esophageal pH record-ings, may demonstrate that the patient has GER, butsuch testing does not prove a link between the GER andrespiratory symptoms. Therefore, a trial of antacid ther-apy of at least 4–6 weeks may be necessary to determinewhether the symptoms can be attributed to GER. Even ifsymptoms decrease over time with antacid therapy, thepatient can still have asthma that is being exacerbated by GER.

Although foreign body aspiration usually presentswith acute onset of symptoms, unwitnessed inhalationof a relatively small foreign object can result in moreindolent symptoms of cough and wheeze that can bemistaken for asthma. Although the aspiration event itselfmight not be identified, the parent can usually pinpointthe precise day symptoms started. In addition, unlikeasthma, the symptom intensity in the patient with foreignbody aspiration usually is high initially, and stays thesame or even decreases slightly over time. The wheeze, ifpresent, will usually be homophonous and can often belocalized. There is minimal relief after bronchodilatoruse, and if the child is old enough to perform spirometry,a fixed expiratory airflow obstruction might be present.If foreign body aspiration is being considered, thoroughairway endoscopy should be performed.

Chronic aspiration due to swallowing dysfunction canalso produce cough and wheeze, resulting in an erro-neous diagnosis of asthma. Although typically occurringin patients with underlying neurologic disease or subtleupper airway anatomic abnormalities, swallowing dys-function can also occur in an otherwise normal child. Inmost cases, the symptoms occur only during oral feed-ing, and are otherwise absent. However, symptoms mayoccur from aspiration of oral or nasopharyngeal secre-tions or from gastric refluxate. This latter scenario ismostly limited to patients with neurodevelopmentalchallenges. Patients with suspected swallowing dysfunc-tion should be evaluated by a speech therapist in con-junction with swallowing videoradiography. Gastricradionuclide scan might show aspiration of gastric reflux-ate, but usually only massive aspiration will be detectedwith this test. Aspiration of oropharyngeal secretions isdemonstrated by a radionuclide salivagram.

Patients with intrinsic intrathoracic airway abnormal-ities can present with wheezing and difficulty breathing.These abnormalities, ranging from tracheobronchomalacia


Table 6-2 Differential Diagnosis

Disease Diagnosis

Rhinitis ClinicalSinusitis CT of sinusesGastroesophageal reflux Radionuclide scan, pH probeForeign body EndoscopyChronic aspiration Swallowing study, salivagramAirway compression Endoscopy, CT, MRICystic fibrosis Sweat test

to bronchial stenosis, can be congenital or acquired.Characteristically the wheeze is homophonous, and thedifficulty in breathing occurs during respiratory chal-lenges such as with exercise and during respiratory tractinfections. There is no relief with bronchodilator admin-istration, and wheezing can increase after bronchodilatoruse in patients with tracheomalacia or bronchomalacia.Spirometry in these patients reveals fixed airflow obstruc-tion. Classically, airway endoscopy has been used tocharacterize the airway abnormality. More recently, fixed-caliber airway abnormalities have been evaluated usinghigh-resolution computed tomography, while dynamicairway collapse has been demonstrated using cine-computed tomography.

Extrinsic intrathoracic airway compression can alsomimic asthma, and presents with the same characteris-tics as intrinsic airway abnormalities. The airways inthese cases are usually compressed either by an aberrantvessel or by a mediastinal tumor. The compressed areacan be visualized by airway endoscopy, but thisapproach will not definitively identify the compressingobject. Computed tomography with intravenous con-trast is the investigation of choice if airway compressionis suspected.

Cystic fibrosis may be mistaken for asthma, particu-larly in younger children or in CF patients who havemild disease. Symptoms can be identical, and relief mayoccur after bronchodilator therapy. Spirometry can benormal, or airflow obstruction can be present and pos-sibly reversible with bronchodilator administration.Non-specific triggers, such as exercise or fumes, mayexacerbate symptoms. Pathognomonic productivecough and failure to thrive may be subtle or absent.Although cystic fibrosis occurs most commonly in

Caucasians, it is found in patients of all ethnic back-grounds. A sweat test or genetic testing for cystic fibro-sis should be strongly considered when evaluating achild with cough, wheeze, and labored breathing, espe-cially if symptoms are present from early childhood anddigital clubbing is present.

CLASSIFICATION OF ASTHMA SEVERITY

Once the diagnosis of asthma is confirmed, the sever-ity of disease should be classified in order to guide ther-apy. National guidelines provide an outline for theassessment of severity1. Similar to the diagnostic criteriafor asthma, severity is mainly assessed by report of symp-toms, and the classification is therefore limited by theaccuracy of the reporter. Information solicited for classi-fication of severity includes the frequency of symptomoccurrence within a defined period and the subjectiveassessment of the impact of these symptoms on activitiesof daily living. Spirometry is also used for classificationfor those patients who can reliably perform pulmonaryfunction testing.

To minimize inaccuracy that may result from memorylimitations, the frequency and severity of symptoms arerecounted by the historian within a defined 2–4 weektime period.

The initial publication of the National Institutes ofHealth Guidelines for the Diagnosis and Treatment ofAsthma identified four categories of severity1: mild inter-mittent, mild persistent, moderate persistent, and severepersistent. These categories of severity, along with treat-ment recommendations, are summarized in Table 6-3.The word “persistent” actually refers to the persistence

Asthma 105

Table 6-3 Classification of Asthma Severity

Severity Symptom Frequency Lung Function (% predicted) Recommended Therapy

Mild intermittent < 2 days/week FEV1 > 80% Short-acting beta-agonist (SABA) PRN< 2 nights/month<3 episodes/year

Mild persistent ≥ 2 days/week FEV1 > 80% Low-dose inhaled corticosteroid (ICS)≥ 2 nights/month Leukotriene modifier ≥ 3 episodes/year Cromones

MethylxanthinesModerate persistent Daily FEV1 80–60% Moderate-dose ICS

1 night/week orCombination ICS plus:

(a) long-acting beta-agonist (LABA) or(b) leukotriene modifier

Severe persistent Continuous during day FEV1 < 60% Combination high-dose ICS or oral corticosteroidEvery night plus long-acting beta-agonist (LABA),

leukotriene modifier, methylxanthine

of symptoms, rather than the persistence of the severityor of the disease. Therefore, patients with mild persist-ent asthma have fewer symptoms that affect activities ofdaily living to a lesser degree than those with moderateasthma. As symptom frequency and activity limitationincrease, the severity escalates to moderate or severe.However, a patient with mild persistent asthma can stillhave a severe exacerbation. In fact, a study of asthmamortality revealed that a third of patients who died fromasthma were classified as having mild asthma21.

The classification of mild intermittent asthma pro-vides for an interesting paradox. As a chronic disease,asthma is always present in an affected individual, yetthe disease may be quiescent and produce no symptomsfor months. However, the potential for onset of symp-toms, or even an asthma exacerbation, exists even forpatients with very intermittent symptoms. In addition,airway inflammation can be present at low levels, belowthe threshold that would cause discernible symptoms ormeasurable changes in lung function, in patients with so-called intermittent asthma. Therefore, this term issomewhat misleading, since it is not possible to discerneasily whether it is the disease process that is presentonly intermittently or the symptoms.

So-called exercise-induced asthma exists as a sub-classification of mild intermittent asthma22. This term isalso misleading, since exercise does not confer asthmaon the would-be athlete, but rather brings out the symp-toms of asthma. In these cases exercise by itself is not atrigger in the usual sense. Exercise of all but the briefestduration causes an increase in minute ventilation, andthis increase overwhelms the normal heating and humid-ification process in the upper respiratory system andallows cooler, drier air into the lower airways. In theory,the cooler, drier air irritates the bronchial airways of theperson with asthma, and asthma symptoms arise. Thiseffect is more intense in an individual experiencing anasthma exacerbation, and leads to speculation thatasthma symptoms during exercise may be an indicator ofthe relative degree of inflammation of the airway. If thistheory is true, it suggests that patients with exercise-induced asthma have persistent airway inflammation, andtherefore should receive daily anti-inflammatory therapy.Indeed, in many patients who present with complaintsof asthma symptoms only with exercise, a careful historyreveals that they also have asthma symptoms at othertimes. However, it should be noted that while anti-inflammatory therapies decrease the degree of airwaycompromise, as measured by exercise testing, they donot completely ablate the reduction in expiratory flowobserved in patients with asthma.

Since asthma can be highly variable from day to day,season to season, and year to year, patients may movefrom one classification to another independent of medicalintervention. Asthma symptoms also episodically worsen,

and this should be termed an asthma exacerbation. Thepopular term “asthma attack” should be avoided, since itdescribes the patient as a victim, and the disease as anepisodic aggressor. Asthma exacerbations can varywidely in severity, and there is no uniform classification.The term “status asthmaticus” is still employed todescribe a serious asthma exacerbation. Classically, thisterm was used when a patient with obvious respiratorycompromise did not improve significantly after threesubcutaneous injections of a sympathomimetic, andimplied that the patient was at risk to develop respira-tory failure and would require intensive inpatient ther-apy. Presently, the term is sometimes applied in a similarfashion, but more often describes a patient who is notwheeze-free after three consecutive treatments with an inhaled bronchodilator. While this term does imply a serious condition that warrants at least inpatient therapy, it has less precision in describing the actualcondition of the patient.

THERAPY FOR ASTHMA

Pharmacologic Therapy

The overall objective of therapy for the child withasthma is to maintain disease control. The specific goalsof therapy are:• Minimal (ideally no) chronic symptoms, including

nocturnal symptoms• Minimal (infrequent) exacerbations• No emergency visits• Minimal (ideally no) use of as-needed

beta2-agonist• No limitations on activities, including exercise• Near-normal pulmonary function test• Minimal (or no) adverse effects of medication.

Asthma therapies can be categorized in three ways: aschronic and acute therapy, as inhalation and systemictherapy, and as anti-inflammatory and bronchodilatortherapy. While it is helpful to consider the availableasthma therapies within these classification schemes,there is overlap in each grouping. For example, anti-inflammatory medications are the mainstays of chronictherapy but are also used in acute therapy. Similarly, the systemic availability of inhaled medications is dose-dependent, and some anti-inflammatory medica-tions may also cause some degree of bronchodilation.Therefore, the classification of asthma therapy is helpfulin understanding the application of the therapy in thecontext of treating a patient with asthma, but not as a way of describing the inherent properties of the medications.

Since asthma is confined to the airways, inhalationtherapy is employed as a kind of “topical” therapy inorder to limit drug exposure to the target organ and


to avoid systemic side effects. This elegant concept,however, is fraught with practical difficulties. First, med-ications need to be developed into a formulation thatcan be safely and effectively inhaled. This limits the med-ications to those that are completely soluble in aqueoussolutions with a neutral pH. Second, the respiratory sys-tem is designed to circulate gas in and out of the airwayswhile filtering out particulate matter. Therefore, the sizeof the medication particles has to be in the “respirablerange” (0.5–5 μm); that is, not so large that they gettrapped in the upper airway and not so small that they getexhaled without settling on the airway. Finally, whilechemical absorption occurs to a lesser degree along the airways than in the alveoli, substantial drug absorp-tion can still take place through the bronchial mucousmembranes. Medications should therefore be active atthe airway surface, but should either be poorly absorbedinto the circulation or be systemically inactive. Consideringthese limitations, effective inhalation therapy is difficultto achieve.

Inhaled medications are mostly delivered either bynebulization or with metered-dose inhalers. Nebulizationis a process by which energy is applied to a solid or liquidto produce a vapor. The earliest nebulization therapyinvolved applying heat to a liquid to produce steam orburning a substance to produce smoke. Modern nebu-lization techniques utilize either vibration or jet streamsof gas to produce a vapor. Ultrasonic nebulizers work byproviding vibrational energy to a discrete amount of liquid. While this method can nebulize a large amount offluid within a short time, the resultant vapor particles arelarge and tend to settle out on the upper airway surfaces.Jet nebulizers utilize a high-velocity gas stream, providedeither by a compressed gas source or by a compressor,to broach a gas-liquid interface and “drag” the liquid particles into the stream, producing a vapor. Jet nebuliz-ers take longer to aerosolize a discrete amount of liquid,but produce more particles that are within the respirablerange.

While jet nebulizers seem easy to use, they are ineffi-cient as drug delivery devices. Inhalation of the vapordischarged in the vicinity of the nose and mouth, the so-called blow by technique, delivers less than 10% of thenebulized medication into the lower airways. Using amask over the nose and mouth at the point of deliveryimproves this percentage to about 15%. In the best-casescenario, in which the patient receives the vapor using amouthpiece while sitting or standing, inhaling slowlyand deeply, and holding the breath for 5–10 seconds,delivery can be improved to 25–30%. Furthermore, med-ication delivery using jet nebulizers is time-consuming.Depending on the power of the compressor, it usuallytakes 5–15 minutes to nebulize 3 ml of liquid fully. Inaddition, the bulkiness of the compressor and the needfor a power source limit the portability of this therapy.

Asthma 107

Considering the inefficiency and use limitations of this delivery method, it should be used only if the med-ication cannot be delivered safely and effectively by anyother means.

Metered-dose inhalers (MDIs) are available in twoforms: as pressurized canisters (pMDIs) and as dry pow-der inhalers (DPIs). Both devices deliver a discrete quan-tity of medication per administration cycle, hence“metered-dose,” and therefore an MDI contains a setnumber of doses. Medication in the pMDI is dischargedfrom the canister by actuating the inhaler. In most cases,this is achieved by compressing a triggering device,although some pMDI are breath-actuated and are triggeredby the patient inhaling at the mouthpiece. Medicationfrom a DPI is delivered by active inhalation from thepatient.

MDIs are portable, less expensive, and more efficientat medication delivery than nebulizers, but are more dif-ficult to use correctly. Medication from a pMDI is dis-charged at a high initial velocity. If a patient dischargesa pMDI while the mouthpiece is at the lips, much of themedication will impact the oropharyngeal structures andwill be swallowed, thereby decreasing the amount of med-ication delivered to the airways. Even in a well-coordinatedindividual, only 15–25% of the medication will reach thelower airways by this method.

Efficiency increases if the patient uses a spacer, whichis a conduit that provides a set distance between thepMDI and the lips. Medication delivery can be furtheroptimized using a fixed-volume holding chamber. Thisdevice is a spacer modified with valves that hold themedication in the chamber until the patient inhales.Both spacers and holding chambers can be fitted witheither a mouthpiece, or a mask for infants and childrenwho cannot use a mouthpiece. When using these devices,the patient should actuate the inhaler then either take aslow deep breath and hold the breath for 5–10 seconds,or take 6–10 normal breaths while the mask or mouth-piece is in place.

To use a DPI, patients must initiate an inhalation thatis above a set minimum flow rate. This forceful and sus-tained inhalation is necessary to extract the medicationfrom the inhaler. Therefore, this device should not beused by infants or children who cannot generate therequired inspiratory flow rate. Once the inhalation iscompleted, the patient should hold his or her breath for5–10 seconds.

While asthma is a chronic disease, there are episodicexacerbations that can occur, regardless of the severity.Therefore, both chronic and acute therapies are needed.The primary goals of long-term asthma therapy, referredto as controller therapy, include preventing exacerba-tions, decreasing or eliminating symptoms, and optimiz-ing lung function. Achieving these goals should result inan improved quality of life, as long as the therapies

imposed do not negatively impact the patient. The thera-pies, therefore, should be maximally effective but easy to implement and free of adverse experiences. Sincethe pathophysiology of asthma is caused by airwayinflammation and bronchoconstriction, asthma treatmentshould reduce and prevent inflammation and relax airwaysmooth muscle. The goals of acute therapy are to reversethe progression of an exacerbation and provide for a rapidrecovery to control of disease at baseline.

Controller Therapy

Inhaled CorticosteroidsInhaled corticosteroids (ICSs) provide the most effec-

tive anti-inflammatory therapy that can be used longterm with relative safety. ICSs are available in formula-tions for nebulization and in pMDIs and DPIs.

Corticosteroids enter the cell and bind to glucocorti-coid receptors at the nucleus. ICSs inhibit a broad spec-trum of inflammatory processes in the airway. ICSs alsoupregulate beta-agonist receptors, theoretically increas-ing the effectiveness of bronchodilators that stimulatethese receptors. However, ICSs also have the potentialof causing side effects attributed to glucocorticoids. For this reason, the daily dose of ICS should be as low aspossible while achieving the therapeutic goals.

Generally, therapeutic effectiveness and side effects aredose-dependent. However, topical potency and systemicbioavailability are two properties of ICSs that further dictate the relative benefits and risks of their use.Topical potency describes the degree of inflammatorywheal reduction achieved by a specified dose of the glu-cocorticoid, so that an ICS with a high topical potencycan reduce inflammation at a lower dose. Systemicbioavailability defines the amount of circulating gluco-corticoid that results from a fixed inhaled dose, so thatan ICS with a low systemic bioavailability will result in aminimal amount of glucocorticoid in the systemic circu-lation. Therefore, the ideal ICS will have a high topicalpotency and low systemic bioavailability.

In children with asthma, daily use of ICS decreasessymptom and exacerbation frequency and improves pul-monary function and exercise tolerance. Although somepatients may exhibit a “first dose” effect, usually patientswill not show improvement in symptom control untilthey have received at least 1 week of daily therapy. Thestarting dose of ICS is based on the severity classificationof the patient at the time of evaluation, and should beadequate to effect a significant reduction in symptomswithin 2 weeks. In most cases, the therapeutic effect willplateau in 6–8 weeks, and at this point the dose may bedecreased in a stepwise fashion. However, it is prudentto maintain the initial dose of ICS until the patient hascontact with some of the usual asthma triggers or weath-ers an exacerbation, in order to judge the effectiveness

of the dose in preventing symptoms and decreasing theseverity of exacerbations. If the patient demonstrates tol-erance to trigger exposure with few or no symptoms orhas a shorter or less severe exacerbation, the dose maybe decreased.

With each change in dose, the patient should be re-evaluated at regular intervals, and symptom and exacer-bation frequency and severity should be reviewed.Pulmonary function tests should also be performed at eachfollow-up visit. An increase in symptom or exacerbationfrequency or severity, or a decline in lung function, mayindicate that the ICS dose should be increased. In anindividual patient, the ICS dose may be titrated up ordown over time, and periodic re-evaluation is critical todetermine the lowest dose of ICS that will achieve thetherapeutic goals.

Since the majority of children have mild asthma, symp-tom control will be achieved at the lowest possible dailydose, and caregivers or health care providers are oftentempted to discontinue ICS therapy, either for a season(“medication holiday”) or indefinitely. In children whohave had persistent asthma symptoms over the age of 4 years this practice usually results in a relapse of symp-toms, or even an exacerbation. If ICS therapy is discon-tinued on a trial basis, an ICS, along with the means toadminister it, should be readily available. Therapy shouldbe reinitiated at the first indication that symptoms havereturned. Such patients should be evaluated yearly for areturn of asthma symptoms, and pulmonary function testsshould be obtained. ICS therapy should be reinstituted ifthere is a report of asthma symptoms, decreased exercisetolerance, or if there is a decline in lung function.

There are no data from placebo-controlled studies thatdemonstrate a benefit from the use of ICS as a short-termtherapy for exacerbations of asthma. However, observa-tions from a few case-control studies suggest that increas-ing the dose of ICS at the beginning of an exacerbationmay decrease the need for systemic corticosteroid use.

There are potential local and systemic side effectsrelated to ICS use. The most common side effect of ICSuse is oropharyngeal candidiasis. This side effect canusually be avoided by having the patient rinse theoropharyngeal cavity after ICS use and by the use of aspacer or holding chamber to minimize oropharyngealdeposition. Occasionally, dysphonia and reflex coughare associated with ICS use, and are more common inpatients who do not use a holding chamber duringadministration. Evidence to date suggests that chronicuse of ICS does not cause alterations in dental enamel orrespiratory tract mucosa and does not predispose theuser to dental caries or bacterial and viral infections.

Systemic side effects of chronic ICS use involve bonemetabolism and possible adrenal suppression. In the firstyear of use of some ICSs a small reduction in growthvelocity has been demonstrated. However, longer-term


studies of ICS use in children, as well as follow-up studies,suggest that there is no difference in ultimate heightbetween patients who use ICS as children and controls23.Biochemical evidence of bone resorption has beenobserved in both adults and children during ICS use.However, changes in bone mineral density have not beendetected in patients using ICSs in daily doses less than500 μg. Treatment with high doses of ICS has been associ-ated with suppression of the hypothalamic-pituitary-adrenal (HPA) axis in children, but doses less than 400 μgdaily are not normally associated with any significantsuppression. Rarely, posterior subcapsular cataracts havebeen associated with high-dose ICS use, but have notbeen reported at doses of ICS under 400 μg per day.

Systemic GlucocorticoidsIn patients with severe asthma or those who have

allergic bronchopulmonary aspergillosis, chronic systemicglucocorticoid therapy may be necessary. In thesepatients, therapy is initiated at a dose that will controlsymptoms, and then the dose is gradually tapered to thelowest dose that will still control symptoms. Often, thedose can be reduced to once every other day. Despite the use of low, alternate-day dosing, serious side effectsof chronic glucocorticoid use can still occur. At the onsetof chronic systemic glucocorticoid use, blood pressureand height should be measured. Baseline bone densito-metry and an ophthalmologic evaluation should also beperformed, and repeated annually. Patients requiringchronic systemic glucocorticoid use should be evaluatedfrequently, and blood pressure and height should becarefully tracked at each visit.

Cromolyn Sodium and NedocromilCromolyn sodium and nedocromil (cromones) are

non-steroidal inhaled anti-inflammatory medications thatare available as a nebulized formulation (cromolyn) andas pMDIs. Their mechanism appears to involve theblockade of chloride channels, and it is speculated thatthese drugs modulate mast cell mediator release andeosinophil recruitment to provide long-term control ofsymptoms. Their anti-inflammatory effect is moderatecompared with ICSs and therefore they are not usuallyrecommended as monotherapy. They are also less con-venient to use than are ICS, because they must be usedseveral times throughout the day for maximum effec-tiveness. However, these medications have an excellentsafety profile.

Leukotriene ModifiersLeukotriene modifiers (LMs) block the effects of

leukotrienes, biochemical mediators released from mastcells, eosinophils, and basophils. Leukotrienes havebeen demonstrated to contract airway smooth muscle,increase vascular permeability, increase mucus secre-tion, and attract and activate other inflammatory cells inthe airways of patients with asthma24. LMs are available

as oral medications and are prescribed once or twicedaily. Data from studies to date suggest that while LMswork well to control asthma symptoms in some patients,they are not effective in others. LMs are considered to bealternative therapy to ICSs, and are generally consideredto be effective as monotherapy only in patients withmild asthma. However, the concomitant use of LMs withICSs often allows for a reduction of the ICS dose whilemaintaining the same degree of symptom control. LMsshould not be used as quick-relief agents. LMs also havea benign side effect profile.

MethylxanthinesMethylxanthines are relatively weak bronchodilators

that are administered systemically. They have been used for treatment of acute exacerbations as well as forlong-term control of asthma symptoms. The most commonmethylxanthine used for asthma treatment is theophylline.In addition to its bronchodilator effects, theophylline hasalso been shown to increase respiratory drive and sen-sitivity to blood pCO2, and to increase diaphragmatic contractility. These latter effects make theophylline a use-ful drug for patients with asthma who are in impendingrespiratory failure.

Because of their variable absorption and high sideeffect profile, methylxanthines are presently consideredless favorable for daily use. In addition, drug levels must bemonitored to assure that they are within the therapeuticrange, especially because metabolism can be affected bysimultaneous use of other medications or viral infections,and toxic levels are associated with serious side effects,such as seizures and cardiac arrhythmias.

Long-Acting Beta-AgonistsLong-acting beta-agonists (LABAs) have both a longer

onset of action (about 20 minutes) and a longer durationof action (up to 12 hours) compared with short-actingbeta2-agonists. Presently, all are available in the UnitedStates only as DPIs, although an MDI form of salmeterolis available in Europe and Canada. Side effects, such astachycardia and jitteriness, are much less common withLABAs than with short-acting beta-agonists, provided thatthe LABA is not overused. LABAs should only be used inconjunction with ICS therapy when asthma symptomsare incompletely controlled by ICSs alone. Their use hasbeen shown to permit a significant reduction in the doseof ICS required for symptom control25. LABAs are espe-cially useful for children with persistent nocturnal symp-toms or exercise-induced asthma (EIA). Because theironset of action is relatively long, LABAs should not beused as quick-relief medication for treatment of acuteexacerbations.

Anti-immunoglobulin EAnti-immunoglobulin E therapy has been shown to

decrease the frequency of asthma exacerbations and toallow for a decrease in ICS daily dose. Anti-IgE reduces

Asthma 109

free serum IgE levels and therefore averts inflammatorycell degranulation by preventing the binding of IgE to itshigh-affinity receptor. Anti-IgE is administered by injec-tion and is given monthly. Because of the cost and com-plexity of this therapy, its use is generally confined topatients with moderate or severe asthma.

The assessment of the severity of disease determinesthe plan of maintenance therapy for a patient. As diseaseseverity increases, the daily dose of ICS increases, andother medications can be used in conjunction with ICSs tomaintain disease control. When initiating therapy, the phi-losophy of treatment is to gain control then “step down.”Therefore, initial therapy will utilize the regimen that willmost likely achieve disease control, and subsequent ther-apy should be judiciously reduced to establish the lowestamount of medication required to maintain control. TheNational Institutes of Health Guidelines for the Diagnosisand Treatment of Asthma1,26 recommends a stepwiseapproach to the pharmacologic management of asthma.These recommendations are summarized in Table 6-3.

Since the mainstay of asthma management is daily useof controller medications over many years, concernsabout the medications’ effects and side effects should beexplored and addressed to assure adherence27. This isespecially true regarding ICS use. Many families andpatients are reluctant to use steroids at all, let alone for along period of time. Therefore, patients and caregiversshould be educated about the benefits of ICS use as wellas the common side effects and how to minimize or prevent them.

Acute Therapy

Short-Acting Beta-AgonistsShort-acting beta-agonists (SABAs) have been the

mainstay of acute asthma treatment in children for manyyears. These drugs are by far the most effective “quick-relief” bronchodilators available and therefore are thefirst-line treatment for acute asthma exacerbations.Although earlier preparations of beta-agonists stimulatedboth beta-1 and beta-2 receptors (i.e., isoproterenol,isoetharine), more recent preparations are considered“selective” because they stimulate primarily beta-2receptors. As such, they cause fewer extrapulmonarysymptoms such as tachycardia, although side effects areexperienced with frequent or higher doses. These drugsare available in oral tablet or liquid, inhaled MDI, DPI ornebulizer solution, or intravenous preparation. Rapid-acting beta2-agonists preferably should be given viainhalation to maximize efficacy and minimize side effects.However, delivery of inhaled medication may be sub-optimal in patients with acute respiratory distress andairway narrowing. In these clinical situations, subcuta-neous or intravenous administration of beta-agonist maybe more effective than inhaled therapy.

Onset of action of short-acting beta2-agonists is usuallywithin 5 minutes when given by inhalation. The typicalduration of bronchodilation produced by a single dose ofrapid-acting inhaled beta2-agonist in children is 1–5 hours.Side effects of beta2-agonists include tremors, tachycar-dia, “hyperactivity,” and hypokalemia. During frequent orcontinuous administration of beta-agonists during acuteexacerbations, patients should be observed for these sideeffects, and the dose should be decreased in amount andfrequency as tolerated as quickly as possible.

Beta2-agonists should always be prescribed as quick-relief therapy for all patients with asthma unless thepatient has a well-defined intolerance for any form of thedrug. The patient should use the beta2-agonist as neededfor symptom relief. Sporadic use of beta2-agonist generallysignifies good disease control, whereas patients who areusing their beta2-agonist frequently probably require addi-tional controller therapy. For patients with exercise-relatedsymptoms, inhalation of beta2-agonists can offer significantprotection against exercise-induced symptoms28.

Anticholinergic agents have a limited role in the treat-ment of children with asthma. Like beta-agonists, theycause relaxation of airway smooth muscle, but by thecholinergic, not adrenergic, pathway. There is some evi-dence that concomitant use of anticholinergic agentswith inhaled beta2-agonists provides additive benefit insevere asthma exacerbations29. Their effectiveness inlong-term management of asthma has not been demon-strated. Anticholinergics are available in formulation fornebulization as well as in pMDI for inhalation.

Systemic GlucocorticoidsSystemic glucocorticoids are often required to treat

asthma exacerbations. Oral glucocorticoids should be usedin patients who develop asthma symptoms that do notfully diminish with the use of short-acting beta-agonists.Intravenous glucocorticoids may be administered inpatients who cannot tolerate oral medications, but thereare no data demonstrating that intravenous administra-tion is superior to oral dosing in terms of efficacy.

In general, prednisone or prednisolone in doses of1–2 mg/kg per day should be prescribed for a duration of3–7 days. Therapy of longer duration may be necessary inpatients with severe disease or in patients who haveexperienced an exacerbation in the recent past. There isno evidence to suggest that twice-daily dosing is supe-rior to once-daily dosing, and morning administration ofglucocorticoid will decrease the incidence of sleep dis-ruption experienced by some patients. There is no needto taper the dose of glucocorticoid unless the course oftherapy is longer than 7 days, the patient recently finisheda course of systemic steroid therapy, or the patient receiveschronic systemic glucocorticoid therapy. Side effects ofshort-term systemic glucocorticoid therapy include waterretention, mood changes, and increased appetite.


Asthma exacerbations can occur at any time, but theyoccur less frequently in patients whose disease is wellcontrolled. An exacerbation can develop quickly, usuallyas a result of exposure to a trigger such as a viral infec-tion or an allergen that causes airway inflammation.However, an exacerbation can also develop slowly, witha more gradual pattern of deterioration that may reflectfailure of long-term management to control airwayinflammation adequately.

It is important to recognize the asthmatics who are atincreased risk for severe or even fatal asthma. Patientswith a history of near-fatal asthma requiring intubationand mechanical ventilation have a 19-fold increased riskof needing intubation during subsequent exacerbations.Other risk factors include: patients who have had a hos-pitalization or emergency care visit for asthma in thepast year; patients who are not currently using inhaledglucocorticosteroids or who are dependent only, ormostly, on rapid-acting inhaled beta2-agonists; andpatients with a history of non-adherence with an asthmamedication plan. In addition, significant morbidity andmortality are most often associated with failure to rec-ognize the severity of the exacerbation30.

Initiation of appropriate therapy at the earliest possiblesigns of deteriorating control of asthma is important in thesuccessful management of asthma exacerbations31,32.Initial treatment of an asthma exacerbation should start athome. Parents and patients should be instructed to startacute relief medication, i.e., short-acting beta2-agonists,with the first signs or symptoms of an asthma exacerba-tion. There is some evidence that increasing the dose of ICSs, together with recurrent doses of short-actingbeta2-agonist, can resolve an acute asthma exacerbationfaster compared with inhaled beta2-agonist use alone.Studies have also suggested that increasing ICS therapyat the first signs of upper respiratory infection can pre-vent an asthma exacerbation33. Failure to respond tothese initial measures should prompt further evaluationand treatment by medical caregivers. Medical attentionshould be sought if the patient is at a high risk forasthma-related death, the response to the bronchodilatoris not prompt and sustained for at least 3 hours, or thereis no improvement or even deterioration 2–6 hours afterglucocorticosteroid treatment is started.

The primary therapy for an asthma exacerbation in amedical facility is the repetitive administration of rapid-acting inhaled beta2-agonist and the early introduction ofsystemic glucocorticosteroids. The patient should beclosely monitored, since children with asthma may dete-riorate rapidly. Oxyhemoglobin saturation should alsobe assessed to insure that there is adequate oxygen saturation. Patients who are hypoxemic should receivesupplemental oxygen34. Along with the increase ininflammation and airway swelling, small areas of atelec-tasis form secondary to mucous plugging. These areas

lead to ventilation perfusion (V•

/Q•

) imbalances, which inturn cause a decrease in oxygen saturation. Occasionally,the oxygen saturation will drop as inhaled beta-agonist is given. This phenomenon is thought to reflect anincrease in V

•

/Q•

mismatch due to the vasodilatory effectof albuterol. Persistent oxyhemoglobin desaturationoften suggests a potential severe exacerbation, and patientswith low oxygen saturation in room air should be consid-ered for admission to the hospital. If blood gas tensionsare measured in a patient with an asthma exacerbation,the pCO2 should be below 40 torr. A normal or high pCO2in this clinical scenario at best suggests a severe exacer-bation and may signify impending respiratory failure.

Addition of an anticholinergic drug might be consid-ered if the improvement following recurrent doses ofalbuterol is not satisfactory. Ipratropium bromide can beadded to the beta-agonist, as some studies showed anadded benefit of the practice in acute settings. If little orno improvement is seen following initial intensive man-agement, the patient will probably require continuedaggressive therapy and expert monitoring, with admis-sion to the hospital.

Hospital management of the patient with asthmashould provide continuous therapy that is modulatedbased on frequent assessment. In addition to assessingvital signs and oxyhemoglobin saturation, work ofbreathing and gas excursion should be taken intoaccount in tandem. The presence or absence of wheezeis less relevant, since wheeze may be present in a patientwho is nearly fully recovered and may be absent in apatient with impending respiratory failure.

Frequent or continuous beta-agonist inhalationshould be administered, along with systemic glucocorti-coid therapy. Supplemental oxygen should be adminis-tered if needed, and intravenous fluids should be providedif the patient cannot maintain adequate oral hydration. As the patient improves, bronchodilator therapy can bereduced. Patients who fail to improve despite therapyshould be assessed for comorbidities, and patients whosecondition worsens should be transferred to an intensivecare setting. In some cases, patients appear to improve interms of decreased work of breathing but continue tohave low oxyhemoglobin saturation. It is likely thatatelectasis has occurred in these patients, and airwayclearance and increased activity out of bed will hastenthe resolution of this comorbidity.

It should be noted that full recovery from the exacerba-tion is often gradual, and medications for the exacerbationmay need to be continued for several days to sustain reliefof symptoms and improvement in pulmonary function.

Non-Pharmacologic Therapy

As with any chronic disease, the cornerstone of successful asthma therapy lies with patient education.

Asthma 111

In order to insure adherence with therapy and propermedication administration, the patient and caregiversshould have a thorough knowledge of asthma and asthmatherapy. It is important that patients and caregiversunderstand what asthma is and that it is a chronic diseasethat is constantly present, regardless of the presence orabsence of symptoms.

Education should start at the time of diagnosis andshould be incorporated into each visit35. The key factsthat should be repeatedly assessed are the patient’s andfamily’s understanding of the basic facts about asthma,the role of medications, correct technique of inhaler use,environmental control measures, and when and how totake rescue medications36.

All patients should have a written management planthat outlines the patient’s daily therapy, how to recognizesigns of deterioration and assess the severity of symptoms,and when to modify or augment treatment, or obtainmore specialized care if appropriate (Figure 6-4). Thistreatment plan should be devised with the specific knowl-edge of the patient’s and caregiver’s lifestyle and means,and ideally it is done in partnership with the patient andcaregiver. Developing an asthma action plan togetherwith the patient and caregiver involves the patients (orthe family) in their own management plan. A “joint effort”will increase the probability that the plan can be carriedout successfully in terms of daily schedule and the amountof medications. The final written management planshould be shared with all potential caregivers, includingday care providers and school health care workers.

Each asthma patient has triggers that can lead to anacute exacerbation. It is important for each patient tosort out each precipitating factor and try to avoid themas much as possible. Such factors include allergens (envi-ronmental and household), air pollutants (cigarettesmoking), respiratory infections, exercise and hyperven-tilation, weather changes, sulfur dioxide, foods and drugs,and extreme emotional expression.

One of the most common exacerbating factors inasthma is allergic sensitization. To eliminate these externalfactors one must first attempt to determine the patient’sexposure to allergens. This can be done mostly by review-ing the patient’s exposure history or by using skin testing.If an allergen is not found, but there is a strong clinical sus-picion for an allergic component of asthma, or if there isan allergen that cannot be completely avoided (e.g., grass,trees), a trial of antihistamine medication, with or withoutnasal steroid preparation, should be instituted with a goalof symptom control. In some patients, immunotherapy(allergy vaccines or “shots”) is warranted.

COMPLICATING FACTORS

Once a diagnosis of asthma is made, the severity classified, and the appropriate treatment plan is given

and explained, a reasonable control of symptoms shouldbe expected. However, in some cases the patient’ssymptoms do not diminish despite what seems to beappropriate therapy. This often gives rise to so-calledsteroid-dependent asthma patients. Although there are afew patients who do require low-dose systemic steroids tocontrol their disease, this condition is rare in pediatrics.In such cases there is often a complicating factor thathas not been discovered or properly treated.

The most common pitfall in asthma management ispoor adherence to the asthma management plan.Reasons for poor adherence include a lack of under-standing of disease chronicity, the patient’s poor per-ception of his or her asthma severity, concerns about thesafety and efficacy of medication, and low treatmentexpectations. Good patient education that includesexplanation of the disease and its pathophysiology, aswell as the medications’ mechanisms of action and sideeffects, increases the patient’s understanding andacceptance of treatment. Reassessment of the patient’sor family’s perception of the disease and the treatmentplan, with recurrent exploration of treatment barriers,will assure better adherence and cooperation.

Another common reason for treatment failure is theincorrect use of inhaled medications. Errors in inhaledmedication administration include using an inhaler thatno longer contains medication, improper operation ofthe device, and failure to actuate the inhaler, inhale themedication properly, or use a holding chamber. At eachvisit the correct use of MDI, DPI or nebulizer should beassessed, and the correct method for determining therefill time of the device should be confirmed.

Continued exposure to triggers is another cause forincomplete symptom control. Questions about exposureto animals or tobacco smoke should be asked in relationto all venues the child may visit. If trigger avoidance hasbeen maximized, an evaluation for allergic triggers andcandidacy for immunotherapy should be considered.

Comorbid conditions, such as rhinitis, sinusitis37, andgastroesophageal reflux38, should be considered inpatients who do not respond fully to appropriate con-troller therapy. Rhinitis or sinusitis may cause (throughinflammation or infection) continuous irritation of thesinopulmonary tree. Allergic rhinitis should be treatedwith antihistamines and intranasal steroids, while rhinitisshould be treated with decongestants. Sinusitis should betreated with a suitable antibiotic regimen, along withdecongestants to allow drainage of the sinuses.

Gastroesophageal reflux (GER) has frequently beenshown to coexist with asthma. Often, uncontrolledasthma can, in turn, worsen GER through hyperinflationand increased intra-abdominal pressure. An assessmentfor GER should always be considered in a patient whoseasthma is uncontrolled despite therapy.

Allergic bronchopulmonary aspergillosis (ABPA), anextreme sensitivity to the mold Aspergillus fumigatus,


Asthma 113

Figure 6-4 Typical asthma action plan, detailing prescription for controller (every day) medica-tions and steps to be taken in case of an escalation of asthma symptoms. (Courtesy of The CHOPAsthma Initiative.)


MAJOR POINTS

• Asthma is a common, chronic disease that affectsinfants, children, adolescents, and adults, and itsseverity, course, and progression are variable bothamong patients and within an individual patient.

• The precise etiology of asthma is not known,although there appear to be both genetic andenvironmental factors involved.

• The diagnosis of asthma is made primarily by historyof symptoms that are recurrent, occur in responseto a trigger, and are reversible with asthmamedications; the most common symptom is cough.

• A successful treatment plan for asthma includesdaily controller therapy, availability of relievertherapy, and thorough patient education.

• When patients with asthma fail to improve despitethe proper prescription of controller therapy, aninvestigation of potential complicating factorsshould be performed.

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and aspirin sensitivity are rare entities in children withasthma. However, these conditions can also result inpoor asthma control. The diagnosis for ABPA is usuallycentered on a very high serum IgE level, while the diag-nosis of aspirin sensitivity is discovered by careful history.Since the evaluation and treatment of these entities iscomplex, patients suspected of having these disordersshould be evaluated by an asthma specialist.

Finally, a consideration of misdiagnosis or incompleteevaluation must be considered in the pediatric patientwith asthma who fails to demonstrate improvementdespite what seems to be proper therapy. Referral to anasthma specialist should be considered in cases wherethe patient is not meeting the goals of therapy after suit-able interventions have taken place or if the patientrequires specialty testing, has severe asthma, or has a his-tory of life-threatening exacerbations.

5. Tuffaha A, Gern JE, Lemanske RF Jr. The role of respiratoryviruses in acute and chronic asthma. Clin Chest Med21:289–300, 2000.

6. Djukanovic R, Feather I, Gratziou C, Walls A, Peroni D,Bradding P, et al. Effect of natural allergen exposure duringthe grass pollen season on airways inflammatory cells andasthma symptoms. Thorax 51:575–581, 1996.

7. Nafstad P, Kongerud J, Botten G, Hagen JA, Jaakkola JJ. Therole of passive smoking in the development of bronchialobstruction during the first 2 years of life. Epidemiology8:293–297, 1997.

8. Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB,Boehmer SJ, Krawiec M, et al. Atopic characteristics of chil-dren with recurrent wheezing at high risk for the develop-ment of childhood asthma. J Allergy Clin Immunol114:1282–1287, 2004.

9. Martinez FD, Helms PJ. Types of asthma and wheezing. EurRespir J Suppl 27:3s–8s, 1998.

10. Guilbert TW, Morgan WJ, Krawiec M, Lemanske RF, Jr.,Sorkness C, Szefler SJ, et al. The Prevention of Early Asthmain Kids study: design, rationale and methods for theChildhood Asthma Research and Education network.Control Clin Trials 25:286–310, 2004.

11. Dunnill MS. The pathology of asthma, with special referenceto changes in the bronchial mucosa. J Clin Pathol 13:27–33,1960.

12. Jacoby DB, Costello RM, Fryer AD. Eosinophil recruitmentto the airway nerves. J Allergy Clin Immunol 107:211–218,2001.

13. Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM.Asthma. From bronchoconstriction to airways inflammationand remodeling. Am J Respir Crit Care Med 161:1720–1745,2000.

14. Abramson MJ, Hensley MJ, Saunders NA, Wlodarczyk JH.Evaluation of a new asthma questionnaire. J Asthma28:129–139, 1991.

15. Bye MR, Kerstein D, Barsh E. The importance of spirome-try in the assessment of childhood asthma. Am J Dis Child146:977–978, 1992.

16. American Thoracic Society. Standardization of spirometry,1994 update. Am J Respir Crit Care Med 152:1107–1136,1995.

17. Cockcroft DW, Hargreave FE. Airway hyperresponsiveness.Relevance of random population data to clinical usefulness.Am Rev Respir Dis 142:497–500, 1990.

18. Frischer T, Meinert R, Urbanek R, Kuehr J. Variability ofpeak expiratory flow rate in children: short and long termreproducibility. Thorax 50:35–39, 1995.

19. Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F.Perennial rhinitis: an independent risk factor for asthma innonatopic subjects: results from the European CommunityRespiratory Health Survey. J Allergy Clin Immunol104:301–304, 1999.

20. Field SK. Gastroesophageal reflux and asthma: are theyrelated? J Asthma 36:631–644, 1999.

REFERENCES

1. National Heart, Lung, and Blood Institute. National AsthmaEducation Program. Expert Panel Report. Guidelines forthe diagnosis and management of asthma. J Allergy ClinImmunol 88:425–534, 1991.

2. The International Study of Asthma and Allergies inChildhood (ISAAC). Worldwide variations in the preva-lence of asthma symptoms. Eur Respir J 12:315–335, 1998.

3. Ramsey CD, Celedon JC. The hygiene hypothesis and asthma.Curr Opin Pulm Med 11:14–20, 2005.

4. Holgate ST. Genetic and environmental interaction in allergyand asthma. J Allergy Clin Immunol 104:1139–1146, 1999.

21. Turner MO, Noertjojo K, Vedal S, Bai T, Crump S,Fitzgerald JM. Risk factors for near-fatal asthma. A case-con-trol study in hospitalized patients with asthma. Am J RespirCrit Care Med 157:1804–1809, 1998.

22. Randolph C. Exercise-induced asthma: update on patho-physiology, clinical diagnosis, and treatment. Curr ProblPediatr 27:53–77, 1997.

23. The Childhood Asthma Management Program ResearchGroup. Long-term effects of budesonide or nedocromil inchildren with asthma. N Engl J Med 343:1054–1063, 2000.

24. Szefler SJ. Current concepts in asthma treatment in children.Curr Opin Pediatr 16:299–304, 2004.

25. Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, Lemanske RF Jr., Sorkness CA, et al. Long-acting beta2-agonistmonotherapy vs continued therapy with inhaled corticos-teroids in patients with persistent asthma: a randomizedcontrolled trial. JAMA 285:2583–2593, 2001.

26. National Asthma Education and Prevention Program.Expert Panel Report. Guidelines for the diagnosis and man-agement of asthma: update on selected topics 2002. J AllergyClin Immunol 110(5 Suppl):S141–219, 2002.

27. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-doseinhaled corticosteroids and the prevention of death fromasthma. N Engl J Med 343:332–336, 2000.

28. Sears MR, Taylor DR, Print CG, Lake DC, Li QQ, Flannery EM,et al. Regular inhaled beta-agonist treatment in bronchialasthma. Lancet 336:1391–1396, 1990.

29. Rebuck AS, Chapman KR, Abboud R, Pare PD, Kreisman H,Wolkove N, et al. Nebulized anticholinergic and sympath-omimetic treatment of asthma and chronic obstructive air-ways disease in the emergency room. Am J Med 82:59–64,1987.

30. Rodrigo G, Rodrigo C. Assessment of the patient with acuteasthma in the emergency department. A factor analytic study.Chest 104:1325–1328, 1993.

31. Cowie RL, Revitt SG, Underwood MF, Field SK. The effectof a peak flow-based action plan in the prevention of exac-erbations of asthma. Chest 112:1534–1538, 1997.

32. Jones KP, Mullee MA, Middleton M, Chapman E, Holgate ST.Peak flow based asthma self-management: a randomisedcontrolled study in general practice. British ThoracicSociety Research Committee. Thorax 50:851–857, 1995.

33. Ververeli K, Chipps B. Oral corticosteroid-sparing effects ofinhaled corticosteroids in the treatment of persistent andacute asthma. Ann Allergy Asthma Immunol 92:512–522,2004.

34. Lipworth BJ, Clark RA, Dhillon DP, Brown RA, McDevitt DG.Beta-adrenoceptor responses to high doses of inhaledsalbutamol in patients with bronchial asthma. Br J ClinPharmacol 26:527–533, 1988.

35. Wasilewski Y, Clark NM, Evans D, Levison MJ, Levin B,Mellins RB. Factors associated with emergency depart-ment visits by children with asthma: implications forhealth education. Am J Public Health 86:1410–1415, 1996.

36. Evans D. To help patients control asthma the clinician must be a good listener and teacher. Thorax 48:685–687,1993.

37. Watson WT, Becker AB, Simons FE. Treatment of allergicrhinitis with intranasal corticosteroids in patients with mildasthma: effect on lower airway responsiveness. J AllergyClin Immunol 91:97–101, 1993.

38. Nelson HS. Gastroesophageal reflux and pulmonary disease.J Allergy Clin Immunol 73:547–556, 1984.

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116

CHAPTER

7 Cystic FibrosisJUDITH A. VOYNOW, M.D.

THOMAS F. SCANLIN, M.D.

Definition

Genetics

Pathophysiology

Respiratory Tract

Gastrointestinal Tract

Sweat Glands

Reproductive Organs

Diagnosis

Clinical Evaluation

Pulmonary Function Tests

Sputum Microbiology

Chest Radiography

Nutrition

Reproductive Function

Therapy

Management of Pulmonary Disease

Mucociliary Clearance

Chest Physiotherapy

Antibiotics

Bronchodilators and Anti-inflammatory Therapy

Oxygen and Non-invasive Assisted Ventilation

Lung Transplantation

Management of Nutrition and Gastrointestinal Disease

Nutritional Support

Salt Replacement

Treatment of DIOS

Ursodeoxycholic Acid

Liver Transplantation

Summary

DEFINITION

Cystic fibrosis (CF) is an autosomal recessive disordercaused by mutations in a gene that encodes for a chlo-ride channel and ion conductance regulator, the cysticfibrosis transmembrane conductance regulator (CFTR).This disease occurs predominantly in Caucasians and is

ultimately lethal with a median survival of approximately31 years. The disorder affects exocrine glands with themajor manifestations involving the gastrointestinal andrespiratory tracts. The primary manifestations of the dis-ease include protein and fat malabsorption, and recur-rent bronchitis with organisms such as Pseudomonasaeruginosa leading to bronchiectasis and, ultimately,respiratory failure. Another cardinal feature of the dis-ease is excessive chloride concentrations in sweat,which is the basis for the first diagnostic test for the dis-ease. CF is difficult to diagnose and manage due to thegreat variability in its presentation and clinical course.Since the identification of the CFTR gene in 1989, therehave been significant advances in our understanding ofthe pathogenesis of the disease, which have spurred thedevelopment of new molecular approaches to therapy.This chapter will review the latest information on thegenetic, molecular, and cellular basis of the disease, andthen focus primarily on the clinical manifestations, com-plications, diagnosis, and current management of CF.

GENETICS

Cystic fibrosis is inherited as an autosomal recessivetrait. In the United States, the incidence of disease inCaucasians is approximately 1 in 3300, and in African-Americans, 1 in 15,000. The frequency of unaffected heterozygote Caucasian carriers is 1 in 25 (reviewed inWelsh et al.1 and Robinson and Scanlin2).

As mentioned above, CF is caused by mutations in thegene encoding a protein called the cystic fibrosis trans-membrane conductance regulator (CFTR). This genewas first identified in 19893 as a candidate gene for CFbecause of the linkage between the most common muta-tion of the gene and disease-affected individuals in largefamily cohorts. Complementation studies demonstratedthat transfection of the normal CFTR gene into native CF

Cystic Fibrosis 117

cells corrected a major physiologic abnormality in CFcells, abnormal chloride ion transport4. This provided theformal proof that mutations in the CFTR gene are respon-sible for CF.

The CF gene is located on chromosome 7, and is a 230 kb gene containing 27 exons. The most commonmutation, a three-base pair deletion in exon 10, results indeletion of phenylalanine at position 508 (ΔF508). TheΔF508 mutation accounts for approximately 66% of allelicmutations causing CF. To date, more than 1000 mutationshave been reported1; however, only five other mutations—G542X, G551D, W1282X, N1303K, R553X—occur atgreater than 1% frequency. CF mutations are localizedthroughout the CFTR gene but fall into five major cate-gories of CFTR dysfunction5 (Figure 7-1). Class I muta-tions, including nonsense mutations such as G542X andW1282X, result in failure to transcribe mRNA and, thus,cause absence of CFTR protein. Class II mutations, includ-ing the most common mutation, DF508, cause abnormalprotein folding, aberrant trafficking and, subsequently,protein degradation. Class III mutations, includingG551D, permit proper protein processing and localiza-tion but cause loss of ion channel function. Class IV

mutations, such as R117H and R334W, allow normalprotein processing and localization but reduce normalion conduction properties. Class V mutations, includingmutations in the CFTR gene promoter and introns, affecttranscription, translation, or protein processing, and mayresult in mild CF disease or isolated disorders such ascongenital bilateral absence of the vas deferens6 or idiopathic pancreatitis7.

Manifestations of CF disease may be affected by mod-ifier genes independent of CFTR gene mutations. Forexample, a modifier locus on chromosome 19 segregateswith patients who have meconium ileus8. Another strik-ing example is the correlation between mutations in themannose-binding lectin gene and increased severity ofCF lung disease9.

PATHOPHYSIOLOGY

The CF gene encodes an integral membrane glycopro-tein containing 1480 amino acids. The protein structureincludes two transmembrane domains, two nucleotide-binding fold domains with sites for ATP binding, and a

INormal VIVIIIII

Nosynthesis

Reducedsynthesis

Alteredconductance

Block inregulation

Molecular Consequences of CFTR Mutations

Block inprocessing

NonsenseG542X

Frameshift394delTT

Splice junction1717–1G→A

MissenseA455E

Alternativesplicing

3849+10kbC→T

MissenseR117H

MissenseG551D

Missense

AA deletionΔF508

Figure 7-1 Classification of CFTR mutations by molecular and biochemical abnormalities. Thisschematic depicts the effect of different classes of CFTR mutations on expression and function inthe cell. Class I mutations block mRNA transcription. Class II mutations prevent normal CFTR pro-tein processing and localization. Class III mutations permit CFTR localization at the apical mem-brane but inhibit chloride channel conductance. Class IV mutations result in partial chloridechannel conductance. Class V mutations affect transcription, translation or protein processingresulting in reduced CFTR expression at the apical membrane. Examples of mutations in each classare depicted below the cell models. Epithelial cell models with finger-like projections depict cilia atthe apical surface. Fully processed CFTR protein is depicted by the grey circles embedded amongthe cilia at the apical surface of the cells.


large regulatory or R domain that has several consensussites for protein kinase A- or C-mediated phosphorylation(Figure 7-2). CFTR is localized to the apical compartmentof epithelial cells in the respiratory, gastrointestinal andgenitourinary tracts, and sweat and salivary ducts. CFTRfunctions as an apical chloride channel; normal functionrequires correct protein localization to the apical mem-brane of the cell, as well as both nucleotide binding andphosphorylation. In addition to chloride transport, CFTRregulates other epithelial ion channels including an outwardly-rectifying chloride channel, an apical sodiumchannel, a potassium channel, and a chloride/bicarbonateexchanger1. CFTR may also regulate intra- and extracellu-lar protein transport, and regulate post-translational pro-cessing of glycoproteins which would explain theobservation that CF glycoproteins have greater fucosecontent and less sialic acid content than glycoproteinsfrom normal epithelial cells2,10.

The absence of CFTR function alters the balance offluid and protein, and the composition of glycoproteinsin exocrine gland secretions. These alterations result inabnormal biochemical properties of the secretions thatimpair mucociliary clearance in the lungs, promote col-onization with pathogenic organisms in the airways, andimpede normal flow in biliary and pancreatic ducts, lead-ing to the manifestations of the disease.

Respiratory Tract

Although the airways appear normal morphologically atbirth, impaired mucociliary clearance, early colonizationwith pathogenic bacteria, and a robust neutrophilic inflam-matory response occur early in infancy. The earliest patho-logic findings involve inflammation and mucus obstructionof the distal bronchioles. Within mucus plugs, pathogenicorganisms tend to colonize and proliferate. Patients are col-onized early with Staphylococcus aureus, Haemophilusinfluenzae, Escherichia coli, and Klebsiella sp. In laterstages of the disease, Pseudomonas aeruginosa and otherGram-negative organisms predominate; these organisms

create large supercolonies within mucus plugs calledbiofilms that protect them from phagocytosis.

In response to chronic bacterial colonization, neu-trophilic inflammation is established. Neutrophil phago-cytosis of Pseudomonas aeruginosa is inefficient, and thelarge load of neutrophils in the airway is not cleared, lead-ing to neutrophil necrosis and release of mediators andcellular debris. Neutrophil inflammatory products such asprotease and neutrophil elastase injure airway epitheliumand activate increased mucin production11 and excessivemucus secretion12. Furthermore, neutrophil DNA13 and fil-amentous actin14 significantly increase mucus viscosity.

Gradually, the increases in mucus volume and viscositypromote further bacterial proliferation and neutrophil-predominant inflammation. Following viral infections,these changes occur more acutely. Patients then experi-ence an exacerbation of bronchitis, usually manifestedby increases in respiratory rate, inspiratory intercostaland supraclavicular retractions, and diffuse, coarse,inspiratory crackles. Leukocytosis is common. The chestradiograph demonstrates worsening hyperinflation, peri-bronchiolar thickening, and nodular or cystic densities.Pulmonary function tests usually decline with decreasesin forced expiratory flows and forced expiratory vol-umes, and increases in air trapping. With recurrentcycles of bronchitis, mucus obstruction, and neu-trophilic inflammation, bronchiectasis results. This usu-ally occurs first in the upper lobes and progressesthroughout the lungs. In advanced disease, severe dif-fuse mucus obstruction of bronchiectatic airways causesventilation–perfusion mismatching and hypoxemia. If untreated, chronic hypoxemia triggers pulmonaryhypertension and cor pulmonale. Bronchiectasis alsoincreases the risk of other complications including pneu-mothorax and hemoptysis. Late in the course, as thelung disease progresses, the bronchiectatic airwaysobstruct airflow to parenchymal tissue leading to acuteand chronic hypercapnia, and respiratory failure.

The upper respiratory tract is also involved in CF.Patients can develop nasal polyposis or chronic sinusitis

MSD1

NBD1

N

NBD2C

Lipidbilayer

R Domain

MSD2

Figure 7-2 Map of CFTR functional peptidedomains. CFTR peptide domains within a lipid bilayerare depicted. MSD, membrane spanning domains;NBD, nucleotide binding domains; R domain, regula-tory domain.

Cystic Fibrosis 119

reflecting increased mucus production and stasis. Indeed,since allergic polyps are rare in the pediatric age group,nasal polyposis is an indication to evaluate for CF.

Gastrointestinal Tract

Many mutations of CFTR result in viscous secretionsthat obstruct the pancreatic exocrine ducts and result infailure to secrete proteases such as chymotrypsin andtrypsin, lipases, amylases, and bicarbonate into the duo-denum. Secretion of bicarbonate is an important ele-ment of pancreatic function since it neutralizes stomachacid and thus permits activation of pancreatic enzymes.A cycle of destruction and obliteration of the exocrinepancreatic ducts leads to cystic dilatation of the ductsand fibrosis of the pancreatic parenchyma. In advancedstages of disease, the islet of Langerhans cells aredestroyed causing insulin-dependent diabetes mellitus.CF patients may also develop acute inflammation of thepancreas, precipitating pancreatitis. This occurs morecommonly in those patients whose pancreatic functionis better preserved.

In most CF patients, pancreatic exocrine insufficiencyis present early in the course of the disease. Ten totwenty percent of newborns with CF present withmeconium ileus, an obstruction of the intestine causedby sticky, viscous meconium stool. Approximately 14%of newborns with CF will have meconium plug syn-drome, a syndrome of delayed meconium passage due toa meconium plug or cast in the sigmoid or descendingcolon. This is usually diagnosed and cleared by gastro-graffin enema15. Infants lack the ability to digest fat andprotein in their diet, and present with failure to thriveand frequent, bulky, greasy stools. Abnormal bulkystools may result in rectal prolapse, or partial or totalobstruction of the distal ileum resulting in distal intes-tinal obstructive syndrome (DIOS). DIOS presents with abdominal cramping, distension, and sometimesvomiting. If left untreated, patients can be at risk forabdominal perforation and life-threatening peritonitis. Inaddition to precipitating DIOS, a fecal impaction canbecome a lead point within the intestines to induceintussusception.

In the last 10 years, fibrosing colonopathy, a conditionassociated with ingestion of high (>6000 units lipase/kgper meal) concentrations of pancreatic enzymes has beendescribed. Patients complain of abdominal pain, oftenbloody diarrhea, and poor weight gain. The colonic wallbecomes thickened and non-distensible, and in its mostadvanced state, local or generalized strictures occur.When present, surgical excision of the stricture is usuallyrequired. Careful monitoring of enzyme dosing will avoidmost cases of fibrosing colonopathy.

The biliary tract of the liver and the gall bladder are alsoaffected in CF. The primary mechanism of liver disease is

inspissated secretions obstructing biliary ducts. The ear-liest pathologic findings are focal biliary cirrhosis withprolonged obstructive jaundice starting at 2–8 weeks ofage. Infants with significant hepatic involvement thusdemonstrate prolonged direct hyperbilirubinemia. Insome patients, focal cirrhosis progresses to diffuse cirrhosis and portal hypertension. Occasionally, progres-sion of hepatic disease is marked by elevated liverenzymes, but often this progression is silent. Withadvanced portal hypertension, splenic enlargement fol-lows with platelet sequestration. An ominous finding ishematemesis, which is likely due to development ofesophageal or gastric varices. Hepatic failure may ensue,associated with ascites, hyperammonemia, encephalopa-thy, and loss of hepatic synthetic function. Approximately5% of patients die of liver failure.

Stasis of bile flow and abnormal bile acid compositioncause gall bladder complications including cholelithiasis,and cholecystitis.

Sweat Glands

The sweat glands appear morphologically normal, butthe ability of the sweat duct to absorb chloride isimpaired in CF due to loss of CFTR function. This abnor-mality results in hypertonic sweat with increased chlorideand sodium concentrations. Salt losses can increase dra-matically from increased perspiration due to high ambienttemperature during the summer, increased exertion, orfever. Excessive sweat sodium and chloride lossesincrease the risk for dehydration with hypochloremic/hyponatremic metabolic alkalosis.

Reproductive Organs

In female patients, cervical mucus has increased viscosity. However, mucus changes do not appear toaffect fertility, as a significant number of women with CFare able to conceive and carry pregnancies to term. Themajor factors affecting outcome of pregnancy are gen-eral health and nutritional status of the mother16. In con-trast, male infertility is common in CF (greater than 98%of male patients). This is due to obstruction of the vasdeferens in utero resulting in atresia or absence at birth.Spermatogenesis and testicular development are normalin males.

