Abstract
Background:
Children with severe respiratory syncytial virus (RSV) bronchiolitis in infancy have increased risks of asthma and reduced lung function in later life. There are limited studies on the longitudinal changes of lung function and bronchial hyperreactivity from early to late childhood in infants hospitalized for RSV bronchiolitis.
Methods:
In a prospective cohort of 206 children with their first episode of RSV-confirmed bronchiolitis in the first year of life, 122 had spirometry performed at least twice between 5–16 years of age. Methacholine bronchoprovocation was available in 127 and 79 children at 7 and 12 years of age, respectively. Longitudinal changes in FEV1, FVC, and FEV1/FVC z-scores and methacholine PC20 were analyzed.
Results:
55% of the study cohort (N = 122) were male, and 55% were Caucasian. During follow-up, longitudinal changes in z-scores for pre- and post-bronchodilator FEV1 (P < .0001) FVC (P < .0001) and FEV1/FVC (P < .0001 for pre- and 0.007 for post-bronchodilator) from age 5 to 10–16 years were observed. Declined lung function in late childhood was significantly associated with gender, physician diagnosis of asthma, and allergic sensitization. PC20 geometric mean increased from 0.28 mg/mL at 7 years to 0.53 mg/mL at 12 years of age, and the frequency of abnormal bronchial hyperreactivity decreased from 96% to 78% (P = .0003).
Conclusions:
Following severe RSV bronchiolitis, there appear to be significant longitudinal changes in pre- and post-bronchodilator lung function during childhood. The study has several limitations including significant dropouts and the lack of a control group and post-bronchodilator measurements. Bronchial hyperreactivity is common in children following severe RSV bronchiolitis; however, it appears to decrease as they enter late childhood.
Keywords: bronchial hyperreactivity, bronchiolitis, longitudinal changes, lung function, respiratory syncytial virus, spirometry
1 |. INTRODUCTION
Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis leading to hospitalization in young children.1 Nearly all children are infected with RSV by 2 years of age.2 This disease causes a substantial burden on healthcare systems worldwide.3 Acute severe RSV bronchiolitis in early childhood is associated with long-term morbidities including recurrent wheezing, asthma, and changes in lung function in later life.4–6
Lower respiratory tract infection (LRTI) caused by RSV was one of the risk factors for persistently low lung function trajectory extending from preadolescence into the fourth decade of life in The Tucson Children’s Respiratory Study.7 Previous studies demonstrated that children with severe RSV bronchiolitis in infancy had lower pre- and post-bronchodilator lung function into adolescence and adulthood, compared to children with no history of severe RSV illnesses, and many children had persistent bronchial hyperresponsiveness (BHR). 6,8–12 No previous studies have explored lung function trajectory in children following RSV LRIs compared to their early childhood by using z-scores of lung functions.
We aimed to determine if children with severe RSV bronchiolitis in infancy had a decline in their lung function into late childhood and whether patient baseline characteristics predict the changes in lung function in these children.
2 |. METHODS
There were 1222 children with a positive nasopharyngeal swab for RSV at St. Louis Children’s Hospital from 1998 to 2001; 206 children fulfilled the eligibility criteria and were enrolled in the RSV Bronchiolitis in Early Life (RBEL) prospective cohort study. Selection of the study population and characteristics were previously described in detail.13 The inclusion criteria for the study included infants 12 months of age or less admitted to the emergency department or hospitalization for bronchiolitis with a positive nasopharyngeal swab for RSV by polymerase chain reaction (PCR) and physiciandocumented wheezing during acute illness. Exclusion criteria were a history of previous wheezing or a diagnosis of asthma, congenital anomalies of the heart or lung, cystic fibrosis diagnosed in the patient or immediate family, regular use of anti-gastroesophageal reflux medication, bronchodilators, or anti-inflammatory medications. The demographic data, environmental exposures, and family and personal history of atopic diseases were obtained from the child’s parents at enrollment. The study was approved by the Washington University School of Medicine Institutional Review Board. Informed consent was obtained from parents or guardians.
