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Severe wheezing exacerbations during the preschool years, a critical time in lung growth and development, may lead to airway damage and remodeling. Our study linked these events to a partially reversible reduction in lung function present at school age.
Asthma exacerbations have been linked to progressive loss of lung function in school-age children and adults.(1) Previous longitudinal studies have suggested that lung function deficits in children with persistent wheezing are established by school age, and these deficits can persist into adulthood.(2–4) Since, the first several years of life are a critical time in lung growth and development, we hypothesized that recurrent severe wheezing exacerbations during early life could lead to airway remodeling and be associated with reductions in lung function at school age.
Children at high risk for asthma and allergic disease based on parental histories of asthma and/or allergies were enrolled in the Childhood Origins of ASThma (COAST) study from birth, and the timing, etiology and severity of respiratory illnesses were followed prospectively as previously described. (5) Severe exacerbations were defined, per ATS criteria, as an episode requiring systemic corticosteroids.(6) Pre-bronchodilator (5–8 years of age) & post-bronchodilator (6–8 years of age) spirometry was performed at scheduled annual visits. Acceptability of spirometry was determined based upon criteria published by Eigen and colleagues.(7) A total of 225 children completed acceptable spirometry between 5–8 years of age, and were included in this analysis. The cohort was divided into 4 groups based upon wheezing history during the first 3 years of life: no wheezing illness (n=111), mild to moderate wheezing only (n=69), 1 severe wheezing episode requiring oral corticosteroids (OCS) (n=23), and recurrent (>1) severe wheezing episodes requiring OCS (n=22). Mixed-effect linear regression models were used to assess the effect of group on lung function between ages 5 and 8 years. These models included child as a random effect and group, age and the interaction between group and age as fixed effects, with asthma, gender, height, weight, race, smoke exposure and aeroallergen sensitization as control variables. In the absence of significant interactions between age and group, lung function differences by group are presented as least squares means or marginal mean for a balanced population across age and the other covariates. Fisher’s protected LSD method was used to account for multiple comparisons between the 4 groups.
The characteristics of children in each of the four groups defined by wheezing and exacerbation histories are shown in Table 1. Children with ≥2 severe exacerbations had a higher rate of asthma at school age compared to the rest of the cohort. Early aeroallergen sensitization within the first two years of life was additionally noted to be associated with higher rates of severe exacerbations. There were no differences among groups for height, weight, gender, race, or smoke exposure.
Children with a history of recurrent severe wheezing exacerbations during the first 3 years of life had significantly reduced pre-bronchodilator forced expiratory volume in 1 sec (FEV1) at school age (1.26 (95% CI 1.19–1.34) liters (L)) when compared to children with no wheezing (1.37 (1.32–1.41) L, p= 0.01), mild to moderate wheezing only (1.34 (1.30–1.39) L, p= 0.05) and only 1 severe episode requiring OCS (1.38 (1.31–1.45) L, p=0.02). Similar differences in forced expiratory volume in 0.5 seconds (FEV0.5) at school age were seen among these groups (Figure 1a). In contrast, there were no significant differences in FEV0.5 or FEV1 among children with no wheezing, mild to moderate wheezing only, or only 1 severe episode requiring OCS (Figure 1a). Post-bronchodilator differences in FEV0.5 and FEV1 between children with histories of recurrent severe wheezing exacerbations and the other 3 groups of children were not statistically significant (Figure 1b).
In this study, we utilized requirement for systemic steroids as a marker for illness severity to demonstrate that children with recurrent severe wheezing exacerbations during the first 3 years of life had lower lung function at school age when compared to children with a single severe exacerbation, mild to moderate wheezing only, or no wheezing history. These findings have important potential implications because prior studies have shown that abnormalities in lung function present at school age persist at least into early adulthood.(2;3)
The reductions in lung function present in this high-risk cohort are consistent with the effects of severe exacerbations on lung function in older children and adults with asthma reported by O’Byrne and colleagues.(1) However, in our study, these reductions in lung function were at least partially reversible with a bronchodilator, whereas O’Byrne and colleagues reported post-bronchodilator differences in patients with severe exacerbations, particularly those individuals not taking an inhaled corticosteroid. The observational nature of COAST and the numbers of children in each group in our study does not allow us to determine whether treatment impacted our findings.
The results of our study suggest that severe episodes of wheezing during this critical time in lung growth and development, which were associated with a greater likelihood of asthma at school age, may have deleterious effects on the airways. We hypothesize that these events, typically associated with viral respiratory infections, lead to airway damage and remodeling, and plausible mechanisms by which this may occur have been described.(8) Further, it is possible that these more severe episodes lead to enhanced damage and perhaps a more prolonged remodeling process. When this occurs recurrently, it is particularly problematic for the developing young child. Importantly, remodeling and airway changes typical of asthma can occur in children between 1 and 3 years of age.(9) The partial post-bronchodilator reversibility seen in the recurrent exacerbation group in our study suggests that these children may not yet have fixed obstruction; however, it will be interesting to longitudinally assess for progressive loss of lung function in these children with early recurrent exacerbations.
A limitation of this study is the lack of baseline lung function measurements from the first several years of life, preventing us from definitively determining whether these severe wheezing episodes caused progressive loss of lung function, were due to an initial low baseline lung function, or both. However, data from the Tucson Children’s Respiratory Study suggest that abnormalities in lung function may not be present during the first year of life but develop during early childhood in children with persistent wheezing.(3)
Our findings highlight the importance of close follow-up for children with histories of severe exacerbations during early life and suggest that preventing additional severe wheezing episodes could impact subsequent morbidity due to loss of lung function. Thus, novel strategies for the prevention of wheezing exacerbations, particularly in preschool children, are sorely needed.
Supported by NIH grants: R01 HL61879, P01 HL70831, M01 RR03186, and 1UL1RR025011 from the Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources (NCRR)
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