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Early sensitization is associated with reduced lung function from birth into adulthood

2015; Elsevier BV; Volume: 137; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2015.10.030

1097-6825

Louisa Owens, Ingrid A. Laing, Guicheng Zhang, Peter N. Le Souëf,

Chronic Obstructive Pulmonary Disease (COPD) Research

Early sensitization, which develops within the first few years of life, is associated with altered functional and clinical respiratory outcomes in childhood and adolescence.1Illi 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 (597) Google Scholar, 2Simpson A. Tan V.Y. Winn J. Svensen M. Bishop C.M. Heckerman D.E. et al.Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study.Am J Respir Crit Care Med. 2010; 181: 1200-1206Crossref PubMed Scopus (333) Google Scholar, 3Turner S. Fielding S. Mullane D. Cox D.W. Goldblatt J. Landau L. et al.A longitudinal study of lung function from 1 month to 18 years of age.Thorax. 2014; 69: 1015-1020Crossref PubMed Scopus (54) Google Scholar Our group has recently shown that these infants have a lung function deficit from just 1 month of age.3Turner S. Fielding S. Mullane D. Cox D.W. Goldblatt J. Landau L. et al.A longitudinal study of lung function from 1 month to 18 years of age.Thorax. 2014; 69: 1015-1020Crossref PubMed Scopus (54) Google Scholar Early sensitization is also a risk factor for persistent wheeze during childhood.1Illi 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 (597) Google Scholar, 4Kusel 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 (580) Google Scholar However, its influence on lung function and symptoms through to adulthood has not been assessed. Using a longitudinal respiratory and immunologic birth cohort, we assessed the influence of early sensitization on lung function and respiratory outcomes from infancy through to early adulthood. Our hypothesis was that the reduction in lung function seen in this group at an early age would continue through to adulthood and be associated with persistent wheeze. Our cohort, the Perth Infant Asthma follow-up cohort, was recruited antenatally from an urban Australian maternity hospital between 1987 and 1990, as previously described, with no preselection for family history of asthma or atopy.5Young S. Sherrill D.L. Arnott J. Diepeveen D. LeSouef P.N. Landau L.I. Parental factors affecting respiratory function during the first year of life.Pediatr Pulmonol. 2000; 29: 331-340Crossref PubMed Scopus (88) Google Scholar Assessments in infancy at 1, 6, and 12 months of age included infant lung function testing using the rapid thoracoabdominal compression technique; airway responsiveness testing with a histamine challenge; skin prick testing to rye grass pollen, cow's milk, egg white, Dermatophagoides pteronyssinus, and Dermatophagoides farinae; and a respiratory/allergy questionnaire. At 6, 11, 18, and 24 years of age, assessments included spirometry; airway responsiveness testing with a histamine challenge; skin prick testing as in infancy, with the addition of mixed grass, cat pellet, dog dander, cockroach, Alternaria tenuis and Aspergillus fumigatus; and a respiratory/allergy questionnaire. Further details of the methods used in this study can be found in the Methods section in this article's Online Repository at www.jacionline.org. Infant lung function measurement (ie, maximal expiratory flow at functional residual capacity [V'maxFRC]), was adjusted for weight, height, sex, and maternal in utero smoking and is reported as percent predicted.5Young S. Sherrill D.L. Arnott J. Diepeveen D. LeSouef P.N. Landau L.I. Parental factors affecting respiratory function during the first year of life.Pediatr Pulmonol. 