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

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Abstract

Methods and findings

We 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.

Author summary

Introduction

The current paradigm of asthma pathophysiology suggests that an inflammatory process in the airways leads to progressive bronchial hyperreactivity and lung function deficits [1]. 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 [26]. Furthermore, reticular basement membrane and airway smooth muscle thickness are unrelated to inflammatory cell counts in bronchial biopsies [7]. 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].

We aimed to study this alternative paradigm with rigorous prospective assessment of disease duration and remission. Spirometry and bronchial reactivity to methacholine were assessed in neonates [10,11]. Neonatal spirometry was volume-anchored and therefore comparable to repeated assessments of spirometry and bronchial reactivity during childhood [1215]. Effort-independent measures of airway resistance and measures of bronchial reactivity were recorded until age 13 years.

Methods

This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (S1 STROBE Checklist).

The study was nested in Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000): a Danish prospective birth cohort study of 411 infants born during 1998–2001 to mothers with a history of asthma [16]. At enrollment at age 1 month, we excluded any child with a history of symptoms of lower airway infection or neonatal mechanical ventilation, preterm birth (gestational age < 36 weeks), or any congenital abnormality or systemic illness. The children were examined at half-yearly scheduled visits until age 7 years, and again at age 13 years, including assessments of lung function 11 times during childhood. Thus, longitudinal lung function assessment during childhood was a strong and predefined focus of COPSAC2000, which is detailed in the cohort baseline paper [16], but there was no prospective analysis plan for how to model the data with respect to asthma development.

The local ethics committee (KF 01-289/96) and the Danish Data Protection Agency (2015-41-3696) approved the study. Both parents gave oral and written informed consent before enrollment.

Bronchial reactivity

Exercise challenge.

At 7 years, the child exercised on a motor-driven treadmill for at least 4 minutes with a pulse rate >80% of the maximal pulse [19] breathing fully dehumidified atmospheric air through a facemask (Hans Rudolph, Kansas City, MO, US). Spirometry was performed before, and 1, 3, 5, 10, and 15 minutes after exercise using the maximum percentage decline in FEV1 from baseline within 10 minutes after exercise as the outcome.

We excluded lung function measurements in children with respiratory tract symptoms in the preceding week and if β2-agonists had been used within the preceding 12 hours. Bronchial challenge test results were excluded if the child had a respiratory infection in the preceding 3 weeks [21].

Asthma diagnosis

Age 1 month–7 years.

Asthma was diagnosed according to a predefined validated quantitative diary-based algorithm [22]. If the child experienced 5 episodes of troublesome lung symptoms within 6 months, daily symptoms for 4 weeks, or acute severe symptoms requiring hospitalization, high-dose ICS, or systemic corticosteroids, then a 3-month course of budesonide 200 μg bid (Spirocort, AstraZeneca, Cambridge, UK) was prescribed, and the child was examined by a chest X-ray and a sweat chloride test to exclude other chronic lung disorders. Asthma was diagnosed in children relapsing after ICS withdrawal within the following year, defined as either 2 episodes within 3 months or 2 consecutive weeks with symptoms, which resulted in a 6-month course of ICS and an additional 12-month course at subsequent relapses. Remission was defined as the child being without symptoms and treatment for 1 year.

Statistical analyses

Baseline characteristics of included versus excluded children were compared using Fisher’s exact test, Student’s t test, and Wilcoxon 2-sample test.

The relationship between development of FEVz, MMEFz, sRawz, and PDz in the first 13 years of life and asthma status was analyzed with mixed models taking repeated participant measurements into account. The statistic extracted from these mixed models was the fixed effect of group, i.e., asthma versus no asthma. To test the effect of the normalization of the lung function measurements, which was done to enable comparison of measurements conducted at varying ages, we also ran the analyses with raw, untransformed data and subsequently investigated the normal distribution of the residuals from the different models with Q-Q plots.

The cold dry air challenge by spirometry (6 years) and exercise challenge (7 years) were only performed once for each child, and the cross-sectional difference in these measures between children with asthma and without asthma was analyzed by Student’s t test comparison of means.

