Early-life risk factors for reversible and irreversible airflow limitation in young adults: findings from the BAMSE birth cohort

We aimed to determine prevalence and early-life risk factors for reversible and irreversible airflow limitation in young adults from the general population. Among young adults in their 20s, the prevalence was 5.3% for reversible airflow limitation and 2.0% for irreversible airflow limitation. While parental asthma was the only risk factor for development of reversible airflow limitation, the risk factors for development of irreversible airflow limitation were current asthma, childhood respiratory tract infections and asthma, and exposure to air pollution.


ABSTRACT
We aimed to determine prevalence and early-life risk factors for reversible and irreversible airflow limitation in young adults from the general population. Among young adults in their 20s, the prevalence was 5.3% for reversible airflow limitation and 2.0% for irreversible airflow limitation. While parental asthma was the only risk factor for development of reversible airflow limitation, the risk factors for development of irreversible airflow limitation were current asthma, childhood respiratory tract infections and asthma, and exposure to air pollution.
It has been shown that impaired lung function in children and young adults is associated with an increased risk of chronic obstructive pulmonary disease (COPD) later in life. 1 2 Recently, airflow limitation defined as pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) below the lower limit of normal (LLN) was observed in 4% of adults aged 20-29 years who have less than 5 pack-years tobacco load, and up to 7% in participants who have 5 pack-years or more tobacco load. 3 However, few published studies addressed reversible airflow limitation and irreversible airflow limitation in young adults. Given this, we aimed to determine the prevalence and early-life risk factors for reversible airflow limitation and irreversible airflow limitation in young adults from the general population.
A total of 1932 participants in the populationbased birth cohort Barn/Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) performed valid pre-BD and post-BD lung function measurements at the 24-year follow-up. 4 5 Lung function was tested according to American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria as previously described. 6 Post-BD lung function was tested 15 min after administration of 400 µg salbutamol. 'Normal lung function' was defined as pre-BD and post-BD FEV 1 /FVC ≥LLN, 7 'Reversible airflow limitation' as pre-BD FEV 1 /FVC <LLN but post-BD FEV1/ FVC≥LLN, and 'Irreversible airflow limitation' as pre-BD and post-BD FEV 1 /FVC <LLN. ORs and 95% CIs for risk factors in relation to reversible airflow limitation or irreversible airflow limitation, selected based on previous literature and availability in BAMSE, were estimated using multivariable logistic regression in R (V.4.0.2).
The prevalence of reversible airflow limitation was 5.3% (n=103, 95% CI 4.3% to 6.3%), and irreversible airflow limitation 2.0% (n=39, 95% CI 1.4% to 2.6%) at the 24-year follow-up. Forty-nine per cent reported respiratory symptoms in those with irreversible airflow limitation compared with 25% in those with normal lung function (table 1). In addition, participants in the irreversible airflow limitation group also reported more cough, but not more mucus production, during winter mornings. Besides, there were reports of more respiratory symptoms (defined as troublesome breasing, chest tightness or wheezing) and pneumonia events during the last 12 months in the irreversible airflow limitation group. However, no such differences were observed for the groups with reversible airflow limitation and normal lung function. There were lower pre-BD FEV 1 and post-BD FEV 1 (by design, online supplemental table E1), higher pre-BD FVC and post-BD FVC, and higher reversibility (change in FEV 1 and change in FEV 1 % baseline) in the reversible and irreversible airflow limitation groups compared with the group with normal lung function. Fifteen and 2.9% of participants with irreversible and reversible airflow limitation had post-BD FEV 1 lower than LLN, respectively, compared with 1.5% in the group with normal lung function (online supplemental table E1). No substantial difference was observed for other variables, except higher body mass index (BMI) was observed in participants with irreversible airflow limitation (table 1). In logistic regression models adjusted for age, gender and BMI, several indicators of early life infections and respiratory diseases, environmental exposures and current asthma were risk factors associated with irreversible airflow limitation (table 2). In mutually adjusted analyses, respiratory syncytial virus (RSV) infection/pneumonia during infancy, nitrogen oxide (NO x ) exposure during age 0-1 years, childhood asthma during age 0-4 years and current asthma were independent risk factors for irreversible airflow limitation (table 3). For reversible airflow limitation, parental asthma and childhood asthma during age 0-4 and 8-12 years, NO x exposure during age 8-12 years and current asthma were associated factors. In mutually adjusted analyses, parental asthma alone was an independent risk factor for reversible airflow limitation.
In summary, we found the overall prevalence of reversible and irreversible airflow limitation to be rather high (5.3% and 2.0%, respectively), considering the young age of the participants. Individuals with irreversible airflow limitation more often reported current respiratory symptoms and pneumonia compared with those with normal lung function. Besides, more severe lung function impairments were observed in individuals with irreversible airflow limitation. Thus, there was a substantial disease burden in participants with irreversible airflow limitation. Results from previous epidemiology studies demonstrate that abnormal lung development plays an important role in the development of COPD and a substantial proportion of subjects diagnosed with COPD after age 50 could be traced back to a relatively low peak lung function in their 20s. 8 Our current findings extend those results by demonstrating that irreversible airflow limitation is present in young adults. This was observed despite most of them being nonsmokers, and ever-smokers having smoked on average less than one pack-year. Moreover, although only 28% of the irreversible airflow limitation subjects were classified as having current asthma, enhanced airway reversibility was observed, which suggests that, at this early stage of disease, reversibility is to some extent present.
In our study, early-life respiratory infections (RSV infection/ pneumonia) and exposure to air pollutants, as well as childhood asthma, were identified as strong risk factors for irreversible airflow limitation. Given that air pollution levels in Stockholm are comparatively low by international standards, this makes the current findings alarming in a global context. Early risk factors may influence lung function development in a negative manner that will likely track with age, 9 and in the current study, these early lung insults were even stronger risk factors for irreversible airflow limitation than smoking exposure in childhood and active smoking in adolescence. Thus, early-life exposure to air pollutants emerges as an important risk factor, known to be associated with not only lung development, 6 but also with childhood pneumonia 10 and asthma. 11 In our study, the only identified independent risk factor for reversible airflow limitation was parental asthma, which suggests that the reversible airflow limitation phenotype relates primarily to asthma heredity, rather than to impaired lung development.
Our study has the drawback of a relatively small irreversible airflow limitation sample size and only around 50% of the initial 4089 cohort participants provided pre-BD and post-BD  spirometry data at 24 years of age. However, no selection bias could be identified so far in the BAMSE cohort. 4 In conclusion, this study forwards evidence that among young adults in their 20s, the prevalence was 5.3% for reversible airflow limitation and 2.0% for irreversible airflow limitation. While parental asthma emerges as the only risk factor for development of reversible airflow limitation, the risk factors for development of irreversible airflow limitation were current asthma, childhood respiratory tract infections and asthma, and exposure to air pollution.