2000; 29: 331-340Crossref PubMed Scopus (88) Google Scholar Asthma diagnosis was based on a physician's diagnosis only. For the skin prick tests, the mean of a wheal's largest diameter and its perpendicular were measured at 15 minutes. Atopy was defined as a positive skin prick test response with at least 1 wheal ≥3 mm larger than that elicited by the negative control. Early sensitization was defined as at least 1 positive skin prick test response by 12 months of age. Numbers at each follow-up were 247 at 1 month, 196 at 6 months, 171 at 12 months, 123 at 6 years, 194 at 11 years, 142 at 18 years, and 111 at 24 years. The comparison between those seen and not seen at each assessment can be seen in Table E1 in this article's Online Repository at www.jacionline.org. Early sensitization (19% of the infants) was longitudinally associated with a persistent reduction in lung function from 1 month to 24 years of age when adjusted for in utero smoke exposure (Wald = 9.3, P = .002). The reduction was statistically significant for V'maxFRC at 1 month, FEV1/forced vital capacity (FVC) ratio at 24 years, and both forced expiratory flow at 25% to 75% of forced vital capacity (FEF25-75) and FEV1 at 6 and 24 years of age in cross-sectional analyses (Fig 1). The difference in lung function between the early sensitization and no early sensitization groups did not change significantly from 1 month (V'maxFRC) to 24 years of age (FEF25-75; 0.4 vs 0.671 internal z scores, P = .64). Eczema was present in 46% of infants with early sensitization compared with 21% of those without early sensitization, with an increased odds ratio of 3.1 (P = .018). Airway responsiveness was not associated with early sensitization at any assessment. However, when we adjusted for the effect of airway responsiveness on lung function, early sensitization was only associated with FEF25-75 at age 24 years (B = 12.9; 95% CI, 1.3-24.6; P = .03). Current atopy (a positive skin prick test response at the concurrent assessment) did not correlate with lung function at any age. There was no association between either parental atopy determined based on a positive skin prick test response (V'maxFRC, 113.2% vs 112.9%; P = .98), maternal IgE levels (R = −0.008, P = .93) or infant cord IgE levels (R = −0.04, P = .61) and infant lung function. Early sensitization was associated with a 3-fold increased odds of having a history of physician-diagnosed asthma at age 6 years. This association was not seen at later years. However, there was an association between early sensitization and increased risk of wheeze in the previous 12 months at 18 and 24 years of age. Current atopy had an increased odds of a history of asthma at each assessment. Early sensitization increased the odds of current atopy at 6 years of age only (Table I).Table IEarly sensitization, atopy, and respiratory outcomes at each assessment6 y11 y18 y24 yOR (95% CI)P valueOR (95% CI)P valueOR (95% CI)P valueOR (95% CI)P valueEarly sensitization and asthma3.3 (1.3-8.5).0121.3 (0.5-3.4).542.3 (0.9-6).0972.3 (0.9-5.9).78Early sensitization and wheeze3.1 (0.96-9.9).061.4 (0.5-4.2).542.8 (1.05-7.4)∗Adjusted for current smoking..0395.2 (1.8-15.1)∗Adjusted for current smoking..002Current atopy and asthma2.4 (1.1-5.4).0332 (0.98-3.9).0543.2 (1.4-7.2).0053.4 (1.09-11).039Early sensitization and current atopy3.8 (1.3-11.5).0171.9 (0.8-4.4).141.34 (0.53-5.4).92.0 (0.6-6.6).3Values in boldface indicate statistical significance.OR, Odds ratio.∗ Adjusted for current smoking. Open table in a new tab Values in boldface indicate statistical significance. OR, Odds ratio. A recent article from our cohort found early sensitization was associated with reduced lung function from infancy to adolescence, and we have now shown that this effect extends into adulthood.3Turner S. Fielding S. Mullane D. Cox D.W. Goldblatt J. Landau L. et al.A longitudinal study of lung function from 1 month to 18 years of age.Thorax. 2014; 69: 1015-1020Crossref PubMed Scopus (54) Google Scholar The deficit was consistently maintained throughout childhood, with no significant change over time. This suggests there is an antenatal difference in lung physiology in those with sensitization early in life compared with those who have it later or not at all, but this defect is fixed and does not progress with time. Sensitization, which develops before 3 years of age, is also associated with more persistent wheeze in children than if it develops later, and our study extends this association into adulthood.1Illi 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 (597) Google Scholar, 4Kusel 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 (580) Google Scholar FEF25-75 best correlates with infant V'maxFRC values because they are both measuring flow at low lung volumes.6Mullane D. Turner S.W. Cox D. Goldblatt J. Landau L.I. le Souef P.N. Reduced infant lung function, active smoking, and wheeze in 18-year-old individuals.JAMA Pediatr. 