Date Published: January 8, 2019
Publisher: Public Library of Science
Author(s): Henrik Wegener Hallas, Bo Lund Chawes, Morten Arendt Rasmussen, Lambang Arianto, Jakob Stokholm, Klaus Bønnelykke, Hans Bisgaard, Aziz Sheikh
Abstract: BackgroundStudies have shown that airway obstruction and increased bronchial reactivity are present in early life in children developing asthma, which challenges the dogma that airway inflammation leads to low lung function. Further studies are needed to explore whether low lung function and bronchial hyperreactivity are inherent traits increasing the risk of developing airway inflammation and asthmatic symptoms in order to establish timely primary preventive initiatives.Methods and findingsWe investigated 367 (89%) of the 411 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort born to mothers with asthma, who were assessed by spirometry and bronchial reactivity to methacholine from age 1 month, plethysmography and bronchial reversibility from age 3 years, cold dry air hyperventilation from age 4 years, and exercise challenge at age 7 years. The COPSAC pediatricians diagnosed and treated asthma based on symptom load, response to inhaled corticosteroid, and relapse after treatment withdrawal according to a standardized algorithm. Repeated measures mixed models were applied to analyze lung function trajectories in children with asthma ever or never at age 1 month to 13 years. The number of children ever versus never developing asthma in their first 13 years of life was 97 (27%) versus 270 (73%), respectively. Median age at diagnosis was 2.0 years (IQR 1.2–5.7), and median remission age was 6.2 years (IQR 4.2–7.8). Children with versus without asthma had reduced lung function (z-score difference, forced expiratory volume, −0.31 [95% CI −0.47; −0.15], p < 0.001), increased airway resistance (z-score difference, specific airway resistance, +0.40 [95% CI +0.24; +0.56], p < 0.001), increased bronchial reversibility (difference in change in forced expiratory volume in the first second [ΔFEV1], +3% [95% CI +2%; +4%], p < 0.001), increased reactivity to methacholine (z-score difference for provocative dose, −0.40 [95% CI −0.58; −0.22], p < 0.001), decreased forced expiratory volume at cold dry air challenge (ΔFEV1, −4% [95% CI −7%; −1%], p < 0.01), and decreased forced expiratory volume after exercise (ΔFEV1, −4% [95% CI −7%; −1%], p = 0.02). Both airway obstruction and bronchial hyperreactivity were present before symptom debut, independent of disease duration, and did not improve with symptom remission. The generalizability of these findings may be limited by the high-risk nature of the cohort (all mothers had a diagnosis of asthma), the modest study size, and limited ethnic variation.ConclusionsChildren with asthma at some point at age 1 month to 13 years had airway obstruction and bronchial hyperreactivity before symptom debut, which did not worsen with increased asthma symptom duration or attenuate with remission. This suggests that airway obstruction and bronchial hyperreactivity are stable traits of childhood asthma since neonatal life, implying that symptomatic disease may in part be a consequence of these traits but not their cause.
Partial Text: The current paradigm of asthma pathophysiology suggests that an inflammatory process in the airways leads to progressive bronchial hyperreactivity and lung function deficits . An alternative hypothesis is causality in the opposite direction, i.e., that reduced airway caliber and bronchial hyperreactivity are inherent and stable traits that increase the risk of asthmatic symptoms, exaggerated hyperreactivity, and intermittent airway obstruction from a superimposed inflammatory process. In support of this, anti-inflammatory inhaled corticosteroid (ICS) treatment does not affect the natural course of lung function in children [2–6]. Furthermore, reticular basement membrane and airway smooth muscle thickness are unrelated to inflammatory cell counts in bronchial biopsies . This alternative causal direction from airway obstruction and bronchial hyperreactivity to asthma symptoms implies that prevention must take place before symptom debut and maybe even before birth [8,9].
This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (S1 STROBE Checklist).
Of the 411 children enrolled at 1 month of age in COPSAC2000, follow-up to age 13 was available for 367 (89%). The number of children ever versus never developing asthma in their first 13 years of life was 97 (27%) versus 270 (73%), respectively (Fig 1). A total of 54 (56%) children remitted before age 13 years; 14 (14%) remitted but relapsed later during childhood. Median age at diagnosis was 2.0 years (IQR 1.2–5.7), median remission age was 6.2 years (IQR 4.2–7.8), and median duration of asthma was 4.0 years (IQR 2.2–5.3). The mean age of the mother at the birth of the child was 30.0 years, and 39% of the children had older siblings. There were no significant differences in baseline characteristics between included and excluded children (Table 1).