Advances in pediatric and adult asthma
2005; Elsevier BV; Volume: 115; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2004.12.1123
ISSN1097-6825
AutoresStanley J. Szefler, Andrea Apter,
Tópico(s)Pediatric health and respiratory diseases
ResumoLast year's review on adult and pediatric asthma highlighted reports related to asthma genetics, the importance of upper airway management, the costs of asthma, and the importance of early recognition and intervention. This year we will organize our discussion to review recent reports related to the origins and persistence of asthma in both adults and children. We highlight Journal publications from 2004, along with recent key publications from other medical journals, to provide a perspective on the rapidly developing areas of genetics, including pharmacogenetics, respiratory infection, biomarker measurements, and asthma pharmacotherapy. This new understanding of the pathogenesis of asthma combined with clinical applications of genetics and biomarkers should lead to new management strategies. Asthma management is likely to change in the coming years from a strategy directed to the best outcome in groups of patients to an individualized approach to assessment and management. Last year's review on adult and pediatric asthma highlighted reports related to asthma genetics, the importance of upper airway management, the costs of asthma, and the importance of early recognition and intervention. This year we will organize our discussion to review recent reports related to the origins and persistence of asthma in both adults and children. We highlight Journal publications from 2004, along with recent key publications from other medical journals, to provide a perspective on the rapidly developing areas of genetics, including pharmacogenetics, respiratory infection, biomarker measurements, and asthma pharmacotherapy. This new understanding of the pathogenesis of asthma combined with clinical applications of genetics and biomarkers should lead to new management strategies. Asthma management is likely to change in the coming years from a strategy directed to the best outcome in groups of patients to an individualized approach to assessment and management. In last year's review we highlighted reports related to asthma genetics, the need to control upper airways symptoms for asthma management, the pharmacoeconomics of asthma, and early recognition and intervention.1Apter A.J. Szefler S.J. Advances in adult and pediatric asthma.J Allergy Clin Immunol. 2004; 113: 407-414Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar A National Heart, Lung, and Blood Institute Working Group recently identified priorities for asthma research, including immunology, asthma exacerbations, airway remodeling, genetics, therapeutics, and vascular features of asthma.2Busse W. Banks-Schegel S. Noel P. Ortega H. Taggart V. Elias J. Future research directions in asthma. An NHLBI Working Group Report.Am J Respir Crit Care Med. 2004; 170: 683-690Crossref PubMed Scopus (66) Google Scholar, 3Lazaar A.L. Panettieri R.A. Is airway remodeling clinically relevant in asthma?.Am J Med. 2003; 115: 652-659Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar This year's review will focus on the origins and persistence of asthma as 2 broad categories of asthma pathogenesis (Fig 1).Impact of asthmaThe international variations in the severity, control, and management of asthma were reported on by Rabe et al.4Rabe K.F. Adachi M. Lai C.K.W. Soriano J.B. Vermeire P.A. Weiss K.B. et al.Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys.J Allergy Clin Immunol. 2004; 114: 40-47Abstract Full Text Full Text PDF PubMed Scopus (780) Google Scholar A substantial effect of asthma on loss of schooldays and workdays, a significant proportion of patients that continue to have symptoms and lifestyle restrictions, a high proportion of adults as current smokers, low use of preventive therapy (including those used in patients with severe asthma), and low use of objective lung function testing are noted worldwide.Vargas et al5Vargas P.A. Simpson P.M. Wheeler J.G. Goel R. Field C.R. Tilford J.M. et al.Characteristics of children with asthma who are enrolled in a Head Start program.J Allergy Clin Immunol. 2004; 114: 499-504Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar evaluated the characteristics of children at risk for asthma in a Head Start program. These young children with asthma had significant environmental tobacco smoke exposure, were highly atopic and symptomatic, and did not receive appropriate medication treatment. Becker et al6Becker J.M. Rogers J. Rossini G. Mirchandami H. D'Alonzo G.E. Asthma deaths during sports: report of a 7-year experience.J Allergy Clin Immunol. 