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Asthma OverviewRonald Balkissoon, MD, MSc, DIH, FRCPCNational Jewish Medical and Research Center, The University of Colorado

School of Medicine, 1400 Jackson Street, Room J215, Denver, CO 80206, USA

In the United States, asthma a ff ects over 22 million people and accountsfor over 4000 deaths every year [1]. Asthma is a clinical diagnosis based ona symptom complex of episodic shortness of breath typically associated withwheezing, chest tightness, and cough and with objective physiological evi-dence of variable and reversible airow obstruction with bronchial hyperres-ponsiveness. Airway inammation plays a key role in the pathogenesisof asthma and ongoing research indicates that the underlying biology of asthma is complex and heterogeneous. Airway remodeling is presumed tobe a result of undertreatment of airway inammation. However, several fea-tures of airway remodeling may not be a direct result of airway inamma-tion and may be driven by genetics and factors as yet unappreciated.Inhaled corticosteroids remain the mainstay controller maintenance therapyfor most asthmatics while other anti-inammatory medications, such as leu-kotriene receptor antagonists, 5 lipoxygenase inhibitors or anti-IgE agents,may be helpful for certain individuals.

An assessment of the severity of a patients asthma is important as a basisfor deciding on initial therapeutic interventions. However, for deciding if ther-apy needs to be stepped up or stepped down, it is important to establish a pa-tients personal best and arrange subsequent follow-up to ensure the patient isoptimally controlled. Researchers are now focused on improving our under-standing of the biological heterogeneity of asthma and increasing our capabil-ity to biologically phenotype patients by assessment of airway inammationand/or pharmacogenomics. These novel clinical assessment tools will allowfor better individualized therapy for asthma patients. This article presentsour current understanding of the biological heterogeneity of asthma andreviews some of the key features of the latest proposed recommendations of

the National Asthma Education and Prevention Program Guidelines [2].

E-mail address: [email protected]

0095-4543/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.pop.2007.09.008 primarycare.theclinics.com

Prim Care Clin Office Pract

35 (2008) 4160
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Burden of illness

Asthma is one of the most common chronic medical conditions in thedeveloped world and is increasing in its prevalence in less developed coun-tries as well. In the United States, over 22.2 million people are diagnosedwith asthma [3]. Over 12.2 million people su ff er asthma exacerbations(requiring increased asthma therapy and/or additional interventions) eachyear [3]. The total annual costs of asthma in the United States in 2002were estimated to be $16.1 billion of which $11.5 billion were direct costsrelated to medical expenses and $4.5 billion were indirect costs related tolost work productivity and school days as well as mortality. There were24.5 million lost workdays and 12.8 million missed school days in 2003due to asthma [4]. There were almost half a million hospitalizations relatedto asthma in 2002, which approximates to about 16 hospitalizations per10,000 population in the United States compared with 19.8 for diabetesand 37.4 for coronary atherosclerosis [3]. There were over 4200 asthmadeaths in 2002 [3,4], indicating that over 11 people per day die of asthmain the United States. Many of the asthma deaths occur in otherwise healthyyoung productive individuals. Many of these deaths were almost certainlypreventable if patients were treated more aggressively for their asthma.Data from the Salmeterol Multicenter Asthma Research Trial (SMART)showed that a number of those whose death was related to asthma hadlow use of inhaled corticosteroids despite having severe asthma [5].

What is asthma?

The clinical presentation of asthma includes typical symptoms of episodicdyspnea variably associated with other symptoms, such as chest tightness,wheezing, and coughing. Typical triggers for asthma symptoms include

allergens, exertion, cold air, irritant exposures, and strong odors. The hall-mark features of asthma include reversible airow obstruction ( O 12%improvement in forced expiratory volume in 1 second [FEV 1 ] with a mini-mum of 200-mL improvement postbronchodilator), bronchial hyperrespon-siveness, and airway inammation, which most often involves an elevationin sputum eosinophils [6] and or elevations in exhaled nitric oxide [6]. Whilethese elements represent the clinical features that lead to the diagnosis of asthma, these clinical features are not unique or the sole domain of asthmaand these clinical characteristics are seen in a wide assortment of respiratory

disorders. The symptom complex, the physiological features, and even cer-tain histological features found in asthma are also found in other obstructiveairway diseases and even in interstitial lung diseases that have an obstructivecomponent, such as sarcoidosis and hypersensitivity pneumonitis. Further-more, bronchoscopic and sputum studies that have examined the inamma-tory features of patients who have the clinical diagnosis of asthma revealthat there is indeed signicant heterogeneity in the magnitude and types

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of inammatory cells and mediators involved in various patients that t theclinical phenotype we refer to as asthma. This biological diversity is part of

the explanation for the variable response to pharmacological and nonphar-macological interventions observed in the asthma population.