We subsequently investigated whether development of FEVz, MMEFz, sRawz, and PDz prior to onset of asthma was different from their development in children never developing asthma. This was done in mixed models comparing FEVz, MMEFz, sRawz, and PDz measurements obtained before diagnosis in children developing asthma with measurements in children never developing asthma, evaluating the fixed effect of group, i.e., asthma versus no asthma. As an ancillary analysis, we also investigated by t tests whether neonatal FEV0.5, FEF50, and PD15 were different in neonates who subsequently developed asthma versus neonates who did not develop asthma.

The effect of duration of asthma in the first 13 years of life on lung function development, i.e., whether lung function declined over time with increasing disease length, was investigated by calculating the duration of symptomatic disease preceding each lung function measurement. The mixed models used for this analysis were adjusted for time since remission and estimated the slope of the lung function during the period with asthma. The statistic extracted from these mixed models was the fixed effect of time, i.e., disease length in the observation period. To further investigate whether asthma status affected measures of FEVz, MMEFz, sRawz, and PDz over time, age at measurement was included in the analyses as an interaction term.

Finally, lung function development after remission of asthma was analyzed in mixed models by evaluating the change over time in FEVz, MMEFz, sRawz, and PDz after remission, evaluating the fixed effect of time since remission.

As post hoc analyses, we investigated development of FEVz, MMEFz, sRawz, and PDz in children with remission of asthma, i.e., early-transient symptoms, compared to children with persistent symptoms and children never developing asthma. We also investigated development of lung function in children with asthma who had specific allergen sensitization at age 13 year compared to children with asthma without sensitization. These post hoc analyses were done to investigate whether there were specific lung function trajectories in different wheeze phenotypes and whether development of atopy influenced the trajectories. The analyses were done with mixed models, evaluating the fixed effect of wheeze phenotype and sensitization status.

The effect of missing observations for longitudinal values for FEVz, MMEFz, sRawz, and PDz was investigated by multiple imputation (for details see S1 Text).

All analyses were performed in R with the package lme4 (version 1.1.14) [25] for linear mixed models as well as the package mice (version 3.3.0). All estimates are presented with 95% confidence intervals; p-values < 0.05 were considered significant. The graphical presentations of the results were made with ggplot2 (version 3.0.0), and the longitudinal curves of FEVz, MMEFz, and sRawz development were smoothed with loess regression function.

The data are available in S1 Data.

Results

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).

Lung function development in relation to asthma status

The development of FEVz from age 1 month to 13 years in children ever versus never diagnosed with asthma in this period is depicted in Fig 2A, illustrating that children developing asthma already had reduced FEVz as neonates, which persisted until age 13 years as a stable trait without progression or attenuation during childhood (z-score difference, −0.31 [95% CI −0.47; −0.15], p < 0.001). The development of MMEFz was similar to that of FEVz (Fig 2B) (z-score difference, −0.44 [95% CI −0.60; −0.27], p < 0.001). sRawz measurements from age 3 to 13 years showed increased sRaw from age 3 years among children ever versus never developing asthma, which was sustained till age 13 years without progression or attenuation (Fig 2C) (z-score difference, +0.40 [95% CI +0.24; +0.56], p < 0.001). Finally, bronchial reactivity to methacholine (PDz) was persistently increased from age 1 month until age 13 years in children ever versus never diagnosed with asthma in that period (Fig 2D) (i.e., reduced PDz; z-score difference, −0.40 [95% CI −0.58; −0.22], p < 0.001) (Table 2). A sensitivity analysis utilizing the raw, untransformed data showed similar results (Table A in S1 Text). Furthermore, transforming the data led to more normalized residuals (Fig A in S1 Text). Finally, analyses using multiple imputation also showed the same differences in lung function development in children ever versus never diagnosed with asthma; although the effect estimates were slightly attenuated, the results remained significant (Table B in S1 Text).