DIAGNOSIS

Because of the heterogeneity and variability of pre-sentations associated with CF, the physician must have ahigh index of suspicion for the disease. Patients with afamily history of CF, or with symptoms or signs consis-tent with CF, should have a diagnostic evaluation for


the disease. Symptoms may be classified by usual age ofpresentation2 (Table 7-1).

Chronic pulmonary symptoms suggestive of CF includechronic or productive cough, chronic wheezing, or pneu-monia with Staphylococcus aureus or Gram-negativebacilli (particularly the mucoid form of Pseudomonasaeruginosa). Gastrointestinal symptoms consistent withCF include meconium ileus or meconium plug, failure tothrive, bulky, greasy or foul-smelling stools, rectal pro-lapse, or prolonged jaundice as an infant. Other historicalfindings suggestive of CF are excessively salty sweat or asalty taste when a child is kissed, chronic sinusitis, anddelayed puberty associated with poor nutritional status.

Clinical findings suggestive of CF include several respi-ratory and gastrointestinal physical findings. Respiratorytract findings include frequent cough, particularly if pro-ductive of mucopurulent sputum, rhonchi, wheezes,crackles, increased anteroposterior chest diameter, nasalpolyposis, and digital clubbing. Gastrointestinal signsinclude hepatosplenomegaly, jaundice, fecal masses, rectalprolapse, failure to thrive, and hypoproteinemic edema.

As part of the evaluation of CF, laboratory findingsmay be helpful both to support the diagnosis in atypicalcases and as an initial evaluation of organ function.Sputum or throat swab cultures should be obtained toassess for pathogenic organisms such as S. aureus and P. aeruginosa. Chest radiographs should be evaluated todetect early signs consistent with bronchiectasis. Inpatients with chronic cough or wheeze, pulmonaryfunction tests are helpful in determining whether airwayobstruction is present and whether the obstruction isreversible with bronchodilators. Laboratory evaluationsof nutritional status, pancreatic sufficiency, and liverfunctions are important corollary information for estab-lishing the diagnosis of CF (Tables 7-2 and 7-3).

In the context of historical, physical, or laboratoryfindings associated with CF, the diagnosis is confirmedby the demonstration of an elevated sweat chloride con-centration by the quantitative pilocarpine iontophoresis

sweat test17. This technically demanding test should onlybe performed at approved CF Centers. It provides aquantitative measure of sweat chloride under conditionsof adequate sweat flow. A sweat test is positive if thechloride concentration is greater than 60 mEq/L; bor-derline values are between 40–60 mEq/L. At least twopositive sweat tests with positive historical, physical,and/or laboratory findings are required to confirm thediagnosis. Several factors can affect interpretation of thetest. Sweat chloride levels increase with age. Conditionsother than CF can cause increased concentrations ofsweat chloride including malnutrition, adrenal insuffi-ciency, hereditary nephrogenic diabetes insipidus, ecto-dermal dysplasia, hypogammaglobulinemia, andfucosidosis18. Alternatively, it is important to recognizethat false negative sweat tests may be due to edema in CFpatients with hypoproteinemia.

Genetic analysis may also be used to confirm the diag-nosis of CF. Two alleles with CF mutations must be iden-tified to confirm the diagnosis. Screening for 32 of themost common alleles yields an overall sensitivity of 90%in diagnosing CF. Therefore, a negative genetic analysisdoes not rule out a diagnosis of CF in an atypical patient.

The serum immunoreactive assay for trypsinogen isused in two states as a screening test for CF in newborns.Serum levels of trypsinogen are often abnormally high inCF due to pancreatic duct obstruction and pancreaticinflammation. However, this test is associated with bothfalse positives and negatives; all positive patients musthave a sweat test or genotyping performed to confirmthe diagnosis. The CFF Consensus Committee recom-mended that the diagnosis of CF should be based on thepresence of one or more characteristic phenotypic fea-tures (Table 7-1) or a history of CF in a sibling, plus lab-oratory evidence of a CFTR abnormality as documentedby elevated sweat chloride concentrations, or identifica-tion of two CF mutations, or in vivo demonstration ofcharacteristic abnormalities in ion transport across thenasal epithelium18.

Table 7-1 Symptoms and Signs Classified by Age of Presentation

Infancy Childhood Adolescence/Adulthood

Meconium ileus Failure to thrive Delayed sexual developmentObstructive jaundice Steatorrhea Obstructive azoospermiaFailure to thrive Heat prostration with hypoelectrolytemia Chronic bronchitis with Pseudomonas aeruginosaEdema with hypoproteinemia “Atypical” asthma with clubbing, Pansinusitis

and anemia bronchiectasis Chronic abdominal pain, idiopathic pancreatitis,Recurrent pneumonia/bronchiolitis Nasal polyps cirrhosisRectal prolapse Rectal prolapse Hemoptysis, pneumothoraxSalty-tasting skin Salty-tasting skin

Cystic Fibrosis 121

CLINICAL EVALUATION

The goal of the clinical assessment of CF patients is toevaluate the function of the lungs (Table 7-2), the gas-trointestinal tract (Table 7-3), and the reproductive tract.This evaluation includes pulmonary function tests, spu-tum microbiology, chest radiography, nutritional status,liver and pancreatic function tests, and reproductivefunction.

Pulmonary Function Tests

Patients perform pulmonary function tests, spirome-try and plethysmography, at regular intervals during rou-tine visits to follow the overall course of the disease, andmore frequently during exacerbations of bronchitis tofollow the course of therapy. The earliest deficits foundare in the forced expiratory flows between 25% and 75% ofthe vital capacity (FEF25–75) and at low lung volumes (i.e., at75% of the vital capacity, FEF75). Decreases in FEF25–75 andFEF75 correlate with obstruction of small bronchioles.

With more advanced disease, obstruction of large airwaysbecomes predominant with diminished forced expiratoryvolume at 1 second (FEV1) and reduced FEV1: forced vital capacity (FVC) ratio (Figure 7-3). In concert withincreasing airway obstruction, air trapping progresses: as measured by plethysmography, hyperinflation relatedto small airway disease is reflected in elevated ratios ofresidual volume to total lung capacity (RV/TLC). Treatmentof acute exacerbations of bronchitis usually results in improvements in pulmonary function. However, overtime, CF causes a relentless deterioration of pulmonaryfunction.

A major challenge in evaluating the pulmonary func-tion of CF patients is that pulmonary function tests arevery effort-dependent, and thus children younger than4–5 years of age cannot reliably perform them. Recently,a procedure for performing pulmonary function testshas been standardized for infants with CF and theequipment is now commercially available. This tech-nique is limited for routine usage because it requiressedation of the infant. This infant pulmonary functiontest uses passive inflation to a preset pressure (30 cm H2O)

Table 7-2 Diagnostic Evaluation of Respiratory Tract Disease

Laboratory Studies Results Consistent with CF Lung Disease

Sputum or throat swab culture S. aureus, H. influenzae, P. aeruginosa, B. cepacia, S. maltophilia; Aspergillus; atypical mycobacteriaChest radiograph/CT scan Hyperinflation, peribronchiolar thickening; late findings: cysts and nodules consistent with

bronchiectasisPulmonary function tests +/− Reversible small airways obstruction, mild air trapping; late findings: severe irreversible large

airways obstruction, severe air trappingBlood gas/oximetry +/− Mild hypoxemia with pulmonary exacerbations; late findings: persistent severe hypoxemia,

hypercapnia, compensated respiratory acidosis

Table 7-3 Diagnostic Evaluation of Gastrointestinal Tract Disease

Laboratory Studies Results Consistent with CF Gastrointestinal Disease

72 h Stool fat, absorption of N-benzoyl-L-tyrosyl-p-amino Measures of pancreatic exocrine sufficiency: if malabsorption present: stool benzoic acid fat >7% of oral fat intake, decreased N-benzoyl-L-tyrosyl-p-amino benzoic acid

absorptionSerum vitamins A and E Measures of adequate supplementationLiver function tests: gamma glutamyl transferase, Measures of liver inflammation: normal or transiently elevated

aspartate transaminase, alkaline phosphataseSerum total protein, prealbumin, prothrombin time Measures of nutrition and liver function: may be abnormalGastrograffin enema Indicated for symptoms of DIOS, intussusceptionUltrasound Indicated to evaluate for cholelithiasis, cirrhosis, volvulusSerum glucose Elevated random glucose suggests diabetes mellitus Electrolytes Screen for salt wasting


Figure 7-3 Pulmonary function tests in CF. A flow–volume curveobtained by spirometry is depicted. Ordinate values are flows andabscissa values are volumes. Normal values are presented as dots.Note that the flows are decreased at all volumes with a concavepattern of the expiratory loop (arrow) demonstrating small airways obstruction.

to achieve a lung volume near total lung capacity, andthen applies a squeeze to the chest during exhalation torecreate a forced vital capacity maneuver19. The totaltest resembles the pulmonary function tests used forolder subjects and therefore makes interpretations ofresults easier to perform and compare with standards.This infant pulmonary function test should be useful toassess early changes in pulmonary function and responseto new therapies.

The arterial blood gas reveals abnormal gas exchangeduring severe exacerbations of bronchitis or in patientswith chronic, end-stage lung disease. Early in the courseof the disease, ventilation–perfusion abnormalities resultin widening of the alveolar–arterial gradient. This abnor-mality reflects inhomogeneities in alveolar ventilation.With disease progression, ventilation–perfusion mis-matching increases and results in progressive hypox-emia. Hypoxemia occurs first during exacerbations ofbronchitis, then during sleep, and finally chronically.With chronic hypoxemic respiratory failure, patients areat risk to develop the complications of pulmonary hyper-tension and cor pulmonale. Initially, ventilation isspared, but with end-stage lung involvement, airwayobstruction is so severe that ventilation is impaired andpatients develop hypercapnia and respiratory acidosis.

Oxyhemoglobin saturation monitoring is a useful indi-cator of respiratory function for patients with underlying

severe lung disease because it is non-invasive and practi-cal for prolonged observation. During exacerbations ofbronchitis in patients with severe airway obstruction,oxyhemoglobin saturations are monitored to detectnighttime or exercise-induced hypoxemia, and to titrateoxygen therapy.

Sputum Microbiology

Sputum samples are routinely assessed for bacterialidentity and antibiotic sensitivities. These data are impor-tant for selecting antimicrobial therapy during acuteexacerbations. Either expectorated sputum or throatswabs during a cough are used for microbiology cul-tures. Early in the course of CF, S. aureus, H. influen-zae, and E. coli are identified. Often within the first fewyears, P. aeruginosa is detected in sputum or throatswab cultures. Once P. aeruginosa is detected in thesputum, it is very difficult to eradicate. As patientsdevelop progressive bronchiectasis, other opportunisticorganisms may colonize the airways including Gram-negative rods such as Burkholderia cepacia andStenotrophomonas maltophilia, molds such asAspergillus fumigatus, and atypical mycobacteria.Expectorated sputum is evaluated for the presence ofthese opportunistic organisms using specialized culturemedia, as these organisms induce exacerbations of bron-chitis, and accelerate disease progression.

Antibiotic sensitivities are routinely determined usingsingle antibiotics. However, at least two centers offerantibiotic synergy studies20 for Gram-negative organismsto determine whether synergy exists for bacterial killingusing combinations of two or three antibiotics.

Chest Radiography

Chest radiographs obtained yearly are a useful measureto detect subtle changes of airway involvement. Chestradiographs are also obtained at the time of acute exacer-bations of bronchitis to evaluate for areas of atelectasisdue to mucus plugging. In patients with minimal or norespiratory tract symptoms, the X-ray film may be normalor have mild findings of peribronchiolar thickening orhyperinflation. With more advanced disease, increased lin-ear markings, cystic changes or nodules are present thatare consistent with bronchiectasis (Figure 7-4). Thesefindings usually are seen initially in the upper lobes andthen progress throughout the lungs. Atelectasis and/orsevere hyperinflation with increased anteroposteriordiameter are also present in advanced disease.

High-resolution chest computed tomography (CT)scanning is a very sensitive method for detectingbronchiectasis. The signet ring sign, a bronchial airwaylarger than its associated blood vessel, is the earliest signof bronchiectasis on CT (Figure 7-5). The high resolution

Cystic Fibrosis 123

Figure 7-4 Chest radiograph of a CF patient with severe lungdisease reveals ring shadows, cystic lesions, and nodular densitiesconsistent with diffuse bronchiectasis.

CT scan is more sensitive than plain radiographs fordetecting bronchiectasis21. Furthermore, the other majortest of pulmonary status, pulmonary function measure-ments, may not deteriorate until multiple lobes of thelung are injured. Therefore, periodic evaluation ofbronchiectasis by CT scan provides the most sensitive

measure of disease progression. With the availability ofhigh-speed CT scans, this modality is now available foruse in young children without sedation.

Nutrition

The evaluation of pancreatic function is a key elementin establishing the diagnosis of CF since almost 90% ofpatients have pancreatic insufficiency. Furthermore, regu-lar evaluation of nutritional status and sufficiency of pan-creatic enzyme replacement are of critical importancebecause nutritional status correlates directly with pul-monary function and prognosis22. Pancreatic insufficiencyis suggested by a history of failure to thrive, or frequent,greasy stools. In older children, a history of bulky, mal-odorous stools, often associated with a voracious appetite,can be elicited. The gold standard measure to evaluate forpancreatic enzyme insufficiency is quantitation of fat mal-absorption. Stool is collected for 72 hours and fat contentis quantified and compared with total fat intake during thesame time period. At least 100 g of fat must be ingested dur-ing the collection period, and a malabsorption coefficientof greater than 7% is considered abnormal. In addition tothis measure, serum levels of fat-soluble vitamins, A, D andE, are helpful to determine whether fat malabsorption ispresent, and also whether supplementation of these vita-mins is adequate. Another approach to assess pancreaticexocrine function is based on measurements of urinarymetabolic products of N-benzoyl-L-tyrosyl-p-aminobenzoicacid, a compound that is ingested orally, hydrolyzed andabsorbed by the small intestine in the presence of pan-creatic enzymes, and then secreted into the urine.

Evaluation of liver function tests is a standard part ofthe routine annual evaluation of CF patients. Especiallyin infancy, there may be transient increase in bilirubin ortransaminase levels that reflects focal biliary obstruction.Unfortunately, progression of biliary cirrhosis can besilent, and patients may present with signs of advancedcirrhosis as an incidental finding on an ultrasound scan.Cirrhosis and portal hypertension precede the develop-ment of esophageal and gastric varices; a potentially life-threatening complication of varices is hematemesis.Patients with hematemesis are evaluated and treated by endoscopy and banding or sclerosis of varices. Thepresence of portal hypertension can be confirmed byultrasound to evaluate the direction of portal and splenicvein flow.

Abdominal pain is a serious complication of CF andcan be due to a plethora of etiologies (Table 7-4).Patients with abdominal pain that is sharp or crampingand localized to the right lower quadrant may have DIOSand require a series of abdominal radiographs to confirmthe diagnosis and rule out other causes of obstruction. Ifa patient presents with intermittent abdominal pain,heme-positive stools, and/or an acute abdomen, the patient

Figure 7-5 Chest CT scan of a CF patient with normal pul-monary function reveals early bronchiectasis with “signet ring”sign, airway thickening, and atelectasis.


Table 7-4 Differential Diagnosis of Abdominal Pain

Distal intestinal obstructive syndromeGastroesophageal refluxPancreatitisCholecystitisCholelithiasisFibrosing colonopathyIntussusceptionVolvulusAbdominal muscle pain related to coughingReferred pain related to basilar pneumoniaOther causes of acute abdomen, for example, appendicitis

should be evaluated by ultrasound to rule out volvulus,fibrosing colonopathy, or intussusception. Severe abdomi-nal pain that radiates to the back and is exacerbated by eat-ing high-fat foods is consistent with acute pancreatitis;abnormal serum amylase and lipase would confirm thisdiagnosis. Finally, pain localized to the right upper quad-rant may be due to gall bladder complications such ascholecystitis or cholelithiasis; these diagnoses would beconfirmed by ultrasound.

In CF, development of insulin-dependent diabetes mel-litus follows from chronic pancreatic inflammation. Fiveto six percent of pediatric CF patients develop diabetes.The frequency of diabetes increases with age to an occur-rence rate of approximately 50% of adult CF patients.CF-related diabetes may be insidious in onset and may takeseveral years for overt symptoms to develop. All patientsare screened annually with a random serum glucose level.If this is elevated (>200 mg/dl) or if patients present withsymptoms consistent with diabetes, then a fasting bloodglucose level is obtained to confirm the diagnosis23. Forpatients who are pregnant or who have unexplained symp-toms consistent with diabetes such as polydipsia, polyuria,poor growth or delayed puberty, a glucose tolerance test isindicated to rule out diabetes.

Reproductive Function

A high percentage of men with CF have infertility dueto congenital absence of the vas deferens. Thus, a semenanalysis should be performed for adult men with CF.Because of the high association of CF mutations with maleinfertility6, men who present with infertility as a primarydiagnosis should have a complete evaluation for CF.

THERAPY

Intensive and comprehensive therapy for CF hasresulted in a significant improvement in life expectancy

and quality of life over the past 50 years24 (Figure 7-6).Although there is no question that comprehensive carehas dramatically changed the course of the disease,there are limited data supporting specific componentsof therapy. At present, the best approach appears to bean individualized therapy program determined by thedegree of organ dysfunction for each patient. An impor-tant aspect of CF care is the network of 100 CF centersthat exist throughout the United States. Most centers usea team approach with physicians, nurses, physical ther-apists, respiratory therapists, nutritionists, genetic coun-selors, and social workers, to provide a comprehensiveapproach to the management of each patient.

Management of Pulmonary Disease

The goals of treatment are to prevent mucus obstruc-tion of airways and to reduce the burden of bacteria andinflammation. Several components of therapy are appliedsimultaneously to achieve these goals25 (Table 7-5).

Mucociliary ClearanceAll treatment programs for CF include a strategy to clear

the airways of viscid, sticky secretions. Mucociliary clear-ance is a mainstay of innate immunity; it reduces bacterialload in the airways and diminishes the associated neu-trophilic inflammation. This clearance is accomplished bya combination of techniques to reduce the viscosity ofsecretions, and to enhance cough clearance of secretions.

Two mucolytic agents, administered by nebulization,are available to reduce sputum viscosity in CF: N-acetyl-cysteine, and recombinant human DNase (Pulmozyme).N-acetylcysteine reduces disulfide bonds and decreasessputum viscosity in vitro. It also has activity as an anti-oxidant agent which may be of benefit in the inflamedmilieu of the CF airway. Its use has been limited by

8524

28

32

36

86 87 88 89 90 91 92 93Year

94 95 96 97 98 99 00 01

Figure 7-6 Graph of predicted survival age for CF patients,1985–2001.

Cystic Fibrosis 125

reports of airway bronchospasm. This problem can bemitigated if it is administered as a dilute preparation inconcert with a bronchodilator. Nebulized N-acetylcysteinehas not been adequately evaluated in a prospective, con-trolled trial in CF26. However, its mucolytic and antioxi-dant properties, and its low cost support a trial of its usein selected patients. Its use remains an integral part ofongoing comprehensive respiratory care in several largeCF centers.

Pulmozyme cleaves neutrophil DNA in sputum thatis a major factor contributing to sputum viscosity.Pulmozyme was approved for use in the United States in1994 following a large prospective, controlled trial demon-strating that following 1 year of Pulmozyme therapy,patients had mildly improved pulmonary function tests,reduced exacerbations of bronchitis, and reduced days ofhospitalization13. However, questions regarding patientselection, timing and duration of use of this expensivedrug remain unanswered. There is currently intenseinvestigation to discover new therapeutic agents that willreduce mucus secretion or alter mucus–epithelial interac-tions as adjunctive therapy to reduce mucus obstructionof airways in CF.

Chest PhysiotherapyChest physiotherapy is a mainstay of CF therapy. The

goal of this therapy is to enhance cough clearance of air-way secretions. A prospective, controlled study hasdemonstrated that regular, daily chest physiotherapy main-tains pulmonary function better over 3 years comparedwith deep breathing and cough alone27. Thus, chest phys-iotherapy is prescribed routinely twice per day, with anincreased frequency during exacerbations of bronchitis.The most widely prescribed method is percussion and

postural drainage. Alternative methods include a percus-sion vest that delivers high-frequency chest wall compres-sion; the Flutter or Acapella devices, pipe-like instrumentswith interrupter structures that produce high frequency,low amplitude vibrations throughout the airways duringforced exhalation; autogenic drainage breathing exercisesdesigned to move secretions from distal to proximal air-ways; positive expiratory pressure devices; aerobic exer-cise; and forced cough maneuvers (reviewed in Prasadand Main28).

AntibioticsAntibiotics are a key element responsible for increased

survival in CF. However, antibiotic regimens are not stan-dardized, and there are many unanswered questions con-cerning antibiotic choices and duration of therapy. Areasonable approach is to use antibiotic therapy to treatan acute exacerbation of bronchitis when signs andsymptoms are consistent with worsening infection(Table 7-6). In early exacerbations, chest physiotherapy isincreased and oral antibiotics are initiated. If outpatienttherapy fails to resolve signs or symptoms, or if symp-toms progress despite therapy, then intravenous antibi-otic therapy is initiated.

Useful oral antibiotic agents for treatment of staphylo-coccal infections include dicloxacillin, cephalexin, amox-icillin/clavulinic acid, and chloramphenicol. ForPseudomonas strains, oral antibiotics including trimetho-prim-sulfamethoxazole, tetracycline, or chloramphenicolmay provide some efficacy early in the course of disease.A quinolone derivative, ciprofloxacin, is effective againstmany strains of Pseudomonas. A major disadvantage ofciprofloxacin is that Pseudomonas strains develop resist-ance to it following prolonged use.

Table 7-5 Components of Therapy for Pulmonary Disease

Chest physiotherapyPercussion and postural drainageHigh-frequency chest wall oscillator (ThAIRapy)Oscillating positive expiratory pressure device (Flutter or Acapella)Intrapulmonary percussive ventilationActive cycle breathing techniquesAerobic exercise

Mucolytic therapy (nebulized)Recombinant human DNase (Pulmozyme)N-acetylcysteine (Mucomyst)

Antibiotic therapy

Bacteria Oral Intravenous Inhaled

S. aureus Amoxicillin + Clavulinic acid Nafcillin; if resistant, vancomycinP. aeruginosa Ciprofloxacin Aminoglycoside + ceftazidime or ticarcillin Tobramycin, colistinResistant P. aeruginosa Aztreonam, piperacillin, imipenem,

meropenemBronchodilator therapy


Table 7-6 Criteria for Exacerbation of Bronchitis

SymptomsIncreased coughPersistent wheezingIncreased sputum productionChange in sputum colorHemoptysisDyspnea on exertionChest pain

SignsWeight lossChanges on chest examination: crackles, wheezes, or decreased

air movementTachypneaRetractionsUse of accessory musclesDecline in pulmonary function testsNew infiltrate or increased peribronchiolar thickening on

chest radiograph

For severe exacerbations of bronchitis, or exacerba-tions that fail to respond to oral antibiotics, there is anarsenal of intravenous antibiotics that are used as the nextline of therapy. For Staphylococcus aureus, oxacillin, or nafcillin are useful agents. If S. aureus is resistant topenicillins, then vancomycin is the agent of choice. ForPseudomonas infections, at least two agents, usuallyincluding an aminoglycoside, are used to provide synergyof antibiotic therapy. Aminoglycosides are titrated to pro-vide higher serum peak concentrations (8–12 μg/ml) thanthose used for non-CF patients in order to achieve adequateconcentrations in such viscous airway secretions. In addi-tion to gentamicin or tobramycin, a third-generationcephalosporin (ceftazidime) or a third-generation peni-cillin (ticarcillin or piperacillin) are used. Other antibioticsthat are used particularly in the case of resistant organismsinclude amikacin, colimycin, aztreonam, meropenem, orimipenem. If S. aureus and Pseudomonas aeruginosaare both present, ticarcillin with clavulinic acid, orpiperacillin with tazobactam, are used in combinationwith an aminoglycoside. Usually intravenous antibioticsare used for 10 days up to 2–3 weeks of total therapy. Thegoals of therapy are to reduce symptoms to the best pre-morbid level, to reverse any decrement in pulmonaryfunction, and to clear any chest radiographic changes.Once their presence is established, it is usually not poss-ible to eradicate S. aureus and P. aeruginosa from theairway. Currently, a large prospective, randomized, con-trolled trial is being initiated under the auspices of theU.S. Cystic Fibrosis Foundation to assess attempts to clearPseudomonas from the airway after it is first detected,and to prolong the time until chronic colonization isestablished.

Two recent studies suggest that antibiotics may be use-ful as maintenance therapy in patients colonized with P. aeruginosa to maintain pulmonary function and reducethe frequency and severity of bronchitis exacerbations. In aplacebo-controlled, randomized, prospective trial over 6 months29, inhaled preservative-free tobramycin, 300 mgtwice per day for alternate months, was shown to maintainpulmonary function. In a 3 month, prospective, placebo-controlled trial30, therapy with oral azithromycin, 250 mgdaily, maintained pulmonary function, reduced measures ofinflammation and improved quality of life. Further investi-gations are currently under way to determine the optimaluse of these agents in CF.

For the special circumstance of allergic bronchopul-monary aspergillosis, oral antifungal therapy in concertwith corticosteroid therapy is useful for reducing airwayinflammation and reactivity31. Atypical mycobacteria pres-ent a special challenge for patients and clinicians. It is dif-ficult to determine when these organisms are contributingto airway infection and inflammation. If sick patients arenot responding to antibiotic therapy, or if they have fever,night sweats, or cachexia, and chest CT scan reveals nod-ules and sputum stain reveals a high concentration of acid-fast bacilli32, then these patients may have an activemycobacterial infection and require multi-drug antimy-cobacterial therapy. Atypical mycobacterial infections arealso extremely difficult to treat as they require multipleantibiotics for prolonged courses and the bacteria developresistance to antibiotics.

Bronchodilators and Anti-inflammatory TherapyBronchodilators, such as short-acting inhaled β2-

agonists, may be useful for CF patients with reversibleairway obstruction; their use can promote improvedmucociliary clearance25. However, some patients withbronchiectasis may worsen with bronchodilator therapybecause these agents will make the central airways morecollapsible and so “paradoxically” decrease airway caliber,especially during cough. Therefore, their use should beindividualized and monitored over time.

Corticosteroids are a useful therapy for patients withsevere airway reactivity associated with exacerbations ofCF bronchitis, or for patients with allergic bronchopul-monary aspergillosis. A recent prospective controlledstudy over 4 years33, demonstrated that alternate-day cor-ticosteroids (1 mg/kg/day) significantly improved pul-monary function compared with placebo-control.However, the study group had diminished linear growthafter 1 year, precluding a general recommendation forchronic steroid therapy in CF.

A more targeted anti-inflammatory agent, ibuprofen,was studied in a 4 year, controlled, prospective trial34.High-dose ibuprofen reduced the deterioration in pul-monary function that occurred in the control group; it was particularly beneficial for the subgroup of teenagers

Cystic Fibrosis 127

Table 7-7 Components of Therapy for Gastrointestinal Disease

NutritionSupplemental fat-soluble vitamins (ADEK)Pancreatic exocrine enzymes (protease, lipase, amylase)High protein, high carbohydrate diet

Nutritional supplements (orally, or via nasogastric tube or gastrostomy tube)

Extra table salt or salty snacksDistal intestinal obstructive syndromeAcute therapy

Polyethylene-glycol-electrolyte solution (orally, or via nasogastric tube or gastrostomy tube)

Gastrograffin enemaSurgical repair

Maintenance therapyCorrect dosage and administration of enzymesFiber laxativesRegular administration of polyethylene-glycol-electrolyte

solutionsHepatobiliary disease

Ursodiol (Actigall)

colonized with Pseudomonas. Since the original publica-tion, concerns have been raised about side effects asso-ciated with this therapy including gastric ulcers anddecreased glomerular filtration rate, limiting its wide-spread acceptance.

With the promise of improved pulmonary outcomesbut the limitations due to side effects, the current anti-inflammatory agents have limited use. However, otheranti-inflammatory agents such as montelukast are cur-rently being evaluated in CF.

Oxygen and Non-invasive Assisted VentilationWith progressive respiratory failure, and the develop-

ment of persistent hypoxemia, patients have an increasedrisk of secondary pulmonary hypertension and cor pulmonale. To prevent these complications, supplemen-tal oxygen therapy is initiated by nasal cannulae. Oncehypoxemia or hypercapnia is detected and becomeschronic, patients have 50% mortality at 2 years35. Non-invasive assisted ventilation with bilevel positive airwaypressure (BLPAP) is a useful temporary modality to sup-port patients’ ventilation while they are awaiting lungtransplantation.

Lung TransplantationFor patients with impending respiratory failure, lung

transplantation offers a last resort as a therapy. The twomost common approaches for transplant are double lungcadaveric transplant, or transplantation of two livingrelated donor lobes. The current criteria for considera-tion of lung transplantation include progressive pul-monary impairment manifested by FEV1 <30% predicted,increasing functional impairment including increasingfrequency of hospitalizations, and major life-threateningcomplications such as massive hemoptysis36. The cur-rent waiting time for transplant surgery in the UnitedStates is 2–3 years, depending on the recipient’s bloodtype. Although the immediate outcome results have sig-nificantly improved, with 80% survival at 1 year, thelong-term complications of chronic rejection still limitlong-term success with survival rates of approximately50% at 5 years.

Management of Nutrition andGastrointestinal Disease

CF patients require therapy to replace missingexocrine enzymes, enhance nutrition, replete wastedsalt, and to treat intestinal complications (Table 7-7).

Nutritional SupportPatients with CF require an initial evaluation and then

re-evaluation over time to assess their pancreaticexocrine function. As most patients have some degree ofpancreatic exocrine insufficiency, supplementalenzymes are ingested with food. The enzyme prepara-tions are enteric-coated capsules with microspheres

containing lipase, protease and amylase. Titration ofenzyme dosage is determined by quality and frequencyof bowel movements, by weight gain, and by measuresof adequate fat absorption such as normal vitamin A, D,and E levels. In some cases, enzymes are ineffectivedespite higher than expected dosing. This may be due toinadequate bicarbonate secretion into the duodenum;such patients often benefit from a trial of H2-blockers orproton pump inhibitors to reduce the acidity of theintestine and permit optimal enzyme activity. In additionto enzyme supplementation, patients require supple-mentation with the fat-soluble vitamins, A, D, E, and K.

Patients with CF have high resting energy require-ments37. These caloric requirements increase dramati-cally during exacerbations of bronchitis. Furthermore,pulmonary function directly correlates with nutritionalstatus22. For these reasons, patients are encouraged toeat a high calorie, high protein diet. As pulmonary dis-ease progresses, if the caloric needs outpace thepatient’s ability to achieve daily calorie requirements,alternative modes of nutritional therapy are imple-mented including nasogastric or gastrostomy tube night-time feedings. With a supplemental high calorie formuladelivered at night, patients can increase daily calorieintake by 1000–2000 calories per day.

Salt ReplacementBecause of increased electrolyte loss, especially during

the summer and with exercise, CF patients are encouragedto increase their intake of table salt. Infant formulas aresupplemented with one-quarter teaspoon of salt per day.


Figure 7-7 Gastrograffin enema of a CF patient with fibrosingcolonopathy reveals narrowing of the transverse colon (arrow).

Treatment of DIOSDIOS is often a recurrent acute problem; therefore

management is targeted to both the acute events andlong-term prevention. For acute management, if theobstruction is partial with no abdominal distension, then a hyperosmolar agent such as polyethylene-glycol-electrolyte solution delivered orally or via naso-gastric tube, is useful to dislodge the fecal mass. Ifobstruction is severe, or the patient is unable to toleratethe hyperosmolar agent via the stomach, then a gastro-graffin enema should be performed to clear theobstructed stool. Finally, if the obstruction is completeand unresponsive to gastrograffin enema, or the patientis toxic, surgery may be required to clear the obstruc-tion. Recurrent obstructions can result from failure totake enzymes, insufficient enzyme dosing, low duodenalpH so that enzyme therapy is relatively ineffective, orcolonic abnormalities such as fibrosing colonopathy38.Risk of fibrosing colonopathy is associated with veryhigh enzyme supplementation; patients with recurrentDIOS should be evaluated by gastrograffin enema to ruleout fibrosing colonopathy (Figure 7-7). If fibrosingcolonopathy or incorrect enzyme supplementation areruled out, then preventive therapy can be initiatedincluding fiber supplements or regular therapy with apolyethylene-glycol-electrolyte solution.

Ursodeoxycholic AcidThe findings of hepatosplenomegaly or elevated liver

enzymes suggest that further evaluation for biliary cir-rhosis is indicated. As part of a complete evaluation,infectious etiologies of hepatitis are investigated. Anultrasound examination is extremely useful to evaluatefor cirrhosis and to evaluate the biliary tract includingthe gall bladder. Once cholestasis, fibrosis, or cirrhosis isdiagnosed, then therapy with ursodeoxycholic acid isinitiated. This therapy may improve bile flow and reducehepatic inflammation39, but its effectiveness in reducing

the risk of cirrhosis is not known. When cirrhosis becomessymptomatic with hyperammonemia, encephalopathyand poor synthetic function, then medical treatmentincludes salt restriction, protein restriction, and diuretics.Lactulose increases gut motility, and neomycin reducesthe load of enteric bacteria; both therapies help to controlhyperammonemia.

Liver TransplantationThis therapy is reserved for patients with complica-

tions of cirrhosis that are recalcitrant to medical therapy.Outcomes are similar to those for patients undergoingliver transplantation for other etiologies40.

SUMMARY

CF is a complex disorder affecting many organ sys-tems with remarkable heterogeneity in presentation andclinical course. Current therapies have significantlyimproved quality of life and long-term outcomes. Yet,this disease still causes early mortality. Further signifi-cant improvements in outcome await therapeutic break-throughs based on new information about the cellularand molecular pathogenesis of the disease.

MAJOR POINTS

1. CF is an autosomal recessive disease caused bymutations in the cystic fibrosis transmembraneconductance regulator gene on chromosome 7.

2. CF can be diagnosed by a quantitative pilocarpineiontophoresis sweat test or by genetic testing.

3. CF-associated pulmonary disease is characterizedby chronic bronchitis with pathogenic organismsincluding S. aureus and P. aeruginosa, leading tobronchiectasis and respiratory failure.

4. CF associated gastrointestinal disease ischaracterized by pancreatic exocrine insufficiencyleading to failure to thrive, and distal intestinalobstruction syndrome. Other gastrointestinalcomplications include cholestatic liver disease,pancreatitis, and diabetes.

5. Therapy is palliative and targeted to optimizemucociliary clearance, treat chronic bronchitis,replace pancreatic enzymes, and optimizenutrition.

��

REFERENCES

1. Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cysticfibrosis. In Scriver CR, Beaudet AL, Sly WS, Valle D, editors:The metabolic and molecular bases of inherited disease, 8thedition, pp. 5121–5188. New York: McGraw-Hill, 2001.

2. Robinson C, Scanlin TF. Cystic fibrosis. In Fishman AP, edi-tor: Pulmonary diseases and disorders, pp. 803–824. NewYork: McGraw-Hill, 1997.

3. Kerem BS, Rommens JM, Buchanan JA, Markeiwicz D, CoxTK, Chakravarti A, et al. Identification of the cystic fibrosisgene: genetic analysis. Science 245:1073–1080, 1989.

4. Rich DP, Anderson MP, Gregory RJ, Cheng SH, Paul S,Jefferson DM, et al. Expression of cystic fibrosis transmem-brane conductance regulator corrects defective chloridechannel regulation in cystic fibrosis airway epithelial cells.Nature 347:358–363, 1990.

5. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloridechannel dysfunction in cystic fibrosis. Cell 73:1251–1254,1993.

6. Chillon M, Casals T, Mercier B, Bassas L, Lissens W, Silber S,et al. Mutations in the cystic fibrosis gene in patients withcongenital absence of the vas deferens. N Engl J Med332:1475–1480, 1995.

7. Cohn JA, Friedman KJ, Noone PG, Knowles MR, SilvermanLM, Jowell PS. Relation between mutations of the cysticfibrosis gene and idiopathic pancreatitis. N Engl J Med339:653–658, 1998.

8. Zielenski I, Corey M, Rozmahel R, Markeiwicz D, Aznarez I,Casals T, et al. Detection of a cystic fibrosis modifier locusfor meconium ileus on human chromosome 19q13. NatGenet 22:128–129, 1999.

9. Garred P, Pressler T, Madsen HO, Frederiksen B, Svejgaard A,Hoiby N, et al. Association of mannose-binding lectin geneheterogeneity with severity of lung disease and survival incystic fibrosis. J Clin Invest 104:431–437, 1999.

10. Rhim AD, Stoykova L, Glick MC, Scanlin TF. Terminal gly-cosylation in cystic fibrosis (CF): a review emphasizing theairway epithelial cells. Glycoconj J 18:649–659, 2001.

11. Voynow JA, Rosenthal Young L, Wang Y, Horger T, RoseMC, Fischer BM. Neutrophil elastase increases MUC5ACexpression in A549 lung carcinoma cells. Am J Physiol276:L835–L843, 1999.

12. Lundgren JD, Rieves RD, Mullol J, Logun C, Shelhamer JH.The effect of neutrophil proteinase enzymes on the releaseof mucus from feline and human airway cultures, RespirMed 88:511–518, 1994.

13. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, NashML, Ramsey BW. Effect of aerosolized recombinant humanDNase on exacerbations of respiratory symptoms and onpulmonary function in patients with cystic fibrosis. N EnglJ Med 331:637–642, 1994.

14. Vasconcellos CA, Allen PG, Wohl ME, Drazen JM, JanmeyPA, Stossel TP. Reduction in viscosity of cystic fibrosis sputum in vitro by gelsolin. Science 263:969–971, 1994.

15. Ziegler M. Meconium ileus. Curr Probl Surg 3:731-777, 1994.

16. Palmer J, Dillon-Baker C, Tecklin JS, Wolfson B, Rosenberg B,Burroughs B, et al. Pregnancy in patients with cystic fibrosis.Ann Intern Med 99:596–600, 1993.

17. Stern RC. The diagnosis of cystic fibrosis. N Engl J Med 336:487–491, 1997.

18. Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis:a consensus statement. J Pediatr 132:589–595, 1998.

19. Castile R, Filbrun D, Flucke R, Franklin W, McCoy K. Adult-type pulmonary function tests in infants without respira-tory disease. Pediatr Pulmonol 30:215–227, 2000.

20. Lang BJ, Aaron SD, Ferris W, Hebert PC, MacDonald NE.Multiple combination bactericidal antibiotic testing forpatients with cystic fibrosis infected with multiresistantstrains of Pseudomonas aeruginosa. Am J Respir Crit CareMed 162:2241–2245, 2000.

21. Brody AS. Cystic fibrosis: when should high-resolutioncomputed tomography of the chest be obtained? Pediatrics101:1071, 1998.

22. Zemel BS, Jawad AF, FitzSimmons S, Stallings VA.Longitudinal relationship among growth, nutritional status,and pulmonary function in children with cystic fibrosis:analysis of the Cystic Fibrosis Foundation National CFpatient registry. J Pediatr 137:374–380, 2000.

23. Moran A, Hardin D, Rodman D, Allen HF, Beall RJ,Dorowitz D, et al. Diagnosis, screening and management ofcystic fibrosis related diabetes mellitus: a consensus con-ference report. Diabetes Res Clin Prac 45:61–73, 1999.

24. Cystic Fibrosis Foundation. Patient registry 2001 annualreport. Bethesda, MD: CFF.

25. Ramsey BW. Management of pulmonary disease in patientswith cystic fibrosis. N Engl J Med 335:179–188, 1996.

26. Duijvestijn YCM, Brand PLP. Systematic review of N-acetyl-cysteine in cystic fibrosis. Acta Paediatr 88:38–41, 1999.

27. Reisman JJ, Rivington-Saw B, Corey M, Marcotte J,Wannamaker E, Harcourt D, et al. Role of conventionalphysiotherapy in cystic fibrosis. J Pediatr 113:632–636,1988.

28. Prasad SA, Main E. Finding evidence to support airway clear-ance techniques in cystic fibrosis. Dis Rehab 20:235–246,1998.

29. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB,Williams-Warren J, et al. Intermittent administration ofinhaled tobramycin in patients with cystic fibrosis. N EnglJ Med 340:23–30, 1999.

30. Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J.Effect of long term treatment with azithromycin on diseaseparameters in cystic fibrosis: a randomised trial. Thorax57:212–216, 2002.

31. Nepomuceno IB, Esrig S, Moss RB Allergic bronchopul-monary aspergillosis in cystic fibrosis: role of atopy andresponse to itraconazole. Chest 115:364–370, 1999.

32. Hjelte L, Petrini B, Kallenius G, Strandvik B. Prospectivestudy of mycobacterial infections in patients with cysticfibrosis. Thorax 45:397–400, 1990.

33. Eigen H, Rosenstein BJ, FitzSimons S, Schidlow DV. A mul-ticenter study of alternate-day prednisone therapy inpatients with cystic fibrosis. J Pediatr 126:515–523, 1995.

34. Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect ofhigh-dose ibuprofen in patients with cystic fibrosis. N EnglJ Med 332:848–854, 1995.

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35. Kerem E, Reisman J, Corey M, Canny GJ, Levison H.Prediction of mortality in patient with cystic fibrosis. N Engl J Med 326:1187–1191, 1992.

36. Yankaskas JR, Mallory GB Jr. Lung transplantation in cysticfibrosis: consensus conference statement. Chest 113:217–226, 1998.

37. Zemel BS, Kawchak DA, Cnaan A, Zhao H, Scanlin TF,Stallings VA. Prospective evaluation of resting energyexpenditure, nutritional status, pulmonary function, andgenotype in children with cystic fibrosis. Pediatr Res40:578–586, 1996.

38. Smyth RL, vanVelzen D, Smyth AR, Lloyd DA, Heaf DP.Strictures of ascending colon in cystic fibrosis and high-strength pancreatic enzymes. Lancet 343:85–86, 1994.

39. Lindblad A, Glaumann H, Stsrandvik B. A two-year prospec-tive study of the effect of ursodeoxycholic acid on urinarybile acid excretion and liver morphology in cystic fibrosis-associated liver disease. Hepatology 27:166–174, 1998.

40. Milkiewicz P, Skiba G, Kely D, Weller P, Bonser R, Gur U,et al. Transplantation for cystic fibrosis: outcome followingearly liver transplantation. J Gastroenterol Hepatol17:208–213, 2002.

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CHAPTER

8 Primary CiliaryDyskinesia (ImmotileCilia Syndrome–Kartagener Syndrome)DANIEL V. SCHIDLOW, M.D.

JONATHAN STEINFELD, M.D.

Definition

Genetics

Anatomy

Normal Anatomy and Function of Cilia

Ciliary Defects

Pathophysiology


Lower Respiratory Tract

Upper Respiratory Tract

Reproductive System

Situs inversus

Diagnosis

Differential Diagnosis

Treatment

Lower Airway Treatment

Upper Airway Treatment

Prognosis

DEFINITION

Primary ciliary dyskinesia (PCD) is an autosomalrecessive genetic disease, characterized by dysfunctionof the synchronous beating and propulsive function ofciliated epithelia and spermatozoa. Clinical featuresinclude early onset of persistent nasal and paranasalsinus disease, bronchial infection and obstruction. A sub-type of this condition called Kartagener syndrome ischaracterized by mirror-image reversal of thoracic andabdominal organs (situs inversus) and occurs in 50%of affected individuals. Infertility occurs in almost 100%of affected males due to abnormal or absent movement ofspermatozoa. The incidence of this condition is approx-imately 1:30,000 to 1:35,000 live births. The incidenceof Kartagener syndrome is estimated to be roughly halfthat of PCD. The incidence of isolated situs inversus,without ciliary abnormalities is about 1 :11,000 in theUnited States.1

PCD was first described in the beginning of the 20thcentury. The ultrastructural and functional defects ofcilia associated with PCD were described in the 1970sand 1980s, and the terms “immotile cilia syndrome” and“primary ciliary dyskinesia” were coined. Recent researchhas been focused on determining the site for the gene(s)and mutations responsible for this condition. Conditionssimilar to PCD have also been described in animals2.

GENETICS

The pattern of inheritance of PCD appears to be auto-somal recessive, with some rare exceptions3. Higherincidence of this disease has been observed in consan-guineous marriages and certain isolated populationgroups than in the general population. The exact loca-tion of the affected gene and its mutations has not yetbeen determined. Candidate genes have been reportedin both chromosomes 6 and 72,4. There are at least 10 dif-ferent genes that encode dynein and others that encodetubulin, both constituent proteins of cilia. Further, itappears that the presence of situs inversus may be gov-erned by mutations in separate genes that lie close to thePCD gene and interact in some form with it. Genes caus-ing reversal of normal organ asymmetry have beenreported in mice and other animals. In some cases ran-dom orientation occurs; some investigators havereported a gene mutation in chromosome 4 in micewhich in its homozygote state results in 100% of affectedanimals having situs inversus5.

Thus, it appears that the interaction of several genesand mutations and not the product of a single gene muta-tion determines the occurrence of PCD. Further work isnecessary to better understand the relationship betweenciliary defects, situs abnormalities and identification ofgenes and mutations associated with this disease inhumans.


ANATOMY

Normal Anatomy and Function of Cilia

Ciliated epithelium lines the human respiratory tractfrom the posterior third of the nose to the bronchioles.In humans, cilia are present in the paranasal sinuses, theEustachian tubes, the ependymal lining of the centralnervous system, in the male vasa efferentia, and thefemale oviducts, among other structures. Each ciliummeasures 6 μm in length and 250 nm in diameter. Therespiratory tree has 10 cilia per square centimeter. Thesurface of the respiratory tract is “carpeted” with beatingcilia that expel extraneous substances and propel mucusfrom distal areas towards the oropharynx. It is, then,easy to understand how a malfunction of this system willresult in mucus stasis and secondary infection.

The structure of a cilium is complex and consists of anaxoneme, anchored by a basal body and a rootlet to thecell, and it possesses some smaller claw-like formations on its tip (Figure 8-1). The direction in which the basalbody points defines the orientation of the cilium and the

direction of the effective beat. The axoneme containsnine pairs of microtubules which surround a central pairof microtubules, as well as radial spokes and peripheralnexin links, which to a great extent maintain the wheel-like arrangement of the cilium6. Inner and outer armsattach to the microtubules (Figure 8-2). The main struc-tural protein of the doublets is tubulin. The arms (innerand outer) contain dynein, which is a protein classified asan ATPase. Dynein generates the force that results in asliding movement of the microtubules, responsible for ciliary movement. It is generally accepted that the outerdynein arms are mostly responsible for beating frequencywhereas the inner dynein arms together with the radialspokes and nexin links have a role in the waveform of thebeating7. Changes in the structural integrity of theaxoneme can result in abnormal movement that rangesfrom stillness to aberrant patterns of hyperactivity.

Normal cilia beat synchronously in a characteristicwhip-like fashion propelling mucus from the distal air-ways to the nasopharynx. The tips of the cilia will onlytouch the viscous mucus layer when fully extended(effective stroke) and return to the much less viscous

A BFigure 8-1 (A) Electron microscopic view of a longitudinal cut of cilia appearing to be beatingsynchronously. Note that the basal foot processes are aligned in the same direction. (B) Diagram ofa cilium showing the axoneme and the anchoring structures.

Primary Ciliary Dyskinesia 133

A BFigure 8-2 (A) Electron microscopic view of a transverse cut across ciliated epithelium, show-ing the axonemal structure. All cilia are properly oriented within normal relative angles (see text). (B) Diagram of a cross-section of a cilium showing the wheel-like arrangement of the axonemalstructures.

periciliary fluid that lies underneath (recovery stroke)before the next beat (Figure 8-3)6. Neural and chemicalmechanisms, and cell-to-cell signaling control this action.The net effect is the so-called metachronal wave, a con-stant movement similar to the movement of sea or lakewaters casting their particles onto a beach. Effective cil-iary beating requires proper hydration to preserve theintegrity of the layer of fluid in which the organelles areimmersed (periciliary fluid). Both dehydration and over-hydration result in less effective movement of mucus.

Ciliary Defects

In PCD all defects are genetically determined, irre-versible and constant in each affected family. A widerange of abnormalities of ciliary structure has beendescribed, including absence of cilia, excessively longaxonemes, cilia with normal structure but abnormalfunction and orientation, as well as a variety of axonemaldefects (Table 8-1)2,8,9. Because of their genetic origin,

Figure 8-3 Diagram of normal ciliary beating. The cilium movesfrom the resting position in a whip-like fashion until fully extended,subsequently recoiling into the recovery stroke (Reproduced withpermission from Sleigh MA. The nature and action of respiratorytract cilia. In Brain JD, Proctor DF, Reid LM, editors. Respiratorydefense mechanisms. New York: Marcel Dekker, 1977.)


Table 8-1 Primary and Secondary CiliaryAbnormalities in PCD

Ciliary Abnormalities in PCDDynein arms Total or partial absence of inner, outer,

or both types of armsNexin links Absence of nexin links and inner dynein

arms with axonemal disorganizationTubular defects Transposition

Absence of central micro-tubular pairRadial spoke Absence of the head of the spoke

Total absence of spokesNormal structure with random orientation (disorientation)Elongated ciliaAbsence of cilia (ciliary aplasia due to defective ciliogenesis)Secondary (acquired) ciliary abnormalitiesCompound cilia (fusion of two or more cilia)Rupture of ciliary membraneCiliary fragmentationMissing tubulesExtra tubules

affected individuals within a family unit share the identi-cal ultrastructural defect. Ciliary movement abnormali-ties range from total absence to movement resembling awindshield wiper or an eggbeater. Cilia with thesedefects are rendered “dyskinetic,” insofar as their actionis ineffective in propelling mucus adequately, althoughmovement is present.

Widespread ciliary disorientation (or random orienta-tion) even in the absence of structural defects is a sign ofdyskinesia10. Drawing a line through the central tubulepair of adjacent cilia and measuring the relative anglecan determine the orientation of cilia. The line acrossthe central tubule is perpendicular to the direction ofbeating. Angles beyond 25° or 30° are indicative of cil-iary disorientation and disorganized beating.

Smokers, patients with asthma and cystic fibrosis, andindividuals afflicted by viral respiratory infections canexhibit reversible ciliary lesions11,12. In these instances,however, the percentage of cells with ciliary abnormali-ties is much lower than in patients with PCD. Further,many of the defects seen in these conditions (referred toas “secondary,” as opposed to genetically determined)involve the cell membrane and peripheral doublets.Typical secondary defects are compound cilia, wheretwo or more cilia coalesce into one larger structure, andbreaks in the cell membrane with injury to doublets. In some instances dynein arm defects have beendescribed, but, as was stated above, the number ofaffected cells is much lower than in PCD and the defectsare reversible.

PATHOPHYSIOLOGY

Patients with PCD have poor mucociliary clearanceand therefore have ineffective bacterial removal. Therespiratory tract of these individuals is chronically colo-nized with bacteria. Bacteria multiply locally and viru-lence factors accumulate. Bacterial toxins may furtherslow ciliary movement, disrupt their beat, and even leadto further ciliary disorganization13.

Many bacteria, such as Pseudomonas aeruginosa andHaemophilus influenzae, prefer to bind to mucus ratherthan to normal epithelium. When bacteria colonize mucusthey release toxins that damage the underlying epithelium,further enhancing bacterial adhesion and causing damage.Activated neutrophils are attracted to the damaged area inan attempt to clear bacteria. Proteases, reactive oxygenspecies, and elastases attack the bacteria and the lungitself, leading to even more lung inflammation and dam-age13. Chronic infection and obstruction leads to the devel-opment of bronchiectasis, lung scarring and loss offunction. In the sinuses, faulty clearance of mucus and sub-sequent infection causes chronic inflammation and recur-rent exacerbations. Thickening of the mucosa, chronicbacterial infection, and meatal obstruction are the rule.


Lower Respiratory Tract

Pulmonary manifestations can be present as early asin the neonatal period. Recurrent pneumonia and atelec-tasis, often multifocal, have been reported in babies in thenursery. Later in life, recurrences of “chest congestion,”and signs of airways obstruction such as wheezing nottotally responsive to bronchodilator therapy, are commoncomplaints. PCD should be suspected in patients withasthma and severe upper respiratory complaints that donot respond to standard therapy. Chronic respiratoryinfections are the hallmark of PCD. The presence ofchronic mucopurulent expectoration from which bacte-ria are consistently recovered (including Pseudomonasaeruginosa) and bronchiectasis in imaging studies shouldalert clinicians to the diagnosis as well.

Chest radiographs may show areas of atelectasis, infil-trates, hyperinflation, and other changes associated withchronic infections. Peribronchial thickening and nodularcystic lesions with evidence of bronchial dilatation heigh-ten the suspicion of bronchiectatic changes (Figure 8-4).These must be confirmed by computed tomography(CT). Pulmonary function testing may show a wide rangeof severity of obstruction including decreased forced vitalcapacity and forced expiratory flows through large andsmall airways (FEV1 and FEF25–75%). Bronchodilatorresponsiveness is very variable.


Figure 8-4 Complete situs inversus in a patient withKartagener’s syndrome. Dextrocardia in addition to finding theliver on the left side and the stomach on the right. There is an infil-tration with an air bronchogram in the left lung as well as peri-bronchial thickening bilaterally (especially in the left upper andleft lower lobes). Some nodular-cystic lesions are seen in the lowerleft lung field, suggestive of bronchiectasis.

The development of bronchiectasis is a late event in thedisease, which results from untreated infection and airwaysobstruction. In an era of increased recognition of this con-dition due to awareness by pediatric caregivers, findingwidespread or severe bronchiectatic changes in the lungsof these patients is uncommon. Likewise, the onset ofrestrictive disease due to destruction of lung tissue and scar-ring is very unusual in the pediatric population nowadays.

Upper Respiratory Tract

Otitis media and sinusitis are very common and occurearly in life. Most children have protracted or recurrentotitis media with effusion, and conductive hearing lossnecessitating tympanostomy. Mucopurulent nasal secre-tions are a hallmark of this condition, due to persistentnasal and paranasal sinus inflammation and infection.

Frequent exacerbations of sinus disease are common,especially in the ethmoid and maxillary sinuses. Patientsfrequently complain of chronic nasal congestion, puru-lent rhinorrhea, sinus pressure and headaches. Drainagefrom the maxillary sinuses is frequently ineffective, ascilia must be able to move mucus against gravity in orderto drain adequately. Poor mucus clearance, as in the lungs,leads to chronic infection and further inflammatoryresponse by the surrounding tissues14. Twenty percent of

children develop nasal polyps15; many develop chronicnasal obstruction, snoring, postnasal drip, hyponasalspeech, halitosis and a poor sense of smell.

Radiographs of the sinuses frequently show opacitieswith mucosal thickening of the maxillary sinuses. Thepreferred imaging technique is CT of the sinuses whichoften reveals meatal obstruction, air–fluid levels, mucosalthickening, and bone erosion in severe cases. The frontalsinuses are often hypoplastic16.

One conspicuous feature of respiratory disease inPCD is the almost universal need for antimicrobial ther-apy to curb the symptoms, and their common recur-rence upon discontinuation of such therapy. Thus, manyindividuals affected with PCD require ongoing “suppres-sive” antibiotics to avert recurrences.

Reproductive System

Male patients almost universally have immotile sperma-tozoa and are, therefore, sterile. Spermatozoa have normalstructure but are completely immotile. Intracytoplasmicinjection of sperm from men with PCD has been used successfully to fertilize eggs17. Typically, sperm flagellaand respiratory cilia share the same ultrastructural defectin affected individuals. Very rare cases of PCD withmotile sperm have been reported, pointing to the veryheterogeneous nature of this condition1. Women withimmotile cilia may have abnormal ciliary movement inthe oviducts and the fimbriae, however there is no evidence to date to indicate that female fertility isreduced or that affected women have a higher risk forectopic pregnancy18.

Situs inversus

Kartagener syndrome refers to the association ofchronic sinusitis, bronchiectasis and situs inversus, asdescribed by a Swiss physician about 70 years ago. Situsinversus is defined as a complete mirror image of normalorgan placement. Situs inversus as an isolated finding(not associated with ciliary dysfunction) in some peopleis widely known to occur19. Because these individualsare essentially healthy, it is very likely that the true inci-dence of complete situs inversus without underlyingconditions is underreported.

Fifty percent of patients with immotile cilia syndromehave complete situs inversus. What leads to this random-ization of laterality is unclear. It is unknown whether themechanics of abnormal ciliary movement leads to situsinversus. It is possible that a gene that controls left–rightdetermination is related to one of the genes responsiblefor ciliary development. Another hypothesis is that ciliarymovement is necessary for normal organ lateralizationin utero. Absence of dynein arms could lead to lack ofdirection and random visceral situs determination.


Table 8-2 Diagnosis of PCD

ClinicalChronic upper and/or lower respiratory infectionsEarly (neonatal) onsetPurulent rhinorrheaChronic otitisPersistent or refractory sinusitisChronic airways obstruction/mucopurulent expectorationSitus inversusMale infertility (adults)

Laboratory: Phase IChest radiograph (recurrent atelectasis/pneumonia, right middle

lobe syndrome, situs inversus, nodular-cystic lesions)Computed tomogram of the sinuses (pansinusitis,

hypoplasia of frontal sinuses) Computed tomogram of the chest (bronchiectasis)EchocardiogramBiopsy of nasal and tracheal mucosaAnalysis of semen (motility: electron microscopy)Saccharin testStudies of ciliary movement/ciliary cultures

Laboratory: Phase IIaDirect examination of ciliary beatingSaccharin testRadioactively tagged particle test

Laboratory: Phase IIbAnalysis of semen (adolescent/adults)Biopsy of respiratory mucosa/electron microscopyCiliary culture

DIAGNOSIS

Clinicians must consider the diagnosis of PCD in everychild with complete situs inversus. Clear definition oforgan position is necessary, because individuals with othersitus abnormalities are not afflicted by PCD (see below). Itmust also be remembered that not every child with situsinversus has PCD; the constellation of situs abnormalitiesand chronic, severe respiratory disease is indicative.

The diagnosis of PCD in children without situs abnor-malities is difficult, given the similarities between thisand other conditions. PCD becomes almost a diagnosis ofexclusion because it is much less common than respira-tory allergy or cystic fibrosis. A very suggestive feature is the presence of persistent respiratory symptoms—particularly upper airway congestion with otitis, puru-lent rhinitis and sinusitis that abate with antibiotics, butsuffer almost immediate recrudescence after antibioticdiscontinuation.

In the neonate, the diagnosis must be suspected if res-piratory distress is accompanied by unexplained abnor-mal findings on chest radiograph8. Lobar or subsegmentalopacifications are suspicious, especially if they are recur-rent, multifocal and resolve with administration of antimi-crobial drugs and physiotherapy. Purulent rhinitis in anewborn, especially in the absence of other epidemiologichistory, is also suggestive of PCD.

In adult males, infertility associated with chronic res-piratory symptoms should make clinicians suspect thediagnosis. Sperm immotility on analysis of seminal fluidfollowed by ultrastructural examination can be used toconfirm the diagnosis20. Absent spermatozoa alert clini-cians to the diagnosis of cystic fibrosis or Young syn-drome (a disease characterized by chronic sinusitis andlung disease with azoospermia).

The first phase of the diagnosis is the establishment ofthe anatomic abnormalities or lack thereof. This can beaccomplished by a variety of imaging studies listed in Table 8-2. The examination of the paranasal sinuses is,in the opinion of the authors, a very important element inthe diagnostic constellation, in that chronic sinusitis withfrontal sinus aplasia or hypoplasia is almost universal. CTis the best imaging modality in defining this problem.

The first phase of diagnosis also requires the elimina-tion of a more common diagnosis such as cystic fibrosis(sweat test and gene mutation analysis), immune defi-ciency (quantitative immunoglobulin levels) and allergy.The latter, of course, is non-specific, in that it can (andfrequently does) coexist with PCD.

The next phase of diagnosis is the specific diagnosisof PCD and involves tests of ciliary motility and struc-ture. The sequence of tests varies from center to centerand is based in the proficiency with which tests of ciliaryfunction are performed.

The direct microscopic observation of ciliary beatingor the use of phase-contrast videomicroscopy requiresthe brushing or scraping of epithelium from the nose8.Such tests have traditionally been used in combinationwith studies of ciliary ultrastructure from biopsies toconfirm a diagnosis of PCD.

The saccharin test involves the placement of a particleof saccharin on the inferior turbinate and measurement ofthe amount of time before the patients feels a sweet taste(normally 20–30 minutes)21. An alternative is the bron-choscopic placement of radioactively tagged particles inthe lower central airway to follow their trajectory.

Another approach is the inhalation of radioactiveaerosols and measurement of clearance of radioactivityfrom the lung over time. All these methods require thatindividuals remain still for a prolonged period of timewith the head tilted, without evidence of sniffing, sneez-ing, or other maneuvers that would normally acceleratethe movement of particles8. Likewise, cough can greatlyspeed clearance of particles from the lung. These exactingconditions make such functional tests of ciliary movementnotoriously inaccurate in younger individuals who areunable to keep still for prolonged periods of time. Theyare very rough qualitative estimates of ciliary function.