Hence, it is best to think of asthma as a clinical diagnosis that has typicalsymptom and physiological features but also has several biological mecha-nisms that contribute to the nal clinical phenotype. There are several distinctclinical phenotypes of asthma ( Box 1 ) and it is likely that these are the result of environmental factors and di ff erent biological pathways being less or moreactive for di ff erent clinical presentations [7]. We recognize early- versus late-onset asthma [8] and we know that most early-onset asthmatics have environ-

mental allergies whereas late-onset asthmatics are less atopic yet tend to havehigher eosinophil counts in sputum and/or bronchoalveolar lavage [9]. Someasthmatics appear to have primarily nocturnal asthma [10,11] , exercise-in-duced asthma [12], or cough variant asthma [13] in isolation. These patientsmay have distinct biological characteristics that di ff erentiate them from themorecommongroup ofasthmatics that haveany orall of these featuresasa re-ection of poorly controlled disease in general. Meanwhile, some people de-velop occupational asthma related to high molecular weight allergens (eg,our, latex, animal proteins) with classic IgE-mediated allergic reactions ver-

sus low molecular weight antigens, most often such chemicals as isocyanatesor acid anhydrides where the precise mechanism is not as clear [14]. In addi-tion, some individuals develop reactive airways dysfunction syndrome be-cause of single or multiple high-dose exposures to irritants [15]. Finally,some patients have so-called inner-city asthma or urban asthma, whichis based on reports of higher prevalence rates and more severe disease foundin urban populations. This asthma most likely reects a complex interactionof socio-economic, environmental, and, potentially, biological factors.

Box 1. Clinical heterogeneity of asthma

Allergic versus nonallergic asthmaLate- versus early-onset asthmaExercise-induced asthmaNocturnal asthmaCough variant asthmaWork-related asthma

Work-aggravated asthmaOccupational asthma

Large molecular weight (classic IgE)Low molecular weight (Non-IgE)Reactive airways dysfunction syndrome

Inner-city (urban) asthma

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Asthma among urban populations has gained recognition and is an area of focused research [1618] .

Pathogenesis/pathophysiology of asthma

As previously stated, the pathogenesis of asthma is varied and there areseveral biological pathways, inammatory cells, and mediators that playvarying roles in di ff erent patient phenotypes ( Fig. 1 ) [19]. While several in-ammatory cell types may play important roles in asthma, eosinophils haveclassically been identied as part of the most common histological pattern.However, the exact role of eosinophils and their importance remain contro-

versial. Mast cells and basophils, when stimulated by allergen-induced re-lease of IgE from activated B lymphocyte memory cells known as plasmacells, release a host of chemical mediators (interleukin-1, -2, -3, -4, and -5,as well as granulocyte-macrophage colony stimulating factor [GMCSF],interferon g [IFN- g ], and tumor necrosis factor a [TNF- a ]) that lead tobronchoconstriction and recruitment of other inammatory cells, such asneutrophils, T-lymphocytes, and macrophages, which also release inamma-tory mediators and contribute to the inammatory soup. Interleukin-5 is of particular interest because it has a central role in the regulation of eosinophil

production and release from the bone marrow. There are other chemokines,such as RANTES (regulated upon activation in normal T cells, expressedand secreted protein), eotaxin, and macrophage inammatory protein-1 a

Fig. 1. The inammatory cascade of asthma is much more complex than this drawing indicates.Even so, the gure illustrates that several pathways are involved in the pathogenesis of asthma.GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin; MCP-1, mono-cyte chemotactic protein 1; RANTES, regulated upon activation in normal T cells, expressedand secreted protein; Th, T-helper lymphocytes; TNF, tumor necrosis factor.

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that participate in the migration of these inammatory cells to the airway.With such a diversity of cell types involved in the inammatory process, it

is easy to appreciate how there can be signicant heterogeneity in clinicalpresentation and response to therapy simply on the basis of the relative con-tribution of the various cell types and inammatory pathways for any indi-vidual patient.