2004; 113: 264-267Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar focused on asthma deaths in competitive athletes. Those who had fatal asthma exacerbations were usually white males between the ages of 10 and 20 years with mild intermittent or persistent asthma by history. Fatal asthma exacerbations occurred in both competitive and recreational athletes and could be precipitated by a sporting activity.Origins of asthmaExploration of genetic origins is leading to a better understanding of phenotypic variation, which in turn might yield a more individualized approach for medication selection. Openshaw et al7Openshaw P. Yamaguchi Y. Trgoning J. Perspectives in asthma: childhood infections, the developing immune system and the origins of asthma.J Allergy Clin Immunol. 2004; 114: 1275-1277Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar recently categorized the influences on asthma origins as genetic, environmental, and age-related or developmental.GeneticsThe genetic influences on asthma are described in several recent reviews.8Cookson W. Moffatt M. Making sense of the asthma genes.N Engl J Med. 2004; 351: 1794-1796Crossref PubMed Scopus (44) Google Scholar, 9Vercelli D. Genetics, epigenetics, and the environment: switching, buffering, releasing.J Allergy Clin Immunol. 2004; 113: 381-386Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Our discussion addresses pharmacogenetics and gene-environmental interactions.PharmacogeneticsPharmacogenetics examines genetic variability of response to medications, such as glucocorticoids. Matthews et al10Matthews J.G. Ito K. Barnes P.J. Adcock I.M. Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients.J Allergy Clin Immunol. 2004; 113: 1100-1108Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar hypothesized that one mechanism for glucocorticoid resistance is failure of the glucocorticoid receptor to translocate into the nucleus and promote histone acetylation. They found a reduced ability of PBMCs to suppress TNF-α–induced GM-CSF, an activity mediated by histone acetyltransferase, in steroid-dependent and steroid-resistant patients compared with that seen in glucocorticoid-sensitive patients. PBMCs from steroid-dependent and steroid-resistant patients had decreased translocation of the glucocorticoid receptor to the nucleus and reduced histone acetylation. Other mechanisms have previously been reported,11Adcock I.M. Lane S.J. Corticosteroid-insensitive asthma: molecular mechanisms.J Endocrinol. 2003; 178: 347-355Crossref PubMed Scopus (167) Google Scholar, 12Leung D.Y. Hamid Q. Vottero A. Szefler S.J. Surs W. Minshall E. et al.Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta.J Exp Med. 1997; 186: 1567-1574Crossref PubMed Scopus (385) Google Scholar and together this research supports the idea that genetics will lead to individualized approaches to patient care in the future.Szczeklik et al13Szczeklik W. Sanak M. Szczeklik A. Functional effects and gender association of COX-2 gene polymorphism G-765C in bronchial asthma.J Allergy Clin Immunol. 2004; 114: 248-253Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar questioned whether polymorphisms of the promoter of the COX2 gene affect binding of gene transcription factors and clinical relevance. Homozygotes for this allelic variant were more likely to be female and more likely to have increased production of 2 prostaglandins and more severe asthma in aspirin-intolerant asthma.One of the most fascinating reports on pharmacogenetics comes from the National Heart, Lung, and Blood Institute Asthma Clinical Research Network.14Israel E. Chinchilli V.M. Ford J.G. Boushey H.A. Cherniak R. Craig T.J. et al.Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomized, placebo-controlled cross-over trial.Lancet. 2004; 364: 1505-1512Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar In a prospective, randomized, double-blind, cross-over study of adults with mild asthma, they compared regularly scheduled albuterol in 2 sets of homozygotes for a functional polymorphism of the β2-adrenergic receptor. Patients homozygous for an arginine at the 16th amino acid position of the receptor had lower morning peak expiratory flow rates during treatment with regularly scheduled albuterol, with a genotype-attributable treatment difference of 24 L/min (95% CI, −37 to −12). Thus avoiding albuterol might be appropriate for patients with the Arg/Arg genotype. These reports also point to the challenge of understanding the association between gene variability and phenotype in complex diseases like asthma.Study design in genetics researchThe study of genetic susceptibility and gene-environment interactions on the development of asthma is a major area of research. Two general approaches are used: genome-wide screens and candidate gene studies.15Hoffjan S. Nicolae D. Ober C. Association studies for asthma and atopic diseases: a comprehensive review of the literature.Respir Res. 2003; 4: 14-25Crossref PubMed Scopus (165) Google Scholar, 16Hoffjan S. Ober C. Present status on the genetic studies of asthma.Curr Opin Immunol. 