We tend to prefer to secure an anatomic diagnosisover all other methods. Samples of mucosa must beobtained from at least two sites, often the posterior thirdof the nose and the carina. It is essential that one sampleat least be obtained deep enough in the respiratory tree(i.e., trachea) to assure a minimum effect of inflamma-tion and a maximum recovery of ciliated cells. Samplesmust be delicately and proficiently handled, and placedin glutaraldehyde—NOT in saline solution or formalde-hyde. Properly handled samples should be examined byelectron microscopy with transverse and longitudinalcuts to determine axonemal structure as well as orienta-tion. The diagnosis can thus be confirmed. Viral infec-tions or chronic inflammation can result in thedenudation of nasal mucosa, or secondary changes in cil-iary function and structure that can interfere with thediagnosis21. Thus, biopsies should ideally be obtainedafter a course of antibiotics and while the patient is notexperiencing an intercurrent illness or an exacerbation.

A more recently described approach is the in vitroculture of ciliated epithelium22. The cilia thus generatedexpress the primary genetically induced abnormalities,without the secondary defects caused by inflammation.This approach is especially useful in patients withdefects other than dynein-arm deficiency (especiallyouter) in whom the nature of the ciliary defects visual-ized is unclear23.

DIFFERENTIAL DIAGNOSIS

Asplenia and polysplenia are conditions associatedwith abnormalities of visceral position that can occa-sionally be easily confused with Kartagener syndrome.Characteristically, these patients can have complex con-genital heart disease, random positioning of abdominalorgans with livers that occupy the entire mid-abdomen(situs ambiguus), absent inferior vena cava, and intes-tinal malrotation, among other defects. Asplenic patientsare prone to sepsis caused by encapsulated organismsand have Howell–Jolly bodies on the peripheral smear.

In the absence of situs inversus, the differential diagno-sis must include cystic fibrosis, B-cell immune deficiency,and severe respiratory allergies. Table 8-3 summarizes thesalient characteristics of the most important conditionsincluded in the differential diagnosis of PCD.

TREATMENT

Regular care and periodic evaluations by subspecial-ists are helpful to maintain health in these patients. It isimportant to remember these individuals have a normalimmune system and should, therefore, receive all child-hood immunizations. Influenza vaccination on a yearly

basis should be added to their regimen. Patients shouldhave access to physiotherapists, otolaryngologists, audiol-ogists, and, when necessary, urologists and gynecologists2.When the patient is old enough to cooperate, periodicpulmonary function testing, radiographs and sputum cul-tures should be done to monitor the patient’s course andadjust therapy.

The two most important therapies for PCD are theaggressive use of antibiotics and the clearance of mucus.The goal of medical treatment is to avoid complicationsof sinusitis, bronchial obstruction and bronchiectasisdue to infection and mucus stasis.

Lower Airway Treatment

Daily chest physiotherapy allows for improved mucus clearance. This includes chest clapping, breathingtechniques, and postural drainage twice a day8. Newermechanical devices include mechanical vests, flutterdevices, Thera PEP masks and other newly developedtechniques.

Bacteria often colonize the damaged respiratory tractof patients with PCD. The aggressive use of antibioticsmay help to decrease bacterial colonization. Antibioticsmay be given orally, via nebulizer, and intravenously.Sputum cultures, while imperfect, may provide the iden-tification and antibiotic sensitivities of specific bacteria.While bronchoalveolar lavage has a superior diagnostic

Table 8-3 Differential Diagnosis of PCD

Condition Differentiating feature

Other situs abnormalities Severe cardiac diseaseAsplenia–polysplenia Sepsis (capsulated organisms)

Howell–Jolly bodies (asplenia)Discordant situs

Cystic fibrosis Intestinal malabsorptionMucoid strains of P. aeruginosa in

sputumPositive sweat testPositive mutation analysisSemen analysis: aspermia (adults)

B-cell immune deficiency Severe respiratory and systemicinfections with unusual organisms

Abnormal immunoglobulin levelsRespiratory allergies Positive allergy tests

Increased IgE levelsSeasonalityNormal oropharyngeal flora

Primary ciliary dyskinesia Situs inversus (50% of patients)Abnormal ciliary biopsyProminent upper airway diseaseSemen analysis: absent or abnormal

movement of spermatozoa (adults)

yield, its routine performance may subject patients tounnecessary risk.

Upper Airway Treatment

There is no standard of care for treatment of otitismedia with effusion in patients with PCD16. Some physi-cians advocate bilateral myringotomy tube insertionwhen patients have impaired speech, language, or edu-cational development. However, these patients oftencontinue to have chronic discharge from their tubes.Patients may also be treated with unilateral myringotomytube insertion. Hearing aids are helpful and less invasive.They may be used in conjunction with myringotomytubes or on their own. As many patients experience a spontaneous resolution of hearing abnormalities, hearing aids may not be necessary after childhood8.

Chronic sinusitis may need to be treated surgically. Aninferior meatus antrostomy is helpful because it allowsgravitational sinus drainage. Other procedures, such asethmoidectomy and frontal sinus recess surgery, may alsobe beneficial14. Functional endoscopic sinus surgery alsocreates a pathway for drainage, aeration, and medical ther-apy24. Even after surgery, patients will clinically benefitfrom nasal washes, topical corticosteroids, and systemicantibiotics (Table 8-4)8.

Prognosis

PCD is a chronic and potentially debilitating disease,but it is not a lethal condition. Early diagnosis and aggres-sive therapy are aimed at avoiding complications, espe-cially bronchiectasis and lung scarring. Proper care canassure reasonable well-being and ability to participatefully in all aspects of life.

SUGGESTED READING

1. Schidlow DV. Primary ciliary dyskinesia (the immotile ciliasyndrome). Ann Allergy 73:457–468, 1994.

2. Sleigh MA. Ciliary function in mucus transport. Chest 80:791–795, 1981.

3. Knowles MR, Boucher RC. Mucus clearance as a primaryinnate defense mechanism for mammalian airways. J ClinInvest 109:571–577, 2002.

REFERENCES

1. Afzelius BA. Immotile cilia syndrome: past, present, andprospects for the future. Thorax 53: 894–897, 1998.

2. Meeks M, Bush A. Primary ciliary dyskinesia. PediatrPulmonol 29:307–316, 2000.

3. Narayan D, Krishnan SN, Upender M, Ravikumar TS, et al. Unusual Inheritance of primary ciliary dyskinesia(Kartagener’s syndrome). J Med Genet 31:493–496, 1994.

4. Pan Y, McCaskill CD, Thompson KH, Hicks J, et al. Paternalisodisomy of chromosome 7 associated with complete situsinversus and immotile cilia. Am J Hum Genet 62:1551–1555,1998.

5. Yokohoma T, Copeland N, Jenkins NA, Montgomery CA, et al. Reversal of left–right asymmetry: a situs inversusmutation. Science 260:679–682, 1993.

6. Sleigh MA, Blake JR, Liron N. The propulsion of mucus bycilia. Am Rev Respir Dis 137:726–741, 1988.


MAJOR POINTS

1. Primary ciliary dyskinesia (PCD) leads to recurrentupper and lower airway infections due toineffective mucus clearance.

2. One half of all patients with PCD also havecomplete situs inversus (known as Kartagenersyndrome).

3. Aside from very rare case reports, men with PCDhave immotile sperm.

4. There are in vitro fertility methods that allow menwith PCD to have children.

5. Infections, asthma, and other airway diseases canlead to temporary ciliary dysfunction.

6. The electron microscopic diagnosis of PCD isdifficult to accomplish and must be attemptedseveral weeks after resolution of infection.

7. The treatment of PCD centers around aggressivetreatment of infection with antibiotics and mucusclearance.

8. Patients with PCD benefit from a multidisciplinaryteam approach, regular care and periodic healthcare visits.

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Table 8-4 Treatment of Respiratory Problems of PCD

Lower airwayMucus clearance techniquesContinuous or intermittent antibioticsTreatment of reversible airways obstructionTherapy similar to asthmaAlpha-dornasea

Upper airwayContinuous or intermittent antibioticsSinus lavagesNasal corticosteroidsEndoscopic sinus surgeryAlpha dornasea

aOff-label use. Some clinicians use inhalation via mask to enhance thinningand clearance of purulent respiratory secretions.


7. de Iongh RU, Rutland J. Ciliary defects in healthy subjects,bronchiectasis, and primary ciliary dyskinesia. Am J RespirCrit Care Med 151:1559–1567, 1995.

8. Bush A, Cole P, Hariri M, Mackay I, et al. Primary ciliarydyskinesia: diagnosis and standards of care. Eur Respir J 12:982–988, 1998.

9. DeBoeck K, Jorissen M, Wouters K, et al. Aplasia of respiratory tract cilia. Pediatr Pulmonol 13:259–265, 1992.

10. Rutland J, de Iongh RU. Random ciliary orientation: a cause of respiratory tract disease. N Engl J Med 323:1681–1684,1990.

11. Rayner CFJ, et al. Ciliary disorientation in patients withchronic upper respiratory tract inflammation. Am J RespirCrit Care Med 151:800–804, 1995.

12. Rossman CM, et al. Nasal ciliary ultrastructure and functionin patients with primary ciliary dyskinesia compared with that in normal subjects and in subjects with variousrespiratory diseases. Am Rev Respir Dis 129:161–167,1984.

13. Dowling RB, Wilson R. Bacterial toxins which perturb ciliaryfunction and respiratory epithelium. Soc Appl BacteriolSymp Ser 84(27S):138–148S, 1998.

14. Hulka GF. Head and neck manifestations of cystic fibrosisand ciliary dyskinesia. Otolaryngol Clin North Am 33:1333–1341, 2000.

15. Levison H, et al. Pathophysiology of the ciliary motility syndromes. Eur J Respir Dis 64(127S):102–116, 1983.

16. El-Sayed Y, Al-Sarhai A, Al-Essa AR. Otological manifestationsof primary ciliary dyskinesia. Clin Otolaryngol 22:266–270,1997.

17. von Zumbusch A, Fiedler K, Mayerhofer A, et al. Birth ofhealthy children after intracytoplasmic sperm injection intwo couples with male Kartagener’s syndrome. Fertil Steril70:643–646, 1998.

18. Afzelius BA, Eliasson R. Male and female infertility problemsin the immotile-cilia syndrome. Eur J Respir Dis 64(127S):144–147, 1983.

19. Splitt MP, Burn J, Goodship J. Defects in the determina-tion of left–right asymmetry. J Med Genet 33:498–503, 1966.

20. Munro NC, Currie DC, Lindsay KS, Ryder TA, et al. Fertilityin men with primary ciliary dyskinesia presenting with respiratory infection. Thorax 49:684–687, 1994.

21. Canciani M, et al. The saccharin method for testing mucocil-iary function in patients suspected of having primary ciliarydyskinesia. Pediatr Pulmonol 5:210–214, 1988.

22. Jorissen M, Van Der Schveren B, Van Der Berghe, Cassiman JJ.The preservation and regeneration of cilia on human epithelial cells cultured in vitro. Arch Otorhinolaryngol 246:308–315, 1989.

23. Jorissen M, Van Der Schveren B, Van Der Berghe, Cassiman JJ.Ciliogenesis in cultured human nasal epithelium. ORL J Otorhinolaryngol Relat Spec 52:368–374, 1990.

24. Parsons DS, Green BA. A treatment of primary ciliary dys-kinesia: efficacy of functional endoscopic sinus surgery.Laryngoscope 103:1269–1272, 1993.

140

CHAPTER

9 PulmonaryComplications ofImmunologicDisordersANAND C. PATEL, M.D.

CLEMENT L. REN, M.D.

Infectious Pulmonary Complications

of Immunodeficiency

Complications of Neutrophil Defects

Complications Associated with B Lymphocyte Disorders

Pulmonary Infections Associated with T Lymphocyte Disorders

Overview of T Cell Disorders

Severe Combined Immunodeficiency

Other T Cell Defects

Non-infectious Pulmonary Complications of

Immunodeficiency

Pulmonary Complications Associated with Human

Immunodeficiency Virus Infection

Infectious Complications of HIV Infection

Non-infectious Complications of HIV Infection

Pulmonary Complications Related to HIV Therapy

Pulmonary Evaluation of the Patient with

Immunodeficiency

Treatment of Pulmonary Complications

Summary

The average 4-year-old child inhales approximately600 liters of air a day, exposing the lung to large quan-tities of potential pathogens. To protect against poten-tial infection, the respiratory tract has a wide variety ofdefense mechanisms, including a mucociliary barrier,the innate immune system, and the adaptive immunesystem. Although abnormalities in the mucociliary sys-tem and innate immunity have been described and canlead to pulmonary complications, these conditions arequite rare and not well characterized. In contrast,defects in the adaptive immune system and its effectorcells have been extensively studied on a molecular andcellular level, and there is considerable information con-cerning the acquisition of lung disease and its treat-ment. For this reason, this chapter will focus onpulmonary complications arising from defects in adap-tive immunity.

INFECTIOUS PULMONARYCOMPLICATIONS OFIMMUNODEFICIENCY

Each component of the immune system serves a spe-cific role in host defense. A deficiency in any one elementof the immune system renders individuals susceptible tospecific groups of pathogens. Table 9-1 summarizes thepattern of infections seen in the different immunodefi-ciency syndromes.

Complications of Neutrophil Defects

Polymorphonuclear neutrophils (PMNs) are the pri-mary phagocytic cells of the immune system. They playa key role in eliminating opsonized bacterial and fungalpathogens through release of proteolytic enzymes andreactive oxidant species (ROS). This function may beimpaired through abnormalities in cell adhesion, cell signaling, cell number, granule function or formation, andintracellular killing 1.

The most common PMN disorder is chronic granulo-matous disease (CGD), with an estimated incidence of 1 in 200,000 in the United States1,2. The primary defect in CGD is a loss of NADPH oxidase function. CGD exists in X-linked and autosomal recessive forms, depending onwhich gene coding for the NADPH oxidase complex ismutated; the X-linked form is more common. Loss ofNADPH oxidase activity leads to a markedly reduced oxida-tive burst following phagocytosis. PMNs from patientswith CGD can phagocytose bacteria but cannot kill them,leading to the development of multiple large granulomas.Organisms that express catalase are particularly resistant tokilling by PMNs from CGD patients, because catalase neu-tralizes any residual ROS produced by these patients byhydrolyzing superoxide to hydrogen peroxide. The most

Pulmonary Complications of Immunologic Disorders 141

Table 9-1 Typical Pathogens Associated withSpecific Immunodeficiencies

Element of the Typical Immune System Example PulmonaryAffected Diseases Pathogens

Neutrophils CGD S. aureus,A. fumigatus

B lymphocytes XLA, CVID S. pneumoniae,H. influenzae

T lymphocytes Severe: SCID PCP, viruses, fungiLess severe: Bacterial

A-T, WAS pneumonia

common catalase-positive organisms that cause pul-monary infections in CGD are Staphylococcus aureus andAspergillus species. Burkholderia cepacia, Nocardiaspecies, and Serratia marcescens can also cause pul-monary infections in this group of patients1.

Patients with CGD present with atypical or unusuallysevere lymphadenitis, skin abscesses, pneumonia, and/orhepatomegaly secondary to infections with the afore-mentioned agents. Less common initial presentationsinclude intestinal lymphadenitis that can cause a diarrheaand colitis picture that can be mistaken for Crohn’s disease. Data from a national registry of 368 CGD patientsin the United States provide considerable insight into thepulmonary complications of CGD3. Eighty percent of thepatients in the registry had had pneumonia at least once.Aspergillus was the most common causative organism,responsible for 41% of pneumonias. Aspergillus pneumo-nia with or without dissemination was also the most com-mon cause of death in patients with CGD, causing 35% ofdeaths in the series. Staphylococcus species caused 12% ofpneumonias. B. cepacia was the third most commoncause of pneumonia (8% of all cases), but the secondmost common cause of death (18%). Other pathogensreported to cause pneumonia in these patients includeNocardia, Mycobacteria, and Gram-negative bacteria.

A recent trend in the epidemiology of pulmonaryinfections in CGD is the growing incidence ofAspergillus as the primary pulmonary pathogen. Thistrend probably reflects advances in the treatment ofCGD. Trimethoprim/sulfamethoxazole (TMP/SMX) pro-phylaxis was introduced in 1990, and has been effectivein reducing the frequency of serious bacterial infec-tions1. The other therapy that has had a major impact onthe clinical course of CGD has been interferon-gamma(IFN-γ). The precise mechanism by which IFN-γ acts inCGD is unclear, although there is some evidence that itaugments the oxidative burst in CGD patients4. A largemulticenter trial of IFN-γ therapy in CGD patients showed

a significant reduction in both bacterial and fungal infec-tions5. The combination of these two therapies has sig-nificantly reduced bacterial infections, but has had a lessdramatic effect on serious fungal infections (Figure 9-1).

Pulmonary abscesses also occur frequently in patientswith CGD. Sixteen percent of patients in the registry hada lung abscess at some point in their course. Of those,the most common organism isolated was Aspergillus(23%), although Nocardia species, B. cepacia, andStaphylococcus species can also cause abscesses3.

Other PMN disorders include leukocyte adhesion molecule (LAM) deficiency, hyper-IgE syndrome, andChediak–Higashi syndrome1. LAM deficiency results fromdefects in expression of either integrin or selectin adhe-sion molecules on the surface of leukocytes. Withoutthese adhesion molecules, PMNs cannot migrate to sitesof infection. Delayed umbilical cord separation, markedleukocytosis, and chronic severe skin infections are com-mon presenting signs. Hyper-IgE syndrome is a rare dis-order of unknown etiology associated with impairedPMN function. Patients typically present with coarsefacial features, recurrent skin infections, and extremelyhigh serum IgE levels (Figure 9-2). Chediak–Higashi syn-drome (CHS) is an autosomal recessive disorder resultingfrom mutations in a lysosomal protein transport gene.Patients with CHS have multiple abnormalities, includingreduced PMN phagocytosis and chemotaxis. In general,pulmonary complications in these disorders are verysimilar to those of CGD.

Complications Associated with BLymphocyte Disorders

B lymphocytes are the only source of immunoglobu-lin (Ig), or antibody6. There are five different Ig isotypes:IgM, IgG, IgA, IgD, and IgE. B cells initially can makeonly IgM and IgD, but with appropriate T lymphocytehelp they will switch to making other isotypes.Immunoglobulins play a key role in the opsonization andclearance of encapsulated bacterial organisms. Thuspatients with B cell deficiencies are prone to infectionwith these organisms, primarily S. pneumoniae(Pneumococcus) and H. influenzae. In contrast,because T cell function is intact, patients tend to havenormal defenses against viruses, fungi, and mycobacteria.Because maternal IgG crosses the placental barrier,infants with B cell disorders receive passive protectionfrom infection for the first 6 to 9 months of life. Afterthis age, patients will present with recurrent bacterialinfections of the middle ear, sinuses, and lungs.Complications such as mastitis are common. Sepsis andosteomyelitis may also be seen6.

The most severe forms of B cell disorders arise fromdefects in B cell development, leading to near totalabsence of circulating B cells. Of this group, X-linked


A B

Figure 9-1 (A) Chest CT scan of a 22-year-old man with CGD who had a 2 kg weight loss over 2 weeks and complained of chest pain for 1 month. The study demonstrates several nodules in theright lung (arrows). There is also a patchy density in the right upper lobe and right middle lobe adja-cent to the heart (small arrows). The patient had been receiving ciprofloxacin and itraconazole prophylaxis. (CT image courtesy of Avrum N. Pollock, M.D., FRCPC and Kathleen Sullivan, M.D.,Ph.D.) (B) Thoracoscopic biopsy of one of the nodules demonstrates poorly formed suppurativegranulomata (wide arrows) with central necrosis (thin arrows) and surrounding organizing pneu-monia. Culture of the lesion grew a fungus, Paecilomyces lilicanus. Hematoxylin and eosin stain,magnification ×20. (Photomicrograph courtesy of Bruce Pawel, M.D.)

Figure 9-2 Chest CT scan of a 20-year-old man with hyper-IgEsyndrome. There are numerous bullae in the right lung along withcystic bronchiectasis. The large cystic lesion in the left lung was amultiloculated abscess arising from the major fissure, which hadbeen percutaneously drained of 500 cc of purulent fluid. In culture,the fluid grew methicillin-resistant Staphylococcus aureus and non-typeable Haemophilus influenzae. (CT image courtesy of Avrum N.Pollock, M.D., FRCPC and Kathleen Sullivan, M.D., Ph.D.)

agammaglobulinemia (XLA), or Bruton’s disease, is themost common. The molecular defect in XLA is due tomutations in the Bruton’s tyrosine kinase (BTK) gene6.Absence of BTK results in a block in B cell maturation atthe pre-B cell stage. Thus patients with XLA have no cir-culating B cells and make no antibody of any kind.Pulmonary infections are very common in XLA, mainlydue to S. pneumoniae and H. influenzae7. In contrast toother B cell disorders, patients with XLA can developPneumocystis carinii pneumonia (PCP)6. The reason forthis is unclear, although it may be related to the role ofB cells as antigen-presenting cells. Alternatively, it maybe that loss of BTK function leads to subtle defects in cellular immunity.

Common variable immunodeficiency (CVID) is thename given to a heterogeneous group of disorders char-acterized by varying degrees of hypogammaglobulinemiawith or without other abnormalities of T cell function6.Patients with CVID usually have normal numbers of Bcells, but the function of these cells is impaired. Otherimmunologic abnormalities that can be seen in CVIDinclude impaired lymphocyte proliferative response toantigens, deficiency of antigen-primed T cells, increased


macrophage activation, and reduced production and/orexpression of cytokines. CVID can frequently occur inolder children or adults following a viral infection, and itis sometimes referred to as acquired hypogammaglobu-linemia. Although CVID patients may have subtle defects in T cell function, they rarely develop opportunistic infec-tions. More commonly, patients with CVID are prone torecurrent bacterial infections, generally of the sinopul-monary tract. Because the condition may present in laterchildhood and the diagnosis may be delayed, many of these

patients have bronchiectasis at the time of presentation8

(Figure 9-3).IgG subclass deficiency is a subset of CVID character-

ized by low normal or mildly reduced total IgG and selec-tive decreases in one or more of the four IgG subclasses6.Although symptomatic disease has been described inassociation with all four IgG subclasses, IgG2 subclassdeficiency is the syndrome that has been best described.Patients with IgG2 subclass deficiency present withrecurrent sinopulmonary infections; most patients also

A B

CFigure 9-3 (A) Posterior-anterior chest radiograph of a 10-year-old male with CVID, demonstrat-ing persistent densities in the left lower lobe and lingula. He had been treated for asthma from infancyuntil age 8 years, when he presented with severe bilateral pneumonia and staphylococcal sepsis. A spu-tum culture at the time of this radiograph grew non-typeable H. influenzae. (Image courtesy of AvrumN. Pollock, M.D., FRCPC, and Howard B. Panitch, M.D.) B, C. Chest CT scans of the same patient,demonstrating mild, diffuse bronchiectasis of the right middle lobe and lingula (B) and of the left lowerlobe (C). (Images courtesy of Avrum N. Pollock, M.D., FRCPC and Howard B. Panitch, M.D.)


Figure 9-4 Chest radiograph of a 16-year-old male with IgA andIgG3 subclass deficiencies, and possible deficient antibodyresponse to polysaccharide antigens. He presented with a 2 dayhistory of upper respiratory symptoms, fever, diarrhea and vomit-ing. The study shows consolidation of the right lower lobe alongwith a right-sided pleural effusion. The sputum grew only normaloropharyngeal flora and a blood culture was sterile. He had a 2 year history of recurrent episodes of pharyngitis and sinusitis,and was treated approximately monthly with antibiotics for recurrent upper respiratory illnesses before the diagnosis of hisimmunodeficiency was made. (Image courtesy of Avrum N.Pollock, M.D., FRCPC and Kathleen Sullivan, M.D., Ph.D.)

carry the diagnosis of asthma9. Although their total IgGmay be normal, they fail to make high titers of antibodyagainst encapsulated organisms, such as S. pneumoniaeand H. influenzae.

IgA deficiency is one of the most common antibodydeficiencies, with an approximate incidence of 1 in 400to 3000 individuals in the general population6. Mostpatients with IgA deficiency are asymptomatic, perhapsbecause of compensatory protection by IgG. Those whoare symptomatic are at increased risk of gastrointestinaland sinopulmonary infections. Symptomatic IgA defi-ciency is often seen in association with IgG subclass deficiency (Figure 9-4).

The introduction of intravenous immunoglobulin(IVIG) replacement therapy has had a significant impacton the morbidity and mortality of B cell immunodefi-ciencies6,10. IVIG is prepared from pooled plasma col-lected from a large number of donors. As a bloodproduct, IVIG does carry a potential risk for pathogentransmission. However, improved purification protocolshave rendered this risk extremely small. IVIG therapysignificantly reduces the incidence and severity of pneu-monia and other respiratory tract infections in patientswith XLA, CVID, and other antibody deficiency syn-dromes10. However, bronchiectasis can still develop insome patients in spite of IVIG therapy8,11.

Pulmonary Infections Associated withT Lymphocyte Disorders

Overview of T Cell DisordersT lymphocytes play important roles in both coordinat-

ing the adaptive immune system as well as actively elimi-nating foreign pathogens11. T cells can be roughlydivided into two major subsets. Helper T (TH) cells usu-ally express the cell surface receptor CD4, whereas cyto-toxic T lymphocytes (CTLs) usually express CD8 and areresponsible for cell-mediated immune responses. THcells are critical for B cell activation and optimal antibodyproduction. Helper T cells also coordinate the activity ofCTLs. Because of the multiple roles that T cells play in theimmune system, impairment of their function may haveprofound consequences for immunity.

Severe Combined ImmunodeficiencySevere combined immunodeficiency (SCID) is the

term used to identify the most severe forms of T cell dis-orders. SCID can result from a diverse array of geneticmutations that affect lymphocyte production, develop-ment, metabolism, or cell signaling12. Regardless of theunderlying genetic defect, the immunologic conse-quence is that there is near total loss of T cell number orfunction. Because B and T lymphocytes develop from asingle lymphoid lineage, many cases of SCID are alsoassociated with absent B cells. In those cases with resid-ual circulating B cells, the lack of T cell help rendersthem non-functional.

The loss of T cell function in SCID patients leads to theirbeing susceptible to opportunistic infections such asPneumocystis carinii, fungi, and viruses. Patients withSCID tend to present early in infancy because of the severeloss of immune function. Pulmonary infections are a com-mon initial presenting sign in SCID, and up to 67% of SCIDpatients present with pulmonary disease at diagnosis13

(Figure 9-5). In patients with pulmonary complaints atpresentation, 60% present with a persistent pulmonaryinfiltrate and chronic cough, while the other 40% presentwith more acute symptoms of respiratory distress second-ary to pneumonia. P. carinii is the most common cause ofpneumonia and is associated with significant mortality(43%) (Figure 9-6). Bacterial pneumonia can also occur,with K. pneumoniae, S. pneumoniae, and S. aureus beingthe most common pathogens isolated. Viral infections,though not common at presentation, also contribute tomorbidity and mortality in these patients. In patients nottreated with immunoreconstitution, pulmonary diseaseremains a significant cause of morbidity and mortality.Subsequent pulmonary infection can occur in 80–100% ofpatients after initial diagnosis13.

Other T Cell DefectsBesides SCID, immunodeficiency can also arise from

other, less severe, defects in T cell function. Because some


Figure 9-5 Chest radiograph of a 21/2-month-old infant withSCID and parainfluenza 3 infection. Note the narrowed medi-astinum, resulting from absence of a thymus. The lungs demon-strate diffusely increased interstitial markings and subsegmentalatelectasis in the left lower lobe. This infant had seborrheic der-matitis and chronic cough and congestion. (Image courtesy ofAvrum N. Pollock, M.D., FRCPC and Kathleen Sullivan, M.D., Ph.D.)

Figure 9-6 Silver stain of bronchoalveolar lavage fluid from apatient with Pneumocystis carinii pneumonia. The protozoanappears as cysts, each containing anywhere from one to eight ovalbodies called sporozoites. (Courtesy of Howard B. Panitch, M.D.)

degree of residual T cell function persists in these otherconditions, the severity of disease tends to be less than thatof SCID. Pulmonary complications, however, continue tobe common in this group of patients.

DiGeorge syndrome results from errors in the forma-tion of the third and fourth pharyngeal pouches duringembryogenesis, resulting in hypoplasia or complete

absence of the thymus, and parathyroid glands12. Othermidline structures may also be affected, such as theheart and great vessels, craniofacial bones and tissues,and upper limbs. The immunologic defect is due tothymic dysplasia and ranges from a severe depression ofT cell function in patients with no thymus, to near nor-mal function in patients with mild thymic hypoplasia. Incontrast to SCID, DiGeorge syndrome patients are notcommonly infected with P. carinii. Bacterial pneumoniawith Gram-negative organisms is more commonly seen.Severe respiratory syncytial virus (RSV) infections havealso been reported.

Wiskot–Aldrich syndrome (WAS) is an X-linked reces-sive syndrome caused by mutations in the Wiskott–Aldrich Syndrome Protein (WASP) gene12. The classicclinical triad of WAS is thrombocytopenia, eczema, andrecurrent bacterial infection. Although the exact func-tion of WASP is still undetermined, loss of WASP func-tion results in an inability to generate antibody topolysaccharide antigens. WAS patients are therefore sus-ceptible to recurrent infections with bacteria that formpolysaccharide capsules, such as S. pneumoniae and H. influenzae. Although the sites of infection tend to bethe middle ear and sinuses, pneumonia can also be seenin this group of patients. Later in life, there is also anincreased incidence of PCP.

Ataxia-telangiectasia (A-T) is a complex multisystemautosomal recessive syndrome, with abnormalities of thenervous system, endocrine system, skin, liver, andimmune system12. Immune dysfunction in A-T is variableand affects both T and B cells. Although A-T is classifiedas a T cell immunodeficiency, B cell dysfunction due toloss of T cell help is the primary immune problem. IgAand IgG subclass deficiencies are commonly seen inpatients with A-T. Pulmonary infections are a commoncomplication in A-T, and a significant cause of mortality.Pneumonia in patients with A-T tends to be caused bybacteria, such as S. pneumoniae, S. aureus, H. influen-zae, Mycoplasma pneumoniae, and P. aeruginosa. RSVand cytomegalovirus (CMV) can also cause lower respi-ratory tract infection in these patients, but fungi,mycobacteria, and P. carinii rarely are pathogens in thisdisease12. The underlying defect in A-T involves a defect inDNA repair, and patients with A-T are at high risk for thedevelopment of malignancy. In some patients with A-T, pulmonary lymphoma has led to cavitary lesions onchest radiographs that were mistaken for pneumonia14. Itis therefore important to consider the possibility of malig-nancy when evaluating patients with A-T and pulmonarysymptoms and to pursue an appropriate investigation.

Hyper-IgM (HIgM) syndrome is characterized by normal or elevated serum IgM levels with decreased or absent levels of IgG, IgA, and IgE12. HIgM syndromeexists in both an X-linked and autosomal recessive form.About 55–65% of the patients have the X-linked form,


which is due to mutations in the gene for CD40 ligand(CD154), a T cell surface molecule critical for inductionof B cell isotype switch. Because of the absence of CD154,B cells from X-linked HIgM patients can only make IgM,with little or no production of other Ig isotypes. An auto-somal recessive form also exists, where the defect appearsto be due to mutations in a cytidine deaminase gene.Bacterial pneumonia is the most common pulmonarycomplication in HIgM syndrome (Figure 9-7), but PCP alsooccurs in the X-linked form, indicating that CD154 alsoplays a role in T cell function.

NON-INFECTIOUS PULMONARYCOMPLICATIONS OFIMMUNODEFICIENCY

In addition to impaired host defense, patients withimmunodeficiency can also develop dysregulated immuneresponses15. Non-infectious pulmonary diseases that havebeen reported in association with immunodeficiencyinclude interstitial lung disease, bronchiolitis obliterans,and hypersensitivity pneumonitis. CVID and A-T are themost common conditions associated with the above disor-ders8,12, although they have been reported in other immun-odeficiencies16. Allergic bronchopulmonary aspergillosishas also been seen in patients with CGD17.

PULMONARY COMPLICATIONSASSOCIATED WITH HUMANIMMUNODEFICIENCY VIRUS INFECTION

Human immunodeficiency virus (HIV) infection is themost common cause of acquired immunodeficiency18.HIV infects CD4 positive helper T cells, leading to theirloss. As HIV infection progresses, patients have a neartotal depletion of CD4 T cells. The loss of helper T cellsimpairs both CTL function as well as B cell function.

Infectious Complications of HIV Infection

PCP is one of the most common complications ofHIV18,19. PCP infections in HIV infected patients carry ahigh degree of morbidity and mortality18. Prophylaxisagainst PCP is an important part of HIV treatment andcan be accomplished with either TMP/SMX or inhaledpentamidine.

In endemic areas of developing nations, Mycobacte-rium tuberculosis (TB) has emerged as a major pulmonarycomplication in HIV-infected patients18. TB infectionstend to be more severe and difficult to treat in HIV-infected patients. Non-tuberculous mycobacteria, such asMycobacterium avium complex (MAC) can also cause sig-nificant pulmonary disease in adults with HIV. In contrast,

A BFigure 9-7 Chest CT scan of a 13-year-old female with hyper-IgM syndrome and a 4 day historyof fever, fatigue, and shortness of breath. The images demonstrate bronchiectasis with a “tree-in-bud” pattern in the posterior segment of the right upper lobe (A), as well as bronchiectasis of theright middle lobe (B). The patient presented at age 6 years with a history of recurrent pneumonia,sinusitis, and otitis media, for which ventilation tubes were placed on three different occasions. Shewas treated with monthly infusions of IVIG. Quantitative culture by bronchoalveolar lavage yielded>105 colonies of α-hemolytic streptococci. (Images courtesy of Avrum N. Pollock, M.D., FRCPC andHoward B. Panitch, M.D.)


the incidence of severe pulmonary MAC disease is less inHIV infected children20.

Respiratory viral infections are another common com-plication in HIV infection. RSV, influenza A and B, andparainfluenza viruses can all cause severe lung disease inHIV-infected infants21. CMV can also cause pulmonary dis-ease. However, because CMV is often shed asymptomati-cally, the diagnosis of true pneumonitis should rest uponevidence of systemic dissemination (e.g., retinitis or hep-atitis) or demonstration of viral inclusion bodies in lungbiopsy specimens.

The other major group of respiratory pathogens in HIV-infected individuals is fungi. Histoplasmosis infection israre, but when present it occurs as disseminated diseasethat often includes reticulonodular, miliary, and/or lobarinfiltrates. It can often progress to septic shock and deathif untreated. Cryptococcus and Coccidiomycosis can alsocause pulmonary disease. Pulmonary aspergillosis pres-ents as invasive pulmonary disease rather than asaspergilloma, and can be life-threatening, with poor prog-nosis despite antifungal therapy20.

Although patients with HIV primarily suffer fromopportunistic infections as a consequence of their loss ofcellular immunity, bacterial infections are also common,especially in children19,20,22. These occur despite normalor even elevated immunoglobulin levels in patients withHIV, because the loss of CD4 positive helper T cellsresults in a failure to generate effective specific antibodytiters. S. pneumoniae is the most common cause of bac-terial pneumonia in this patient population. Other com-mon organisms include S. aureus, Group A Streptococcus,E. coli, P. aeruginosa, H. influenzae, and Salmonella.

Non-infectious Complications of HIVInfection

Dysregulation of the immune system is another conse-quence of HIV infection, leading to an increased incidenceof non-infectious disorders of the lung18,19. In children, themost common non-infectious pulmonary complication islymphocytic interstitial pneumonitis (LIP). The precisepathogenesis of LIP is unknown; it is thought to represent adysregulated immunologic response to Epstein–Barr virusinfection. Between 30% and 40% of perinatally infected chil-dren will have LIP, with an average age of 2.3 years at pres-entation. Typically, patients with LIP present with gradualonset of cough and dyspnea. Generalized lymphadenopathyand clubbing are associated clinical findings. The chestradiograph demonstrates diffuse reticulo-nodular densities,frequently with hilar adenopathy. LIP is usually quiteresponsive to systemic corticosteroid therapy, which is thefirst line of treatment for this condition. The condition mayrecur, requiring repetitive courses of oral corticosteroids.

In addition to LIP, a non-specific interstitial pneu-monitis (NIP) can also occur in HIV-infected patients,

although this is less common in children. NIP is thoughtto result from localized CTL activity against HIV-infectedcells in the lung parenchyma. Therefore it is more com-monly seen early in HIV infection, when there is stillsome residual CD4-positive T cell activity present.However, it can occur at any stage of the disease.

Pulmonary Complications Related to HIVTherapy

Highly active anti-retroviral therapy (HAART) againstHIV infection was introduced in the mid-1990s. HAARThas had a dramatic effect on the prognosis and clinicalcourse of HIV infection18. One result of increased survivalhas been the increased incidence of chronic lung diseases,such as bronchiectasis23. The restoration of immune func-tion in patients with previously longstanding immuno-deficiency has also led to unexpected complicationsresulting from either exuberant inflammatory responsesor unmasking of latent opportunistic infections24. Thesecomplications are summarized in Box 9-1. As immunefunction is restored, there is an increased inflammatoryresponse against underlying latent mycobacterial infec-tions, both TB as well as MAC. HAART may also be asso-ciated with reactivation of latent PCP, leading to acuterespiratory failure. Non-infectious complications that havebeen reported with HAART include a sarcoid-like syn-drome, hypersensitivity pneumonitis, and pulmonaryhypertension24. Although most published reports havefocused on adult patients, it is likely that this same phe-nomenon will be seen in children as HAART increasinglybecomes the standard of care in HIV treatment.

PULMONARY EVALUATION OF THEPATIENT WITH IMMUNODEFICIENCY

The approach to evaluating a patient with immuno-deficiency is summarized in Box 9-2. The evaluation beginswith a thorough history and physical examination. The history should focus on symptoms of chronic infec-tion or bronchiectasis. The patient or patient’s parents

Box 9-1 Pulmonary Complications of HAART

Increased inflammatory responses to:MACTBPCP

Sarcoid-like syndromeHypersensitivity pneumonitisPulmonary hypertension


should be questioned about the presence of cough andsputum production. Symptoms of wheezing may suggestan asthma or reactive airways disease component.Elements of the physical examination of particular impor-tance include the patient’s height and weight, chest exam-ination, and extremity examination. The height andweight provide important information about the patient’snutritional status, which may be compromised in the set-ting of chronic pulmonary disease. Auscultation of thechest is important to identify areas of localized crackles orwheezes. The presence of digital clubbing on extremityexamination is an indication of underlying bronchiectasis.Other important aspects of the physical examinationinclude evidence of skin infections, absence of lymphoidtissue (e.g., tonsils and lymph nodes), and evidence ofchronic or frequently recurring otitis media.

Radiography is an important tool in the evaluation of pul-monary disease in immunodeficient patients. Plain chestradiographs can reveal areas of atelectasis or infiltrate.Although large areas of bronchiectasis can be seen by plainradiographs, high-resolution computed tomography (CT)is a more sensitive tool for the detection of early or mildbronchiectasis11,25. CT is also helpful for delineating lesionssuch as pulmonary abscesses or lymph node pathology.

The results of pulmonary function tests (PFTs) inimmunodeficient patients depends on the underlying pulmonary pathology. Patients with bronchiectasis demon-strate an obstructive pattern. Patients with interstitial lungprocesses will have a restrictive pattern, and the diffusioncapacity may also be decreased. PFTs can be helpful in

establishing the severity of disease and in tracking diseaseprogression. PFTs can also provide objective assessment ofresponse to medications, such as bronchodilators.

Bronchoscopy can be important both for acute com-plications as well as for chronic conditions. For patientspresenting with acute pulmonary symptoms, bron-choscopy with bronchoalveolar lavage (BAL) can help inthe diagnosis of infections such as PCP. For patients withbronchiectasis who cannot expectorate sputum, BAL canprovide information about the organisms colonizing thelower respiratory tract. Bronchoscopy can also be helpfulin studying the airway anatomy, especially in patients inwhom there is concern for compression of the bronchiby enlarged reactive lymph nodes. In most cases, flexiblefiberoptic bronchoscopy can be safely performed underconscious or deep sedation on this group of patients.

TREATMENT OF PULMONARYCOMPLICATIONS

Treatment of the underlying immune defect is thebest way to prevent pulmonary complications. IFN-γ hasbeen shown to improve phagocytic cell function inpatients with CGD, leading to a reduced incidence ofinfections5. For patients with SCID or other T cell disor-ders, bone marrow transplantation can result in completecorrection of the immune defect12. Antibody deficiencysyndromes can be treated with IVIG replacement ther-apy6. HAART has had a dramatic impact on survival andthe rates of infection in patients with HIV18. It is likelythat as our understanding of the molecular and cellularbasis of congenital and acquired immunodeficiencyincreases, more therapies aimed at correcting the under-lying defect will become available.

Although specific therapy for immunodeficiencies isavailable, not all patients are candidates for bone marrowtransplantation, and other therapies may not lead to com-plete absence of pulmonary complications. In this situa-tion, antibiotic prophylaxis can be used to reduce theincidence of pulmonary infections. The choice of anti-biotic depends on the pathogens most likely to be involvedin the underlying disease process. For CGD, prophylaxisagainst S. aureus is indicated, whereas for T cell immuno-deficiencies and HIV infection prophylaxis against P. carinii is the major concern. Itraconazole prophylaxisfor Aspergillus in CGD has been used at some centers26,but the potential benefits of prophylaxis must be weighedagainst the known risks of increased drug resistance27,28.

Many patients with immunodeficiency still developbronchiectasis, as a result of either delayed diagnosis or continued infection despite treatment. This is especiallycommon in patients with B cell disorders such as XLA and CVID. Treatment of bronchiectasis due to immuno-deficiency is similar to that seen in other conditions25.

Box 9-2 Evaluation of the Patient withImmunodeficiency

HistoryDelayed umbilical cord separation?History of infections?Sites and etiologies of infections?

Physical examinationHEENT

Presence of tonsilsChest

CracklesWheezes

ExtremitiesLymphadenopathyClubbing

Radiographic imagingChest radiographHigh-resolution computed tomographyEvidence of bronchiectasis?

Pulmonary function testingRestrictive versus obstructive pattern

Bronchoscopy


Airway clearance in the form of chest physiotherapy orother techniques is important to prevent accumulation ofpurulent secretions in the respiratory tract. Antibiotics areused to treat acute exacerbations of lung disease as well asto maintain control of chronic infection. For this lattergoal, intermittent administration of inhaled tobramycinhas been shown to improve lung function without anincrease in bacterial resistance in patients with bronchiec-tasis due to cystic fibrosis29. Although there are no pub-lished reports of its use in bronchiectasis due toimmunodeficiency, it has been used anecdotally for thispurpose and a large multicenter trial of this medication inbronchiectasis is currently under way.

For patients with irreversible or progressive respira-tory failure, lung transplantation is an option. In general,the 5 year survival rate following lung transplantation isaround 55%30. Lung transplantation has been performedon patients with immunodeficiency, but there are lim-ited data on their clinical outcomes8,31. There are no datathat focus specifically on immunodeficient recipients.Any decision for lung transplantation in this patientpopulation requires a careful consideration of the risksand benefits of this procedure.

SUMMARY

Pulmonary complications are common in patients withimmunodeficiency, and pulmonary infections are fre-quently the initial presenting sign in this patient popula-tion. Pneumonia and other respiratory tract infectionscontinue to occur in these patients, despite treatment forthe underlying disorder and supportive measures, such asantibiotic prophylaxis. In addition to infectious complica-tions, non-infectious pulmonary disorders also can occurin this group of patients. The patient with HIV infectionpresents an entirely different set of pulmonary complica-tions, and the advent of HAART has led to the emergenceof new pulmonary manifestations in patients with HIVinfection. The clinician dealing with immunodeficientpatients must remain vigilant for these complications.

REFERENCES

1. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseasescaused by defects in phagocytes. N Engl J Med 343:1703–1714, 2000.

2. Goldblatt D, Thrasher AJ. Chronic granulomatous disease.Clin Exp Immunol 122:1–9, 2000.

3. Winkelstein JA, Marino MC, Johnston RB Jr., et al. Chronicgranulomatous disease. Report on a national registry of 368patients. Medicine (Baltimore) 79:155–169, 2000.

4. Ezekowitz RA, Dinauer MC, Jaffe HS, et al. Partial correctionof the phagocyte defect in patients with X-linked chronicgranulomatous disease by subcutaneous interferon gamma.N Engl J Med 319:146–151, 1988.

5. Gallin JI. Interferon-gamma in the management of chronicgranulomatous disease. Rev Infect Dis 13:973–978, 1991.

6. Ballow M. Primary immunodeficiency disorders: antibodydeficiency. J Allergy Clin Immunol 109:581–591, 2002.

7. Lederman HM, Winkelstein JA. X-linked agammaglobuline-mia: an analysis of 96 patients. Medicine 64:145–156, 1985.

8. Cunningham-Rundles C, Bodian C. Common variableimmunodeficiency: clinical and immunological features of248 patients. Clin Immunol 92:34–48, 1999.

9. Umetsu DT, Ambrosino DM, Quinti I, et al. Recurrentsinopulmonary infection and impaired antibody responseto bacterial capsular polysaccharide antigen in childrenwith selective IgG-subclass deficiency. N Engl J Med 313:1247–1251, 1985.

10. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intra-venous immunoglobulin in the prevention of pneumoniain patients with common variable immunodeficiency. J Allergy Clin Immunol 109:1001–1004, 2002.

11. Kainulainen L, Varpula M, Liippo K, et al. Pulmonary abnor-malities in patients with primary hypogammaglobulinemia.J Allergy Clin Immunol 104:1031–1036, 1999.

12. Buckley RH. Primary cellular immunodeficiencies. J AllergyClin Immunol 109:747–757, 2002.

13. Deerojanawong J, Chang AB, Eng PA, et al. Pulmonary diseases in children with severe combined immune deficiencyand DiGeorge syndrome. Pediatr Pulmonol 24:324–330,1997.

14. Yalcin B, Kutluk MT, Sanal O, et al. Hodgkin’s disease andataxia telangiectasia with pulmonary cavities. PediatrPulmonol 33:399–403, 2002.

15. Conces DJ Jr. Noninfectious lung disease in immunocom-promised patients. J Thorac Imaging 14:9–24, 1999.

16. Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrumof X-linked hyper-IgM syndrome. J Pediatr 131:47–54, 1997.

17. Eppinger TM, Greenberger PA, White DA, et al. Sensitizationto Aspergillus species in the congenital neutrophil disorders,chronic granulomatous disease and hyper-IgE syndrome. J Allergy Clin Immunol 104:1265–1272, 1999.

18. Moylett EH, Shearer WT. HIV: clinical manifestations. J Allergy Clin Immunol 110:3–16, 2002.

MAJOR POINTS

1. Pulmonary complications are common in childrenwith immunodeficiency, and are often thepresenting illness.

2. The type of pulmonary infections will depend onthe specific area of the immune system affected.

3. Early diagnosis and treatment of immunodeficienciescan prevent pulmonary complications.

4. Chest CT, bronchoscopy, and pulmonary functiontesting can be helpful in evaluating pulmonarydisease in patients with immunodeficiency.

�

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19. Bye MR. Human immunodeficiency virus infections andthe respiratory system in children. Pediatr Pulmonol19:231–242, 1995.

20. Perez MS, Van Dyke RB. Pulmonary infections in childrenwith HIV infection. Semin Respir Infect 17:33–46, 2002.

21. Madhi SA, Schoub B, Simmank K, et al. Increased burden ofrespiratory viral associated severe lower respiratory tractinfections in children infected with human immunodefi-ciency virus type-1. J Pediatr 137:78–84, 2000.

22. Mofenson LM, Yogev R, Korelitz J, et al. Characteristics of acute pneumonia in human immunodeficiency virus-infected children and association with long term mortality risk. National Institute of Child Health andHuman Development Intravenous ImmunoglobulinClinical Trial Study Group. Pediatr Infect Dis J 17:872–880,1998.

23. Sheikh S, Madiraju K, Steiner P, et al. Bronchiectasis inpediatric AIDS. Chest 112:1202–1207, 1997.

24. Robles AM. HAART and evolving pulmonary manifestationsof HIV. Pulmon Perspect 19:9–11, 2002.

25. Barker AF. Bronchiectasis. N Engl J Med 346:1383–1393,2002.

26. Mouy R, Veber F, Blanche S, et al. Long-term itraconazoleprophylaxis against Aspergillus infections in thirty-twopatients with chronic granulomatous disease. J Pediatr125:998–1003, 1994.

27. Dannaoui E, Borel E, Monier MF, et al. Acquired itracona-zole resistance in Aspergillus fumigatus. J AntimicrobChemother 47:333–340, 2001.

28. Warris A, Weemaes CM, Verweij PE. Multidrug resistancein Aspergillus fumigatus. N Engl J Med 347:2173–2174, 2002.

29. Ramsey BW, Pepe MS, Quan JM, et al. Intermittent admin-istration of inhaled tobramycin in patients with cystic fibro-sis. Cystic Fibrosis Inhaled Tobramycin Study Group. NEngl J Med 340:23–30, 1999.

30. Huddleston CB, Bloch JB, Sweet SC, et al. Lung transplan-tation in children. Ann Surg 236:270–276, 2002.

31. Hill AT, Thompson RA, Wallwork J, et al: Heart lung transplantation in a patient with end stage lung disease due tocommon variable immunodeficiency. Thorax 53:622–663,1998.

151

CHAPTER

10 Pneumonia andBacterial PulmonaryInfectionsCHARLES W. CALLAHAN, D.O.

Etiology of Pneumonia

Pulmonary Pathophysiology and Clinical Signs

and Symptoms of Pneumonia

Fever

Cough

Tachypnea

Retractions

Thoracoabdominal Asynchrony

Auscultatory Changes

Chest Pain

Grunting

Cyanosis

Diagnostic Evaluation of the Child with Pneumonia

Clinical Syndromes of Bacterial Pulmonary Infection

Tracheitis

Acute Bronchitis

Chronic Bronchitis

Bronchiectasis

Newborn with Pneumonia

Well-appearing Infant with Pneumonia

Ill-appearing Infant with Pneumonia

Well-appearing Toddler or Child with Pneumonia

Child with Pneumonia

Adolescent with Pneumonia

Other Bacterial Infections of the Respiratory System

Pulmonary Abscess

Empyema and Parapneumonic Effusion

Unusual Pneumonias

The ancient Greeks knew that the lungs were essentialin bringing life from the air into the body. They called thebreath, “pneuma” a word they also used for “spirit” and“wind.” The organs responsible for moving the “pneuma”into the body from the air were the “pneumon.” Andwhen these organs were ill or inflamed, the process wascalled “pneumonia.” With no knowledge of oxygen or gasexchange, they recognized the lungs’ crucial role for life.

But the same life-giving contact with the air also poses oneof the body’s greatest dangers.

The lungs have far greater contact with the surround-ing environment and its microbial threats than any otherpart of the body. An average newborn baby has a bodysurface area of 0.2 m2. The surface area of the infant’slungs is 3–4 m2, as much as 20 times greater. As the infantmatures, the disparity increases. An adult with a body sur-face of 2 m2 has a pulmonary surface area of 70 m2. Thishuge pulmonary surface area contacts the outside worldwith every tidal breath, drawing in potential contagiondozens of times each minute. It is no surprise that respir-atory illnesses are the most common cause of death forchildren in the developing world. Two million childrendie across the globe every year from pneumonia.

The term “lower respiratory tract infection (LRI)”encompasses not only infections of the airspaces andpulmonary parenchyma (i.e., pneumonia), but also infec-tions of the airways below the glottis (e.g., tracheitis,bronchitis). Although deaths from LRIs have declined inthe United States by more than 90% since the 1930s,respiratory-associated mortality still remains a commonproblem for children in developed nations. Twenty-fiveto forty infants and young children out of 1000 can beexpected to contract an LRI per year in the UnitedStates. The number in school-age children is half that,and in adolescents one third. In their study of childrenwith LRI in an ambulatory setting in North Carolina,Denny and Clyde diagnosed nearly 6000 cases of LRIover an 11-year period1. The diagnosis in 15% of thecases was croup, characterized by hoarseness and inspi-ratory stridor. In 34% it was tracheobronchitis (rhonchi),in 29% bronchiolitis (airway obstruction and/or wheez-ing), and in 23% pneumonia (crackles on auscultation orconsolidation on radiograph) (Table 10-1). Viruses werethe cause of nearly all the infections they reported; 35%from parainfluenza and 22% from respiratory syncytial


virus (RSV), for example. In only 15% of cases was a typeof bacterium implicated, the atypical Mycoplasma pneu-moniae. Significantly, all the agents isolated wereresponsible for each of the four clinical syndromes of LRIidentified by the authors in different children1.

ETIOLOGY OF PNEUMONIA

A variety of factors affect the infectivity of a particularinfectious agent in a given child, and influence the con-ditions that lead to the development of pneumonia oranother LRI. Host-specific factors, such as nutritional sta-tus and age, contribute to the development as well as theseverity of an infection after exposure to an agent.Mortality from measles pneumonia is markedly higher inchildren with vitamin A deficiency, for example. Thechild’s age is directly related to the size of his or her res-piratory tree, and the relative effect that an infection canhave on the airways or lung parenchyma. A millimeter ofcircumferential narrowing in the central airway of a 4-month-old infant can decrease the diameter of the air-way by 64%, whereas the same millimeter of swellingnarrows an adolescent’s airway by only a third. Thus, theclinical syndrome caused by the same agent in each ofthese two children will be markedly different. Themonth of the child’s birth also influences the infectionsto which he or she is prone. Children born in the latesummer are more susceptible to the viral respiratoryinfections of winter, when the advantages of maternalantibody may abate, breastfeeding stops as the motherreturns to work, and cold, wet conditions favor thespread of infections such as RSV. There is also evidencethat preceding viral infection predisposes a child to devel-oping bacterial pneumonia, as the normal pulmonarydefense mechanisms may be impaired by the effect of the virus.

There are a number of additional “host-specific” fac-tors that influence the development of a LRI in a givenchild. In general, pneumonia occurs when the normalpulmonary defense mechanisms are deficient or over-whelmed. Children with bypassed upper respiratorytracts, such as those with tracheostomies, will be moreprone to LRI. The plastic of the tracheostomy tube in theupper respiratory tract also disrupts the mucociliaryblanket, increasing the risk for infection. In other chil-dren, recurrent aspiration from gastroesophageal refluxor dysfunctional swallowing will also impair mucociliaryclearance of the airways. Cystic fibrosis is another exam-ple of a disease leading to disrupted mucociliary clear-ance and increased proclivity to infection. Children withmusculoskeletal disease have impaired cough and airwayclearance. Congenital lung anomalies such as bron-chogenic cysts and sequestrations can also becomeinfected because of poor airway clearance. Additionally,there are a number of specific conditions that impair thechild’s immune response including defects in cellularand humoral immunity and changes in the biochemicalairway milieu.

In addition to host factors, physical and biochemicalcharacteristics of the infecting organism have an effecton the type and severity of the LRI. The magnitude ofthe infective load of a microbial agent, as well as theagent’s size relative to the child’s airway, influence theagent’s infectivity. Infants with smaller airways have ahigher deposition rate for the same-sized microbials thando older children and adults. Specific strains of virusesand bacteria are more infectious than others. In onestudy, Pneumococcus serotype 1 caused 24.4% of casesof complicated pneumonia, and only 3.6% of the uncom-plicated cases. In at least one study, the majority ofsevere RSV infections were caused by serotype A2.

Infections of the airspaces and parenchyma presentwith different clinical and laboratory findings comparedwith infections of the airways. The following are typicalsigns of pneumonia; presentation and laboratory find-ings of airway infections will be discussed with the par-ticular type of infection below.

PULMONARY PATHOPHYSIOLOGY ANDCLINICAL SIGNS AND SYMPTOMS OFPNEUMONIA

Viruses cause the majority of cases of LRI in children.While these infections can be severe and life-threatening,they are usually self-limited. Viral respiratory tract infec-tions are the subject of Chapter 15. However, they sharewith bacterial infections a common range of pathophysi-ologic effects on the lungs and airways, and a number ofclinical signs and symptoms. Table 10-2 summarizes theclinical signs and symptoms of pneumonia in children.

Table 10-1 Syndromes of Lower Respiratory Tract Infection

Croup: Cough with hoarseness and inspiratorystridor

Bronchitis: Cough with rhonchi, no wheezing or stridor

Bronchiolitis: Cough with expiratory wheezing and evidence of airway obstruction (hyperinflation on chest radiograph or subcostal retractions)

Pneumonia: Cough with pulmonary consolidation (crackles on auscultation or consolidation on chest radiograph)

(Adapted from Denny FW, Clyde WA. Acute lower respiratory tract infectionsin nonhospitalized children. J Pediatr 108:635–646, 1986.)

Pneumonia and Bacterial Pulmonary Infections 153

Table 10-2 Signs and Symptoms Suggestive of Pneumonia

FeverCoughTachypnea

Infants 2 months >60 bpmInfants 2–12 months >50 bpm>12 months >40 bpm

RetractionsThoracoabdominal asynchrony

(“see-saw breathing”)Auscultation

Heterophonous wheezing small airway obstructionHomophonous wheezing large airway obstructionCoarse crackles/rhonchi mucus in large airwaysFine crackles/rales airspace consolidation

Chest painGruntingCyanosis

Fever

Infectious agents reach the airways and parenchyma ofthe lung through the bloodstream or through the inspiredair. The majority of agents that cause pneumonia in chil-dren are air-borne pathogens, and gain entry to the bodythrough the respiratory tract. The inhaled or aspirated par-ticles impact at some level of the respiratory tree, multiplyand stimulate an inflammatory response and the migrationof neutrophils to the affected area. Lobar pneumoniadevelops in one of two ways: either the infection expandsand affects surrounding airspaces, or the patient becomesbacteremic and seeds other areas of the lung. The initialstage of infection involves vascular engorgement and infil-tration with inflammatory cells, and the inflammationleads to fever. The “red hepatization” phase of lobar pneu-monia refers to the color of the lung on gross section, andis characterized microscopically by fibrin deposition andred blood cells in the airspaces. In the “gray hepatiza-tion” phase the fibrin strands and inflammatory cellsdegenerate. In the final “yellow hepatization” phase theinflammatory cells and macrophages predominate and,in uncomplicated cases, resolution begins. The natureand intensity of the leukocytic infiltration determinesthe degree of fever. In cases of pneumococcal pneumo-nia, the fever may precede other symptoms, is oftenassociated with an abrupt onset and shaking chills, andmay exceed 104°F (40°C).

Cough

Cough can be both a symptom (the reason the parentbrings the child to the office) and a sign (observed by

the provider during the visit). Myelinated fibers of thevagus nerve innervate receptors in the larynx, upper tho-racic airway to the carina and the proximal regions ofthe major bronchi. Nonmyelinated “C-fibers” innervatereceptors in the interstitium and interalveolar spaces.Chemical, osmotic, inflammatory and mechanical irri-tants stimulate cough receptors in the larynx and airway.Primarily, chemical and inflammatory mediators stimu-late the interstitial receptors. Pulmonary infectionincreases mucus production and inflammation, affectingreceptors in the interstitium and airways, leading tocough. Cough is an important presenting symptom ofLRI in children. In a survey conducted in our clinic inJanuary 2000, cough was the complaint in 8% of 2725patients. Eleven percent of the children with coughwere diagnosed with an LRI. For many, cough was botha sign and a symptom. Children with cough during thevisit were significantly more likely to be diagnosed withlower respiratory disease (including asthma) than thosewithout cough during the visit. Sixty-one percent of children diagnosed with LRI had cough during the officevisit, in contrast with less than a third of the childrendiagnosed with upper respiratory tract infection(Roberts S, Sheets S, Callahan C, unpublished data,January 2000).

Tachypnea

The inflammatory cascade that results from a bacter-ial infection of the lung parenchyma increases endovas-cular leakage in the interstitium and airspaces of thelung, altering the viscoelastic forces and surface tensionof the affected lung units. In addition, edema andincreased secretions in the airway increase airwayresistance. If a sufficient number of lung units and asso-ciated airways are affected, the dynamic compliance ofthe lung (the combination of static and dynamic forcesto be overcome, described as movement of volume perpressure change) will decrease, so that a greater nega-tive intrapleural pressure will have to be generated tosustain the same tidal volume. Thus, the child will haveto work harder to maintain oxygenation and ventilation.In order to preserve the same minute ventilation (respi-ratory rate times tidal volume) most efficiently in theface of decreased compliance, the child will respirewith smaller tidal volumes at a higher rate. Tachypnea isa sensitive sign of pneumonia in children. It is bestmeasured by auscultation over a period of 60 seconds.Rates measured at shorter time intervals (15 or 30 sec-onds) and multiplied, tend to overestimate the respira-tory rate by 3–4 breaths a minute. Tachypnea is definedas a respiratory rate greater than 60 breaths per minutein an infant younger than 2 months of age, greater than50 in infants 2–12 months and greater than 40 in chil-dren over 1 year old.