While eosinophils have a central role in the pathogenesis of typical asthma,their exact role is still under investigation. Studies with a monoclonal antibodythat binds to interleukin-5, thus blocking a potent stimulus for the maturationand release of eosinophils, have not shown that obstructing the release of eo-sinophils profoundly changes theseverity of bronchial hyperresponsiveness or

the clinical course for many asthmatics despite signicantly reducing the eo-sinophils seen in biopsy or induced sputum specimens [20].

T-helper (Th) lymphocytes are also recognized as having a central role inthe inception and progression of asthma. It has beenproposed that individualspredisposed to developing allergic asthma have an imbalance favoring Th-2cells, which produce a family of cytokines that mediate allergic inammation,including interleukin-4, -5, -6, -9, and -13, rather than favoring Th-1 cells,which normally produce cytokines to ght infection, such as interleukin-2and IFN- g . The hygiene hypothesis suggests that reduced exposure to other

children, frequent antibiotic use, and reduced exposure to certain infections(eg, tuberculosis, measles, and hepatitis A) promote the development of a Th-2 phenotype more prone to respond to environmental allergens. Thisgene-by-environment interaction is o ff ered as a plausible explanation for theobserved higher prevalence of asthma in Westernized countries [21,22] .

Wenzel [23] have determined that some asthmatics have a neutrophil-pre-dominant inammatory pattern or no signicant inammation at all butrather extensive smooth muscle hypertrophy and mucous gland hyperplasia.Kraft and others [24] have shown that some asthmatic patients have a small

airway (bronchiolar) inammation that may be di ffi cult to target with in-haled medication.Patients with severe persistent asthma and indeed fatal asthma have

additional airway features, including mucous gland hyperplasia, mucousplugging, collagen deposition, basement membrane thickening, bronchialsmooth muscle hypertrophy, new blood vessel growth, and goblet cell hyper-plasia ( Fig. 2 ). These are the key elements of what is referred to as airway re-modeling. Much remains to be learned about the pathogenesis of airwayremodeling and why some asthmatics are more prone todevelop it thanothers.

While undertreatment of the inammatory component of asthma likely con-tributes to the development of airway remodeling, it is clear that other factors,particularly genetic predisposition and environmental exposures, may makesome asthmatics more prone to develop airway remodeling [25].

Szeer and colleagues [26] have shown that some patients have a relativeinsensitivity to the anti-inammatory e ff ects of steroids. These ndings andobservations help us understand at least part of the reason why some

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asthmatics are more di ffi cult to control than others. By improving our un-derstanding of this heterogeneity ( Box 2 ) and guring out ways to assessit by noninvasive means, we will be able to biologically phenotype patientsand tailor therapy accordingly.

Clinical assessment of asthma

Assessing for the presence of asthma

As noted above, patients suspected of having asthma typically present witha history of episodic shortness of breath associated with chest tightness andvariable wheezing and coughing. Typically there are a number of triggers,

Fig. 2. Key elements for assessing asthma severity. ( Adapted from National Heart, Lung, andBlood Institute. Expert panel report: guidelines for the diagnosis and management of asthma.1991. Bethesda (MD): U.S. Department of Health and Human Services; 1991, National Insti-tutes of Health publication 913042.)

Box 2. Summary of variable biological characteristics in asthma

Eosinophilic predominantNeutrophil predominantNoninammatory (smooth muscle hypertrophy and mucous

gland hyperplasia)Small airway predominantBeta-receptor polymorphismsSteroid insensitivity:

Abnormal glucocorticosteroid absorption and/or metabolismGlucocorticoid receptor polymorphisms

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such as extremes of air temperature and humidity; air pollution; strong odors,such as from perfume and cleaning agents; dust; and smoke. If individuals are

known to be atopic, then exposure to common environmental allergens, suchas trees, weeds, grasses, animal dander, mold, dust mites, and cockroaches,canbe potent triggers for their symptoms,dependingon their particular atopicprole. Because between 10% and 20% of adult asthma may be work related[27], adult-onset asthmatics should always be asked regarding occupationalexposures and hobbies that may expose them to potential allergens.

For younger nonsmoking patients with a typical history, many cliniciansmake a diagnosis of asthma and start therapy without consulting other spe-cialists. Many patients with this symptom complex are diagnosed with

asthma by their primary care physicians without any physiological baselineassessment, such as pre- and postbronchodilator response. This is subopti-mal. A baseline physiological assessment is essential for gathering data toestablish severity as well as to assess when a patient has reached his orher personal best. Furthermore, a physiological assessment could reveala nonobstructive pattern suggesting interstitial lung disease. Also, a physio-logical assessment could show that a patients degree of dyspnea is dispro-portionate to his or her spirometry, in which case other diagnoses shouldbe considered and further testing performed.

