Arnaldo Cantani

Pediatric Allergy, Asthma and Immunology

Pediatric Allergy,AsthmaandImmunology

123

With 649 Figures in 728 Partfigures, 341 in Color and 741 Tables

Arnaldo Cantani

Arnaldo Cantani, Prof. Dr.Allergy and Clinical Immunology Division Department of Pediatrics University of Rome “La Sapienza”Via G. Baglivi, 700161 Rome, Italye-mail: acantani@pelagus.it

Title of the original Italian edition:Allergologia e immunologia pediatrica – dall’infanzia all’adolescenza© 2000 Verduci Editore – Roma, ISBN 88-7620-545-4

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To my beloved wife for so much help she has given me and for so much time I robbed her of.

Science cannot be restricted by the narrow frame of a book:

it is generally intolerant of frames

Pediatric Allergy,Asthma and Immunology is a new dis-cipline that finds its foundation in this book, whoseroots linke me to Elena and Luisa Businco, with whom Ifounded the first Italian Pediatric Allergy Division some30years ago, now called the Pediatric Allergy and Im-munology Division. There I discovered this world,where I had the chance to revive the significance of thethree Ss: science, safety and sympathy. Children andtheir parents consult us in the hope of finding scientificand medical knowledge as well as assurance and under-standing sympathy, all necessary prerequisites for thesuccessful outcome of our everyday tasks.Above all, oneshould appreciate how much the pediatrician–allergistis, more than any other doctor, dedicated to the care ofhis or her patients, since he or she must either deal withcases of extreme severity, such as anaphylactic shock, orperform ordinary jobs, such as giving suggestions onthe diets or the furnishings of the home. The pediatri-cian–allergist should always find out how to protect theinfant, the child and the adolescent against discrimina-tion because of their allergy. With proper prescriptionsand appropriate recommendations, such an objective isalways within reach, and both the child and his or herparents will profit from a better quality of life.

The earliest roots of this book developed from myeveryday work in the Pediatric Allergy and Immunolo-gy Division and have grown while preparing lessonsand courses to be delivered to medical students andpostgraduates in pediatrics. Of course, this ongoingwork has found its expression in a host of papers thathave inspired several chapters within this book. How-ever, my primary aim was not one of doing somethingnecessary; I have hoped only to do something that isuseful to someone. With this book, I hope to have of-fered convincing proofs and foundations to colleaguescommitted to pediatric allergy and immunology. Oftenits main goal is one of prevention, in all senses and us-ing all resources, as Arnaldo Cantani Sr. wrote in 1877in the preface to the first edition of his Textbook of Clin-ical Pharmacology: “ … only corresponding with ameticulous study and the greatest exactness to the precise indications of the case, the drugs may be use-–ful to the patient … in the belief that air, water, and

alimentation are the first and most powerful means tobe well.”

Pediatric allergy and immunology is a multidiscipli-nary field of research today, and familiarity with currentconcepts is important for medical students, for clini-cians in every pediatric specialization and for re-searchers in this attractive area.However, the issue is notbenefited by an easy approach, because pediatric allergyand immunology has characteristic features both differ-ent and larger in scope than adult allergy. Nor can wedisregard significant events such as the atopic-march,the inexorably accelerating prevalence of atopic dis-eases, which develop in 80%–90% of cases within thevery first months and years of life, while the intenseefforts of research scientists and the greater awarenessof pediatricians and of dedicated parents have widenedthe positive results of prevention and treatment. Theavalanche of immunological progress shows no sign ofabating in this new millennium. I have therefore begunwith the fundamental concepts of basic immunology,whose inferences are relevant to the later chapters. Forexample, I have attempted to offer an exhaustive discus-sion in Chap.1 to the interested reader trying to under-stand the significance of adhesion molecules from thepathogenic point of view. Therefore, after the chapterson fetal-neonatal immunology and the mucosal im-mune system, the neonate at risk of atopy, the geneticand environmental predisposing factors and the epi-demiology and natural history of atopic diseases, awhole chapter encompasses the diagnosis of allergy,from the clinical history to the provocation tests. Thebook progresses chapter by chapter to elucidate thespectrum of several diseases, including atopic dermati-tis, food allergy, asthma, rhinoconjunctivitis, and to dis-cuss specific immunotherapy (SIT) for these diseases. Italso places great emphasis on specialist disorders suchas sinusitis and otitis media with effusion, which are fre-quently associated with allergic diseases. Many pagesare devoted to autoimmune diseases, primary immuno-deficiencies and to pediatric HIV infection. The last twochapters are comprehensively built on the earlier ones,introducing two emerging important advances, malnu-trition and the immune system and another of capitalimportance,atopy prevention,which sums up the wealthof new data.

Until recently, the expansion of immunology wasundervalued. In this breakthrough my major thrust was

Preface

VII

to attest to the ferments of activity that have revolution-ized, so to say, the exciting new area of research, such asthe therapeutic strategies exemplified by the switchfrom Th2 to Th1 lymphocytes in the immune systemmanipulations through SIT and anti-IgE therapy, genetherapy of primary immunodeficiencies and the mater-nofetal treatment of HIV infection. A growing body ofliterature is shaping our knowledge of the fetal immunesystem. We are now aware that the fetus can be im-munocompetent from the 18th to 20thweek of in-trauterine life, and that from the 22ndweek it can reactto food and inhalant allergens of maternal origin, sug-gesting that heredity and maternal intake of foods ordrugs or allergen inhalation may anticipate the founda-tions of pediatric allergy and immunology in intrauter-ine life, thus requiring an advancement of preventivemeasures. In this context, immunology is the new mile-stone when one refers to the so-called collagen diseases,revisited as a deviation from the normal mechanisms ofself-recognition, to the viruses that deceive the immunesystem, modulating apoptosis at will, and to the im-munological components of breast milk, rich in prebi-otics and TLRs and protecting infants even from dia-betes. From this viewpoint we cannot underestimate theimpact of transgenic foods and pesticides, which arerevolutionizing foods, and of polluted air breathed bynewborns. Among the food offenders, the first levelrefers to hidden allergens, or those regularly absentfrom the labels, and the growing number of cross-reac-tions, with the remarkable latex–fruit syndrome and themite–mollusc correlations. The role of infectious agentscould likely be the opposite of current theories, namelythat of protecting infants from the onset of allergic dis-ease, whose higher frequency could be favored by theimprovement in the standard of living. The hygiene hy-pothesis is intriguing, but milk may kill by inhalation,casein may remain active for 2,500years and egg for500years. We move forward in pediatric allergy and im-munology: fascinating findings focus on the increasingnumber of wheezing infants and on the success of de-sensitization shared by food-allergic and asthmaticchildren, thus leaving these children without disease.Immunodeficiencies are radically cured by bone mar-row transplantation, autoimmune diseases are startingto be cured with stem cell transplantation, diabetesseems to be cured by mother–daughter transplantationof pancreatic cells and immunodeficiencies by bonemarrow transplantation. HIV infection can be “cured”by prevention.

In the presentation of the diverse conditions, I havepreferred a complete description in a traditional se-quence, beginning with an introduction, the definitionsand the epidemiology, then continuing with the im-munological characteristics, pathogenesis, symptoms,diagnosis and treatment. Further, being compelled todeal with aspects sometimes so distant or different hascertainly implied possible errors in measure and acertain degree of overlap. A very hard task was that of

selecting, among the relevant literature in an unendingstream of data on pathogenic and therapeutic aspects,the most significant ones, especially in the field of pedi-atrics. It is not always easy and productive to interweavebasic and clinical material. I have tried to inform thereader more comprehensively following a logical pro-gression,synthetically reviewing the most recent state ofthis rapidly advancing specialization, leaving in thebackground the data pertaining to the basic knowledgeof pediatricians and allergist–immunologists.

My purpose was also that of lightening the text withthe aid of approximately 1,400 high-quality figures cov-ering basic aspects and tables abounding with practicalinformation facilitating day-to-day diagnosis and man-agement. My approach has been that of utilizing the fig-ures and tables as both a commentary and an extensionof the text. The appendices complete the volume, whilethe abbreviations and acronyms are listed separately. Inaddition, I have adopted the Système International desUnités (SI) where appropriate. At the end of each chap-ter a list of references includes leading articles and sub-specialty reviews, so that readers are referred to numer-ous points of departure from which to explore furtherthe subjects closer to their interests.

I have attempted, therefore, to offer to dedicatedpediatricians and family practitioners a comprehensive,clear and timely distillation of current informationmaking it possible to keep abreast of recent advancesand to acquire the basic principles necessary in theirpractice. The careful reader will find practical advice onwhich to base actions that will block the atopic and im-munological march by preventing, managing and treat-ing allergic–immunological diseases, and by appropri-ately informing parents, without neglecting to raisepublic awareness of the threat posed by the march andto provide the means to stop it. Managing childhoodatopic and immune disorders requires a new strategy.Millions of children and their parents expect diseaseprevention and cure, and allergists or immunologistsare challenged to provide interventions that achieveoptimal health from childhood to adulthood. I hope thatstudents and postgraduate doctors willing to find adetailed reference for this fascinating and demandingarea of pediatrics and willing to develop an allergic–im-munological viewpoint will succeed in identifying thediverse pathologies and will be motivated to becomemore actively involved in the daily health needs ofatopic infants, children and adolescents.

I am deeply grateful to my wife, María Susana Cam-postrini, who assisted me in this challenging enterpriseand helped me to add expressive illustrations to thebook. I wish to acknowledge the assistance of severalcolleagues for their helpful discussions and contribu-tions, including Doctors Daniele Ceccoli, Franco Frati,Oreste Marciano and my referees Professors EmanueleErrigo and Massimo Fiorilli. The consultation of nu-merous journals was of particular help, especially in the libraries of the Pediatric Department of Rome Uni-

VIII Preface

versity “La Sapienza”and Rome University “Tor Vergata,”the Pediatric Department of Sassari University, theNational Council for Scientific Research, the Italian Institute of Public Health and several university libraries of the Hospital Policlinico Umberto I where Iwork, especially the Department of Experimental Medi-cine. I extend my gratitude to many colleagues and pub-lishers who have kindly provided many figures includ-ing the late Professor Luisa Businco and the UCB thatkindly supplied many figures related to the SCORADand ETAC studies. In particular, I am deeply indebted to Professors Molkhou, Revillard and Wüthrich andtheir publishers. My thanks to Professors Mogi, Ringand Wüthrich, who presented me with their books and Professors Bernstein, Brandtzaeg, Buckley, Gerrard,Patriarca, Roos and Sullivan for sending me reprints not easily found otherwise. I owe particular gratitude

to Springer-Verlag and especially to Ms Ute Bujard for her meticulous editing skills that allowed the publica-tion of this book. I would also like to thank Martha Bergwhose excellent assistance helped me very much.

To offer a wide panorama of results, several data havebeen presented throughout the book and reported inthe tables and in the figures, independently of how thechildren were identified as affected with allergic-im-munologic disease. Of course I do not expect that myopinions or my suggestions “to live better with allergy”meet the unconditioned favor of all readers: I would begrateful if they would point out “the errors and theomissions”so that I can correct them in a future edition.

Rome, September 2007Arnaldo Cantani

IXPreface

Head Title

XI

For those who believe that I may not be the best suitedperson to present Pediatric Allergy, Asthma and Im-munology by Arnaldo Cantani, I would like to explainthe reasons that encouraged me – a specialist of adultdisease of intellectual development, with professionalexperiences substantially different from those of theauthor – to agree to his request with great pleasure.These reasons are either of a personal nature or of amore general and ideological nature.

Professor Cantani’s knowledge has its deep roots inhis extensive work at the Department of Pediatrics ofthe University of Rome “La Sapienza” and especially atthe chair of the late Professor E. Rezza. Only recently,however, when I had more frequent opportunities ofcollaborating with him, was I struck by the profound“team spirit” that Arnaldo Cantani feels for pediatricallergy and immunology as well as by his exactness andprecision in dealing with the commitment necessary toreport his own experience.