2002; 14: 709-717Crossref PubMed Scopus (126) Google Scholar Genome-wide screens can be used to discover genetic markers in families associated with a clinical phenotype like asthma. The screen identifies a region, and finer mapping (positional cloning) is used to recognize variations in individual genes associated with a disease phenotype. Another approach starts by considering candidate genes, genes whose functions are known and related to asthma pathophysiology, and seeks polymorphisms within these genes. Case-control designs compare individuals with the disease phenotype with individuals without this phenotype.Genetic susceptibilityAsthma susceptibility gene research provides clues to the underlying pathobiology of asthma.17Raby B.A. Silverman E.K. Kwiatkowski D.J. Lange C. Lazarus R. Weiss S.T. ADAM33 polymorphisms and phenotype associations in childhood asthma.J Allergy Clin Immunol. 2004; 113: 1071-1078Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 18Leung T.F. Tang N.L. Li C.Y. Lam C.W. Wong G.W. Fok T.F. Association between TARC C-431T and atopy and asthma in children.J Allergy Clin Immunol. 2004; 114: 199-202Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 19Oguma T. Palmer L.J. Birben E. Sonna L.A. Asano K. Lilly C.M. Role of prostanoid DP receptor variants in susceptibility to asthma.N Engl J Med. 2004; 351: 1752-1763Crossref PubMed Scopus (127) Google Scholar, 20Heinzmann A. Ahlert I. Kurz T. Berner R. Deichmann K.A. Association study suggests opposite effects of polymorphisms within IL8 on bronchial asthma and respiratory syncytial virus bronchiolitis.J Allergy Clin Immunol. 2004; 114: 671-676Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Raby et al17Raby B.A. Silverman E.K. Kwiatkowski D.J. Lange C. Lazarus R. Weiss S.T. ADAM33 polymorphisms and phenotype associations in childhood asthma.J Allergy Clin Immunol. 2004; 113: 1071-1078Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar conducted a family-based association study of ADAM33 polymorphisms. ADAM33 might play a role in airway remodeling in asthma that is resistant to corticosteroids.21Apter A.J. Clinical advances in adult asthma.J Allergy Clin Immunol. 2003; 111: S780-S784Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 22Howard T.D. Postma D.S. Jongepier H. Moore W.C. Koppelman G.H. Zheng S.L. et al.Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations.J Allergy Clin Immunol. 2003; 112: 717-722Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar Raby et al17Raby B.A. Silverman E.K. Kwiatkowski D.J. Lange C. Lazarus R. Weiss S.T. ADAM33 polymorphisms and phenotype associations in childhood asthma.J Allergy Clin Immunol. 2004; 113: 1071-1078Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar found no single nucleotide polymorphism association with asthma. They indicated that previous conflicting reports could have used a population that was either too selective, the association could have occurred by chance, or the true asthma susceptibility locus could be near but not at the ADAM33 location.Hoffjan et al23Hoffjan S. Ostrovnaja I. Nicolae D. Newman D.L. Nicolae R. Gangnon R. et al.Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy.J Allergy Clin Immunol. 2004; 113: 511-518Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar studied wheezing infants with respiratory tract infections and the development of asthma and allergy. Genetic variations in cytokine response profiles (IL-5, IL-10, IL-13, and IFN-γ) and atopic phenotypes were determined prospectively. A polymorphism of the β chain of the high-affinity IgE receptor (FCER1B 237Gly) and a polymorphism of nitric oxide synthase (NOS2A) were each associated with reduced IL-13 responses in cord blood; individuals having both polymorphisms had the lowest levels of IL-13 in cord blood. The IL13 (IL13 110Gln) allele was associated with increased IgE levels at year 1. An allelic variant of colony-stimulating factor was associated with a greater increase in IL-5 response in the first year.Environmental influencesGene-environment interactions influence the pathogenesis of complex diseases like asthma. Gene expression might be different in microenvironments (cellular) and macroenvironments and might change as environments evolve.9Vercelli D. Genetics, epigenetics, and the environment: switching, buffering, releasing.J Allergy Clin Immunol. 