Arnaldo Cantani Pediatric Allergy,Asthma and Immunology Arnaldo Cantani Pediatric Allergy, Asthma and Immunology With 649 Figures in 728 Partfigures,341 in Color and 741 Tables 123 Arnaldo Cantani,Prof.Dr. ISBN-10 3-540-20768-6 Allergy and Clinical Immunology Division Springer Berlin Heidelberg NewYork Department ofPediatrics ISBN-13 978-3-540-20768-9 University ofRome “La Sapienza” Springer Berlin Heidelberg NewYork Via G.Baglivi,7 Library ofCongress Control Number:2004117336 00161 Rome,Italy e-mail:[email protected] Title ofthe original Italian edition: Allergologia e immunologia pediatrica – dall’infanzia all’adolescenza © 2000 Verduci Editore – Roma,ISBN 88-7620-545-4 This work is subject to copyright. 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Product liability:The author and the publishers cannot guar- antee the accuracy ofany information about dosage and appli- cation contained in this book.In every individual case the user must check such information by consulting the relevant litera- ture. Editor:Dr.Ute Heilmann,Heidelberg,Germany Desk Editor:Dörthe Mennecke-Bühler,Heidelberg,Germany Cover design:Frido Steinen-Broo,Pau,Spain Production:Martha Berg,Heidelberg,Germany Reproduction and typesetting: AM-productions GmbH,Wiesloch,Germany Printing and binding:Stürtz GmbH,Würzburg,Germany 21/3151bg – 5 4 3 2 1 0 Printed on acid-free paper To my beloved wife for so much help she has given me and for so much time I robbed her of. VII Preface Science cannot be restricted alimentation are the first and most powerful means to by the narrow frame ofa book: be well.” it is generally intolerant offrames Pediatric allergy and immunology is a multidiscipli- nary field ofresearch today,and familiarity with current Pediatric Allergy,Asthma and Immunology is a new dis- concepts is important for medical students, for clini- cipline that finds its foundation in this book, whose cians in every pediatric specialization and for re- roots linke me to Elena and Luisa Businco,with whom I searchers in this attractive area.However,the issue is not founded the first Italian Pediatric Allergy Division some benefited by an easy approach,because pediatric allergy 30years ago,now called the Pediatric Allergy and Im- and immunology has characteristic features both differ- munology Division. There I discovered this world, ent and larger in scope than adult allergy.Nor can we where I had the chance to revive the significance ofthe disregard significant events such as the atopic-march, three Ss: science, safety and sympathy. Children and the inexorably accelerating prevalence of atopic dis- their parents consult us in the hope offinding scientific eases,which develop in 80%–90% of cases within the and medical knowledge as well as assurance and under- very first months and years of life, while the intense standing sympathy,all necessary prerequisites for the efforts of research scientists and the greater awareness successful outcome ofour everyday tasks.Above all,one ofpediatricians and ofdedicated parents have widened should appreciate how much the pediatrician–allergist the positive results of prevention and treatment. The is,more than any other doctor,dedicated to the care of avalanche ofimmunological progress shows no sign of his or her patients,since he or she must either deal with abating in this new millennium.I have therefore begun cases ofextreme severity,such as anaphylactic shock,or with the fundamental concepts of basic immunology, perform ordinary jobs,such as giving suggestions on whose inferences are relevant to the later chapters.For the diets or the furnishings of the home.The pediatri- example,I have attempted to offer an exhaustive discus- cian–allergist should always find out how to protect the sion in Chap.1 to the interested reader trying to under- infant,the child and the adolescent against discrimina- stand the significance of adhesion molecules from the tion because oftheir allergy.With proper prescriptions pathogenic point of view.Therefore,after the chapters and appropriate recommendations,such an objective is on fetal-neonatal immunology and the mucosal im- always within reach,and both the child and his or her mune system,the neonate at risk of atopy,the genetic parents will profit from a better quality oflife. and environmental predisposing factors and the epi- The earliest roots of this book developed from my demiology and natural history of atopic diseases, a everyday work in the Pediatric Allergy and Immunolo- whole chapter encompasses the diagnosis of allergy, gy Division and have grown while preparing lessons from the clinical history to the provocation tests.The and courses to be delivered to medical students and book progresses chapter by chapter to elucidate the postgraduates in pediatrics. Of course, this ongoing spectrum ofseveral diseases,including atopic dermati- work has found its expression in a host of papers that