As Past President of the European Academy of Aller-gology and Clinical Immunology, I am fully aware ofthe problems, both general and specific, that pertain tothe discipline of “pediatric allergy and immunology.”The opportunity to acknowledge this discipline as anautonomous specialization is of primary necessity,espe-cially in north European centers. This orientation isopposed by some pediatric specialists or allergy special-ists. However, it should be appreciated that pediatricallergy and immunology differs widely from that ofadults, as evidenced by this textbook. This difference isparticularly important not only in the newborn periodbut above all in the diseases typical and specific to thepediatric age as well as in those also common to adultpatients, of wholly peculiar physiopathologic, diagnos-tic and therapeutic characteristics. These current pointsof view are confirmed by the recent proposal to consid-er both internal medicine and pediatrics as commonbranches of the allergology and clinical immunology

specialization, as well as the decision of the EuropeanAcademy of Allergology and Clinical Immunology tocreate a Section of Pediatric Allergology, thus satisfyingthe need to gather under a single roof specialists ofthe “general” discipline, thereby recognizing and war-ranting the importance and autonomy of the pediatricallergologist.

Professor Cantani’s book is a concrete and cogentcontribution to the foundation of pediatric allergy–immunology. This book is an impressive and compre-hensive documentation of the progress in the under-standing and management of allergic–immunologicdisorders of infants, children and adolescents, and isdivided into 24 chapters illustrated by more than 1,400tables and figures that are helpful in clarifying complexpoints. I have greatly appreciated the author’s approachof discussing, in addition to the ontogeny of the immunesystem, mucosal immunology and the typical pathologyof infantile immediate hypersensitivity with its veryearly onset age, the mechanisms underlying specificdisease states such as the developing neonatal immuneresponse, autoimmune disease, immune deficienciesand pediatric AIDS, which are increasingly recognizedas complex diseases. Such an approach entails, in fact,that one’s eyes be kept open to the complexity of clinicalallergology and immunology, and widened beyond thelimited field of atopic disease and the “atopic march” tothe genetic relation to atopy and bone marrow trans-plantation.

A critical analysis of how this complex and detailedinformation is condensed into a readable textbook sug-gests the author’s far-sighted attitude: on the one handthe painstaking precision of the scientist (see the list ofabbreviations that opens the book), and on the other themore typical Latin inclination to prefer clinical reason-ing, which, even in its subjectivity, always represents theessential distinguishing feature between the clinicalprofessor and accurately programmed reasoning.

Foreword

The findings of several schools and disciplines differ-ent from those of Professor Cantani are critically evalu-ated, and the virtues of single authorship, compared tomulti-authored textbooks that often lack sufficient co-ordination and revision by the editor, are evidentthroughout the book.

All chapters have reference lists with citations thatwill be stimulating for those interested in more in-depthstudy. Moreover, the suggestions at the end of eachchapter and the numerous discussions, also in the formof tables and figures, promote an expert starting pointfor diverse specialists interested in evidence-basedmedicine, be they allergists, immunologists, pediatri-cians or practitioners.As a result, the reader has at handa doubly useful book: one to be studied and consulted,the other to be read with pleasure, a book to be ap-proached critically.

Although he had the excellent collaboration andeditorial assistance of Springer-Verlag throughout thepreparation of this textbook, Arnaldo Cantani hasundertaken alone the fascinating burden of puttingtogether Pediatric Allergy, Asthma and Immunology.I therefore compliment the author on assembling anoutstanding opus in the interest of pediatric allergy andimmunology and in the training of all those concernedwith the “march.”Anyone who cares for allergic childrenor wants to learn about immune diseases will surelybenefit from frequent consultations of this textbook.I hope that the book will provide pleasure and insight toall prospective readers.

Rome, May 2007Sergio Bonini

XII Foreword

1 Immunology

Historical Milestones . . . . . . . . . . . . . . . . 1The Immune System . . . . . . . . . . . . . . . . . 1

Systems of Immunity . . . . . . . . . . . . . . . 2Organs and Cells of the Immune System . . . . . . 4Cells of the Immune System . . . . . . . . . . . . . 9

Two Families of Lymphocytes . . . . . . . . . . 9Structure and Molecular Framework . . . . . . 25

T and B Cell Receptors . . . . . . . . . . . . . . . . 56T-Cell Antigen Receptors . . . . . . . . . . . . 57B-Cell Antigen Receptors . . . . . . . . . . . . 59

Immunogens, Antigens and Allergens . . . . . . . 60Epitopes and Paratopes . . . . . . . . . . . . . 61Antibodies . . . . . . . . . . . . . . . . . . . . 64Idiotypes and Anti-idiotypes . . . . . . . . . . 67

The HLA System . . . . . . . . . . . . . . . . . . . 74Initial Phase of the Immune Response . . . . . . . 79

Functions of HLA Molecules and Antigen Processing . . . . . . . . . . . . . 79

Cells of the Immune System Participating in Immune Responses . . . . . . . . . . . . . . . . 82

Additional Cells . . . . . . . . . . . . . . . . . . 97Afferent Phase of Immune Response . . . . . . . . 99

Antigen Processing and Presentation . . . . . . 99Lymphocyte Activation . . . . . . . . . . . . . . . 103

Role of T Lymphocytes . . . . . . . . . . . . . . 104Role of B Lymphocytes . . . . . . . . . . . . . . 106Expression of Genes and Transcriptional Activity . . . . . . . . . . . 107Signal Transduction . . . . . . . . . . . . . . . 109Mean Values of Lymphocyte Populations and Subpopulations and of Other Immune Cells . . . . . . . . . . . 111

Central Phase of the Immune Response:Synthesis of IgE Antibodies . . . . . . . . . . . . . 116

A Two-Signal Model for Induction of IgE Synthesis . . . . . . . . . . . . . . . . . . 116

Immune Responses . . . . . . . . . . . . . . . . . . 123Immediate and Delayed Reactions . . . . . . . 123Hypersensitivity Reactions . . . . . . . . . . . 124

Mediators . . . . . . . . . . . . . . . . . . . . . . . 129Primary Mediators . . . . . . . . . . . . . . . . 130Secondary Mediators . . . . . . . . . . . . . . . 133

Mechanisms of Cell Adhesion:Interleukins and Adhesion Molecules . . . . . . . 133

Mechanisms of Cellular Adhesion . . . . . . . 135Integrins . . . . . . . . . . . . . . . . . . . . . . 136Selectins . . . . . . . . . . . . . . . . . . . . . . 138Relationships Between ILs and Adhesion Molecules . . . . . . . . . . . . . 140Chemokines . . . . . . . . . . . . . . . . . . . . 140Leukocyte Trafficking and Migration . . . . . . 148

Interrelations with Other Organs . . . . . . . . . . 151Innate Immunity . . . . . . . . . . . . . . . . . . . 152Therapeutic Perspectives . . . . . . . . . . . . . . 171Allergens . . . . . . . . . . . . . . . . . . . . . . . 174

Allergen Standardization . . . . . . . . . . . . 175Standardization Techniques . . . . . . . . . . . 175Transgenic Foods . . . . . . . . . . . . . . . . . 182Allergen Characteristics . . . . . . . . . . . . . 183References . . . . . . . . . . . . . . . . . . . . . 202

2 Fetal and Neonatal Immunology and the Mucosal Immune System

Immunodeficiency and Immaturity . . . . . . . . 221Fetal–Neonatal Immune System:Immunocompetence or Immune Depression? . . . 222Ontogeny of the Immune System . . . . . . . . . . 225

T Cells . . . . . . . . . . . . . . . . . . . . . . . 229B Cells . . . . . . . . . . . . . . . . . . . . . . . 231Phagocyte Cells . . . . . . . . . . . . . . . . . . 233Complement Factors . . . . . . . . . . . . . . . 233

Neonatal Immunodeficiency . . . . . . . . . . . . 234Cellular Immunity . . . . . . . . . . . . . . . . 234Humoral Immunity . . . . . . . . . . . . . . . 236Innate Immunity . . . . . . . . . . . . . . . . . 237

Mucosal Immune System . . . . . . . . . . . . . . 238Immune Components of the Intestinal Mucosa . . . . . . . . . . . . . 239

Nutrition and Absorption of Antigenic Macromolecules . . . . . . . . . . . . 247

Immunology of Breast Milk . . . . . . . . . . . 248Immunology of Colostrum . . . . . . . . . . . 254Experimental Studies on Neonatal Tolerance and/or Immunocompetence . . . . . . . . . . . 258

Local Immunity in the Respiratory Mucosa . . . . 259Local Immunity in the Skin . . . . . . . . . . . . . 261

Pediatricians and Neonates . . . . . . . . . . . 262References . . . . . . . . . . . . . . . . . . . . . 262

Contents

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3 Neonatal Immunology:The Neonate at Risk of Atopy

The Neonate at Risk: Predisposing Factors . . . . 269Supplementary Feeding in Maternity Wards . . 270

Prenatal Sensitization . . . . . . . . . . . . . . . . 270Methods of Predicting the Development of Allergic Disease . . . . . . . . . . . . . . . . . . 272

Alternative Tests to CBIgE Determination . . . 272Pediatricians and Neonates at Risk . . . . . . . 280References . . . . . . . . . . . . . . . . . . . . . 281

4 Genetic and Environmental PredisposingFactors

Genes and Atopy . . . . . . . . . . . . . . . . . . . 285Genetics of Atopy . . . . . . . . . . . . . . . . . . . 285

Genome-Wide Screens . . . . . . . . . . . . . . 288Candidate Genes for Asthma and Atopy . . . . 288Other Regions of Interest . . . . . . . . . . . . 294Genetics of Pediatric Atopic Disease . . . . . . 297

Prenatal Genetic Factors and the Fetal Immune System . . . . . . . . . . . 306Postnatal Genetic Factors and Related Influence . 307Environmental Factors . . . . . . . . . . . . . . . . 309

Residential Influences . . . . . . . . . . . . . . 311Aeroallergens . . . . . . . . . . . . . . . . . . . 313Environmental Pollutants . . . . . . . . . . . . 321

Immunotoxicology . . . . . . . . . . . . . . . . . . 327Environmental Tobacco Smoke . . . . . . . . . 335Hygiene Hypothesis . . . . . . . . . . . . . . . 346Interactions Between Genetic and Environmental Factors . . . . . . . . . . . 347Pediatricians, Genotype, Phenotype and Early Predisposing Factors . . . . . . . . . 347References . . . . . . . . . . . . . . . . . . . . . 349

5 Epidemiology and Natural History of Atopic Disease

Epidemiology . . . . . . . . . . . . . . . . . . . . . 363Lack of Uniformity of Diagnostic Parameters . . . 363Age at Onset . . . . . . . . . . . . . . . . . . . . . . 365

Atopic March . . . . . . . . . . . . . . . . . . . 366Atopic Dermatitis . . . . . . . . . . . . . . . . . . 373Oral Allergic Syndrome . . . . . . . . . . . . . . . 380Urticaria and Angioedema . . . . . . . . . . . . . 380Allergic Contact Dermatitis . . . . . . . . . . . . . 380Food Allergy . . . . . . . . . . . . . . . . . . . . . 381Asthma . . . . . . . . . . . . . . . . . . . . . . . . 384Allergy to Inhalants . . . . . . . . . . . . . . . . . 399Allergic Rhinitis . . . . . . . . . . . . . . . . . . . 402Allergic Conjunctivitis . . . . . . . . . . . . . . . . 408Insect Allergy . . . . . . . . . . . . . . . . . . . . . 408

Prevalence of Atopic Disease at Various Ages . . . 408Prevalence of Immunodeficiencies . . . . . . . . . 409

Pediatricians and Epidemiology . . . . . . . . 409References . . . . . . . . . . . . . . . . . . . . . 410

6 Diagnosis of Pediatric Allergy

From History to Clinical–Functional Examination 421Allergy History . . . . . . . . . . . . . . . . . . . . 422

Family Allergy History . . . . . . . . . . . . . . 422Personal Allergy History . . . . . . . . . . . . . 422Past and Present Allergy History . . . . . . . . 423Present Allergy History for Atopic Dermatitis and Food Allergy . . . . . . . . . . . . . . . . . 423Present Allergy History for Urticaria and Angioedema and Additional Skin Allergies 424Present Allergy History for Asthma Rhinoconjunctivitis . . . . . . . . . 424Environmental History . . . . . . . . . . . . . . 424

Medical Examination . . . . . . . . . . . . . . . . 425Diagnosis Type . . . . . . . . . . . . . . . . . . 430