2.1 |. Patient follow-up and data collection
Telephone interview with parents or guardians was conducted every 3 to 6 months to monitor children’s respiratory symptoms, physician-diagnosed asthma and any change in the personal history of atopy, environmental exposure, or family history. Active asthma is defined when parent-reported physician-diagnosed asthma was accompanied by wheezing over the last one year of follow-up. Active wheezing is defined as any wheezing reported over the last year of follow-up.
Skin-prick tests for 8 aeroallergens (GREER®, NC, USA) including mite mix (D farinae and D pteronyssinus), cockroach mix (American/ German), cat epithelia/dander, dog epithelia, grass mix, weed mix, tree mix, and mold mix were performed at age 3 and 7 years. Tests were read at 15–20 minutes, and we identified a positive reaction as a wheal greater than or equal to 3 mm, after subtracting the negative control, as positive.
Blood samples were obtained at entry for total IgE levels by nephelometry and complete blood count with differentials of white blood cells for a percentage of eosinophils. Dust samples (n = 109) were collected from enrolled infants’ homes within the first 2 years of enrollment and analyzed, as described previously.4
2.2 |. Spirometry and methacholine testing
Children were asked to return for spirometry during scheduled yearly visits between the ages of 5 and 12 years and once after 12 years of age. Spirometry was performed with a portable KoKo office spirometry® (nSpire Health), software version 4.11 by following the acceptability and repeatability criteria of American Thoracic Society (ATS) guidelines.14 Weight and height were obtained at each visit for spirometry. Obesity was defined as ≥ 95th percentile for BMI-for-gender and age.
Z-scores of FEV1, FVC, and FEV1/FVC were calculated using Global Lung Initiative (GLI)-2012 desktop software.16 All tests were reviewed by two blinded reviewers for quality assurance purposes, and only tests that met with ATS standard guidelines were included.
Methacholine challenge test (MCT) was performed twice, between age 6–8 years old and between age 10–14 years old, following ATS standard guidelines.17 The tests were rescheduled if children were unable to perform acceptable-quality spirometry, if the FEV1 was < 70% of predicted values, or if restricted medications were used too close to the time of the test.17 Bronchial hyperresponsiveness (BHR) is defined as a provocative concentration of methacholine required to decrease FEV1 by 20% (PC20) of ≤8 mg/mL.18
2.3 |. Statistical methods
We included data from children who had ATS-acceptable spirometry performed on at least two follow-up visits from age 5 to 16. Descriptive statistics included the number of children and percent for categorical variables and mean with SDs for continuous variables. Comparison of means among groups was conducted using analysis of variance (ANOVA) or Kruskal-Wallis tests as appropriate. Comparisons of proportions among groups were conducted using chi-square tests. A repeated-measures linear mixed model was used to assess longitudinal changes in z-scores of spirometry values and interaction between covariates and changes across time. Linear contrasts were used to compare mean values of spirometry between age groups. Pearson correlations were estimated to evaluate the association between BMI percentile and birth weight/height and lung function z-scores. Univariable and multivariable linear regression analyses were used to explore the relationships between covariates and changes in lung function over time. P-values < .05 were considered statistically significant. Data were analyzed using SAS software versions 9.3 and 9.4 (SAS Institute Inc).
3 |. RESULTS
Of the 206 children enrolled into the RSV bronchiolitis cohort in the first year of life, 122 (59%) had ATS-acceptable spirometry obtained on at least two follow-up visits, with the first spirometry obtained either at age 5 or 6 years. The reasons for missing longitudinal spirometry data in 84 children included dropouts (n = 25), lost-to-follow-up without spirometry (n = 36), and lost-to-follow-up with only one ATS-acceptable spirometry obtained (n = 23). 96, 94, 62, and 84 children had ATS-acceptable spirometry obtained at age 5, 6, 7–9 (mean 7.6 ± 0.4), and 10–16 years (mean 12.1 ± 1.5), respectively.
Overall characteristics of children with longitudinal lung function data are summarized in Table 1, and the characteristics by age at entry are summarized in Table S1. At the latest follow-up visit, 60% had been diagnosed with asthma by their physicians, and nearly half of these children had wheezing over the last year of follow-up. We compared the characteristics of the children missing longitudinal lung function data (n = 84) to those in the current study to assess potential follow-up bias. Children with longitudinal lung function data had a higher rate of physician-diagnosed asthma (59% versus 43%, P = .03), but a lower rate of active wheezing (37% versus 52%, P = .04). There was no significant difference in the rate of active asthma and other variables of interest between children with and without longitudinal lung function (Table S2).