tis,food allergy,asthma,rhinoconjunctivitis,and to dis- have inspired several chapters within this book.How- cuss specific immunotherapy (SIT) for these diseases.It ever,my primary aim was not one ofdoing something also places great emphasis on specialist disorders such necessary; I have hoped only to do something that is as sinusitis and otitis media with effusion,which are fre- useful to someone.With this book,I hope to have of- quently associated with allergic diseases. Many pages fered convincing proofs and foundations to colleagues are devoted to autoimmune diseases,primary immuno- committed to pediatric allergy and immunology.Often deficiencies and to pediatric HIV infection.The last two its main goal is one ofprevention,in all senses and us- chapters are comprehensively built on the earlier ones, ing all resources,as Arnaldo Cantani Sr.wrote in 1877 introducing two emerging important advances,malnu- in the preface to the first edition ofhis Textbook ofClin- trition and the immune system and another of capital ical Pharmacology: “ … only corresponding with a importance,atopy prevention,which sums up the wealth meticulous study and the greatest exactness to the ofnew data. precise indications of the case,the drugs may be use- Until recently, the expansion of immunology was –ful to the patient … in the belief that air,water,and undervalued.In this breakthrough my major thrust was VIII Preface to attest to the ferments ofactivity that have revolution- selecting,among the relevant literature in an unending ized,so to say,the exciting new area ofresearch,such as stream of data on pathogenic and therapeutic aspects, the therapeutic strategies exemplified by the switch the most significant ones,especially in the field ofpedi- from Th2 to Th1 lymphocytes in the immune system atrics.It is not always easy and productive to interweave manipulations through SIT and anti-IgE therapy,gene basic and clinical material.I have tried to inform the therapy ofprimary immunodeficiencies and the mater- reader more comprehensively following a logical pro- nofetal treatment of HIV infection.A growing body of gression,synthetically reviewing the most recent state of literature is shaping our knowledge ofthe fetal immune this rapidly advancing specialization, leaving in the system. We are now aware that the fetus can be im- background the data pertaining to the basic knowledge munocompetent from the 18th to 20thweek of in- ofpediatricians and allergist–immunologists. trauterine life,and that from the 22ndweek it can react My purpose was also that oflightening the text with to food and inhalant allergens ofmaternal origin,sug- the aid ofapproximately 1,400 high-quality figures cov- gesting that heredity and maternal intake of foods or ering basic aspects and tables abounding with practical drugs or allergen inhalation may anticipate the founda- information facilitating day-to-day diagnosis and man- tions ofpediatric allergy and immunology in intrauter- agement.My approach has been that ofutilizing the fig- ine life, thus requiring an advancement of preventive ures and tables as both a commentary and an extension measures.In this context,immunology is the new mile- ofthe text.The appendices complete the volume,while stone when one refers to the so-called collagen diseases, the abbreviations and acronyms are listed separately.In revisited as a deviation from the normal mechanisms of addition,I have adopted the Système International des self-recognition,to the viruses that deceive the immune Unités (SI) where appropriate.At the end ofeach chap- system, modulating apoptosis at will, and to the im- ter a list ofreferences includes leading articles and sub- munological components of breast milk,rich in prebi- specialty reviews,so that readers are referred to numer- otics and TLRs and protecting infants even from dia- ous points of departure from which to explore further betes.From this viewpoint we cannot underestimate the the subjects closer to their interests. impact of transgenic foods and pesticides, which are I have attempted, therefore, to offer to dedicated revolutionizing foods,and of polluted air breathed by pediatricians and family practitioners a comprehensive, newborns. Among the food offenders, the first level clear and timely distillation of current information refers to hidden allergens, or those regularly absent making it possible to keep abreast of recent advances from the labels,and the growing number ofcross-reac- and to acquire the basic principles necessary in their tions,with the remarkable latex–fruit syndrome and the practice.The careful reader will find practical advice on mite–mollusc correlations.The role ofinfectious agents which to base actions that will block the atopic and im- could likely be the opposite ofcurrent theories,namely munological march by preventing,managing and treat- that ofprotecting infants from the onset ofallergic dis- ing allergic–immunological diseases,and by appropri- ease,whose higher frequency could be favored by the ately informing parents, without neglecting to raise improvement in the standard ofliving.The hygiene hy- public awareness ofthe threat posed by the march and pothesis is intriguing,but milk may kill by inhalation, to provide the means to stop it. Managing childhood casein may remain active for 2,500years and egg for atopic and immune disorders requires a new strategy. 