2013; 167: 368-373Crossref PubMed Scopus (32) Google Scholar However FEV1 is the most commonly reported lung function variable reported in patients with asthma and chronic obstructive pulmonary disease. We showed that early sensitization is associated with lower FEV1, FEV1/FVC ratio, and FEF25-75 value at 24 years of age. Given that the diagnosis and severity coding for chronic obstructive pulmonary disease are based on FEV1 and FEV1/FVC ratio, factors associated with a reduction might be considered potential targets for disease prevention or treatment.7Qaseem A. Wilt T.J. Weinberger S.E. Hanania N.A. Criner G. van der Molen T. et al.Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society.Ann Intern Med. 2011; 155: 179-191Crossref PubMed Scopus (818) Google Scholar Infant lung function testing was performed by using the tidal breathing rapid thoracoabdominal compression technique because the raised volume technique was not developed until 1995.8Turner D.J. Stick S.M. Lesouef K.L. Sly P.D. Lesouef P.N. A new technique to generate and assess forced expiration from raised lung volume in infants.Am J Respir Crit Care Med. 1995; 151: 1441-1450Crossref PubMed Scopus (91) Google Scholar The newer method detects significant differences in V'maxFRC values easier than the old tidal method; however, this potentially makes our findings even more clinically relevant. Skin prick test responses in infants can be difficult to interpret because of smaller wheal reactions; however, we kept the same cutoff of 3 mm in infants to reduce the likelihood of false-positive results. Unfortunately, we do not have serum IgE levels or allergen exposure data from infancy, which might have given us further information regarding the link between sensitization and lung function.9Lynch S.V. Wood R.A. Boushey H. Bacharier L.B. Bloomberg G.R. Kattan M. et al.Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children.J Allergy Clin Immunol. 2014; 134: 593-601.e12Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar These study findings extend those in previous studies and show that development of atopy very early in life is associated with measurable differences in lung function and respiratory morbidity from infancy, which persist into adulthood. The early onset of atopy and a lung function reduction suggest an antenatal trigger or cause. Further investigation into the possible causal links between these 2 might provide a target to prevent early sensitization and the associated persistent lung function deficit that begins in infancy. Our cohort, the Perth Infant Asthma follow-up cohort, was recruited antenatally from an urban Australian maternity hospital between June 1987 and November 1990, as previously described.E1Young S. Le Souef P.N. Geelhoed G.C. Stick S.M. Turner K.J. Landau L.I. The influence of a family history of asthma and parental smoking on airway responsiveness in early infancy.N Engl J Med. 1991; 324: 1168-1173Crossref PubMed Scopus (383) Google Scholar Subjects were not selected based on family history of asthma or atopy. Those born at less than 37 weeks' gestation or who had respiratory symptoms before their first assessment at 1 month of age were excluded. All assessments were approved by the Human Ethics Committee of Princess Margaret Hospital for children. Parental consent was obtained for each assessment up to 11 years, and subjects themselves consented for the 18- and 24-year assessments. Parents completed a questionnaire antenatally detailing their history of asthma, atopy, and smoking. Both had a skin prick test at enrollment, and a maternal serum IgE sample was taken. Infants were assessed at 1, 6, and 12 months of age with infant lung function, airway responsiveness, and skin prick testing, as well as a parental questionnaire. At 6, 11, 18, and 24 years of age, subjects completed spirometry, airway responsiveness, and skin prick testing, as well as a respiratory questionnaire. The rapid thoracoabdominal compression technique during tidal breathing was used to determine V′maxFRC while the infants were sedated with chloral hydrate.E2Sly P.D. Tepper R. Henschen M. Gappa M. Stocks J. Tidal forced expirations. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. European Respiratory Society/American Thoracic Society.Eur Respir J. 2000; 16: 741-748Crossref PubMed Scopus (129) Google Scholar The average of 5 acceptable values was recorded. Reported V′maxFRC values are adjusted for maternal smoking during pregnancy, sex, length, and weight, according to a previously described formula.E3Young S. Sherrill D.L. Arnott J. Diepeveen D. LeSouef P.N. Landau L.I. Parental factors affecting respiratory function during the first year of life.Pediatr Pulmonol. 2000; 29: 331-340Crossref PubMed Scopus (101) Google Scholar Airway responsiveness was assessed by using doubling concentrations of nebulized histamine from 0.125 to 8 mg/mL. Testing was discontinued once V′maxFRC values had decreased by 40% or the maximum dose had been administered.E4Stick S.M. Turnbull S. Chua H.L. Landau L.I. Lesouëf P.N. Bronchial responsiveness to histamine in infants and older children.Am Rev Respir Dis. 1990; 142: 1143-1146Crossref PubMed Scopus (20) Google Scholar Spirometry was assessed with a portable spirometer (Pneumocheck Spirometer 6100; Welch-Allyn, Skaneateles Falls, NY).E5Standardization of spirometry, 1994 update. American Thoracic Society.Am J Respir Crit Care Med. 1995; 152: 1107-1136Crossref PubMed Scopus (6340) Google Scholar FEV1, FVC, and FEF25-75 values are reported as percent predicted of the reference standard adjusted for age, sex, and height.E6Knudson R.J. Slatin R.C. Lebowitz M.D. Burrows B. The maximal expiratory flow-volume curve. Normal standards, variability, and effects of age.Am Rev Respir Dis. 1976; 113: 587-600PubMed Google Scholar Bronchodilator was not given before testing. Airway responsiveness was assessed by using a histamine challenge with handheld glass dosimeters and the Yan technique.E7Yan K. Salome C. Woolcock A.J. Rapid method for measurement of bronchial responsiveness.Thorax. 1983; 38: 760-765Crossref PubMed Scopus (611) Google Scholar Increasing histamine concentrations were inhaled until there was a decrease in FEV1 of 20% or the maximum cumulative dose of 7.8 μmol was reached. The dose-response slope was calculated as the percentage decrease in FEV1 divided by the cumulative histamine dose.E8Peat J.K. Salome C.M. Bauman A. Toelle B.G. Wachinger S.L. Woolcock A.J. Repeatability of histamine bronchial challenge and comparability with methacholine bronchial challenge in a population of Australian schoolchildren.Am Rev Respir Dis. 1991; 144: 338-343Crossref PubMed Scopus (42) Google Scholar Skin prick tests for the parents and infants at 1, 6, and 12 months of age included 5 allergens: rye grass pollen, cow's milk, egg white, D pteronyssinus, and D farinae.E9Pepys J. Skin tests for immediate, type I, allergic reactions.Proc R Soc Med. 1972; 65: 271-272PubMed Google Scholar, E10Skin prick testing for the diagnosis of allergic disease. A manual for practitioners. In: Australasian Society of Clinical Immunology and Allergy, editor. ASCIA skin prick testing working party; 2013. Available at: https://www.allergy.org.au/images/stories/pospapers/ASCIA_SPT_Manual_November_2013.pdf. Accessed July 17, 2015.Google Scholar From 6 years of age, skin prick tests also included mixed grass, cat pellet, dog dander, cockroach, A tenuis, and A fumigatus. Positive and negative controls of histamine and saline were used. The mean of 2 perpendicular diameter measurements of the wheal was recorded at 15 minutes. A positive result was a wheal of 3 mm or more larger than that elicited by the negative control. Recorded V′maxFRC values at 1, 6, and 12 months of age were adjusted by using a previously validated formula,E3Young S. Sherrill D.L. Arnott J. Diepeveen D. LeSouef P.N. Landau L.I. Parental factors affecting respiratory function during the first year of life.Pediatr Pulmonol. 