Viral persistence & the microbiome in bronchiolitis and risk of recurrent wheeze

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 DESCRIPTION (provided by applicant): Bronchiolitis is the #1 cause of infant hospitalization in the USA. Small cohort studies (n<210) suggest that ~50% of hospitalized infants with bronchiolitis will develop childhood asthma. Unfortunately, it remains unclear which infants will develop asthma and this knowledge gap has hindered primary prevention efforts. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01 AI-87881; Camargo, PI) is a 17-center prospective cohort study that completed enrollment of 926 infants hospitalized with bronchiolitis (85% ward, 15% intensive care unit) in April 2014. At start of the hospitalization, site investigators collected nasopharyngeal aspirates, nasal swabs, and blood, including items needed for the modified asthma predictive index (mAPI) and DNA. We also have extensive interview and medical records data. In an unfunded add-on study, site teams collected a nasal swab at hospitalization, and parents collected nasal swabs 3-weeks after the hospitalization and again over the summer when the child was healthy. There are extensive interview and survey data; and comprehensive medical records. Follow-up data include biannual parent interviews (~90% follow-up to date), and annual review of medical records. For timing reasons, the primary outcome of the 5- year U01 grant is recurrent wheezing by age 3 years. However, all participants were consented for follow-up to age 6 years to permit ascertainment of asthma. This revised R01 application includes preliminary data generated by testing nasal swabs from 102 participants at both hospitalization and 3 weeks later using 16S rRNA and real-time PCR and sequencing of respiratory syncytial virus and rhinovirus. Although these pilot data are underpowered, the statistically non-significant results suggest novel relations between the nasal microbiota, viral persistence, and recurrent wheezing. We found that increasing Gammaproteobacteria (e.g., Moraxella) was associated with an increased (OR 1.8, P=0.18), and increasing Lactobacillales (e.g., Lactobacillus) a decreased (OR 0.27, P=0.22), odds of recurrent wheezing by a median age of 2.2 years. Similarly, we found an increase in Gammaproteobacteria was associated with an increased (OR=1.9, P=0.19) and Lactobacillales with a decreased odds (OR=0.14, P=0.05) of viral persistence. Viral persistence is defined as having the same virus (delayed clearance) or a different virus (sequential infection) 3 weeks after hospitalization. And children with viral persistence had a non-significant increase in the odds of recurrent wheezing by a median age of 2.2 years (OR 1.8, P=0.21). Using the summer nasal swabs, we also examine if the dysbiosis present at hospitalization persists several months later. The R01 would provide funds to test the almost 2,000 nasal swabs from the entire MARC-35 cohort. We have >80% power in all Aims. The investigators are NIH-funded researchers with expertise in their fields. The study advances the primary prevention of asthma, and matches well with the 2009 NIH strategic plan for pediatric respiratory research.