Di ff erential diagnosis of asthma

When patients rst present and, perhaps more importantly, when patientsdont respond optimally to asthma therapy, the provider must consider theconditions that may mimic or exacerbate asthma ( Box 3 ). In the adult popu-lation, the most common conditions that need to be ruled out in asthmaticsare allergic or nonallergic rhinitis with postnasal drainage, gastroesophagealreux disease, and, in smokers who have smoked more than 10 packs per year,

Box 3. Differential diagnosis of asthma

Chronic bronchitisChronic obstructive pulmonary diseasePostnasal dripGastroesophageal reux diseaseParadoxical vocal fold motion disorder (vocal cord dysfunction)Aspiration

Chronic mycoplasma infectionBronchiectasisBronchiolitis (constrictive, obliterative, related to collagen

vascular diseases)Hypersensitivity pneumonitisSarcoidosis

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chronic obstructive pulmonary disease. Patients with allergic rhinitis mayhave signicant postnasal drainage that leads to cough wheezing and short-

ness of breath that can mimic asthma. Patients with gastroesophageal reuxdisease can have bronchoconstriction just as a result of acid reuxed into theesophagus stimulating bronchoconstriction through a neural reex, or theymay induce bronchoconstriction as a result of reuxate being aspirated intothe lungs [28]. Paradoxical vocal fold motion disorder (PVFMD), also knownas vocal cord dysfunction (VCD), may mimic or complicate asthma. The par-adoxical closure of the vocal folds classically during inspiration, but also seenduring expiration, is associated with cough wheezing and shortness of breathand often coexists with postnasal drip and gastroesophageal reux disease

[28]. Some patients who have PVFMD and laryngopharyngeal reux (reuxinto the throat) without frank gastroesophageal reux disease may havePVFMD in isolation. Some such patients may microaspirate this reuxate,leading to asthma symptoms or reports of recurrent pneumonia.

In the past, we thought of chronic obstructive pulmonary disease patientsas generally having a minimal bronchodilator response and no evidence of airway hyperresponsiveness. Now we recognize that many patients witha clinical history and histological features closely compatible with chronicobstructive pulmonary disease have higher signicant bronchodilator re-

sponse, evidence of airway hyperresponsiveness, or both [29]. Truncatedow-volume loops and laryngoscopic ndings of paradoxical closure con-rm the diagnosis. Many lung conditions can have asthmatic features, in-cluding sarcoidosis, hypersensitivity pneumonitis, and, to a much lesserextent, other interstitial lung diseases. Bronchiectasis, a dilation of airwaysdue to chronic inammation causing destruction of the airway wall, canpresent with symptoms and objective physiological assessments similar tothose of asthma. Allergic bronchopulmonary mycosis, chronic colonizationof the airways leading to an allergic response, is often a complication of

asthma but may also develop in patients who have bronchiectasis for otherreasons, such as cystic brosis, primary ciliary dyskinesia, and immunode-ciency states, such as common variable immunodeciency, which renderpatients more susceptible to recurrent infections. Patients who have postin-fectious bronchiolitis or bronchiolitis for any number of other reasons, un-derlying collagen vascular disease and certain prescription and illicit drugsmay have a clinical presentation suggestive of asthma.

Assessment of severity

Because of the importance of an asthma diagnosis, the initial assessmentof asthma severity should include an assessment of symptoms and lung func-tion. Recommendations in this article follow the latest version of guidelinesfrom the National Asthma Education and Prevention Program (NAEPP)(draft available for review online until March 2007 but currently unpub-lished) in preference over the last published update in 2002 [30]. In otherwise

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healthy asthmatics, assessment of lung function often reveals normal valuesthat may underestimate the severity of their disease. This means the assess-

ment of symptoms, such as the frequency of nocturnal awakenings, the needfor rescue short-acting beta-agonist, the amount of school or work missed,and impact on overall quality of life often reveals a greater severity than re-ected by pre- or postbronchodilator spirometry. Fuhlbrigge and colleagues[31] conducted a telephone survey of over 42,000 households and found3273 homes with asthmatic adults ( O 16 years old) who answered questionsfrom the NAEPP Panel II Severity Criteria Questionnaire. Over 77.3% of the patients interviewed had moderate or severe persistent asthma, about7.3% met criteria for intermittent asthma, and 15.4% meet the criteria for

mild persistent asthma. It is still imperative, however, that asthmatics be as-sessed with objective measures of lung function, such as peak ow monitor-ing and routine spirometry.