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Fig 2. Development of z-scored measures of lung function and bronchial reactivity from 1 month to 13 years.

z-Scores for (A) forced expiratory volume (FEVz), (B) maximal mid-expiratory flow (MMEFz), (C) specific airway resistance (sRawz), and (D) provocative dose of methacholine (PDz). Dashed lines represent 95% confidence intervals; grey triangles indicate timing of measurements. The vertical bars in (D) indicate the exact distribution in terms of age of sampling of the raw data.

https://doi.org/10.1371/journal.pmed.1002722.g002

In order to test whether the relationship between lung function development and asthma status varied with age, we introduced the interaction term asthma status × age at measurement in the models. This analysis showed that there was no interaction between asthma status and age for lung function measurement (Table C in S1 Text), suggesting that these are predetermined traits established in early life and stable throughout childhood. An ancillary analysis of neonatal FEV0.5, FEF50, and PD15 showed significantly decreased forced flows and increased reactivity to methacholine in neonates developing asthma within their first 13 years of life compared to neonates never diagnosed with asthma (Table D in S1 Text).

Children who developed asthma during the first 13 years of life compared to children never developing asthma also had increased bronchodilator response (absolute difference: FEV1, +3% [95% CI +2%; +4%], p < 0.001; MMEF, +6% [95% CI 0%; 12%], p = 0.04; sRaw, −4% [95% CI −6%; −2%], p < 0.001), reduced post-bronchodilator z-scores for FEV1 (−0.16 [95% CI −0.34; 0.01], p = 0.07) and MMEF (−0.35 [95% CI −0.54; −0.16], p < 0.001), and increased post-bronchodilator z-score for sRaw (+0.22 [95% CI +0.06; +0.38], p = 0.007).

Reactivity to cold dry air was increased among children ever versus never having asthma (absolute difference: FEV1, −4% [95% CI −7%; −1%], p = 0.007; MMEF, −8% [95% CI −15%; −1%], p = 0.03; and sRaw, +9% [95% CI +5%; +13%], p < 0.001). Additionally, children ever versus never diagnosed with asthma experienced a significantly larger drop in FEV1 after exercise challenge at age 7 years (absolute difference: FEV1, −4% [95% CI −7%; −1%], p = 0.02) (Table 2).

Lung function development in relation to transient versus persistent asthmatic symptoms

Among the 97 children who fulfilled the diagnostic criteria for asthma, 54 children had a transient phenotype and remitted before age 13 years, whereas the remaining 43 children had persistent asthmatic symptoms requiring continued ICS by age 13 years. Lung function development in children with transient asthmatic symptoms compared to children never diagnosed with asthma showed reduced FEVz (z-score difference, −0.30 [95% CI −0.51; −0.08], p = 0.008) and reduced MMEFZ (−0.36 [95% CI −0.59; −0.14], p = 0.002) from age 1 month to 13 years, and increased sRawz from age 3 years to 13 years (+0.27 [95% CI +0.06; +0.48], p = 0.01). PDz was reduced among transiently asthmatic versus healthy children, i.e., indicating increased airway reactivity, but this difference was not significant (−0.15 [95% CI −0.39; +0.09], p = 0.23).

There were no differences in development of FEVz, MMEFz, or sRawz among children with transient versus persistent asthmatic symptoms, whereas children with transient compared to persistent symptoms had less airway reactivity to methacholine, i.e., higher PDz (+0.48 [95% CI +0.15; +0.80], p = 0.004) (Fig 3; Table E in S1 Text).

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Fig 3. Development of z-scored measures of lung function and bronchial reactivity from 1 month to 13 years in children with transient asthma, children with persistent asthma, and children never developing asthma.

z-Scores for (A) forced expiratory volume (FEVz), (B) maximal mid-expiratory flow (MMEFz), (C) specific airway resistance (sRawz), and (D) provocative dose of methacholine (PDz). Dashed lines represent 95% confidence intervals; grey triangles indicate timing of measurements.

https://doi.org/10.1371/journal.pmed.1002722.g003

Discussion

Strengths and limitations

The primary strength of this study is the thorough single-center close clinical surveillance of a cohort with a follow-up of 89% till age 13 years. The children were seen for clinical evaluation and lung function assessment at the age of 1 month and thereafter at least half-yearly until age 7 years and again at 13 years. Until age 7 years, the parents filled daily diary cards describing the child’s troublesome lung symptoms, thereby diminishing recall bias [26]. Asthma was diagnosed and treated by the COPSAC pediatricians only according to a predetermined algorithm with a conservative definition based on symptom load and response to and relapse after a standard dose and period of ICS [22], thus avoiding diagnostic heterogeneity. Children with asthma were seen for scheduled 3-monthly visits and for unscheduled acute visits during worsening of symptoms and continued daily symptom diary recording beyond age 7 years if symptoms persisted.