Retractions (“Chest-Indrawing”)

Decreased dynamic respiratory compliance, as dis-cussed above, reflects changes in the tissue properties ofthe lung as well as increased airway resistance. Either ofthese conditions can be the result of pneumonia ininfants and children. Because the chest wall of the infantor young child is more compliant than that of an adult, itis more pliable and deforms inward more easily whenthe child decreases intrathoracic pressure in an attemptto move air into stiffer lungs. Examination of the childwill reveal retraction of the soft tissue above the clavi-cles or between the ribs. Depression of the sternum canalso reflect greater work of breathing in infants and chil-dren with pneumonia. When inflammation of peripheralairways causes enough obstruction to result in air trap-ping, the diaphragm will become depressed or flattened.Subsequently, contraction of the flattened diaphragmdraws in the soft tissues below the ribcage. Thus, sub-costal retractions are the clinical sign of hyperinflation.

Thoracoabdominal Asynchrony (“See-SawBreathing”)

Depression of the diaphragm during inspiration dis-places the abdominal contents. Normally, the outwardmovement of the abdomen occurs at the same time asthe rise of the thorax from inspiration. This symmetricmovement is referred to as thoracoabdominal syn-chrony. Observed from the side, the infant’s chest andbelly appear to rise and fall at the same time in healthyinfants. Children with pulmonary infection very oftenhave diminished respiratory compliance and increasedairway resistance. The movement of air into the lungs,and the rise of the chest, is delayed after the diaphragmcontracts, so the abdominal contents are displacedslightly before the chest rise occurs. The resulting asym-metry is called thoracoabdominal asynchrony, whichcan be measured objectively experimentally but, evenbetter, noted easily by the careful observer. The extremeof thoracoabdominal asynchrony occurs when the chestwall sinks inward as the abdomen moves outward. Thisparadoxical motion is referred to as “see-saw breathing”and reflects severe respiratory distress.

Auscultatory Changes

Auscultation of the chest of an infant or young child isdifficult because the child is often frightened and unco-operative. Experienced providers learn that it is helpful tolisten to the child while he or she is still on the mother’slap, before examining ears, eyes or throat, and ideallybefore the child is placed on the examination table. It isoften helpful to talk to and touch the child before placingthe stethoscope on the chest, and occasionally the child

will remain quiet during auscultation if he or she isallowed to lie against the parent while the provider listensto the posterior lung fields. Generally speaking, percus-sion for consolidation is not helpful for the same reasons.Breath sounds over the consolidated area, however, willsound coarse or “vesicular,” like listening over the tra-chea, because sound is transmitted better in the fluid-filledconsolidated lung than in air-filled areas. Airway inflam-mation associated with LRIs can result in airway narrow-ing and wheezing. As discussed in Chapter 2, small airwayobstruction causes “heterophonous” or “polyphonic”wheezing, while central airway obstruction causes“homophonous” or “monophonic” wheezing that oftencan be heard at the mouth without the use of a stetho-scope. Crackles are caused by the sudden, explosiveopening of tiny narrowed or collapsed airways on inspira-tion. Tachypnea and crackles are the most sensitive pre-dictors of LRI in infants and children.

Chest Pain

There are no pain sensors in the pulmonaryparenchyma. Pulmonary pain comes from significantinflammation of large airways, or more commonly frompleural involvement. Infection that occurs close to thesurface of the lung causes changes in the pleural surface.The visceral pleura will become inflamed and disrupted,so that the smooth interface with the parietal pleura islost. Thus with breathing, the raw surface of the visceralpleural membrane rubs against that of the parietal pleuracausing pain. Of course, an inflammatory or infectiousprocess in the pleural space, such as empyema, can alsolead to inspiratory or “pleuritic” chest pain.

Grunting

Small children and infants with pneumonia may pres-ent with a “grunting” expiratory sound. These childrenoften have loss of pulmonary volume due to their infec-tious process. The grunting noise is caused by approxi-mation of the vocal cords during expiration. This airwaynarrowing elevates the intraluminal airway pressure andresults in a concomitant increase in distending pressurefor the airspaces.

Cyanosis

Loss of functional airspaces due to infection andinflammation leads to mismatching of ventilation andpulmonary perfusion. If unventilated lung units continueto be perfused in sufficient number, the mean oxygensaturation will decrease. Subtle decreases in oxygenationcan be detected by pulse oximetry before they are evi-dent to the provider. Although it may not be immedi-ately dangerous, a hemoglobin saturation less than 95%


in a child is abnormal. A rough rule to estimate the par-tial pressure of oxygen in the blood based on the satura-tion is “40-50-60, 70-80-90”: at 90% saturation, the oxygentension is approximately 60 mmHg, at 80% it is 50 mmHgand at 70% it is 40 mmHg. Local cyanosis can result fromvenous stasis and vascular instability in young infantsand children, often associated with decreases in ambienttemperature. It does not represent decreased oxygensaturation, and in fact pulse oximetry will be normal.Generalized cyanosis is noted in the oral mucosa and lips,nailbeds, ears and malar regions, and occurs when theconcentration of reduced hemoglobin exceeds 5–6 g/100ml blood. For a child with a hemoglobin concentrationof 12 g/100 ml, this requires that the saturation be as lowas 50–60% before cyanosis becomes visible3.

DIAGNOSTIC EVALUATION OF THECHILD WITH PNEUMONIA

Pneumonia is a clinical diagnosis. It should be sus-pected in the febrile child with cough, tachypnea (espe-cially out of proportion to the degree of fever) andcrackles. Studies conducted to determine the sensitivity ofclinical signs and symptoms of pneumonia generally use apositive radiograph as the “gold standard” for the pres-ence of pneumonia. However, a normal chest radiographin a febrile, ill-appearing child with cough, tachypnea andcrackles should not deter the clinician from initiatingtreatment for pneumonia, as the radiograph can lagbehind the clinical findings by several days.

There are three radiographic patterns used to describepneumonia. Alveolar or airspace disease with consolida-tion and air-bronchograms characterizes lobar pneumonia.In the vast majority of cases, bacterial organisms gainaccess to the distal airways and airspaces by inhalationor aspiration of oropharyngeal secretions in the presenceof inadequate or impaired pulmonary defenses. Theinfection may be limited initially to a lobe or segment ofthe lung, and in fact may initially appear radiographicallyas a subsegmental consolidation or “round” pneumonia.The infection can spread to adjacent segments along air-ways or through the intra-alveolar connections: thepores of Kohn, and canals of Lambert and Martin. Lobarpneumonia is most often caused by Streptococcus pneu-moniae in the United States. Type B Haemophilusinfluenzae was another cause of this clinical syndromebefore widespread vaccination against the organismbegan in the 1980s.

The second type of radiographic finding results frominfection of the airways with a bacterial agent, with sub-sequent airway obstruction and spread to airspaces. Thispattern, called bronchopneumonia, may not be distin-guishable from airspace disease if the radiograph isobtained later in the course. Pathologically, the airways

become infected and ulcerated. On the chest radiographthere will be prominence of the bronchovascular mark-ings and later, multiple ill-defined nodular opacificationsdevelop with coalescence to airspace disease. The mecha-nism of this infectious process is thought to be aspiration oforopharyngeal or gastric contents. Staphylococcus aureusis a frequently implicated source, as are the Gram-negativeorganisms, anaerobes and Legionella pneumoniae.

Interstitial pneumonias cause the third radiographicpattern. They primarily affect the tissue spaces betweenalveoli and vasculature, rather than the airspaces. Theseinfections begin with aspiration of infectious agents lead-ing to a bronchopneumonia with spread of the infectiondistally along the interstitial spaces. Radiographically,thickened linear (interlobular septa) markings can beseen early in the course of the disease. Reticular densitieson a chest radiograph result from “summation” of linearinterstitial lines. Here, the two-dimensional view of athree-dimensional object (the lung) causes linear opaci-fications that occur at a wide range of angles to intersectone another when projected onto the radiographic film.A nodular pattern may result from a combination of bothlinear and reticular opacities overlaying one another andcausing larger opacities. The reticulonodular radi-ographic pattern represents the range of different sizedopacities. Infections with a number of organisms causethis radiographic pattern, including viruses. In children,the atypical bacteria Mycoplasma pneumoniae,Chlamydia trachomatis, and Chlamydia pneumoniaeare common causes. Indeed, it is worth noting that thereis no single pathognomonic radiographic pattern forMycoplasma pneumonia in children4. Table 10-3 sum-marizes radiographic patterns and includes an agent thatmay (but does not always) present with the correspon-ding radiographic picture. Radiographic evidence ofpneumonia generally resolves within 4–6 weeks, andpersistent opacifications beyond that suggest inadequatepulmonary drainage, a chronic, persistent problem or

Table 10-3 Radiographic Patterns of Pneumonia

Alveolar/Airspace (e.g., Streptococcus pneumoniae)ConsolidationAir bronchograms

Bronchopneumonia (e.g., Staphylococcus aureus)Bronchovesicular markingsNodular opacificationConsolidation

Interstitial (e.g., Mycoplasma pneumoniae)LinearReticularNodularReticulonodularGround-glass


the possibility of an anatomic lung anomaly. Childrenwhose radiographic infiltrates persist beyond this pointwarrant referral to a pediatric pulmonologist.

The laboratory evaluation of children with pneumoniausually adds little to the diagnosis. If a child is able to pro-duce a sputum sample for analysis, however, Gram stainand culture can direct therapy towards the causativeorganism. Blood cultures are routinely obtained on ill,hospitalized children with pneumonia, although theywill not usually be positive. While earlier literature sug-gested that as many as 25% of children with pneumo-coccal pneumonia will have a positive blood culture, in amore recent review of 580 children aged 2–34 months witha diagnosis of pneumonia, only 1.6% of the children hadpositive blood culture. In all nine cases, Pneumococcuswas the agent isolated5. Latex agglutination tests for bac-terial antigens in collected urine are more sensitive thanblood cultures and may provide additional information.A leukocyte count greater than 15,000 cells per high-power field (hpf) predicts those children who willrespond to antibiotics within 48 hours (and who arelikely to have pneumococcal disease). Erythrocyte sedi-mentation rate and C-reactive protein levels will both beelevated in bacterial diseases, although neither is com-pletely sensitive nor specific for pulmonary infection.Serum sodium may be decreased in children with bacter-ial pneumonia and a component of the syndrome of inap-propriate antidiuretic hormone secretion. Additionally, alow serum phosphorus level may be a predictor of illnessseverity in patients with pneumonia admitted to the hos-pital. No single symptom, sign or laboratory test is ade-quately sensitive and specific to predict the presence ofpneumonia in a child6,7. In fact, the best predictor forthe presence of pneumonia (compared with the radi-ograph) is the “overall clinical impression” of theprovider prior to obtaining the radiographic study.

CLINICAL SYNDROMES OF BACTERIALPULMONARY INFECTION

Bacterial diseases of the respiratory tract in childrenoccur as recognizable clinical syndromes. Pneumonia inmost children will follow a predictable clinical course,and the specific etiology of the infection can often beinferred based upon the child’s presentation, symptomsand signs. Viruses cause the overwhelming majority ofLRIs in children and infants, including all of the clinicalsyndromes described by Denny and Clyde1 in addition topneumonia. Thus, antibiotics are not necessary for mostchildren with respiratory tract infection. The provider,however, must recognize the clinical syndromes thatcan be the result of bacterial infection, remember thatthese infections can be life-threatening and cause rapidclinical deterioration, and take aggressive steps toward

intervening in affected children. The following scenariosillustrate important points about various clinical syn-dromes, which will lead the clinician to consider a diag-nosis of bacterial infection of the lower respiratory tract.

Tracheitis

CaseThe pediatrician was called to the emergency room

to evaluate a 14-month-old child of a close friend withfever, cough, and stridor in the winter months. Her pres-entation was very typical for viral laryngotracheobron-chitis (LTB) although she had shown improvement inher initial symptoms over the previous 2 days. Now,however, the child seemed somewhat sicker than theusual child with croup, and was considerably fussier. Inaddition, her temperature exceeded 103°F (39.5°C) onpresentation. She was stridulous at rest and tachypneic,though not hypoxemic. During the physical examinationof her oropharynx, a normal epiglottis was visualized, butthere were copious purulent secretions in her hypophar-ynx. A repeat of the same examination revealed the samecopious secretions when her stridor became worsesometime later, and she remained febrile. As her clinicalcondition deteriorated, the decision was made for elec-tive, rapid sequence intubation, and when the endotra-cheal tube was introduced through her vocal cords, alarge amount of pus was noted. Suctioning of her endo-tracheal tube revealed secretions containing many neu-trophils. The sputum sample grew pure colonies ofStaphylococcus aureus. Bronchoscopy several days laterconfirmed the diagnosis of bacterial tracheitis.

This bacterial infection of the central airway usuallybegins with a viral respiratory tract infection in a childless than 3 years of age. A clue to the diagnosis is that thechild begins to recover from the initial illness but the clin-ical course subsequently worsens. Presumably, the virusdisrupts the normal airway defenses and Staphylococcusaspirated from the nasopharynx into the airway infectsthe mucosal epithelium. Neutrophils migrate into thearea and the combination of necrotic mucosa, bacteria,white blood cells and fibrin strands form a membranealong the tracheal wall that can extend into the bronchi.The condition is sometimes referred to as “pseudomem-branous croup” for this reason.

Conservative management of the child with bacterialtracheitis in a pediatric intensive care unit with earlyintubation is the most important part of treatment.While death can result from sepsis, most deaths in thisdisease occur from airway obstruction and hypoxemia.Antibiotic coverage should target Staphylococcusaureus, and a third-generation cephalosporin (ceftriax-one) is sufficient to treat the infection until therapy canbe tailored to sputum culture results. Patients oftenremain intubated for up to a week, and are a challenge


to keep adequately sedated. Little is known about thelikelihood of long-term sequelae, although it is not diffi-cult to imagine that patients could develop trachealstenosis or tracheomalacia following a severe infection.

Acute Bronchitis

CaseA nine-year-old was evaluated for protracted cough and

fever of 101°F (38.5°C). He complained of chest pain, espe-cially with coughing spells. He was treated in the emer-gency room a week ago with guaifenesin and amoxicillinfor “bronchitis,” but there had been no improvement. Healso complained of headache and abdominal pain. He wasnot ill-appearing on examination, but he coughed duringthe examination. Auscultation of his chest revealed coarserhonchi. A chest radiograph showed no evidence ofpneumonia, but some mild, bilateral peribronchial thick-ening was present. A serum Mycoplasma enzyme-linkedimmunoassay for IgM was positive.

In more than 80% of cases, acute bronchitis in chil-dren is caused by viruses. Rhinovirus, parainfluenza,influenza, and RSV are frequently implicated in this clin-ical syndrome. As a primarily viral illness, acute bronchi-tis is self-limited and requires no specific antimicrobialtherapy. Few bacteria have been implicated as causes ofacute bronchitis in childhood, aside from the atypicalbacterium Mycoplasma pneumoniae. Mycoplasma wasalso the most frequently identified agent in a study ofyoung American soldiers with protracted cough (>21days) who probably had bronchitis. Eighty-five percenthad an agent isolated, and in 61% of cases the agent wasMycoplasma. Bordetella species and Chlamydia pneu-moniae were the other two agents most commonlyidentified8. Pertussis is a common cause of protractedcough and bronchitis in older children and adults. In areview of 442 adolescents (older than 12 years of age)and adults with prolonged cough syndrome (1–8 weeks)19.9% had laboratory evidence of Bordetella pertussis9.Importantly, there are no bacterial causes of acute bron-chitis in childhood for which amoxicillin is an appropri-ate treatment, despite the frequency of its use for thissyndrome in a variety of clinical settings.

Acute bronchitis is caused by inhalation of infectiousagents, which bind to receptors on airway epithelium,multiply and induce an inflammatory response. Coughreceptors are stimulated directly by inflammatory media-tors, and by the increased mucus production that accom-panies the inflammatory response. The clinical syndromeis characterized by cough, and rhonchi or coarse wheez-ing on auscultation, without evidence of inspiratory stri-dor (thereby excluding extrathoracic airway obstruction)or small airway wheezing. Cough usually follows 3–4 daysof nasal congestion and increased mucus production, andrepresents spread of the infection to the large, subglottic

airways where the highest density of cough receptorscan be found. The cough is frequently productive, andthe presence of neutrophils in the sputum is common.

Treatment of acute viral bronchitis is supportive, andthere is little indication for cough suppressants.Guaifenesin derivatives and over-the-counter cough sup-pressants are generally of little or no value, despite thefrequency with which they are prescribed. Cough gen-erally resolves within 3 weeks, and most clinicians willbegin to consider other etiologies for cough, includingchronic bacterial bronchitis or sinusitis, when it persistsbeyond 21 days. However, one placebo-controlled trialof antibiotics for children with suspected sinusitisshowed little benefit. Children were randomized after 2weeks of symptoms to treatment with amoxicillin/clavu-lanate, amoxicillin or placebo. Fourteen days after treat-ment, there was no difference between any of the threegroups in sinus symptom score10. Thus, the specific eti-ology of protracted cough in these children is not clear,and may represent dysfunction or persistent inflamma-tory effects of the infection on the cough receptor.

Chronic Bronchitis

CaseA mother brought her 9-month old infant to the pedi-

atric pulmonologist for persistent cough, congestion,wheezing and “noisy breathing.” The child developed asevere cough during an episode of RSV bronchiolitis at 3 months of age. The cough had never resolved. Thechild’s cough was present both day and night, was oftenassociated with paroxysms, and sounded “loose” to themother. The mother also mentioned that she often felt “rat-tling” in the baby’s chest. The child was drinking 12 ounces of formula four or five times a day in addition tobottles of juice, and had frequent regurgitation. In fact thebaby had always been “spitty.” On examination, the childwas not tachypneic, had wheezing audible without astethoscope, and homophonous (“central”) wheezing andcoarse rhonchi on auscultation. Fiberoptic bronchoscopywas notable for erythematous, edematous, friable airways.A bronchoalveolar lavage revealed numerous neutrophils(normally macrophages predominate) and lipid-ladenmacrophages (suggestive of aspiration from her clinicallydiagnosed gastroesophageal reflux). The lavage culturegrew >105 cfu of non-typeable Haemophilus influenzae.She was treated with 21 days of amoxicillin/clavulanate.Her mother was counseled to decrease the volumes of liquid consumption, and the child experienced completeresolution of her symptoms.

The diagnosis of chronic bacterial bronchitis in pedi-atrics is controversial. Many infectious disease and pul-monary experts do not believe that it exists. However,there is clearly a subset of children who develop persist-ent cough and bronchorrhea following a viral infection


or accompanying persistent insult to the airways such asmicroaspiration of stomach contents or exposure toenvironmental tobacco smoke. The etiology of thechronic symptoms is suspected to be similar to that ofchronic bronchitis in adults: disruption of the normalepithelial barriers of the airway by an acute or chronicinsult followed by bacterial colonization, infection andassociated inflammatory response.

A series of 30 children evaluated at St. Christopher’sHospital for Children over a 4-year period is representa-tive. Average age (+/− SD) was 14 +/− 18 months (range1 month to 8 years). Respiratory symptoms had beenpresent for an average (+/− SD) of 8 +/− 8 months (range1 month to 3 years), either on a continuous or frequentlyrecurrent basis. Thirteen of 30 (43%) of subjects hadbeen prescribed 10-day courses of oral antibiotics astreatment for otitis media, possible sinusitis, or “bron-chitis”; amoxicillin was most commonly prescribed. Inmost cases, antibiotics had been ineffective in reducingrespiratory symptoms. In 6 cases, parents reported thatantibiotics had been associated with transient improve-ment, but symptoms returned shortly after antibioticswere discontinued.

The children presented with chronic cough (77%) orrecurrent wheezing that did not resolve completely withbronchodilators and corticosteroids (83%). Physicalexamination revealed homophonous (“central”) wheez-ing in 57% of the children. Many of the children also hadasthma (97%) or gastroesophageal reflux (40%). In 63% ofthe bronchoscopies, Moraxella catarrhalis was recov-ered and in 29% non-typeable Haemophilus influenzaewas found in significant numbers by quantitative culture.The children were treated with a beta-lactamase resistantantibiotic and 87% of the children experienced resolu-tion or improvement of the symptoms (C. Papastamelos,C. Callahan, B. Alpert, H. Panitch, J. Allen, D. Schidlow,unpublished data 1992–1996.)

Additional agents may cause chronic bacterial bron-chitis in children. Vaccine-induced immunity toBordetella pertussis is not life-long, and this agent cancause tracheobronchitis. It should be suspected in ado-lescents and young adults who have protracted episodesof cough that is often paroxysmal and may lead to post-tussive vomiting. Mycobacterium tuberculosis can alsocause endobronchial disease in children and adoles-cents, often as a recurrence of a previous infection.Children will have productive cough that does notrespond to the usual antibiotic therapy. The chest radi-ograph may demonstrate calcifications, and induced spu-tum or gastric lavage may reveal acid-fast bacilli.

The primary care provider should suspect chronicbronchitis in infants and children with persistent symp-toms of cough and an abnormal physical examinationsuggestive of bronchorrhea associated with a history or suspected ongoing airway insult. Asthma should be

considered and, if the history is suggestive, these childrenshould be treated aggressively with corticosteroids andbronchodilators. If the cough persists greater that 14 days,despite an adequate course of corticosteroids (5–10 days)and bronchodilator therapy, a course of beta-lactamase-resistant antibiotics is a reasonable next step in treatingthese children. If the symptoms persist despite 3 weeks ofappropriate treatment, the child should be referred to apediatric pulmonologist and considered for diagnosticbronchoscopy with bronchoalveolar lavage11.

Bronchiectasis

CaseA 2-year-old child experienced an episode of choking

and coughing after eating a small tree-seed in August. Hisinitial radiograph showed mild hyperinflation, but nobronchoscopy was performed. His radiograph was nor-mal a week later. He continued to have cough, however,and was treated with two courses of antibiotics for pre-sumed pneumonia by a different clinician. His coarsecough persisted, and several providers noted coarsecrackles on auscultation. He had no digital clubbing. Inlate September, a chest radiograph showed abnormalitiesof his left lower lobe (Figure 10-1), and a CT scan demon-strated a small segment of bronchiectasis (Figure 10-2).

Bronchiectasis is a condition of dilated, damaged air-ways usually due to chronic inflammation, infection andobstruction. It has been considered an “orphan” diseasebut it is common in the developing world, and is likelymore common in the developed world than is currentlyrecognized.

The pathology of bronchiectasis has been recognizedfor more than a century yet the reasons why some chil-dren develop bronchiectasis and others do not remainsunclear. Airway obstruction and mucus stasis, coupledwith chronic infection and inflammation of thebronchial wall, leads to bronchiectasis in animal modelsof the disease. Inflammation usually results from bacter-ial infection or “colonization” of the airways, either as aprimary process (e.g., aspiration syndromes), or second-ary following airway injury (e.g., viral respiratory tractinfection). Airway injury can occur as a result of mechan-ical obstruction (e.g., prolonged foreign body aspiration)or as a result of injury from a single potent pathogen,such as adenovirus or Mycoplasma pneumoniae.Pertussis, measles, and tuberculosis remain childhooddiseases that predispose children at risk to subsequentbronchiectasis12.

Children develop bronchiectasis after an insult to therespiratory tree. They present with symptoms of chronic,productive cough and crackles on auscultation. Half ofchildren have clubbing at presentation. The plain film willoften be normal, but may reveal bronchial dilation, vol-ume loss or bronchial wall thickening. The “tram-track”


sign that can be present on a chest radiograph of a patientwith bronchiectasis refers to parallel linear densitiesreflecting thickened bronchial walls seen in longitudinalsection. The “signet ring” sign on CT examination is adilated airway in cross-section that is larger than its asso-ciated artery. Definitive diagnosis is made with thin-sec-tion, high-resolution computed axial tomography of thechest demonstrating dilated peripheral bronchi withthickened bronchial walls.

Children with bronchiectasis suffer from inadequatepulmonary drainage, and therapy of affected lobes gen-erally involves vigorous chest physiotherapy with pos-tural drainage often several times a day. Short-termcourses of antibiotics are often given to decrease bacter-ial colonization or infection, and sputum cultures can beused to guide therapy. The outcome of these children

cannot be predicted, as in some cases clinical and radi-ographic evidence of bronchiectasis can disappear whenunderlying conditions (e.g., chronic aspiration) areaddressed. Surgical resection of the affected lobe is indi-cated in cases where children develop repeatedepisodes of pulmonary sepsis in the bronchiectatic lobe.Table 10-4 summarizes the clinical syndromes andmicrobiology of bacterial airway infections.

Newborn with Pneumonia

CaseA pediatric intern was called to the delivery room to

assess a term newborn infant with respiratory difficulty.The infant was less than 2 hours old. His respiratory effortremained labored and he grunted with each exhalation.

Figure 10-1 Chest radiograph of a child with bronchiectasis.


His mother’s prenatal history was unknown, and her laborwas too rapid for her to have had any prenatal antimicro-bial screening or antibiotics. She reported having had ababy die in the first days of life from an infection. Thisinfant was tachypneic with a respiratory rate of 75 breaths per minute. He had decreased breath soundsbilaterally with rare fine crackles. His airway was intubated

for severe respiratory distress and his radiograph demon-strated bilateral “ground-glass” alveolar filling (Figure 10-3).His white blood cell count was 2200 cells/hpf and hisplatelet count was 66,000/ml. His clinical condition dete-riorated despite antibiotic therapy. Both initial blood cul-tures grew group B beta-hemolytic streptococcus (GBBS)within 6 hours. He died before he was 12 hours old.

Figure 10-2 High-resolution CT scan of a child with bronchiectasis.

Figure 10-3 Chest radiograph of an infant with GBBS pneumonia.


Table 10-4 Bacterial Infections of the Airway

Clinical Syndrome Typical Age Symptoms Signs Etiology Treatment

Tracheitis 1 month–6 years Fever Stridor Staphylococcus Nafcillin/oxacillinCroupy cough

Acute bronchitis 6 months–2 years Cough Rhonchi Mycoplasma Macrolide9–15 years Fever Viruses Symptomatic

Chronic bronchitis 5 months–15 years Cough Homophonous wheezeWheezing Rhonchi Moraxella catarrhalisNoisy breathing Non-typeable Amoxicillin/clavulanateRattling in chest Haemophilus

Bronchiectasis 2–6 years Productive cough Crackles Viruses (adenovirus) Chest physiotherapyRecurrent Rhonchi Pertussis Postural drainage

pneumonia Tuberculosis Beta-agonistsChest pain Aspiration Periodic antibiotics

Figure 10-4 Chest radiograph of a child with cytomegaloviruspneumonia.

The pretreatment and screening of mothers for GBBShas made a significant impact on the prevalence of“early” GBBS disease in the newborn, so that residentstraining today are much less likely to see a child with thiscondition than those who trained 15 years ago. Prenataland perinatal pneumonia can also be caused by col-iforms such as Escherichia coli, anerobes, and Listeriamonocytogenes. Babies can present with very subtle ini-tial symptoms including the full spectrum of respiratorydistress from mild to life-threatening, temperature insta-bility, feeding intolerance, and metabolic derangementsincluding hypoglycemia. Often, there is little that can bedone once they are delivered, so that maternal prenatalscreening and treatment become the most importantfactors in infant survival.

Since newborns are immunocompromised by defini-tion, a number of different opportunists includingPseudomonas aeruginosa can cause infection in infantshospitalized for extended periods. Viruses includingcytomegalovirus and fungi such as Candida albicanscan also cause pneumonia in infants. These agentsshould be suspected in babies who do not respond tostandard therapy. Initial therapy should include aggres-sive evaluation for sepsis including blood and urine cul-tures, and antibiotics targeting the most commoncauses. Typically, an aminoglycoside or third-generationcephalosporin and ampicillin are chosen as initial ther-apy. Newborns with pneumonia should be cared for inneonatal intensive care units where expertise inmechanical ventilation is available if needed.

Well-Appearing Infant with Pneumonia

CaseA 7-week-old infant was admitted to the pediatric

ward with hypoxemia and cough. The child was still

eating fairly well and there was no history of fever. Onexamination, the child was not ill-appearing but his res-piratory rate was 70–80 breaths per minute when awake.He had some scattered crackles on examination, andmild subcostal retractions. The chest radiograph showedpatchy opacifications and hyperinflation (Figure 10-4).Evaluation for bacterial infection was negative; how-ever, a urine culture grew cytomegalovirus (CMV) andthe serum CMV IgM was positive. The child recoveredfrom this illness, but had recurrent episodes of wheez-ing and dyspnea with variable responsiveness to bron-chodilators and oral corticosteroids.

Stagno and his colleagues described the “afebrile pneu-monia syndrome of infancy” more than two decades ago13.


They reported a group of 104 infants (age 1–3 months)who were not consistently ill-appearing and who had asyndrome of cough, tachypnea and radiographic findingsof pneumonia. Eighty-three percent of the infants theyreported were afebrile, and 77% had rales (crackles).Paroxysmal cough was uniformly noted. Fifty percent ofthese hospitalized infants required supplemental oxygen,and 15% required mechanical ventilation. They stayed inthe hospital an average of 17 days.

The investigators isolated four agents from theseinfants with pneumonia: Chlamydia trachomatis (25%),Ureaplasma urealyticum (21%), cytomegalovirus(20%), and Pneumocystis carinii (18%). This last organ-ism, long felt to be a protozoan, has recently been iden-tified to be a phylogenetic fungal species and reclassifiedas Pneumocystis jiroveci. Pneumonia from this organ-ism is still referred to as “PCP”: Pneumocystis pneumo-nia. In many cases, multiple organisms were recoveredfrom the same infant with this clinical syndrome.Organisms were identified by culture and in the case ofPneumocystis, by counter immunoelectrophoresis andindirect immunofluorescence of serum. These studiesare not available in every clinical setting today, so asidefrom culture for CMV, the other organisms are seldomisolated. Thus the diagnosis is often made clinically13.

Infants with this clinical syndrome will often requirehospitalization because of hypoxemia or decreased feed-ing due to respiratory difficulty. If the child is to be man-aged as an outpatient, he or she should be followed dailyuntil the clinical symptoms begin to improve signifi-cantly. Additionally, the parents should be given spe-cific, concrete signs and symptoms to watch for thatmight herald deterioration. Treatment is usually empiric,and includes oral erythromycin for 3 weeks primarily totreat chlamydial infection. In a follow-up study, 46% ofthe children had recurrent episodes of wheezing and air-way obstruction, requiring medical therapy14.

Ill-Appearing Infant with Pneumonia

CaseAn 11-month old girl presented to the emergency room

with a fever of 102°F (39°C), congestion, cough and a his-tory of “grunting” respirations. The infant was not eatingwell. On examination the child was ill, but not septic-appearing. The chest was clear to auscultation and a chestradiograph was normal. The child was discharged with adiagnosis of viral respiratory tract infection and instruc-tions to follow-up in a pediatric clinic in the morning. Theparents did not return to the doctor the next morning, butinstead returned a day later, after the child developed pro-gressive respiratory distress. A chest radiograph showed alarge left-sided pneumonia. The child’s blood culture grewStaphylococcus aureus, and despite heroic measures thechild succumbed to overwhelming sepsis 48 hours later.

It is easy to forget that pneumonia in children ispotentially a life-threatening illness. Most bacterial infec-tions in this age group are preceded by a viral respiratorytract infection. Historically, influenza virus has beenidentified as a frequent preceding infection. Many of thenear 25 million deaths worldwide during the 1918–1919influenza epidemic are thought to have been from sec-ondary bacterial pneumonia. It is likely that the viralinfection alters the ability of the respiratory tract to resistinfection from inhaled or aspirated bacterial pathogens.

Infants with pneumonia will often be tachypneic andmay have grunting respirations. They can also have othersigns associated with sepsis: fever, poor feeding, andlethargy. Initial radiographs may be normal despite find-ings on physical examination. The diagnosis of a respira-tory tract infection will often be made on the basis ofclinical findings, and the decision to attempt to diagnoseor treat for bacterial disease may be a subjective one.Children with fever should be evaluated according toestablished protocols. Under 1 month of age, all childrenwith fever and no identifiable source should undergo asepsis evaluation, and receive inpatient intravenousantibiotic therapy. In older infants and children, a highindex of suspicion for pneumonia should be maintained.Any infant or young child with pneumonia should be fol-lowed closely. The child with a lower respiratory tractinfection should be seen again within 24 hours of theinitial visit for a reassessment, regardless of whether bac-terial disease is suspected on the initial presentation.Serious, even life-threatening bacterial illness may not beapparent at first.

Pneumonia in an ill-appearing infant is most often dueto Streptococcus pneumoniae. Haemophilus influenzae,Type B (HIB) was seen previously but has diminishedwith the successful vaccination programs for this organ-ism. Pockets of invasive HIB disease still occur in thedeveloped world, and an immunization history is animportant part of the evaluation of a child with pneu-monia. Staphylococcus aureus may also cause severepneumonia in infants and young children. Fortunately, itis not a common cause in the developed world. It shouldbe suspected in a child who develops a rapid “white-out”pattern of consolidation radiographically. Children withstaphylococcal pneumonia develop pleural disease in upto 90% of cases, and pneumatoceles develop in half ofchildren. This agent should be suspected especially inchildren with pneumonia and pulmonary abscess orempyema.

When bacterial pneumonia is suspected and the childappears only mildly or moderately ill, ampicillin is anacceptable initial intravenous agent to use pending cul-ture results. Penicillin-resistant Pneumococcus, how-ever, has been recognized with increasing frequencysince 1978. Organisms produce one or more proteinswith variable affinity for penicillin. Approximately 10% of


Pneumococcus isolates are penicillin resistant. Resistanceto ceftriaxone is uncommon, and occurs in less than2.5% of isolates. Therefore, when the child appears ill,initial treatment should be with a second- or third-generation cephalosporin (cefuroxime or ceftriaxone)for Pneumococcus or HIB. If the child is septic andPneumococcus is suspected, treatment should beginwith vancomycin. If Staphylococcus is suspected, treat-ment with penicillinase resistant penicillin (nafcillin oroxacillin) should be started.

Well-Appearing Toddler or Child withPneumonia

CaseA 4-year-old preschooler stayed home from his nurs-

ery school for 2 days with low-grade fever, rhinitis, andcough. His symptoms became worse and his motherbrought him to your office. He had paroxysms of cough,especially at night, but was relatively well betweenepisodes. He did not cough during the visit, and he hadno previous history of severe cough with respiratoryinfections, or with exercise. On examination he was nottachypneic. He had mild rhinitis. Auscultation of hischest revealed diffuse heterophonous wheezing (smallairway obstruction) and fine crackles. He had nohepatomegaly and no digital clubbing. A chest radi-ograph revealed scattered interstitial infiltrates and mildhyperinflation.

Viral pneumonias are not the focus of this chapter,yet deserve mention because they are the most commoncause of pneumonia in children of any age. The child inthis case was well-appearing, but viruses can certainlycause severe, life-threatening infections. The most com-monly isolated viruses in children with LRIs are parain-fluenza (35%), RSV (22%), influenza virus (12%),adenovirus (7%) and assorted others (enterovirus, rhi-novirus, 9%). Mycoplasma pneumoniae is responsiblefor 15% of infections1.

The absence of severe episodes of cough with otherrespiratory tract infections and exercise makes a diagno-sis of asthma less likely. Most viral pneumonia beginswith inhaled infectious agents, and the airways are com-monly involved. Thus wheezing and hyperinflation (sub-costal retractions) are frequently noted. A chestradiograph may be normal. It may also show interstitialor airspace disease.

Children with LRI managed in an ambulatory settingshould be followed daily until the symptoms of respira-tory tract infection begin to resolve. Follow-up is criticalbecause it is difficult to predict the course of pneumo-nia. In addition, viral pneumonia may become secondar-ily infected with a bacterial pathogen and parents maynot be sophisticated enough to recognize respiratorydeterioration in their children.

Child with Pneumonia

CaseA 7-year-old girl with a viral respiratory tract infection

awoke one night with shaking chills, worsening of cough,malaise and fever. She also complained of right-sidedchest pain. On presentation to her pediatrician in themorning, she was ill-appearing and had a temperature of104°F (40°C). Her respiratory rate was 42 breaths perminute and auscultation of her chest revealed crackleson her posterior right lung fields. A chest radiographshowed a right-sided opacification. Her white blood cellcount was 21,000 WBC/hpf. A course of amoxicillin/clavulanate PO was started, but she returned to herphysician 2 days later with persistent fever, worseningcough, and increased difficulty breathing. A repeat radi-ograph revealed complete opacification of her right lung(Figure 10-5). Room air pulse oximetry was 87%. Bloodcultures obtained on her original presentation grewStreptococcus pneumoniae.

She was admitted to the hospital for intravenousantibiotics, but her respiratory condition deteriorated.She was transferred to the pediatric intensive care unitwhere she was intubated and started on mechanical ven-tilation. Her hypoxemia was unresponsive to increasinglevels of positive pressure on conventional ventilation soshe was started on a high-frequency oscillator ventilator.She stabilized, but a pleural effusion and eventual pneu-mothorax on the right side necessitated chest tubeplacement 2 days later. She remained on high-frequencyventilation for 2 weeks, before returning to conventionalventilation and extubation after a total of more than 3weeks of ventilator therapy. She recovered but her radi-ograph remained abnormal, with decreased volume onthe right (Figure 10-6).

Pneumococcal pneumonia in childhood usually pres-ents as a distinct, clinical syndrome characterized by anacute onset and fever. It is not rare. Laboratory studiesreveal leukocytosis, and sputum Gram stain in older chil-dren will demonstrate more than 25 WBC/hpf and Gram-positive diplococci. The spectrum of pneumonia fromthis organism can vary from a very mild course managedin an ambulatory setting, to the severe case of compli-cated pneumococcal pneumonia presented here.Complicated pneumonia is characterized by significantpleural effusion often requiring chest tube placementand, in some cases, pulmonary necrosis.

Children with complicated pneumonia are morelikely to be older (45 vs. 27 months in one series)2, aremore likely to present with chest pain and to requiredecortication for pleural disease. In the same series,complicated pneumonia was caused by pneumococcalserotypes 1, 6, 14, and 19 in 24% of cases, as opposed to3.6% of the children with uncomplicated pneumonia.Serotype 1, which accounted for 24% of complicated


pneumonia, is not included in the currently licensedpneumococcal vaccine.

Children who develop pneumococcal pneumonia areoften carriers of this organism. Twenty to forty percentof children are carriers, and risk factors for the develop-ment of invasive pneumococcal disease include frequentepisodes of otitis or upper respiratory tract infections(>3 in 6 months) and daycare attendance. Organisms areaspirated or inhaled, and escape the lung’s extensivedefense systems, including the mechanical barriers ofthe upper airway, the mucociliary blanket and cough,and the macrophages and humoral defenses of the distalairways. Onset of symptoms is usually abrupt with shak-ing chills and spiking fever. Younger children may pres-ent with febrile seizure2.

Ambulatory children with suspected pneumococcalpneumonia should be treated with high-dose amoxicillinor a cephalosporin. Children ill enough to require hos-pitalization should receive a second- or third-generationcephalosporin or ampicillin in combination with sulbac-tam. Vancomycin or clindamycin should be used forseverely ill children with suspected complicated pneu-mococcal disease.

Adolescent with Pneumonia

CaseA previously healthy 16-year-old stayed home from

school with headache, abdominal pain, and sore throat.She did not have any nasal congestion, but developedparoxysms of cough. She developed a fever of 101°F(38.5°C) and generalized malaise. After 4 days of symp-toms and progressive cough, her mother took her to thephysician. She was uncomfortable, but not ill-appearing.She was not hypoxemic or tachypneic. Auscultation of her chest revealed crackles and heterophonouswheezing. She had a mild erythematous maculopapularexanthem. A chest radiograph revealed mild, bilateralincreased interstitial infiltrates (Figure 10-7). A completeblood count disclosed a mild anemia and the smear suggested hemolysis. Bedside serum cold agglutinins werepositive (Figure 10-8), and serologic testing for Mycoplasmapneumoniae IgM was positive >1:32. She was treated withoral doxycycline, and recovered uneventfully within 2 weeks, although episodes of cough persisted for twoadditional weeks.

Figure 10-5 Chest radiograph of a child with overwhelming Streptococcus pneumoniae pneumonia.


Figure 10-6 Chest radiograph of resolved complicatedStreptococcus pneumoniae pneumonia.

Figure 10-7 Chest radiograph of an adolescent with Mycoplasma pneumonia.

Pneumonia due to Mycoplasma pneumoniae wascalled “atypical” initially because, in 1935, it did notrespond to the typical pneumonia treatment, sulfon-amides. It is also sometimes called “walking” pneumoniabecause it does not render affected children so sick thatthey are confined to bed. The onset of symptoms, in con-trast to Pneumococcus, is usually insidious with malaise,low-grade fever and cough. Rhinitis is significant for itsabsence, and can help the clinician discern Mycoplasmafrom viral pneumonia due to adenovirus, which canhave a similar clinical course. Pharyngitis is frequentlynoted, but may be more prominent in atypical pneumo-nia due to Chlamydia pneumoniae, another of thecauses of this clinical syndrome. Headache and abdomi-nal pain are also frequently seen.

The physical examination will often provide no addi-tional clues to help discern the specific cause of pneumo-nia. Clinical signs of pneumonia will often be present,including crackles, wheezes or coarse breath sounds.However, they may be absent early in the course of the dis-ease. A range of different rashes may be noted from a slighterythematous eruption in mildest cases, to life-threateningStevens–Johnson syndrome. Cardiac involvement has alsobeen noted in some cases, including myocarditis and peri-carditis leading to signs and symptoms of congestive heartfailure. Rarely, hepatitis may occur and hepatomegaly willbe noted on physical examination.


There is no pathognomonic pattern of the chest radi-ograph for children with Mycoplasma pneumonia. Theradiograph can be completely normal. Bilateral interstitialinfiltrates may be noted, or there may be a unilateral lobarinfiltrate. Parapneumonic pleural effusion may occur in upto 20% of children with Mycoplasma pneumonia when it iscarefully sought. There is usually no reason for pleurocen-tesis in these children. Serologically, the immunogenicity ofMycoplasma leads to production of a host of antibodies,including one to the red blood cell “I/I antigen” that causescold agglutination of the blood cells. While this antibodymay be absent in up to half of children with Mycoplasma,its presence in this clinical setting would make the diag-nosis of a Mycoplasma infection all but assured. If blood isbeing drawn anyway, the clinician can perform the bed-side “cold agglutinin” test for Mycoplasma15.

Two to three milliliters of blood are placed in a small“blue-top” sodium citrate blood tube. The blood is placedin a cup of ice water for several minutes, then removed,

Figure 10-8 Bedside serum cold agglutinins (from the collec-tion of Dr. Jim Bass).

held in front of a white piece of paper, tilted and rolledslowly between the fingers. Clumps of red blood cellswill be visible lining the surface of the tube, and theclumps dissolve when the tube is warmed by holding it inthe closed hand for several minutes. In a true positive test,this process can be repeated multiple times. This predom-inantly IgM antibody may lead to a mild hemolytic anemiain some children. A positive cold agglutinin test shouldbe confirmed with serologic evaluation for the presenceof anti-Mycoplasma IgM. This test will diagnose an acuteinfection, as culture for Mycoplasma is costly and notavailable in every clinical setting.

Chlamydia pneumoniae is the other agent commonlyassociated with atypical or “walking” pneumonia, althoughthe specific diagnosis is even more difficult to make.Pharyngitis and hoarseness in an adolescent or young adultwith interstitial pneumonia who does not have rhinitisshould prompt the clinician to consider Chlamydia inaddition to Mycoplasma. While erythromycin is generallyconsidered the first choice for therapy in this syndrome,there is some evidence that Chlamydia is more suscep-tible to tetracycline than to erythromycin16. Doxycyclineis an excellent agent for the treatment of this syndromein children 12 years and older. Other macrolides are also effective and the newer agent, azithromycin, showsgreatest effectiveness in experimental settings.

OTHER BACTERIAL INFECTIONS OF THERESPIRATORY SYSTEM

Pulmonary AbscessTwo populations of children develop pulmonary

abscess: otherwise healthy children who develop severepneumonia and abscess are said to have primary pul-monary abscess. In 62% of cases, Staphylococcus aureusis the etiology. Children with underlying disorders ofswallowing or effectiveness of the cough reflex, such aschildren with static encephalopathy, comprise the othergroup and can develop secondary pulmonary abscess. Inthese children, Staphylococcus is the cause of theabscess in only a third of cases, and two thirds of thecases are caused by other agents including anaerobicorganisms and coliforms. In either group, the conditionis generally first suspected when the abscess is noted on achest radiograph obtained in an ill child with pneumonia(Figure 10-9).

Children with pulmonary abscess present with highfever, cough, chest pain and sputum production. The radi-ograph will demonstrate air–fluid levels in most cases. Inone series the right lung was more commonly affected,and associated pleural effusion was common17. Childrenwith primary abscess generally respond to therapy withantibiotics, usually for 2–3 weeks. It may take 14 days for


fever to resolve. Antibiotics to cover Staphylococcus andanaerobes should be considered. For this reason, clin-damycin or penicillin and metronidazole therapy can beused. Other excellent alternatives are ticarcillin in combi-nation with clavulanate, or ampicillin and sulbactam.

Younger children and children with underlying disor-ders that impair cough mechanisms often require surgi-cal drainage. Options include the radiographicplacement of small bore “pigtail”-type catheters, or opendrainage. Children with pulmonary abscess should bemanaged in a medical center where pediatric specialtyand surgical support is available, but children with thiscondition can be expected to recover completely. Inone series of almost a dozen children, three-quarters hadnormal pulmonary functions when assessed 9 years afterthe diagnosis17.

Empyema and Parapneumonic Effusion

Children with bacterial pneumonia near the pleural sur-face will frequently develop parapneumonic effusions. Theconcomitant bacterial infection leads to sympatheticinflammation of the pleura, and increased pleural fluid pro-duction. Typically, the fluid will have low numbers ofwhite blood cells, and a low LDH concentration. The ini-tial treatment for parapneumonic effusion is to treat theunderlying pneumonia. Children with simple effusions willdefervesce quickly and no further treatment of the effusion

is required, although radiographic evidence may persist forweeks. The only reasons for pleurocentesis in this settingare clinical deterioration of the patient with need formicrobiologic diagnosis, and respiratory compromise dueto the mass effect of the pleural fluid.

Empyema occurs when the bacterial infection breaksinto the pleural space, and causes infection. Childrenwill often have persistent, elevated temperature andmarked pleuritic chest pain. Analysis of fluid obtained bypleurocentesis will demonstrate large numbers of whitecells and often organisms on Gram stain, low pH (<7.2)and high levels of LDH (typically above 1000 IU/l).

The chest radiograph demonstrates layering of the effu-sion on lateral decubitus films if the fluid is free-flowing,or blunted costophrenic angles with smaller volumes offluid. Air–fluid levels may also be noted in children withpleural infections due to gas-producing organisms. CT ofthe chest is sensitive and specific for effusion, and thepresence of significant pleural thickening on CT scan isrelatively specific for empyema (Figure 10-10). Ultrasoundis useful in determining whether the fluid is free flowing,and whether there are septations or loculations. The pres-ence of intrapleural septae, echogenicity of the pleuralfluid or pleural thickening all are consistent with a com-plicated empyema and suggest the need for more aggres-sive surgical drainage of the pleural space.

Like children with pulmonary abscess, children withempyema should be cared for in a center with pediatric

Figure 10-9 Chest radiograph of a child with Staphylococcus aureus pneumonia and abscess(from the collection of Dr. Jim Bass).


Figure 10-10 High-resolution CT scan of a child with complicated Streptococcus pneumoniaepneumonia, empyema, pleural thickening, and free pleural air.

specialists, and thoracic surgeons capable of assistingwith drainage of the pleural space when needed. Goalsin the treatment of children with empyema include elim-ination of the infection, re-expansion of the lung, returnof respiratory function, elimination of complications andreduced recovery time. Therapy with antibiotics alone isoften effective, but may lead to a protracted hospitalcourse. Chest tube placement is most effective whenused early in the course of the disease, with antibiotictreatment. This combination is sufficient treatment formany children with uncomplicated effusion.Fibrinolytics can be instilled through the chest tube, andin many studies therapy with streptokinase or urokinasehave been demonstrated to be effective in treating locu-lated pleural effusion. However, there are no pediatricstudies comparing the use of fibrinolytics with otherforms of treatment.

Thoracotomy with removal of the pleural “peel”(decortication) is a major surgical procedure, but earlysurgical intervention in children whose empyema willinvariably require surgical therapy has been shown tohasten resolution of the infection, and shorten thechild’s hospital course. The ideal time for interventionseems to be between 2 and 6 weeks after the onset ofsymptoms. Sooner than 2 weeks into the course, thepleural fibrin “peel” is rarely organized enough to facili-tate surgical removal. Beyond 6 weeks, the thickenedfibrin is adherent to the pleura, and difficult to remove.

Another new option in the management of some chil-dren with empyema is video-assisted thorascopic decor-tication (VATD). This technique utilizes two surgicaltrocars: one with a video camera and the other as a portfor surgical instruments. In smaller children, the ports

may be too small to be effective for the removal of thicksecretions and debris. However, in experienced hands,this technique is as effective as open thoracotomy. Thusfar small comparative studies between VATD and chesttube placement with fibrinolysis have shown someadvantage to the video-assisted technique, but con-trolled trials have not been conducted18.

In summary, a child with parapneumonic effusionshould be treated for the underlying pneumonia withappropriate antibiotic therapy and drainage of the effu-sion should not be attempted unless essential for diag-nosis or to alleviate respiratory distress. If the child doesnot respond to appropriate therapy, or has worseningeffusion or persistent fever, he or she should be sus-pected of having empyema. Empyema requires chesttube placement and fibrinolysis is indicated if the tubefails to drain the effusion. If the effusion persists, CT ofthe chest or ultrasound should be used to determinewhether the effusion is organized or septated. Dependingon the expertise of the consulting surgeon, thoracotomyor VATD and chest tube drainage will speed resolution ofthe symptoms and shorten the hospital stay. Table 10-5summarizes infections of the pulmonary parenchymaand pleural space.

Unusual Pneumonias

There are a host of unusual causes of pneumonia thatgenerally affect children who are “unusual”: those whoare immunodeficient or have received immunosuppres-sive therapy. Commonly, these are children who havebeen treated for malignancy or who have received tissuetransplantation, children with inflammatory diseases


such as connective tissue disorders, and those with pri-mary immunodeficiencies and acquired immunodefi-ciency (AIDS).

An opportunistic organism should be suspected at the outset in any immunocompromised child with pneumonia. Viruses (herpesviruses, CMV, varicella),fungi (Aspergillus, Mucor, Pneumocystis), bacteria(Pseudomonas, nontuberculous mycobacterium), andother organisms (Toxoplasma, Cryptosporidium) canall cause pneumonia in this population. Therapy shouldbe initiated with broad-spectrum antibiotics, and aggres-sive measures must be taken to identify the cause of the

infection. Sputum examination and culture is the firststep, and should proceed when therapy is begun inolder children and adolescents along with blood culturesand the appropriate antigen studies. If the child fails torespond to broad-spectrum therapy, invasive proceduresmust be performed in order to identify the organism.Flexible fiberoptic bronchoscopy with bronchoalveolarlavage or transbronchial biopsy is the first invasive pro-cedure to be considered. If this procedure is unfruitful,transthoracic needle biopsy using ultrasound or CTguidance is the next method of choice. Finally, openlung biopsy or thorascopic biopsy is the standard to

Table 10-5 Bacterial Infections of the Parenchyma and Pleura

Clinical Syndrome Typical Age Symptoms Signs Etiology Treatment

PneumoniaNewborn Birth Respiratory distress Tachypnea Group B beta- Ampicillin and

Grunting Retractions hemolytic aminoglyco-Cyanosis Crackles Streptococcus side

Escherichia coliListeria monocytogenes

“Well” Infant 2 weeks–3 months Crackles Afebrile Chlamydia ErythromycinStaccato cough Heterophonous pneumoniaeCongestion wheeze Cytomegalovirus

Tachypnea Ureaplasma urealyticumPneumocystis jiroveci

“Ill” Infant 2 weeks–6 months Fever Respiratory distress Streptococcus CeftriaxoneCough Tachypnea pneumoniae VancomycinRespiratory distress Crackles Staphylococcus

aureusHaemophilus

influenzae, Type B“Well” child 7 months–5 years Rhinitis Afebrile Viruses Symptomatic

Cough RhonchiCongestion Heterophonous

wheeze“Ill” child 7 months–5 years Fever and chills Tachypnea Streptococcus Ceftriaxone

Productive cough Crackles pneumoniaeMalaise Percussion dullnessChest pain

Child/adolescent 6 years–adult Fever Crackles Mycoplasma MacrolideMalaise Rhonchi pneumoniae“Hacking” cough Chlamydia Tetracycline

pneumoniae

Abscess 2 weeks–adult Fever Crackles Staphylococcus Cough Percussion dullness aureus Ceftriaxone

Anaerobic Clindamycinorganisms Penicillin and

metronidazoleEmpyema 6 months–adult Fever Tachypnea Streptococcus

Cough Crackles pneumoniae CeftriaxoneStaphylococcus aureus Nafcillin/oxacillin

Pleuritic pain Pleural rub Haemophilus influenzae, Type B Vancomycin


Table 10-6 When to Refer to a Pediatric PulmonarySpecialist

Severe, life-threatening infectionRecurrent pneumonia (> 3 episodes per year)Recurrent croup or bronchitis (> 3 episodes per year)Pneumonia unresponsive to therapyProgressive pneumonia despite therapyComplicated pneumonia (abscess or empyema)Unusual organism causing pneumoniaPhysical examination findings suggestive of chronic disease

(i.e., clubbing)Persistent pulmonary infiltrate > 6 weeks after resolution of

symptoms

which all other diagnostic procedures are compared.Aggressive effort to obtain tissue diagnosis of an oppor-tunistic pneumonia offers the immunocompromisedchild the best chance for survival.

The primary care provider in the ambulatory or thecommunity hospital setting can manage most childrenwith uncomplicated pneumonia. An “unusual“ pneumo-nia or any pneumonia in an “unusual child,” i.e., onewith altered immune competence, requires more spe-cialized care. It is one of a list of different clinical syn-dromes of lower respiratory tract infection that warrantmore in-depth investigation by a pediatric pulmonaryspecialist (Table 10-6). In every case, it is essential thatthe provider consider the possible etiologies based onthe child’s presentation and clinical syndrome.Aggressive recognition and appropriate antimicrobialtherapy are the keys to a successful outcome19,20.

MAJOR POINTS

1. Viruses are the cause of most lower respiratorytract infections in children.

2. Cough in the office may predict the presence oflower respiratory tract disease in children, and atleast should prompt a careful examination of thepatient’s chest.

3. Tachypnea and crackles are the most sensitivepredictors of LRI in infants and children.

4. Pneumonia is a clinical diagnosis. A normal chestradiograph in a febrile, ill-appearing child withcough, tachypnea and crackles should not deter theclinician from initiating treatment for pneumonia.

5. The most important component of treatment of achild with tracheitis is conservative managementof the child in a pediatric intensive care unitwith early intubation.

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MAJOR POINTS —Cont’d

6. Guaifenesin derivatives and other over-the-counter cough suppressants are generally of littleor no value in the treatment of children withrespiratory tract infections, despite the frequencywith which they are prescribed.

7. Suspect chronic bacterial bronchitis in infantsand children with persistent symptoms of coughand an abnormal physical examination suggestiveof bronchorrhea associated with a history ofairway insult.

8. Chlamydia trachomatis, Ureaplasmaurealyticum, cytomegalovirus, and Pneumocystisshould be suspected in infants who present withafebrile pneumonia.

9. Under a month of age, all children with fever and noidentifiable source should have a sepsis evaluation,and receive inpatient intravenous antibiotic therapy.

10. Children with lower respiratory tract infectionmanaged in an ambulatory setting should befollowed daily until the symptoms of respiratorytract infection begin to resolve.

11. Younger children and children with underlyingdisorders that impair cough mechanisms oftenrequire surgical drainage of pulmonary abscess.

12. A child with parapneumonic effusion should betreated for the underlying pneumonia withappropriate antibiotic therapy, and drainage of theeffusion should not be attempted unless essentialfor diagnosis or to alleviate respiratory distress.

13. Aggressive efforts to obtain tissue diagnosis of anopportunistic pneumonia offers the immuno-compromised child the best chance for survival.

14. The primary care provider in the ambulatorysetting or the community hospital can managemost children with uncomplicated pneumonia.

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ACKNOWLEDGMENT

“The views and opinions expressed in this manuscriptare those of the authors and do not reflect the official policy or position of the Department of the Army, theDepartment of Defense, or the United States Government.”

REFERENCES

1. Denny FW, Clyde WA. Acute lower respiratory tract infections in nonhospitalized children. J Pediatr 108:635–646,1986.

2. Tan TQ, Mason EO, Wald ER, et al. Clinical characteristicsof children with complicated pneumonia caused byStreptococcus pneumoniae. Pediatrics 110:1–6, 2002.

3. Polgar G. A functional analysis of symptoms and therapeu-tic measures in respiratory disorders of newborn infants.Pediatr Clin North Am 20:303–322, 1973.


4. Correa AG, Starke JR. Bacterial pneumonia. In Kendig’s disorders of the respiratory tract in children, 6th edition,pp 485–503. Philadelphia: WB Saunders, 1998.

5. Shah SS, Alpern ER, Zwerling L, McGowan KL, Bell LM.Risk of bacteremia in young children with pneumoniatreated as outpatients. Arch Pediatr Adolesc Med 157:389–392, 2003.

6. Sankaran RT, Mattana J, Pollack S, Bhat P, Ahuja T, Patel A,Singhal PC. Laboratory abnormalities in patients with bac-terial pneumonia. Chest 111:595–600, 1997.

7. Grossman LK, Caplan SE. Clinical, laboratory and radiolog-ical information in the diagnosis of pneumonia in children.Ann Emerg Med 17:43-46, 1988.

8. Vincent JM, Cherry JD, Nauschuetz JD et al. Prolongedafebrile nonproductive cough illness in American soldiersin Korea: a serologic search for causation. Clin Infect Dis30:534–539, 2000.

9. Senzilet LD, Halperin SA, Spika JS, Alagaratnam M, Morris A,et al. Pertussis is a frequent cause of prolonged cough illness in adults and adolescents. Clin Infect Dis 32:1691–1697, 2001.

10. Garbutt JM, Golsstein M, Gellman E, Shannon W,Littenberg B. A randomized, placebo-controlled trial ofantimicrobial treatment for children with clinically diag-nosed acute sinusitis. Pediatrics 107:619–625, 2001.

11. Smith TF, Ireland TA, Zaatari GS, Gay BB, Zwiren GT,Andrews G. Characteristics of children with endoscopically

proved chronic bronchitis Am J Dis Child 139:1039–1044,1985.

12. Callahan C, Redding G. Bronchiectasis in children: An orphandisease that persists. Pediatr Pulmonol 33:492–496, 2002.

13. Stagno S, Brasfield DM, Brown MB et al. Infant pneumonitisassociated with cytomegalovirus, Chlamydia, Pneumocystisand Ureaplasma: a prospective study. Pediatrics 68:322–329, 1981.

14. Brasfield DM, Stagno S, Whitley RJ, et al. Infant pneumoni-tis associated with cytomegalovirus, Chlamydia,Pneumocystis and Ureaplasma: follow-up. Pediatrics79:76–83, 1987.

15. Shebab ZM. Mycoplasma infections. In Taussig LM, Landau LI,editors: Pediatric respiratory medicine, pp 737–742. St. Louis:Mosby, 1999.

16. Thom DH, Grayston JT. Infections with Chlamydia pneumoniae, strain TWAR. Clin Chest Med 12:245–256,1991.

17. Asher MI, Spier S, Bland N, et al. Primary lung abscess inchildhood. Am J Dis Child 136:491–494, 1982.

18. Lewis RA, Feigin RD. Current issues in the diagnosis andmanagement of pediatric empyema. Semin Pediatr InfectDis 13:280–288, 2002.