Many clinicians rely on spirometry as the best or most objective assessmentof asthma severity and/or control. However, studies have shown that simplespirometry has a poor correlation with symptoms [32]. Many factors likelycontribute to this discordance between spirometry, symptoms, and the sever-ity of asthma and these factors have varying importance from one patient toanother. Patients vary in sensitivity to their own dyspnea [33,34] . Hence,

some patients have signicant symptoms with relatively well preserved lungfunction, while others have minimal reported symptoms but signicantlyreduced lung function. Also, some asthma patients who have well-preservedbaseline lung function also have signicant bronchial hyperreactivity suchthat with various stimuli, such as irritant odors, particulate, allergens, orexercise, they can have profound bronchospasm with cough, chest tightness,wheezing, and shortness of breath, but because of a robust response to bron-chodilator they return to normalor perhaps even supernormal baseline values.For some patients, asthma may a ff ect smaller airways more than large airways

and severity may be underestimated because there is a poor correlationbetween FEV 1 and small airway involvement. Hence, it is not enough tomeasure spirometry. One must evaluate several elements (as outlined above)to assess an asthmatics severity and level of control. The severity level isdetermined by assigning a severity level for each category (daytime symptoms,nocturnal symptoms, rescue albuterol use, corticosteroid use, spirometry, andpeak ow assessment) and identifying the highest severity level found in any of these categories. For example, a patient with perfectly normal lung functionbut daily symptoms and use of albuterol would be in the very severe category

despite normal lung function.

Assessing asthma risk

In addition to assessing an asthmatics severity, it is also important toestablish that persons risk for serious adverse outcomes. Hence patientsshould be asked about the frequency and severity of exacerbations. These

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questions should cover, for example, medication and medical attentionrequirements; stays in emergency rooms, hospital wards and intensive care

units; and experience with ventilation. Furthermore, it is important to askabout the use of oral steroids and to include lung function in this assess-ment. Recent studies have suggested that measurements of inammatorymarkers, such as sputum eosinophils and exhaled nitric oxide, mightimprove assessments of severity and risk for serious adverse outcomes [35].

Assessing control

The goals of asthma therapy are to achieve total asthma control and todene the personal best for each individual patient. In working toward thesegoals, the principal aims are to reduce impairment and risk. Reducingimpairment means to improve or minimize chronic symptoms and rescueinhaler use and to maintain lung function and activity levels while meetingthe patients and his or her familys expectations. Reduction of risk involvespreventing exacerbations, minimizing urgent care visits or hospitalization,and preventing loss of lung function with optimum pharmacotherapy withminimal or no adverse e ff ects. The Asthma Control Test is a standardizedquestionnaire that has been validated and shown to be as instructive as spi-rometry and standard questions ( Box 4 ).

When assessing the degree of asthma severity and control, it is importantto know whether or not the patient is on controller medication. If the patientis not on controller medications, then the clinician uses the criteria above toestablish severity and degree of control. If the patient is on controller medi-cations, then the clinician must also use the criteria outlined above but, inaddition, include what level of controller medication is required to keep thepatient under control or at his or her best level of control. Obviously the asth-matic who requires high-dose inhaled corticosteroids and long-acting beta-agonists may achieve good control but is clearly severe when one takes intoaccount the medication needed to keep at that level of control.

A preliminary draft of the latest version of the NAEPP asthma guidelineshas provided evidenced-based recommendations for the management of asthma for infants through adults [2]. The grading system proposed in thelatest NAEPP guidelines is outlined in Box 5 .