The diagnostic algorithm for asthma, which was based on quantitative symptom assessments verified at scheduled and acute care visits to the research unit and response to ICS treatment, could identify asthmatic children with transient, recurrent viral-induced wheeze and children with a persistent phenotype with or without atopy. This is apparent as approximately half of the children diagnosed according to the algorithm had transient symptoms and remitted before age 13 years. The median age at diagnosis was 2 years, implying that a large proportion of the cases were children whose initial episode of wheezing was related to an infection, but half of these children had ICS-dependent asthma by age 13 years. Importantly, not all children with asthma will respond to ICS initially, and because lack of ICS response cannot exclude asthma, we excluded other chronic lung diseases by means of chest X-ray and a sweat chloride test for cystic fibrosis.

A significant advantage of the study is the longitudinal repetitive lung function assessments performed at 11 time points during childhood by means of spirometry and plethysmography as well as bronchial reactivity to cold dry air, exercise, and methacholine challenge in accordance with recognized guidelines [1720,27]. We did most measurements in the age range from 3 to 7 years; therefore, the shape of the curves is likely to be influenced by the readings at 1 month and 13 years. Still, the birth cohort design assured that lung function was assessed (1) before the debut of symptoms and asthma diagnosis, (2) repeatedly every 6 months in children with and without asthma, and (3) after remission in children outgrowing their asthma. This allowed us to scrutinize how lung function trajectories develop in children with asthma during childhood and how they are affected by duration and remission of symptoms. Our interaction analyses showed no evidence of age influence on the difference in lung function development in children with versus without asthma, but the low numbers in our cohort may preclude us from detecting subtle differences with age.

It is a strength of our study that neonatal spirometry was performed using the raised volume rapid thoracoabdominal compression technique, providing volume-anchored measurements [10], which makes its results comparable with the forced volumes obtained by spirometry later in childhood. This is an important difference compared to previous studies of neonatal lung function in relation to asthma and lung function development during childhood, which used non-volume-anchored methods [1214,28]. Assessment of tidal breathing patterns is one such method, which is less sensitive, has high intra-individual variability [29,30], and yields results not associated with volume-anchored measurements later in childhood [13].

One previous study of 95 children investigated airway reactivity from age 1 month throughout childhood, but used a non-volume-anchored assessment of histamine challenge that did not correlate with the FEV1-based histamine challenge results at school age, highlighting the same problem of using different approaches to determine neonatal lung function and lung function later in childhood [12,31,32].

The limitations of our study are the relatively small sample size, the limited ethnic variation, and the high-risk nature of the COPSAC2000 cohort, which hamper the generalizability of the findings. However, mothers without asthma might be reluctant to have their neonates investigated so thoroughly by lung function testing during sedation. Children of asthmatic mothers are a priori at higher risk of asthma and may experience more severe symptoms and have poorer lung function. However, the children not developing asthma also had asthmatic mothers, and we do not expect the relationship between symptoms and lung function development to be different due to asthma predisposition.

We observed z-score differences in lung function trajectories with magnitudes between 0.3 and 0.4 in children who developed asthma compared to children not developing asthma. This overall difference in lung function development is not in the abnormal range, which would be less than −2 z-scores, but it should be kept in mind that we excluded measurements obtained during exacerbations, which may have diminished the overall difference between children with versus without asthma.

Interpretation

We found that airway obstruction and bronchial hyperreactivity related to asthma are fixed traits from age 1 month to age 13 years, without further deterioration from disease duration or improvement after symptom remission. These findings have important implications for our understanding of the underlying pathology, indicating that the symptomatic phases of childhood asthma are not causing the airway obstruction and bronchial hyperreactivity typical of asthma. Instead, we propose that airway obstruction and bronchial hyperreactivity are inherent traits that increase the risk of developing airway inflammation and asthmatic symptoms during childhood. This may explain the lack of effect from early intervention with ICS, which was unable to change the natural course of asthma with respect to both symptom burden and lung function development [26].