19. Schidlow DV, Callahan C. Pneumonia. Pediatr Rev17:300–309, 1996.

20. Gaston B. Pneumonia. Pediatr Rev 23:132–140, 2002.

172

CHAPTER

11 TuberculosisGAIL L. RODGERS, M.D.

The Organism and Pathogenesis

Transmission


Pulmonary Disease

Extrapulmonary Tuberculosis

Diagnosis

Treatment

Tuberculosis (TB) has plagued mankind for millennia.It is estimated that one third of the world’s population isinfected with Mycobacterium tuberculosis. There are anestimated 8 million new cases a year and up to 2 millionannual deaths1. Children represent approximately 1.3million new cases and 400,000 deaths annually. The vastmajority of cases (95%) occur in the developing world.Public health efforts in the United States were respon-sible for a steady decrease in the case rate from 100 cases/100,000 persons in 1930 to 10 cases/100,000 persons in1984. An unexpected 20% increase in reported casesoccurred in the United States between 1984 and 19922.The increase in pediatric cases was substantial; a 51%increase was seen in children less than 15 years of agefrom 1988 to 19923. Contributory factors for this increasewere a decrease in public health infrastructure, increasedimmigration from countries with high prevalence oftuberculosis, socioeconomic factors such as poverty,homelessness, illicit drug use and incarceration, and theepidemic of human immunodeficiency virus infection.Since 1992 there has been a yearly decrease in tuber-culosis cases in the United States, from 26,673 cases in1992 to 15,078 cases in 20024–6. The prevalence oftuberculosis in the United States in 2002 was the lowestever at 5.2 cases/100,000 persons, representing a 68.4%decline in rates since 19926. This decrease has beenhighly significant in the pediatric population and in US-born persons, with less of a decrease in foreign-bornpersons6. For the first time ever, in 2002, foreign-bornpersons accounted for the majority (51%) of cases in the

United States6. The most common native countries for for-eign-born persons with TB are Mexico, the Philippines,Vietnam, India, China, Haiti, and South Korea6. The over-all dramatic decrease in TB in the United States is dueprimarily to strengthening of public health programsthat emphasize prompt identification of cases with edu-cation of healthcare workers, contact investigation andaggressive institution of directly observed therapy thatensures both availability of antituberculous medicationsand patient compliance. Other important contributorymeasures include improvement in infection-control poli-cies and practices in hospitals, jails, and prisons7.

THE ORGANISM AND PATHOGENESIS

TB is caused by the pleomorphic, aerobic acid-fastbacillus, Mycobacterium tuberculosis. It requires specialmedia to sustain its growth, which is slow. The bac-terium replicates once every 24 hours, thus requiringweeks to months for visible growth in the laboratory.

Overall, acquisition of TB, known as infection, is mainlycaused by factors extrinsic to the host and related to expo-sure to a contagious individual. If infection produces noclinical disease it is known as latent TB. Progression tosymptomatic disease after infection is caused by factorsintrinsic to the host, mainly immunologic mechanisms thatcan kill, contain, or allow progression of the bacilli.

The pathogenesis of TB starts with the inhalation ofinfectious droplet nuclei. These are small enough toavoid entrapment by the mucociliary defenses and reachthe lung where they are ingested by macrophages. Atthis point the mycobacteria have one of two fates: theyare killed by the macrophage without establishment ofinfection or they persist within the macrophage wherethey can replicate. As the mycobacteria replicate theydisseminate to all organs of the body via the bloodstreamand lymphatics. At this time the infection can become

Tuberculosis 173

clinical and manifest as primary tuberculous pneumoniaor as miliary disease, although in the majority of infectedpersons the immune system contains the infection and itbecomes latent.

The complex immune mechanisms that govern theinteraction of the host with the tuberculous bacilli are thekey to understanding of TB8,9. In response to mycobacte-ria, lung macrophages elaborate cytokines. Thesecytokines, tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), and multiple chemokines, act together to con-tain the infection. Some bacilli are able to multiply andcause lysis and death of the macrophages. These bacillimigrate to regional lymph nodes within dendritic cells,which function as antigen presenting cells. Antigen-specific response occurs when the dendritic cells elabo-rate cytokines and present mycobacterial antigens toCD4+ T cells. These cells play an essential role in the hostdefense against mycobacteria by producing cytokines,particularly interferon–γ (IFN-γ) and IL-2. IFN-γ in turnactivates macrophages to inhibit or kill M. tuberculosis.The efficiency of the CD4+ T cell response determineswhether active infection will ensue or whether latencywill be established. This response is responsible for theproduction of delayed hypersensitivity manifested as apositive skin reaction to purified protein derivative(PPD). The importance of the CD4+ T cell response isseen clinically in a wide variety of hosts who are atincreased risk of reactivating latent TB as they becomeimmunocompromised. The most notable example isHIV-infected persons, who are at significantly higher riskof reactivation of latent TB (10% per year) in comparisonwith healthy individuals, whose risk is 10% over theirlifetime10,11. The risk of TB in HIV-infected individuals isinversely related to their CD4+ T cell count; Alpert et al.12 found that 81% of HIV patients with TB had CD4+

T cell counts less than 200/mm3. Because of the associa-tion between TB and HIV, all patients with tuberculousdisease should be tested for HIV infection.

The immune response and hypersensitivity that occurto the tuberculosis antigens are responsible for the patho-logic features associated with TB. In efforts to contain theinfection, the components of the immune system organizeinto granulomas and incomplete necrosis occurs, givingthe distinctive pathologic appearance of caseous necrosis.

The immune system’s response to M. tuberculosisalso explains the higher risk of disease following expo-sure and infection in children compared with adults. Therisk of young children with untreated infection develop-ing symptomatic TB is up to 43% in those less than 1 yearof age and 24% in those aged 1–5 years, compared with2% for adults >30 years13. The age-related immunedefects postulated to enhance the risk in childreninclude: impaired alveolar macrophage killing (despitenormal numbers) secondary to high concentration oflung surfactant, less efficient antigen presentation,

decreased monocyte chemotaxis, and decreased IFN-γand TNF-α production by natural killer cells and T lym-phocytes9. In addition, the proximity to an infectious pri-mary caretaker has been postulated as a factor for theincreased risk in infants.

Other factors associated with susceptibility to TB dis-ease include genetic variations14,15, race16, and environ-mental factors.

TRANSMISSION

TB is transmitted from person to person via the respi-ratory route. The infectious bacilli are contained indroplet nuclei that are less than 10 μm in diameter.Droplet nuclei are expelled from the lungs of an infectedperson usually by coughing, although infection has beenassociated with talking loudly and singing. The dropletnuclei dry and disperse rapidly but due to their sizethese airborne particles may remain suspended forhours. The droplet nuclei are highly infectious, sinceonly a few bacilli contained in one droplet nucleus arerequired for infection and an infected adult can expelapproximately 3000 droplet nuclei with one cough.

The degree of contagiousness is influenced by severalfactors such as the presence of acid-fast bacilli (AFB) onsputum smears, cough, duration and intensity of expo-sure, environmental ventilation, and host characteristics.The most important factor is the presence of AFB on spu-tum smear. Studies have shown that among householdcontacts of smear-positive cases the rates of tuberculinpositivity (i.e., infection) are 30–50% above those amongage-matched community controls, and in contacts ofsmear-negative cases the tuberculin positivity is approx-imately 5%17. The likelihood of AFB smear positivity isenhanced by cavitary lung lesions, which are usually fullof bacilli.

Since children rarely have cavitary lung lesions, trans-mission from children is rare. However, if cavitary lesionsare present, children may be the infectious source18,19.Most outbreaks involving children (daycare, schools,children’s hospitals) have been traced to adults withactive contagious disease. Coughing is also important,with those with a greater number of coughs at higherrisk of transmitting TB.

The effect of duration and intensity of exposure hasbeen detailed in various outbreaks. These have beenseen in offices, clinics, hospitals, classrooms, buses andairplanes, among others. In these situations, the distancefrom the infected person and the duration of contactwere significantly associated with infection. In a schoolbus outbreak where the driver was the infectioussource, children who sat in the front of the bus, close tothe driver, and for longer periods of time were morelikely to be infected20. Kenyon described transmission


during a long airplane flight in which the index patienthad multidrug-resistant TB. Passengers seated withintwo rows of the index patient were more likely to havepositive tuberculin skin tests21. In hospital outbreaks,the intensity of exposure may be more important thanduration. Fourteen percent of employees exposed for 4 hours in an emergency department to an intubatedpatient who required frequent suctioning, became posi-tive22. Ventilation has become an important factor for TBtransmission, highlighted by outbreaks aboard ships, injails, and hospitals.

To decrease the risk of transmission in hospital settings,strict infection control practices are recommended23. Forpatients with known or suspected TB, these include iso-lation in a negative-pressure room and respiratory pro-tection with N95 respirators for all who enter. Specialattention should be paid to cough-inducing proceduressuch as nebulization therapy, which has been associatedwith enhanced transmission24. An employee health pro-gram that performs routine PPD testing is essential inrecognizing conversions and monitoring employees foractive disease25,26.

Host characteristics may be important factors in trans-mission. Persons with a positive PPD may be somewhatimmune to acquisition of a second infection, althoughreinfection has occurred in immunocompromisedpatients. Being immunocompromised does not affect thelikelihood of infection but greatly influences the risk ofdisease. Furthermore, immunocompromised patientsmay transmit more effectively, if the disease has anunusual presentation or extrapulmonary manifestationsthat delay diagnosis and proper implementation of infec-tion control measures.


Pulmonary Disease

Primary infection in children is usually asymptomatic.Occasionally, patients will have mild fever and coughheralding infection, but these usually resolve without inter-vention. Symptomatic infection, known as primary pul-monary tuberculosis, occurs more commonly in infantsand small children. Forty to fifty percent of infected infantshave symptoms or radiographic abnormalities comparedwith 10% of older children. This syndrome is characterizedby fever, respiratory symptoms, failure to thrive, pulmo-nary infiltrate(s), and enlarged regional lymphadenopathy(Figures 11-1, 11-2). Sometimes the lymphadenopathycauses obstruction followed by segmental atelectasis. Insmall children this may mimic foreign body aspiration.Although lymphadenopathy and pulmonary infiltrate/atelectasis are the classic findings in pulmonary TB, anyradiographic findings can be associated with TB. Thus, it

is of vital importance to inquire about risk factors for TBin any patient with pneumonia. Frequently the sympto-matic small infant or child is the first recognized personwith TB in a family with a contagious adult contact.Vallejo et al. studied 47 infants under 1 year of age withTB and found that there was an infectious adult contactin 68% of cases27. The common symptoms recognized inadults such as night sweats, anorexia, and weight lossare usually absent in infants and children.

Infrequently primary pulmonary disease becomesprogressive with an enlarging pulmonary focus that mayliquefy in the center resembling a lung abscess. Thesepatients are usually symptomatic with fever, severe cough,anorexia, and night sweats. Although primary pleural andpericardial TB are rare in children a pulmonary cavity canrupture into the pleura and/or pericardium. The pleuramay show a hypersensitivity response to bacilli releasedfrom a subpleural focus. Pleural fluid characteristically hasbetween 100 and 1000 white blood cells/mm3, predomi-nantly polymorphonuclear leukocytes, high protein andlow glucose. Pleural fluid smears for AFB are typically negative and biopsy of the pleura is usually needed tomake the diagnosis. Pericardial involvement can bedetected by echocardiography. Pericardial fluid is usuallyserofibrinous or hemorrhagic and, like the pleura, directAFB smear is usually negative. Pericardial biopsy is oftenAFB-smear-positive and culture-positive. Although these

Figure 11-1 Frontal radiograph of the chest demonstrates lefthilar adenopathy.

Tuberculosis 175

Figure 11-2 Lateral radiograph of the chest demonstrates bilat-eral hilar adenopathy. Note airway compression by enlarged nodes.

extrapulmonary foci conveyed a high mortality in the pre-treatment era, full recovery is the rule with current therapy.

More than half of children with pulmonary TB arecompletely asymptomatic. Most come to medical atten-tion as a result of contact investigation of an adult case,although infants and small children may be missed incontact evaluations due to the lack of comfort of evalua-tors with infants. Lobato found many missed opportuni-ties for TB prevention in children younger than 5 years;improvements in contact investigation may have pre-vented TB in 17 of the 43 children evaluated28. Childrenmay also come to attention as part of routine medicalcare in which a PPD is placed. These asymptomatic chil-dren may have moderate or severe pulmonary disease.

Most untreated cases of pulmonary TB in children willresolve. Sequelae that may be seen as a result of pul-monary TB include calcifications and parenchymal scar-ring that may lead to pulmonary complications.

Older children and adolescents can have reactivationdisease. For reasons that are not totally understood ado-lescence is a high-risk period for reactivation disease.These patients frequently present, as do adults, with

symptoms of fever, productive cough, chest pain, nightsweats, anorexia, weight loss, and hemoptysis. Radio-graphically, upper lobe disease is usually evident withinfiltrate or cavitary lesions.

Extrapulmonary tuberculosis

Since the tuberculous bacilli disseminate throughoutthe body after primary infection, any organ can be a siteof reactivation and clinical disease. Infants and immuno-compromised hosts, especially those with acquiredimmune deficiency syndrome (AIDS), are most likely tohave extrapulmonary TB. Twenty-five percent of chil-dren evaluated by Burroughs et al.29 with TB had extra-pulmonary disease. Most had concomitant pulmonaryinvolvement but 13 of 156 had extrapulmonary diseaseonly. Miliary disease is the most common serious, dis-seminated form of TB and occurs most frequently ininfants. It usually occurs as a complication of primaryinfection in which there is a massive mycobacteremiaand clinical disease manifests in more than two organs.Miliary disease commonly presents as an indolent infec-tion with low-grade fevers, malaise, and failure to thrive.Respiratory symptoms are not usually prominent initiallybut with time pulmonary involvement becomes evidentwith respiratory distress, and the chest radiograph mayshow the characteristic miliary pattern (so named becausethe appearance is similar to millet seeds) (Figure 11-3).Hepatosplenomegaly is usually present as is generalizedlymphadenopathy. PPD testing is negative in approxi-mately 30% of patients with miliary disease. Diagnosis ofmiliary disease requires a high index of suspicion. In onereview premortem diagnosis was established in only one-third of children30. Often, liver or bone marrow speci-mens are required for diagnosis. With adequate treatmentthe prognosis of miliary TB is excellent.

A miliary pattern on the chest radiograph can also beseen in neonates with congenital TB. Congenital TB isexceedingly rare because it requires placental and/or amniotic fluid infection for transmission of bacilli to thefetus31. Blackall found three affected patients among 100infants of mothers with active TB32. Patients with congen-ital TB present in the neonatal period with symptoms com-patible with septicemia, commonly respiratory distress,hepatosplenomegaly, and often have a miliary pattern onthe chest radiograph. Some may have a more indolentcourse. A very high index of suspicion is required to makethis diagnosis since many infected mothers are asympto-matic and only diagnosed after diagnosis of the infant.

Although most cases of mycobacterial lymphadenitisin children are caused by non-tuberculous mycobac-teria (NTM), commonly M. avium-intracellulare and M. kansasii, lymphadenitis is the most common extrapul-monary manifestation of TB. It occurs most frequently inthe lymph nodes of the neck and supraclavicular regions.


Figure 11-3 Frontal and lateral radiographs demonstrate a diffuse nodular pattern indicative ofmiliary tuberculosis.

Differentiating lymphadenitis caused by NTM from thatcaused by M. tuberculosis may be difficult. Pulmonaryinvolvement is not seen in normal children with NTMinfection and is seen in the majority of children withtuberculous lymphadenitis. The PPD is frequently posi-tive with TB and although it may cause a reaction in NTMinfection, it is usually <10 mm. Assessment of risk factorsfor TB and epidemiologic investigation are essential inmaking the distinction between TB and NTM lympha-denitis. Often culture of drainage or excisional biopsy isnecessary to establish the correct diagnosis.

Other extrapulmonary forms of TB disease includecentral nervous system infection, with TB meningitisbeing the most serious complication. Disease can also beseen in bones (typically vertebrae), joints, skin, and thegastrointestinal and genitourinary systems.

DIAGNOSIS

Tuberculin skin tests (TST) such as the PPD, alsoknown as the Mantoux test, are routinely used to evalu-ate for TB infection. This test is a standardized productcomposed of M. tuberculosis proteins. The multiplepuncture test (Tine test) is a non-standardized test thatshould not be used. Proper application of the PPD is

imperative for an accurate result; 0.1 ml (5TU) is appliedintradermally to produce a wheal. In 48–72 hours a cellmediated response will be elicited in patients who havebeen infected with TB. Induration in those with a posi-tive test may remain for days to weeks. The incubationperiod for this response to occur after exposure to TB is2–12 weeks. This response is manifest as an induratedarea surrounding the site of application. The diameter ofinduration transverse to the long axis of the forearm ismeasured. Studies evaluating skin reaction in patientswith TB and those without have yielded interpretativecriteria. Interpretation is based on the pretest probabilitythat the patient has TB; populations with low preva-lence, at low risk, should not be tested routinely sincemost reactions will be falsely positive. Thus, to interpreta PPD skin test one must first do a risk assessment forTB (Table 11-1). Reactions that are immediate or accel-erated, usually occurring within 24 hours of placement,represent hypersensitivity to polysaccharides or com-ponents in the diluent and do not represent positivereactions to TB. Erythema alone does not constitute apositive reaction and only induration should be meas-ured. Unfortunately, antigens present in NTMs maycross-react with TB antigens present in the PPD test.Reactions secondary to NTMs are typically smaller than10 mm. Vaccination with Bacille Calmette-Guérin (BCG),

Tuberculosis 177

Table 11-1 Definitions of Positive Tuberculin Skin Test Results in Infants, Children, and Adolescents

Induration Interpret as Positive in:

>5 mm Children in close contact with known or suspected contagious cases of TBChildren suspected of having TB diseaseChildren receiving immunosuppressive therapy or with immunosuppressive conditions, including HIV infection

≥10 mm Children at increased risk of disseminated disease:Younger than 4 yearsWith underlying medical conditions such as Hodgkin disease, lymphoma, diabetes, chronic renal failure and/or malnutrition

Children with increased exposure to tuberculosis disease:Children born or whose parents were born in areas of high TB prevalenceChildren frequently exposed to high-risk persons, i.e., HIV-infected, homeless, illicit drug users, nursing home residents,

incarcerated or institutionalized, or migrant farmersChildren who travel to or immigrated from high-prevalence regions of the world

≥15 mm Children >4 years of age without any risk factors

(Adapted from American Academy of Pediatrics. Tuberculosis. In Pickering LK, editor: Red Book: 2003 Report of the Committee on Infectious Diseases, 26th edition,pp 648–658. Elk Grove Village, IL: American Academy of Pediatrics, 2003.)

Figure 11-4 Frontal radiograph of the chest demonstrates leftupper lobe atelectasis in a patient with pulmonary tuberculosis.

which is routinely done in infancy throughout theworld, may produce a positive PPD test, but within ayear most are less than 10 mm. Thus, the current rec-ommendation is to interpret PPD results in BCG-vacci-nated individuals as though they had never beenvaccinated. Approximately 10% of children with activepulmonary TB will not respond to skin testing and up tohalf with miliary disease and/or tuberculous meningitismay have an initial negative test. Frequently thesebecome positive during the course of therapy. Anergytesting is not recommended because a standardized pro-tocol does not exist and many patients who have TB mayhave global anergy or anergy solely to TB antigens. Thus,a positive anergy test with a negative Mantoux test in apatient with suspected TB would not deter one from fur-ther evaluation and treatment33.

The chest radiograph is the next step in evaluation of achild with a positive PPD. The most common abnormali-ties include mediastinal lymphadenopathy, consolidation,and interstitial densities, although any abnormality may becompatible with TB (Figures 11-4, 11-5, 11-6). Computedtomography (CT) may be more sensitive for pulmonaryinvolvement in the symptomatic patient with a normalchest radiograph, but there is no role for CT in asymp-tomatic patients with positive skin tests and negativechest radiographs34.

Microbiologic investigation is essential in patients whoare symptomatic and in those with a positive PPD skintest and a positive chest radiograph. The only exceptionto this is patients whose known contact has microbio-logic proof of M. tuberculosis with available susceptibil-ity data. Evaluation of expectorated sputum for AFB is thegold standard for diagnosis of TB. In children, obtainingsputum can be difficult and obtaining first morning gastricaspirates on 3 consecutive days, if done in a standardized

manner, has been shown to have good sensitivity (presumably because of swallowing of pulmonary secre-tions which pool in the stomach)35. Although most are not AFB-smear-positive due to low organism load, cul-ture of gastric aspirates can be positive in up to 70% of infants and 50% of children with pulmonary TB36.Abadco and Steiner demonstrated that obtaining gastricaspirates was more sensitive than performing bronchoalve-olar lavage for isolation of M. tuberculosis in children37. Forpatients with extrapulmonary disease, specimens shouldbe obtained from the affected site, although the positiveculture rate is only approximately 50%34.


Figure 11-5 Axial contrast-enhanced CT scan demonstratesnecrotic right hilar and subcarinal adenopathy.

Figure 11-6 Frontal radiograph of the chest demonstrates alarge right pleural effusion in a patient with tuberculosis.

Conventional culture methods usually take 3–8 weeksfor growth to be detected, although newer systems withbroth media have decreased that interval to 1–3 weeks.

Recently, nucleic acid amplification assays (polymerasechain reaction [PCR] using the insertion sequenceIS6110 as the target for DNA) have been developed forthe diagnosis of TB. In limited pediatric studies PCR hada sensitivity of 40% and a specificity of 80%, which is not

significantly better than culture38. Use of PCR tests inpediatrics is limited by Food and Drug Administrationapproval for sputum samples only, poor sensitivity andspecificity on gastric aspirates and false positives in pedi-atric patients with M. avium-intracellulare38–40. At pre-sent, routine use of PCR methodology in pediatrics cannotbe recommended.

TREATMENT

Mycobacteria are present in infected tissues in differentstages. Some are rapidly dividing, others exhibit spurts ofmetabolic activity, and some may be dormant. Access tomycobacteria in macrophages can be difficult for somedrugs. Since mycobacteria are in these different growingcycles and may exhibit primary drug resistance, a basicprinciple is to use combination antituberculous therapy.The goal of antituberculous therapy is to make thepatient non-contagious rapidly and to cure the disease.In pediatric patients, an immunocompetent host with asusceptible organism and assured compliance has a100% response rate to therapy with less than 5% risk ofrelapse. Recent comprehensive guidelines for treatmentof TB have been established by the American ThoracicSociety, Centers for Disease Control and Prevention andInfectious Diseases Society of America as well as theAmerican Academy of Pediatrics41,42. The most commonregimen for treatment of susceptible TB strains is shown inTable 11-2. Treatment protocols for patients with mul-tidrug-resistant TB must be individualized and consultationwith a specialized treatment center is recommended41.

Treatment for all pediatric patients with tuberculousdisease should be monitored by directly observed therapy(DOT). DOT is performed by the public health depart-ment and involves providing the antituberculous drugsdirectly to the patient and watching as he or she swallowsthe medications. This is the best way to assure complianceand success of therapy43,44.

For patients with HIV infection, the American Academyof Pediatrics recommends consultation with a specialistand continuation of therapy for 9 months42.

Corticosteroids have been used as adjunctive therapyin the treatment of TB. Evidence-based recommenda-tions are present for use of corticosteroids in tuber-culous pericarditis and central nervous system diseaseincluding meningitis41,45.

New treatment strategies have emerged from knowl-edge of the immunobiology of TB. These include administration of aerosolized INF-γ and subcutaneous IL-246,47. Thus far these have been studied in patientswith multidrug-resistant TB with good outcomes. This isa new and promising area of TB research.

Although a vaccine for TB exists, BCG vaccine, it is ofvery limited efficacy; estimates of efficacy have ranged

Tuberculosis 179

Table 11-2 Recommended Treatment Regimens for Drug-Susceptible TB in Infants, Children, and Adolescents

Infection/Disease Category Treatment

Latent infection (positive Mantoux test, Isoniazid (INH) daily for 9 months if INH-susceptiblenegative chest radiograph) Rifampin (RIF) daily for 9 months if INH-resistant

Consult specialist if INH- and RIF-resistantPulmonary and extrapulmonary TB INH, RIF and pyrizinamide (PZA) daily or twice a weeka for 2 months, followed by INH

except TB meningitis and RIF for 4 monthsIn areas of high prevalence of resistance add ethambutal (ETH) or aminoglycoside for initial

2 months or until susceptibilities knownConsult specialist for multidrug-resistant TB

TB meningitis INH, RIF PZA, ETH or aminoglycoside daily for 2 months, followed by INH and RIF daily ortwice a weeka for 7–10 months

(Adapted from American Academy of Pediatrics. Tuberculosis. In Pickering LK, editor: Red book: 2003 Report of the Committee on Infectious Diseases, 26th edition,pp 648–658. Elk Grove Village, IL: American Academy of Pediatrics, 2003.)aDrugs can be given twice weekly under directly observed therapy (DOT).

MAJOR POINTS

1. Diagnosis of tuberculosis (TB) in children requiresa high index of suspicion. Since pulmonary TB canmanifest in many ways one must inquire about riskfactors for TB in patients presenting withpulmonary disease.

2. In view of the close association between TB and HIV,all pediatric patients with TB should be HIV-tested.

3. The Mantoux test or PPD is used for evaluation ofTB infection. The multiple puncture test (Tinetest) is not standardized and should not be used.The PPD test is read 48–72 hours after placementand induration, not erythema, is measured. Tointerpret the PPD skin test one must take intoaccount the patient’s risk for TB.

4. Treatment of TB is highly effective. To assureadherence with therapy, all patients with TBshould be monitored by directly observed therapy,through the public health department.

�

�from 0 to 100%, with an average efficacy of 50%48. Thehighest efficacy is in prevention of disseminated diseaseand death in neonates, thus its continued use worldwidein areas of high TB prevalence. Major limitations of BCGare lack of standardization and side effects that can besevere and life-threatening in immunocompromisedinfants. Because of the current limitation of BCG and theworldwide burden of TB, one third of the world’s popula-tion is infected; development of an effective, safe vaccineis an international public health priority. Vaccines underdevelopment include whole-cell live, whole-cell inacti-vated, subunit, DNA and prime-boost vaccines48,49. Severalvaccines show promise and are undergoing human trials48.

REFERENCES

1. Dye C, Scheele S, Lolin P, et al. Global burden of tuber-culosis: estimated incidence, prevalence and mortality bycountry. JAMA 282:677–686, 1999.

2. CDC. Reported tuberculosis in the United States, 1993. Atlanta:US Department of Health and Human Services, CDC, 1994.

3. Ussery XT, Valway SE, McKenna M, et al. Epidemiology oftuberculosis among children in the United States: 1985 to1994. Pediatr Infect Dis J 15:697–704, 1996.

4. CDC Tuberculosis morbidity—United States, 1997. MMWR47:253–257, 1998.

5. Bloom BR. Tuberculosis: the global view. N Engl J Med346:1434–1435, 2002.

6. Trends in tuberculosis morbidity—United States, 1992–2002.MMWR 52:217–222, 2003.

7. Frieden TR, Fujiwara PI, Washko RM, et al. Tuberculosis in New York City: turning the tide. N Engl J Med 333:229–233, 1995.

8. Schluger NW, Rom WN. The host immune response to tuberculosis. Am J Respir Crit Care Med 157:679–691,1998.

9. Smith S, Jacobs RF, Wilson CB. Immunobiology of child-hood tuberculosis: a window on the ontogeny of cellularimmunity. J Pediatr 131:16–26, 1997.

10. Selwyn PA, Hartel D, Lewis VA, et al. A prospective studyof the risk of tuberculosis among intravenous drug userswith human immunodeficiency virus infection. N Engl JMed 320:545–550, 1989.

11. Guelar A, Gatell JM, Verdejo J, et al. A prospective study ofthe risk of tuberculosis among HIV-infected patients. AIDS7:1345–1349, 1993.

12. Alpert PL, Munsif SS, Gourevitch MN, et al. A prospectivestudy of tuberculosis and human immunodeficiency virusinfection: clinical manifestations and factors associatedwith survival. Clin Infect Dis 24:661–668, 1997.


13. Starke JR, Jacobs RF, Jereb J. Resurgence of tuberculosis inchildren. J Pediatr 120:839–855, 1992.

14. Bellamy R, Ruwende C, Corrah T, et al. Variations in theNRAMP1 gene and susceptibility to tuberculosis in WestAfricans. N Engl J Med 338:640–644, 1998.

15. Goldfeld AE, Delgado JC, Thim S, et al. Association of anHLA-DQ allele with clinical tuberculosis. JAMA 279:226–228, 1998.

16. Stead WW, Senner JW, Reddick WT, et al. Racial differencesin susceptibility to infection by Mycobacterium tuberculosis.N Engl J Med 322:422–427, 1990.

17. Sepkowitz KA. How contagious is tuberculosis? Clin InfectDis 23:954–962, 1996.

18. Curtis AB, Ridzon R, Vogel R, et al. Extensive transmissionof Mycobacterium tuberculosis from a child. N Engl J Med341:1491–1495, 1999.

19. Ridzon R, Dent JH, Valway S, et al. Outbreak of drug-resistanttuberculosis with second-generation transmission in a highschool in California. J Pediatr 131:863–868, 1997.

20. Rogers EFH. Epidemiology of an outbreak of tuberculosisamong school children. Public Health Rep 77:401–409, 1962.

21. Kenyon TA, Valway SE, Ihle W, et al. Transmission of mul-tidrug resistant Mycobacterium tuberculosis during a longairplane flight. N Engl J Med 334:933–998, 1996.

22. Haley CE, McDonald RC, Rossi L, et al. Tuberculosis epidemicamong hospital personnel. Infect Control Hosp Epidemiol10:204–210, 1989.

23. Guidelines for preventing the transmission ofMycobacterium tuberculosis in health-care facilities, 1994.MMWR 43(RR13):1–132, 1994.

24. Nelson JD, McCracken GH. TB in day-care. Pediatr InfectDis J [Oct]:[Yellow Pages], 1998.

25. Bock NN, Sotir MJ, Parrott PL, et al. Nosocomial tuberculo-sis exposure in an outpatient setting: evaluation of patientsexposed to healthcare providers with tuberculosis. InfectControl Hosp Epidemiol 20:421–425, 1999.

26. Bolyard EA, Tablan OC, Williams WW, et al. Guideline forinfection control in healthcare personnel, 1998. InfectControl Hosp Epidemiol 19:407–463, 1998.

27. Vallejo JG, Ong LT, Starke JR. Clinical features, diagnosis, andtreatment of tuberculosis in infants. Pediatrics 94:1–7, 1994.

28. Lobato MN, Mohle-Boetani JC, Royce SE. Missed opportu-nities for preventing tuberculosis among children youngerthan five years of age. Pediatrics 106:1–6, 2000.

29. Burroughs M, Beitel A, Kawamura A, et al. Clinical presen-tation of tuberculosis in culture-positive children. PediatrInfect Dis J 18:440–446, 1999.

30. Hussey G, Chisholm, T. Kibel M. Miliary tuberculosis in chil-dren: a review of 94 cases. Pediatr Infect Dis J 10:832, 1991.

31. Cantwell MF, Shehab ZM, Costello AM, et al. Brief report:congenital tuberculosis. N Engl J Med 330:1051–1054, 1994.

32. Blackall PB. Tuberculosis: maternal infection of the new-born. Med J Aust 1:1055–1058, 1969.

33. Slovis BS, Plitman JD, Haas DW. The case against anergytesting as the routine adjunct to tuberculin skin testing.JAMA 283:2003–2007, 2000.

34. Starke JR. Diagnosis of tuberculosis in children. PediatrInfect Dis J 19:1095–1096, 2000.

35. Pomputius WF, Rost J, Dennehy PH, et al. Standardization ofgastric aspirate technique improves yield in the diagnosis oftuberculosis in children. Pediatr Infect Dis J 16:222–226,1997.

36. Khan EA, Starke JR. Diagnosis of tuberculosis in children.Increased need for better methods. Emerging Infect Dis1:115–123, 1995.

37. Abadco DL, Steiner P. Gastric lavage is better than bron-choalveolar lavage for isolation of Mycobacterium tuber-culosis in childhood pulmonary tuberculosis. Pediatr InfectDis J 11:735–738, 1992.

38. Smith KC, Starke JR, Eisenach K, et al. Detection ofMycobacterium tuberculosis in clinical specimens fromchildren using a polymerase chain reaction. Pediatrics97:155–160, 1996.

39. Delacourt C, Poveda JD, Chureau C, et al. Use of poly-merase chain reaction for improved diagnosis of tubercu-losis in children. J Pediatr 126:703–709, 1995.

40. Pierre C, Oliver C, Lecossier D, et al. Diagnosis of primarytuberculosis in children by amplification and detection ofmycobacterial DNA. Am Rev Respir Dis 147:420–424,1993.

41. American Thoracic Society, CDC, and Infectious DiseasesSociety of America. Treatment of tuberculosis. MMWR52(RR-11):1–77, 2003.

42. American Academy of Pediatrics. Tuberculosis. In Pickering LK, editor: Red book: 2003 Report of theCommittee on Infectious Diseases, 26th edition, pp 648–658.Elk Grove Village, IL: American Academy of Pediatrics, 2003.

43. Weis SE, Slocum PC, Blais FX, et al. The effect of directlyobserved therapy on the rates of drug resistance and relapsein tuberculosis. N Engl J Med 330:1179–1184, 1994.

44. Chaulk CP, Moore-Rice K, Rizzo R, et al. Eleven years ofcommunity-based directly observed therapy for tuberculosis.JAMA 274:945–951, 1995.

45. Dooley DP, Carpenter J, Rademacher S. Adjunctive corti-costeroid therapy for tuberculosis: a critical reappraisal ofthe literature. Clin Infect Dis 25:872–887, 1997.

46. Condos R, Rom WN, Schluger NW. Treatment of multidrug-resistant pulmonary tuberculosis with interferon- γ via aerosol.Lancet 349:1513–1515, 1997.

47. Johnson B, Bekker LG, Ross S, et al. Recombinant inter-leukin-2 adjunctive therapy in multidrug resistant tubercu-losis. Novartis Found Symp 217:99–106, 1998.

48. Fordham von Reyn C, Vuola JM. New vaccines for the prevention of tuberculosis. Clin Infect Dis 35:465–474,2002.

49. Young DB. Current tuberculosis vaccine development.Clin Infect Dis 30:S254–256, 2000.

181

CHAPTER

12 Interstitial LungDiseasesBRIAN P. O’SULLIVAN, M.D.

Primary (Idiopathic) Interstitial Lung Disease in Adults

Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis

Desquamative Interstitial Pneumonia

Acute Interstitial Pneumonia

Respiratory Bronchiolitis-Associated Interstitial Lung Disease

Non-specific Interstitial Pneumonia

Bronchiolitis Obliterans with Organizing Pneumonia

Lymphoid Interstitial Pneumonia

Pediatric Interstitial Lung Diseases

Chronic Pneumonitis of Infancy (CPI)

Cellular Interstitial Pneumonia (CIP)

Pulmonary Interstitial Glycogenosis (PIG)

Persistent Tachypnea of Infancy (PTI)

Follicular Bronchiolitis (FB)

Lymphocytic Interstitial Pneumonia (LIP)

Surfactant Protein Diseases

Diagnosis and Treatment of ILD

Secondary Forms of ILD

Summary

The lungs consist of a fine, lacy network ofparenchyma and blood vessels surrounding air spaces.The normal alveolar wall is extremely thin, in someplaces as little as 0.3 μm thick, allowing close approxi-mation of red blood cells in the capillaries to air in thealveolar space (Figure 12-1). The surface area of the gasexchange apparatus in an adult is 50–100 m2. Theextremely thin, large surface area of the lung is possibledue to the fact that 95% of epithelial lining cells are ofthe type 1 variety—cells which become attenuated andspread very thinly across the blood–air interface. Theother 5% of epithelial lining cells are surfactant-produc-ing type 2 cells. Fibroelastic tissue containing fibroblasts,collagen, and elastic fibers in combination with pul-monary capillaries makes up the rest of the alveolar wall(Figure 12-2). Under usual circumstances a red blood cellpassing through the lung can become fully saturated

with oxygen in just 0.25 seconds, approximately one-third of the time it spends in an alveolar capillary.

Interstitial lung disease (ILD) is the result of an insultto the lung, which leads to inflammation of the alveolarstructures (alveolitis). With chronic inflammation thereis increased production of fibroblasts and matrix-connective tissue components. The resultant fibrosisand increased cellularity lead to a thickened alveolar-cap-illary membrane, abnormal gas exchange, and decreasedtissue elasticity. Clinically, these changes are expressedas hypoxemia and restrictive lung disease. Although evo-lution from stimulus to clinically apparent ILD soundssimple, it is likely that the true pattern of developmentof ILD is much more complex and involves repeatedstimuli, environmental exposures in addition to the orig-inal insult, host genetic factors (e.g., inflammatoryresponse, immune cell production, wound healing), andchance. Thus, it is impossible to predict who will developILD even in the familial forms (where the penetrance ofILD is far below 100%).

The term ILD comprises an amorphous class of pul-monary disease and can mean different things to differ-ent physicians. The most all-encompassing definition ofILD is that of a process which leads to thickening of alve-olar septa and resultant interference with gas exchangeand pulmonary mechanics. Many disease states lead toan end stage consisting of thickened alveolar walls,including rheumatologic disorders, inflammatory boweldisease, vasculitis, hematologic diseases, infection, andreaction to exogenous substances including allergens,medications, and illicit drugs. Most commonly, no incit-ing agent or disease is identified and the term idiopathicor cryptogenic is applied to the process.

Traditionally, internists think of the entities usualinterstitial pneumonia (UIP) and desquamative intersti-tial pneumonia (DIP) when ILD is discussed. Included inthis category is idiopathic pulmonary fibrosis (IPF), the


A BFigure 12-1 Photomicrographs demonstrating the close approximation of red blood cells to airin the lung. (A) Section of lung from a dog which was fixed while being perfused. Note that the capillary network forms a sheet of blood in contact with the alveolar air. (B) Electron micrographshowing the extremely thin blood–air barrier, as little as 0.3 μm in places. BM, basement membrane;C, capillary; EC, erythrocyte; EP, alveolar epithelium; EN, capillary endothelium; FB, fibroblasts; IN,interstitium. Large arrow shows the diffusion pathway across four layers: surfactant (not shown),cell membranes and interstitium, plasma, and red blood cell membrane. (Reproduced with permis-sion from West JB. Respiratory physiology, the essentials. Philadelphia: Lippincott, Williams &Wilkins, 2000.)

Table 12-1 Glossary

UIP Usual interstitial pneumoniaDIP Desquamative interstitial pneumoniaAIP Acute interstitial pneumoniaNSIP Non-specific interstitial pneumoniaLIP Lymphocytic interstitial pneumoniaIPF Idiopathic pulmonary fibrosisRBILD Respiratory bronchiolitis-associated interstitial lung

diseaseBOOP Bronchiolitis obliterans with organizing pneumoniaPTI Persistent tachypnea of infancyPIG Pulmonary interstitial glycogenosisCPI Chronic pneumonitis of infancyCIP Cellular interstitial pneumonia

clinical correlate to UIP1–3. A glossary of ILD termsappears in Table 12-1. Until recently, the pediatrician has had little information about pathophysiology orprognosis when the term ILD was used for his or herpatient. Fortunately, this has changed dramatically overthe last decade with multiple reports of myriad forms of ILD in patients under 21 years of age4–10. In fact, afield full of confusing and overlapping names with analphabet-soup of abbreviations with which once onlyinternists had to struggle has become a minefield forpediatricians, too11.

A recent consensus statement from the AmericanThoracic Society and the European Thoracic Society hasbrought a semblance of order if not complete clarity tothe confusing array of ILD classifications1. There is someoverlap in conditions and rare reports of adult-type ILDin children; however, in many ways the idiopathic formsof ILD comprise two distinct entities in children and

Interstitial Lung Diseases 183

adults. Most adult forms of ILD occur later in life (rarelyprior to age 50 years) and are associated with tobaccouse. In contrast, pediatric ILDs not clearly associatedwith infection, drug toxicity, or systemic diseases tendto occur in the first months or years of life and are notrelated to tobacco smoke exposure.

It is important to review the adult entities, both due totheir historical importance and because they are used asa basis for describing all ILD, adult and pediatric. Thischapter will review the classical internal medicine con-cept of ILD, the recent revelations specific to pediatricILD with an emphasis on the idiopathic forms, and a briefoverview of secondary causes of ILD.

PRIMARY (IDIOPATHIC) INTERSTITIALLUNG DISEASE IN ADULTS

Hamman and Rich described patients with an acuteform of ILD in 1936, but it was not until the mid-1970sthat Liebow offered the various classifications of ILD, alist of varieties of “interstitial pneumonias,” which wereto become used popularly12. Much time and energy has been expended on categorizing these entities in a

reliable and scientifically sound manner. This has provedimportant for research purposes, for providing prognosticinformation to patients, and for guiding therapy. Today’scategories of adult ILD are very close to those Liebow orig-inally proposed and include: UIP (the pathologic descrip-tion of the clinical disease known as IPF), DIP, acuteinterstitial pneumonia (AIP, the disease Hamman and Richoriginally described13), respiratory bronchiolitis-associatedinterstitial lung disease (RBILD), non-specific interstitialpneumonia (NSIP), bronchiolitis obliterans with organiz-ing pneumonia (BOOP), and histiocytosis-X (Langerhancell histiocytosis)1,2.

Usual Interstitial Pneumonia/IdiopathicPulmonary Fibrosis

IPF is a disease state typified by shortness of breath,bibasilar crackles, restrictive lung disease, impaired gasexchange with reduced diffusing capacity of carbonmonoxide, evidence of diffuse infiltrates on plain radio-graph and CT scan of the chest, and biopsy demonstratedinflammation, fibrosis, or both1,2. In these clinical, radio-graphic, and pulmonary function respects it is similar to allthe ILDs. IPF is differentiated from the other ILDs by

RBCEP1

C F

EP2

EP2

EN CAP M

A B

Figure 12-2 Line drawings depicting alveolar architecture. (A) Low-power rendering of a terminalbronchiole demonstrating the large surface area and lacy construction of the acinus. (B) Cut surfaceof the alveolar wall. The alveolar wall consists of many cell types, all of which may be involved inILD. C, connective tissue; CAP, capillary; EP1, epithelial type 1 cell; EP2, epithelial type 2 cell; EN,endothelial cell; F, fibroblast; M, basement membrane; RBC, red blood cell. (Reproduced with per-mission from Crystal RG, Bitterman P, Rennard SI, Hance AJ, Keough BA. Interstitial lung diseasesof unknown cause: disorders characterized by chronic inflammation of the lower respiratory tract.N Engl J Med 310:154–166, 1984.)


the pathologic changes of UIP seen on light microscopicevaluation of lung biopsy specimens. UIP is defined asconsisting of heterogeneous pathologic changes withalternating areas of normal lung, interstitial inflammation,fibrosis, and honeycomb changes. There are scatteredfibroelastic foci in fibrotic zones and the subpleural,peripheral parenchyma is most severely involved. Fibroticareas characteristically vary in age and activity.

What stimulates the chronic inflammation and fibrosisseen in UIP is unclear but that the stimulus is on-goingover a long period of time is evident by the chronicity ofthe disease and the variable stages of the pathologicchanges seen on biopsy specimens. As with many dis-ease states, IPF is likely caused by a superimposition ofgenetic susceptibility and environmental exposure. Upto 75% of patients with IPF have been found to be cur-rent or former cigarette smokers in large epidemiologicstudies. In addition, latent viral infections have beenimplicated as causative agents. UIP/IPF is extremelyuncommon in childhood, with two-thirds of patientsgreater than age 60 years and a median age of diagnosisof 66 years.

IPF is a progressive illness with median survival after the biopsy-proven diagnosis of UIP being only 3 years.Although anti-inflammatory and anti-fibrotic therapies havebeen used extensively there is still no good, proven ther-apy for IPF. Interferon gamma-1b decreases expression ofgenes for transforming growth factor beta and connectivetissue growth factors in lung tissue and may blunt thechronic fibrosis seen in IPF. A report of immune modula-tion with interferon gamma-1b and low dose prednisoloneshowed some promise14. At this time IPF remains a poorlyunderstood disease with a dismal prognosis.

Desquamative Interstitial Pneumonia

DIP is an uncommon disease even in the rarefiedworld of ILDs, accounting for less than 3% of all ILD.This disease is most commonly seen in cigarette smokersin their thirties and forties. The clinical signs and symp-toms are similar to those of UIP but occur on a more sub-acute (weeks to months) rather than chronic scale.Pathologic examination of lung tissue shows a diffuse,uniform alveolar accumulation of macrophages with lit-tle fibrosis and only mild or moderate thickening of alve-olar walls. DIP lacks the scarring and architecturalremodeling seen in UIP1,2.

The pathologic differences between DIP and UIP arestriking, yet over the years many have contended that theyare one illness with DIP representing the early, inflamma-tory stage of a disease process which progresses to theburned-out, fibrotic picture of UIP. Although initiallyappealing, there is insufficient evidence to support a the-ory of DIP and UIP lying at different ends of one diseasespectrum. There are no biopsy-proven reports of DIP

progressing to UIP and several reports of sequentialbiopsies in DIP patients showing no such progression.Similarly, no patients with early IPF/UIP show patho-logic changes consistent with DIP. The differentiationbetween DIP and UIP is more than academic as DIP hasa better response to steroid therapy and an overall sur-vival rate of about 70% after 10 years as compared withthe very poor prognosis with IPF/UIP.

Acute Interstitial Pneumonia

Louis Hamman and Arnold Rich described a smallseries of patients seen at Johns Hopkins UniversityHospital in reports published in 1935 and 194415. Thesephysicians used the term “acute diffuse interstitial fibrosis” to describe their findings. Today the so-calledHamman–Rich syndrome is more appropriately classifiedas AIP. Unfortunately, for many years the eponym hasbeen used far too loosely to include many forms of acuteand chronic ILD, further confusing the issues surround-ing ILD nomenclature. The recent consensus statementreport requires the presence of a clinical syndrome ofacute respiratory distress syndrome (ARDS) in an idio-pathic setting with biopsy confirmation of diffuse alveo-lar damage with organization in order to make thediagnosis of AIP1. As the name implies, this entity israpid in onset and can be accompanied by fever, cough,and shortness of breath. Chest roentgenograms demon-strate bilateral airspace disease consistent with theunderlying diffuse alveolar damage and mimickingARDS. Mortality is high and there have been reports ofsurvivors having progression to end-stage pulmonaryfibrosis. Fortunately, in some cases there is completehealing and return to normal function.

Respiratory Bronchiolitis-AssociatedInterstitial Lung Disease

This syndrome is generally restricted to current or for-mer cigarette smokers. The presentation of cough,increased work of breathing, and crackles is similar tothat of other ILD patients. Patients with RBILD may havemixed obstructive and restrictive defects on pulmonaryfunction testing. Biopsy demonstrates a bronchocentricdistribution of luminal pigmented macrophages.Peribronchial fibrosis is seen, as is hyperplasia of type 2pneumocytes. Cessation of cigarette smoking is the keyto therapy for this disease.

Non-specific Interstitial Pneumonia

NSIP is manifested as varying degrees of inflammationand fibrosis that are uniformly distributed within theinterstitium of the lung. This entity was first describedby Katzenstein and Fiorelli16 in 1994 in their report of a


group of patients with ILD that did not fit readily into thepreviously described categories. NSIP is known to havea better prognosis than UIP and over the past decade hasacquired defined characteristics recognizable on high-resolution CT scanning. The defining pathologic differ-ence between NSIP and UIP is the lack of temporalheterogeneity in NSIP samples. That is, the pathologicchanges are uniform in NSIP, all being in the same stageof evolution; whereas in UIP the pathologic changes arein variable stages. The key difference between NSIP andDIP is the paucity of alveolar macrophages seen in theformer whereas such airspace debris is the hallmark ofthe latter (the so-called desquamation of cells into thealveoli). There appears to be a strong correlationbetween NSIP and connective tissue disorders, especiallyscleroderma and polymyositis.

Bronchiolitis Obliterans with OrganizingPneumonia

Idiopathic BOOP is seen in the fifth and sixth decadesof life and is characterized by a peripheral distribution ofopacities on chest X-ray films. Pathologically, BOOPconsists of excessive proliferation of granulation tissuewithin small airways and alveolar ducts. There is chronicinflammation in the surrounding alveoli and buds ofgranulation tissue may spread from alveolus to alveolusthrough the pores of Köhn. The fibrosis tends to be ofuniform age suggesting a specific, acute insult, in con-trast to the heterogeneous changes seen in UIP/IPF.Clinically, BOOP may present similarly to UIP/IPF butsome distinguishing features do exist. For example, dueto its more acute presentation, clubbing is less common

in BOOP than in UIP/IPF. Unlike many of the ILDs,BOOP is responsive to steroid therapy with recovery intwo-thirds of patients. Idiopathic BOOP is rarely seen inchildren and when it does occur it is in association withanother systemic illness. In children, BOOP is most likelyto be seen secondary to bone marrow transplant orinfection. Figures 12-3 and 12-4 show radiographic stud-ies and biopsy findings from an infant with systemiclupus erythematosus who developed BOOP.

Lymphoid Interstitial Pneumonia

In the adult population LIP is a disease associatedwith lymphoproliferative disorders, dysproteinemia,Sjögren syndrome, or viral infection (human immunode-ficiency virus [HIV], Epstein–Barr virus [EBV]). IdiopathicLIP is felt to be very rare17. This disorder is characterizedby monotonous polyclonal lymphoid cell infiltrates sur-rounding airways and expanding the lung interstitium.Viral-induced lymphoid proliferation leading to LIP is seenin some children with HIV or EBV infections. A relatedcondition consisting of more localized follicles of lymphoidhyperplasia known as follicular bronchitis/bronchiolitishas been reported occasionally in adults and children.Pediatric LIP and follicular bronchiolitis are discussedbelow.

PEDIATRIC INTERSTITIAL LUNGDISEASES

ILD is not a common problem in children. Therefore,collecting data on a large cohort of patients diagnosed

A BFigure 12-3 Chest X-ray film (A) and CT scan (B) from a 15-month-old child who had recurrentrespiratory problems. This severe pneumonia was initially thought to be measles pneumonia due toa positive viral titer. This later proved to be a false- positive reaction and the child was found to havesystemic lupus erythematosus (SLE) and bronchiolitis obliterans with organizing pneumonia (BOOP).Note the patchy alveolar infiltrates (small arrows) and ground-glass opacities (large arrows).


and treated in a uniform manner is difficult. The mostcomprehensive attempts to describe the pattern of pri-mary (idiopathic) ILD in children have been by Fan andLangston in the United States and Nicholson, Bush, andcolleagues in the United Kingdom.

The clinical presentation of ILD in childhood is simi-lar to that in adults: shortness of breath, increased workof breathing, hypoxemia, tachypnea, and diffuse, fine,“Velcro-like” crackles. In addition, children with ILDoften demonstrate the unique sign of failure to thrive.The age range for presentation of ILD can be from birththrough adolescence, although in our experienceyounger children are more likely to have idiopathic ILDwhereas older children tend to have ILD secondary to anunderlying systemic disease or drug/toxin. The triad offailure to thrive, fine crackles, and hypoxemia in aninfant is highly suggestive of ILD and is grounds for CTscan and lung biopsy once more common causes ofchronic lung disease of infancy have been ruled out.

For many years lung biopsies from infants and chil-dren with ILD were described in terms of the adult cate-gories listed above. This was unfortunate since thecausative factors seen in adults (such as cigarette smok-ing) do not apply to children and the prognoses of manyof the childhood ILDs are clearly different from those ofthe adult forms. In addition, whatever insult that causesILD is also superimposed on lung development in chil-dren, an issue not relevant to adult pathologies. Morerecently, a number of separate entities seemingly uniqueto pediatric patients have been described. These newcategories of ILD render the previously used adult classi-fication system obsolete and allow for a more systematicgathering of information regarding ILD in children. Fanand Langston have proposed several variants of the adult

schema7,9 whereas Nicholson et al.18 prefer to classifypediatric ILD according to the defined adult histopatho-logic patterns. The latter investigators ignore the newerdesignations of pediatric ILD such as cellular interstitialpneumonitis (CIP), persistent tachypnea of infancy(PTI), and pulmonary interstitial glycogenosis, and lumpmost children into the categories of LIP or NSIP. Placing amajority of the childhood ILDs into a category (NSIP)which even those who use the adult system recognize as aplace-holder until more definitive diagnoses come to lightdoes not seem fruitful. It is more beneficial for pediatricpulmonologists and pathologists to modify the categoryof NSIP by breaking it into component parts.

Pediatric ILDs as defined by Fan and Langston includechronic pneumonitis of infancy (CPI), cellular interstitialpneumonia (CIP), persistent tachypnea of infancy withneuroendocrine cell hyperplasia (PTI), pulmonary intersti-tial glycogenosis (which may simply be a better histologicdescription of CIP), and surfactant protein deficiencies7,9.Of note is the tremendous overlap between the surfactantprotein deficiencies and the other categories of ILD ininfancy and childhood. A growing number of studies impli-cate surfactant protein (SP)-B and C gene mutations in avariety of adult ILDs (UIP, DIP, NSIP) and pediatric ILDs(CIP, CPI)19–24. The following sections will focus on thevarious classes of pediatric ILDs, but it should be kept inmind that despite the histologic differences seen, it is pos-sible that surfactant protein dysfunction plays a role in thepathogenesis of many of them.

Chronic Pneumonitis of Infancy (CPI)

First described by Katzenstein et al.25 in 1995, CPI ischaracterized by marked alveolar septal thickening,

A BFigure 12-4 (A) An area of organizing pneumonia from child with BOOP secondary to SLE. Notethe fibroblastic cells forming an airway plug at top center (hematoxylin and eosin, ×200). (B) Trichromestain showing collagen deposition with a fibroblastic plug (Masson trichrome stain, ×200).


hyperplasia of type 2 pneumocytes and an alveolar exudatecontaining macrophages and eosinophilic debris. Althoughinflammatory cells are not commonly seen, Katzenstein et al. felt that this histologic picture best reflected slowlyresolving pneumonia in immature lungs. Children with CPIpresent early in life; symptoms may begin as early as 2weeks of age and virtually all infants with CPI have symp-toms by 1 year of age. Presenting symptoms are non-spe-cific and typical for a child with chronic lung disease:cough, respiratory distress, and failure to thrive. Outcomewas not good in the original cohort. Of 8 patientsdescribed 4 died, 1 underwent lung transplantation, and 3 had residual severe respiratory impairment. Non-surgicaltherapy included corticosteroids and hydroxychloroquine,neither of which produced dramatic results.

More recently, the marked type 2 pneumocyte hyper-plasia seen in CPI has led some to question if it is a form ofcongenital SP-C dysfunction and not the result of an infec-tious disease. This is supported by the familial nature of theillness in 2 of the 8 originally described cases.

Cellular Interstitial Pneumonia (CIP)

CIP presents with respiratory distress, tachypnea,“Velcro-like” crackles on examination, and hypoxemia.Schroeder et al.26 noted that symptoms generally presentin the first few days of life. In fact, our experience hasbeen that children with CIP may be initially diagnosed ashaving transient tachypnea of the newborn only to havethat diagnosis rescinded when it becomes apparent thatthe tachypnea is not at all transient.

Chest radiographs show a bilateral, diffuse interstitialpattern and CT scans confirm these finding (Figure 12-5).We have found this presentation so uniform and com-pelling that we move quickly to lung biopsy to confirm

Figure 12-5 Chest radiograph from a 1-month-old child withcellular interstitial pneumonia (CIP). There is a diffuse increase ininterstitial markings without focal infiltrates.

the diagnosis in children presenting in this manner.Obviously, other causes of tachypnea and cough in thenewborn such as cystic fibrosis, aspiration, tracheo-esophageal fistula, and neonatal infection must be ruledout before proceeding to biopsy.

Lung biopsies in children with CIP show a diffuseinterstitial process occupying the intra-alveolar septa(Figure 12-6). The infiltrate is comprised mostly of histio-cytes but lymphocytes are also present. Spindle-shapedhistiocytes in the interstitium are common. Generally,there is no increase in collagen and no fibrosis, and type2 pneumocytes are not hyperplastic; this is in markedcontrast to findings in CPI.

The prognosis in CIP is quite good. Children with thisprocess respond to oral corticosteroids and/or hydroxy-chloroquine and we have even had success with inhaledcorticosteroids in one case (unpublished). Because ofthe small number of known cases and reports of the useof non-randomized, anecdotal therapy regimens it isunclear whether the primary therapy for CIP should besteroids, hydroxychloroquine or supportive care await-ing spontaneous resolution of the disease. Althoughthere is no definitive therapy, most pediatric pulmo-nologists do treat these infants with anti-inflammatorydrugs and most children show improvement over thefirst few years of life.

Pulmonary Interstitial Glycogenosis (PIG)

A variant of neonatal ILD called pulmonary interstitialglycogenosis (PIG) has been described by Canakis et al.27. There is much in common between PIG and CIPincluding presentation very early in life, interstitialchanges on chest radiographs, and expansion of theinterstitium with spindle-shaped histiocytes. Canakis et al. also found glycogen in cells in the interalveolarsepta (Figure 12-7). Since this is not normally present inthese cells, the authors postulated a developmentalabnormality in differentiation of mesenchymal cells. Thelight microscopic and clinical findings are very similarwhen comparing PIG and CIP. However, sinceSchroeder et al. did not look for glycogen in biopsiesfrom their patients with CIP it is unknown whetherthese two entities are one-and-the-same or are two sepa-rate diseases. It is not surprising that the children withPIG showed the same good response to corticosteroidsand hydroxychloroquine as seen in CIP. Further studies onboth existing and newly diagnosed cases of CIP and PIGwill need to be done to determine whether these are twodistinct classes of ILD or two descriptions of one entity.

Persistent Tachypnea of Infancy (PTI)

Another of the milder forms of ILD in infants is per-sistent tachypnea of infancy (PTI)28. Patients with PTI do


A BFigure 12-6 Histology of CIP. (A) Hypercellularity of alveolar walls is evident. (B) Higher magnification demonstrates the presence of histiocytes and spindle-shaped cells in the alveolarsepta (hematoxylin and eosin).

A B

C

Figure 12-7 Histologic picture of pulmonary interstitial glycogenosis from a 3-month-old infant.(A) Diffuse interstitial thickening. (B) Higher-magnification view of interalveolar septa. Arrowsdemonstrate round and spindle-shaped cells with pale cytoplasm. (C) Periodic acid–Schiff stainshows massive amounts of glycogen (arrow). (Reproduced with permission from Canakis AM, et al.Pulmonary interstitial glycogenosis. Am J Respir Crit Care Med 165:1557–1565, 2002.)


Figure 12-8 Lymphoid interstitial pneumonia (LIP) caused byEpstein–Barr virus infection. The interstitium is expanded andfilled with lymphocytes and occasional plasma cells. Normal lungarchitecture is completely lost. Lymphocyte marker studiesshowed polyclonality, typical of LIP and inconsistent with tumor.

not have significant cough but do have marked tachyp-nea, retractions, crackles, and hypoxemia presenting inthe first year of life. Hyperinflation and increased inter-stitial markings are seen on chest X-ray films. Lungbiopsy demonstrates mild increase in airway smoothmuscle, increased alveolar macrophages, and increasedepithelial cells within the distal airways, which are neu-roendocrine in origin. Children with this disorder do nothave a striking response to corticosteroid therapy but do show mild improvement over time. Supplementaloxygen may be required for months to years.

Follicular Bronchiolitis (FB)

Follicular bronchiolitis is another milder form of ILD,which has been described in adults and children29,30. FBpresents similarly to CIP and PTI with tachypnea, crack-les, and diffuse interstitial findings on chest imagingstudies. Histologically, FB is characterized by lymphoidproliferation resulting in hyperplastic follicles ofbronchus-associated lymphoid tissue that compress thesmall intrathoracic airways. FB generally presents in thefirst 2 months of life and then slowly resolves over the next 2–4 years, although older children may be leftwith mild obstructive disease. FB does not appear to beresponsive to steroid therapy.

Lymphocytic Interstitial Pneumonia (LIP)

LIP in childhood is most frequently seen in combina-tion with HIV/AIDS17. LIP was seen commonly in the1980s prior to the advent of highly active anti-retroviraltherapy (HAART) for children with HIV infections.Histologically, LIP in children is essentially the same as inadults. The hallmark of LIP is a monotonous polyclonallymphocytic infiltration of the interalveolar septa. Theincidence of LIP is markedly lower in the era of HAARTtherapy for HIV infection, but LIP must still be consid-ered in the differential diagnoses of unexplained respira-tory disease in a child with AIDS. Other viruses can leadto a lymphocytic infiltration of alveolar walls and casereports exist of infants and young children with EBV-associated LIP31. Figure 12-8 shows the histologic changesseen in a teenage girl with LIP caused by EBV infection.This child presented with a sub-acute history of fever,night sweats, and increasing shortness of breath.Therapy with corticosteroids (without anti-viral agents)proved beneficial.

Surfactant Protein Diseases

Although they comprise a relatively small percentageof the entire surfactant moiety, surfactant proteins B andC (SP-B, SP-C) play a vital role in the spreading, adsorp-tion, and stability of surfactant19,20. These small proteins

(SP-B is 79 amino acids long and SP-C is 33–34 aminoacids long) are necessary for normal surfactant functionand consequent alveolar integrity. Lack of pulmonarysurfactant due to prematurity, aspiration, lung injury, ormutations in surfactant genes causes respiratory failure.

