Natural history of asthma: Persistence versus progression—does the beginning predict the end?
2008; Elsevier BV; Volume: 121; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2008.01.006
ISSN1097-6825
AutoresReynold A. Panettieri, Ronina Covar, Evalyn N. Grant, Elizabeth V. Hillyer, Leonard B. Bacharier,
Tópico(s)Chronic Obstructive Pulmonary Disease (COPD) Research
ResumoEnvironmental exposures during the early years and airway obstruction that develops during this time, in conjunction with genetic susceptibility, are important factors in the development of persistent asthma in childhood. Established risk factors for childhood asthma include frequent wheezing during the first 3 years, a parental history of asthma, a history of eczema, allergic rhinitis, wheezing apart from colds, and peripheral blood eosinophilia, as well as allergic sensitization to aeroallergens and certain foods. Risk factors for the development of asthma in adulthood remain ill defined. Moreover, reasons for variability in the clinical course of asthma—persistence in some individuals and progression in others—remain an enigma. The distinction between disease persistence and disease progression suggests that these are different entities or phenotypes. There is currently no consensus on whether disease progression requires either airway inflammation or airway remodeling or the combination of the two. For patients with irreversible airway obstruction, inflammation might, in part, be necessary but perhaps not entirely sufficient to induce the irreversible component, some of which could be attributed to alterations in the structure of the bronchial wall. Intervening with intermittent or daily inhaled corticosteroids in high-risk infants and children does not prevent disease progression or impaired lung growth. These findings, however, might not apply to adults, and further study in adults is needed to determine the effect of inhaled corticosteroid therapy on disease progression. Environmental exposures during the early years and airway obstruction that develops during this time, in conjunction with genetic susceptibility, are important factors in the development of persistent asthma in childhood. Established risk factors for childhood asthma include frequent wheezing during the first 3 years, a parental history of asthma, a history of eczema, allergic rhinitis, wheezing apart from colds, and peripheral blood eosinophilia, as well as allergic sensitization to aeroallergens and certain foods. Risk factors for the development of asthma in adulthood remain ill defined. Moreover, reasons for variability in the clinical course of asthma—persistence in some individuals and progression in others—remain an enigma. The distinction between disease persistence and disease progression suggests that these are different entities or phenotypes. There is currently no consensus on whether disease progression requires either airway inflammation or airway remodeling or the combination of the two. For patients with irreversible airway obstruction, inflammation might, in part, be necessary but perhaps not entirely sufficient to induce the irreversible component, some of which could be attributed to alterations in the structure of the bronchial wall. Intervening with intermittent or daily inhaled corticosteroids in high-risk infants and children does not prevent disease progression or impaired lung growth. These findings, however, might not apply to adults, and further study in adults is needed to determine the effect of inhaled corticosteroid therapy on disease progression. Asthma is a multifactorial heterogeneous disorder, in essence a syndrome comprising different phenotypes that manifest similarly with cough, wheeze, shortness of breath, and chest tightness. Once considered to be simply a manifestation of intermittent bronchospasm and hypersecretion, the episodic symptoms of asthma are now known to occur on a background of persistent airway inflammation and airway remodeling.1Bousquet J. Jeffery P.K. Busse W.W. Johnson M. Vignola A.M. Asthma. From bronchoconstriction to airways inflammation and remodeling.Am J Respir Crit Care Med. 2000; 161: 1720-1745Crossref PubMed Scopus (1582) Google Scholar The patterns of inflammation and remodeling vary among individuals. Similarly, the clinical course of asthma varies substantially among individuals and is often quite unpredictable. Reasons for the variability in the clinical course of asthma—persistence in some individuals and progression in others—remain an enigma. Moreover, the temporal course and causes of chronic airway inflammation and remodeling, as well as the interplay between these key histopathologic changes in asthma, are poorly defined. This review will summarize our current understanding of wheezing disorders in infancy and childhood, the factors determining asthma development, the causes of asthma persistence and progression, the roles of inflammation and airway remodeling in disease progression, and the therapeutic implications of current knowledge. Unanswered questions and fertile areas for future research are identified. Community-based longitudinal studies examining outcomes for early wheezers have provided insights into the development of asthma.2Phelan P.D. Robertson C.F. Olinsky A. The Melbourne Asthma Study: 1964-1999.J Allergy Clin Immunol. 