Asthma management for infants to age 11

For children from infancy through to the age of 4 ( Box 6 ), there is A-levelevidence that inhaled corticosteroids for patients with persistent asthma aresafe and e ff ective rst-line therapy. Because few drugs are ever studied inthis patient population, the level of evidence for use of long-acting beta-agonists, montelukast, and oral steroids at higher severity stages is no higherthan D. For children between ages of 5 to 11, studies have shown the benetof inhaled corticosteroids at all stages of therapy (level A evidence) and

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Box 4 . Asthma Control Test for patients 12 years old

1. In the past 4 weeks, how much of thetime did your asthma keep you from getting as muchdone at work, school or at home? Score:1 All of the time _____2 Most of the time _____3 Some of the time _____4 A little of the time _____5 None of the time _____

2. During the past 5 weeks, how oftenhave you had shortness of breath? Score:1 More than once a day _____2 Once a day _____3 Three to six times a week _____4 Once or twice a week _____5 Not at all _____

3. During the past 4 weeks, how often did your asthmasymptoms (wheezing, coughing, shortness of breath,chest tightness, or pain) wake you up at nightor earlier than usual in the morning? Score:1 Four or more nights a week _____2 Two or 3 nights a week _____3 Once a week _____4 Once or twice _____5 Not at all _____

4. During the past 4 weeks, how often haveyou used your rescue inhaler or nebulizer medication(such as albuterol)? Score:1 Three or more times per day _____2 One or two times per day _____3 Two or three times per week _____4 Once a week or less _____5 Not at all _____

5. How would you rate your asthma controlduring the past 4 weeks? Score:1 Not controlled at all _____2 Poorly controlled _____3 Somewhat controlled _____4 Well controlled _____5 Completely controlled _____

Level of control based on composite score: 20, controlled; 1619, not wellcontrolled; 15, very poorly controlled regardless of patients self assessment of control in question 5. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/ epr3/resource.pdf . Accessed February 5, 2007.

Courtesy of QualityMetric, Inc., Lincoln, RI; with permission. Copyright 2002QualityMetric Incorporated. Asthma Control Test is a trademark of QualityMetricIncorporated.Availableat: http://www.asthmacontrol.com . AccessedDecember14,2006.

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increasing doses of inhaled corticosteroids in combination with long-actingbeta-agonists as preferred treatment for steps two through ve (level B evi-dence). The use of these medications in addition to long-term oral steroidsremains a consensus opinion because few studies are done on this patientpopulation ( Box 7 ).

Asthma treatment for those 12 years or older

For patients 12 years old and older, inhaled corticosteroids are the main-

stay of therapy for all steps of asthma care with increasing doses throughsteps 2 to 6 (level A evidence) ( Box 8 ). For patients with mild moderate

Box 5. Grading system for evidence-based recommendations

Level A evidence: based on randomized, controlled trials withrich body of data

Level B evidence: based on randomized, controlled trials withlimited body of data

Level C evidence: based on nonrandomized trials andobservational studies

Level D evidence: based on panel consensus judgment

Box 6. NAEPP draft guidelines for stepped approachto managing asthma in children aged 0 to 4 years

Step 1 (intermittent asthma): short-acting beta-agonist as neededStep 2 (mild persistent asthma)

Preferred: low-dose inhaled corticosteroid (supported by level

A evidence)Alternatives: montelukast (supported by level A evidence) or

cromolyn (supported by level B evidence)Step 3 (moderate to severe persistent asthma): medium-dose

inhaled corticosteroid (supported by level D evidence)Step 4 (moderate to severe persistent asthma): medium-dose

inhaled corticosteroid and either montelukast or long-actingbeta-agonist (supported by level D evidence)

Step 5 (moderate to severe persistent asthma): high-dose inhaled

corticosteroid and either montelukast or long-actingbeta-agonist (supported by level D evidence)

Step 6 (moderate to severe persistent asthma): high-dose inhaledcorticosteroid and either montelukast or long-actingbeta-agonist and/or oral corticosteroid (supported bylevel D evidence)

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asthma (stage 3) long-acting beta-agonists can be added to low-dose corti-costeroids if moderate-dose corticosteroids cause too many side e ff ects orare poorly tolerated (level A evidence). When patients have more severe dis-ease, long-acting beta-agonists are considered for adding to medium- tohigh-dose steroids (level B evidence).

