Airway obstruction and bronchial reactivity from age 1 month until 13 years in children with asthma: A prospective birth cohort study

Abstract

Background

Studies 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 findings

We investigated 367 (89%) of the 411 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC ₂₀₀₀) 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 [ΔFEV ₁], +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 (ΔFEV ₁, −4% [95% CI −7%; −1%], p < 0.01), and decreased forced expiratory volume after exercise (ΔFEV ₁, −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.

Conclusions

Children 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.

Abstract

Hans Bisgaard and colleagues analyze cohort data for evidence as to whether symptomatic asthma is the cause or consequence of early-life airway obstruction and bronchial hyperreactivity.

Author summary

Why was this study done?

• It is believed that asthma develops from inflammation in the lungs that leads to loss of lung function, but low lung function may be an inherent trait in children at risk of asthma instead of a consequence of inflammation.

• It is important to explore whether low lung function is an inherent trait that increases the risk of developing airway inflammation and asthma in order to establish primary preventive initiatives for low lung function.

What did the researchers do and find?

• Ninety-seven children who developed asthma and 270 children without asthma from the Danish COPSAC ₂₀₀₀ birth cohort born to mothers with asthma were studied extensively with longitudinal lung function measurements from age 1 month to 13 years.

• Lung function was measured by spirometry from age 1 month and plethysmography from age 3 years, including assessments of bronchial reversibility to inhaled β2-agonist from age 3 years. Bronchial reactivity was assessed by methacholine challenge from age 1 month, cold dry air hyperventilation from age 4 years, and exercise challenge at age 7 years.

• Children developing asthma had reduced lung function from age 1 month throughout childhood compared to the children without asthma.

• The lung function deficit was present before the children developed asthma, did not progress with symptoms, and remained even if symptoms ceased.

What do these findings mean?

• Low lung function appears to begin in early childhood in a group of children who will develop asthma. The lung function trait is established prior to development of airway inflammation and asthma, and does not worsen with increased duration of asthma symptoms. As airway obstruction and increased bronchial reactivity manifest as early as 1 month of age, it is possible that preventive measures undertaken during pregnancy will be most effective.