2002; 109: 189-194Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, 3Martinez 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 (3344) Google Scholar, 4Taussig L.M. Wright A.L. Holberg C.J. Halonen M. Morgan W.J. Martinez F.D. Tucson Children's Respiratory Study: 1980 to present.J Allergy Clin Immunol. 2003; 111: 661-675Abstract Full Text Full Text PDF PubMed Scopus (538) Google Scholar, 5Sears M.R. Greene J.M. Willan A.R. Wiecek E.M. Taylor D.R. Flannery E.M. et al.A longitudinal, population-based, cohort study of childhood asthma followed to adulthood.N Engl J Med. 2003; 349: 1414-1422Crossref PubMed Scopus (1063) Google Scholar, 6Croner S. Kjellman N.I. Natural history of bronchial asthma in childhood. A prospective study from birth up to 12-14 years of age.Allergy. 1992; 47: 150-157Crossref PubMed Scopus (129) Google Scholar, 7Illi S. von Mutius E. Lau S. Niggemann B. Gruber C. Wahn U. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study.Lancet. 2006; 368: 763-770Abstract Full Text Full Text PDF PubMed Scopus (613) Google Scholar Although these study results differ to a certain extent, possibly because of different study populations and measured parameters, some general patterns have emerged. Many children experience 1 or more wheezing episodes before the age of 3 years, often in association with a respiratory virus.8Singh A.M. Moore P.E. Gern J.E. Lemanske Jr., R.F. Hartert T.V. Bronchiolitis to asthma: a review and call for studies of gene-virus interactions in asthma causation.Am J Respir Crit Care Med. 2007; 175: 108-119Crossref PubMed Scopus (179) Google Scholar, 9Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (604) Google Scholar Some have asthma, but the majority do not. For example, in the Tucson Children's Respiratory Study, a longitudinal birth cohort study, the prevalence of wheezing with lower respiratory tract illness was 32%, 17%, and 12% in the first, second, and third years of life, respectively.4Taussig L.M. Wright A.L. Holberg C.J. Halonen M. Morgan W.J. Martinez F.D. Tucson Children's Respiratory Study: 1980 to present.J Allergy Clin Immunol. 2003; 111: 661-675Abstract Full Text Full Text PDF PubMed Scopus (538) Google Scholar Overall, one third of children had at least 1 respiratory tract illness with wheezing before the age of 3 years; 60% of these children were no longer wheezing at age 6 years.3Martinez 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 (3344) Google Scholar Four groups of children were identified at the age of 6 years (n = 826), as follows: (1) never wheezed (52%); (2) 1 or more respiratory tract illnesses with wheezing before the age of 3 years but no wheezing at age 6 years (transient wheezers, 20%); (3) no wheezing before the age of 3 years but wheezing at age 6 years (late-onset wheezers, 15%); and (4) wheezing both before age 3 years and at age 6 years (persistent wheezers, 14%).3Martinez 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 (3344) Google Scholar The persistent wheezers were more likely than other children to have mothers with asthma, increased serum IgE levels both in their first year and at age 6 years, and normal lung function in their first year but diminished function at age 6 years. By contrast, the transient wheezers were more likely to have mothers who smoked but not mothers with asthma; transient wheezers had diminished airway function both before age 1 year and at age 6 years and did not have increased serum IgE levels or skin test reactivity. The patterns of wheezing prevalence and lung function did not change significantly among these children from age 6 to 16 years.10Morgan W.J. Stern D.A. Sherrill D.L. Guerra S. Holberg C.J. Guilbert T.W. et al.Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence.Am J Respir Crit Care Med. 2005; 172: 1253-1258Crossref PubMed Scopus (550) Google Scholar Children enrolled in a birth cohort in Manchester, England, were similarly classified by parentally reported wheezing history before age 3 years and by age 5 years (n = 463) into 4 groups of never wheezers (54%), transient early wheezers (25%), late-onset wheezers (5%), and persistent wheezers (17%).11Lowe L.A. Simpson A. Woodcock A. Morris J. Murray C.S. Custovic A. Wheeze phenotypes and lung function in preschool children.Am J Respir Crit Care Med. 2005; 171: 231-237Crossref PubMed Scopus (180) Google Scholar For those who had wheezed before age 3 years (persistent and transient early wheezers), poor lung function (assessed by specific airway resistance) at age 3 years predicted the persistence of wheezing at age 5 years. In a multivariate model the 2 independent predictors of persistent wheezing were increased airway resistance and allergic sensitization at age 3 years. By comparison, for children who had not wheezed before age 3 years (never wheezers and late-onset wheezers), neither lung function nor allergic sensitization predicted subsequent symptoms at age 3 years.11Lowe L.A. Simpson A. Woodcock A. Morris J. Murray C.S. Custovic A. Wheeze phenotypes and lung function in preschool children.Am J Respir Crit Care Med. 2005; 171: 231-237Crossref PubMed Scopus (180) Google Scholar The German Multicentre Allergy Study assessed the role of early-life allergic sensitization and exposure to perennial allergens (house dust mite and dog and cat hair) in a cohort of 1314 children followed from birth to age 13 years.7Illi S. von Mutius E. Lau S. Niggemann B. Gruber C. Wahn U. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study.Lancet. 2006; 368: 763-770Abstract Full Text Full Text PDF PubMed Scopus (613) Google Scholar Symptoms resolved for most (90%) of the children who were repeated wheezers at 5, 6, or 7 years but who did not have atopy (specific IgE, <0.35 kU/L); importantly, these children retained normal lung function at puberty. Instead, those children who wheezed and also had atopy during the first 3 years of life showed loss of lung function at age 7 years. Lung function results were especially poor at ages 7 and 13 years for those with atopy and exposure to high levels of perennial allergens early in life.7Illi S. von Mutius E. Lau S. Niggemann B. Gruber C. Wahn U. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study.Lancet. 2006; 368: 763-770Abstract Full Text Full Text PDF PubMed Scopus (613) Google Scholar In the longitudinal studies in New Zealand and Melbourne, lung function deficits were evident in children with asthma by 9 to 10 years of age and persisted into adulthood.2Phelan P.D. Robertson C.F. Olinsky A. The Melbourne Asthma Study: 1964-1999.J Allergy Clin Immunol. 2002; 109: 189-194Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, 5Sears M.R. Greene J.M. Willan A.R. Wiecek E.M. Taylor D.R. Flannery E.M. et al.A longitudinal, population-based, cohort study of childhood asthma followed to adulthood.N Engl J Med. 2003; 349: 1414-1422Crossref PubMed Scopus (1063) Google Scholar The New Zealand birth cohort study followed more than 1000 children from age 9 years to age 26 years and examined persistence, remission, and relapse of wheezing.5Sears M.R. Greene J.M. Willan A.R. Wiecek E.M. Taylor D.R. Flannery E.M. et al.A longitudinal, population-based, cohort study of childhood asthma followed to adulthood.N Engl J Med. 2003; 349: 1414-1422Crossref PubMed Scopus (1063) Google Scholar At the age of 26 years, among the 613 subjects with complete data, those with persistent or relapsing wheezing (27%) had a higher prevalence of sensitivity to house dust mite and cat allergen and of airway hyperresponsiveness, as well as lower lung function measurements than those whose wheezing did not persist or relapse (46%). In addition, those with persistent wheezing had lower lung function at each assessment relative to those without persistent wheezing.5Sears M.R. Greene J.M. Willan A.R. Wiecek E.M. Taylor D.R. Flannery E.M. et al.A longitudinal, population-based, cohort study of childhood asthma followed to adulthood.N Engl J Med. 2003; 349: 1414-1422Crossref PubMed Scopus (1063) Google Scholar The Melbourne Asthma Study prospectively followed, from ages 7 to 42 years, a randomly selected cohort of 479 children born in 1957 who had a past history of wheezing.2Phelan P.D. Robertson C.F. Olinsky A. The Melbourne Asthma Study: 1964-1999.J Allergy Clin Immunol. 2002; 109: 189-194Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, 12Horak E. Lanigan A. Roberts M. Welsh L. Wilson J. 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Bowes G. et al.Childhood asthma and lung function in mid-adult life.Pediatr Pulmonol. 1997; 23: 14-20Crossref PubMed Scopus (197) Google Scholar Loss of lung function was evident by age 14 years among children with severe asthma but did not progress with time (Fig 1).2Phelan P.D. Robertson C.F. Olinsky A. The Melbourne Asthma Study: 1964-1999.J Allergy Clin Immunol. 