Immunoallergic Diagnosis . . . . . . . . . . . . . 431In vivo Immunoallergic Tests . . . . . . . . . . 431Skin Prick Tests . . . . . . . . . . . . . . . . . . 431Prick + Prick Testing . . . . . . . . . . . . . . . 436Patch Test or Epicutaneous Test . . . . . . . . . 438Photopatch Testing . . . . . . . . . . . . . . . . 439

In vitro Immunoallergic Tests . . . . . . . . . . . . 439Total Serum IgE . . . . . . . . . . . . . . . . . . 439Specific IgE Antibody Determination . . . . . . 441

Prerequisites, Advantages and Disadvantages of Diagnostic Tests . . . . . . . . . . . . . . . . . . 445

Advantages and Disadvantages of In vivo Tests 446Advantages and Disadvantages of In vitro Tests 447

Future Diagnostic Avenues . . . . . . . . . . . . . 451Recombinant Allergens . . . . . . . . . . . . . 451CD203c . . . . . . . . . . . . . . . . . . . . . . 451

Provocation Tests . . . . . . . . . . . . . . . . . . . 452Conjunctival Testing . . . . . . . . . . . . . . . 452Nasal Testing . . . . . . . . . . . . . . . . . . . 452Bronchial Provocation Testing . . . . . . . . . . 453Overall Evaluation of Provocation Tests . . . . 455Conjunctival Provocation Test . . . . . . . . . . 455Nasal Provocation Test . . . . . . . . . . . . . . 455Bronchial Provocation Test . . . . . . . . . . . 456Additional Tests . . . . . . . . . . . . . . . . . 456

Pulmonary Function Testing . . . . . . . . . . . . 457Peak Expiratory Flow Rate . . . . . . . . . . . . 457Spirometry . . . . . . . . . . . . . . . . . . . . 462Pulmonary Function Tests in Children Under 12 Months to 6–7 Years . . . 464

Medicolegal Aspects of Immunoallergic Testing . 466Pediatricians and Diagnostic Whereabouts . . 467References . . . . . . . . . . . . . . . . . . . . . 467

XIV Contents

7 Atopic Dermatitis

The First Clinical Manifestation of Atopy . . . . . 473Skin Immunopathophysiology . . . . . . . . . . . 474

The Role of Skin Surface Barrier . . . . . . . . 474Skin Immune System . . . . . . . . . . . . . . . . . 475

Relationships Between Skin and Immune System . . . . . . . . . . . . . . . 475

Pathogenesis . . . . . . . . . . . . . . . . . . . . . 479Genetics . . . . . . . . . . . . . . . . . . . . . . 479

Immune Dysfunctions . . . . . . . . . . . . . . . . 481Cell-Mediated Immunity . . . . . . . . . . . . . 481Humoral Immunity: Role of IgE Antibodies . . 483Role of T Lymphocytes . . . . . . . . . . . . . . 487Langerhans Cells . . . . . . . . . . . . . . . . . 490Interleukins and AD . . . . . . . . . . . . . . . 491IgE and Histamine-Releasing Factors . . . . . . 492A Concluding Pathogenic Hypothesis . . . . . 493

Biochemical Dysfunctions . . . . . . . . . . . . . . 493Additional Biochemical or Pharmacophysiological Anomalies . . . . . 495

Additional Pathogenic Factors . . . . . . . . . . . 495Role of Infections . . . . . . . . . . . . . . . . . 495Role of Food Factors . . . . . . . . . . . . . . . 497Role of Food Additives . . . . . . . . . . . . . . 497Role of Aeroallergens . . . . . . . . . . . . . . . 497

Pathophysiology of Itching . . . . . . . . . . . . . 499Irritant Effects . . . . . . . . . . . . . . . . . . 500

Clinical Presentation . . . . . . . . . . . . . . . . . 500Additional Clinical Features . . . . . . . . . . . 502

Complications . . . . . . . . . . . . . . . . . . . . 506Additional Complications . . . . . . . . . . . . 507Association with Other Atopic Diseases . . . . 507Association with Nonatopic Diseases . . . . . . 508

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 508Differential Diagnosis . . . . . . . . . . . . . . 509

Management . . . . . . . . . . . . . . . . . . . . . 512General and Local Hygienic and Preventive Measures: Acute Phase . . . . . 512Local Aspecific Cutaneous Treatment . . . . . . 515Medical Treatment . . . . . . . . . . . . . . . . 516Specific Antiallergic Measures . . . . . . . . . . 521Additional Measures to Be Suggested to Parents . . . . . . . . . . . . . . . . . . . . . 521Antiasthmatic Measures . . . . . . . . . . . . . 522

Relationships Between AD and FA . . . . . . . . . 522Epidemiology . . . . . . . . . . . . . . . . . . . 523Pathophysiology . . . . . . . . . . . . . . . . . 523

Pathogenesis . . . . . . . . . . . . . . . . . . . . . 523Experimental Studies . . . . . . . . . . . . . . 523Clinical Studies . . . . . . . . . . . . . . . . . . 524

Clinical Presentation . . . . . . . . . . . . . . . . . 525Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 526Treatment . . . . . . . . . . . . . . . . . . . . . . . 527Course and Prognosis . . . . . . . . . . . . . . . . 527

Pediatricians and AD . . . . . . . . . . . . . . . 529References . . . . . . . . . . . . . . . . . . . . . 529

8 Other Allergic Skin Disorders

A Skin Panorama . . . . . . . . . . . . . . . . . . . 539Urticaria-Angioedema Syndrome . . . . . . . . . 539

Etiopathogenesis . . . . . . . . . . . . . . . . . 540Pathogenesis of Hereditary Angioedema . . . . 544Pathogenesis of Urticaria . . . . . . . . . . . . 545Clinical Presentation . . . . . . . . . . . . . . . 547Physical Urticaria . . . . . . . . . . . . . . . . . 548Diagnosis . . . . . . . . . . . . . . . . . . . . . 553Treatment . . . . . . . . . . . . . . . . . . . . . 557Prevention . . . . . . . . . . . . . . . . . . . . . 558

Allergic Contact Dermatitis . . . . . . . . . . . . . 558Etiopathogenesis . . . . . . . . . . . . . . . . . 559Etiological Agents . . . . . . . . . . . . . . . . 561Clinical Presentation . . . . . . . . . . . . . . . 567Types of ACD . . . . . . . . . . . . . . . . . . . 567Diagnosis . . . . . . . . . . . . . . . . . . . . . 571Treatment . . . . . . . . . . . . . . . . . . . . . 574

Protein Contact Dermatitis . . . . . . . . . . . . . 576Phytodermatitis . . . . . . . . . . . . . . . . . . . 577Allergic Photodermatitis . . . . . . . . . . . . . . 577

Contact Dermatitis by Seawater Organisms . . 579Allergic Vasculitis . . . . . . . . . . . . . . . . . . 580

Immunopathogenesis . . . . . . . . . . . . . . 581Clinical Presentation . . . . . . . . . . . . . . . 582Prominent Vasculitis Syndromes in Children . 583Diagnosis . . . . . . . . . . . . . . . . . . . . . 587Treatment . . . . . . . . . . . . . . . . . . . . . 588Pediatricians and Other Cutaneous Allergies . 588References . . . . . . . . . . . . . . . . . . . . . 589

9 Food Allergy

One Allergy, Several Allergies . . . . . . . . . . . . 595Pathogenesis . . . . . . . . . . . . . . . . . . . . . 596

Immune Mechanisms . . . . . . . . . . . . . . 596In Utero Sensitization . . . . . . . . . . . . . . 600Postnatal Sensitization . . . . . . . . . . . . . . 601

Immunology of the Gastrointestinal Tract . . . . . 602GALT Regulation of Effector Functions . . . . 609Oral Tolerance: Experimental Data . . . . . . . 611Oral Tolerance: Factors that Condition Its Induction and Maintenance . . . . . . . . . 613

Cow’s Milk Allergy . . . . . . . . . . . . . . . . . . 616Clinical Manifestations . . . . . . . . . . . . . . . 616

Systemic Manifestations . . . . . . . . . . . . . 618Gastrointestinal Manifestations . . . . . . . . . 619Respiratory Manifestations . . . . . . . . . . . 622Other Food-Induced Manifestations . . . . . . 622

Allergy to Other Foods . . . . . . . . . . . . . . . . 625Allergy to Single Foods . . . . . . . . . . . . . 625

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 636Diagnostic Elimination Diets . . . . . . . . . . 637Food Challenge Test . . . . . . . . . . . . . . . 640Challenge Procedure . . . . . . . . . . . . . . . 640

XVContents

Evaluation of Food Challenge Testing . . . . . . . 644Dietary Treatment . . . . . . . . . . . . . . . . . . 647

Allergy to Single Foods . . . . . . . . . . . . . 663Diet Duration . . . . . . . . . . . . . . . . . . . 669Prevention of FA . . . . . . . . . . . . . . . . . 670Medical Treatment . . . . . . . . . . . . . . . . 671

Acquisition of Oral Tolerance . . . . . . . . . . . . 671FA-Caused Death . . . . . . . . . . . . . . . . . . . 678Oral Allergy Syndrome . . . . . . . . . . . . . . . 679Bird-Egg Syndrome . . . . . . . . . . . . . . . . . 682

Pediatricians and FA . . . . . . . . . . . . . . . 682References . . . . . . . . . . . . . . . . . . . . . 682

10 Pseudoallergy and Food Immunotoxicology

Allergy and Pseudoallergy . . . . . . . . . . . . . 697Pseudoallergy to Food Additives . . . . . . . . . . 699Pharmacological Reactions . . . . . . . . . . . . . 710Enzymatic Reactions . . . . . . . . . . . . . . . . . 714Metabolic Reactions . . . . . . . . . . . . . . . . . 715Toxic Reactions . . . . . . . . . . . . . . . . . . . . 715Anaphylactoid Reactions . . . . . . . . . . . . . . 718Immunotoxicology . . . . . . . . . . . . . . . . . . 718

Food Immunotoxicology . . . . . . . . . . . . 720Pediatricians, Pseudoallergy,and Immunotoxicology . . . . . . . . . . . . . 721References . . . . . . . . . . . . . . . . . . . . . 721

11 Asthma

Pediatric Asthma . . . . . . . . . . . . . . . . . . . 725Defense Mechanisms in the Airways . . . . . . . . 727Genetic Factors . . . . . . . . . . . . . . . . . . . . 729Pathogenesis . . . . . . . . . . . . . . . . . . . . . 732

Role of Immune Inflammation . . . . . . . . . 732Role of the Inflammatory Cells . . . . . . . . . 737The Role of IgE . . . . . . . . . . . . . . . . . . 749Role of the Mediators . . . . . . . . . . . . . . 750Role of Cytokines . . . . . . . . . . . . . . . . . 751

Airway Remodeling . . . . . . . . . . . . . . . . . 752Role of Bronchial Hyperreactivity . . . . . . . 756Endogenous Factors . . . . . . . . . . . . . . . 757Main Exogenous Factors . . . . . . . . . . . . . 765

Predisposing Factors . . . . . . . . . . . . . . . . . 765Anatomical and Physiological Predisposing Factors . . . . . . . . . . . . . . . . . . . . . . . 765Predisposing or Etiological Factors . . . . . . . 767

Drugs to Be Used and Routes of Administration . 772Routes of Administration . . . . . . . . . . . . 772Age Ranges for Inhalant Therapy . . . . . . . . 777Dosages for the Very Young . . . . . . . . . . . 778Drugs to Be Used . . . . . . . . . . . . . . . . . 778

Bronchiolitis . . . . . . . . . . . . . . . . . . . . . 793Asthma . . . . . . . . . . . . . . . . . . . . . . . . 802Clinical Presentation . . . . . . . . . . . . . . . . . 805Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 805

Severe Asthmatic Attack – Status Asthmaticus 808

Treatment . . . . . . . . . . . . . . . . . . . . . . . 812Treatment of Acute Asthma Attack . . . . . . . 812Treatment of Status Asthmaticus . . . . . . . . 814Treatment of Episodic, Frequent, Chronic and Other Forms of Asthma . . . . . . . . . . . 822Death by Asthma . . . . . . . . . . . . . . . . . 838Prevention . . . . . . . . . . . . . . . . . . . . . 842Preventive Therapy . . . . . . . . . . . . . . . . 842Outcome . . . . . . . . . . . . . . . . . . . . . . 847