TABLE 1.
Characteristics of children with longitudinal spirometrya following severe RSV bronchiolitis in infancy
| Characteristics | All subjects (N = 122) |
|---|---|
| Demographics | |
| Age at entry, [d] | 136 ±103 |
| Male gender, n (%) | 67 (54.9) |
| Caucasian race, n (%) | 67 (54.9) |
| Wheezing/Asthma history | |
| MD-diagnosed asthma, n (%) | l2 (59.0) |
| Active wheezing, n (%) | 45 (36.9) |
| Active asthma, n (%) | 33 (2l.0) |
| Bronchiolitis history | |
| Lowest oxygen saturations, N = 113 | 91 ± l |
| Length hospital stay, [d], N = 121 | 3.4 ± 2.8 |
| Pregnancy history | |
| Duration of pregnancy, [w], N = 192 | 38.4 ± 1.9 |
| Birth weight, [g], N = 194 | 3211 ± 595 |
| Birth length, [cm], N = 168 | 50.5 ± 3.6 |
| Family history | |
| History of maternal asthma at entry, n (%) | 26 (21.3) |
| History of maternal atopic diseases at entry, n (%) | 53 (43.4) |
| History of first-degree relatives with asthma at entry, n (%) | 52 (42.6) |
| History of first-degree relatives with atopic diseases at entry, n (%) | 50 (59.5) |
| Other histories and exposures | |
| Personal history of eczema at entry, n (%) | 1l (14.0) |
| Intrauterine exposure to cigarette smoke, n (%) | 31 (25.4) |
| Postnatal exposure to cigarette smoke, n (%) | 42 (34.4) |
| History of daycare attendance at entry, n (%) | 34 (30.1) |
| Exposures to allergens in high levels in the first 3 years of life, N = 109 | |
| Feldl > 8000 ng/g | 33 (30.3) |
| Canfl > 8000 ng/g | 33 (30.3) |
| Blag1 > 8000 ng/g, | 11 (10.2) |
| Derfl > 2000 ng/g | 22 (20.2) |
| Derpl > 2000 ng/g | l (6.4) |
| Exposure to at least one allergen in a high level | l2 (66.1) |
| Allergen sensitization to environmental allergens at age 3–7, n(%), N = 81 | 48 (59.3) |
| BMI percentile at age 5–6, median (interquartile range), N = 112 | ll (51 – 95) |
| Obesity (BMI > 95th %tile) at age 5–6, N = 112 | 29 (26) |
Longitudinal spirometry was defined by having at least two spirometry values beyond baseline measurements performed at ages 5–6 y.
3.1 |. Changes in lung function following severe RSV bronchiolitis into late childhood
We found a significant change in z-scores of pre-bronchodilator FEV1, FVC, and FEV1/FVC across time from 5 to 10–16 years, P < .0001 for each measure. To evaluate if there was a particular time period during which the change of lung functions occurred, we compared z-scores of lung functions between each age group. There was an increase in pre-bronchodilator FEV1 and FVC z-scores from age < 7 to age 7–9; however, this was followed by a decline from age 7–9 to age 10–16 years (all P < .0001). Pre-bronchodilator FEV1/FVC z-scores decreased from age 5 to 6 and 6 to 7–9 (all P < .0001), and then, it became steady at age 10 to 16 years (Table 2, Figure 1). In a subset of 33 children that had longitudinal post-bronchodilator lung function at follow-up visits, we also found significant decline in FEV1, FVC, and FEV1/FVC z-scores across time from baseline (Table S3, Figure S1).
TABLE 2.
Pre-bronchodilator lung function at age 5, 6, 7–9, and 10–16 years following severe RSV bronchiolitis in infancy
| Age (years) | |||||
|---|---|---|---|---|---|
| Z-scores of lung function parameter | 5 (n = 96) | 6 (n = 94) | 7–9 (n = 62) | 10–16 (n = 84) | P-value |
| FEV1 | 0.2 ± 1.1 | 0.4 ± 1.0 | 0.4 ± 1.2 | −0.4 ± 0.8 | <.0001 |
| FVC | 0.2 ± 1.2 | 1.0 ± 1.3 | 1.4 ± 1.5 | −0.05 ± 0.8 | <.0001 |
| FEV1/FVC | 0.1 ± 1.3 | −0.6 ± 1.5 | −1.1 ± 1.5 | −0.6 ± 1.0 | <.0001 |
Note: Data represent mean ± SD.