500years.We move forward in pediatric allergy and im- Millions of children and their parents expect disease munology:fascinating findings focus on the increasing prevention and cure, and allergists or immunologists number of wheezing infants and on the success of de- are challenged to provide interventions that achieve sensitization shared by food-allergic and asthmatic optimal health from childhood to adulthood.I hope that children, thus leaving these children without disease. students and postgraduate doctors willing to find a Immunodeficiencies are radically cured by bone mar- detailed reference for this fascinating and demanding row transplantation,autoimmune diseases are starting area ofpediatrics and willing to develop an allergic–im- to be cured with stem cell transplantation, diabetes munological viewpoint will succeed in identifying the seems to be cured by mother–daughter transplantation diverse pathologies and will be motivated to become of pancreatic cells and immunodeficiencies by bone more actively involved in the daily health needs of marrow transplantation.HIV infection can be “cured” atopic infants,children and adolescents. by prevention. I am deeply grateful to my wife,María Susana Cam- In the presentation of the diverse conditions,I have postrini,who assisted me in this challenging enterprise preferred a complete description in a traditional se- and helped me to add expressive illustrations to the quence,beginning with an introduction,the definitions book.I wish to acknowledge the assistance of several and the epidemiology, then continuing with the im- colleagues for their helpful discussions and contribu- munological characteristics, pathogenesis, symptoms, tions,including Doctors Daniele Ceccoli,Franco Frati, diagnosis and treatment. Further, being compelled to Oreste Marciano and my referees Professors Emanuele deal with aspects sometimes so distant or different has Errigo and Massimo Fiorilli. The consultation of nu- certainly implied possible errors in measure and a merous journals was of particular help, especially in certain degree of overlap.A very hard task was that of the libraries ofthe Pediatric Department ofRome Uni- Preface IX versity “La Sapienza”and Rome University “Tor Vergata,” to Springer-Verlag and especially to Ms Ute Bujard for the Pediatric Department of Sassari University, the her meticulous editing skills that allowed the publica- National Council for Scientific Research, the Italian tion ofthis book.I would also like to thank Martha Berg Institute of Public Health and several university whose excellent assistance helped me very much. libraries of the Hospital Policlinico Umberto I where I To offer a wide panorama ofresults,several data have work,especially the Department ofExperimental Medi- been presented throughout the book and reported in cine.I extend my gratitude to many colleagues and pub- the tables and in the figures,independently ofhow the lishers who have kindly provided many figures includ- children were identified as affected with allergic-im- ing the late Professor Luisa Businco and the UCB that munologic disease.Of course I do not expect that my kindly supplied many figures related to the SCORAD opinions or my suggestions “to live better with allergy” and ETAC studies.In particular,I am deeply indebted meet the unconditioned favor ofall readers:I would be to Professors Molkhou, Revillard and Wüthrich and grateful if they would point out “the errors and the their publishers. My thanks to Professors Mogi, Ring omissions”so that I can correct them in a future edition. and Wüthrich, who presented me with their books and Professors Bernstein,Brandtzaeg,Buckley,Gerrard, Rome,September 2007 Patriarca, Roos and Sullivan for sending me reprints Arnaldo Cantani not easily found otherwise.I owe particular gratitude XI HFoeraedw Toirtdle For those who believe that I may not be the best suited specialization,as well as the decision of the European person to present Pediatric Allergy, Asthma and Im- Academy of Allergology and Clinical Immunology to munology by Arnaldo Cantani,I would like to explain create a Section ofPediatric Allergology,thus satisfying the reasons that encouraged me – a specialist of adult the need to gather under a single roof specialists of disease of intellectual development, with professional the “general”discipline,thereby recognizing and war- experiences substantially different from those of the ranting