Present and Future Prospects . . . . . . . . . . . . 848Anti-IgE . . . . . . . . . . . . . . . . . . . . . . 848Leukotriene Modifiers . . . . . . . . . . . . . . 848

Other Pediatric Allergic Lung Disease . . . . . . . 850Extrinsic Allergic Alveolitis . . . . . . . . . . . 850Allergic Bronchopulmonary Aspergillosis . . . 851Pediatricians and Pediatric Asthma . . . . . . . 853References . . . . . . . . . . . . . . . . . . . . . 853

12 Allergic Rhinitis

The Airway Entrance . . . . . . . . . . . . . . . . . 875Nasal Immunology . . . . . . . . . . . . . . . . . . 878

Immunopathology . . . . . . . . . . . . . . . . 879Etiological Factors . . . . . . . . . . . . . . . . . . 886

Anatomical–Physiological Factors Differentiating Children from Adults . . . . . . 889Classification . . . . . . . . . . . . . . . . . . . 889

Seasonal Allergic Rhinitis . . . . . . . . . . . . . . 889Perennial Allergic Rhinitis . . . . . . . . . . . . . 894Treatment . . . . . . . . . . . . . . . . . . . . . . . 897

Identification and Elimination of Principal Allergens . . . . . . . . . . . . . . 897Antihistamines . . . . . . . . . . . . . . . . . . 897Anticholinergics . . . . . . . . . . . . . . . . . 901Cromones . . . . . . . . . . . . . . . . . . . . . 901Corticosteroids . . . . . . . . . . . . . . . . . . 901Anti-LT . . . . . . . . . . . . . . . . . . . . . . 903Specific Immunotherapy . . . . . . . . . . . . . 903Prevention . . . . . . . . . . . . . . . . . . . . . 903Quality of Life . . . . . . . . . . . . . . . . . . . 903Pediatricians and Allergic Rhinitis . . . . . . . 905References . . . . . . . . . . . . . . . . . . . . . 905

13 Specific Immunotherapy

Specific Therapy for Pediatric Asthma and Rhinitis . . . . . . . . . . . . . . . . . . . . . . 911SIT Efficacy: Clinical Effects . . . . . . . . . . . . . 916SIT Efficacy: Immunological Effects . . . . . . . . 920Considerations Before Initiating SIT . . . . . . . . 927General Criteria of SIT Execution . . . . . . . . . 927Treatment Chronology . . . . . . . . . . . . . . . . 929Adverse Reactions . . . . . . . . . . . . . . . . . . 932

Treatment of Local and Systemic Reactions . . 935Comparison Between SIT and Pharmacotherapy . . . . . . . . . . . . . . 937

XVI Contents

Present and Future Perspectives . . . . . . . . . . 938Present Perspectives . . . . . . . . . . . . . . . 939Comparison of Traditional (SC) SIT and Other Routes . . . . . . . . . . . . . . . . . 943Future Perspectives . . . . . . . . . . . . . . . . 943Long-Term Perspectives . . . . . . . . . . . . . 950Pediatricians and SIT . . . . . . . . . . . . . . 951References . . . . . . . . . . . . . . . . . . . . . 951

14 Eye Allergy and Immunology

Eye Disorders . . . . . . . . . . . . . . . . . . . . . 961Pathophysiology . . . . . . . . . . . . . . . . . 961

Ocular Immunology . . . . . . . . . . . . . . . . . 962Conjunctiva-Associated Lymphoid Tissue . . . 962Immune Functions . . . . . . . . . . . . . . . . 966

Allergic Conjunctivitis . . . . . . . . . . . . . . . . 968Vernal Keratoconjunctivitis . . . . . . . . . . . . . 972Atopic Keratoconjunctivitis . . . . . . . . . . . . . 977Giant Papillary Conjunctivitis . . . . . . . . . . . 978Ocular Contact Allergy . . . . . . . . . . . . . . . 980Acute Edematous Conjunctivitis . . . . . . . . . . 981Blepharitis . . . . . . . . . . . . . . . . . . . . . . 981Keratitis . . . . . . . . . . . . . . . . . . . . . . . . 981Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . 982New Therapeutic Perspectives . . . . . . . . . . . . 984

Pediatricians and Eye Allergy . . . . . . . . . . 985References . . . . . . . . . . . . . . . . . . . . . 985

15 Other Allergic OtorhinolaryngologicalDiseases

Von Waldeyer’s Ring . . . . . . . . . . . . . . . . . 991Nasal-Associated Lymphoid Tissue . . . . . . . . . 991Tonsil Immunology . . . . . . . . . . . . . . . . . 993Otitis Media with Effusion . . . . . . . . . . . . . . 998

Immunopathology . . . . . . . . . . . . . . . 1000Pathogenesis . . . . . . . . . . . . . . . . . . 1002Clinical Presentation . . . . . . . . . . . . . . 1005Diagnosis . . . . . . . . . . . . . . . . . . . . 1006Treatment . . . . . . . . . . . . . . . . . . . . 1007

Sinusitis . . . . . . . . . . . . . . . . . . . . . . . 1009Pathophysiology . . . . . . . . . . . . . . . . 1010Allergic Sinusitis . . . . . . . . . . . . . . . . 1014Relationship Between Asthma,Allergic Rhinitis, and Sinusitis . . . . . . . . . 1015Clinical Presentation . . . . . . . . . . . . . . 1016Diagnosis . . . . . . . . . . . . . . . . . . . . 1017Treatment . . . . . . . . . . . . . . . . . . . . 1019Pediatricians and ORL Diseases . . . . . . . . 1021References . . . . . . . . . . . . . . . . . . . . 1021

16 Allergy and Central Nervous System and Other Allergies

Introduction . . . . . . . . . . . . . . . . . . . . 1029Migraine and Allergy . . . . . . . . . . . . . . . . 1029

Psychological and Neurological Factors and Allergic Disease . . . . . . . . . . . . . . 1033

Chronic Fatigue Syndrome . . . . . . . . . . . . 1037Clinical Presentation of Other Systems . . . . . . 1042

Clinical Ecology . . . . . . . . . . . . . . . . . 1046Pediatricians, Migraine, and Other Allergies 1048References . . . . . . . . . . . . . . . . . . . . 1049

17 Allergy to the Venom of Hymenoptera and Other Insects

Historical Data . . . . . . . . . . . . . . . . . . . 1055Characteristics of Hymenoptera . . . . . . . . . 1056

Genetic and Environmental Factors . . . . . . 1060Etiopathogenesis . . . . . . . . . . . . . . . . 1062Clinical Presentation . . . . . . . . . . . . . . 1062Diagnosis . . . . . . . . . . . . . . . . . . . . 1064Treatment . . . . . . . . . . . . . . . . . . . . 1066

Biting Insect Allergy . . . . . . . . . . . . . . . . 1068Prevention . . . . . . . . . . . . . . . . . . . . 1070Pediatricians and Insect Allergy . . . . . . . . 1070References . . . . . . . . . . . . . . . . . . . . 1071

18 Autoimmune Diseases

Dysregulation of the Immune System . . . . . . 1075Etiopathogenesis . . . . . . . . . . . . . . . . . . 1077

Etiopathogenetic Mechanisms . . . . . . . . . 1079Juvenile Rheumatoid Arthritis . . . . . . . . . . 1085

Etiopathogenesis . . . . . . . . . . . . . . . . 1085Drugs of Tomorrow . . . . . . . . . . . . . . . 1099

Inflammatory Bowel Disease . . . . . . . . . . . 1100Etiopathogenesis . . . . . . . . . . . . . . . . 1102Ulcerative Colitis . . . . . . . . . . . . . . . . 1105Crohn’s Disease . . . . . . . . . . . . . . . . . 1105

Autoimmune Hematological Disorders . . . . . . 1110Autoimmune Lymphoproliferative Syndrome 1110Autoimmune Neutropenia . . . . . . . . . . . 1110Diabetes . . . . . . . . . . . . . . . . . . . . . 1111

Systemic AIDs . . . . . . . . . . . . . . . . . . . . 1117Systemic Lupus Erythematosus . . . . . . . . 1117Juvenile Dermatomyositis . . . . . . . . . . . 1124Juvenile Scleroderma . . . . . . . . . . . . . . 1127Pediatricians and Autoimmune Diseases . . . 1131References . . . . . . . . . . . . . . . . . . . . 1131

XVIIContents

19 Allergic and Pseudoallergic Reactions to Drugs

Pediatric Drug-Induced Disorders . . . . . . . . 1147Etiopathogenesis . . . . . . . . . . . . . . . . . . 1148

Predisposing Factors . . . . . . . . . . . . . . 1155Clinical Presentation . . . . . . . . . . . . . . . . 1158

Clinical Features . . . . . . . . . . . . . . . . 1159Additional Drug-Induced Reactive Syndromes . . . . . . . . . . . . . . 1182Characterization of Various Drugs and Categories of Drugs . . . . . . . . . . . . 1184Uncommon Reactions to Drugs . . . . . . . . 1190

Diagnosis . . . . . . . . . . . . . . . . . . . . . . 1190Skin Test Indications and Application . . . . 1194Challenge Testing . . . . . . . . . . . . . . . . 1196

Treatment . . . . . . . . . . . . . . . . . . . . . . 1196Drug-Related Deaths . . . . . . . . . . . . . . . . 1197Prevention . . . . . . . . . . . . . . . . . . . . . . 1197

Pediatricians and Drug-Induced Allergies and Pseudoallergies . . . . . . . . . . . . . . 1197References . . . . . . . . . . . . . . . . . . . . 1198

20 Anaphylaxis

Historical Outline . . . . . . . . . . . . . . . . . . 1205Physiopathology . . . . . . . . . . . . . . . . 1206Histopathology . . . . . . . . . . . . . . . . . 1207

Pathogenesis . . . . . . . . . . . . . . . . . . . . 1207Risk Factors . . . . . . . . . . . . . . . . . . . . . 1210

Anaphylactoid Reactions . . . . . . . . . . . . 1221Others . . . . . . . . . . . . . . . . . . . . . . 1221

Clinical Presentation . . . . . . . . . . . . . . . . 1222Diagnosis . . . . . . . . . . . . . . . . . . . . . . 1225Immediate Treatment . . . . . . . . . . . . . . . 1228

Pediatricians and Anaphylaxis . . . . . . . . . 1236References . . . . . . . . . . . . . . . . . . . . 1236

21 Malnutrition and the Immune System

Immunological Effects of Child Malnutrition . . 1243Protein-Energy Malnutrition . . . . . . . . . . . 1244Micronutrient Deficiency . . . . . . . . . . . . . 1249

Vitamin Deficiency . . . . . . . . . . . . . . . 1249Trace Element Deficiency . . . . . . . . . . . 1251

Essential Fatty Acid Deficiency or Excess . . . . . 1253Other Causes of Malnutrition . . . . . . . . . . . 1255

Immunological Effects of Neonatal Malnutrition . . . . . . . . . . . . 1257Clinical Presentation . . . . . . . . . . . . . . 1259Diagnosis . . . . . . . . . . . . . . . . . . . . 1260Treatment . . . . . . . . . . . . . . . . . . . . 1260Pediatricians, Malnutrition, and the Immune System . . . . . . . . . . . . . . . . . . . . . . 1261References . . . . . . . . . . . . . . . . . . . . 1261

22 Primary Immunodeficiencies

A World in Motion . . . . . . . . . . . . . . . . . 1265Immunodeficiency and Atopy . . . . . . . . . . . 1265Immunodeficiencies Associated with Hyper-IgE 1269Immunodeficiency with Autoimmunity . . . . . 1270Primary Immunodeficiencies . . . . . . . . . . . 1270Predominantly B-Cell Immunodeficiency . . . . 1276

X-Linked Agammaglobulinemia or Bruton Tyrosine Kinase Deficiency . . . . 1276Gene Deletion for H Chains . . . . . . . . . . 1277k and l Chain Deficiency . . . . . . . . . . . . 1277Selective Ig Deficiency . . . . . . . . . . . . . 1279Selective Antibody Deficiency with Normal Ig Isotypes . . . . . . . . . . . . 1281Selective Deficiency of Other Igs . . . . . . . 1281Common Variable ID . . . . . . . . . . . . . . 1281Not-X-Linked Hyper-IgM . . . . . . . . . . . 1282Transient Hypogammaglobulinemia of Infancy . . . . . . . . . . . . . . . . . . . . 1282