A repeated-measures linear mixed model was used to evaluate changes in lung function across time.
FIGURE 1.
Pre-bronchodilator lung function trajectories in children from 5 to 10–16 y old following severe RSV bronchiolitis in infancy. (line in red—95% CI does not include zero for pairwise comparison, and planned contrasts were used to test for significant differences of the mean values of spirometry between age groups) A. Changes in FEV1 Z-score, B. Changes in FVC z-scores, and C. Changes in FEV1/FVC z-scores
3.2. |. Predictors of changes in lung function following severe RSV bronchiolitis into late childhood across time
We sought to evaluate factors that may predict changes in lung function z-scores in these children. Male gender, physician-diagnosed asthma by age 6, and exposure to cat allergen in a high level were negatively associated with pre-bronchodilator FEV1 z-scores at age 10–16 years (Table 3). Physician-diagnosed asthma by age 6 years and allergic sensitization at age 3–7 years were also associated with a decline in FEV1/FVC z-scores. There was a weak correlation between BMI percentile at age 5–6 and FEV1 z-scores (r = 0.3, P = .02); and between BMI percentile at age 5–6 and FVC z-scores (r = 0.3, P = .02). Other factors were not significantly associated with changes in lung function across time in these children (Table S4).
TABLE 3.
Predictors associated with longitudinal changes in lung function across time following severe RSV bronchiolitis in infancy
| Change in Z-scores | Predictors | Predicted change in z-scores | 95% Confidential Interval of change in z-scores | P-value |
|---|---|---|---|---|
| Univariable | ||||
| FEV1 | Male gender | −0.35 | −0.69 to −0.01 | .047 |
| MD-diagnosed asthma by age 6 | −0.49 | −0.83 to −0.16 | .004 | |
| Allergic sensitization at age 3– 7 | −0.34 | −0.73 to 0.05 | .09 | |
| Can f1 > 8000 ng/g | −0.44 | −0.83 to −0.05 | .03 | |
| BMI percentile at age 5 or 6a | 0.08 | 0.01 to 0.14 | .02 | |
| FVC | BMI percentile at age 5 or 6 a | 0.08 | 0.01 to 0.14 | .02 |
| FEV1/FVC | Allergic sensitization at age 3–7 | −0.66 | −1.1 to −0.2 | .006 |
| MD-diagnosed asthma by age 6 | −0.44 | −0.88 to −0.01 | .044 | |
| Multivariable | ||||
| FEV1 | Male gender | −0.52 | −0.84 to −0.19 | .002 |
| MD-diagnosed asthma by age 6 | −0.55 | −0.88 to −0.21 | .002 | |
| BMI% tile at age 5 or 6 | 0.08 | 0.01 to 0 0.14 | .02 | |
| Canf1 > 8000 ng/g | −0.19 | −0.57 to 0.19 | .3 | |
| FVC | BMI %tile at age 5 or 6 | 0.08 | 0.01 to 0.14 | .02 |
| MD-diagnosed asthma by age 6 | −0.19 | −0.54 to 0.16 | .3 | |
| FEV1/FVC | Allergic sensitization at age 3–7 | −0.54 | −1.03 to −0.05 | .03 |
| MD-diagnosed asthma by age 6 | −0.33 | −0.79 to 0.13 | .2 |
Note: Other factors included in the analyses: race, active asthma, active wheezing, history of eczema, daycare attendance, intrauterine/postnatal smoke exposures, obesity at age 6, family history of atopy, maternal history of atopy, and exposure to at least one allergen at high levels in the first 3 y of life.
The BMI percentile variable was re-scaled such that the slope estimates correspond to the change in spirometry outcomes for every 10 BMI percentile increase.