Knock-out mice lacking the SP-B gene develop respi-ratory failure immediately after birth. Analogously, thereare reports of infants homozygous for a mutation in SP-Bproduction who have respiratory failure unresponsive tostandard therapies including exogenous surfactantadministration. Infants with these mutations present inrespiratory distress in the first 24–48 hours of life withclinical findings consistent with surfactant deficiency. SP-B deficiency is generally inherited as an autosomalrecessive mutation and carriers of one mutation do nothave clinically apparent lung disease. Although completeSP-B deficiency is associated with respiratory failure anddeath in the newborn period, uncommon mutationswhich cause a partial deficiency have been associatedwith chronic ILD in childhood21. Histologically such dis-orders may show accumulation of extracellular proteins,epithelial cell dysplasia, and pulmonary fibrosis.

SP-C is a very highly hydrophobic protein and accountsfor about 4% of surfactant by weight. It enhances thespreading and stability of surfactant phospholipids. It mayalso play a role in routing, processing, and trafficking ofother proteins. Light and electron microscopy frompatients with SP-C deficiency shows atypia and hyper-plasia of alveolar type 2 cells with numerous abnormallamellar bodies and thickened alveoli. An inflammatoryhypercellularity consisting of lymphocytes, plasma cellsand peribronchial lymphoid aggregates may be seen.Therapy for SP-C deficiency is not standardized at present.


Table 12-2 Clinical Presentation of ILD

Cough 77%Dyspnea 71%Exercise intolerance 65%Crackles 60%Tachypnea 54%Onset of symptoms in first year of life 50%Retractions 46%Frequent respiratory tract infections 44%Wheeze 40%Failure to thrive 35%Clubbing 29%Cyanosis 19%

(From Fan and Langston4 and Fan et al.5)

100

50

PO

2 m

m H

g

00 .25

Exercise

Alveolar

Normal

Abnormal

Grossly abnormal

.50 .75

Figure 12-9 Oxygenation of blood as it passes through a pul-monary capillary when diffusion is normal or abnormal. Whenblood spends a full 0.75 seconds in the capillary PO2 may be normaleven if diffusion is decreased by an interstitial disease. However,under conditions that increase cardiac output (exercise), blood PO2cannot reach normal levels in the diseased lung. Normal PO2 cannotbe achieved even at rest in the grossly abnormal lung. (Reproducedwith permission from West JB. Respiratory physiology, the essen-tials. Philadelphia: Lippincott, Williams & Wilkins, 2000.)

There have been reports of success with both oralsteroids and hydroxychloroquine in adults and childrenwith SP-C deficiency.

Mutations in the SP-C gene have been linked to famil-ial forms of ILD22–24. Interestingly, adults and children inthese kindreds have carried a variety of diagnoses, notnecessarily consistent within one family. The fact thatpeople with abnormalities in SP-C production have vari-ously been said to have UIP, DIP, NSIP, LIP, and CIPleads to the obvious question: Are surfactant protein defi-ciencies the common cause of many “idiopathic” ILDs?Amin et al.22 reported a kindred with SP-C deficiencyincluding three affected members said to have NSIP, IPF,and LIP. In this study, the investigators looked at surfac-tant proteins in bronchoalveolar lavage (BAL) fluid andused older adults with IPF as a control group. Althoughall three family members had low levels of SP-C in BALfluid, the IPF patients in the control group all had normalamounts of surfactant proteins in BAL fluid. Clearly,then, SP-C deficiency does not account for all cases of ILD. However, the idea that many forms of ILD cur-rently considered disparate may in fact be related at amolecular level is tantalizing.

Diagnosis and Treatment of ILD

Children with ILD present with a constellation ofsigns and symptoms generally including shortness ofbreath, dyspnea with exercise (which in the very younginfant may mean dyspnea with feeding), hypoxemia,tachypnea, retractions, and crackles on auscultation(Table 12-2). The majority of children with idiopathicILD present in the first year of life4,32 and in these infan-tile forms tachypnea is the most common presentingsymptom with crackles the most common auscultatoryfinding. Babies with ILD often have low pulse oximetry,too, but in milder cases normoxia can be maintained at

rest. Since the amount of time the red blood cell spendsin the pulmonary capillary is crucial for oxygenation ininterstitial diseases, anything that increases red cell transittime (i.e., increased cardiac output) can unmask hypox-emia that is not evident at rest (Figure 12-9). In our clinicwe often have older children walk or run up and downa corridor and monitor pulse oximetry during exercise.Infants have pulse oximetry monitored while feeding.

The crackles in children with ILD tend to be diffuse,fine and “Velcro-like” in nature. Any child with tachyp-nea and crackles should be suspected of having ILDalthough cystic fibrosis, aspiration due to swallowingdysfunction or gastroesophageal reflux disease, and car-diac disease are more common causes of these symptoms.A chest roentgenogram should be obtained in order tolook for increased interstitial markings. Plain chest X-rayfilms are not as sensitive as CT scans; a normal chest radi-ograph does not rule out the diagnosis of ILD. A CT scanof the chest should be obtained in any child for whomthe diagnosis is suspected. In virtually all cases whereinterstitial disease is seen on the CT scan a lung biopsywill be needed to make an accurate diagnosis. It isimportant to get an adequate sample of tissue for all thetests that may need to be performed, including electronmicroscopy, standard light microscopy stains, stains forfibrin and collagen, and stains for hemosiderin and lipid-laden macrophages, exhaustive microbiology studies,and flow cytometry. Thus, the small sample obtained by


Table 12-3 Causes of Secondary Interstitial LungDiseases

Collagen vascular diseasesSystemic lupus erythematosusJuvenile rheumatoid arthritisSjögren syndrome

VasculitisPulmonary renal syndromes

Wegener’s granulomatosisSystemic lupus erythematosusGoodpasture syndrome

Cardiovascular disordersTotal or partial anomalous pulmonary venous returnCor triatriatumHereditary hemorrhagic telangiectasia

Inflammatory bowel diseaseAspiration syndromes

Swallowing dysfunctionGastroesophageal reflux diseaseTracheo-esophageal fistulaLipid aspiration (lipoid pneumonia)

InfectionsEpstein–Barr virusHIVMycoplasmaImmunoglobulin G-subclass deficiency

OtherDust/sand inhalation (chronic)NeurofibromatosisSarcoidosisTuberous sclerosis

Table 12-4 Partial List of Drugs Reported to Cause ILD

Amiodarone GoldActinomycin D MethotrexateBleomycin MitomycinBusulfan NitrofuantoinCephalosporins PenicillamineChlorambucil PhenytoinCyclophosphamide SulfamethoxazoleDocetaxel Sulfasalazine

transbronchial biopsy is not adequate and open or tho-racoscopic biopsy is necessary. Making a specific diag-nosis has therapeutic and diagnostic implications andshould be pursued vigorously. Of particular importanceis ruling out non-idiopathic and treatable causes of ILDsuch as infection, aspiration, or rheumatoid disease.Blood tests for defects in the surfactant protein genes areavailable on a research basis. Even with a biopsy, how-ever, a large percentage of cases cannot be neatly placedinto one of the previously mentioned ILD categories.

Treatment of idiopathic ILD depends in part onwhich form of the disease one is dealing with. CIPresponds well to steroids and hydroxychloroquine, butFB does not. LIP may require therapy with steroids andacyclovir if secondary to EBV infection. Surfactant proteindeficiencies do not have specific therapies at present.Corticosteroids (2 mg/kg/day initially) remain the main-stay of therapy for many of the ILDs. Unfortunately, ther-apy may need to be continued for prolonged periods oftime (months or more) leading to undesirable sideeffects. Intravenous pulse therapy with methylpred-nisolone is an alternative way to treat ILD. High doses ofsteroids are given at monthly intervals, generally 10–30mg/kg up to a maximum of 1 g, for at least 3 months.After this initial therapy, pulses can be used intermit-tently for flares of the disease or continued monthly asneeded. Pulse therapy has the advantage of limitingsteroid-related side effects but requires monthly intra-venous infusions for 3 days. Placement of an indwellingcentral catheter for children needing long-term therapyallows for home therapy.

Hydroxychloroquine (10 mg/kg/day) alone or in com-bination with steroids has significant efficacy for somechildren with ILD and can act as a steroid sparing agent.Hydroxychloroquine can cause retinal problems andchildren receiving it must have periodic ophthalmologicexaminations. As opposed to adult ILDs, therapy withsteroids or hydroxychloroquine, singly or in combina-tion, can lead to excellent outcome in infants with ILD32.Other drugs used in the therapy of ILD includecyclophosphamide, azathioprine, and methotrexate.

Secondary Forms of ILD

A variety of other diseases and chemical exposures(including medications) can lead to lung disease consist-ing of interstitial changes and abnormalities in gasexchange. A full discussion of these diseases is beyondthe scope of this chapter, but a partial list of diseases andchemical agents which can cause ILD are included inTables 12-3 and 12-4. The non-pulmonary diseases mostcommonly associated with ILD are inflammatory innature (e.g., vasculitis, rheumatoid diseases, inflamma-tory bowel disease) or cardiac diseases which lead topulmonary venous engorgement. In addition, many

drugs can cause ILD although relatively few are used inotherwise well children.

Cardiac disease that causes pulmonary vascular prob-lems represents up to 9% of children originally felt tohave ILD33. Occlusion of return of pulmonary blood flowto the left atrium leads to pulmonary venous congestionand interstitial changes. The most common cause of thisproblem is total or partial anomalous pulmonary venousreturn. Cor triatriatum, in which there is a fibromuscu-lar membrane which subdivides the left atrium into a


MAJOR POINTS

1. Pediatric interstitial lung diseases consist of adiffuse group of diseases which are distinct fromthe adult forms of ILD.

2. Any child with tachypnea, crackles, andhypoxemia should be evaluated for ILD.

3. The prognosis in pediatric ILD is better than in theadult form of the disease.

4. Therapy consists of supportive care and anti-inflammatory drugs.

5. Surfactant protein defects may underlie many of the ILDs.

�

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posterosuperior chamber that receives blood from thepulmonary veins and an anteroinferior chamber which isthe true left atrium, also leads to increased pulmonaryvascular pressures and interstitial changes34. Cor triatria-tum should be considered in any child with unexplainedtachypnea. Diffuse pulmonary vascular malformationssuch as hereditary hemorrhagic telangiectasia may alsomimic ILD.

Inflammatory bowel disease can be seen in associa-tion with BOOP or granulomatous lung disease35,36. Thevasculitides which cause pulmonary-renal syndrome(Goodpasture syndrome, Wegener’s granulomatosis, sys-temic lupus erythematosus [SLE]) often present withacute pulmonary hemorrhage37. However, the earliestlung changes can consist of interstitial granuloma forma-tion and a picture clinically indistinguishable from someforms of ILDs.

Finally, chronic aspiration and infection can lead toILD-like changes in the pulmonary parenchyma. Childrensuspected of having ILD should be evaluated for cysticfibrosis, swallowing dysfunction, gastroesophagealreflux disease, and immune defects prior to undergoinglung biopsy38.

SUMMARY

Interstitial lung disease is an uncommon problem inpediatrics. There are a large number of sub-classes ofILD; the current classification schemes are cumbersomeand at times confusing with inconsistent use of adult andpediatric categories. Because these diseases are rare andill-defined, tissue diagnosis is necessary in most cases.Although the early literature portrayed these diseases ashaving poor prognosis, more recent studies demonstratethat in some forms of ILD the outlook is quite good withtherapy and occasionally even without therapy.

REFERENCES

1. Katzenstein ALA, Myers JL. Idiopathic pulmonary fibrosis:clinical relevance of pathologic classification. Am J RespirCrit Care Med 157:1301–1315, 1998.

2. Gross TJ, Hunnighake GW. Idiopathic pulmonary fibrosis.N Engl J Med 345:517–525, 2001.

3. King TE Jr., et al. Idiopathic pulmonary fibrosis: diagnosisand treatment. Am J Respir Crit Care Med 161:646–664,2000.

4. Fan LL, Langston C. Chronic interstitial lung disease inchildren. Pediatr Pulmonol 16:184–196, 1993.

5. Fan LL, et al. Clinical spectrum of chronic interstitial lungdisease in children. J Pediatr 121:867–872, 1992.

6. Dinwiddie R, Sharief N, Crawford O. Idiopathic interstitialpneumonitis in children: a national survey in the UnitedKingdom and Ireland. Pediatr Pulmonol 34:23–29, 2002.

7. Fan LL, Langston C. Pediatric interstitial lung disease: child-ren are not small adults. Am J Respir Crit Care Med 165:1466–1467, 2002.

8. Langston C, Fan LL. The spectrum of interstitial lung dis-ease in childhood. Pediatr Pulmonol Suppl 23:70–71, 2001.

9. Langston C, Fan LL. Diffuse interstitial lung disease ininfants. Pediatr Pulmonol Suppl 23:74–76, 2001.

10. Fan LL, et al. Evaluation of a diagnostic approach to pedi-atric interstitial lung disease. Pediatrics 101:82–85, 1998.

11. Nicholson AG. Classification of idiopathic interstitial pneu-monias: making sense of the alphabet soup. Histopathology41:381–391, 2002.

12. Liebow AA. Definition and classification of interstitial pneumonias in human pathology. Prog Respir Res 8:1–31,1975.

13. Olson J, Colby TV, Elliott CG. Hamman–Rich syndromerevisited. Mayo Clin Proc 65:1538–1548, 1990.

14. Ziesche R, et al. A preliminary study of long term treatmentwith interferon gamma-1b and low dose prednisolone inpatients with idiopathic pulmonary fibrosis. N Engl J Med341:1264–1269, 1999.

15. Askin FB. Back to the future: the Hamman–Rich syndromeand acute interstitial pneumonia. Mayo Clin Proc 65:1624–1626, 1990.

16. Katzenstein ALA, Fiorelli RF. Nonspecific interstitial pneu-monia/fibrosis: histologic features and clinical signifi-cance. Am J Surg Pathol 18:136–147, 1994.

17. Swigris JJ, et al. Lymphoid interstitial pneumonia: a narra-tive review. Chest 122:2150–2164, 2002.

18. Nicholson AG, et al. The value of classifying interstitialpneumonia in childhood according to defined histologicpatterns. Histopathology 33:203–211, 1998.

19. Whitsett JA. Genetic basis of familial interstitial lung dis-ease: misfolding or function of surfactant protein C. Am J Respir Crit Care Med 165:1201–1204, 2002.

20. Whitsett JA, Weaver TE. Hydrophobic surfactant proteins inlung function and disease. N Engl J Med 347:2141–2148,2002.


21. Nogee, LM, et al. Allelic heterogeneity in hereditary surfac-tant B (SP-B) deficiency. Am J Respir Crit Care Med 161:973–981, 2000.

22. Amin RS, et al. Surfactant protein deficiency in familialinterstitial lung disease. J Pediatr 139:85–92, 2001.

23. Nogee LM, et al. A mutation in the surfactant protein Cgene associated with familial interstitial lung disease. N Engl J Med 344:573–579, 2001.

24. Thomas AQ, et al. Heterozygosity for a surfactant protein-C gene mutation associated with usual interstitial pneu-monitis in one kindred. Am J Respir Crit Care Med165:1322–1328, 2002.

25. Katzenstein ALA, et al. Chronic pneumonitis of infancy.Am J Surg Pathol 19:439–447, 1995.

26. Schroeder SA, Shannon DC, Mark EJ. Cellular interstitialpneumonitis in infants: a clinicopathologic study. Chest101:1065–1069, 1992.

27. Canakis AM, et al. Pulmonary interstitial glycogenosis. AmJ Respir Crit Care Med 165:1557–1565, 2002.

28. Deterding RR, et al. Persistent tachypnea of infancy (PTI)—a new entity. Pediatr Pulmonol Suppl 23:72–73,2001.

29. Kinane TB, et al. Follicular bronchitis in the pediatric population. Chest 104:1183–1186, 1993.

30. Howling SJ, et al. Follicular bronchiolitis: thin-section CTand histologic findings. Radiology 212:637–642, 1999.

31. Mueller GA, Pickoff AS. Pediatric lymphocytic interstitialpneumonitis in an HIV-negative child with pulmonaryEpstein–Barr virus infection. Pediatr Pulmonol 36:447–449,2003.

32. Dinwidie R, Sharief N, Crawford O. Idiopathic interstitialpneumonitis in children: a national survey in the UnitedKingdom and Ireland. Pediatr Pulmonol 34:23–29, 2002.

33. Sondheimer HM, et al. Pulmonary vascular disorders mas-querading as interstitial lung disease. Pediatr Pulmonol20:284–288, 1995.

34. Howowitz MD, et al. Cor triatriatum in adults. Am Hear J 126:472–474, 1993.

35. Camus P, et al. The lung in inflammatory bowel disease.Medicine 72:151–183, 1993.

36. Al-Binali AM, et al. Granulomatous pulmonary disease in achild: an unusual presentation of Crohn’s disease. PediatrPulmonol 36:76–80, 2003.

37. O’Sullivan BP, Erickson LA, Niles JL. Case records of theMassachusetts General Hospital: Case 30-2002. N Engl J Med 347:1009–1017, 2002.

38. Popa V, Colby TV, Reich SB. Pulmonary interstitial diseasein Ig deficiency. Chest 122:1594–1603, 2002.

194

CHAPTER

13 PulmonaryComplications ofNeuromuscularDiseaseJULIAN L. ALLEN, M.D.

Common Neuromuscular Diseases of Childhood

and Adolescence

Upper Versus Lower Motor

Neuron Disease

Lower Motor Neuron Diseases

Muscular Dystrophies

Myasthenia Gravis

Charcot Marie Tooth Disease

Spinal Muscular Atrophy

Combined Upper and Lower Motor

Neuron Disease

Spina Bifida

Spinal Cord Injury

Upper Motor Neuron Disease

Cerebral Palsy

The Respiratory Muscles and Chest Wall:

Normal Function

Diaphragm

Intercostal Muscles

Abdominal Muscles

Upper Airway Muscles

Swallow Function

Cough Mechanism

Chest Wall Function

Compliance

Chest Wall Motion

The Respiratory Muscles and Chest Wall

in Neuromuscular Disease

Strength

Fatigue

Chest Wall in Neuromuscular Disease

Chest Wall Motion

Chest Wall Compliance

Scoliosis

Upper Airway Obstruction

Swallowing Dysfunction

Cough

Evaluation of the Patient with Neuromuscular Disease

History


Chest Radiograph


Special Studies

Arterial Blood Gas, Oxygen Saturation, End-Tidal CO2

Nocturnal Polysomnography

Swallow Function Studies

Respiratory Inductive Plethysmography

Test of Respiratory Muscle Fatigue

Prevention and Treatment of Respiratory Complications

of Neuromuscular Disease

General Supportive

Nutrition

Vaccines

Team Approach to Care

Swallowing Disorders and Aspiration

Prevention of Aspiration

Pneumonia and Atelectasis

Respiratory Muscle Function

Strength: Role of Rest and Training

Fatigue

Pulmonary complications are common in pediatric neu-romuscular diseases, and represent the leading cause ofdeath in many of them. These complications are prevent-able and treatable, however, and aggressive diagnosis andtreatment can in many cases increase life expectancy.Pulmonary complications often arise from final pathwayscommon to neuromuscular diseases as a whole, althoughcertain complications are unique to various disorders. Thischapter will summarize the major characteristics of neuro-muscular diseases likely to lead to pulmonary disorders, dis-cuss the physiology and pathophysiology of how suchpulmonary complications arise, and discuss an approach totheir evaluation, prevention and treatment.

Pulmonary Complications of Neuromuscular Disease 195

34

5

2

1Striated muscle

LMN

6UMNKEY1 muscle disease, e.g. MD

2 neuromuscular junction, e.g. myastheniagravis

3 peripheral neuropathy, e.g. CharcotMarie Tooth

4 lower motor neuron disease, e.g. SMA

5 spinal cord injury, e.g. spina bifida

6 upper motor neuron disease, e.g. CP

Spinal cord

Figure 13-1 Upper motor neuron (UMN) and lower motor neuron (LMN) diseases: site of lesion.

COMMON NEUROMUSCULAR DISEASESOF CHILDHOOD AND ADOLESCENCE

Upper Versus Lower Motor Neuron Disease

Neuromuscular disorders can broadly be divided intodiseases that affect the muscle, the lower motor neuron,and the upper motor neuron (Figure 13-1). Diseases thataffect the muscle and the lower motor neuron usually leadto flaccid and hypotonic muscles (with certain excep-tions, e.g., myotonic dystrophy) and diminished deep ten-don reflexes. Diseases that affect the upper motor neuronusually lead to hypertonic muscles and hyperactive deeptendon reflexes due to release of inhibitory impulses fromthe upper motor neuron. Both disorders lead to muscleweakness on voluntary contraction.

Lower Motor Neuron Diseases

Muscular DystrophiesMuscular dystrophies are characterized by progres-

sive muscular weakness starting in infancy or childhood.Duchenne muscular dystrophy (MD) is the second mostfrequent lethal genetic disorder in humans, has an inci-dence of 1:3500 male births, with a carrier frequency of1 in 2000, and is inherited as an X-linked recessive dis-ease. New mutations in the dystrophin gene account for30% of cases. Boys with Duchenne MD typically presentas toddlers with mild muscle weakness, waddling, andfrequent falling. They gradually lose motor milestones sothat by the time they are in elementary school they oftenneed braces and by middle school, progress to needingwheelchairs. Pseudohypertrophy, especially of the calf

muscles, and an elevated CPK are highly suggestive ofthis disorder. Mean age of death is 20 years, usually fromprogressive cardiac or respiratory disease. DuchenneMD is a multisystem disorder, causing a skeletal myopa-thy, encephalopathy with behavioral disorders and cog-nitive defects, cardiomyopathy, and dysfunction of thesmooth muscle of the vessels and gastrointestinal tract.The disease is caused by mutations in the dystrophingene at the Xp21 locus. Diagnosis can be made by mus-cle biopsy or DNA mutation analysis. Becker MD pres-ents in a similar fashion to Duchenne MD, and is causedby a different deletion of the same gene, but is generallymilder and presents later. While the mean age at whichpatients with Duchenne MD become wheelchair-dependent is 11 years, patients with Becker MD remainambulatory until age 16 years. Treatment with pred-nisone may delay the age at which these patientsbecome wheelchair-dependent.

Table 13-1 lists the other various common musculardystrophies. Limb girdle MD can present as an autosomaldominant, an autosomal recessive or an X-linked disorder.Myotonic dystrophy is characterized by distal weakness,inability to relax muscle contractions, and prematureaging and anesthetic deaths. Its mode of inheritance isautosomal dominant. Congenital myotonic dystrophypresents in a biphasic fashion, characterized by poor suckand respiratory effort, but transient improvement after theneonatal period. Other congenital myopathies includenemaline myopathy, central core disease and centronu-clear myopathy. Nemaline myopathy is characterized byvariable onset and severity, ptosis, bulbar weakness,sleep hypoventilation, and autosomal dominant or reces-sive inheritance. Central core disease can present withmalignant hyperthermia.

Myasthenia GravisMyasthenia gravis presents in an acquired, immune-

mediated form, with circulating antibodies to the acetyl-choline receptor on striated muscle. A congenitalmyasthenic syndrome also exists, caused by maternalantibodies. Myasthenic disorders are characterized byptosis, ophthalmoparesis, bulbar weakness causing aspi-ration, and limb girdle weakness. They may be episodic.

Table 13-1 Common Muscular Dystrophies of Childhood

Duchenne muscular dystrophyBecker muscular dystrophyFascioscapulohumeral dystrophyLimb girdle muscular dystrophyCongenital muscular dystrophyEmery–Dreyfuss muscular dystrophyMyotonic dystrophy


Diagnostic characteristics include increasing fatiguewith repetitive stimulation and improved strength withedrophonium (tensilon). Treatment includes immunesuppression and thymectomy.

Charcot Marie Tooth DiseaseCharcot Marie Tooth disease presents with a distal

neuropathy, characteristically affecting the peronealnerve, and resulting in pes cavus and foot drop. Bulbarneuropathy can rarely occur. Characteristic changes areseen on the electromyogram (EMG) and nerve conduc-tion velocity studies.

Spinal Muscular AtrophySpinal muscular atrophy is the most common fatal

neuromuscular disease of infancy with an incidence of1:18,000 to 25,000. It is inherited as an autosomal reces-sive disorder, and its gene has been localized to chromo-some 5q11-q13. Two candidate genes have been cloned:the survival motor neuron genes SMN1 and SMN2, andthe neuronal apoptosis inhibitory protein (NAIP) gene.SMA is a genetic disease of the anterior horn cell causingdegeneration of the alpha motor neuron. Diagnosis iscommonly made by muscle biopsy and EMG; CPK levelsare normal. The most common form, Type I SMA(Werdnig–Hoffman disease) has its onset before 6 monthsof age. Infants present with floppiness, weak cry, andfeeding and breathing problems; they cannot sit andoften they are noted to have diminished fetal movementsin utero. Type I SMA is rapidly progressive, and infantsusually die in the first 2 years of life without ventilatorysupport of some kind. Type III SMA (Kugelberg–Welanderdisease) presents later in life, frequently in the second orthird year, and is more slowly progressive, with patientsfrequently able to walk and to live beyond the thirddecade. These children present with gait disturbances,scoliosis and muscle fasciculations. Type II SMA has anintermediate course between Types I and III; patientscan sit but not walk alone, and with medical interven-tion frequently survive to the second or third decade.

Combined Upper and Lower Motor Neuron Diseases

Spinal cord lesions can cause upper motor neuroninjury to the nerves passing through the long tracts atthe level of the lesion, and lower motor neuron injury atthe level of the injury itself.

Spina BifidaSpina bifida with meningomyelocele is a congenital

disorder which can affect any spinal level. It is one of themost common developmental disorders of the centralnervous system, with an incidence of 0.2–0.4/1000 livebirths. It most commonly affects the lumbosacral spine,and can be associated with Arnold–Chiari malformation ofthe brainstem. The higher the level of spinal involvement,

the more likely it is to affect the muscles of respiration.Urinary retention and constipation in these patients cancause significant abdominal distension and worsen a pul-monary restrictive defect by pushing up on thediaphragms.

Spinal Cord InjurySpinal cord injury resulting from trauma that causes

vertebral fractures, crush or compression injuries canoccur at any level. Lesions from C3 to C5, resulting intetraplegia, affect diaphragmatic function by interrupt-ing phrenic nerve traffic and also affect the intercostalmuscles whose innervation is below the level of thelesion (T1–T12). Lesions between T1 and T12 result inprogressively less severe respiratory muscle weakness,as the lesion level is lowered and the motor injury con-verts from tetraplegia to paraplegia. These patients canhave impaired cough mechanisms, however, since theinnervation of the expiratory abdominal muscles arisesfrom T5 to L1. Lesions below T12, resulting in paraple-gia, have little effect on the respiratory muscles or thoseinvolved in the cough reflex.

Upper Motor Neuron Diseases

Cerebral PalsyCerebral palsy results from a wide range of neonatal

brain insults. It is more common in infants born prema-turely with complicated neonatal courses, and can be aconsequence of periventricular leukomalacia or intraven-tricular hemorrhage, especially of the more severe vari-eties (grades III and IV). Occasionally it is seen in childrenwithout obvious neonatal brain injury. While the musclesare weak, they may be hypertonic and hyper-reflexic.However, many of the pulmonary complications are simi-lar to those of diseases due to lower motor neuron disease,and result from weak ineffective cough and uncoordinatedswallowing mechanisms leading to aspiration.

THE RESPIRATORY MUSCLES ANDCHEST WALL: NORMAL FUNCTION

Diaphragm

The diaphragm’s action as a piston that decreasesintrapleural pressure is its best-known mechanism. Twoother mechanisms assist the diaphragm in its inspiratoryaction. The area of apposition of the diaphragm againstthe inner chest wall (Figure 13-2) places its fibers in a ver-tical orientation, which, when acting on the downward-declinated lower ribs, lifts them up and out in what istermed the “bucket handle effect.” In addition, a signifi-cant portion of the abdomen actually lies within the ribcage; the positive intra-abdominal pressure during inspi-ration thus helps expand the lower rib cage. These latter


two mechanisms are less effective in young infants and inchildren and adults with obstructive lung disease, inwhom the diaphragms are relatively flat resulting in adiminished area of apposition.

Intercostal Muscles

The intercostal muscles are aided in their inspiratoryand expiratory actions by the direction of orientation oftheir fibers. If their fibers were oriented vertically, theywould exert equal inspiratory and expiratory actions,depending on the point of fixation of the top and bot-tom ribs. The diagonal orientation of the fibers allows forpreferential inspiratory and expiratory activity, depend-ing on the torque developed on the upper and lower ribsbetween which they are inserted. The external inter-costal muscles therefore exert a primarily inspiratoryaction whereas the internal intercostals exert primarilyan expiratory action on the rib cage. Since normallyinspiration is active and expiration is passive, the latterare usually active only during active expiration, such asin exercise or obstructive lung disease.

Abdominal Muscles

Contraction of the rectus abdominis and abdominalobliques increases intra-abdominal pressure and raisesthe diaphragm, thus assisting with expiration. These mus-cles, too, are usually only active during exercise or inpatients with obstructive airway disease. They also serveto preserve the radius of curvature of the diaphragm inpatients with flattened diaphragms due to obstructiveairway disease and air trapping. Thus, they aid thediaphragm’s inspiratory action by increasing the area ofapposition (see above).

Upper Airway Muscles

Although not often considered muscles of respiration,the upper airway muscles contract phasically with inspi-ration, preventing upper airway collapse. This mechanismis dysfunctional in some patients with neuromuscular dis-ease due to upper airway muscle weakness. They canhave upper airway obstruction when asleep, or duringboth sleep and wakefulness. In young healthy infants,partial adduction of the vocal cords (glottic braking) isoften used to slow expiration, thereby maintaining end-expiratory lung volume. When this mechanism is lost ininfants with neuromuscular disease, low end-expiratorylung volume can result in reduced pulmonary oxygenstores and atelectasis.

Swallow Function

Numerous motor neuron groups are involved in theprotection of the airway from aspiration during swallow-ing. Food materials have the potential to go in four direc-tions during swallowing: back out the mouth, out thenose, into the airway and into the esophagus. Since thelatter pathway is the only appropriate one, the functionof these various motor neuron groups is to disable theother three pathways, and enable a successful swallow. Aswallow is initiated by a voluntary action (oral phase), butonce initiated is completed entirely by reflex mecha-nisms (pharyngeal and esophageal phases). During swal-lowing initiation, food is swept backward by the tongue.This action prevents egress of food through the mouth byapposition of the tongue against the palate. The softpalate is elevated, preventing nasopharyngeal aspiration.The trachea is elevated against the epiglottis, preventingaspiration into the airway. (This action is impaired in

Figure 13-2 Functional anatomy of the rib cage. (A) Zone of apposition. (Reproduced with per-mission from: DeTroyer A, Estenne M. Clin Chest Med 9:175–193, 1988.) (B) Bucket-handle effect.(Reproduced with permission from DeTroyer A, Loring SH. Action of the respiratory muscles. In: Macklem PT, Mead J, editors: Handbook of physiology: the respiratory system. Mechanics ofbreathing, sect 3, vol III, part 2, p 453. Bethesda, MD: American Physiological Society, 1986.)


7.5

6.0

4.5

3.0

1.5

Vol

ume

(I)

�30 �20 �10 0

Pressure (cm H2O)

W

w

L

I

40302010

Figure 13-3 Respiratory system pressure–volume (PV) curves inthe normal subject (continuous line) and the patient with neuro-muscular disease (broken lines). Pressure is on the x-axis and vol-ume on the y-axis. The slope of each curve at a given lung volumerepresents the compliance at that volume. Passive end-expiratorylung volume is represented by the point at which outward chestwall recoil is equal and opposite to inward lung recoil (filled cir-cles in normal subject, open circles in patients with neuromuscu-lar disease). L, normal lung curve; W, normal chest wall curve; l, neuromuscular lung curve; w, neuromuscular chest wall curve.(Reproduced with permission from DeTroyer A, Estenne M. Therespiratory system in neuromuscular disorders. In Roussos C, edi-tor. The thorax. Lung biology in health and disease, pp 2177–2212.New York: Marcel Dekker, 1995.)

patients with a tracheostomy, in whom the position ofthe trachea is relatively fixed.) Finally, the pharyngealconstrictors dilate, opening the esophagus to accept thefood bolus, thereby initiating the primary esophagealperistaltic wave. Weakness, spasticity or incoordinationof any of the motor neuron groups involved in swallow-ing can predispose patients with neuromuscular diseaseto aspiration and aspiration pneumonia.

Cough Mechanism

The cough reflex starts with stimulation of irritantreceptors with afferents in the vagus nerve (cranialnerve X). Following inspiration to near total lung capac-ity, closure of the glottis and contraction of the abdomi-nal wall muscles, the glottis is suddenly opened resultingin upward movement of the diaphragm and expulsion ofair at velocities of up to 600 miles per hour (950 km/h).The abdominal muscles involved in developing the driv-ing pressures necessary for cough include the externaloblique (efferent nerves T7–T12), the internal oblique(T7–L1), and the rectus abdominis (T6–T12). Weaknessof the abdominal muscles can significantly reduce theeffectiveness of the cough in clearing the airway of foreignparticles.

Chest Wall Function

ComplianceCompliance is that mechanical property that relates a

structure’s pressure to its volume; the greater thechange in pressure for a given change in volume, thestiffer (more elastic, or less compliant) that structure issaid to be. Both the lungs and the chest wall have theirown elastic properties, and together these determine theelastic properties of the respiratory system (Figure 13-3).There is a normal range for both lung and chest wallcompliance: if the lungs and chest wall are too stiff, theyrequire excess energy demands to perform the work ofbreathing. If the chest wall is too compliant, chest wallmotion will be inefficient when negative intrathoracicpressure causes inspiratory paradoxical inward chest wallmovement. This can result in energy inefficiencies as well.Abnormally high chest wall compliance can also lead toreductions in end-expiratory lung volume (Figure 13-3).

Chest Wall MotionObservation of chest wall motion can provide clues

about underlying lung and chest wall function. Normalchest wall motion is synchronous, that is, the rib cageand abdomen both move outward during inspiration andinward during expiration. Respiratory inductive plethys-mography can provide a quantitative assessment of res-piratory timing mechanics. Two inductance bands areplaced on the torso, one around the rib cage and onearound the abdomen. Motions of the compartments are

translated into an electrical current with output to arecorder. One convenient way to measure timing rela-tionships between the two compartments is to plot ribcage versus abdominal motion in an x–y plot (Figure 13-4).Normal synchronous motion is represented by a straightline with a positive slope, asynchronous motion by vari-ous degrees of “looping” and paradoxical motion by astraight line with a negative slope.

THE RESPIRATORY MUSCLES ANDCHEST WALL IN NEUROMUSCULARDISEASE

Strength

Patients with neuromuscular disease routinely havevarying degrees of respiratory muscle weakness. Theconsequences of inspiratory respiratory muscle weak-ness are wide-ranging. One effect, low tidal volumebreathing, can predispose to atelectasis, decreased vitalcapacity, and a decreased tidal volume to dead spaceratio resulting in carbon dioxide retention. It is oftencharacterized by a rapid respiratory rate. Reduced inspi-ratory muscle strength can also predispose to respira-tory muscle fatigue. Decreased expiratory muscle


m/s�0 m/s�0.71 m/s�1.0 m/s�0.71 m/s�0

ParadoxicAsynchronousSynchronous

RC

AB

Ø�0° Ø�45° Ø�90° Ø�135° Ø�180°

Figure 13-4 Lissajous figures of rib cage (RC) versus abdominal wall (AB) motion. Increasingphase angle, ∅, is an index of increasing thoraco-abdominal asynchrony. For phase angles 0° < ∅ <90°, sin ∅ = m/s; for 90° < ∅ < 180°, ∅ = 180 – μ, where sin μ = m/s. (Reproduced with permission from Allen JL, Wolfson MR, McDowell K, Shaffer TH. Am Rev Respir Dis 141:337–342,1990.)

Pump

Pump Load

Respiratory success

Respiratory failure

Load

Mechanical Factors

Figure 13-5 The ability of the respiratory pump to exceed themechanical load of the respiratory system determines whether res-piratory “success” or failure ensues. (Reproduced with permissionfrom Allen JL. Monaldi Arch Chest Dis 51:230–235, 1996.)

strength reduces the ability to cough effectively, and isresponsible for major morbidity due to inability toremove airway secretions. Respiratory muscle strengthcan be assessed by measuring the pressure that the res-piratory muscles are able to generate against an occlu-sion. Normal values of inspiratory and expiratory musclepressures have been published for both children andadults. Maximal pressure is also dependent on lung vol-ume, as it can be affected by the length–tension curve ofthe respiratory muscles as well as the inward or outwardelastic recoil of the chest wall. Normal values for maxi-mal inspiratory pressures in both children and adultsrange from 80–120 cm H2O; normal values for maximalexpiratory pressure can exceed 200 cm H2O.

Fatigue

Fatigue is defined as the inability to sustain a givenmuscle task after repeated exertions. Patients with neu-romuscular weakness are more likely to develop respira-tory muscle fatigue because the force the musclesgenerate during breathing is a greater percentage of themaximal force they are able to generate. Muscle fatiguecan ultimately lead to task failure, which in the case ofthe respiratory muscles, leads to respiratory failure. Thiscan occur acutely, e.g., in the setting of an aspirationpneumonia, or more insidiously, in which case the failingrespiratory muscles may need to be supported by someform of non-invasive or invasive chronic ventilation. Thedevelopment of respiratory failure ultimately occurswhen there is an imbalance between the load againstwhich the respiratory muscles must act, including elasticand resistive components, and the ability of the respira-tory pump to overcome the load (Figure 13-5).

Chest Wall in Neuromuscular Disease

Chest Wall MotionObservation of chest wall motion (Figure 13-6) can pro-

vide valuable clues to the site and cause of respiratorymuscle weakness. Diaphragmatic weakness results in pas-sive upward motion of the diaphragm as the now domi-nant intercostal muscles develop negative intrathoracicpressure; this results in outward chest wall and inwardabdominal motion during inspiration. Intercostal muscleweakness with sparing of the diaphragm, such as thatseen in patients with spinal cord injuries below C3–5, ischaracterized by inward rib cage and outward abdominalwall motion during inspiration, as the rib cage is suckedinward by the negative intrapleural pressure developedby the contracting diaphragm.


Chest Wall ComplianceInfants with neuromuscular disease often have para-

doxical inward chest wall motion during inspiration, astheir highly compliant rib cage with diminished inter-costal muscle tone responds to negative intrathoracicpressure. High chest wall compliance can also lead todiminished end-expiratory lung volume, as the outwardchest wall recoil is less able to withstand the inward lungrecoil. This, in addition to the effects of low tidal vol-umes mentioned above, can lead to atelectasis andreduced oxygen stores.

Studies have shown that chest wall compliance, whilehigh in infancy, is reduced in adults with neuromusculardisease. This may be due to the long-term effects of lowtidal volume breathing in these patients, leading to con-tractures of the costo-vertebral joints.

ScoliosisNeuromuscular imbalance of the paraspinal muscles

often leads to scoliosis in patients with neuromusculardisorders. Such scoliosis, when severe (greater than 40°or so), can add to the effects of the underlying neuro-muscular disease in diminishing vital capacity and totallung capacity.

Upper Airway Obstruction

Several factors predispose patients with neuromuscu-lar disease to sleep-disordered breathing; one of them isthe development of upper airway obstruction. This canoccur in the setting of obesity characteristic of certainmuscle disorders such as Duchenne MD. However,patients with neuromuscular disease are at an increasedrisk of upper airway obstruction during sleep even in the absence of obesity. The negative intrapharyngealpressures generated by the Bernoulli effects of flowthrough the upper airway will collapse the pharynx and

AB

RC

A B

RC

AB

Intercostal

Chest wall motion: site of weakness

Diaphragm

Figure 13-6 Konno–Mead figures in patients with neuromuscu-lar disease during breathing at rest. The filled circle represents end-expiration. (A) Intercostal weakness. As the abdominal wall (AB)moves out, the rib cage (RC) is drawn inward. (B) Diaphragmaticparalysis. As the rib cage expands the diaphragm moves passivelyupwards and the abdominal wall is drawn inwards.

hypopharynx if the upper airway muscles are too weakto resist this collapsing force. Negative pressure ventila-tion (tank or cuirass) in patients who require assistedventilation due to respiratory failure exacerbates thismechanism by increasing the flows (and Bernoulliforces) through the upper airway.

Swallowing Dysfunction

Since the motor neurons largely responsible for thetiming and sequence of the swallow reflex lie in thebrainstem, swallow dysfunction is usually seen inpatients with lesions affecting the brainstem or descend-ing upper motor neurons that form synapses with thesebrainstem motor neurons. Evaluation and treatment ofswallowing dysfunction are discussed below.

Cough

Since the afferent nerves of the cough reflex passthrough the brainstem and the efferent nerves descend to the level of T6 through L1, lesions in the brainstem or affecting the descending pathways or spinal levels fromT6 to L1 can diminish the effectiveness of cough. The further caudal the lesion is, the less the deleterious effectwill be. Treatment of inadequate cough reflex is discussedbelow.

EVALUATION OF THE PATIENT WITHNEUROMUSCULAR DISEASE

History

The history should focus on aspects of the underlyingillness that would lead to respiratory complications.Ascertain the length of time the patient has beenaffected by neuromuscular disease and its severity; func-tional scores such as the Vignos score1 are helpful. Askabout recurrent pneumonias or episodic pulmonary con-gestion suggesting aspiration. Ask about the quality ofthe patient’s cough—strong or weak. Symptoms such assnoring, which suggest upper airway obstruction,should be sought. Ascertain whether the patient useshome oxygen, nocturnal ventilatory support or cough-assist devices such as manually assisted cough tech-niques or the mechanical in/ex-sufflator. Family historyshould be obtained to help assess the nature of theunderlying neurologic condition, and to ascertain pre-disposition to airway hyper-reactivity apart from thatwhich is related to aspiration. An immunization historyshould be obtained—ask about the influenza vaccine andin young infants, passive respiratory syncytial virus (RSV)immunization. A careful nutritional history should beobtained, including use of nasogastric or gastrostomy tubefeedings. Ask about choking or gagging with feeding,


Table 13-2 Peripheral Muscle Strength

0 No flicker of muscle activity1+ Flicker2+ Able to move with gravity removed (horizontal plane)3+ Moves against gravity4+ Weakness5+ Full muscle strength

Figure 13-7 Chest radiograph of a patient with neuromusculardisease. Note the chronic “bell-shaped” chest, the atelectasis of theright lung due to an aspiration event, and the scoliosis partially corrected by surgery.

and nasopharyngeal aspiration. Gastroesophageal refluxis more common among patients with neuromusculardisease and can predispose to pulmonary aspiration aswell. History of scoliosis and its progression and treat-ment should be obtained.


In addition to the routine physical examination, thereare several special areas to which particular attentionshould be paid. A careful nutritional assessment toinclude height, weight, and body mass index (BMI) per-centiles should be performed. Adequacy of the gagreflex should be ascertained as an index of airway pro-tective mechanisms against aspiration. The patientshould be asked to cough voluntarily, so that assessmentof the cough quality and strength can be made.Respiratory assessment should include, in addition tothorough auscultation of the lungs, observation of chestwall motion, which can provide clues to the site of res-piratory muscle weakness (intercostals versus diaphrag-matic, see “Chest Wall Motion,” above). Presence anddegree of scoliosis should be noted. A careful neurologicassessment, including cranial nerve examination, periph-eral muscle strength (Table 13-2), sensory level, whichcan give clues to level of spinal cord injuries, and deeptendon reflexes, should be performed. Assessment offacial skin breakdown should be made if the patient isbeing treated with non-invasive positive pressure venti-lation through a nasal mask.

Chest Radiograph

The chest radiograph (Figure 13-7) should be evalu-ated for evidence of chronic aspiration. The degree ofscoliosis should be ascertained. The position of thediaphragm should be noted as well as the symmetry ofthe hemidiaphragms. If diaphragmatic paralysis is sus-pected, fluoroscopy is helpful in its demonstration.

Pulmonary Function Testing (Table 13-3)

Respiratory muscle weakness causes decreases in vitalcapacity. Total lung capacity is reduced as well, so the effect

is a classic “restrictive” defect on lung function testing.The defect is usually apparent at both extremes of thevital capacity; not only is total lung capacity reduced butalso residual volume can be elevated, due to inability ofthe weak expiratory muscles to distort the chest walldown to a normal residual volume. The decrease in vitalcapacity is proportional to the reduction in respiratorymuscle strength and therefore to severity of neuro-muscular weakness (Figure 13-8). As patients with pro-gressive neuromuscular diseases deteriorate, e.g., inDuchenne MD, there is a progressive loss of vital capacity(Figure 13-9). Appropriate corrections of predicted values

Table 13-3 Pulmonary Function Tests in Neuromuscular Disease

TLC ↓VC ↓RV ↓, NL, or ↑RV/TLC ↑FEV1 ↓MMEF ↓FEV1/VC NL


Theoretical

Vita

l Cap

acity

(%

of P

redi

cted

)

1008060

Respiratory Muscle Strength(% of Predicted)

4020

100

80

60

40

20

Figure 13-8 Decrease in vital capacity in patients with neuro-muscular disease. The decreases are proportional to the decreasein maximal respiratory pressures. (From DeTroyer A, Borenstein S,Cordier R. Analysis of lung volume restriction in patients with res-piratory muscle weakness. Thorax 35:603–610, 1980.)

Normal

Duchenne

200150100

Height/Arm Span

VC

, lite

rs

50

6

5

4

3

2

1

00

Figure 13-9 Vital capacity (VC) in patients with neuromusculardisease. The increase in VC with growth is reduced comparedwith normal. (Modified from Jenkins JG, Bohn D, Edmonds JF,Levison H, Barker GA. Evaluation of pulmonary function in mus-cular dystrophy patients requiring spinal surgery. Crit Care Med10:645–649, 1982.)

for patients with scoliosis must be made; otherwiseresults expressed as percent predicted value may be over-estimated. In patients with severe scoliosis, the arm spanis often used instead of the height in arriving at the cor-rect predicted lung function value.

Flows are also reduced in patients with neuromuscu-lar disease, but this does not usually signify airflowobstruction. Flows are reduced because flow is a volumemoved per unit time, and flows are usually reduced pro-portionally to the reduction in lung volume. For this reason, the FEV1/VC ratio is usually normal, and this ratioremains the single best discriminator between restrictiveand obstructive lung disease in a patient with a low vitalcapacity. Likewise, the flow–volume curve of a patientwith neuromuscular disease usually has a close to normalshape, though restricted in size, as opposed to the typical“scooped” flow–volume curve of a patient with obstruc-tive disease (Figure 13-10). Near residual volume, flowsmay abruptly drop from the descending limb of thecurve, a phenomenon that has been termed “falling off”the curve. It is indicative of a sudden decrease in flow asresidual volume is reached and the expiratory musclescan no longer distort the chest wall to a lower lung volume.

Tests of maximal inspiratory and expiratory strengthare very helpful in assessing likelihood of respiratoryproblems and fatigue. Normal values have been dis-cussed above in the section on the respiratory musclesand chest wall in neuromuscular disease. Patients areasked to inhale and exhale maximally through a mouth-piece that is occluded, and the resulting pressure ismeasured. Technical difficulties can arise in patients in whom oral muscle weakness is so severe that they are not able to form an adequate seal around the mouthpiece of the pressure-testing equipment. In suchpatients, nasal sniff pressure measurement can be a useful alternative in laboratories experienced in itsmeasurement.

Flow

Volume

Figure 13-10 Typical changes in the flow volume curve in a patient with neuromuscular disease. The arrows point out the reduced total lung capacity (�), peak flow ( ), elevated residual volume ( ) and abrupt reduction of flows at residual volume (�).

➡

➡


Special Studies

Arterial Blood Gas, Oxygen Saturation, End-Tidal CO2Respiratory pump failure is characterized by carbon

dioxide retention as minute ventilation decreases. Thedegree of carbon dioxide elimination can be assessed byseveral means. Arterial blood gases remain the gold stan-dard, and can be performed with minimal discomfortwith appropriate use of EMLA cream and subcutaneouslidocaine. They also give information about pH andoverall acid–base balance as well as pO2. In patients withhypoventilation due to neuromuscular disease, but with-out significant pulmonary pathology, the pO2 is usuallyreduced in proportion to the elevation of CO2, resultingin a normal alveolar–arterial (A–a) gradient for oxygen.While measurement of oxygen saturation by pulse oxime-try yields accurate results in most circumstances, slightreductions in pO2 from normal will not be detected.However, since clinically significant differences are prob-ably more important, pulse oximetry remains a very use-ful tool. End-tidal CO2 measurement is useful primarily inpatients who are supported by some form of mechanicalventilation, and in whom trends of CO2 are of interestfollowing interventions or changes in ventilatory sup-port. A set of serum electrolytes, and specifically a serumbicarbonate, reflecting renal compensation, provides avery useful average indicator of whether CO2 retentionis occurring. Practically speaking, this and home pulseoximetry provide very effective tools for monitoring aneuromuscular disease patient’s gas exchange and over-all respiratory pump function.

Nocturnal PolysomnographyPatients with neuromuscular disease are prone to the

development of nocturnal hypoxemia for several rea-sons. Upper airway obstruction has been discussedabove and tends to be magnified during sleep whenupper airway control is not as active as during wakeful-ness. In addition, patients with neuromuscular diseasecan develop nocturnal hypoxemia in the absence of day-time hypoxemia and in the absence of upper airwayobstruction. This is in part due to nocturnal hypoventi-lation when the low tidal volume present during daytimebreathing is exaggerated. It also results from a decreasein end-expiratory lung volume due to loss of intercostalmuscle tone. If end-expiratory lung volume drops belowthe lung volume at which there is closure of small air-ways, the result will be areas of low ventilation/perfusionand consequent hypoxemia. This can occur in asympto-matic patients, so it is best to periodically assess patientswith advanced neuromuscular disease with polysomnog-raphy. One approach2 is to obtain polysomnogramsevery year in patient whose vital capacity is greater than60% and whose maximum inspiratory and expiratory

pressures (MIPs and MEPs) are greater than 60 cm H2O,and every 6 months in patient whose vital capacity is lessthan 60% and/or MIP/MEP less than 60 cm H2O.

Swallow Function StudiesSwallow function studies are an essential part of the

evaluation of patients with suspected aspiration. A radi-ologist in conjunction with a speech therapist wellversed in the evaluation of disorders of deglutition shouldperform these studies. At least three different textures—thin liquid, thick liquid, and solids—should be offered,and the barium study should be assessed for nasopharyn-geal aspiration, pooling of contrast in the valecula, orfrank aspiration below the vocal cords. If aspiration isobserved, rapid clearance by an effective cough mecha-nism should be sought. Aspiration of oral secretions canalso be demonstrated by nuclear medicine “salivagrams,”in which a small amount of tracer is introduced into themouth (Figure 13-11).

Respiratory Inductive PlethysmographyRespiratory inductive plethysmography has been used

to quantitate the degree of asynchrony between rib cageand abdominal motion. It can give valuable clues as towhether respiratory muscle weakness is primarily inter-costal or diaphragmatic, when timed to the phase of therespiratory cycle (Figure 13-6). It can also be used to non-invasively gauge frequency and tidal volume in infants.

Tests of Respiratory Muscle FatigueTests of respiratory muscle fatigue are not in wide-

spread use but their use is being investigated in the eval-uation of patients in whom chronic non-invasive orinvasive mechanical ventilation is being considered. Thetension time index compares the average pressure gen-erated by the diaphragm during inspiration to the maxi-mal pressure the diaphragm is able to develop, andprovides a useful predictor of the likelihood of respira-tory fatigue. In patients with neuromuscular disease,muscle weakness resulting in low maximal pressureswill increase this term in spite of normal pressures devel-oped during the breath, thus predicting that fatigue willbe more likely in patients with neuromuscular diseaseeven in the absence of intrinsic lung disease.

PREVENTION AND TREATMENT OFRESPIRATORY COMPLICATIONS OFNEUROMUSCULAR DISEASE

General Supportive

NutritionNutritional assessment and treatment is paramount in

patients with neuromuscular disorders. Undernutritionis common, for various reasons. As patients with neuro-muscular disease deteriorate, there may be reduced oralintake due to uncoordinated swallow, esophagitis due to


uncontrolled gastroesophageal reflux, and anorexia dueto advanced underlying illness. Recurrent pulmonaryinfections and chest wall stiffness can lead to increasedcaloric expenditure by increasing the basal metabolicrate and work of breathing. Patients or caretakers some-times voluntarily reduce caloric intake in an effort to assistpatients with activities of daily living under the impres-sion that weight loss may reduce the work that the mus-cles of locomotion and posture must perform. In addition,in patients who are wheelchair-bound, parents and care-takers may intentionally limit weight gain in order to facil-itate transfers from bed to chair, home to car, etc.

Obesity is a characteristic of certain neuromuscular disorders (e.g. Duchenne MD) and can lead to difficulty inambulation as well as obstructive sleep apnea, describedabove.

A complete nutritional history should include currentdiet, types of early and later feeds, nutritional and vitamin/mineral supplements, appetite, food allergies, chewingand swallowing problems, and type, quantity and scheduleof gastrostomy tube feedings if applicable, including watersupplements. If malnutrition is a concern, a 3-day caloriecount should be performed. Careful serial measurementsof growth curves including height, weight, head circum-ference, and BMI should be performed. Since the BMIdepends on both a weight and a height measurement, thisindex may be overestimated in patients with severe scol-iosis; potentially the use of arm span rather than heightmay correct for this. The usefulness of anthropometric

measurements such as skin fold thickness are unknown;measures such as midarm circumference as an assessmentof nutritional status are probably misleading in patientswith primary muscle disorders.

Assessment should be made of vitamin and mineralstatus. Careful attention to calcium intake and overallbone health is also important; scoliosis will worsen ifosteoporosis is a complicating feature; dual energy X-rayabsorptiometry (DXA) scans are indicated if osteoporo-sis is suspected.

There is controversy about optimal nutritional statusin patients with neuromuscular disease. Although it maybe unrealistic to expect that a patient with muscle wast-ing be 50th percentile for corrected BMI, an attemptshould be made to arrive at an ideal BMI and make surethat it is maintained over time. It should be rememberedthat muscle wasting may be due to malnutrition as wellas the underlying neuromuscular disorder, and everyattempt should be made to maintain optimal nutrition inthese patients in order that their weakness not be exac-erbated by poor nutritional status. High calorie (e.g., 24–27calorie per ounce) formulas may be used in infancy, andnutritionally complete formulas such as Pediasure andEnsure, or supplements such as Scandishakes and Boost,may be used in older children and young adults. If caloricintake is inadequate as assessed by a 3-day diet record,and if it cannot be improved upon, continuous nasogas-tric or gastrostomy tube feedings at night may beemployed; this reduces, but does not eliminate, the risk

Figure 13-11 Nuclear medicine salivagram demonstrating frank aspiration into the tracheo-bronchial tree during a swallowing effort.


of aspiration due to gastroesophageal reflux. In patientsin whom aspiration during swallowing is an unaccept-able risk, all feedings may be switched over to bolus gas-trostomy tube feeds during the day.

Constipation should be aggressively evaluated andtreated. Severe constipation can cause abdominal disten-sion, push up on the diaphragms and cause an increasedrestrictive pulmonary process. We have seen severe con-stipation precipitate respiratory failure in patients withsevere restrictive disease from underlying neuromuscu-lar problems. Its presence may be detected by history,physical examination and flat plate of the abdomen.

In obese patients, judicious use of caloric restricteddiets is indicated.

VaccinesIn addition to routine childhood immunizations,

infants with neuromuscular disorders should be consid-ered for RSV prophylaxis if they have pulmonary com-plications. This should be continued for at least the first2 years of life. Routine influenza vaccinations should begiven yearly unless contra-indicated. Although mostpatients do not have specific immune deficiencies, pneu-mococcal vaccines such as pneumovax and Prevnarshould be considered, since the consequences of a pneu-mococcal pneumonia can be devastating in this patientgroup.

Team Approach To CareNo patient requires interdisciplinary and multidisci-

plinary care more than the patient with a chronic neu-romuscular disorder (Table 13-4). In addition to the careof a primary care physician, the input of a pediatric neu-rologist, orthopedist, and pulmonologist is ideal.Appropriate subspecialty trained nurse practitionersplay an invaluable role in the day-to-day management. Inaddition, cardiology consultation will be necessary inpatients with complicating cardiomyopathies as part oftheir underlying disorders. In spinal-cord-injuredpatients, or others with problems related to sacral motor

neurons, the input of a urologist, and perhaps renal spe-cialist, is necessary. Physical therapists are crucial forcreating a program designed to maintain mobility in otherwise under-used joints and in teaching chest phys-iotherapy. Speech therapists will be helpful in the assess-ment and treatment of swallowing dysfunction, andoccupational therapists play an invaluable role in assist-ing with the many activities of daily living. The impor-tance of a nutritionist has been stressed above. A socialworker and case manager will assist with dealing withfinancial and insurance issues, and with the myriad psy-chosocial problems facing these children and families.The challenge is providing these multiple services in asingle setting; many hospitals have multidisciplinary clin-ics where nearly all the above input can be achievedwithin the constraints of a half-day or day-long visit. Thisis particularly important for patients requiring daytimechronic ventilatory assistance, in whom mobility may beimpaired.

Swallowing Disorders and Aspiration

The importance of swallowing function in preventingaspiration pneumonias has been discussed above. Onceswallowing dysfunction has been diagnosed, the mostimportant decision is whether it is safe to continue oralfeedings. Speech therapists expert in the diagnosis andmanagement of swallowing dysfunction should be con-sulted; they will assess what texture(s) of foods allow forthe most successful swallowing in a given patient. Manytimes, patients who aspirate thin liquids will be able toprotect their airway while swallowing thick liquids orsolids. Patients who do not exhibit frank aspiration, butwho are at an aspiration risk by virtue of pooling of foodin their hypopharynx or valecula, can be taught tech-niques such as “dry swallows,” in which repeated swal-lowing efforts are made after the initial swallow of a foodbolus in an effort to clear pooled food particles.

Prevention of Aspiration

Prevention of aspiration is paramount, and relies onhome chest physiotherapy and cough assistance.Abdominally assisted coughing, use of a mechanical in/exsufflator device, percussion vest and/or intrapulmonarypercussive ventilation are very effective. Oropharyngealsecretions should be suctioned before the application ofthese devices to the airway.

Pneumonia and Atelectasis

Pneumonia and atelectasis should be considered med-ical emergencies in patients with advanced neuromus-cular disease; they often necessitate hospitalization eventhough the patient “looks well.” There are two reasons

Table 13-4 Team Approach to Care of the Patientwith Neuromuscular Disease

NeurologistPulmonologistCardiologistOrthopedistNutritionistNurse practitionerCase managerSocial workerPhysical therapistOccupational therapistSpeech therapist


for this: first, patients with neuromuscular disorders maynot display classic signs of respiratory distress such assuprasternal, subcostal and intercostal retractions, sincethe development of the negative intrapleural pressuresnecessary to produce retractions requires sufficient res-piratory muscle strength to lower pleural pressure. Thusin patients with neuromuscular disease, alternate clinicalassessments such as respiratory rate, heart rate, senso-rium, pulse oximetry and, if necessary, arterial bloodgases should be employed. Second, although patientswith neuromuscular disease and an intercurrent respira-tory illness who have a new area of atelectasis on chestradiograph often initially look well in the emergencydepartment, they are experiencing a deterioration intheir ability to clear secretions which is often progres-sive; it is not uncommon to have such patients senthome, only to be admitted several days later with a wors-ening chest radiograph. Prompt admission for aggressiveantibiotic therapy, chest physiotherapy and bronchodila-tors, and treatment with cough-assist devices can oftenpre-empt a prolonged hospital course.

Respiratory Muscle Function

Strength: Role of Rest and TrainingThere is controversy over whether weak muscles

should be rested or trained. In patients with neuro-muscular disease, however, there is evidence that favors

**

Time (months)

Pim

ax (

cmH

2O)

PRE

120

110

100

90

80

70

60

50

RMT

0 3 6 9 12 18

Figure 13-12 Effects of resistive loaded training on respiratorymuscle strength in normal subjects (filled triangles), normal con-trols (open triangles), subjects with neuromuscular disease (filledsquares), and controls with neuromuscular disease (open diamonds).In this study, only those patients with neuromuscular disease whounderwent respiratory muscle training (RMT) demonstrated a sig-nificant increase in respiratory muscle strength during the trainingperiod (asterisks). (Reproduced with permission from Gozal D,Thiriet P. Respiratory muscle training in neuromuscular disease:long-term effects on strength and load perception. Med Sci SportsExerc 31:1522–1527, 1999.)

Pump

Pump Load

Respiratory success

Respiratory failure

Load

Mechanical Factors

Figure 13-13 Techniques to reduce respiratory muscle fatigueeither decrease the respiratory load or increase the ability of the pump.

both approaches. Respiratory muscle training has beenevaluated in several studies. In general, while no changesin vital capacity have been seen, several studies reportimprovements in maximal respiratory pressures gener-ated by the respiratory muscles (Figure 13-12). This canbe accompanied by a decreased respiratory load percep-tion. However, both improvements revert to baselinewhen respiratory muscle training is discontinued.Respiratory muscle rest is discussed in the next section.