Combined T-Cell and B-Cell Deficiency . . . . . 1283T–B+ SCID . . . . . . . . . . . . . . . . . . . . 1283IL7R Deficiency . . . . . . . . . . . . . . . . . 1286T–B– SCID . . . . . . . . . . . . . . . . . . . . 1286T+B– SCID . . . . . . . . . . . . . . . . . . . . 1289IL2 Deficiency (IL2Ra-Chain Gene Mutations) 1290X-Linked Hyper-IgM (or Hyper-IgD) or CD154 Deficiency Syndrome (XHIgMS) . . 1290Purine-Nucleoside Phosphorylase Deficiency 1293HLA Deficiency . . . . . . . . . . . . . . . . . 1294CD3g, CD3d, CD3e, CD3z Deficiency . . . . . 1295ZAP-70 Deficiency or Selective CD8 Deficiency . . . . . . . . . . 1295TAP-2 Deficiency . . . . . . . . . . . . . . . . 1296NFAT Deficiency . . . . . . . . . . . . . . . . 1296NK-Cell Deficiency . . . . . . . . . . . . . . . 1296Undifferentiated SCID . . . . . . . . . . . . . 1297

Predominantly T-Cell Defects . . . . . . . . . . . 1297Primary CD4 T-Cell Deficiency . . . . . . . . 1297Primary CD7 Deficiency . . . . . . . . . . . . 1297Primary CD45 Deficiency . . . . . . . . . . . 1297Multiple IL Defects . . . . . . . . . . . . . . . 1298Nezelof Syndrome . . . . . . . . . . . . . . . 1298Fas (CD95) Deficiency . . . . . . . . . . . . . 1298

Other Well-Defined ID Syndromes . . . . . . . . 1298Wiskott-Aldrich Syndrome . . . . . . . . . . 1298Ataxia-Telangiectasia . . . . . . . . . . . . . . 1301DiGeorge Syndrome . . . . . . . . . . . . . . 1303X-Linked Lymphoproliferative Syndrome . . 1305Hyper-IgE Syndrome . . . . . . . . . . . . . . 1305Chédiak-Higashi Syndrome . . . . . . . . . . 1307Griscelli Disease . . . . . . . . . . . . . . . . 1307

Phagocyte Deficiency . . . . . . . . . . . . . . . . 1307Chronic Granulomatous Disease . . . . . . . 1307Leukocyte Adhesion Deficiency . . . . . . . . 1312Deficiency of Multiple Leukocyte Integrins . 1314Glucose-6-Phosphate-Dehydrogenase Deficiency . . . . . . . . . . . . . . . . . . . . 1314

XVIII Contents

Myeloperoxidase Deficiency . . . . . . . . . . 1314Specific Granule Deficiency . . . . . . . . . . 1315Neutropenia . . . . . . . . . . . . . . . . . . . 1315Shwachman Syndrome . . . . . . . . . . . . . 1316Leukocyte Mycobactericidal Defect . . . . . . 1317

Complement Deficiency . . . . . . . . . . . . . . 1318C1 Deficiency . . . . . . . . . . . . . . . . . . 1318C1q Deficiency . . . . . . . . . . . . . . . . . 1319C4 Deficiency . . . . . . . . . . . . . . . . . . 1319C2 Deficiency . . . . . . . . . . . . . . . . . . 1320C3 Deficiency . . . . . . . . . . . . . . . . . . 1320C5 Deficiency . . . . . . . . . . . . . . . . . . 1320C6 Deficiency . . . . . . . . . . . . . . . . . . 1320C7 Deficiency . . . . . . . . . . . . . . . . . . 1320C8 Deficiency . . . . . . . . . . . . . . . . . . 1321C9 Deficiencies . . . . . . . . . . . . . . . . . 1321C1 Inhibitor Deficiency . . . . . . . . . . . . . 1321Factor I Deficiency . . . . . . . . . . . . . . . 1321Factor H Deficiency . . . . . . . . . . . . . . . 1321Factor D Deficiency . . . . . . . . . . . . . . . 1321Properdin Deficiency . . . . . . . . . . . . . . 1321Children with RRIs . . . . . . . . . . . . . . . 1322Immunodeficiency . . . . . . . . . . . . . . . 1324Clinical Presentation . . . . . . . . . . . . . . 1327Diagnosis and Differential Diagnosis . . . . . 1327

Treatment . . . . . . . . . . . . . . . . . . . . . . 1333Antibody Deficiency . . . . . . . . . . . . . . 1333T-Cell PID . . . . . . . . . . . . . . . . . . . . 1333Bone Marrow Transplantation . . . . . . . . . 1335Children with RRIs . . . . . . . . . . . . . . . 1340Pediatricians, PID and RRIs . . . . . . . . . . 1341References . . . . . . . . . . . . . . . . . . . . 1342

23 Pediatric AIDS

Twenty-Five Years of Science . . . . . . . . . . . . 1359HIV . . . . . . . . . . . . . . . . . . . . . . . . . . 1359Etiopathogenesis . . . . . . . . . . . . . . . . . . 1363

Pediatric HIV Infection . . . . . . . . . . . . . . 1371Pathogenesis of HIV Transmission in Childhood 1375Clinical Presentation . . . . . . . . . . . . . . . . 1380

Diagnosis . . . . . . . . . . . . . . . . . . . . 1387Treatment . . . . . . . . . . . . . . . . . . . . . . 1394Outcome . . . . . . . . . . . . . . . . . . . . . . . 1410Current Implications . . . . . . . . . . . . . . . . 1410

Pediatricians and HIV-Positive Children . . . 1416References . . . . . . . . . . . . . . . . . . . . 1416

24 Prevention of Allergic Disorders

Preventing Atopic March: A Priority . . . . . . . 1433Primary Prevention . . . . . . . . . . . . . . . . 1434Role of Diet . . . . . . . . . . . . . . . . . . . . . 1434

Prenatal Role of Diet . . . . . . . . . . . . . . 1434Role of Postnatal Diet . . . . . . . . . . . . . 1435

Role of Allergen Avoidance . . . . . . . . . . . . 1442Immune Interventions . . . . . . . . . . . . . 1444

Dietary Prevention and Environmental Measures . . . . . . . . . . . 1444Secondary Prevention . . . . . . . . . . . . . . . 1460

Avoiding Allergen Contacts . . . . . . . . . . 1460Airborne Allergens . . . . . . . . . . . . . . . 1460

Preventing Allergen Entry or Mast Cell Degranulation . . . . . . . . . . . . 1485

Modifying the State of Sensitization Using Available Aids . . . . . 1485Mad Cow Disease . . . . . . . . . . . . . . . . 1479Transgenic Foods . . . . . . . . . . . . . . . . 1479Hygiene Hypothesis . . . . . . . . . . . . . . 1480Tertiary Prevention . . . . . . . . . . . . . . . 1486

New Frontiers . . . . . . . . . . . . . . . . . . . . 1487References . . . . . . . . . . . . . . . . . . . . 1490

Appendices . . . . . . . . . . . . . . . . . . . . 1505

References not indicated . . . . . . . . . . . . 1553

Subject Index . . . . . . . . . . . . . . . . . . . 1555

Figure Credits . . . . . . . . . . . . . . . . . . . 1615

XIXContents

A AlimentumAA Amino acidAA Arachidonic acid AA Aspartic acida2M a2 Macroglobulina2M-R a2 Macroglobulin receptorAAAAI American Academy of Allergy,

Asthma and ImmunologyAab AutoantibodyAag AutoantigenAAF Amino acid formulaAAP American Association of PediatricsAAPSNAD American Association of Pediatrics

Subcommittee of Nutrition and Allergic Disease

ABA Allergic bronchopulmonary aspergillosis

ABC AbacavirAC Allergic conjunctivitisACAAI American College of Allergy, Asthma

and ImmunologyACAT Automated computerized axial

tomographyACC 1-Aminocyclopropane-1-carboxylic acidACD Allergic contact dermatitisACE Angiotensin-converting enzymeACh AcetylcholineACT Immune-activating cytokineACT-2 Immune-activating cytokine-2AD Atopic dermatitisAD Autosomal dominantADA Adenosine deaminaseADAM a Disintegrin and a metalloproteinase

The English medical abbreviations have been cross-referencedusing Davis NM Medical Abbreviations, 8th edn, NM DavisAssociates, Huntington Valley, 1997. To offer a wide panoramaof results, several data have been presented throughout thebook and reported in the tables independently of how the chil-dren were identified as affected with atopic disease. Drug avail-ability has been assessed. Regarding drug usage, several tablesspecify the chemical names, types of packaging, administra-tion routes and, where possible, the pediatric doses and sched-ules of treatment. I have taken care to make sure that the infor-mation is correct at the time of publication; however, the ulti-mate responsibility rests with the prescribing physician.

ADCC Antibody-dependent cell-mediated cytotoxicity

ADD Average daily doseADGL Dihomo-g-linolenic acidADHD Attention-deficit hyperactivity disorderADH Antidiuretic hormoneADNI Selective antibody deficiency

with normal Ig isotypesADR Adrenergic receptorADR Adverse drug reactionADRB2 a2-Adrenergic receptorsAEA Antiendomysial antibodiesAEA Antierythrocyte autoantibodyAECA Antiendothelial cell antibodiesAF Anchoring filamentsAF Aspergillus fumigatusAFP a-FetoproteinAGA Antigliadin antibodiesAh Aromatic hydrocarbonsAHS Anticonvulsant hypersensitivity

syndromeAIC Amb a 1 immunostimulatory

oligodeoxynucleotide conjugateAICDA Activation-induced cytidine deaminaseAID Autoimmune diseaseAID Activation-induced cytidine deaminaseAIDS Acquired immunodeficiency syndromeAIHA Autoimmune hemolytic anemiaAIM Activation inducer moleculeAIN Autoimmune neutropeniaAKC Atopic keratoconjunctivitisALA a -LactalbuminALCAM Activated leukocyte cell adhesion

molecule (CD166)Alfaré Alimentation facilement résorbableAllergen Allergy generatorALPS Autoimmune lymphoproliferative

syndromeAML Acute myeloblastic leukemiaAMLR Autologous mixed lymphocyte reactionANA Antinuclear antibodyANCA Antineutrophil circulating antibodiesANF Antinuclear factorANP Atrial natriuretic peptideANS Autonomic nervous systemAOM Acute otitis mediaAP-1 Activator protein-1

Abbreviations

XXI

AP-1 Apolipoprotein 1Apaf 1 Apoptotic protease activating factor 1APC Antigen-presenting cellsAPO-1 Apoptosine-1 (CD95)APP Acute-phase proteinsAPR Acute-phase responseAPT Aptamil HAAPT Atopy patch testAPV AmprenavirAR AlfaréAR Allergic rhinitisAR Autosomal-recessiveAR3 Apoptose receptor 3ARAM Antigen recognition activation motifARC Allergic rhinoconjunctivitisART Antiretroviral therapyASA Acetylsalicylic acidASAT Aspartate aminotransaminaseASCT Autologous stem cell transplantationASO Allele-specific oligonucleotideAST Antistreptolysin titerATA Ataxia-telangiectasiaATAC Activation-induced, T cell-derived,

and chemokine-relatedATG Antithymocyte globulinATM Ataxia-telangiectasia mutatedATP Deoxyadenosine triphosphateAU Allergy unitAUR Allergy unit by RASTAXT Deoxyadenosine nucleotidesAZT Azidodeoxythymidine

BaDF Basophil activating factorBALF Bronchoalveolar lavage fluidBALT Bronchus-associated lymphoid tissueBAU Bioequivalent allergy unitBCF Basophil chemotactic factorBCG Bacillus Calmette-GuérinBcl-2 B cell lymphoma-2BcR B cell receptorBDP Beclomethasone dipropionateBE Base excessBf B factorBGP-1 Biliary glycoprotein-1BH1 to BH4 Bcl-2 homology domainsBHA Butylated hydroxyanisoleb-HCB b-Hexachlorobenzeneb-HCH b-HexachlorocyclohexaneBHR Bronchial hyperreactivityBHT Butylated hydroxytoluenebid bis in die, twice a dayb.i.d. Bis in die, twice a dayBIV Bovine immunodeficiency virusBK BradykininbLG b-Lactoglobulinb2-m b2-MicroglobulinBM Basement membraneBM Bone marrow