The multivariable analysis revealed that male gender, physician-diagnosed asthma by age 6, and lower BMI percentile by age 6 were all independently associated with a decline in FEV1 z-scores in late childhood. For every 10% tile increase in BMI percentile at age 5–6, there was a 0.08 increase in FEV1 z-score (P = .02). In addition, allergic sensitization at age 3–7 was independently associated with a decline in lung function of z-scores of FEV1/FVC (Table 3, and Table S5).
3.3 |. Airway hyperresponsiveness following severe RSV bronchiolitis
One hundred and twenty-seven (62%) and 79 (38%) children had MCT at mean ages of 6.6 (range 5.7 – 7.9) and 11.7 years old (range 10 −13.9), respectively. Of those participants that had bronchial hyperreactivity (PC20 ≤ 8 mg/ml) at the initial testing, there was an increase in geometric mean (95% CI) of PC20 from 0.28 (0.15 to 0.53) mg/ml (arithmetic mean 0.75 ± 0.95) at 7 years to 0.53 (0.27 to 1.03) mg/ml (arithmetic mean 1.53 ± 1.93) at 12 years of age (P = .003) (Figure 2). In the subgroup of 75 children who had MCT at both time points, the prevalence of significant bronchial hyperreactivity decreased from 96% at 6 years to 78% at 12 years of age (P = .0003).
FIGURE 2.
Comparison on geometric mean of PC20 at the mean age 7 and age 12 y old
4 |. DISCUSSION
We demonstrated that children with severe RSV bronchiolitis in infancy experience a significant change in trajectories in pre- and post-bronchodilator lung function across time from age 5–6 years to late childhood. Factors that were associated with a decline of lung function included male, physician diagnosis of asthma, BMI, and allergic sensitization. We also showed that the majority of children continued to have bronchial hyperresponsiveness 12 years following severe RSV bronchiolitis.
Further analysis of the changes in lung function across age intervals demonstrated a transient increase in both pre-bronchodilator FEV1 and FVC z-scores from age <7 to 7–9 years followed by a subsequent decline into age 10–16 years. Furthermore, the FEV1 z-score was lower than the FVC at 10–16 years contributing to a reduced FEV1/FVC ratio in the last interval of follow-up. The trajectory of change in lung function in children with severe RSV bronchiolitis found in our study was different from patterns of lung growth described in children with mild-to-moderate asthma in the Childhood Asthma Management Program or Tucson birth cohort studies.7,19 This could be secondary to differences in study population with nearly half of children in our study having a family history of atopy and one third of children having allergic sensitization, as the similar pattern of lung function decline have been described in a separate cohort of children with asthma who had comorbidities of atopic dermatitis and allergic rhinitis.20 The high rates of atopic diseases in our study were likely related to the study location where we have some of the highest rates in the country.21 The rate of maternal history of asthma in our cohort was similar to previously reported.4
Although the average z-scores in late childhood remained above the lower limit of normal range, our finding of a pattern of decreasing lung function from the initial to later testing during childhood reflects that severe RSV bronchiolitis in the first year of life may affect long-term lung growth in these children. Declines in lung function early in life have been shown to be a potential predictor of chronic obstructive pulmonary disease (COPD) in adulthood. 7,19 R SV L RTI i n t he f irst 3 years o f l ife i s a ssociated with persistently low trajectories of lung function from childhood to adulthood, and this may predispose them to COPD. 7 The pathogenesis of lung function deficits following RSV infection remains unclear. These children might have reduced lung function at baseline, and RSV bronchiolitis was the first manifestation of their underlying deficit. However, only 4% and 11% of children in our cohort had reduced FEV1 a nd FEV1/FVC z-scores, respectively, (<−1.64) at the initial evaluation. Airway remodeling and hyperreactivity induced by severe viral respiratory illnesses may also play a role. 22–24 Our findings support the growing evidence that early life exposures, especially severe lower respiratory tract infections, could affect subsequent lung function growth.25
Physician-diagnosed asthma early in childhood was a significant predictor of subsequent decline in lung function. This finding is consistent with previous literature demonstrating persistently impaired lung function during adolescence in children who were previously diagnosed with asthma in early life.26,27 Our finding that male gender is associated with impaired lung function into late childhood following RSV bronchiolitis could be related to underlying asthma predisposition in boys.4,5 We have previously demonstrated that early allergic sensitization following RSV bronchiolitis is a risk factor for asthma by age 7.4 In this study, we found that allergic sensitization was also associated with lung function decline and this is consistent with other studies.19,28
Others have demonstrated obesity is associated with impaired lung function in both asthmatics and nonasthmatics.29,30 However, obesity at age 6 was not found to be a significant predictor of declined lung function trajectory in late childhood in our study. This discrepancy could be due to a small proportion of children in our cohort who had obesity at age 6 (only 25% had BMI ≥ 95th percentile for gender and age). Although the frequency of intrauterine and postnatal cigarette smoke exposure of children in our cohort is higher than the smoking rate for adults in Missouri (~19%),21 we did not find either measure of cigarette smoke exposure to be a significant predictor of lung function in our cohort.