FatigueEfforts to delay the onset of existing respiratory mus-

cle fatigue or to reduce existing fatigue can be thoughtof as restoring the balance between the respiratorypump and the respiratory load. These efforts are aimedat increasing the ability of the pump and alleviating theload (Figure 13-13).

Interventions that help decrease the elastic and resis-tive loads against which the respiratory muscles mustoperate include those that reduce chest wall rigidity byincreasing range of motion (deep breathing exercises,incentive spirometry, mechanical in/exsufflator devicesand possibly assisted ventilation, either invasive or non-invasive). In addition, any measures that improve pul-monary toilet, mobilize secretions and reduce atelectasis(chest physiotherapy, mechanical in/exsufflator devices,bronchodilators), also decrease airways resistance andimprove compliance and should be a part of eachpatient’s daily routine. Frequency (daily, BID, TID, QIDor prn) should be dictated by the clinical picture.

Chronic assisted ventilation can help increase theendurance of the respiratory pump by reducing fatigue.Over-reliance on mechanical ventilation has the theoret-ical disadvantage of contributing to respiratory muscleatrophy, so judgment must be used in how many hoursa day assisted ventilation is provided, and should prob-ably be the minimal number of hours necessary to avoidfatigue. Unfortunately, there are currently no proven


ways to reliably assess respiratory muscle fatigue or itstreatment in this setting. Complications of non-invasiveventilation can include upper airway obstruction inpatients treated with negative pressure cuirass or tankventilators (as described above) and facial skin break-down in patients ventilated non-invasively through anasal mask. Meticulous attention to nasal skin care atpressure points, use of alternate (at least two) maskdesigns in a given patient, and reducing the tightness ofthe seal around the nose by allowing small amounts ofair leak may help avoid this complication. We prefer theuse of nasal masks to full-face masks, especially in thehome setting, to reduce the risk of aspiration. In patientsin whom 24-hour ventilation is necessary, tracheostomyand mechanical ventilation allows more head mobility,communication and overall comfort compared withmask ventilation. Use of speaking valves in patients withtracheotomies, even in those patients who are venti-lated, allows for vastly improved vocalization and speechas long as there is sufficient leak to allow for expirationaround the tracheostomy tube. There are many ways tochoose ventilator settings which will accomplish goalsof maintaining adequate end-expiratory lung volume(PEEP), adequate lung and chest wall expansion (peakpressure or tidal volume adjustments), degree of respira-tory muscle rest achieved (pressure support and ventila-tor rate), and near-normal blood gases (all of the aboveplus FIO2). Ventilators the size of laptop computers arenow available which can be attached to a wheelchairand provide the ventilator-dependent patient with optimal mobility.

REFERENCES

1. Archibald KC, Vignos PJ. A study of contractures in musculardystrophy. Arch Phys Med Rehabil 39:150–157, 1959.

2. Gozal D. Pulmonary manifestations of neuromuscular disease with special reference to Duchenne muscular dystro-phy and spinal muscular atrophy. Pediatr Pulmonol 29:141,2000.

SUGGESTED READING

Allen JL. Respiratory function in children with neuromusculardisease. Monaldi Arch Chest Dis 51:230, 1996.

Schramm CM. Current concepts of respiratory complications ofneuromuscular disease in children. Curr Opin Pediatr 12:203,2000.

MAJOR POINTS

1. Neuromuscular disorders that result in pulmonarycomplications can include diseases affecting anysite along the neuromuscular axis, including theupper motor neuron, the lower motor neuron, theneuromuscular junction and the muscle itself.

2. Normal neuromuscular function is essential (1) in performing the pump function of respiration,(2) in maintaining upper airway patency duringinspiration, (3) in protecting the airway fromaspiration by the presence of a normal swallow

�

�

MAJOR POINTS—Cont’d

mechanism, and (4) (once this mechanism isbroached) in clearing aspirated secretions by aneffective cough.

3. Abnormalities of the above functions in patientswith neuromuscular disease result, respectively, in(1) respiratory muscle fatigue and failure, (2) upperairway obstruction, especially during sleep, (3) swallowing dysfunction, and (4) weak coughleading to recurrent atelectasis and pneumonia.

4. The pulmonary evaluation of patients withneuromuscular disease has many components andmay include, in addition to a specialized physicalexamination, imaging studies, tests of lungfunction, respiratory muscle strength and fatigue,gas exchange, polysomnography, and swallowingfunction studies.

5. Many newer supportive therapies exist to preventand treat pulmonary complications ofneuromuscular diseases. These include aggressiveoptimization of nutritional status, andinterdisciplinary programs designed to preventaspiration using swallowing training, and to preventatelectasis and pneumonia using assisted coughtechniques and chest physiotherapy. Additionally,the judicious use of non-invasive ventilation cansupport fatigued respiratory muscles and helpprevent chronic respiratory failure.

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208

CHAPTER

14Respiratory Failure in ChildrenDANIEL J. WEINER, M.D.

Introduction and Definition

Etiologies

Pathophysiology

Ventilation

Oxygenation

Gas Transport to the Periphery

V./Q

.Relationships

Diagnosis and Monitoring of Patients with

Respiratory Failure

Blood gases

Pulse Oximetry and Capnography

Imaging

Pulmonary Function Measurements

Management

Conventional Therapies


Non-invasive Positive-Pressure Ventilation

Inhaled Nitric Oxide

Extracorporeal Membrane Oxygenation

Non-traditional Therapies

Prone Positioning

Negative-Pressure Ventilation

High-Frequency Oscillatory Ventilation

Liquid Ventilation

The Recovery Phase

Summary

INTRODUCTION AND DEFINITION

Respiratory failure occurs when the respiratory systemcan no longer adequately transfer oxygen into or carbondioxide from the blood. “Adequate” transfer is somewhatsubjective, and there are thus no strict criteria that definerespiratory failure. In adults, a pO2 < 60 torr while breath-ing supplemental oxygen (FiO2 > 0.6), or pCO2 > 50 torrare frequently used as guidelines, but these values arearbitrary and should be used with caution. Some chil-dren may be clinically stable despite this hypoxemia or

hypercarbia, and treatments should be tailored to thechild and not to these laboratory values.

Respiratory failure can be “acute” or “chronic,” andthese terms, too, are ill defined. One use of the termsaddresses whether the disease process itself is insidiousin onset (weeks to months or longer, such as might becaused by muscular dystrophy) or rapid in onset (min-utes to hours, such as might be caused by a toxic inhala-tion), while others use the term to describe the durationof assisted ventilation. For purposes of this review,“acute” or “chronic” respiratory failure will describe theduration of the disease process.

One cause of acute respiratory failure arises from theacute respiratory distress syndrome (ARDS). This wasoriginally termed the adult respiratory distress syn-drome, first described in 19671, although the originalcase series included one pediatric patient, and the ill-ness may be seen in patients of all ages. It may be causedby numerous pulmonary insults. Criteria for ARDSinclude:• Predisposing illness• Respiratory distress and hypoxemia refractory to

supplemental oxygen• Bilateral pulmonary infiltrates• Absence of cardiac failure

Here, “hypoxemia” is usually defined as the ratioPaO2/FiO2 < 200, and “absence of cardiac failure” is usu-ally defined as a pulmonary capillary wedge pressure < 18 cm H2O. A less stringent definition (PaO2/FiO2

< 300) has been used to describe “acute lung injury”2.Inconsistent application of these diagnostic criteria

makes studying the epidemiology of ARDS, as well asoptimal management, very challenging. It is estimatedthat 1–4% of all admissions to pediatric critical care unitsare due to ARDS. Mortality has remained high (40–60%)despite many advances in critical care, and is higher if multiple organ dysfunction is present. Despite the het-erogeneous nature of ARDS, it is nonetheless considereda prototype disease for studying respiratory failure.

Respiratory Failure in Children 209

Table 14-1 Causes of Respiratory Failure

(a) CNS Causes• Congenital central hypoventilation syndrome• Brainstem malformations (e.g., Dandy–Walker cyst,

Arnold–Chiari)• Medication effects (e.g., narcotics)• Infections (e.g., meningitis)

(b) Pump Causes• Muscular dystrophy (e.g., Duchenne, Becker)• Spinal muscular atrophy (e.g., Werdnig–Hoffman)• Demyelinating diseases (e.g. Guillain–Barré)• Disorders of the neuromuscular junction (e.g., myasthenia

gravis, medications)• Chest wall disorders (e.g., scoliosis, Jeune syndrome)

(c) Lung Causes• Infections (e.g., pneumonia, bronchiolitis, bronchiectasis)• Inflammatory airway obstruction (e.g., asthma, inhalational

injury)• Vascular disorders (e.g., veno-occlusive disease, pulmonary

hypertension)• Congenital lung anomalies (pulmonary hypoplasia, cystic

adenomatoid malformation, diaphragmatic hernia)

There are many other causes of acute respiratory fail-ure (see below). At high risk are patients with chronicrespiratory insufficiency (e.g., due to neuromuscularweakness) who may have further deterioration withintercurrent infections, aspiration of secretions, or forother reasons. These patients may be said to have acute-on-chronic respiratory failure.

In this chapter, we will examine the causes, pathophys-iology, and management of respiratory failure in children.

ETIOLOGIES

Respiratory failure can be caused by defects any-where along the pathway that results in normal respira-tion. These can be grouped into three main areas: thecentral nervous system (CNS, responsible for respiratorydrive), the chest wall and respiratory muscles (respon-sible for generating the force to inspire), and the lung(responsible for gas exchange). A partial list of disordersin each of these areas is given in Table 14-1.

PATHOPHYSIOLOGY

To understand the derangements that occur in respi-ratory failure, we must first consider the normalprocesses of gas exchange. We will separately considerventilation (the movement of air, responsible for elimi-nation of CO2) and oxygenation. Indeed, respiratory failure is sometimes further described as “hypoxemic” or

“hypercapneic” respiratory failure, although frequentlythese two processes are disordered in the same patient.

Ventilation

The volume of gas that enters and leaves the lungswith each breath is termed the tidal volume (Vt); physio-logic tidal volumes are approximately 5–7 ml/kg. Minuteventilation (V

•E) is the amount of gas entering and leav-

ing the lungs per minute, and is calculated by multiply-ing the tidal volume by the respiratory rate. A portion ofthe tidal volume resides in the conducting airways whereno gas exchange occurs (the anatomic dead space).Similarly, no gas exchange occurs in the tubing connect-ing the ventilator to the patient; this, too, can be thoughtof as dead space (Vd). Alveolar ventilation (V

•A) refers

to the amount of gas that is available for gas exchange,which is defined as RR × (tidal volume − dead space vol-ume). The most convenient way to gauge alveolar venti-lation is to measure the arterial partial pressure of CO2;increases in alveolar ventilation decrease PaCO2:V

•A = k ×

(V•

CO2/pCO2) where V•CO2 is CO2 production.

In patients with lung disease, some portions of thelung, despite the presence of alveoli, do not participatein gas exchange for one reason or another. This volumeof lung is termed the alveolar dead space. When takentogether with the anatomic dead space, the sum istermed the physiologic dead space (Figure 14-1). Thiscan be measured using Bohr’s method, which is basedon the principle that all exhaled CO2 comes from thealveoli rather than the anatomic dead space: VD/VT =(PACO2−PECO2)/PACO2, where PACO2 is the partial pres-sure of CO2 in the alveolus, and PECO2 is the partial pres-sure of CO2 in the mixed exhaled gas. Measuring thealveolar partial pressure is difficult, but in normal sub-jects it is nearly identical to the arterial partial pressureof CO2 (PaCO2). Therefore, by measuring the PaCO2 andmixed expired CO2 (this requires collection of exhaledgas in a bag), we can estimate the ratio of physiologic deadspace volume to tidal volume. This is normally 0.2–0.3 butmay rise significantly in disease states.

Increased dead space is one cause of hypercapnea inpatients because for a given minute ventilation, as deadspace ventilation increases, alveolar ventilation decreases.Other causes include hypoventilation (most common), orincreased CO2 production (such as occurs in malignanthyperthermia or sepsis). Hypoventilation results from avariety of abnormalities in respiratory drive, or inadequategeneration of respiratory muscle force (Table 14-1a, b).

Oxygenation

The partial pressure of oxygen in the alveolus (PAO2)can be predicted from the alveolar gas equation:

PAO2 = PiO2 − (PaCO2/R) = [(PB − PH2O) × FiO2 − (PaCO2/R)]


Figure 14-1 Dead space and alveolar ventilation in normal (left) or diseased states. Vd/Vt in thenormal situation is approximately 0.3. A pulmonary embolus is depicted in the center panel, andobstructive airway disease in the right panel. The heavy black bars denote anatomic dead space; theshaded circles denote alveolar dead space. When dead space is increased, the minute ventilationmust increase dramatically to maintain alveolar ventilation.

where PB is barometric pressure, PH2O is the partial pres-sure due to water vapor, PAO2 is the alveolar partial pres-sure of oxygen, PiO2 is the inspired partial pressure ofoxygen, R is the respiratory quotient, and FiO2 is theinspired fraction of oxygen. From this one can see thatthe amount of oxygen in the alveolus is maximally deter-mined by barometric pressure and the fraction of oxygenin the air; this maximum is decreased by CO2 production;the respiratory quotient, R, is a measure of the metabolicrate of the tissues (CO2 production/O2 consumption). Atsea level, barometric pressure is 760 torr, and the partialpressure due to water vapor is 47 torr; the fraction ofoxygen in air is 21% (most of the rest being nitrogen).Therefore, the partial pressure of oxygen in inspired air is(760 − 47) × 0.21, or 150 torr. The A–a gradient is cal-culated as the difference between the alveolar oxygentension (from the alveolar gas equation) and the arterialoxygen tension (from a blood gas measurement). TheA–a gradient can be useful in identifying the cause ofhypoxemia.

From the alveolar gas equation, two of the several causesof hypoxemia can be demonstrated. At high altitude,barometric pressure is much lower, reducing PiO2.Additionally, an elevated pCO2 due to obstructive lungdisease or hypoventilation will increase the PaCO2/Rratio, decreasing PAO2. The other causes of hypoxemia areshunt, ventilation–perfusion (V

•/Q

•) mismatch (the most

common), and diffusion block (rare in pediatrics). Thesewill be dealt with in more detail later.

By examining the alveolar gas equation, it is apparentthat a normal pCO2 cannot be presumed from a normalpO2 (or more practically clinically, from a normal oxy-hemoglobin saturation), especially when the patient isreceiving supplemental oxygen. A patient receiving nosupplemental oxygen (21%) could have a normal SpO2

(95%) and pO2 (~80 torr), and the pCO2 could be at most55 torr. However, a patient whose FiO2 is 30% couldhave the same measures of oxygenation and yet have a pCO2 of 107 torr! The clinician should not be falsely

reassured about the adequacy of ventilation by a normal saturation in a patient with respiratory distress.

Gas Transport to the Periphery

Oxygen is carried in the blood in two forms: dissolvedand bound to hemoglobin. The dissolved amount (0.003 ml O2/100 ml blood/mmHg PO2) contributes onlya small amount to the total content of oxygen in the blood.In contrast, 1.36 ml of oxygen can combine with eachgram of hemoglobin. The percentage of hemoglobin thatis bound to oxygen is termed the oxyhemoglobin satu-ration and may be affected by temperature, pH, pCO2,and structural changes in the hemoglobin molecules.The relationship between arterial oxygen tension andoxygen saturation is described by the oxyhemoglobindissociation curve (Figure 14-2).

The curve has a flat portion where the saturation isminimally affected by changes in pO2, and a steep por-tion where tissues can withdraw large amounts of oxy-gen (i.e., large change in saturation) for small decreasesin capillary pO2. The curve shifts to the right (i.e., has a

1009080706050403020100

0 50 100

pO2

SaO

2

150

Figure 14-2 The oxyhemoglobin dissociation curve. Note thesigmoidal shape of the curve, with a steep segment (where mostunloading of oxygen occurs) and flatter portions (where littlechange in saturation occurs despite large changes in pO2).


lower saturation for the same PaO2) for increases in tem-perature, acidity (Bohr effect), and 2,3-diphosphoglyc-erol (2,3-DPG) concentration. Muscle that is exercising,for instance, usually has an increased temperature due toincreased blood flow. It also has increased acidity becauseof lactate production, and these effects act in concert onoxygen binding to facilitate providing extra oxygen tothe muscle. Banked blood usually has very low amountsof 2,3-DPG; this deficiency increases the avidity of thehemoglobin for oxygen, impairing delivery to the tissues.

The oxygen content of arterial blood (CaO2) then canbe calculated by adding the dissolved and boundamounts of oxygen in the blood:

CaO2 = (0.003 ml/torr × PaO2 torr) + (1.36 ml/g × Hb g × % saturation) = ml O2/dl blood

It can be seen from this equation that most oxygen isbound to hemoglobin; oxygen content is related to oxygensaturation in a linear fashion. Notice that the oxygen con-tent can be increased by increasing the PaO2 or saturation,or by increasing the hemoglobin. Both methods are some-times used in the care of patients with hypoxemic respira-tory failure. Oxygen delivery (to the tissues) is calculatedby multiplying the oxygen content by the cardiac output(CO). Transfusions may increase the oxygen content, butthey may also decrease CO by increasing blood viscosity.The net effect, then, could be a decrease in oxygen deliv-ery to the tissues if the decrease in cardiac output is greaterthan the increase in CaO2 after transfusion.

Carbon dioxide can be transported in three forms: dis-solved (5%), as carbamino compounds (5%), and as bicar-bonate ion (90%). In the erythrocyte and in the presenceof carbonic anhydrase, CO2 combines with water to produce carbonic acid, which then dissociates intobicarbonate and a proton:

CO2 + H2O ⇔ H2CO3 ⇔ H+ + HCO3−

Some of these protons can combine with oxygenatedhemoglobin, allowing for unloading of oxygen and load-ing of CO2; this process facilitates the necessary gas trans-port at the tissue level and is known as the Haldaneeffect. In the pulmonary capillary, oxygen can displaceprotons from hemoglobin, which can then combinewith bicarbonate, generating CO2 to be exhaled.

V•/Q

•Relationships

Effective delivery of oxygen to the body’s cellsrequires a precise balance between ventilation of lungunits and blood flow to those units. Imbalances in theserelationships, termed ventilation–perfusion (V

•

A/Q•

)ratios, are the most common cause of hypoxemia inpatients. There are two extremes of V

•

A/Q•

imbalance:shunt and dead space. Shunt refers to situations wherethere is blood flow (Q

•> 0) that comes into contact with

non-ventilated lung units (V•

A = 0) or does not come intocontact with the lung at all; in these situations, V

•

A/Q•

= 0.Shunts can be “irreversible” or “fixed” such as intracar-diac shunts or intrapulmonary shunts (e.g., arteriove-nous malformations). They are designated “irreversible”or “fixed” because they do not respond to hyperoxia.“Reversible” shunts are really areas of very low V

•

A/Q•

which will respond to hyperoxia (see below). Deadspace refers to situations where airflow (V

•

A > 0) comesinto contact with non-perfused lung units (Q

•= 0), such

as occurs in a pulmonary embolus. The blood gas abnor-mality resulting from shunt is hypoxemia, while thatresulting from increased dead space is hypercarbia. Inbetween the two extremes, varying degrees of V

•

A/Q•

mis-match can exist.

Any disease process that alters ventilation or perfu-sion will likely result in some imbalance in V

•

A/Q•

ratios.For example, acute airway obstruction or lobar atelectasisdecreases ventilation to lung units. Autoregulation ofpulmonary blood flow reduces but does not completelyeliminate perfusion of these regions. Furthermore, theredirected blood will pass by other alveoli whose venti-lation will not be adequate for the increased perfusion.Both phenomena result in regions with a decreasedV•

A/Q•

ratio. The oxygen and CO2 tensions in the alveolusand end-capillary blood will approach that of mixedvenous blood (Figure 14-3).

In contrast, a pulmonary embolism ablates blood flowto certain regions without affecting ventilation, increas-ing the V

•

A/Q•

ratio. The oxygen and CO2 tensions in theaffected alveolus will approach those in the inspired gas.

Quantifying V•

A/Q•

relationships is very difficult. Thesimplest estimation of imbalances in V

•

A/Q•

can beobtained by calculation of the A–a gradient. This gradi-ent is usually very small (<15 torr), but will be elevated ifthere is a block in diffusion, V

•

A/Q•

imbalance, or shunt.Note that in the other respiratory causes of hypoxemia(low inspired oxygen tension or hypoventilation), thealveolar pO2 and arterial pO2 will both be equallydepressed, resulting in a normal A–a gradient. More com-plicated techniques to measure V

•

A/Q•

ratios (i.e., multi-ple inert gas exhalation technique, MIGET) can describethe distribution of V

•

A/Q•

relationships in the lung, but arenot readily clinically available.

As discussed above, hypoxemia due to “irreversible”(e.g., intracardiac) shunts cannot be corrected with sup-plemental oxygen. Consider a two-compartment lung,one compartment with normal V

•

A/Q•

relationships and theother compartment with perfusion but no ventilation(shunt). The “normal” compartment has an oxygen satu-ration of 98% and pO2 of 110 torr, but the “shunt” com-partment has a saturation of 75% and pO2 of 40 torr (i.e.,similar to values in mixed venous blood). Although overlysimplistic, let us also assume that the two units receiveequal amounts of blood flow. At first glance, one might


assume that the pO2 of the blood mixed from these twocompartments would be the average of the tensions ofthe two compartments (110 + 40/2 = 75 torr). Whenmeasured, however, the pO2 of the mixed blood is foundto be only 53 torr! This demonstrates that the mixed bloodpO2 is determined by the mixing of the oxygen contents ofthe individual compartments (Figure 14-4). This is in partbecause the poorly saturated, shunted blood readily

picks up oxygen from the better-saturated blood, reducingthe pO2 of the mixed blood. It is also due to the fact thatthe oxyhemoglobin dissociation curve (and the oxygencontent curve) is not linear, but rather sigmoidal. To con-firm this, we can calculate the oxygen content of the“normal” unit [(1.36 × 0.98 × 15) + (0.003 × 110)] and the“shunt” unit [(1.36 × 0.75 × 15) + (0.003 × 40)], assum-ing a value for hemoglobin of 15 gm/dl. The two contents

Figure 14-3 Matching of ventilation and perfusion in normal (center) or disease (left, right) con-ditions. In conditions of shunt (left), the partial pressures of oxygen in the alveolus and pulmonarycapillary pressures will equilibrate to values near that of mixed venous blood. In conditions of deadspace (right), the partial pressures of oxygen in the inspired gas and the alveolus will equilibrate.

Predicted pO2 byaveraging O2 contents

Average O2 content ofmixed lung units

Predicted pO2 byaveraging pO2’s

100

90

80

SaO

2

70

60

50

40

30

20

10

00 20 40 60 80

pO2

100 120 140 1600

5

10

SaO2CaO2Shunt unitNormal unitMixed unit

15

20

Figure 14-4 Oxyhemoglobin saturation and oxygen content as a function of the partial pressureof oxygen.


(20.3 ml/dl and 15.4 ml/dl) are then averaged to be 17.8 ml/dl; this corresponds to a pO2 of 53 torr.

Now imagine that 100% oxygen is administered tothis lung. The “shunt” region, by definition, does notreceive any more oxygen. The “normal” unit now has apO2 of 663 torr and a saturation of 100%. The oxygencontent of the blood, however, has changed minimallyas this lung unit was already on the flat upper part of theoxygen dissociation curve. The saturation has onlyincreased 2% and the dissolved pO2 increase is negligible(1.66 ml/dl). The average of the two contents is then[(1.34 × 1.0 × 15) + (0.003 × 663)] + [(1.34 × 0.75 × 15) +(0.003 × 40)]/2 = (22.1 + 15.1)/2 = 18.7 ml/dl; this corre-sponds to a saturation of 91% and pO2 of ~64 torr, notthe 352 torr which would be predicted from averagingpO2 values.

When treating patients with hypoxemia refractory tosupplemental oxygen, disease processes that causeshunting must be considered and treated. Hypoxemiacan also be due to a “reversible” shunt related to V

•

A/Q•

mismatch. This hypoxemia can be improved with admin-istration of supplemental oxygen, because “reversible”shunts represent areas of low (but not zero) V

•

A/Q•

. Theselung units sit on the steep portion of the oxygen dissoci-ation curve. Since they receive some (but not normal)ventilation, supplemental oxygen will increase their oxy-gen tension, which may be enough to move the lung unitonto the flat portion of the oxygen dissociation curve andattain a normal saturation and therefore higher oxygencontent.

Fick’s law can be used to estimate the “shunt frac-tion”. This law assumes that the oxygen content of theblood leaving the heart is the sum of oxygen from thepulmonary capillaries (non-shunted) and from shuntedregions (either within the lung or extrapulmonary).Mathematically,

Q•

t × CaO2 = Q•

c × CcO2 + Q•

s × Cv–O2

This equation can be rearranged to calculate the“shunt fraction,” Q

•

s/Q•

t = (CcO2 − CaO2)/(CcO2 − CvO2),where Q

•

s is the shunted blood flow, Q•

t is the total bloodflow, CcO2 is the pulmonary capillary blood oxygen

content, CaO2 is the arterial blood oxygen content, andCv–O2 is the mixed venous blood oxygen content.

Taken together, the measurements of dead space,shunt fraction, and A–a gradients for O2 and CO2 cangive meaningful insight into the maldistribution of venti-lation and perfusion, and help identify the cause(s) ofrespiratory failure (Table 14-2).

DIAGNOSIS AND MONITORING OFPATIENTS WITH RESPIRATORY FAILURE

Blood Gases

Measurement of gas tensions in arterial blood (ABG)have long been the standard for monitoring patients at riskfor or already in respiratory failure. They provide informa-tion about oxygenation, ventilation, and the acid–base sta-tus which reflects pulmonary and renal homeostasis. Bloodgas analyzers measure pH, pO2, and pCO2; the reportedsaturation is calculated from the pO2 and the oxyhemoglo-bin saturation curve, and the reported HCO3

− is calculatedfrom the pH, pCO2, and Hb using a nomogram. ObtainingABGs can be painful for the patient, but there is usuallyadequate time to apply topical anesthetics. Alternativessuch as sampling capillary (CBG) or venous (VBG) bloodare frequently employed. CBGs obtained from a warmedextremity are a closer representation of arterial pCO2 andpH than are VBGs, which frequently represent local tissueacid–base status; neither alternative is particularly accuratefor assessment of arterial pO2. Proper collection and han-dling of the specimen is important; excess heparin in thecollection syringe may alter the pH of the collected blood,while air bubbles will equilibrate the patient’s pO2 andpCO2 with room air (150 torr and 0 torr, respectively).Samples should be processed rapidly or placed on ice to decrease ongoing metabolism of oxygen within thesample. A systematic approach should be utilized in inter-preting blood gas values. The observed pO2, SaO2 andCO2 must be interpreted in the context of the FiO2 andthe patient’s respiratory rate. A complete description of blood gas interpretation is beyond the scope of thischapter, but several excellent reviews are referenced3,4.

Table 14-2 Causes of Hypoxemia

A–a O2 Increased pO2 with Gradient A–a CO2 Gradient Increased FiO2 Q

.s/Q

.t

V./Q

.mismatch, low V

./Q

.� Normal Yes �

V./Q

.mismatch, high V

./Q

.Normal � Yes Normal

Hypoventilation Normal Normal Yes NormalShunt (irreversible) � Normal No �Diffusion block � Normal +/− �Low inspired FiO2 Normal Normal Yes Normal


1%

Q

1 sec

Figure 14-5 Capnogram tracings. The normal capnogram (toptracing) has a rectangular wave pattern, exhibiting a rapid ascend-ing slope, an almost 90° angle to the alveolar plateau, the end-tidalpeak, and a vertical descending slope. In the presence of obstruc-tive disease (bottom tracing), the capnogram loses its rectangularshape and is sometimes described as a “shark fin.”

Pulse Oximetry and Capnography

The advent of non-invasive pulse oximetry (SpO2) hasmade feasible the continuous monitoring of oxygenationin patients with respiratory failure. This allows much morerapid detection of changes in clinical status than do inter-mittent measurements of blood gases. The technique isbased on light absorption by oxygenated and reducedhemoglobin at two different (visible and infrared) wave-lengths. It should be noted that this technique is subject toseveral sources of error. Carboxyhemoglobin absorbs visi-ble light in a way similar to oxygenated hemoglobin, andcan cause artificially high SpO2 measurements in patientswith carbon monoxide poisoning. In contrast, methemo-globin absorbs visible light in a way similar to reducedhemoglobin, frequently resulting in artificially low meas-ured SpO2 (approximately 85–88%). Additionally, theoximeter signal depends on detection of a pulsatile wave-form, and poor perfusion or edema may interfere withreadings. Patient motion is the most common cause of arti-factual readings, and comparison of the pulse raterecorded by the oximeter and that from electrocardio-graphic monitoring provides one method of determiningthe accuracy of the reading. With these caveats, continu-ous pulse oximetry is extremely useful for monitoring ofpatients in respiratory failure.

As previously noted, normal oximetry values do notassure normal ventilation. Exhaled gas can be analyzedfor CO2 concentration (usually also by infrared lightabsorption), and the waveform can be displayed contin-uously, by a capnograph. The normal capnogramdemonstrates a flat initial portion (from dead space withno CO2), followed by a rapid and sharp increase inexhaled CO2 (as alveolar gas begins to empty), and a sub-sequent plateau as alveoli empty during exhalation(Figure 14-5). In the healthy lung, the concentration ofCO2 at the end of a breath (ETCO2) closely approximates

arterial pCO2. In disease states, however, capnographycan render inaccurate measurements. Increased deadspace may dilute alveolar CO2 with gas devoid of CO2, andthe ETCO2 could underestimate arterial CO2. Similarly,exhaled gas that does not reach the sensor (e.g., due toleak) will result in an artifactually low ETCO2. Absence ofa plateau in the capnogram suggests the presence of air-way obstruction (Figure 14-5). Because of these possibleerrors, as well as the technical difficulties in measure-ment of humidified gases, the ETCO2 should be corre-lated with measurement of CO2 in blood. Additionally,the interpretation of the ETCO2 value will be facilitatedby the capnogram waveform, as described above.

Imaging

As mentioned earlier, the presence of bilateral pul-monary infiltrates is one of the diagnostic criteria for ARDS.In the early stages (0–24 hours) of ARDS, the chest radio-graph may appear normal or reflect mild interstitial edema.As the disease progresses, there will be progressive atelec-tasis, interstitial edema, and ground-glass opacification ofthe airspaces. In the later stages, air bronchograms andmore dense consolidations appear. The standard chestradiograph can help detect complicating factors or alter-native diagnoses such as cardiogenic pulmonary edema aswell as pneumothorax, or improper positioning of endo-tracheal tubes or central catheters. The resolution of radio-graphic changes in ARDS may be quite slow, and thebenefit of daily radiographs in the ICU setting has not beenwell demonstrated.

Computed tomography (CT) studies obtained inpatients with ARDS surprisingly have demonstrated thatthe disease is not as homogeneous as would be suspectedfrom the plain radiograph. Indeed, the dependent por-tions of the lung are significantly more densely opacifiedthan the non-dependent regions. This observation of agravity-dependent gradient of disease was important inconsidering the use of prone positioning in the treatmentof ARDS (Figure 14-6). CT has also been used to study theeffects of other treatments such as positive end-expiratorypressure (PEEP) and liquid ventilation in ARDS.

Pulmonary Function Measurements

Measurements of pulmonary function in patients withrespiratory failure can guide therapy, particularly in adjust-ing ventilator support. In children receiving mechanicalventilation, bedside measurements of lung mechanics(e.g., respiratory system compliance, resistance) canallow rational adjustments of distending pressures orother ventilator settings, as well as providing objectivedata regarding response to therapy (i.e., bronchodilators,diuretics) and assessments of disease course. Bedside estimates of compliance and resistance can be made bymeasuring changes in pressure (usually between peak


Figure 14-6 CT images of ARDS in supine (upper panel), prone(middle panel), and return to supine position (lower panel). Notehow gravity-dependent densities shift from dorsal to ventral withinminutes when the patient is turned prone. (From Gattioni, et al.Am J Respir Crit Care Med 164:1701–1711, 2001.)

inspiratory pressure, PIP, and the end-expiratory pressure,PEEP, or the plateau pressure, Pplat) and changes in volume (exhaled tidal volume) (Figure 14-7). Specifically,compliance is calculated as the change in volume (Vt)divided by the change in pressure (Pplat − PEEP), andresistance as change in pressure (PIP − Pplat) divided byflow (Vt/inspiratory time).

Measurement of the plateau pressure requires an end-inspiratory hold, a technique available on many com-mercial ventilators. The patient must also be relaxed andallowed to exhale passively. Some newer ventilatorsmeasure breath-by-breath dynamic compliance andresistance. Graphic displays of pressure–volume orflow–volume curves can provide additional informationabout pulmonary mechanics5, and can provide rapidfeedback to the clinician making ventilator adjustments.

MANAGEMENT

When Eli’sha came into the house, he saw the child lyingdead on his bed. So he went in and shut the door upon thetwo of them, and prayed to the Lord. Then he went up andlay upon the child, putting his mouth upon his mouth, hiseyes upon his eyes, and his hands upon his hands; and as hestretched himself upon him, the flesh of the child becamewarm. Then he got up again, and walked once to and fro inthe house, and went up, and stretched himself upon him; thechild sneezed seven times, and the child opened his eyes.

Kings II 4:32

This may be one of the earliest recorded reports of“assisted ventilation” or resuscitation in a pediatric patient.In the following section, we will consider more com-monly used treatments for pediatric patients with respi-ratory failure. The goals of most ventilation strategies areto normalize gas exchange while minimizing lung injuryor cardiovascular compromise.

Conventional Therapies

Positive-Pressure VentilationThe majority of patients with acute respiratory failure

are treated with positive-pressure ventilation through anendotracheal tube. There are numerous different venti-lator modes and styles6, and a full discussion of them isbeyond the scope of this text. However, there are someunderlying principles that are common to most modes:the clinician usually sets a ventilator rate, end-expiratorypressure (PEEP), and inspired fraction of oxygen; theamount of gas delivered by the ventilator can be limitedby pressure or volume, and the duration of inspirationcan by cycled by time or flow. For example, in pressure-limited (sometimes called “pressure controlled”) ventila-tion, the clinician chooses a peak inspiratory pressurethat limits the magnitude of inspiratory pressure deliv-ered over the breath, and the tidal volume of that breath

Pre

ssur

e (c

m H

2O)

Time (sec)

PEEP

Plateau pressure

Peak pressure

Figure 14-7 Airway pressures used to measure lung mechanics.


will vary depending on the lung compliance and resist-ance at the time. In volume-limited (sometimes called“volume controlled”) ventilation, the clinician chooses atidal volume that limits the delivered breath, and thepeak inspiratory pressure used to achieve that volumewill vary depending on the lung compliance and resist-ance (Figure 14-8).

For each of these strategies, the ventilator can be setto deliver a complete breath for each effort initiated bythe patient (assist-control) or to cycle based only on theset rate (control mode, where the patient cannot breathespontaneously between mandatory breaths, or intermit-tent mandatory ventilation, where spontaneous breathsare permitted). Most recent ventilators attempt to syn-chronize the mandated breaths with the efforts of thepatient (synchronized intermittent mandatory ventila-tion), to avoid the uncomfortable delivery of a breathwhen the patient wishes to exhale (Figure 14-9).

In addition, many ventilators offer pressure supportwhere patient-initiated efforts trigger delivery of flow upto a preset pressure level, which the patient can termi-nate. In contrast to assist-control ventilation, pressuresupport ventilation affords partial, not complete supportfor patient-triggered breaths. In fact, if pressure supportis used as the sole mode of support, the patient controls

most aspects of the ventilation. For this reason, it is feltto be a “comfortable” mode for the patient.

Positive end-expiratory pressure (PEEP) can help min-imize airway collapse and maintain lung volume. This lat-ter function of PEEP may improve lung compliance, andallow for ventilation with lower peak pressures. It alsoincreases the mean airway pressure, which can improveoxygenation by improving ventilation–perfusion matching.Central airway collapse (i.e., due to tracheomalacia or bron-chomalacia) may be overcome by PEEP. However, excessPEEP could overdistend the lung, decreasing compliance.

Positive-pressure ventilation, while life-sustaining, alsohas adverse physiologic consequences. By increasing alve-olar pressure, it may decrease blood flow to intra-alveolarcapillaries, resulting in ventilation–perfusion mismatch.High intrathoracic pressures (related to PIP or PEEP) havethe potential to decrease venous return to the heart.Additionally, very high transmural pressures could causerupture of some lung tissue resulting in pneumothorax.

It is usually not possible to decide a priori which ven-tilator or mode will be optimal for a patient with a givendisease, and frequent bedside assessments are the bestguide. With whatever mode of ventilation is chosen,many adjustments in the acute setting are usuallyneeded. These should be guided by assessment of

Time (sec) Time (sec)

Volume

Pressure

Flow

Figure 14-8 Left: Volume-limited ventilation. Note the square wave flow pattern. Right: Pressure-controlled ventilation. Note the decelerating flow pattern.

Time (sec) Time (sec)

Volume

Pressure

Flow

Figure 14-9 Left: Synchronized intermittent mandatory ventilation. Note the larger, mandatedbreaths and the smaller, spontaneous breaths. Right: Assist-controlled ventilation. Note the negativepressure (initiated by the patient, arrows), triggering the assisted breath.


patient comfort and synchrony with the ventilator,blood gas determinations, non-invasive monitoring(SpO2, ETCO2), and in some cases, measurements oflung mechanics. For example, worsening hypercarbiacan be addressed by increasing minute ventilation byincreasing either the ventilator rate or tidal volume.Worsening hypoxemia can be addressed by increasinginspired fraction of oxygen or mean airway pressure.

Ventilator-induced lung injury (from “volutrauma”, i.e.,overdistension of the lung, or “barotrauma”, i.e., highpressures in the airway) can be minimized by strategies tominimize transmural pressures. Additionally, attention topeak airway pressures and mean airway pressures is nec-essary. Indeed, it is now accepted practice to allow forsome degree of hypercarbia, rather than attempting toachieve eucapnea, if a normal pCO2 can only be obtainedthrough the use of high airway pressures. This “permissivehypercapnea” strategy recognizes the need to balance nor-malization of blood gases against the potential to causeairway and lung injury. Overdistension of the lung can berecognized from the pressure–volume curve (displayed bymany hospital ventilators).

For patients with chronic respiratory failure, severalventilators are available for home use. Some of these arefairly simple (i.e., providing only volume-limited ventila-tion), while others provide many of the same modes ashospital ventilators (Table 14-3).

Home ventilators can be powered by a portable battery, further enhancing patient mobility. Monitoringin the home setting is usually accomplished by pulseoximetry, and sometimes capnography. Care of thehome ventilator patient requires a team approach,which necessitates participation by nurses, respiratorytherapists, physicians, and most importantly trained family caregivers7.

Non-invasive Positive-Pressure VentilationNon-invasive positive-pressure ventilation (NIPPV) is

typically provided via a nasal interface (masks or prongs,Figure 14-10), and delivers flow in a pressure-supportpattern.

The most commonly used style is termed bi-level posi-tive airway pressure (BLPAP), in which the clinicianchooses an inspiratory positive airway pressure (IPAP)and expiratory positive airway pressure (EPAP); the venti-lator cycles between these two pressures. The inspiratoryflow from the ventilator (to reach IPAP) is usually trig-gered by the patient, and terminated when the inspiratoryflow rate has decreased to a predetermined percentage ofinitial flow rate. A “back-up” rate can be set if there areconcerns about patient ability to trigger the ventilator, orabnormalities in respiratory drive. Newer BLPAP genera-tors include features that allow time-cycled termination ofthe breath, and a “ramp” function which slowly increasesthe inspiratory pressures over a period of 15–30 minutesto allow patients to accommodate to the pressures.

NIPPV has been used more commonly for chronicrespiratory failure, especially in patients who requiresupport for only a portion of the day or for patients whorefuse endotracheal intubation8. More recently, NIPPVhas also been used for acute respiratory failure withgood success9. It obviates the need for an artificial air-way, thus enhancing patient communication and poss-ibly decreasing the risk of infectious complications.Complications of NIPPV can be related to the mask/interface, and include skin or nasal irritation; any persistentarea of facial erythema is worrisome and requires measuresto prevent ulcer formation. Anxiety can develop, resultingfrom a feeling of claustrophobia from the mask, high airflow rates, or ineffective ventilation. Air leakage throughthe mouth can result in ineffective ventilation, and leakagearound the interface can cause irritation of the eyes.Gastric distension can occur, as the airflow is not directedsolely to the airway, but to the esophagus as well. If this issevere, it can be treated with nasogastric tube decompres-sion. Close monitoring for these complications is war-ranted in the care of patients receiving NIPPV.

Inhaled Nitric OxidePreviously called “endothelial-derived relaxing factor”,

nitric oxide (NO) mediates (amongst other things) vascu-lar smooth muscle relaxation via cGMP-dependent

Table 14-3 Ventilators Used in the Home Setting

Pressure- Volume- Pressure Continuous control control Support CPAP Flow

LTV (Pulmonetics) ✓ ✓ ✓ ✓ ✓

T-Bird (Bird Ventilators) ✓ ✓ ✓ ✓

LP-10 (Puritan Bennett) ✓

PLV-100 (Respironics) ✓

HT-50 (Newport) ✓ ✓ ✓ ✓ ✓


protein kinases. The discovery that a gas could act as anendogenous messenger resulted in the Nobel Prize beingawarded to Drs. Robert Furchgott, Louis Ignarro, andFerid Murad in 1998, and nitric oxide was named“Molecule of the Year” by the journal Science in 1992. NOis produced by the pulmonary vascular endothelium bynitric oxide synthetases (NOS), which can be constitutiveor inducible, from L-arginine. It has been well demon-strated that inhaled nitric oxide (iNO) decreases pul-monary artery pressure, and because it is rapidly (seconds)inactivated upon binding hemoglobin, it has minimaleffects on peripheral vascular tone. Additionally, when themolecule is administered by inhalation, it will be preferen-tially delivered to areas with good ventilation, thus pre-serving hypoxic vasoconstriction in areas that are poorlyventilated and possibly improving ventilation–perfusionmatching in areas that are well ventilated. It has been used with good results in neonates with persistent

pulmonary hypertension of the newborn, demonstratingimprovement in oxygenation and reduced need forextracorporeal membrane oxygenation (ECMO). iNO(Innomax, INO Therapeutics) was approved by the U.S.Food and Drug Administration (FDA) in 1999 for use inneonatal hypoxemic respiratory failure. As with manytherapies, there is less clear evidence that iNO benefitsolder patients with respiratory failure. Indeed, in a ran-domized, double-blinded trial of 385 adults with ARDS,there was no effect of iNO on mortality or ventilator-freedays. Patients with ARDS in whom pulmonary hyperten-sion is a predominant pathophysiologic mechanism aremore likely to benefit from iNO. The therapy is not with-out potential complications; oxidation of NO producesmethemoglobin, as well as free radical species includingsuperoxide and peroxynitrite, which can be cytotoxic.Because of these toxicities, care and monitoring of patientsreceiving iNO includes carefully measuring delivered gas

A B

C

Figure 14-10 Nasal masks (A, B) and prongs (C) used for non-invasive positive-pressure ventilation.


Figure 14-11 Circuit configuration for veno-venous extracor-poreal membrane oxygenation (ECMO). Venous blood is drainedfrom the right femoral vein, oxygenated, and pumped back to theright atrium. (From Zwischenberger JB, Steinhorn RH, Bartlett RH.ECMO: extracorporeal cardiopulmonary support in critical care,2nd edition, p 24. Ann Arbor, MI: Extracorporeal Life SupportOrganization [ELSO], 2000.).

concentrations, scavenging exhaled gases for nitrogendioxide, and measuring serum methemoglobin levels.

Extracorporeal Membrane OxygenationThe techniques that underlie the use of extracorporeal

membrane oxygenation (ECMO; also known as extracor-poreal life support, ECLS) were developed in the early1950s by cardiothoracic surgeons, and extended topatients outside of the operating room in the early1970s10–12. The main principle is that the gas exchangefunctions of the lung (oxygenation and ventilation) canbe provided by an artificial membrane in place of thealveolar-capillary membrane. While this support is pro-vided extracorporeally, many of the detrimental pul-monary effects of mechanical ventilation can beminimized. The goal of this strategy is to support thepatient while allowing the underlying disease (pneumonia,sepsis, persistent pulmonary hypertension, meconiumaspiration) to improve.

It can be sometimes difficult to balance the risks ofECMO (see below) against the potential benefits, andchoosing the optimal time to initiate this therapy is notstraightforward. Commonly, neonatal patients with anoxygenation index (OI = Mean airway pressure × FiO2/PaO2), greater than 40 are considered candidates due totheir high risk of mortality with conventional therapy.Premature infants (<34 weeks) are typically excludeddue to the risk of intracranial hemorrhage; less prema-ture but growth-retarded infants (<2 kg) may not be ableto accommodate the ECMO intravascular catheters. Mostphysicians would consider irreversible lung disease(severe pulmonary hypoplasia or fibrotic processes) orterminal disease (metastatic cancer) to be contraindica-tions, but the literature contains reports of all thesetypes of patients being treated with ECMO.

ECMO can be achieved by two main configurations—veno-arterial (V-A) and veno-venous (V-V) bypass—although the general methods are quite similar (Figure 14-11). For both, blood is drained from the patientvia a large central vein (typically the internal jugular veinor, in larger patients, a femoral vein); drainage occurs bygravity to a reservoir (bladder). The blood is pumped fromthe bladder into the membrane “lung” using a roller pumpthat will de-activate if the bladder is empty; in this way,venous return controls the input into the circuit. The“lung” (usually composed of silicone) allows for diffusionof oxygen (in) and carbon dioxide (out), the rates of whichare dependent on the flow rate of blood through the lungand the partial pressures of the gas on the other side of themembrane (“sweep gas”). Carbon dioxide transfer is soefficient that CO2 usually needs to be added to the gasmixture. After the blood has passed through the lung, it is re-warmed and returned to the patient. In V-A ECMO,the route is typically via the right carotid artery; thus themajority of the flow in this configuration bypasses the

heart and so does not require normal cardiac output; itis therefore preferred in situations of severe cardiac dys-function. It should also be noted that most blood alsobypasses the lungs, and the effects of the lungs beingrelatively unperfused have not been well studied. Ashort length of “bridge” tubing connects the venous(from the patient) and arterial (to the patient) portionsof the circuit, allowing for intermittent periods when thepatient can be temporarily separated from the circuit(during the weaning process, or for maintenance of thetubing). In V-V bypass, the return of the oxygenatedblood occurs through a second lumen of the catheterproviding the venous drainage, and is deposited in theright atrium. Thus, in V-V bypass, there is a certain amountof “recirculation” of oxygenated blood from the circuitthat is re-drained via the venous catheter, complicatinginterpretation of oxygen delivery. Additionally, the flowthrough the circuit is dependent on native cardiac output.As the patient’s underlying disease improves, the flowthrough the ECMO circuit can be gradually decreased,aiming towards decannulation from bypass.

Both V-A and V-V ECMO presently require systemicanticoagulation to prevent clotting in the circuit(heparin bonded circuits are in development), and thisrepresents one potential source of ECMO complications.


Monitoring of the anticoagulation status at the bedsideusually occurs hourly, and adjustments in the rate ofheparin infusion can be made. Indeed, surgery can besafely accomplished while the patient receives ECMOsupport, albeit with increased attention to anticoagula-tion status. Nonetheless, potential for intracranial bleed-ing limits the applicability of this technique in prematureinfants. Other potential complications include infection,circuit failure/rupture, and fluid retention. The vesselsused for bypass are ligated when the patient is decannu-lated, and this results in impairment of venous drainage(VV, jugular vein) and/or arterial supply (VA, carotidartery) to the ipsilateral side of the brain.

Caring for patients on ECMO requires a dedicated multi-disciplinary team, including but not limited to nurses, respi-ratory therapists, neonatal or pediatric intensivists, andsurgeons. Patients require continuous monitoring and fre-quent laboratory studies, medications, and adjustments. Theresources involved in providing this care to an individualpatient, and in maintaining such a program, are extensive.

In neonatal patients, it is clear that use of ECMO hassubstantially improved the survival of infants with persist-ent pulmonary hypertension of the newborn and meco-nium aspiration syndrome. As ECMO centers have gainedexperience over the years, the indications for use ofECMO have been broadened, and it has become more dif-ficult to assess the results. Similarly, in pediatric patients,the causes of respiratory failure are quite varied, compli-cating an analysis of benefits. There are several studiesattempting to address the developmental outcomes ofinfants treated with this therapy, and it seems that mostinfants survive without handicaps markedly different fromthose of other graduates of the NICU.

Non-traditional Therapies

With the exception of negative-pressure ventilation, useof the following therapies has been restricted to ARDS.

Prone PositioningSince the early 1970s, it has been recognized that the

lung disease in ARDS is non-homogeneous, and thatthere is a gravity-dependent gradient of opacification(worse in the dependent regions). Studies using chestCT demonstrated that this distribution shifted whenpatients were placed prone, resulting in better aerationand perfusion of the posterior (and larger) portions ofthe lung, and subsequent better oxygenation. This wasconfirmed in several small clinical studies in adults, andthere are only limited supporting data in pediatricpatients13,14. Complications from prone positioningappear to be uncommon, but can include transient oxy-hemoglobin desaturations or increased secretions, vom-iting, hypotension, and displacement of catheters orendotracheal tubes. Which patients will benefit mostfrom this technique, and how often and for how long toposition patients prone, are unanswered questions.

Negative-Pressure VentilationAs in positive-pressure ventilation, flow of air into the

lungs is dependent upon a pressure gradient betweenthe mouth and the alveoli. In negative-pressure ventila-tion (NPV), this gradient can be achieved by loweringthe body surface pressure below atmospheric pressure.This requires an interface between the negative-pressuregenerator and the patient, and can be a tank (e.g., the“iron lung” of the 1950s poliovirus epidemic), body suit/poncho, or cuirass/shell (Figure 14-12).

One advantage of this mode of ventilation is that itdoes not require an endotracheal tube, and therefore thepatient is able to speak and eat. Additionally, the negativeintrathoracic pressure enhances venous return (in con-trast to possible impairment of venous return with positive-pressure ventilators). Most negative-pressureventilators, however, are not portable. In addition, upperairway collapse may be exacerbated. The ventilators tendto be time-cycled, pressure-limited, but many of thenewer ventilators have modes of ventilation that are

A B

Figure 14-12 Negative-pressure ventilators. (A) The tank (www.porta-lung.com) and (B) cuirassinterfaces are depicted both are connected to the negative-pressure generator (not shown). (Part Bcourtesy of Professor Anne Thomson, Radcliffe Hospital, Oxford, UK.)


similar to their positive-pressure counterparts, includingCNEP (continuous negative expiratory pressure), inter-mittent mandatory ventilation, and assist-control (using anasal cannula to sense patient effort). This mode of ven-tilation may be particularly useful for patients withchronic respiratory failure who require continuous venti-lation but who wish to avoid tracheostomy, or forpatients who find the facial interfaces for non-invasivepositive-pressure ventilation uncomfortable.

High-Frequency Oscillatory VentilationHigh-frequency ventilation (HFOV) has the potential

to recruit lung units with the use of high mean airwaypressure while limiting ventilator injury by usingextremely small tidal volumes and lower peak inspira-tory pressures. In this way, the lungs are ventilated onthe steeper (more compliant) portion of the pres-sure–volume curve. In fact, the tidal volumes that wouldbe achieved by these pressure swings are smaller thanthe anatomic dead space. Gas exchange, therefore,occurs by means other than those typical for traditionalventilation, and includes molecular diffusion and pen-dulluft (gas mixing that occurs within the lung). In thismode of ventilation, the modifiable parameters are Paw(mean airway pressure), oscillating frequency (usually5–10 Hz, or 300–600 breaths/minute), FiO2, and pres-sure amplitude (usually set to result in visible chest wallshaking). Some institutions utilize aggressive re-recruit-ment maneuvers (rapid increases in Paw) to achievemaximum effectiveness of HFOV. However, disconnect-ing the patient from the ventilator for suctioning, trans-port, etc., can result in loss of recruited lung units.Additionally, spontaneous breathing during this type ofventilation is ineffective, and patients are usually para-lyzed and deeply sedated.

A randomized trial comparing HFOV and conven-tional ventilation in 70 pediatric patients with ARDS15

demonstrated no differences in important clinical out-comes (e.g., mortality). In a post-hoc analysis, there wasa lower mortality in the subgroup of patients treatedonly with HFOV. In most institutions, HFOV is used as arescue therapy for pediatric patients rather than as a pri-mary mode of treatment.

Liquid VentilationLiquid ventilation aims to achieve gas exchange in the

lung via inhalation of an inert fluid (e.g., a perfluoro-chemical) in place of the gases normally filling the lung.Perfluorochemicals have a very high density (approxi-mately twice that of water), low viscosity, low surfacetension, and a very high solubility for oxygen and carbondioxide. There are several potential advantages to thisstrategy. First, the liquid-filled lung has no air–liquidinterfaces; this dramatically reduces surface tension andimproves lung compliance. Secondly, perfluorochemi-cals distribute more evenly than gas in the diseased lung,

thus potentially allowing for widespread drug delivery.This distribution effect also allows the liquid to recruitatelectatic lung units, improving ventilation–perfusionmatching. Additionally, because they are nearly com-pletely immiscible with most other liquids, perfluoro-chemicals may enhance removal of airway debris, whichfloats to the top of the perfluorochemical. This effect hasbeen noted in infants treated for meconium aspiration anda child with hydrocarbon aspiration16. Liquid ventilationhas been attempted using either completely liquid-filledlungs (total liquid ventilation) or partially filled lungs incombination with standard gas ventilation (also known asPAGE, or perfluorochemical assisted gas exchange). Inpartial liquid ventilation (PLV), the lungs are typicallyinflated with a volume of perfluorochemical equivalent tothe functional residual capacity, or about 30 ml/kg.

In one preliminary study of partial liquid ventilation inpremature infants with respiratory distress syndrome,oxygenation and lung compliance improved17. In anuncontrolled phase II study in adults with ARDS, PLV-treated patients demonstrated a decreased mortalitycompared with patients treated with conventional gas ventilation. However, a recently completed phaseII–III trial with 311 adult ARDS patients at 56 centers in the United States, Canada, and Europe (AlliancePharmaceuticals), failed to demonstrate any improve-ment in mortality or ventilator-free days. In this study,the control group had a very low mortality (15%), whichmay be due to newer strategies for traditional gas venti-lation. At present, liquid ventilation must be consideredstrictly experimental.

The Recovery Phase

In some situations, as the acute lung injury resolves,withdrawal of ventilatory support may become possible.Strategies include incremental reductions in ventilatorpressures or rate and daily attempts to discontinue ven-tilator support (“sprints”). The choice of weaning strat-egy depends, in part, on the cause of the acute lunginjury. The optimal manner in which a patient is liber-ated from support remains controversial18,19. Some chil-dren with chronic respiratory failure that improves (e.g.,the older child with bronchopulmonary dysplasia) mayalso be candidates for liberation from mechanical ventila-tion. In these situations, too, there is great variability inhow to accomplish this goal. At the author’s institution,frequent telephone assessments are made with informa-tion provided by parents or home caregivers. This infor-mation (which includes growth measurements,assessments of stamina for play or therapies as well asoxygenation and ventilation, and tolerance of “sprints”)guides decisions about moving forward in the process ofliberation.


MAJOR POINTS

1. Normal transport of oxygen and carbon dioxiderequires careful matching of ventilation and perfusion.

2. Respiratory failure can occur from a multitude ofcauses involving all aspects of the respiratorysystem, including the respiratory drive center, chestwall, respiratory muscles, and gas exchange units.

3. Treatment goals for acute respiratory failureinclude supporting organ function while recoveryfrom the underlying injury occurs.

4. Optimal ventilator strategy cannot be determined a priori, and requires frequent reassessment andmonitoring of the patient.

5. Chronic respiratory failure may be treated in thehome setting using a multidisciplinary team approach.

�

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SUMMARY

Children may experience respiratory failure fromdiverse causes that can affect respiratory drive, respira-tory muscles, or gas exchange units. A wide spectrum oftherapies (including positive-pressure ventilation, nega-tive-pressure ventilation, and non-invasive ventilation)are routinely involved in the management of respiratoryfailure. Other therapies (ECMO, nitric oxide, liquid ven-tilation) are reserved for cases where standard therapieshave failed. The overall goal of management is to main-tain gas exchange and oxygen delivery while minimizingiatrogenic lung injury as the underlying cause of the res-piratory failure is treated. Chronic ventilation is increas-ingly used in the home setting for children with chronicrespiratory failure. It is to be hoped that research in allthese areas will result in continued improvements in sur-vival and pulmonary and developmental outcomes.

REFERENCES

1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet II:319–323, 1967.

2. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K,Hudson L, Lamy M, LeGall JR, Morris A, Spragg R. Report ofthe American-European consensus conference on ARDS:definitions, mechanisms, relevant outcomes and clinicaltrial coordination. The Consensus Committee. IntensiveCare Med 20:225–232, 1994.

3. Williams AJ. ABC of oxygen: assessing and interpreting arte-rial blood gases and acid–base balance [review]. Br Med J 317:1213–1216, 1998.

4. Shapiro BA. Arterial blood gas monitoring [review]. CritCare Clin 4:479–492, 1988.

5. Sinha S, Nicks J, Donn S. Graphic analysis of pulmonarymechanics in neonates receiving assisted ventilation. ArchDis Child Fetal Neonatal Ed 75:F213–F218, 1996.

6. Tobin MJ. Advances in mechanical ventilation. N Engl J Med 344:1986–1996, 2001.

7. Panitch H, Downes J, Kennedy J, Kolb S, Parra M, Peacock J,Thompson M. Guidelines for home care of children withchronic respiratory insufficiency. Pediatr Pulmonol21:52–56, 1996.

8. Meduri GU, Fox RC, Abou-Shala N, Leeper KV, WunderinkRG. Noninvasive mechanical ventilation via face mask inpatients with acute respiratory failure who refused endo-tracheal intubation. Crit Care Med 22:1584–1590, 1994.

9. Corbetta L, Ballerin L, Putinati S, Potena A Efficacy of non-invasive positive pressure ventilation by facial and nasalmask in hypercapnic acute respiratory failure: experiencein a respiratory ward under usual care. Monaldi Arch ChestDis 52:421–428, 1997.

10. Bartlett RH, Fong SW, Woldanski C, Hung E, Styler D,MacArthur C. Hematologic responses to prolonged extra-corporeal circulation (ECC) with microporous membranedevices. Trans Am Soc Artif Intern Organs 21:250–257,1975.

11. Hill JD, O’Brien TG, Murray JJ, Dontigny L, Bramson ML,Osborn JJ, Gerbode F Prolonged extracorporeal oxygena-tion for acute post-traumatic respiratory failure (shock-lungsyndrome). Use of the Bramson membrane lung. N Engl J Med 286:629, 1972.

12. Hill JD, De Leval MR, Fallat RJ, Bramson ML, Eberhart RC,Schulte HD, Osborn JJ, Barber R, Gerbode F. Acute respi-ratory insufficiency. Treatment with prolonged extracor-poreal oxygenation. J Thorac Cardiovasc Surg 64:551–562,1972.

13. Numa AH, Hammer J, Newth CJ. Effect of prone and supinepositions on functional residual capacity, oxygenation, andrespiratory mechanics in ventilated infants and children.Am J Respir Crit Care Med 156:1185–1189, 1997.

14. Curley MA, Thompson JE, Arnold JH. The effects of earlyand repeated prone positioning in pediatric patients withacute lung injury. Chest 118:156–163, 2000.

15. Arnold JH, Hanson JH, Toro-Figuero LO, Gutierrez J, Berens RJ, Anglin DL. Prospective, randomized compari-son of high-frequency oscillatory ventilation and conven-tional mechanical ventilation in pediatric respiratoryfailure. Crit Care Med 22:1530–1539, 1994.

16. Pranikoff T, Gauger PG, Hirschl RB. Partial liquid ventilation ina child on extracorporeal life support. Asaio J 42:317–320,1996.

17. Leach CL, Greenspan JS, Rubenstein SD, Shaffer TH,Wolfson MR, Jackson JC, DeLemos R, Fuhrman BP. Partialliquid ventilation with perflubron in premature infantswith severe respiratory distress syndrome. The LiquiVentStudy Group. N Engl J Med 335:761–767, 1996.

18. Hess DR. Liberation from mechanical ventilation: weaningthe patient or weaning old-fashioned ideas? Crit Care Med30:2154–2155, 2002.

19. Scheinhorn DJ, Chao DC, Stearn-Hassenpflug M Liberationfrom prolonged mechanical ventilation. Crit Care Clin18:569–595, 2002.