BM Breast milkBMA Breast milk allergyBMI Body mass indexBMT Bone marrow transplantBP Blood pressurebp base pairBPI Bacterial permeability increasing

proteinBPO Benzyl-penicilloylBPT Bronchial provocation testBSA B-superantigensBSA Bovine serum albuminBSE Bovine spongiform encephalopathyb-TG b-ThromboglobulinBtk Bacillus thuringiensis subspp. kurstakiBtk Bruton’s tyrosine kinaseBTS Benzothiazole bisulfideBtt Bacillus thuringiensis subspp.

tenebrionisBU Biologic unitsBUD Budesonidebw Body weight

C Constantc-ANCA Cytoplasmic antineutrophil circulating

antibodiesC/EDPa CCAAT/enhancer binding protein aC/EDP CCAAT/enhancer binding protein hC1-INH C1-inhibitorC4 bp C4-binding proteinC8 bp C8-binding proteinCA CapsidCAF CD8 T-cell antiviral factorCALC CalcitonincALL Common acute lymphoblastic leukemiaCALLA Common acute lymphoblastic leukemia

antigenCALT Conjunctiva-associated lymphoid tissuecAMP Cyclic adenosine monophosphateCAP Chemiluminescent assayCAP ChloramphenicolCARD Caspase activation and recruitment

domainCATCH 22 Cardiac abnormalities, Abnormal facies,

Thymic hypoplasia, Cleft palate,Hypocalcemia, chromosome 22

CB Cord bloodCBC Complete blood countCBIgE Cord blood IgECBMC Cord blood mononuclear cellsCCP Complement control proteinCCR CC chemokine receptorCD Celiac diseaseCD Cluster of differentiationCD Crohn’s diseaseCd CadmiumCD11a/CD18 LFA-1CD11b/CD18 CR3 Mac-1

XXII Abbreviations

CD11c/CD18 CR4 p150,95CDC Centers for Disease Control

(and Prevention)CDR Complementarity-determining regionsCEA Carcinoembryonic antigenced Cell-death defectiveCF Cystic fibrosisCFC ChlorofluorocarbonCFS Chronic fatigue syndromeCFU Colony-forming unitCFU-GM Colony-forming unit, granulocytes

and monocytesCFU-S Colony-forming unit, spleenCFU-T Colony-forming unit, thymusCGD Chronic granulomatous diseaseCGM1 CEA gene member 1CGM6 CEA gene member 6cGMP Cyclic guanosine monophosphateCGRP Calcitonin gene-related peptideCH50 Hemolytic complement 50%CHARGE Coloboma, Heart anomalies,

Atresia of choanae, Retardation,Genital hypoplasia, Ear anomalies

CHF Casein hydrolyzed formulaCI Confidence intervalsCIC Circulating immune complexesCID Combined immunodeficiencyCIE Crossed immunoelectrophoresisCIEV Caprine infectious encephalitis virusCIITA Class II transactivatorCJD Creutzfeldt-Jakob diseaseCKR-SF Cytokine receptor superfamilyCl ChlorineCLA Conjugated linoleic acidCLA Cutaneous lymphocyte-associated

antigenCLA System-chemiluminescent immunoassayCLC Charcot-Leyden crystalsCLE-0 Consensus lymphokine element-0CLE-1 Consensus lymphokine element-1CLE-2 Consensus lymphokine element-2CLIP Class II associated invariant

chain peptideCM Cow’s milkCMA Cow’s milk allergyCMI Cell-mediated immunityCMV CytomegalovirusCN CalcineurinCNO Chronic nasal obstructionCNS Central nervous systemCO2 Carbon dioxideCon-A Concanavalin ACOV Mean coefficient of variationCpG Deoxycytidyl-deoxyguanosine dinu-

cleotideCPK Creatinine phosphokinaseCPS CapsaicinCPT Conjunctival provocation test

CR Complement receptorCR Crossed reactionsCr ChromiumCR3 Complement receptor type 3CREST Calcinosis-Raynaud-Esophageal

(motility disorders)-Sclerodactyly-Telangiectasia

CRH Corticotropin-releasing hormoneCRIE Crossed radioimmunoelectrophoresisCRP C reactive proteinCS CorticosteroidsCsA Cyclosporin ACSF Cerebrospinal fluidCSF Colony stimulating factorCSM Costimulatory moleculeCT Computerized tomographyCTAP-III Connective tissue-activating protein-IIICTL Cytotoxic T lymphocytesCTLA-4 Cytotoxic T lymphocyte-associated

antigen-4 (CD152)Cu CopperCVID Common variable immune deficiencyCXCR CX chemokine receptor

D Dalton (1.6605655 ¥ 10–24 g)D Diversityd4T StavudineDAF Decay accelerating factor (CD55)DAG DiacylglycerolDALIA Distribution-analyzing latex

immunoassayDARC Duffy antigen receptor complexDBPC Double-blind, placebo-controlledDBPCCT Double-blind, placebo-controlled

challenge testDBPCFC Double-blind, placebo-controlled

food challengeDC Dendritic cellsDC-CK1 Dendritic cell chemokine-1DCC Double-blind, controlledddC ZalcitabineDDE Dichlorophenyl-dichloroetheneddI DideoxyinosineddI DidanosineDDT DichlorodiphenyltrichloroethaneDEP Diesel exhaust particlesDer f Dermatophagoides farinaeDer p Dermatophagoides pteronyssinusDES DiethylstilbestrolDGS DiGeorge syndromeDGSC DiGeorge syndrome, completeDGSP DiGeorge syndrome, partialDGST DiGeorge syndrome, transientDHA Docosahexaenoic acidDHST Delayed hypersensitivity skin testDIC Disseminated intravascular coagulationDM Diabetes mellitusDMARDs Disease-modifying antirheumatic drugs

XXIIIAbbreviations

DMN DimethylnitrosamineDMV Daily mean variationsDN Double negativeDNA Deoxyribonucleic acidDNCB DinitrochlorobenzeneDP Double positiveDPG DiphenylguanidineDPI Dry powder inhalerDPU Delayed pressure urticariaDR D-relatedDSCG Disodium chromoglycateDTH Delayed-type hypersensitivityDYM DynorphinDZ Dizygotic (twins)

E-L-R Glutamic acid-leucine-argininee-NANC Excitatory NANCEA Erythrocytes, antierythrocyte

(antibody)EAA Extrinsic allergic alveolitisEAACI European Academy of Allergy

and Clinical ImmunologyEAC Erythrocytes, antierythrocyte

(antibody), complementEACA Epsilon aminocaproic acidEAE Experimental autoimmune encephalitisEAEC Eosinophil adhesion to endothelial cellsEAF Eosinophil-activating factorEBI3 Epstein-Barr virus-induced gene 3EBV Epstein-Barr virusECA Eosinophil chemotactic activityECEF Eosinophil cytotoxicity enhancing factorECF Eosinophil chemotactic factorECHF Extensively casein hydrolysate formulaECHO Enteric cytopathic human orphan

(virus)ECM Extracellular matrixECP Eosinophil cationic proteinECU Extracellular uniqueED Emergency departmentEDIF Epithelium-derived inhibitory factorEDN Eosinophil-derived neurotoxinEDRF Endothelium-derived relaxing factorEDTA Ethylenediaminetetraacetic acidEFA Enhancing factor of allergyEFA Essential fatty acidsEFAD Essential fatty acid dysfunctionEFV EfavirenzEGF Epidermal growth factorEIA Enzyme immunoassayEIA Exercise-induced anaphylaxisEIAV Equine infectious anemia virusELA2 Elastase 2ELAM Endothelial-leukocyte adhesion

molecule (CD62E, LECAM-1)ELC EBI1 ligand chemokineELISA Enzyme-linked immunosorbent assayELISPOT Enzyme-linked immunospot

EM Electron microscopeEM Erythema multiformeEMA Endomysium autoantibodiesENA-78 Epithelial cell-derived neutrophil-

activating protein-78EMK EnkephalinENR Eosinophilic nonallergic rhinitisenv Envelope (of HIV)EPA Eicosapentaenoic acidEPD Enzyme potentiated desensitizationEPO Eosinophil peroxidaseEPSPS 5-Enolpyruvylshikimate-3-phosphate

synthaseER Endoplasmic reticulumERV Expiratory reserve volumeESL-1 E-selectin ligand 1ESPACI European Society of Pediatric Allergy

and ImmunologyESPGAN European Society of Pediatric

Gastroenterology and Nutritionet al. et alii, and othersET Eustachian tubeET-1 Endothelin-1ET-2 Endothelin-2ET-3 Endothelin-3ET-4 Endothelin-4ETAC Early treatment of the atopic childETAC European Task Force on Atopic

DermatitisETD Eustachian tube dysfunctionETO Eustachian tube obstructionETS Environmental tobacco smokeEU European UnionEWHF Extensively whey hydrolyzed formula

FA Food allergyFab Fragment antigen bindingFADD Fas-associated death domainFAE Follicle-associated epitheliumFas APO-1FAS Family atopy scoreFAST Fluoroallergosorbent testFC Flux cytometryFc Fragment crystallizableFcR Fc-ReceptorFCT Food challenge testFDA Federal Drug AdministrationFDC Follicular dendritic cellsFe IronFEF Forced expiratory flowFEF50 Forced expiratory flow at 50%FEIA FluoroenzymeimmunoassayFEIA Food-associated EIAFEV1 Forced expiratory volume in 1 sFFA Free fatty acidsFGF Fibroblast growth factorFH Family historyFHA Family history of atopy

XXIV Abbreviations

FIC Fibroblast-induced chemokineFIS Fetal immune systemFISH Fluorescence in situ hybridizationFIV Feline immunodeficiency virusFKBP FK-506 binding proteinsFMLP Formylmethionyl leucylphenylalaninFN FibronectinFP Fluticasone propionateFR Framework regionFR Free radicalsFRC Functional residual capacityFSA Family score of atopyFVC Flow-volume curvesFVC Forced vital capacity

G-CSF Granulocyte-colony stimulating factorG6PD Glucose-6-phosphate dehydrogenaseGA Gestational ageGABA g-Aminobutyric acidGAD Glutamic acid decarboxylasegag Group-specific antigenGAG GlycosaminoglycanGAL GalaninGal-1 Galectin-1Gal-3 Galectin-3GALT Gut-associated lymphoid tissueGAPs GTPase-activating proteinsGC Germinal centerGCK GlucokinaseGCP-2 Granulocyte chemotactic protein 2GDP Guanosine diphosphateGE Gas exhaustGEF Glycosylation enhancing factorGER Gastroesophageal refluxGHD Growth hormone deficiencyGIF Glycosylation inhibiting factorGINA Global initiative for asthmaGLA g-Linolenic acidGLUT-2 Glucose transporter-2 (protein)GlyCAM-1 Glycosylation-dependent cell adhesion

molecule 1GM Geometric meanGM-CSF Granulocyte macrophage-colony

stimulating factorGM-CSFR Granulocyte macrophage-colony

stimulating factor receptorGMF Genetically modified foodGMO Genetically modified organismGMP Granule-associated membrane proteinGNA Galanthus nivalis agglutininGPC Giant papillary conjunctivitisgps GlycoproteinsGPM Genetic polymorphismGRO Growth-related geneGRP Gastrin-releasing peptideGS Good StartGTP Guanosine triphosphateGvHD Graft-versus-host disease

H HeavyH Humana HAH/P Hypolac/ProfylacHA HemoagglutinationHA HypoallergenicHAART Highly active antiretroviral therapyHAV Hepatitis A virusHBV Hepatitis B virusH-CAM Hematopoietic cell adhesion moleculeHC Head circumferenceHCC-1 Hemofiltrate CC chemokine-1HCV Hepatitis C virusHDE House dust endotoxinHDM House dust miteHE HIV-exposedHEM Heat escape methodHEP Histamine equivalent potencyHEPA High-efficiency particulate