the importance and autonomy of the pediatric author – to agree to his request with great pleasure. allergologist. These reasons are either of a personal nature or of a Professor Cantani’s book is a concrete and cogent more general and ideological nature. contribution to the foundation of pediatric allergy– Professor Cantani’s knowledge has its deep roots in immunology.This book is an impressive and compre- his extensive work at the Department of Pediatrics of hensive documentation of the progress in the under- the University ofRome “La Sapienza”and especially at standing and management of allergic–immunologic the chair of the late Professor E.Rezza.Only recently, disorders of infants, children and adolescents, and is however, when I had more frequent opportunities of divided into 24 chapters illustrated by more than 1,400 collaborating with him,was I struck by the profound tables and figures that are helpful in clarifying complex “team spirit” that Arnaldo Cantani feels for pediatric points.I have greatly appreciated the author’s approach allergy and immunology as well as by his exactness and ofdiscussing,in addition to the ontogeny ofthe immune precision in dealing with the commitment necessary to system,mucosal immunology and the typical pathology report his own experience. of infantile immediate hypersensitivity with its very As Past President ofthe European Academy ofAller- early onset age, the mechanisms underlying specific gology and Clinical Immunology, I am fully aware of disease states such as the developing neonatal immune the problems,both general and specific,that pertain to response, autoimmune disease, immune deficiencies the discipline of “pediatric allergy and immunology.” and pediatric AIDS,which are increasingly recognized The opportunity to acknowledge this discipline as an as complex diseases.Such an approach entails,in fact, autonomous specialization is ofprimary necessity,espe- that one’s eyes be kept open to the complexity ofclinical cially in north European centers. This orientation is allergology and immunology,and widened beyond the opposed by some pediatric specialists or allergy special- limited field ofatopic disease and the “atopic march”to ists. However, it should be appreciated that pediatric the genetic relation to atopy and bone marrow trans- allergy and immunology differs widely from that of plantation. adults,as evidenced by this textbook.This difference is A critical analysis of how this complex and detailed particularly important not only in the newborn period information is condensed into a readable textbook sug- but above all in the diseases typical and specific to the gests the author’s far-sighted attitude:on the one hand pediatric age as well as in those also common to adult the painstaking precision ofthe scientist (see the list of patients,ofwholly peculiar physiopathologic,diagnos- abbreviations that opens the book),and on the other the tic and therapeutic characteristics.These current points more typical Latin inclination to prefer clinical reason- ofview are confirmed by the recent proposal to consid- ing,which,even in its subjectivity,always represents the er both internal medicine and pediatrics as common essential distinguishing feature between the clinical branches of the allergology and clinical immunology professor and accurately programmed reasoning. XII Foreword The findings ofseveral schools and disciplines differ- Although he had the excellent collaboration and ent from those ofProfessor Cantani are critically evalu- editorial assistance of Springer-Verlag throughout the ated,and the virtues ofsingle authorship,compared to preparation of this textbook, Arnaldo Cantani has multi-authored textbooks that often lack sufficient co- undertaken alone the fascinating burden of putting ordination and revision by the editor, are evident together Pediatric Allergy, Asthma and Immunology. throughout the book. I therefore compliment the author on assembling an All chapters have reference lists with citations that outstanding opus in the interest ofpediatric allergy and will be stimulating for those interested in more in-depth immunology and in the training ofall those concerned study. Moreover, the suggestions at the end of each with the “march.”Anyone who cares for allergic children chapter and the numerous discussions,also in the form or wants to learn about immune diseases will surely of tables and figures,promote an expert starting point benefit from frequent consultations of this textbook. for diverse specialists interested in evidence-based I hope that the book will provide pleasure and insight to medicine, be they allergists, immunologists, pediatri- all prospective readers. cians or practitioners.As a result,the reader has at hand a doubly useful book:one to be studied and consulted, Rome,May 2007 the other to be read with pleasure, a book to be ap- Sergio Bonini proached critically.