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CHAPTER

15 Viral Infections of theRespiratory TractMICHAEL R. BYE, M.D.

Croup

Acute Bronchitis, or Upper Respiratory Illness

with Persistent Cough

Bronchiolitis

Pneumonia

Acute Asthma Exacerbation

Viruses cause the overwhelming majority of infec-tions of the respiratory tract in children. In some cases itmay be difficult to differentiate between bacterial andviral disease, but most of the time viruses are causing theinfection. This chapter will start at the larynx and workdown through the airways to the lung parenchyma. Theinfections to be discussed include croup, bronchitis,bronchiolitis, and pneumonia. Although asthma is not aviral disease, acute asthma attacks are often triggered byviral infections. There is therefore a brief discussion ofasthma at the end of this chapter. With each of the infec-tions, the common etiologies, the pathophysiology, andan approach to therapy will be reviewed.

CROUP

Croup is typically a viral infection of the upper air-ways. Croup is also known as laryngotracheobronchitis,suggesting the wide segments of the airway that may beinvolved. Croup is most commonly caused by parain-fluenza, and less frequently by respiratory syncytial virus(RSV). Other, even less common causes include aden-ovirus and rhinovirus. In the era before immunization forHaemophilus influenzae type b, it was often importantto differentiate between acute croup and epiglottitis.With the increasing immunization against that bacterium,bacterial epiglottitis, which can be a life-threatening ill-ness, has become very uncommon. Although croup mayoccur at virtually any age, it typically occurs between the ages of 6 months and 3 years. Because parainfluenza

and RSV cause the majority of cases of croup, most casesof croup occur in the fall through winter months. In theNortheast United States there are occasional summeroutbreaks of parainfluenza with concomitant outbreaksof croup.

Croup typically begins with simple coryza. After 1–2days of coryza, the croup symptoms begin. The hallmarkof the disease is airway obstruction in the extrathoracicairways, especially the subglottic space. Thus the typicalclinical finding is of stridor. This is an inspiratory crow-ing noise generated by air moving through the narrowedextrathoracic airways. The pathophysiology of croupincludes edema and inflammation of the vocal cords andthe subglottic space. As the name indicates, this airwayinflammation and edema will often spread into the tra-chea and the bronchi. In some cases the pathologyextends into the bronchioles as well. Because there isinflammation and swelling of the vocal cords and thesubglottic space, a barky cough may be present, and thecry or voice may be hoarse. For unknown reasons, croupsymptoms often begin at night. The symptoms fre-quently progress for 1–2 days, and remit after 3–7 days.There are usually no sequelae. Since the intrathoracic air-ways can be involved, wheeze may be present, butcrackles are uncommon. Because much of the pathologyis above the carina, gas exchange is rarely affected.Patients will therefore often have normal oxygen satura-tion, unless there is enough obstruction to causehypoventilation. If the airways distal to the carina areinvolved, ventilation–perfusion mismatch may occur andhypoxemia is more likely to occur.

Children with spasmodic croup may not have any pro-drome, and they usually have recurrent disease. In mostcases, despite the recurrence of episodes, an investigationof the airway does not reveal any anatomic abnormalities.These children may have a form of airway reactivity. In such children a combination of corticosteroids andbronchodilators, sometimes in combination with inhaled


epinephrine, can be helpful. Such children may subse-quently develop the more typical lower airway manifesta-tions of asthma.

At physical examination, the child with croup willoften have mild tachypnea. It is advantageous to attemptto maintain laminar flow through the obstructed airwayby keeping the child calm and breathing as slowly aspossible. Elevated respiratory rates and flow rates willresult in more turbulent flow, which will pass throughthe obstructed airway with more difficulty. Trying toexplain this physiology to a 3-year-old is patently absurd.However, children with croup learn to accommodatequickly, and maintain an advantageous respiratory pat-tern, without having read a physiology textbook. As indi-cated above, stridor is a prominent finding in acutecroup. Stridor may be defined as any inspiratory noise.With croup, it is typically a crowing noise that is purelyinspiratory. There may be an exhalatory component ifthere is sufficient obstruction of the subglottic space orif the obstruction extends into the intrathoracic airways.Examination of the chest wall reveals retractions at thelevel of the sternum, and often in the suprasternal chestwall. These are caused by use of the accessory musclesof inspiration, and since the obstruction is primarilyextrathoracic, the child has difficulties getting air in.Because hyperinflation is uncommon with croup, sub-costal retractions are also uncommon. With increasingobstruction, intercostal retractions may occur. As above,wheezes may be heard if the obstruction descends intothe intrathoracic airways, or if the subglottic obstructionis fixed and significant. Crackles are uncommon becausethe pathology rarely progresses into the small airways.The degree of respiratory difficulty is best assessed bythe level of comfort of the child, the presence of stridor,and the severity of the retractions. Assessing air entrywith a stethoscope is important. If the child’s oxygena-tion is not normal, this is a worrisome sign.

The diagnosis of croup is usually a clinical one.Differentiating croup from epiglottitis is no longer amajor issue, as the incidence of Haemophilus influenzaetype b infection is decreasing markedly. An acute laryn-geal foreign body is always a possibility in this age range.However, given the typical clinical scenario, radiographsor endoscopy are not routinely warranted. If radiographsof the neck are obtained, both anteroposterior and lat-eral films give information about the diagnosis. The mostprominent findings occur on the anteroposterior film(Figure 15-1). Normally, if one looks at the subglotticspace on the film, the airway is outlined by “squareshoulders” as the air column juts out from the vocalcords into the subglottic space (Figure 15-1A). Becausein croup the subglottic space is narrowed, the shadowon the film has a “steeplechase” appearance, with amore gradual widening of the airway as one descendsinto the trachea (Figure 15-1B). The lateral neck film often

reveals distension of the hypopharynx, a radiographicdemonstration of the air not entering the airway.

Croup is a self-limited disorder. Therefore, therapy isindicated for those children more severely affected.Thus, acute intervention might be indicated for thosechildren with supplemental oxygen requirements,excessive work of breathing which might interfere withadequate nutrition or lead to respiratory fatigue, or thosewho might otherwise require admission to the hospital.

Mist therapy helps some children with croup.Empirically, both warm mist and cool mist have helped.Therefore an early approach is to bring the child into thebathroom and keep the shower running, developingmist in the room. With small infants, it is important thata parent stay in the bathroom with the infant. Cool mistcan simply be provided by night air. Therefore, a secondstep might be to take the child for a walk around theblock, or for a drive in the car with the windows open.Very often, after these two procedures, the child is wellenough to fall back to sleep. Despite the utility of mist asan early therapy, if the child is admitted to hospital, plac-ing him or her in a mist tent is often counterproductive.This separates the child from the parent, whichincreases the anxiety on the part of the child. As a result,the child’s respiratory rate will increase, making inspira-tory airflow more turbulent. In addition, once the childis in the mist tent, it is difficult to assess the child’s chestwall, critical to the sequential assessment of the childwith croup.

If the child has a history of asthma, the virus causingcroup can also trigger asthma. In those children, bron-chodilators are helpful. In patients with recurrent or spas-modic croup, bronchodilators may also help. However,for most children with croup, beta-agonists are not useful.Corticosteroids have been shown to reduce the severity ofdisease, the length of the disease, and for hospitalizedpatients to reduce transfers to the intensive care unit.Dexamethasone at 0.6 mg per kilogram is effective byboth parenteral and oral routes. One study suggested neb-ulized budesonide 2 mg to be effective. Lower oral dosesof dexamethasone, including 0.3 mg per kilogram and0.15 mg per kilogram, have also been successful.However, the number of patients enrolled in the studieshas been low. Given the relative lack of toxicity, a currentrecommendation might be to use the higher dose of dex-amethasone, given orally. Although dexamethasone is themost commonly studied steroid for croup, there is no rea-son why equivalent doses of prednisone or prednisoloneshould not be effective.

The child who is dyspneic, has supplemental oxygenrequirements, seems fearful or fretful, or has insufficientgas exchange is clearly a candidate for therapy. If admis-sion to hospital is being considered for these or other reasons, therapy should be instituted. The time-honoredtherapy is inhaled epinephrine. This primarily causes

Viral Infections of the Respiratory Tract 225

vasoconstriction in the upper airways, and reduces theswelling in the epithelium. It also acts as a bronchodilator,important for those children with pre-existing asthma.Inhaled epinephrine may be given either as the racemicform, which is time-honored; or as levoepinephrine. Ineither case, the medication should be given through anebulizer. An over-the-counter form of epinephrine existsas a metered dose inhaler. This could be deliveredthrough a valved holding chamber with mask apparatus.We have used this for some children with spasmodiccroup. In these children, the croup is a forme fruste of

asthma, with edema of the upper airway more prominentthan usual. This is not for routine cases of croup.

For many years, there was concern about the poten-tial for rebound obstruction after epinephrine, whereairway mucosal edema might increase as the vasocon-strictive effects of the drug wore off. However, carefulstudies have not borne out this phenomenon. These datasuggest that if the child does not worsen 1–2 hours aftertreatment, it is not likely to happen. At that point thedecision to admit or send the child home can be basedpurely on the current clinical status.

A BFigure 15-1 (A) Normal anteroposterior view of the neck, demonstrating the typical “square-shouldered” appearance of the subglottic space. (B) Anteroposterior view of the neck in a childwith acute laryngotracheobronchitis (croup). Note the extended area of narrowing of the air tracheogram in the immediate subglottic space (arrows). (Radiographs courtesy of Avrum N.Pollock, M.D., FRCPC.)


Children with increasing oxygen requirements or withdeteriorating gas exchange, or in whom progressive res-piratory fatigue appears to be occurring, should be trans-ferred to a Pediatric Intensive Care Unit (PICU). Anadjunct therapy in the PICU might be institution of inhala-tion of a mixture of helium and oxygen. Helium, becauseof its lower density than room air, will move through thenarrowed airways more readily. This reduces the workof breathing and improves gas exchange. The risk of thismixture is the limitation of supplemental oxygen thatcan be given. However, in many cases the improved gasexchange and decreased work of breathing more thancompensate for the difficulty in delivering high oxygenconcentrations, and the child is able to ventilate and oxy-genate adequately. If the respiratory status continues todeteriorate, endotracheal intubation should be consid-ered. The endotracheal tube should be able to bypassthe obstructed airway, and allow for better gas exchangeand oxygenation, until healing of the airway occurs. Thesmallest possible endotracheal tube that allows adequateventilation should be used. Airway intubation should bedone in conjunction with, or by, a pediatric intensivistor pediatric anesthesiologist. Using too large an endotra-cheal tube increases the risk of further damage to theinflamed subglottic space, prolonging the acute damageand increasing the risk of subglottic stenosis after theacute infection has subsided. In most cases, an uncuffedtube should be used, again to reduce mucosal damageand allow healing of the airway wall. The endotrachealtube should be left in place until there is clinical evi-dence of a leak around the tube, suggesting that theswelling has subsided sufficiently, and that the childshould be able to maintain gas exchange and oxygena-tion. We normally continue systemic corticosteroidsuntil the child has been successfully extubated, and fora few days beyond. Unless there is pre-existing asthma orpersisting airway obstruction, we do not routinely uselong-term corticosteroids.

ACUTE BRONCHITIS, OR UPPERRESPIRATORY ILLNESS WITHPERSISTENT COUGH

Bronchitis technically refers to inflammation of theairways. It occurs frequently in children, in conjunctionwith an upper respiratory infection (URI). After theonset of the URI the child will begin to cough, andrhonchi may be heard. Bronchitis in otherwise healthychildren is almost never bacterial, and almost neverrequires antibiotic therapy. The same virus causing theURI usually causes the bronchitis. Symptomatic therapyis usually all that is necessary for bronchitis. There hasbeen no proven benefit to antibiotics, cough suppres-sants or decongestants. A special note should be made

for the child with asthma. When making the diagnosis ofbronchitis in the child with asthma, or the diagnosis ofasthmatic bronchitis, the therapy should be directedtowards the underlying asthma. In most cases asthmaticbronchitis is in fact asthmatic asthma. Once a child hasbeen diagnosed more than two or three times with bron-chitis, or has prominent or prolonged chest symptomswith colds, one should strongly consider the diagnosis ofasthma.

BRONCHIOLITIS

It has been suggested that over 90% of children willbe infected with RSV during the first 2 years of life. Insome children, RSV infection will trigger bronchiolitis.Viruses, including RSV, are the most common cause ofbronchiolitis. Other viruses which can cause bronchioli-tis include parainfluenza and adenovirus. Data show thatthose children who develop bronchiolitis with RSVinfection are likely to have had abnormal lung functionbefore the RSV infection; are likely to have higher hista-mine content in the airways, and specific IgE towardsthe RSV; and are likely to have increased levels of pro-inflammatory cytokines in the blood and airways com-pared with those who experience upper respiratorysymptoms. Children who develop bronchiolitis withRSV infection are at greater risk of subsequently devel-oping asthma. This appears to be at least in part becauseof pre-existing lung abnormalities as well as an abnormalimmune response. Bronchiolitis accounts for significantnumbers of hospital admissions each year, primarily inchildren under 2 years of age. There are some childrenat increased risk of severe disease from RSV infection.These include children with bronchopulmonary dyspla-sia or other chronic lung disease of infancy; childrenwith cyanotic heart disease, or those with significantpulmonary hypertension; and children born at less than32 weeks gestation, even without chronic lung disease.Children with human immunodeficiency virus (HIV)infection have been shown to be more likely to developpneumonia with RSV infection, and to harbor the virusfor longer periods than immunocompetent children.Acute severe bronchiolitis has been described in infantswith cystic fibrosis, and decades ago this accounted forsignificant mortality in affected children. However, thishas not been a major problem for this population inrecent years.

With bronchiolitis, the virus infects the airway epithe-lium and causes intense edema and an inflammatory reac-tion, leading to obstruction of the airways. This ismanifested in the child by tachypnea, hypoxemia fromventilation–perfusion mismatch, wheezing, crackles, andhyperinflation. The latter may be seen on physical examination or on the radiograph. Fever is often present.


The complications of bronchiolitis include hypoxemia,respiratory failure, dehydration from decreased fluidintake, and apnea. The cause of the apnea is unclear, butit is more likely to occur in young infants who were bornprematurely. RSV has a typical season. In the United Statesit starts around October and lasts 5 months, although itmay begin earlier and last longer in some southern states.Occasional summertime epidemics are seen. Childreninfected with HIV are likely to harbor the virus longerthan other children. This can account for sporadic infec-tion as the virus is transmitted to other children.

Bronchiolitis typically starts with rhinorrhea. After 2–3days, cough and wheeze develop. The cough and wheezeclear in 7–14 days, though they may last up to 3–4 weeksin some children. On examination, the child is typicallytachypneic with varying degrees of hypoxemia. The heartrate is usually elevated. The infant may have nasal flaring.Wheezes are a hallmark of the disease, from the intratho-racic airway obstruction. Crackles are heard as the inflam-mation obstructs the small airways. Subcostal retractions

are a manifestation of hyperinflation. Increasing degrees ofrespiratory difficulty will cause intercostal retractions aswell as accessory muscle use. The typical chest radiograph(Figure 15-2) reveals hyperinflation and peribronchialthickening. Areas of atelectasis are not uncommon.

In most cases bronchiolitis is a self-limited illness. Thetherapy of bronchiolitis has been unrewarding and oftendebated. Because these children look and sound likechildren with asthma, they often get the same medica-tions. Most studies show little to no effect from systemiccorticosteroids. Several studies looked at inhaled corti-costeroids after the acute bronchiolitis subsided, andfound no reduction in the frequency of subsequentwheeze. Bronchodilators, especially albuterol, work insome patients. However, most studies show that mostpatients do not benefit from albuterol or theophylline.Therefore, their routine use is discouraged. Early pathol-ogy data showed significant airway edema in infantswith bronchiolitis. Therefore, epinephrine was tried as a means of reducing the airway edema through its

A BFigure 15-2 (A) Anteroposterior chest radiograph of an infant with bronchiolitis. Note thewidened spaces between the ribs reflecting mild hyperinflation, and increased interstitial markings.Bibasilar subsegmental atelectasis is also present. (B) Lateral view of the chest. The diaphragm ismoderately flattened, again reflecting air trapping and hyperinflation. (Radiographs courtesy ofAvrum N. Pollock, M.D., FRCPC.)


α-adrenergic vasoconstriction effect, while simultane-ously providing bronchodilatation by its β-adrenergiceffects. Recent data, in fact, have suggested that inhaledepinephrine is more effective than albuterol at improv-ing clinical score and shortening hospitalization, withfewer side effects. It is critical to remember, however,that most infants with bronchiolitis improve and healspontaneously.

Most patients are not helped by medications, whichhave potential for side effects. One recommendationwould be not to give any treatment unless the childabsolutely requires therapy. A common definition ofrequiring therapy could include either hypoxemia neces-sitating supplemental oxygen, or inability to take ade-quate fluids by mouth. In these cases, inhaledepinephrine might be helpful. One might try albuterol aswell. However, a suggestion has been made that if thealbuterol does not help, it should not be repeated.Routine use of corticosteroids for children with bron-chiolitis is discouraged. If steroids are used in moreseverely ill patients, however, the systemic route (PO,IM or IV) has been shown to be more effective thanadministration by inhalation. Although an excellentadjunct to ill patients with asthma, ipratropium has notbeen shown to be helpful in children with bronchiolitis.If the child has significant hypoxemia, usually defined asoxygen saturation below 90%, supplemental oxygenshould be administered. In addition, if the child wereunable to take adequate fluids, intravenous fluids may benecessary. If there is any question about the child’s abil-ity to maintain the state of hydration, intravenous fluidsshould be considered. There are recent data suggestingan increased incidence of gastroesophageal reflux andaspiration during acute bronchiolitis, which resolveswhen the acute infection has resolved. Recent studiessuggest increased amounts of leukotriene in the urineand endotracheal secretions of children with acute bron-chiolitis. Clinical trials of leukotriene antagonists areanticipated. Unfortunately, only one of these agents isapproved for use in infants, and that approval is down toage 12 months: most ill infants with bronchiolitis arebelow that age.

Recently attempts have been made at preventing seri-ous RSV disease, defined as a lower respiratory illnessrequiring hospitalization. The most helpful products havebeen RSV-specific immunoglobulin (RSV-IVIG), and, morerecently, a monoclonal antibody (palivizumab). Studiesusing the monoclonal antibody have shown a high degreeof safety. Furthermore, children at risk, such as those withbronchopulmonary dysplasia, or children born prema-turely with lung disease, children born prematurely with-out lung disease, children with chronic lung disease, andchildren with congenital heart disease have been shownto experience decreased severity of illness with the mon-oclonal antibody product. It is important to warn parents

that this product does not prevent infection; it onlyreduces the severity of the acute illness. There are no dataas to whether the product reduces the subsequent devel-opment of asthma. Nor are there any data available on thedrug’s effectiveness in other populations. The AmericanAcademy of Pediatrics Committee on Infectious Diseases,in its 2000 Red Book, recommends palivizumab for chil-dren under 2 years of age with chronic lung disease ofinfancy who have required medical therapy within 6 months of the RSV season; infants born at 28 weeks gestation or earlier without chronic lung disease, up to 12 months of age; and infants born between 28 and 32 weeks gestation, up to 6 months of age.

PNEUMONIA

Viruses cause the majority of cases of pneumonia inchildren. Unfortunately, it is often difficult to decidewhether a virus or bacterium has caused pneumonia in aparticular patient. It is a suspicion of many that focal dis-ease associated with high fever is more likely a bacterialprocess, and diffuse disease with wheeze is more likelyto be viral. However, neither of these is an absolute find-ing and, as discussed above, this has been difficult toprove because of a lack of a readily accessible gold stan-dard. While there are factors that lead many to suspectone or the other (Table 15-1), these have been difficultto prove. Part of the problem is in defining a gold stan-dard for pneumonia. A definitive diagnosis of pneumoniawould require obtaining lung tissue such as from a per-cutaneous lung puncture. It would be difficult to imag-ine any institutional review board approving such astudy in children.

In most cases, pneumonia develops either as part of,or shortly after, a viral infection. Thus, unlike in adultswhere pneumococcal pneumonia often has a suddenonset of fever and respiratory symptoms, in childrenthere is usually a prodrome of upper respiratory infec-tion. The child then develops progressive lower respira-tory symptoms, including fever, tachypnea, dyspnea,and associated signs and symptoms including malaise,decreased appetite, and lethargy. Chest pain is uncom-mon unless there is pleural involvement.

On physical examination, the child is often tachyp-neic and tachycardic with fever. Infants will show nasalflaring in an attempt to increase inspiratory airflow, amanifestation of dyspnea. While cyanosis may be pres-ent, oxygen saturation decreases significantly wellbefore this overt manifestation of hypoxemia. Subcostalretractions are a manifestation of hyperinflation, such asseen with diffuse airway disease. Intercostal or supra-clavicular retractions indicate progressive dyspnea. Withmore airways obstruction, the accessory muscles in the neck are used to overcome the increased airway


resistance. Examination of the chest may include crackles,wheeze, and areas of decreased airflow. It is important toremember that crackles do not indicate alveolar disease,and are not necessarily indications of infection.

Crackles occur when the small airways are occluded,such as with inflammation, edema, or infectious materialwithin the airways; or inflammation, edema, or fibrosisoutside the airways. These airways are thus closed andopen as the child progressively inspires, the sound beingcaused as they snap open. Obviously, many diseaseprocesses can cause crackles. Crackles can be part of anasthma attack as the inflammation and edema closethose small airways.

The gold standard for diagnosing pneumonia remainsthe chest radiograph. Obviously, in a child with no pre-existing lung disease who presents with relatively sud-den onset of lower respiratory symptoms and hasfindings including crackles, the diagnosis of pneumoniashould be entertained and treated. In that case a radi-ograph is not necessary. However, with pre-existinglung disease such as asthma, the findings can be ascribedto the underlying disease. In those cases, a radiographmay be helpful. As anyone who has waited for a radi-ograph can attest, the problem of lag of development ofthe radiographic findings is overplayed. Similarly, therole of dehydration in masking a radiographic abnormal-ity is overplayed. It has been shown that overhydrationduring acute pneumonia in dogs worsened the radi-ograph but did not alter the pattern. If a radiograph isabnormal, the abnormalities will often take up to 2 monthsto clear. While an elevated white blood cell count andincreased numbers of polymorphonuclear cells and/orbands will increase the likelihood of a bacterial process,even under those circumstances most infections areviral. If a child is able to produce sputum, its examina-tion can be rewarding. The finding of polymorphonu-clear cells or intracellular organisms strongly suggests anacute bacterial process, and the need for antibiotics.Careful analysis has shown that neither thickness of thesputum nor discoloration correlates with the likelihoodof an acute bacterial process.

ACUTE ASTHMA EXACERBATION

By including asthma in this chapter, I by no meansimply that asthma is a viral disease. However, the major-ity of asthma attacks that get children to the emergencyroom or admitted to hospital are triggered by viral infec-tions. Thus, children with acute asthma attacks willoften have fever, as a manifestation of the viral infectiontriggering the asthma. The physical examination mayinclude wheeze, crackles, and areas of decreased airentry similar to those findings in the child with pneu-monia. If the child with an acute asthma attack has achest radiograph, areas of atelectasis can often be misin-terpreted as acute infiltrates. Just managing the underly-ing asthma, with bronchodilators and corticosteroids,can treat most of these children. Antibiotics are not nec-essary for the majority of these children.

Table 15-1 Factors Favoring a Diagnosis of Viral or Bacterial Pneumonia

Factor Viral Pneumonia More Likely Bacterial Pneumonia More Likely

Prodrome Prodrome to respiratory distress Prodrome to febrile illnessVital signs More tachypneic; less febrile; more hypoxemic Less hypoxemic; higher feverPhysical examination Respiratory distress; wheeze; diffuse crackles; Acute febrile illness; focal crackles;

subcostal retractions egophony; decreased breath soundsRadiograph Hyperinflation; peribronchial thickening Focal infiltrate; effusion

MAJOR POINTS

1. Croup is almost always a viral infection, andantibiotics are almost never required. Systemiccorticosteroids can shorten the course of thedisease, and make the symptoms more manageable.Other acute management includes inhaledepinephrine. Treatment with inhaled epinephrine isno longer considered an automatic indication foradmission to hospital.

2. Bronchiolitis is virtually always a viral infection. Ifa child can eat and oxygenate adequately, therapyis probably not necessary. If therapy is indicated,acute albuterol has been shown to provide relief insome children. If albuterol does not help, and thechild is still having respiratory difficulty, inhaledepinephrine can be tried. The data on systemiccorticosteroids show varying degrees of response.

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Continued


SUGGESTED READING

American Academy of Pediatrics. Respiratory syncytial virus. InPickering L, editor: 2000 Red Book: Report of the Committeeon Infectious Diseases 2000, 25th edition, pp 483–487. ElkGrove Village, IL: American Academy of Pediatrics, 2000.

Berger I, Argaman Z, Schwartz SB, Segal E, Kiderman A, Branski D,Kerem E. Efficacy of corticosteroids in acute bronchiolitis:short-term and long-term follow-up. Pediatr Pulmonol26:162–166, 1998.

Bye MR. Bronchiolitis and bronchitis. In Burg FD, Ingelfinger J,Polin RA, Gershon AA, editors: Gellis & Kagan’s current pediatrictherapy, 17th edition, pp 484–485. Philadelphia: Saunders, 2002.

Bye MR. Persistent or recurrent pneumonia. In Schidlow DV,Smith DS, editors: A practical guide to pediatric respiratory dis-eases, pp 99–103. Philadelphia: Hanley & Belfus, 1994.

Englund JA. Prevention strategies for respiratory syncytial virus:passive and active immunization. J Pediatr 135: 38–44,1999.

Geelhoed GC, Macdonald WBG. Oral and inhaled steroid incroup: a randomized, placebo-controlled trial. PediatrPulmonol 20:355–361, 1995.

Geelhoed GC, Macdonald WBG. Oral dexamethasone in thetreatment of croup: 0.15 mg/kg versus 0.3 mg/kg versus 0.6 mg/kg. Pediatr Pulmonol 20:362–368, 1995.

Geelhoed GC. Croup. State of the art. Pediatr Pulmonol23:370–374, 1997.

IMpact-RSV Study Group. Palivizumab, a humanized respiratorysyncytial virus monoclonal antibody, reduces hospitalizationfrom respiratory syncytial virus infection in high-risk infants.Pediatrics 102:531–537, 1998.

Johnson DW, Jacobson S, Edney PC, et al. A comparison of neb-ulized budesonide, intramuscular dexamethasone, and placebofor moderately severe croup. N Engl J Med 339: 498–503,1998.

Kaditis AG, Wald ER. Viral croup: current diagnosis and treat-ment. Pediatr Infect Dis J 17:827–834, 1998.

Kellner JD, Ohlsson A, Gadomski AM, Wang EE. Bronchodilatorsfor bronchiolitis. Cochrane Database Syst Rev CD001266, 2000.

Khoshoo V, Edell D. Previously healthy infants may haveincreased risk of aspiration during respiratory syncytial viralbronchiolitis. Pediatrics 104:1389–1390, 1999.

Loughlin GM. Bronchitis. In Chernick V, Boat T, editors: Kendig’sdisorders of the respiratory tract in children, 6th edition, p 461.Philadelphia: Saunders, 1998.

Mallory GB Jr., Motoyama EK, Koumbourlis AC, Mutich RL,Nakayama DK. Bronchial reactivity in infants in acute respiratoryfailure with viral bronchiolitis. Pediatr Pulmonol 6:253–259,1989.

Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M,Morgan WJ. Asthma and wheezing in the first six years of life.The Group Health Medical Associates. N Engl J Med332:133–138, 1995.

Rodriguez WJ. Management strategies for respiratory syncytialvirus infections in infants. J Pediatr 135:45–50, 1999.

Sanchez I, De Koster J, Powell RE, Wolstein R, Chernick V.Effect of racemic epinephrine and salbutamol on clinical scoreand pulmonary mechanics in infants with bronchiolitis. J Pediatr 122:145–151, 1993.

Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, AndersonLJ. Bronchiolitis-associated hospitalizations among US children,1980–1996. JAMA 282:1440–1446, 1999.

Tepper RS, Rosenberg D, Eigen H, Reister T. Bronchodilatorresponsiveness in infants with bronchiolitis. Pediatr Pulmonol17:81–85, 1994.

Wong JY, Moon S, Beardsmore C, O’Callaghan C, Simpson H.No objective benefit from steroids inhaled via a spacer ininfants recovering from bronchiolitis. Eur Respir J 15: 388–394,2000.

MAJOR POINTS—Cont’d

At best, the benefits are meager. One recent meta-analysis of steroids in children admitted to hospitalwith bronchiolitis showed the steroids to reducelength of stay by 0.4 days; this means almost 10hours. Nor have steroids been shown to be helpfulfor the prolonged “postbronchiolitis” cough andwheeze so frequently seen.

3. In children who are nonsmokers without underlyingpulmonary disease, bronchitis is usually part of asimple cold. Antibiotics are almost never necessaryin these children. If the child has a pattern ofrecurrent bronchitis, or frequent or prolonged chestsymptoms with colds, consideration must be givento the diagnosis of asthma. In such cases, a trial ofsystemic corticosteroids (prednisone orprednisolone 1–2 mg/kg per day divided BID) andinhaled bronchodilators is often rewarding.

4. The majority of cases of pneumonia in children arecaused by a virus. The likelihood of a bacterialprocess is increased if the child has a high fever,focal findings on examination and radiograph, lackof wheeze, and pleural effusion. If sputum analysisis possible, finding either neutrophils or intracellularorganisms suggests a bacterial etiology.

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231

A

Abdominal muscles, normal function 197N-acetylcysteine 124–5Acid-fast bacilli (AFB) 173, 174Acquired immunodeficiency syndrome (AIDS)

169, 175Actinomycin D 191Acute interstitial pneumonia (AIP) 182,

183, 184Acute respiratory distress syndrome (ARDS)

184, 208, 214, 215Adenotonsillar hypertrophy 17Adenotonsillectomy 86Airway compression syndromes and recurrent

pneumonia 8Albuterol 71, 227Allergens and asthma 96Allergic bronchopulmonary aspergillosis

(ABPA) 3, 112–14Allergy testing 3Alveolar architecture 183Alveolar dead space 209Alveolar gas equation 209–10Alveolar ventilation 209Amikacin 126Amiodarone 191Amoxicillin/clavulinic acid 125, 125, 161Anti-immunoglobulin E therapy 109–10Aortic arch 26, 26, 27, 53, 53, 54, 55, 56Aortoplexy 40Apert syndrome 17Apnea index (AI) 79Apnea/hypopnea index (AHI) 79Apparent life-threatening events (ALTE) 64,

83, 88–9Arnold–Chiari malformation 17, 82, 196, 209Arterial blood gas determination 3, 203Aspergillus fumigatus 112Aspirin sensitivity 114Asthma 95

acute exacerbation by viral infection 229acute therapiesshort-acting beta-agonists (SABAs) 110systemic glucocorticoid therapy 110–11classification 105–6, 105clinical presentation 98–100

chest radiographs 101

Asthma (Continued)clinical presentation (Continued)

diagnostic findings 98laboratory evaluation 100–4methacholine challenge 103spirometry 102

complicating factors 112–14controller therapies

anti-immunoglobulin E therapy 109–10cromolyn sodium and nedocromil 109inhaled corticosteroids (ICSs) 108–9leukotriene modifiers (LMs) 109long-acting beta agonists (LABAs) 109methylxanthines 109systemic glucocorticoid therapy 109

cough 6differential diagnosis 104–5, 104etiology 95–7non-pharmacologic therapy 111–12

Children’s Hospital of PhiladelphiaAsthma Care Plan 113

pathophysiology 97–8pharmacologic therapy 106–8sleep-disordered breathing 90symptom triggers 13wheezing 7

Asynchronous thoraco-abdominal motion 13, 14

Ataxia-telangiectasia 145Atelectasis 205–6Atropine 71Auscultation 2Azathioprine 191Aztreonam 125, 126

B

Bacille Calmette-Guérin (BCG) vaccination176–7, 178–9

Bacterial infections of respiratory system 169,170; see also Pneumonia

empyema and parapneumonic effusion 167–8pulmonary abscess 166–7referral guidelines 170unusual pneumonias 168–70

Barotrauma 217Becker muscular dystrophy 195, 195, 209

Beckwith–Wiedemann syndrome 17Belly dancer’s sign 14N-benzoyl-L-tyrosyl-p-aminobenzoic acid 123Bethanechol 39Biphasic sounds 12Bleomycin 191Blood gas analysis 213Body mass index (BMI) 204Bohr effect 211Bordetella pertussis 157, 158Breathing difficulties and asthma 99–100Bronchi and bronchioles, noisy breathing 18,

31–2Bronchial obstruction, causes 45Bronchial provocation test 4Bronchiectasis 158–9, 159, 160, 161

cough 6recurrent pneumonia 8

Bronchiolitis 226–8, 227Bronchiolitis obliterans with organizing pneu-

monia (BOOP) 182, 183, 185, 185, 186wheezing 7

Bronchitisacute 157, 161, 226chronic 157–8, 161exacerbation 126

Bronchoalveolar lavage (BAL) fluid 190Bronchoconstrictors 39Bronchodilators 70–1Bronchogenic cysts 46–8, 47, 50

recurrent pneumonia 8Bronchomalacia

cough 6recurrent pneumonia 8wheezing 7

Bronchopulmonary dysplasia (BPD) 32, 60clinical manifestations

differential diagnoses 67history 63–4laboratory tests 67–8, 67pathology 68–9, 68, 69physical examination 64–5pulmonary function testing 65–6, 65radiology 66–7, 66, 67

definition 60–1diagnostic criteria 61

incidence 61–2birthweight survival 62

Index

Page numbers in italic, e.g. 215, refer to figures. Page numbers in bold, e.g. 191, denote entries in tables.

Bronchopulmonary dysplasia (Continued)long-term prognosis 72–3pathogenesis 62, 63

glucocorticoids 62–3inflammation and infection 63nutrition 63oxygen toxicity 62positive-pressure ventilation 62vascular hypothesis 63

prevention 73–4sleep-disordered breathing 89–90treatment 69

anti-inflammatory therapy 71diuretic therapy 70inhaled bronchodilators 70–1nutrition 71–2oxygen therapy 69–70prevention of intercurrent viral

infections 72therapeutic modalities 69

Bronchoscopy 7Bruton’s disease 142Bucket-handle motion 196, 197Budesonide 224Burkholderia cepacia 141Busulfan 191

C

Campbell–Williams syndrome 18Candida albicans 161Capnography 214, 214Carboxyhemoglobin 214Cardiac disease and exercise limitation 9Ceftazidime 125, 126Cellular interstitial pneumonia (CIP) 182,

186, 187Central apnea 77Cephalexin 125Cephalosporins 191Cerebral palsy 196Charcot Marie Tooth disease 196Charcot-laden crystals 97Chediak–Higashi syndrome (CHS) 141Chest radiographs 4Chest tightness and asthma 100Children’s Hospital of Philadelphia Asthma

Care Plan 113Chlamydia pneumoniae 155, 166Chlamydia trachomatis 155, 162Chlamydia and cough 6Chlorambucil 191Chloramphenicol 125Choanal stenosis 17Choking (foreign body obstruction)

cough 6noisy breathing 20, 21, 22–3, 24wheezing 7

Chronic granulomatous disease (CGD) 140,142

Chronic lung disease of infancy (CLDI) 60;see also Bronchopulmonary dysplasia(BPD)

Chronic pneumonia of infancy (CPI) 182,186, 186–7

Ciliadefects 133–4, 134normal anatomy and function 132–3,

132, 133Ciprofloxacin 125, 125Colimycin 126Colistin 125

Common variable immunodeficiency (CVID)142–3, 143

Computed tomography (CT) scan 4, 5noisy breathing 32

Congenital malformations 58bronchogenic cysts 46–8, 47, 50congenital cystic adenomatoid malforma-

tion (CCAM) 48–50, 49congenital diaphragmatic hernia 90congenital high airway obstruction syn-

drome (CHAOS) 36congenital lobar emphysema (CLE) 45–6,

45, 45laryngeal atresia and web 35–6, 36–7pulmonary agenesis 43–4, 44pulmonary hypoplasia 44–5pulmonary lymphangiectasis 55–7pulmonary sequestration 50–2, 51, 52tracheal agenesis 36tracheal stenosis 36–8, 38tracheoesophageal fistula (TEF) 40–3, 40,

41–2tracheomalacia 38–40vascular rings 52–5, 53, 53, 54, 55, 56

Constipation 205Continuous positive airway pressure

(CPAP) 39Corticosteroids 71, 126

tuberculosis 178Cough

asthma 98–9chronic 4

bronchoscopy 6causes and typical features 6diagnostic imaging 6history and physical examination 4–5laboratory evaluation 5–6pulmonary function testing 6

neuromuscular disease 200normal reflex 198pneumonia 153

Crackles 15Crohn’s disease 141Cromolyn sodium 109Cromones 109Croup 20, 223–6, 225Curschman’s spirals 97Cyanosis 154–5Cyclophosphamide 191, 191Cystic adenomatoid malformation and

recurrent pneumonia 8Cystic fibrosis (CF) 128

clinical evaluation 121chest radiography 122–3, 123nutrition 123–4pulmonary function tests

121–2, 122reproductive function 124sputum microbiology 122

cough 6definition 116diagnosis 119–20

differential diagnosis of abdominal pain124

evaluation of gastrointestinal tract tissue121

evaluation of respiratory tract tissue 121

signs and symptoms 120genetics 116–117, 117pathophysiology 117–18

gastrointestinal tract 119reproductive organs 119

Cystic fibrosis (CF) (Continued)pathophysiology (Continued)

respiratory tract 118–19sweat glands 119

predicted survival age 124quantitative sweat test 3recurrent pneumonia 8sleep-disordered breathing 90therapy 124

antibiotics 125–6brochodilators and anti-inflammatory

therapy 126–7chest physiotherapy 125DIOS treatment 128, 128liver transplantation 128lung transplantation 127management of nutrition and gastro-

intestinal disease 127–8, 127management of pulmonary disease 124–7mucociliary clearance 124–5nutritional support 127oxygen and non-invasive assisted

ventilation 127salt replacement 127ursodeoxycholic acid 128

wheezing 7Cystic fibrosis transmembrane conductance

regulator (CFTR) 116, 118functional peptide domains 118gene 116–117mutations 117

Cytokines 63, 73Cytomegalovirus (CMV) 145, 147, 161,

161, 162Cytotoxic T lumphocytes (CTLs) 144

D

Daily variation in symptoms 1Dandy–Walker cyst 17, 209Dead space 211, 212Desquamative interstitial pneumonia (DIP)

181, 182, 183, 184Dexamethazone 224Diaphragm, normal function 196–7, 197Diaphragmatic hernia 50, 50Dicloxacillin 125DiGeorge syndrome 145Digital clubbing 2, 2Directly observed therapy (DOT) 178Distal intestinal obstructive

syndrome (DIOS) 119treatment 128, 128

Docetaxel 191Down syndrome 17, 83

risk for obstructive sleep apnea syndrome(OSAS) 84

Dry powder inhalers (DPI) 107Dual energy X-ray absorptiometry (DEXA) 204Duchenne muscular dystrophy (DMD) 90–1,

195, 195, 201, 202, 209Dynein 132, 133Dysphagia and recurrent pneumonia 8

E

Emery–Dreyfuss muscular dystrophy 195Empyema 167–8, 169End-tidal CO2 test 203Epiglottitis 20, 20Epstein–Barr virus (EBV) 147, 185, 189

232 INDEX

Equal pressure point (EPP) 15, 16Escherichia coli 161Esophagram 4Ethambutal (ETH) 179Excessive daytime somnolence (EDS) 81Exercise limitation 8–9

cardiology evaluation 9common causes 9history and physical examination 9pulmonary function testing 9

Exercise testing 4Exhalation, pressure changes 15, 15, 16, 16Expiratory positive airway pressure (EPAP) 217Extracorporeal membrane oxygenation

(ECMO) 219–20, 219Extrathoracic airway resistances 16, 16Extrathoracic obstruction 33Extremely very low birthweight (EVLBW)

64, 73

F

Failure-to-thrive (FTT) 64, 65Fascioscapulohumeral dystrophy 195Fick’s law 213Flow–volume curves 33Fluoroscopy 4Follicular bronchiolitis (FB) 189Forced expiratory volume (FEV) 33Forced vital capacity (FVC) 33, 39Functional residual capacity (FRC) 39

G

Gastroesophageal reflux (GER) 20, 64asthma mimicking 104chronic stridor 10complicating factor in asthma 112cough 6recurrent pneumonia 8

Gentamicin 126Glossoptosis 17Glottis and noisy breathing 17, 21–3Gold 191Group B beta-hemolytic streptococcus (GBBS)

160–1, 160Grunting 154Guillain–Barré syndrome 209

H

Habit cough 6Haemophilus influenzae 20, 155, 157, 158,

162Haldane effect 211Heart failure and wheezing 7Helper T (TH) cells 144Hemangioma 17Heterophonous sounds 15High-frequency oscillatory

ventilation (HFOV) 221Highly active anti-retroviral therapy (HAART)

147, 147, 189Histiocytosis-X 183Homophonous sounds 15Hot-potato voice 19Human immunodeficiency virus (HIV)

infections 146, 189, 226, 227pulmonary complications 146–7

HIV therapy 147

Hyaline membrane disease (HMD) 63Hydroxychloroquine 191Hypercarbia 83Hyper-IgE syndrome 141Hyper-IgM (HIgM) syndrome 145–6, 146Hypoglycemia and chronic stridor 10Hypopharyngeal hypotonia and chronic

stridor 10Hypopharynx and noisy breathing 17, 19–20Hypopnea 77Hypopnea index (HI) 79Hypoventilation 83Hypoxemia 82–3

causes 213

I

Ibuprofen 126–7Idiopathic pulmonary fibrosis (IPF) 181–2,

182, 183–4Idiopathic scoliosis 90IgA deficiency 144, 144Imaging techniques

chest radiographs 4computed tomography (CT) scan 4, 5esophagram 4fluoroscopy 4magnetic resonance imaging (MRI) 4

Imipenem 125, 126Immotile cilia syndrome; see Primary ciliary

dyskinesia (PCD) Immunodeficiency

cough 6recurrent pneumonia 8

Immunoglobulins 3, 34Immunologic disorders, pulmonary

complications 140, 149evaluation 147–8, 148HIV infection 146

infectious complications 146–7non-infectious complications 147

HIV therapy 147infectious complications of

immunodeficiency 140B lymphocyte disorders 141–4neutrophil defects 140–1T lymphocyte disorders 144–6typical pathogens 141

non-infectious complications ofimmunodeficiency 146

treatment 148–9Influenza virus 162Inhaled corticosteroids (ICSs) 71, 108–9Inspiration, pressure changes 14–15, 15, 16, 16Inspiratory capacity (IC) 39Inspiratory positive airway pressure (IPAP) 217Intercostal muscles, normal function 197Interferon-gamma (IFN-γ ) 141Interleukin-6 (IL-6) 63Interstitial lung diseases (ILD) 181–3, 192

glossary of terms 182pediatric diseases 185–6

cellular interstitial pneumonia (CIP) 187chronic pneumonia of infancy (CPI) 186–7diagnosis and treatment 190–1, 190, 190follicular bronchiolitis (FB) 189lymphocytic interstitial pneumonia (LIP)

189, 189persistent tachypnea of infancy (PTI)

187–9pulmonary interstitial glycogenosis (PIG)

187, 188

Interstitial lung diseases (ILD) (Continued)pediatric diseases (Continued)

secondary forms 191–2, 191surfactant protein deficiencies 189–90

primary (idiopathic) disease in adults 183acute interstitial pneumonia (AIP) 184bronchiolitis obliterans with

organizing pneumonia (BOOP)185, 185, 186

desquamative interstitial pneumonia (DIP) 184

lymphocytic interstitial pneumonia(LIP) 185

non-specific interstitial pneumonia (NSIP)184–5

respiratory bronchiolitis-associated inter-stitial lung disease (RBILD) 184

usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF)183–4

Intrathoracic airway resistances 16, 16Intrathoracic obstruction 33Intravenous immunoglobulin (IVIG)

replacement therapy 144Investigative techniques

bronchoscopy 4diagnostic imaging 4history and physical examination 1–2laboratory evaluation 2–3pulmonary function testing 3–4

Ipratropium 71Isoetharine 110Isoniazid (INH) 179Isoproterenol 110

K

Kartagener syndrome; see Primary ciliary dysk-inesia (PCD)

Kugelberg–Welander disease 196Kyphoscoliosis 90

L

Laboratory testsallergy testing 3arterial blood gas determination 3immunoglobulin levels 3sputum culture 3sweat test 3

Langerhan cell histiocytosis 183Laryngeal cysts and chronic stridor 10Laryngeal web and chronic stridor 10Laryngitis 22Laryngomalacia 14, 20

chronic stridor 10Laryngotracheobronchitis (LTB) 156Larynx

congenital malformationsatresia and web 35–6, 36–7congenital high airway obstruction

syndrome (CHAOS) 36noisy breathing 17, 20–1

Legionella pneumoniae 155Leukocyte adhesion molecule (LAM) 141Leukotriene modifiers (LMs) 109Limb girdle dystrophy 195, 195Liquid ventilation 221Listeria monocytogenes 161Loculated pneumothorax 48Long-acting beta agonists (LABAs) 109

Index 233

Lower respiratory tract infection (LRI) 151–2cough 153etiology 152syndromes 152

Lung volume measurement 3–4Lungs; see also Interstitial lung diseases

(ILD) congenital malformations

agenesis 43–4, 44bronchogenic cysts 46–8, 47, 50congenital cystic adenomatoid malforma-

tion (CCAM) 48–50, 49congenital lobar emphysema (CLE) 45–6,

45, 45hypoplasia 44–5pulmonary lymphangiectasis 55–7pulmonary sequestration 50–2, 51, 52vascular rings 52–5, 53, 53, 54, 55, 56

embryology 35, 36obstructive lung diseases and sleep 89

asthma 90bronchopulmonary dysplasia (BPD) 89–90cystic fibrosis (CF) 90treatment 91

photomicrographs 182restrictive lung diseases and sleep

chest wall deformities 90treatment 91ventilatory muscle weakness 90–1

Lymphocytic interstitial pneumonia (LIP) 147,182, 185, 189, 189

M

Macroglossia 17Macrolide 161Magnetic resonance imaging (MRI) 4Mantoux test 176Maximal expiratory flow volume maneuver

(MEFVM) 33Meconium aspiration syndrome 57Medication-induced cough 6Meropenem 125, 126Mesenchymal hamartomas 50Metered-dose inhalers (MDIs) 107Methacholine 39Methacholine challenge 103Methotrexate 191, 191Methylxanthines 109Micrognathia 17Miliary disease 175, 176Minute ventilation 209Mitomycin 191Moebius syndrome 17Moraxella catarrhalis 158Mounier–Kuhn syndrome 18Mucociliary clearance 124–5Multiple sleep latency test (MSLT) 85Muscular dystrophies 195, 195Myasthenia gravis 195–6Mycobacterial lymphadenitis 175–6Mycobacterium avium complex (MAC) 146Mycobacterium avium-intracellulare

175, 178Mycobacterium kansasii 175Mycobacterium tuberculosis 172

as a complication of HIV infections 146pathogenesis of TB 172–3transmission 173–4

Mycoplasma pneumoniae 155, 157, 158,164–5, 164, 166

Myotonic dystrophy 195

N

Nafcillin 125, 126, 161Nasopharyngeal malformations and chronic

stridor 10Nebulizers 107Nedocromil 109Negative-pressure ventilation (NPV)

220–1, 220Nemaline myopathy 195Neuromuscular disease, pulmonary

complications of 194, 207chest wall, neuromuscular disease function

compliance 200motion 199scoliosis 200

chest wall, normal functioncompliance 198, 198motion 198, 199

cough 200motor neuron diseases 195, 195

cerebral palsy 196Charcot Marie Tooth disease 196muscular dystrophies 195, 195myasthenia gravis 195–6spina bifida 196spinal cord injury 196spinal muscular atrophy 196

patient evaluationchest radiograph 201, 201history 200–1physical examination 201, 201pulmonary function testing 201–2,

201, 202special tests 203

prevention and treatmentaspiration prevention 205nutrition 203–5pneumonia and atelectasis 205–6respiratory muscle fatigue 206–7, 206respiratory muscle strength 206, 206swallowing disorders 205team approach to care 205, 205vaccine 205

respiratory muscles, neuromuscular diseasefunction

fatigue 199, 199strength 198–9

respiratory muscles, normal functionabdominal muscles 197cough reflex 198diaphragm 196–7, 197intercostal muscles 197swallow function 197–8upper airway muscles 197

swallowing dysfunction 200upper airway obstruction 200

Neuromuscular diseaseexercise limitation 9recurrent pneumonia 8

Neuronal apoptosis inhibitory protein (NAIP) 196

Neutrophil defects 140–1Neutrophils 118Nitric oxide (NO), inhaled 217–19Nitrofurantoin 191Nocturnal enuresis 81Nocturnal sweating 81Noisy breathing 12, 34

differential diagnosis 16, 17–18bronchi and bronchioles 31–2extrathoracic airway 16–24glottis 21–3

Noisy breathing (Continued)differential diagnosis (Continued)

hypopharynx 19–20intraluminal lesions 30–1intrathoracic airway 24–32larynx 20–1nose and nasopharynx 16–19oropharynx 19subglottis and extrathoracic trachea 23–4trachea, extrinsic compression 25–9trachea, intramural lesions 29–30

evaluation 32–4flow–volume curves 33

history 12–13physical examination 13–16

Non-invasive positive-pressure ventilation(NIPPV) 91, 217, 218

Non-obstructive hypoventilation 79Non-REM sleep 83Non-specific interstitial pneumonia (NSIP)

147, 182, 183, 184–5Non-tuberculous mycobacteria (NTM) 175–6Noonan syndrome 57Nose and nasopharynx, noisy breathing

16–19, 17

O

Obesity 9, 204risk for obstructive sleep apnea

syndrome (OSAS) 84Obstructive apnea 77Obstructive hypoventillation 77–9Obstructive sleep apnea syndrome

(OSAS) 76–7clinical features 79–80

associated medical conditions 80breathing during sleep 80–1daytime symptoms 81–2frequency of signs and symptoms 80nocturnal enuresis 81nocturnal sweating 81nocturnal symptoms 80–1sleep patterns 81

comparison between children and adults 77complications 84

cardiovascular complications 85–6growth impairment 86neurobehavioral and neurocognitive

manifestations 84–5epidemiology 79evaluation 86, 87high-risk groups 84

Down syndrome 84obesity 84post-adenotonsillectomy 84

outcome 87–8physical examination 82physiologic consequences

hypercarbia 83hypoxemia 82–3movements and arousals 83–4sleep and sleep states 83

polysomnography traces 78, 79terminology 77–9treatment 86–7

Omphalocele 90Oropharynx and noisy breathing 17, 19Oxacillin 126, 161Oxygen saturation test 203Oxygen therapy 69–70Oxygen toxicity 62

234 INDEX

Oxyhemoglobin dissociation curve 210Oxyhemoglobin saturation 210, 212

P

Palivizumab 72Papillomas 21Papillomatosis 17Parapneumonic effusion 167–8Partial liquid ventilation (PLV) 221Peak expiratory flow (PEF) monitoring 102Peak inspiratory pressure (PIP) 214–15, 215Penicillamine 191Penicillin-resistant Pneumococcus 162–3Periciliary fluid 133Peripheral muscle strength 201Persistence of the ductus arteriosis (PDA) 64Persistent tachypnea of infancy (PTI) 182,

186, 187–9Pertussis and cough 6Phenytoin 191Physiologic dead space 209Pierre–Robin syndrome 17Piperacillin 125, 126Plateau pressure (Pplat) 215, 215Pneumatoceles, post-infection 48, 50Pneumocystis carinii pneumonia

(PCP) 142, 145as a complication of HIV infections 146

Pneumocystis jiroveci 162Pneumonia 30–1, 151–2, 169, 170, 205–6;

see also Bacterial infections of respiratory system

adolescents 164–6children 163–4, 164clinical syndromes 156

bacterial infection of the airway 161bronchiectasis 158–9, 159, 160, 161bronchitis, acute 157, 161bronchitis, chronic 157–8, 161tracheitis 156–7

diagnosis 155–6radiographic patterns 155

etiology 152infants

ill-appearing 162–3newborn 159–61well-appearing 161–2

recurrent 7–8bronchoscopy 8causes 8diagnostic imaging 8history and physical examination 8laboratory evaluation 8pulmonary function testing 8

referral guidelines 170signs and symptoms 152, 152

auscultatory changes 154chest pain 154cough 153cyanosis 154–5fever 153grunting 154retractions (chest-indrawing) 154tachypnea 153thoracoadbominal asynchrony (see-saw

breathing) 154toddlers, well-appearing 163unusual forms 168–70viral 228–9, 229

Polyethylene-glycol–electrolyte solution 127Polymerase chain reaction (PCR)

amplification 178

Polymorphonuclear neutrophils (PMNs) 140Polysomnography 10, 86, 203

obstructive sleep apnea syndrome (OSAS)78, 79

Polyuria 81Positive end-expiratory pressure (PEEP) 215,

215, 216Positive-pressure ventilation 62, 215–17Post-nasal drip and cough 6Prednisolone 110, 224Prednisone 110, 224Pressurized metered-dose inhalers (pMDIs) 107Primary ciliary dyskinesia (PCD)

anatomyciliary defects 133–4, 134normal anatomy and function of cilia

132–3, 132, 133clinical manifestations

lower respiratory tract 134–5, 135reproductive system 135situs inversus 135upper respiratory tract 135

cough 6definition 131diagnosis 136–7, 136differential diagnosis 137, 137genetics 131pathophysiology 134recurrent pneumonia 8treatment 137

lower airway 137–8, 138prognosis 138upper airway 138, 138

Primary snoring 79Prone positioning 220Prune belly syndrome 90Pseudomonas aeruginosa 30, 116, 118,

120, 161antibiotics 125, 126

Pulmonary abscess 166–7Pulmonary agenesis 43–4, 44Pulmonary edema and wheezing 7Pulmonary function testing

bronchial provocation 4exercise testing 4lung volume measurement 3–4spirometry 3, 3

Pulmonary hemosiderosis and recurrentpneumonia 8

Pulmonary hypoplasia 44–5Pulmonary interstitial glycogenosis (PIG) 182,

187, 188Pulmonary lymphangiectasis 55–7Pulmonary sequestration 50–2, 52

characteristics 51recurrent pneumonia 8

Pulmonary sling 28, 29Pulmozyme 125Pulse oximetry 214Purified protein derivative (PPD) 34, 173, 174

miliary disease 175Pyrizinamide (PZA) 179

R

Rapid eye movement (REM) sleep 83Reactive airways disease (RAD) 71Reactive oxidant species (ROS) 140Respiratory bronchiolitis-associated interstitial

lung disease (RBILD) 182, 183, 184Respiratory disease and exercise limitation 9Respiratory distress syndrome (RDS) 60

Respiratory disturbance index (RDI) 83Respiratory failure 222

definition 208–9diagnosis and monitoring

blood gases 213imaging 214, 215pulmonary function measurements 214–15pulse oximetry and capnography 214,

214etiologies 209, 209management 215

extracorporeal membrane oxygenation(ECMO) 219–20, 219

high-frequency oscillatory ventilation(HFOV) 221

inhaled nitric oxide (NO) 217–19liquid ventilation 221negative-pressure ventilation (NPV)

220–1, 220non-invasive positive-pressure ventilation

(NIPPV) 217, 218positive-pressure ventilation 215–17prone positioning 220recovery phase 221

pathophysiology 209causes of hypoxemia 213gas transport to periphery 210–11, 210oxygenation 209–10ventilation 209, 210ventilation–perfusion relationships 211–13

Respiratory inductive plethysmography 203Respiratory muscle fatigue tests 203Respiratory muscle training 206, 206Respiratory syncytial virus (RSV) 20

asthma 96bronchiolitis 226bronchopulmonary dysplasia (BPD) 72cough 6

Retractions (chest-indrawing) 154Rhinitis and cough 6Rifampin (RIF) 179

S

Salivagrams 203, 204Scoliosis 200Seasonal variation in symptoms 2Serratia marcescens 30, 141Severe combined immunodeficiency (SCID)

144, 145Shunt 211, 212, 213Sinusitis and cough 6Situs inversus 135Sleep-disordered breathing 76, 91–2

central hypoventilation 89congenital central hypoventilation

syndrome (CCHS) 89infants

apnea of infancy 88–9obstructive lung diseases 89

asthma 90bronchopulmonary dysplasia (BPD) 89–90cystic fibrosis (CF) 90treatment 91

obstructive sleep apnea syndrome (OSAS)76–7

clinical features 79–82, 80comparison between children and

adults 77complications 84–6epidemiology 79evaluation 86, 87

Index 235

Sleep-disordered breathing (Continued)obstructive sleep apnea syndrome

(Continued)high-risk groups 84outcome 87–8physical examination 82physiologic consequences 82–4polysomnography traces 78, 79terminology 77–9treatment 86–7

premature infantsapnea of prematurity 88

restrictive lung diseaseschest wall deformities 90treatment 91ventilatory muscle weakness 90–1

Slow wave sleep 83Snoring 79, 80Spina bifida 196Spinal cord injury 196Spinal muscular atrophy 196Spirometry 3, 3, 33

asthma 102Sprints 221Sputum culture 3Squeeze the wheeze technique 2Staphylococcus aureus 20, 23, 30, 120, 141,

155, 156, 162, 166, 167antibiotics 125, 126

Streptococcus pneumoniae 155, 162, 164, 168Stridor, chronic 9

bronchoscopy 10causes 10diagnostic imaging 10history and physical examination 10polysomnography 10

Subcostal retractions 14Subglottic hemangioma and chronic stridor 10Subglottic stenosis 25

chronic stridor 10Subglottis and extrathoracic trachea

noisy breathing 17, 23–4Sudden infant death syndrome (SIDS) 64Sulfamethoxazole 191Sulfasalazine 191Surfactant protein diseases 189–90Swallow reflex

aspiration 205dysfunction 200

cough 6function studies 203, 204normal function 197–8

Sweat test 3Swyer–James–Mcleod syndrome 45, 46Synchronized intermittent mandatory

ventilation 216, 216Systemic glucocorticoid therapy 109Systemic lupus erythematosus (SLE) 185,

185, 186

T

Tazobactam 126Tetracycline 125Theophylline 227Thoracoabdominal asynchrony (see-saw

breathing) 154Thumb sign 20Ticarcillin 125, 126Tidal volume 209Tine test 176Tobacco smoke and asthma 96Tobramycin 125, 126Total anomalous pulmonary venous return

(TAPVR) 56Trachea

congenital malformationsagenesis 36stenosis 36–8, 38tracheoesophageal fistula (TEF) 40–3, 40,

41–2tracheomalacia 38–40

noisy breathingextrinsic compression 18, 25–9intramural lesions 18, 29–30

tracheitis 156–7Tracheoesophageal fistula (TEF) 40, 40, 41–2

clinical features 40–1diagnosis 41–2management 42prognosis 43

Tracheo-esophageal fistula and recurrentpneumonia 8

Tracheomalacia 29, 30, 38–9cough 6diagnosis 39prognosis 40recurrent pneumonia 8treatment 39–40wheezing 7

Transforming growth factor-β (TGF-β) 63Transmural pressure 14Treacher–Collins syndrome 17Trimethoprim/sulfamethoxazole (TMP/SMX)

125, 141Tuberculin skin tests (TST) 176, 177Tuberculosis (TB) 172, 179

clinical manifestationsextrapulmonary tuberculosis 175–6pulmonary disease 174–5, 174, 175

cough 6diagnosis 176–8, 177

chest radiograph 177, 178CT scan 178

pathogenesis 172–3transmission 173–4treatment 178–9, 179

Tubulin 132Tumor necrosis factor-α (TNF-α) 63

U

Upper airway muscles, normal function 197Upper airway resistance syndrome (UARS)

79, 81Ureaplasma urealyticum 63, 162Ursodeoxycholic acid 128Usual interstitial pneumonia (UIP) 181, 182,

183–4Uvulopharyngopalatoplasty 86–7

V

Vancomycin 125, 126Vascular abnormalities 25Vascular endothelial growth factor

(VEGF) 63Vascular malformation and chronic

stridor 10Vascular rings 52–5, 53, 53, 54, 55, 56Ventilation perfusion (V/Q) imbalances 111Vignos score 200Viral infections of respiratory tract 223,

229–30acute asthma exacerbation 229acute bronchitis 226bronchiolitis 226–8, 227croup 223–6, 225pneumonia 228–9, 229

Vocal cord dysfunction (VCD) 7wheezing 7

Vocal cord paralysis and chronic stridor 10Volume-limited ventilation 216, 216Volutrauma 62, 217

W

Werdnig–Hoffman atrophy 209Wheezing 6

asthma 99causes 7diagnostic imaging 7history and physical examination 6–7laboratory evaluation 7pulmonary function testing 7

Wilson–Mikity syndrome 67Wiskot–Aldrich syndrome (WAS) 145

X

X-linked agammaglobulinemia (XLA) 141–2

Y

Young syndrome 136

236 INDEX

pediatric pulmonology

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