Project description:BackgroundSevere bronchiolitis (ie, bronchiolitis requiring hospitalization) during infancy is a major risk factor for childhood asthma. However, the exact mechanism linking these common conditions remains unclear.ObjectivesThis study sought to examine the integrated role of airway microbiome (both taxonomy and function) and host response in asthma development in this high-risk population.MethodsThis multicenter prospective cohort study of 244 infants with severe bronchiolitis (median age, 3 months) examined the infants' nasopharyngeal metatranscriptomes (microbiomes) and transcriptomes (hosts), as well as metabolomes at hospitalization. The longitudinal relationships investigated include (1) major bacterial species (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis), (2) microbial function, and (3) host response with risks of developing asthma by age 6 years.ResultsFirst, the abundance of S pneumoniae was associated with greater risks of asthma (P = .01), particularly in infants with nonrhinovirus infection (Pinteraction = .04). Second, of 328 microbial functional pathways that are differentially enriched by asthma development, the top pathways (eg, fatty acid and glycolysis pathways; false discovery rate [FDR] < 1 × 10-12) were driven by these 3 major species (eg, positive association of S pneumoniae with glycolysis; FDR < 0.001). These microbial functional pathways were validated with the parallel metabolome data. Third, 104 transcriptome pathways were differentially enriched (FDR < .05)-for example, downregulated interferon-α and -γ and upregulated T-cell activation pathways. S pneumoniae was associated with most differentially expressed transcripts (eg, DAGLB; FDR < 0.05).ConclusionsBy applying metatranscriptomic, transcriptomic, and metabolomic approaches to a multicenter cohort of infants with bronchiolitis, this study found an interplay between major bacterial species, their function, and host response in the airway, and their longitudinal relationship with asthma development.
Project description:Air pollution exposures have been suggested as risk factors for childhood respiratory diseases. We investigated proximity to major roads, an indicator of air pollution exposure, and its associations with childhood recurrent wheeze and asthma. We used data from a multicenter prospective cohort study of 921 infants hospitalized for bronchiolitis and recruited from 14 U.S. states. Primary exposure was residential proximity to the nearest major road at birth through age 3 years. Residential distance from nearest major road was divided into four categories: <100, 100-200, 201-300, and >300 m. Outcomes were parent-reported recurrent wheeze by age 3 years and asthma by age 5 years. Associations between residential proximity to major roads and respiratory outcomes were investigated using multivariable Cox proportional hazards modeling and logistic regression, adjusted for confounders. Out of 920 participants with home address data, pooled estimates identified 241 (26%) participants resided within 300 m of a major road, 296 (32%) developed recurrent wheeze by age 3, and 235 out of 858 participants (27%) developed asthma by 5 years. Participants who resided close to a major road had the highest risk of recurrent wheeze (adjusted hazards ratio for <100 m, 1.59, 95%CI: 1.08-2.33) and asthma (adjusted odds ratio for 201-300 m, 1.62, 95%CI: 1.16-2.25), compared to those residing >300 m from a major road. Proximity to major roads is associated with increased risks of recurrent wheeze and asthma in young children.
Project description:Respiratory syncytial virus (RSV) bronchiolitis is not only the leading cause of hospitalization in U.S. infants, but also a major risk factor for asthma development. While emerging evidence suggests clinical heterogeneity within RSV bronchiolitis, little is known about its biologically-distinct endotypes. Here, we integrated clinical, virus, airway microbiome (species-level), transcriptome, and metabolome data of 221 infants hospitalized with RSV bronchiolitis in a multicentre prospective cohort study. We identified four biologically- and clinically-meaningful endotypes: A) clinicalclassicmicrobiomeM. nonliquefaciensinflammationIFN-intermediate, B) clinicalatopicmicrobiomeS. pneumoniae/M. catarrhalisinflammationIFN-high, C) clinicalseveremicrobiomemixedinflammationIFN-low, and D) clinicalnon-atopicmicrobiomeM.catarrhalisinflammationIL-6. Particularly, compared with endotype A infants, endotype B infants-who are characterized by a high proportion of IgE sensitization and rhinovirus coinfection, S. pneumoniae/M. catarrhalis codominance, and high IFN-α and -γ response-had a significantly higher risk for developing asthma (9% vs. 38%; OR, 6.00: 95%CI, 2.08-21.9; P = 0.002). Our findings provide an evidence base for the early identification of high-risk children during a critical period of airway development.
Project description:BackgroundInfants hospitalized for bronchiolitis have a high rate of early childhood asthma. It is not known whether bronchiolitis severity correlates with the risk of early childhood asthma or with asthma-specific morbidity.ObjectivesWe sought to determine whether a dose-response relationship exists between severity of infant bronchiolitis and both the odds of early childhood asthma and asthma-specific morbidity.MethodsWe conducted a population-based retrospective birth cohort study of term healthy infants born from 1995-2000 and enrolled in a statewide Medicaid program. We defined bronchiolitis severity by categorizing infants into mutually exclusive groups based on the most advanced level of health care for bronchiolitis. Health care visits, asthma-specific medications, and demographics were identified entirely from Medicaid and linked vital records files. Asthma was ascertained at between 4 and 5.5 years of age, and 1-year asthma morbidity (hospitalization, emergency department visit, or oral corticosteroid course) was determined between 4.5 and 5.5 years among children with prevalent asthma.ResultsAmong 90,341 children, 18% had an infant bronchiolitis visit, and these infants contributed to 31% of early childhood asthma diagnoses. Relative to children with no infant bronchiolitis visit, the adjusted odds ratios for asthma were 1.86 (95% CI, 1.74-1.99), 2.41 (95% CI, 2.21-2.62), and 2.82 (95% CI, 2.61-3.03) in the outpatient, emergency department, and hospitalization groups, respectively. Children hospitalized with bronchiolitis during infancy had increased early childhood asthma morbidity compared with that seen in children with no bronchiolitis visit.ConclusionTo our knowledge, this is the first study to demonstrate the dose-response relationship between the severity of infant bronchiolitis and the increased odds of both early childhood asthma and asthma-specific morbidity.