2002; 109: 189-194Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar These studies suggest that for children with asthma, environmental exposures and lung function deficits that develop during the early years are important factors in the development of persistent asthma. As noted by Taussig et al,4Taussig L.M. Wright A.L. Holberg C.J. Halonen M. Morgan W.J. Martinez F.D. Tucson Children's Respiratory Study: 1980 to present.J Allergy Clin Immunol. 2003; 111: 661-675Abstract Full Text Full Text PDF PubMed Scopus (538) Google Scholar the fact that serum IgE levels in infancy and not umbilical cord blood IgE levels are associated with later persistent wheezing and asthma3Martinez 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 (3344) Google Scholar suggests that something occurs in the first year of life that either alters or unmasks a child's propensity to respond to allergens. Established risk factors for the development of asthma in childhood include frequent wheezing during the first 3 years, a parental history of asthma, a history of eczema, allergic rhinitis, wheezing apart from colds, and peripheral blood eosinophilia of 4% or greater.14Castro-Rodriguez J.A. Holberg C.J. Wright A.L. Martinez F.D. A clinical index to define risk of asthma in young children with recurrent wheezing.Am J Respir Crit Care Med. 2000; 162: 1403-1406Crossref PubMed Scopus (977) Google Scholar In addition, allergic sensitization to aeroallergens and to certain foods is now recognized as a risk factor.9Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (604) Google Scholar, 15Zeiger R.S. Heller S. The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospective randomized study of combined maternal and infant food allergen avoidance.J Allergy Clin Immunol. 1995; 95: 1179-1190Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 16Kulig M. Bergmann R. Tacke U. Wahn U. Guggenmoos-Holzmann I. 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A clinical index to define risk of asthma in young children with recurrent wheezing.Am J Respir Crit Care Med. 2000; 162: 1403-1406Crossref PubMed Scopus (977) Google Scholar Although the positive predictive value of the API was modest (47.5% for the development of asthma at age 6 years), the negative predictive value was quite high because 91.6% and 84.2% of children with a negative API had not developed asthma by age 6 years and age 13 years, respectively.14Castro-Rodriguez J.A. Holberg C.J. Wright A.L. Martinez F.D. A clinical index to define risk of asthma in young children with recurrent wheezing.Am J Respir Crit Care Med. 2000; 162: 1403-1406Crossref PubMed Scopus (977) Google Scholar This index has been modified to serve as a predictive index for children age 2 years and older (Table I).18Guilbert T.W. Morgan W.J. Zeiger R.S. Bacharier L.B. Boehmer S.J. Krawiec 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 (328) Google Scholar, 19Guilbert T.W. Morgan W.J. Krawiec M. Lemanske Jr., R.F. Sorkness C. Szefler S.J. et al.The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network.Control Clin Trials. 2004; 25: 286-310Abstract Full Text Full Text PDF PubMed Scopus (157) Google ScholarTable IModified Asthma Prediction Index: A clinical index to define asthma risk for children 2 years of age or older, per Guilbert et al,18Guilbert T.W. Morgan W.J. Zeiger R.S. Bacharier L.B. Boehmer S.J. Krawiec 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 (328) Google Scholar versus the original API (Castro-Rodriguez et al14Castro-Rodriguez J.A. Holberg C.J. Wright A.L. Martinez F.D. A clinical index to define risk of asthma in young children with recurrent wheezing.Am J Respir Crit Care Med. 2000; 162: 1403-1406Crossref PubMed Scopus (977) Google Scholar)∗Differences between indices are shown in boldface. A positive mAPI was defined as the child meeting at least 1 major criterion or 2 minor criteria.The child must have a history of ≥4 wheezing episodes with at least 1 physician's diagnosismAPI: Major criteriaOriginal API: major criteria Parental history of asthma Parental history of asthma Physician-diagnosed atopic dermatitis Physician-diagnosed atopic dermatitis Allergic sensitization to ≥1 aeroallergenmAPI: Minor criteriaOriginal API: minor criteria Allergic sensitization to milk, egg, or peanuts Physician-diagnosed allergic rhinitis Wheezing unrelated to colds Wheezing unrelated to colds Blood eosinophils ≥4% Blood eosinophils ≥4%Reprinted with permission from Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB, Boehmer SJ, Krawiec M, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol 2004;114:1282-7.18Guilbert T.W. Morgan W.J. Zeiger R.S. Bacharier L.B. Boehmer S.J. 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