2004; 113: 381-386Abstract Full Text Full Text PDF PubMed Scopus (145) Google ScholarExposures to bacteria and other microorganismsEder et al24Eder W. Klimecki W. Yu L. von Mutius E. Riedler J. Braun-Fahrlander C. et al.Toll-like receptor 2 as a major gene for asthma in children of European farmers.J Allergy Clin Immunol. 2004; 113: 482-488Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar examined the genetic basis for the decreased prevalence of asthma in children raised on animal farms by examining single nucleotide polymorphisms of 2 toll-like receptor genes. Toll-like receptors are mediators of the innate immune system located on antigen-presenting cells and epithelial cells that bind to endotoxin and components of microorganisms prevalent on animal farms. The researchers hypothesized that children on farms have polymorphisms of receptors for these molecules that protect against asthma. They found that farmers' children carrying a polymorphism of TLR2 were less likely to have asthma. No association was found among children from the same rural communities who did not live on farms. Questions to be addressed in further studies include whether nonfarmer parents were less likely to be atopic and whether other characteristics might affect asthma development, such as stress.25Wright R.J. Finn P. Contreras J.P. Cohen S. Wright R.O. Staudenmayer J. et al.Chronic caregiver stress and IgE expression, allergen-induced proliferation, and cytokine profiles in a birth cohort predisposed to atopy.J Allergy Clin Immunol. 2004; 113: 1051-1057Abstract Full Text Full Text PDF PubMed Scopus (210) Google ScholarFageras Bottcher et al26Fageras Bottcher M. Hmani-Aifa M. Lindstrom A. Jenmalm M.C. Mai X.M. Nilsson L. et al.A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children.J Allergy Clin Immunol. 2004; 114: 561-567Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar examined polymorphisms of receptors for bacterial components, TLR4 and CD14, for the association between polymorphisms of TLR4 and CD14 and asthma and allergic rhinitis. They reported lower LPS-induced IL-12 and IL-10 responses associated with a TLR4 polymorphism and independently with asthma. However, there was no association with skin test reactivity or with other atopic diseases. These results conflict with those of Raby et al.27Raby B.A. Klimecki W.T. Laprise C. Renaud Y. Faith J. Lemire M. et al.Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes.Am J Respir Crit Care Med. 2002; 166: 1449-1456Crossref PubMed Scopus (151) Google Scholar Bottcher et al26Fageras Bottcher M. Hmani-Aifa M. Lindstrom A. Jenmalm M.C. Mai X.M. Nilsson L. et al.A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children.J Allergy Clin Immunol. 2004; 114: 561-567Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar also assessed an association of CD14/−159, a polymorphism of the promoter region of the CD14 gene, with the development of atopic symptoms. This polymorphism is associated with low levels of total serum IgE in children28Baldini M. Lohman I.C. Halonen M. Erickson R.P. Holt P.G. Martinez F.D. A polymorphism in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E.Am J Respir Cell Mol Biol. 1999; 20: 976-983Crossref PubMed Scopus (772) Google Scholar, 29Koppelman G.H. Stine O.C. Xu J. Howard T.D. Zheng S.L. Kauffman H.F. et al.Genome-wide search for atopy susceptibility genes in Dutch families with asthma.J Allergy Clin Immunol. 2002; 109: 498-506Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar and low levels of total serum IgE, decreased self-reported hay fever, and allergic rhinitis in adults. Bottcher et al could not find such an association. However, gene-environment interactions are “extremely plastic,” varying over time, environmental exposure, and location at which the gene is expressed, and could explain conflicting reports.9Vercelli D. Genetics, epigenetics, and the environment: switching, buffering, releasing.J Allergy Clin Immunol. 2004; 113: 381-386Abstract Full Text Full Text PDF PubMed Scopus (145) Google ScholarPsychosocial exposuresGenetic susceptibility studies must consider other environmental influences on the development of asthma (eg, socioeconomic and psychologic stress). Wright et al25Wright R.J. Finn P. Contreras J.P. Cohen S. Wright R.O. Staudenmayer J. et al.Chronic caregiver stress and IgE expression, allergen-induced proliferation, and cytokine profiles in a birth cohort predisposed to atopy.J Allergy Clin Immunol. 