Project description:BackgroundBronchiolitis is the leading cause of infants hospitalization in the U.S. and Europe. Additionally, bronchiolitis is a major risk factor for the development of childhood asthma. Growing evidence suggests heterogeneity within bronchiolitis. We sought to identify distinct, reproducible bronchiolitis subgroups (profiles) and to develop a decision rule accurately predicting the profile at the highest risk for developing asthma.MethodsIn three multicenter prospective cohorts of infants (age < 12 months) hospitalized for bronchiolitis in the U.S. and Finland (combined n = 3081) in 2007-2014, we identified clinically distinct bronchiolitis profiles by using latent class analysis. We examined the association of the profiles with the risk for developing asthma by age 6-7 years. By performing recursive partitioning analyses, we developed a decision rule predicting the profile at highest risk for asthma, and measured its predictive performance in two separate cohorts.FindingsWe identified four bronchiolitis profiles (profiles A-D). Profile A (n = 388; 13%) was characterized by a history of breathing problems/eczema and non-respiratory syncytial virus (non-RSV) infection. In contrast, profile B (n = 1064; 34%) resembled classic RSV-induced bronchiolitis. Profile C (n = 993; 32%) was comprised of the most severely ill group. Profile D (n = 636; 21%) was the least-ill group. Profile A infants had a significantly higher risk for asthma, compared to profile B infants (38% vs. 23%, adjusted odds ratio [adjOR] 2⋅57, 95%confidence interval [CI] 1⋅63-4⋅06). The derived 4-predictor (RSV infection, history of breathing problems, history of eczema, and parental history of asthma) decision rule strongly predicted profile A-e.g., area under the curve [AUC] of 0⋅98 (95%CI 0⋅97-0⋅99), sensitivity of 1⋅00 (95%CI 0⋅96-1⋅00), and specificity of 0⋅90 (95%CI 0⋅89-0⋅93) in a validation cohort.InterpretationIn three prospective cohorts of infants with bronchiolitis, we identified clinically distinct profiles and their longitudinal relationship with asthma risk. We also derived and validated an accurate prediction rule to determine the profile at highest risk. The current results should advance research into the development of profile-specific preventive strategies for asthma.
Project description:PURPOSE:The complex interplay between environmental and genetic factors plays an important role in the development of asthma. Several studies have yielded conflicting results regarding the 2 asthma-related risk factors: antibiotic usage during infancy and/or a history of bronchiolitis during early life and the development of asthma. In addition to these risk factors, we also explored the effects of Toll-like receptor 4 (TLR4) polymorphism on the development of childhood asthma. METHODS:This cross-sectional study involved 7,389 middle school students who were from 8 areas of Seoul, Korea, and completed the International Study of Asthma and Allergies in Childhood questionnaire. The TLR4 polymorphism rs1927911 was genotyped in 1,395 middle school students from two areas using the TaqMan assay. RESULTS:Bronchiolitis in the first 2 years of life, antibiotic exposure during the first year of life, and parental history of asthma were independent risk factors for the development of asthma. When combined, antibiotic use and a history of bronchiolitis increased the risk of asthma (adjusted odds ratio [aOR]: 4.64, 95% confidence interval [CI]: 3.09-6.97, P value for interaction=0.02). In subjects with CC genotype of TLR4, antibiotic exposure and a history of bronchiolitis during infancy, the risk of asthma was increased, compared to subjects without these risk factors (aOR: 5.72, 95% CI: 1.74-18.87). CONCLUSIONS:Early-life antibiotic exposures and a history of bronchiolitis are risk factors for asthma in young adolescents. Polymorphisms of TLR4 modified the influence of these environmental factors. Reducing antibiotic exposure and preventing bronchiolitis during infancy may prevent the development of asthma, especially in genetically susceptible subjects.
Project description:ObjectiveEarly life bronchiolitis has been hypothesised to be associated with the subsequent risk of persistent wheezing or asthma. However, the link remains controversial. The objective of our study was to evaluate the association between bronchiolitis before 2 years of age and the late-onset wheezing/asthma.DesignSystematic review and meta-analysis.MethodsPubMed, Embase and Web of Science databases were systematically searched for studies published between 1955 and January 2020. Meanwhile, we also checked through the reference lists of relevant articles to see whether these references included reports of other studies that might be eligible for the review. Cohort and case-control studies assessing the association between early-life bronchiolitis and late-onset wheezing/asthma were included in this meta-analysis. Data were extracted by two independent reviewers. Results were pooled using a random-effects model or fixed-effects model according to the heterogeneity among studies.Results32 original articles with 292 844 participants, which met the criteria, were included in this meta-analysis. Bronchiolitis before 2 years of age was associated with an increased risk of subsequent wheezing/asthma (relative risk=2.46, 95% CI 2.14 to 2.82, p<0.001). After categorising studies into different groups based on age at the end of follow-up, geographical region and study quality, the association still remained significant.ConclusionsThe meta-analysis indicates an association between bronchiolitis before 2 years of age and the wheezing/asthma in later life. Well-designed and highly standardised prospective studies that better address bias due to potential confounding factors are needed to validate the risk identified in our meta-analysis.PROSPERO registration numberCRD42018089453.
Project description:BackgroundChildren 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.MethodsIn 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.Results55% 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).ConclusionsFollowing 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.