2000; 29: 331-340Crossref PubMed Scopus (101) Google Scholar as follows:V'maxFRC/(−63.18−[14.17×sex]+[1.62×ageinweeks]+[3.9596×lengthincentimeters]−[10.39×weightinkilograms]−[14.24×maternalsmokinginpregnancy]×100),where male sex is scored as 1 and female sex is scored as 0. Maternal smoking during pregnancy was scored as 1, and no maternal smoking was scored as 0. Spirometric lung function parameters were expressed as percent predicted based on height, age, and sex.E6Knudson R.J. Slatin R.C. Lebowitz M.D. Burrows B. The maximal expiratory flow-volume curve. Normal standards, variability, and effects of age.Am Rev Respir Dis. 1976; 113: 587-600PubMed Google Scholar V′maxFRC and FEF25-75 variables were also converted to internal z scores to allow for comparison over time. The generalized estimating equation was used to assess whether early sensitization was associated with a persistent reduction in lung function across time after adjusting for inherent covariance in each proband. The relationship between early sensitization, current atopy or parental atopy, and continuous lung function variables was analyzed by using the general linear model and adjusted for in utero smoke exposure at all assessments, asthma from 6 to 24 years of age, and current smoking at 18 and 24 years of age. In utero smoke exposure had 3 categories: none, smoked during part of pregnancy, or smoked throughout pregnancy. Asthma was not adjusted for in infancy because it is generally not diagnosed in this age group. Estimated marginal means (adjusted) are reported. Significant differences in these adjusted means were then analyzed by using an independent-samples t test. Cord IgE and maternal total IgE levels were logarithmically transformed to approach a normal distribution. The correlation between these and infant V′maxFRC value was analyzed by using the Pearson correlation coefficient. The odds for those with early sensitization or atopy having a history of asthma or eczema was assessed by using binary logistic regression, and odds ratios are reported. Asthma diagnosis was based on reported physician's diagnosis only. The odds for those with early sensitization of having recent wheeze were also assessed with binary logistic regression and adjusted for smoking at 18 and 24 years of age. Recent wheeze was recorded only if there were symptoms in the previous 12 months before each assessment. The odds for those with early sensitization of having current atopy based on a positive skin prick test response at each of the follow-up assessments from 6 to 24 years was analyzed with binary logistic regression. Each dose-response slope on the histamine challenge was logarithmically transformed to approach a normal distribution, and geometric means are reported. Early sensitization was defined as at least 1 positive skin prick test response by 12 months of age. Only those who had tests on all 3 occasions (1, 6, and 12 months) or who had positive results were included in the analysis. The standard cutoff P value of .05 was used to assess statistical significance. Statistical analyses were performed with IBM SPSS Statistics for Windows software, version 20.0 (released 2011; IBM, Armonk, NY).Table E1Characteristics of the cohort at recruitment and those followed up at each assessmentBirth cohort (n = 253)6 y (n = 113)11 y (n = 180)18 y (n = 142)24 y (n = 111)Male sex56%55%56%58%57%Birth weight (kg), mean (SD)3.4 (0.48)3.41 (0.46)3.42 (0.5)3.45 (0.47)3.4 (0.49)Parental asthma31%28%30%29%29%V′maxFRC (% predicted) at 1 mo, mean (SD)99 (49.6)99.8 (51)97.4 (42)106∗P < .05. (54.9)105.5 (54.4)In utero smoke exposure32%27%28%25%*P < .05.25%*P < .05.Early sensitization19%19.5%21%19.5%25%*P < .05.Values in boldface indicate statistical significance.∗ P < .05. Open table in a new tab Values in boldface indicate statistical significance.