While it is possible to consider alternative agents for treatment of stage 2asthma, none of the other agents o ff ered as alternatives (eg, cromolyn,

Box 7. NAEPP draft guidelines for stepped approach

to managing asthma in children aged 5 to 11 yearsStep 1 (intermittent asthma): short-acting beta-agonist as neededStep 2 (mild persistent asthma)

Preferred: low-dose inhaled corticosteroid (supported by levelA evidence)

Alternatives: leukotriene receptor antagonist, cromolyn, ortheophylline (each supported by level B evidence)

Step 3 (moderate/severe persistent asthma): medium-doseinhaled corticosteroid alone or low-dose inhaled corticosteroidand either long-acting beta-agonist, leukotriene receptorantagonist, or theophylline (each supported by level Bevidence)

Step 4 (severe persistent)Preferred: medium-dose inhaled corticosteroid and

long-acting beta-agonist (supported by level B evidence)Alternatives: medium-dose inhaled corticosteroid and either

or zileuton, leukotriene receptor antagonist, or theophylline(each supported by level B evidence)

Step 5 (severe persistent)Preferred: high-dose inhaled corticosteroid and long-acting

beta-agonist (supported by level B evidence)Alternatives: high-dose inhaled corticosteroid and either

leukotriene receptor antagonist or theophylline (eachsupported by level B evidence). Consider omalizumab forpatients who have allergies.

Step 6 (severe persistent)Preferred: high-dose inhaled corticosteroid, long-acting

beta-agonist, and oral corticosteroid (supported by level Devidence)

Alternatives: high-dose inhaled corticosteroid, eitherleukotriene receptor antagonist or theophylline, and oralcorticosteroid (supported by level D evidence). Omalizumabmay be considered for patients who have allergies.

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nedocromil, leukotriene receptor antagonists, or theophylline) are as e ff ec-tive as inhaled corticosteroids (level B evidence). The role of zileuton, a 5lipoxygenase inhibitor that reduces the production of leukotriene B-4, re-mains less established but can be considered for patients who have notbeen optimally controlled on inhaled corticosteroids and long-acting beta-agonists and/or leukotriene D-4 receptor antagonists, such as montelukast

(level D evidence). Some work suggests 5 lipoxygenase inhibitors may notonly be useful for patients with asthma associated with an eosinophilic in-ammatory response but also for those with a neutrophilic response [36].

Omalizumab, the new anti-IgE agent, is recommended as adjunctive ther-apy for asthma patients with allergies who are not controlled on high-doseinhaled corticosteroids and long-acting beta-agonists (step 5) and/or oralsteroids (step 6) (level B evidence).

Box 8. NAEPP draft guidelines for stepped approach

to managing asthma in patients aged 12 years and olderStep 1 (intermittent asthma): short-acting beta-agonist as neededStep 2 (mild persistent asthma)

Preferred: low-dose inhaled corticosteroid (supported by levelA evidence)

Alternatives: cromolyn, nedocromil, leukotriene receptorantagonist, or theophylline (each supported by level Bevidence)

Step 3 (moderate persistent asthma)Preferred: medium-dose inhaled corticosteroid alone or

low-dose inhaled corticosteroid and long-actingbeta-agonist (both supported by level A evidence)

Alternatives: low-dose inhaled corticosteroid and eitherleukotriene receptor antagonist (supported by level Aevidence), theophylline (supported by level B evidence), orzileuton (supported by level D evidence)

Step 4 (severe persistent asthma): medium-dose inhaledcorticosteroid and long-acting beta-agonist (supported by levelB evidence)

Step 5 (severe persistent asthma): high-dose inhaledcorticosteroid and long-acting beta-agonist (supported by levelB evidence). Consider omalizumab for patients who haveallergies (supported by level B evidence).

Step 6 (severe persistent asthma): high-dose inhaledcorticosteroid, long-acting beta-agonist, and oralcorticosteroid. Consider omalizumab for patients who haveallergies.

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Theophylline remains on the list of alternative therapies. Some evidenceshows that theophylline may be able to augment steroid responsiveness

through up-regulation of the histone deacetylases, which down-regulatesexpression of inammatory genes [37]. However, ongoing concerns remainabout the narrow therapeutic window for theophylline, which is why itremains a third-tier option for most physicians (level B evidence).

Safety issues

Long-acting beta-agonists

There has been concern recently regarding the safety of such long-actingbeta-agonists as salmeterol and formoterol. SMART [5] examined the safetyof salmeterol compared with placebo in over 26,000 patients. Patients whostated they had a diagnosis of asthma and were on at least one medicationused for asthma (even a short-acting beta-agonist) could be entered into thetrial. Patients who had never been on a long-acting beta-agonist wereexcluded. Patients were given medication for the study duration and werefollowed up only by telephone interview every 4 weeks over the 28 weeksof the study. This study raised concerns because there were increased respi-ratory deaths or life-threatening experiences noted in the African Americanmale population using salmeterol compared with placebo (relative risk 4.1;95% CI, 1.5410.9). The study found that this group also tended to use oralsteroids more frequently, to have more frequent and longer hospitalizations,to have higher rates of intubation, and to use less inhaled corticosteroids asmaintenance therapy compared with the other groups studied.