Our findings are consistent with a follow-up study of children diagnosed with asthma at age 9 years showing that individuals still experiencing symptoms at age 26 years had stable airway obstruction and bronchial reactivity without any progression from the assessments at age 9 years [33]. In addition, a 22-year follow-up of a cohort of 40-year-old adults also showed that reduced lung function at cohort inception remained stable over time [34]. Together with the present study, this suggests that airflow obstruction and bronchial hyperreactivity are inherent and stable deficits measurable already at age 1 month. Thus, even though lung function fluctuates with symptom load and anti-inflammatory treatment over time [35], the lung function trajectory is a static characteristic that might contribute to asthmatic symptoms, exaggerated bronchial reactivity, and intermittent airway obstruction.

Our findings contrast with those of a recent study investigating the development of lung function in children with asthma into adulthood [36], which suggested that the majority of children with asthma (75%) had an abnormal pattern of reduced growth and/or early decline in lung function, i.e., not a stable trait. This difference may be due to the fact that the study only enrolled 5- to 12-year-old children with uncontrolled chronic asthma (symptoms >2 days/week) and severe bronchial hyperreactivity at baseline (>20% drop in FEV1 after methacholine challenge), resembling a minority population of the most severely affected children. Even more important, the participants with reduced growth in lung function already had significantly lower lung function at enrollment, suggesting that their lung function trajectories may be a static characteristic established in early childhood. In line with our findings, another recent study demonstrated increased airway resistance among children with persistent wheeze, which tracked from early to late childhood [37].

We suggest that the propensity to develop asthmatic symptoms due to intrinsic and extrinsic factors is increased by underlying inherent airflow obstruction and bronchial hyperreactivity, which are stable traits without progression due to triggering factors or increased symptom duration. On the other hand, we and other groups have shown that allergic sensitization after the age of 6 years, but not earlier in childhood, is associated with an increased risk of developing asthma [38,39], with different risks for different allergens [40]. This raises the possibility that development of allergy may have a deteriorating effect on the lung function trajectory. However, our data in general argue against such a hypothesis as development of airflow obstruction as measured by FEVz, MMEFz, and sRawz among children with asthma was independent of allergic sensitization at age 13 years, whilst there was a non-significant suggestion of increased airway reactivity among sensitized asthmatic individuals that was significant in the subgroup with sensitization to pollens, which were the most common allergens in our cohort. These findings are in line with a study of 1,719 15-year-old participants in the German GINIplus birth cohort, which did not show any associations between sensitization and spirometric indices in children with asthma [41], but are in contrast to the American TENOR study of 1,261 children aged 6 to 17 years with severe or difficult-to-treat asthma, which showed an association between increased airflow limitation and higher IgE levels [42]. Importantly, both these studies were cross-sectional analyses; a longitudinal study showed that development of lung function from age 1 month until 11 years was unaffected by atopy [13].

Interestingly, we found that all children who fulfilled the diagnostic criteria for asthma compared to children never diagnosed with asthma had increased airway obstruction, i.e., reduced FEVz and MMEFz (age 1 month to 13 years) and increased sRawz (age 3 years to 13 years), irrespective of remission of symptoms or not. Thus, fixed airway obstruction was apparent in children with both a transient and a persistent phenotype and without differences in development of FEVz, MMEFz, and sRawz between the phenotypes, whereas bronchial reactivity to methacholine (PDz) was more pronounced in children with persistent as opposed to transient symptoms. This suggests that airway reactivity in children with transient asthmatic symptoms declines with airway growth through childhood, whereas reduced forced flows and increased airway resistance are fixed traits among children with the transient phenotype, irrespective of airway growth. These findings align with findings from longitudinal lung function measurements from birth until age 16 years in the Tucson Children’s Respiratory Study [43] and from age 3 years until age 11 years in the Manchester Asthma and Allergy Study [37], showing that children with persistent wheeze compared to never wheeze had increased and fixed airway obstruction, which was also apparent for children with early-transient viral-induced wheeze even though they outgrew their symptoms. Furthermore, a smaller Australian study from Perth also showed a suggestion of reduced lung function from birth until age 11 years in children with persistent wheeze, whereas no reduction of lung function was observed for other phenotypes of wheeze [12]. Overall, these studies together with our study suggest a common underlying lung function deficit driving early-transient, typically viral-induced symptoms and persistent symptoms, typically triggered b

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