Approximately two-thirds of children with severe RSV bronchiolitis remained having bronchial hyperreactivity at age 12 years, which represented a significant decline from what we had previously reported in this cohort at age 7 years old.4 Our finding is consistent with a previous study demonstrating the rate of positive bronchial hyperreactivity (defined by PD20 < 4900 mcg) declined from 60% to 48% at 18–20 years later.31,32 However, this latter study did not specify etiology of the bronchiolitis in these children. In the subset of children with MCT at two time points, we found nearly all children had bronchial hyperreactivity at mean age of 7 years which was higher than the rate previously reported.31 This is likely due to a high frequency of physician-diagnosed asthma in our cohort. It is also important to note that some children were not able to complete the methacholine challenge test as they were unable to perform acceptable-quality spirometry.
A limitation of our study was that only 60% of children had spirometry performed beyond age 6 on at least two visits, and only a small subset of children had post-bronchodilator measurements. Our findings are potentially confounded by selection bias, given children who returned for a follow-up spirometry had a higher prevalence of physician-diagnosed asthma. It is also possible that the decline in lung function was influenced by atopy or the combination of atopy and RSV as nearly half of children in our study have a family history of atopy. However, we did not find family history of atopy as a significant factor on the univariate analysis. The nasopharyngeal swab tested only for RSV, so this does not exclude the possibility of co-infections with other viruses that could potentially affect lung functions in these children. We also do not have data on the smoking status at later childhood and environmental exposure to pollution that may have contributed to a decline of lung functions. We do not have a comparison group of healthy controls as most children are exposed to RSV by age 2 not allowing an adequate unexposed population.2 However, the use of z-scores provides a normative value adjusted by relevant factors. Although the majority of children in our cohort had normal spirometry at age 5–6 years old, we have no data on their lung functions prior to the first episode of severe RSV bronchiolitis and could not determine if these children had low lung function at baseline. Lastly, we have information on controller medications in a subset of the cohort (n = 101, 80%). However, the majority of children (92%) were not on any inhaled steroids or montelukast during the study period.
In summary, our study suggested a change in lung function trajectories across ages in children following severe RSV bronchiolitis in infancy. However, the results should be interpreted with cautions due to limitations on the methodology and significant dropouts of children in our study. We have identified that being diagnosed with asthma by age 6 years, male, or sensitized to allergens are all associated with a decline in lung functions in these children. Clinicians should be aware of the negative impact of severe RSV bronchiolitis early in life on children’s subsequent lung growth.
Supplementary Material
Key Message.
Children with severe respiratory syncytial virus bronchiolitis during infancy had a significant change of trajectories of lung functions from age 5–6 years to age 10–16 years. Baseline predictors of a decline in lung functions following severe RSV bronchiolitis during infancy included physician-diagnosed asthma by age 6 years, male gender, and allergic sensitization. Bronchial hyperreactivity is common in children following severe RSV bronchiolitis; however, it appears to decrease as they enter late childhood.
Acknowledgments
Funding information
The study is supported by the National Heart, Lung, and Blood Institute/National Institutes of Health NIH/NHLBI RO1 HL092486 (LB, MC); National Institute of Allergy and Infectious Diseases/National Institutes of Health RO1 U19 AI070489 (MC); and NIH/NCATS UL1 TR000448 (MC).
Footnotes
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1111/pai.13399.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section.
CONFLICT OF INTEREST
The authors have no potential conflict of interest related to the manuscript content.
Editor: Ömer Kalaycı
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