2004; 113: 1051-1057Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar explored the association of caregiver stress with markers of the immune response in the first 2 to 3 months of a child's life. The PBMCs of these children, predisposed to atopy or asthma, had increased total IgE levels and an enhanced allergen-specific proliferative response when stimulated with mite and cockroach antigen. Higher levels of caretaker stress were associated with increased TNF-α levels and reduced IFN-γ levels in stimulated PBMCs. Stress and poor socioeconomic conditions could lead to poorer health.Viral infectionViral infection is thought to contribute to the development of asthma.7Openshaw P. Yamaguchi Y. Trgoning J. Perspectives in asthma: childhood infections, the developing immune system and the origins of asthma.J Allergy Clin Immunol. 2004; 114: 1275-1277Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 30Heymann P.W. Carper H.T. Murphy D.D. Platts-Mills T.A. Patrie J. McLaughlin A.P. et al.Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing.J Allergy Clin Immunol. 2004; 114: 239-247Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 31Camara A.A. Silva J.M. Ferriani V.P. Tobias K.R. Macedo I.S. Padovani M.A. et al.Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.J Allergy Clin Immunol. 2004; 113: 551-557Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 32de Marco R. Pattaro C. Locatelli F. Svanes C. Influence of early life exposures on incidence and remission of asthma throughout life.J Allergy Clin Immunol. 2004; 113: 845-852Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 33Gern J.E. Reardon C.L. Hoffjan S. Nicolae D. Li Z. Roberg K.A. et al.Effects of dog ownership and genotype on immune development and atopy in infancy.J Allergy Clin Immunol. 2004; 113: 307-314Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 34Lemanske R.F. Viral infections and asthma inception.J Allergy Clin Immunol. 2004; 114: 1023-1026Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 35Gern J.E. Viral respiratory infection and the link to asthma.Pediatr Infect Dis J. 2004; 23: S78-S86Crossref PubMed Scopus (70) Google Scholar Heymann et al30Heymann P.W. Carper H.T. Murphy D.D. Platts-Mills T.A. Patrie J. McLaughlin A.P. et al.Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing.J Allergy Clin Immunol. 2004; 114: 239-247Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar compared, in a case-control study, 113 children aged 2 months to 18 years admitted for wheezing with 113 nonwheezing control subjects. Wheezing children less than 3 years of age tended to be admitted between December and March. Respiratory syncytial virus (RSV) was the predominant pathogen. Children older than 3 years tended to be hospitalized between September and November and to have evidence of atopy compared with control subjects.Camara et al31Camara A.A. Silva J.M. Ferriani V.P. Tobias K.R. Macedo I.S. Padovani M.A. et al.Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.J Allergy Clin Immunol. 2004; 113: 551-557Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar studied 132 wheezing children from Brazil from birth to 12 years of age in a case-control study. In children younger than 2 years of age, RSV and family history of allergy were independently associated with wheezing. Interestingly, the RSV infections tended to occur in late summer and early to mid-autumn. Among children 2 to 12 years of age, they found allergy, as measured on the basis of positive serum levels of specific IgE, was the most important risk factor for wheezing. Rhinovirus infection was not associated with wheezing.De Marco et al32de Marco R. Pattaro C. Locatelli F. Svanes C. Influence of early life exposures on incidence and remission of asthma throughout life.J Allergy Clin Immunol. 2004; 113: 845-852Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar conducted a retrospective study of 18,156 European asthmatic subjects aged 0 to 44 years. They found a family history of asthma or allergy and the occurrence of respiratory tract infections independently associated with a higher risk of asthma development. An atopic family history predicted a lower chance of remission throughout life. Wheezing associated with viral infection might be due to a combination of host (eg, atopy) and environmental (eg, rhinovirus) interactions with abnormal immune responses.35Gern J.E. Viral respiratory infection and the link to asthma.Pediatr Infect Dis J. 2004; 23: S78-S86Crossref PubMed Scopus (70) Google ScholarOrigins of asthma: Atopic disordersThe concept of atopic march suggests a progressive development of atopic diseases from infancy, beginning with atopic dermatitis and food allergy and progressing to allergic rhinitis and asthma.36Spergel J.M. Paller A.S. Atopic dermatitis and the atopic march.J Allergy Clin Immunol. 2003; 112: S118-S127Abstract Full Text Full Text PDF PubMed Scopus (873) Google Scholar Both Camara et al31Camara A.A. Silva J.M. Ferriani V.P. Tobias K.R. Macedo I.S. Padovani M.A. et al.Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.J Allergy Clin Immunol. 