(or particle arresting) air (filter)HET Heterozygote, heterozygous15-HETE Hydroxyeicosatetraenoic acidHEV High endothelial venulesHF Hydrolysate formulaHFI Hydrofluorocarbon inhalerHHM Hypogammaglobulinemia

with hyper-IgMHHV Human herpesvirus5-HIAA 5-Hydroxyindoleacetic acidHIES Hyper IgE syndromeHIgES Hyper-IgE syndrome HIgMS Hyper-IgM syndromeHIS Hyper IgE syndromeHIV Human immunodeficiency virusHIV-1 gp120 HIV-1 glycoprotein 120HLA Histocompatibility leukocyte antigensHLA Human leukocyte antigensHML Human mucosal lymphocytesHMMBF Home-made meat-based formulaHNF Hepatocyte nuclear factor 1a, 4aHFC HydrofluorocarbonsHPA Hypothalamus-hypophysis-adrenalHPLC High-performance liquid

chromatographyHR Hazard riskHR (At) high risk (of atopy)HR Heart rateHRF Histamine release factorHRF Homologous restriction factorHRF-P Histamine release factor plateletsHRIF Histamine release inhibition factorHRQL Health-related quality of lifeHRP Horseradish peroxidaseHSP Heat shock proteinsHSCT Hematopoietic stem cell transplantationHSV Herpes simplex virus5-HT 5-HydroxytryptamineHTLV-I Human T-cell leukemia virusHVR Hypervariable regionHZ Homozygote, homozygous

XXVAbbreviations

I-309 I-309 proteini-NANC Inhibitory-NANCI-TAC Interferon inducible T-cell alpha

chemoattractantIA Idiopathic anaphylaxisIa I region-associated antigenIAA Insulin autoantibodiesIAC Immunologically active casein levelsIAP Inhibitors of apoptosis proteinsIAP Integrin associated protein (CD47)IAR Immediate asthmatic reactions

(see LAR)IAW Immunologically active whey protein

levelsIB Ipratropium bromideIBD Inflammatory bowel diseaseIBE Immunoreactive bacterial extractsIBS Irritable bowel syndromeIC IntracytoplasmaticICA Islet-cell antibodiesICAM-1 (CD54) Intracellular adhesion molecule 1ICAM-2 (CD102) Intracellular adhesion molecule 2ICAM-3 (CD50) Intracellular adhesion molecule 3ICAM-4 (CD242) Intracellular adhesion molecule 4ICD International classification of diseasesICD Irritant contact dermatitisICDRG International contact dermatitis

research groupICE Interleukin IL1b converting enzymeICMA Intracellular Mycobacterium aviumICRM Identifiable as casein raw materialICS Inhaled corticosteroidsICT Ice cube testICU Intensive care unitID Immune deficiencyID IntradermallyIDC Interdigitating dendritic cellsIDDM Insulin-dependent diabetes mellitusIDV IndinavirIEF IsoelectrofocalizationIEL Intraepithelial lymphocytesIF ImmunofluorescenceIFN InterferonIFR Inspiratory flow rateIg ImmunoglobulinIgA Immunoglobulin AIgD Immunoglobulin DIgDs Surface immunoglobulin DIgE Immunoglobulin EIgE-BF IgE binding factorsIgE-PF IgE potentiating factor(s)IgE-SF IgE suppressive factor(s)IgG Immunoglobulin GIgG-STS IgG short time sensitization

Igs ImmunoglobulinsIgSC Ig-secreting cellsIgSF Immunoglobulin superfamilyIkB Inhibitor of NF-kBIkB-a Inhibitor of NF-kB, type aIKK Inhibitor of B kinaseIL InterleukinIL1RA IL1 receptor antagonistIM IntramuscularIMN Infectious mononucleosisiNOS Inducible NO synthaseIP-10 Inflammatory protein-10IP-10 Interferon-inducible protein-10IPD-1 Insulin promoter factor 1IP3 Inositol-trisphosphateIPPB Intermittent positive pressure breathingIr Immune responseIRAK IL1R-activating kinaseIRR Incidence rate ratioIRFI Interferon regulatory factor-1IRV Inspiratory reserve volumeISAAC International Study of Asthma

and Allergy in ChildrenISP Immature single positiveISS Immunostimulatory sequencesITAM Immunoreceptor tyrosine-based

activation motifIU International UnitIUIS International Union of Immunological

SocietiesIV IntravenousIVAP In vitro antibody productionIVIg Intravenous immunoglobulins

J JunctionJAK Janus-family kinaseJCA Juvenile chronic arthritisJRA Juvenile rheumatoid arthritisJSC Juvenile scleroderma

kb KilobasekD KilodaltonKS Kaposi’s sarcoma

L LightLA Linolenic acidLAD Leukocyte adhesion deficiencyLAD I Leukocyte adhesion deficiency, type ILAD II Leukocyte adhesion deficiency, type IILAD III Leukocyte adhesion deficiency, type IIILAD IV Leukocyte adhesion deficiency, type IVLAD V Leukocyte adhesion deficiency, type VLAG-3 Lymphocyte activation gene-3LAK Lymphokine activated killerLAM Leukocyte adhesion molecule (CD62L)LAMP Lysosome-associated membrane proteinLAR Late asthmatic reactions (see IAR)

XXVI Abbreviations

LARC Liver and activation-regulatedchemokine

LBP Lipopolysaccharide-binding proteinLBW Low birth weightLC Langerhans cellsLC-SFA Long-chain saturated fatty acidsLCA Leukocyte common antigen (CD45)LCAM Liver cell adhesion moleculeLCP Long-chain polyunsaturated fatty acidsLCP Long-chain PUFALD Lymphocyte-definedLDH Lactate-dehydrogenaseLDL Low-density lipoproteinLESN Lupus erythematosus systemic, neonatalLFA-1 Lymphocyte function-associated

antigen-1 (CD11a/CD18)LFA-2 Lymphocyte function-associated

antigen-2 (CD2)LFA-3 Lymphocyte function-associated

antigen-3 (CD58)LGL Large granular lymphocytesli Invariant chainLIF Leukocyte-inhibiting factorLIP Lymphocyte (lymphoid) interstitial

pneumonitisLMI Leukocyte migration inhibitionLMP Low-molecular-weight polypeptideLMPT Lactulose mannitol permeability testLMW Low molecular weightLod Logarithm of the oddsLPAM-1 Lymphocyte Peyer’s patch HEV

adhesion molecule 1LPAM-2 Lymphocyte Peyer’s patch HEV

adhesion molecule 2LPR Late-phase reactionLPS LipopolysaccharideLR (At) low risk (of atopy)LRTI Lower respiratory tract infectionLST Long synthetic overlapping peptideLST Lymphocyte stimulation testLT LeukotrieneLTB4 Leukotriene B4LTC4 Leukotriene C4LTP Lipid transfer proteinLTR Long terminal repeatsLTT Lymphocyte transformation testLYST Lysosomal trafficking

M MicrofoldmAb Monoclonal antibodiesM-CSF Monocyte/macrophage-colony

stimulating factorM-CSFR Myeloid colony stimulating factor

receptorMAC Membrane attack complexMAC Mid-arm circumferenceMac-1, -2 Macrophage-1 (-2) glycoprotein

(CD11b/CD18)

MACIF Membrane attack complex inhibitoryfactor (CD59)

MAD-2 Monocyte adhesion dependent protein-2MAdCAM-1 Mucosal addressin cell adhesion

molecule-1MAG Myelin associated glycoproteinMALT Mucosa-associated lymphoid tissueMAMC Mid-arm muscle circumferenceMAP Mitogen-activated proteinMAPK Mitogen-activated protein kinaseMAS Macrophage activation syndromeMASP MBL-associated serine proteaseMAST Multiplied allergosorbent testMBL Mannose-binding lectinMBP Major basic proteinMBP Mannose-binding proteinMBP Myeline basic proteinMBT MercaptobenzothiazoleMCAF Monocyte chemotactic and activating

factor (MCP-1)MCC Mast cell chymaseMCD Mad cow diseaseMCP Mast cell proteaseMCP Membrane cofactor protein (CD46)MCP-1 Monocyte chemotactic protein-1MCP-2 Monocyte chemotactic protein-2MCP-3 Monocyte chemotactic protein-3MCP-4 Monocyte chemotactic protein-4MCP-5 Monocyte chemotactic protein-5MCR Monocyte complement receptorMCS Multiple chemical sensitivitiesMCT Medium-chain triglyceridesMDA-7 Melanoma differentiation-associated

factor 7MDC Macrophage-derived chemokineMDI Metered-dose inhalerMDV Mean diurnal variationME Middle earMEEs Middle ear effusionsMEF Mid-expiratory flowMEF25–75 Maximal expiratory flow

at 25%–75% VCMGF Mast cell growth factor (SCF)MGSA Melanocyte growth stimulating activityMHC Major histocompatibility complexMIF (Monocyte) migration inhibiting factormig Monokine inducible by IFN-gmIgD Membrane IgDmIgM Membrane IgMMIIC MHC class II-loading compartmentMIP-1a Macrophage inflammatory protein-1aMIP-1b Macrophage inflammatory protein-1bMIP-2 Macrophage inflammatory protein-2MIP-3a Macrophage inflammatory protein-3aMIP-3b Macrophage inflammatory protein-3bMIPF-1 Myeloid inhibitory factor-1MIPF-2 Myeloid inhibitory factor-2MLC Mixed lymphocyte culture

XXVIIAbbreviations

MLR Mixed lymphocyte reactionMMEF Maximal mid-expiratory flowMMP Matrix metalloproteinaseMMR Measles, mumps and rubella (vaccine)MMWR Morbidity and Mortality Weekly ReportMo MolybdenumMODY Maturity-onset diabetes of the youngMP MonopositiveMPO MyeloperoxidaseMPS Mononuclear phagocyte systemMR Magnetic resonanceMR Mannose receptormRAST Modified RASTMS Multiple sclerosisMSP-R Macrophage-stimulating protein

receptorMT Mantoux testMUD Matched unrelated donorMVM Microvillus membraneMXT MethotrexateMyD88 Myeloid differentiation protein gene 88MZ Monozygous

N NeutralN NutramigenN-CAM Neural cell adhesion moleculeNA Neutrophil antigenNACDG North American Contact Dermatitis

GroupNADP Nicotinamide-adenine dinucleotide

phosphateNADPH Nicotinamide-adenine dinucleotide

phosphate (reduced form)NALT Nasal-associated lymphoid tissueNANC Nonadrenergic noncholinergicNAP-1 Neutrophil-activating factor-1NAP-2 Neutrophil-activating factor-2NARES Nonallergic rhinitis,

eosinophilic subgroupNAT Nucleic acid amplification technologyNBT Nitroblue tetrazolium (test)NC NucleocapsidNCA Neutrophil chemotactic activityNCA Non-cross-reactive antigenNCAM Neural adhesion moleculeNCF Neutrophil chemotactic factorNCF-A Neutrophil chemotactic factor

of anaphylaxisNE Norepinephrinenef Negative factorNEMO NF-kB essential modifierNEP Neutral endopeptidaseNFAT Nuclear factor of activated T cellsNF-kB Nuclear factor kBNFV NelfinavirNGF Nerve growth factorNGFR-SF Nerve growth factor receptor

superfamily

NHR Nasal hyperreactivityNI Nidina HANIDDM Non-insulin-dependent diabetes

mellitusNeuroD-1 Neurogenic differentiation factor 1NK Natural killer cellsNKA Neurokinin ANKAR Natural killer-activating receptorNKAT Natural killer-associated transcriptsNKB Neurokinin BNKIR Natural killer inhibitory receptorNKR Natural killer receptorNKRP-1 Natural killer receptor P-1 (CD161)NKSF Natural killer cell stimulatory factorNN Neonatal neutrophilsNNRTI Non-nucleoside reverse transcriptase

inhibitorsNO Nitric monoxideNO2 Nitric dioxideNOD Nonobese diabeticsNOS Nitric oxide synthaseNP Nutrilon PeptiNPP Nutrilon Pepti PlusNPT Nasal provocation testNPV Negative predictive valueNPY Neuropeptide tyrosine (Y)NRL Natural rubber latexNRTI Nucleoside reverse transcriptase

inhibitorNSAIDs Nonsteroidal anti-inflammatory drugsNT NeurotensinNVP NevirapineNZB New Zealand blackNZW New Zealand white

O2∑– Superoxide anion

O3 ozoneOAS Oral allergy syndromeOCT Oral challenge testODN OligodeoxynucleotidesOFC Open food challengeOME Otitis media with effusionq.i.d. Quarter in die, four times a dayORL OtorhinolaryngologistOVA Ovalbumin