There are legitimate concerns about the overuse of beta-agonist medica-tions causing adverse e ff ects and perhaps even attenuating the beta-recep-tors response to beta-agonists for a subset of asthma patients who havecertain polymorphisms of the beta-receptor ARG-ARG [38]. However,the ndings of SMART likely reect suboptimal compliance with inhaledcorticosteroids. The consequent black box warning imposed by theFood and Drug Administration in the United States emphasizes thatpatients should be optimized on inhaled corticosteroids before the use of long-acting beta-agonists is considered. Hence, while further studies areneeded to clarify the safety of long-acting beta-agonists in asthma patientsthat have certain beta-receptor polymorphisms, the vast majority of asthmapatients are likely to benet from the use of these medications when inhaledcorticosteroids alone are unable to achieve total control or when there areintolerable side e ff ects from higher dose inhaled corticosteroids.

Omalizumab

Omalizumab, a highly humanized monoclonal antibody against IgE, hasbeen shown to reduce exacerbations [3941] and steroid requirements

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[3941] for patients with allergic asthma. Omalizumab has been recommen-ded for use in patients who are not optimally controlled on standard thera-

pies or have signicant side e ff ects from inhaled corticosteroids [42]. Becauseomalizumab is systemically delivered, this agent may be e ff ective in patientswho have signicant smaller airway disease. Earlier in 2007, there were con-cerns raised regarding potentially signicant anaphylactic events [4345]despite the molecule being approximately 95% humanized with a 5% com-plimentary determining region that is mouse derived. Xolair, a brand of omalizumab, received a black box warning that states it should be admin-istered in a monitored medical setting with personnel trained and able tomanage anaphylaxis, but there is no specic time requirement as to how

long patients should be monitored.

Setting up patients with asthma action plans

In devising asthma action plans for patients, perhaps the rst question toask is: Which asthma patients need such a plan? There has been some debateas to whether plans make a di ff erence and some studies have suggested thatoutcomes were not signicantly altered in groups given action plans com-pared with those that were not [4648] . Nonetheless, it is likely that thereare at least some patients for whom action plans are helpful, such as thosewho have frequent exacerbations and those who are poor perceivers or havediffi culty with adherence or compliance.

Asthma action plans should enable the patient and his or her family todeal with any asthma emergency, to detect early signs of an exacerbation,and to intervene promptly to prevent urgent or emergency care visits andhospitalizations. Asthma action plans should contain such information as(1) a list of triggers known to worsen the individuals asthma, (2) typicalsymptoms that suggest a worsening of asthma, (3) peak ow meter readings,and (4) measurements of a personal best and zones with green indicating80% to 100% of personal best, yellow indicating 50% to 79% of personalbest, and red indicating less than 50% of personal best. Peak ow levelsfall and symptoms dictate what actions should be taken, ranging from aller-gen avoidance, to increasing inhaled corticosteroids, to seeking immediatemedical attention ( Fig. 3 ) (refer to http://www.nationaljewish.org/pdf/asthma-action-plan.pdf ).

Summary

The diagnosis of asthma is based on such clinical features as variable air-ow obstruction that is partially if not fully reversible and airway hyperres-ponsiveness that predisposes to episodic bronchospasm following exposureto a variety of triggers, which di ff er from patient to patient. The underlyinginammation and airway biology of asthma is heterogeneous and is part of

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Fig. 3. National Jewish Medical and Research Center Asthma Action Plan. ( Courtesy of National Jewish Medical and Research Center, Denver, CO; with permission.)


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the explanation for the variable response to therapy. New biologics, such asanti-IgE agents, and other new techniques that help to characterize patients

according to their underlying biology will aid in making better choices fortreatment. The new NAEPP asthma guidelines emphasize the importanceof regular monitoring of several factors, including daytime and nighttimesymptoms; interference with school, work, and other activities; rescue albu-terol use; exacerbations; personal assessment of level of control; and lungfunction, so that appropriate choices are made regarding stepping up orstepping down therapy. When feasible, assessment of airway inammationby noninvasive measures, such as sputum eosinophils or exhaled nitricoxide, provide the earliest indications of worsening asthma and allow

treatment interventions earlier, which ultimately may lead to fewer exacer-bations and lower inhaled steroid requirements.

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