2004; 113: 551-557Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar and Heymann et al30Heymann P.W. Carper H.T. Murphy D.D. Platts-Mills T.A. Patrie J. McLaughlin A.P. et al.Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing.J Allergy Clin Immunol. 2004; 114: 239-247Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar found allergy to be a significant risk factor in children older than 2 or 3 years. In a prospective population-based cohort study from Germany, Illi et al37Illi S. von Mutius E. Lau S. Nickel R. Gruber C. Niggemann B. et al.The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.J Allergy Clin Immunol. 2004; 113: 925-931Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar found that atopic dermatitis in infancy is associated with asthma at school age.38Martinez F.D. Wright A.L. Taussig L.M. Holberg C.J. Halonen M. Morgan W.J. Asthma and wheezing in the first six years of life. The Group Health Medical Associates.N Engl J Med. 1995; 332: 133-138Crossref PubMed Scopus (3251) Google Scholar They reported that the onset of wheezing tended to occur before or at the onset of atopic dermatitis.37Illi S. von Mutius E. Lau S. Nickel R. Gruber C. Niggemann B. et al.The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.J Allergy Clin Immunol. 2004; 113: 925-931Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar Guilbert et al39Guilbert T. Morgan W.J. Zeiger R.S. Bacharier L.B. Boehmer S.J. Krawlac M. et al.Atopic characteristics of children with recurrent wheezing at high-risk for the development of childhood asthma.J Allergy Clin Immunol. 2004; 114: 1282-1287Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar examined the atopic profile of 285 children between 2 and 3 years of age with frequent wheeze and a parental history of asthma or a personal history of atopic dermatitis. They found that 61% were sensitized to food allergens or aeroallergens, suggesting sensitization at a young age.37Illi S. von Mutius E. Lau S. Nickel R. Gruber C. Niggemann B. et al.The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.J Allergy Clin Immunol. 2004; 113: 925-931Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 39Guilbert T. Morgan W.J. Zeiger R.S. Bacharier L.B. Boehmer S.J. Krawlac M. et al.Atopic characteristics of children with recurrent wheezing at high-risk for the development of childhood asthma.J Allergy Clin Immunol. 2004; 114: 1282-1287Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar These studies do not examine the relationship of exposure to sensitization or sensitization to symptoms after allergen exposure. Although these and other studies collectively do not support an atopic march,40Alford S.H. Zoratti E. Peterson E.L. Maliarik M. Ownby D.R. Johnson C.C. Parental history of atopic disease: disease pattern and risk of pediatric atopy in offspring.J Allergy Clin Immunol. 2004; 114: 1046-1050Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 41Miranda C. Busacker A. Balzar S. Trudeau J. Wenzel S.E. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation.J Allergy Clin Immunol. 2004; 113: 101-108Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 42de Blic J. Tillie-Leblond I. Tonnel A.B. Jaubert F. Scheinmann P. Gosset P. Difficult asthma in children: an analysis of airway inflammation.J Allergy Clin Immunol. 2004; 113: 94-100Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar they do suggest that the maturity of the immune system at the time of gene-environment interaction influences the development of asthma.Developmental influences on prevention and courseWith respect to primary prevention, Johnson et al,43Cole Johnson C. Ownby D.R. Havstad S.L. Peterson E.L. Family history, dust mite exposure in early childhood, and risk for pediatric atopy and asthma.J Allergy Clin Immunol. 2004; 114: 105-110Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar in a birth cohort, found increased dust mite exposure during infancy was associated with a higher risk for sensitization if parents were atopic but had no protective effect among children whose parents were not atopic. Becker et al44Becker A. Watson W. Ferguson A. Dimich-Ward H. Chan-Yeung M. The Canadian asthma primary prevention study: outcomes at 2 years of age.J Allergy Clin Immunol. 2004; 113: 650-656Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar conducted a randomized trial in 545 high-risk infants to reduce house dust mite, pet, and environmental tobacco smoke exposure. Breast-feeding was encouraged. Those in the intervention group were less likely than control infants to have asthma by the age of 2 years. Kull et al45Kull I. Almqvist C. Lilja G. Pershagen G. Wickman M. Breast-feeding reduces the risk of asthma during the first 4 years of life.J Allergy Clin Immunol. 2004; 114: 755-760Abstract
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