P PregestimilP ProperdinP+P Prick by prickp-ANCA Perinuclear anti-neutrophil circulating

antibodiesp150,95 CD11c/CD18PA Pseudoallergic, pseudoallergyPAA Proteins with anti-infective activityPABA P-aminobenzoic acidPAC Perennial allergic conjunctivitisPACGT Pediatric AIDS Clinical Trials Group

XXVIII Abbreviations

PaCO2 Partial pressure of CO2 in arterial blood

PAF Platelet-activating factorPALS Periarteriolar lymphocyte sheathPAN Periarteritis nodosaPaO2 Partial pressure of O2 in arterial bloodPAR Perennial allergic rhinitisPARC Pulmonary and activation-regulated

chemokinePAS Para-aminosalicylic (acid)PBB Polychlorinated biphenyl compoundsPBL Peripheral blood lymphocytesPBMC Peripheral blood mononuclear cellsPBP Platelet basic proteinPC Particle counterPC Pneumocystis cariniiPC20 Methacholine/histamine provocative

concentration causing a fall in FEV1of 20%

PCB Polychlorinated biphenylsPCD Programmed cell deathPCD Protein contact dermatitispCi PicoCuriePCIIINP Amino terminal propeptide of type III

procollagenPCIP Carboxy terminal propeptide of type I

procollagenPCP Personalized care projectPCP Pneumocystis carinii pneumoniaPCR Polymerase chain reactionPD20 Provocation dose 20PDE PhosphodiesterasePDGF Platelet-derived growth factorPDGFR Platelet-derived growth factor receptor

(CD140)PE Progressive encephalopathyPECAM 1 Platelet endothelial cell adhesion

molecule (CD31)PEF Peak expiratory flowPEFR Peak expiratory flow ratePEFV Partial expiratory flow volume (curve)PEG Polyethylene glycolPEM Protein-energy malnutritionPENTA Pediatric European Network for Treat-

ment of AIDSPF Perch fishPF4 Platelet factor 4PFC Plaque-forming cellsPFM Peak flow meterPFT Pulmonary function testingPG PolygalacturonasePG ProstaglandinPGD Prostaglandin DPGE Prostaglandin EPGF Prostaglandin FPGL Persistent generalized lymphadenopathyPGP9.5 Neuron-specific protein 9.5PH Prophylac/Hypolac

PHA PhytohemagglutininPHI Peptide histidine-isoleucinePHM Peptide histidine-methioninephox Phagocyte oxidasePHV Peptide histidine-valinePI 3K Phosphatidylinositol-3-kinasePID Primary immune deficiencypIgA Polymeric IgApIgR Polymeric Ig receptorPIP2 Phosphatidylinositol-bisphosphatePJ PeptiJuniorPKA Protein kinase APKC Protein kinase CPL PhospholipasePLA Phospholipase APLC Phospholipase CPLCg1 Phospholipase Cg1PLCg2 Phospholipase Cg2PLD Phospholipase DPLH Pulmonary lymphoid hyperplasiaPLP Proteolipid proteinPM10 Particulate matters <10 mmPMA Phorbol myristate acetatepMDI Pressurized metered dose inhalerPMN Polymorphonuclear (leukocytes)PNM Polynucleated neutrophilsPNP Purine nucleoside phosphorylasePNU Protein nitrogen unitspol Polymerasepoly PolyarticularPOP Persistent organic pollutantsPP Peyer’s patchesppb Parts per billionPPD Purified protein derivativePPDA Paraphenylenediamineppm Parts per millionPPV Positive predictive valuePR PregominPR ProteasePR Protein related to pathogenesisPR3 Proteinase 3prn pro re nata, if requiredPRIST Paper radioimmunosorbent testPrP Prion proteinPRU Phadebas RAST unitPS PolysaccharidesPSA Polysaccharide antigenPSGL-1 P-selectin glycoprotein ligand 1 (CD162)PT Patch test(ing)PT Provocation testingPTF Patch test with foodsPTK Protein tyrosine kinasePTP Protein tyrosine phosphatasePUFA Polyunsaturated fatty acidsPUVA Psoralen ultraviolet APV Pulmonary volumePVR Polio virus receptor (CD155)PWHF Partial whey hydrolysate formulaPWM Pokeweed mitogen

XXIXAbbreviations

RA Recombinant allergensRA Rheumatoid arthritisRAG Rice allergenRAG-1 and -2 Recombination-activating gene-1 and -2RANTES Regulated on activation

normal T expressed and secretedRAP RapamycinRAP Rice allergenic proteinRAST Radio allergosorbent testRaw Airway resistanceRBA Radio-binding assayRBC Red blood cellRCA Regulator of complement activationRDA Recommended daily allowanceRES Reticuloendothelial systemREV Rev responsive elementrev Regulator of viral expressionRF Rheumatoid factorRFLP Restriction fragment length

polymorphismRFX5 Regulatory factor X5RGS Regulators of G protein-signalingRH Relative hazardrHuG-CSF Recombinant human G-CSFRIA Radioimmunological assayRint Interrupter resistanceRLS Restless legs syndromeROC Receptor-operated channelsRP Ratio of proportionRR Relative riskRR Respiratory rateRRI Recurrent respiratory infectionsRSR Respiratory system resistanceRSS Conserved recombination signal

sequencesRSV Respiratory syncytial virusRSV-IVIg (Anti)respiratory syncytial

virus-intravenous immunoglobulinsRT Reverse transcriptaseRT-PCR Reverse transcriptase/polymerase chain

reactionRTC Rapid thoracoabdominal compressionRTV RitonavirRx Radiographic

SA SuperantigenSAA Serum amyloid A proteinSAC Seasonal allergic conjunctivitisSAFT Skin application food testSAH S-adenosylhomocysteine,

S-adenosylhomocysteineSALT Skin-associated lymphoid tissueSaO2 Oxygen saturationSAP Serum amyloid P componentSAR Seasonal allergic rhinitisSARAH Skin activity reference allergen/

histamineSARS Severe acute respiratory syndrome

SBHR Spontaneous basophil histamine releaseSC Secretory componentSC SubcutaneousSC-SFA Short-chain saturated fatty acidsSCF Stem cell factor SCID Severe combined immunodeficiencySCN Severe congenital neutropeniaSCORAD Scoring of atopic dermatitisSCT Stem-cell transplantationSCY Small secreted cytokineSD Serologically defined (antigens)SD Standard deviationSDF Stromal cell derived factorSDS Standard deviation scoreSDS-PAGE Sodium dodecylsulfate-polyacrylamide

gel electrophoresisSE Staphylococcal enterotoxinSe SeleniumSEA Staphylococcal enterotoxin ASEB Staphylococcal enterotoxin BSEC Staphylococcal enterotoxin CSED Staphylococcal enterotoxin DSEE Staphylococcal enterotoxin ESEM Standard error of the meanSFA Suppressive factor of allergySGOT Serum glutamic-oxaloacetic

transaminaseSH2, 2, 3 Src homology 2, 3SH2DIA SH2 domain containing gene 1ASHS Schönlein-Henoch syndromeSI Système International des UnitésSIAIC Società Italiana di Allergologia

e Immunologia ClinicaSIDS Sudden infant death syndromesIgA Secretory IgASIgAD Selective IgA defectsIgE Specific IgE (food-specific)sIgG Specific IgGsIgM Secretory IgMSIS Skin immune systemSIT Specific immunotherapySIV Simian immunodeficiency virusSJS Stevens-Johnson syndromeSL Synovial liquidSLAM Signaling lymphocyte activation

moleculeSLC Secondary lymphoid tissue chemokineSLE Systemic lupus erythematosussLex Sialyl-Lewis x (CD15s)SLIT Sublingual immunotherapySMOC Second messenger-operated channelsSO2 S dioxideSOD Superoxide dismutaseSOM SomatostatinSP Single positiveSP Substance PSP-A Surfactant protein ASP-D Surfactant protein D

XXX Abbreviations

SPA Staphylococcus aureus protein ASPB Solid-phase bindingSPEA Staphylococcal pyrogenic exotoxin ASPEB Staphylococcal pyrogenic exotoxin BSPF Soy protein formulaSPT Skin prick testSQ Standardized quality unitSQV SaquinavirsRaw Specific airway resistanceSRBC Sheep red blood cellSRCR-SF Scavenger receptor cysteine-rich

superfamilySSSS Staphylococcal scalded skin syndromeStat Signal transducers and activators

of transcriptionsSTCP-1 Stimulated T cell chemotactic protein-1STS-IgG Short-term sensitizing IgGSV Simian vacuolating (virus)syk Spleen tyrosine kinase

T Tryptase-containing mast cellsT-bet Transcription factors T-box expressed

in T cellsTACTILE T cell activation increased late

expressionTAI Transient autoimmunityTAME Tosylarginine methylesterTAP-1 Transporter associated with antigen

presentation 1TAP-2 Transporter associated with antigen

presentation 2TAPA-1 Target of an antiproliferative antibody 1Tapr T cell and airway phenotype regulatorTAR Transactivation responsive sequenceTARC Thymus and activation-regulated

chemokinetat Trans-activantTB TubercularTC Tryptase and chymase-containing

mast cellsTCA Trichloroacetic acidTCA3 T cell activation gene 3TCC T cell clonesTCDD Tetrachlorodibenzo-p-dioxinTCL T cell lineTcR T cell receptorTdT Terminal-deoxynucleotidyl-transferaseTECK Thymus-expressed chemokineTEN Toxic epidermal necrolysisTF Transcription factorTGF Transforming growth factorTGFR Transforming growth factor receptorTGV Thoracic gas volumeTh T helperThP Th precursorsTHI Transient hypogammaglobulinemia

of infancy

TIF (IL10-related) T-cell derived induciblefactor

TIM T-cell immunoglobulin and mucin (domain)

TLC Total lung capacityTLR Toll-like receptorTM TransmembraneTM4-SF Transmembrane 4 superfamilyTme/Te Percentage of expiratory time to reach

peak tidal flowTMJ Temporomandibular jointTN Triple negativeTNF Tumor necrosis factorTNFR Tumor necrosis factor receptorTNFRSF Tumor necrosis factor superfamily

receptorTNFRSF6 Tumor necrosis factor receptor

superfamily receptor 6Torr Torricelli (1 Torr = 1 mmHg)TPN Total parenteral nutritionTr1 T-regulatory 1TRADD TNFR-1-associated death domainTRUE Thin-layer, rapid use epicutaneous (test)Ts T suppressorTSP-1 Thrombospondin-1TSP Total suspended matterTSST-1 Toxic shock syndrome toxin-1tTG Tissue transglutaminaseTV Tidal volumeTVP Tensor veli palatiniTVP Textured vegetable proteinsTX ThromboxaneTXA2 Thromboxane A2

UC Ulcerative colitisUCBT Umbilical cord blood transplantationUHT Ultra-high temperatureUPA-R Urokinase plasminogen activator

receptorURTI Upper respiratory tract infectionUV Ultraviolet

V VariableV Vivena HAVAP-1 Vascular adhesion proteinVC Vital capacityVCAM-1 Vascular cell adhesion molecule

(CD106)vCJD Variant Creutzfeldt-Jakob DiseaseVI (HIV) virus-infectedvif Viral infective factorVIP Vasoactive intestinal peptideVKC Vernal keratoconjunctivitisVLA Very late antigensVNR Vitronectin receptorVOC Volatile organic compoundsVOC Voltage-operated channelsvpr Viral protein R

XXXIAbbreviations

vpu Viral protein Uvpx Viral protein XVRI Viral respiratory infectionVSV Vesicular stomatitis virusvWF Von Willebrand factorVZV Varicella zoster virus

WARI Wheezing associated respiratory infections

WAS Wiskott-Aldrich syndromeWASp Wiskott-Aldrich syndrome proteinWB Western blotWCC White-cell countWGAA Wheat germ agglutinin antibodies b

WHF Whey hydrolyzed formulaWHO Word Health OrganizationWHO/IUIS Word Health Organization/International

Union of Immunological Societies

XL X linkedXHIMS X-recessive hyper-IgM syndromeXLA X-linked agammaglobulinemiaXLP X-linked lymphoproliferative syndromeXLT X-linked thrombocytopenia

ZAP-70 Zeta-associated protein 70ZDV ZidovudineZn Zinc

XXXII Abbreviations