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.

Public Health Relevance

In a 17-center prospective cohort study of 926 infants hospitalized with bronchiolitis, investigators propose to examine in a diverse U.S. cohort (~52% African-American or Hispanic) a novel relationship between the nasal microbiota, viral persistence, and recurrent wheezing. Results from the proposed study may lead to new treatment strategies for infants with severe bronchiolitis, a condition that often leads to childhood asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI108588-02
Application #
9067912
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Dong, Gang
Project Start
2015-05-14
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
Hasegawa, Kohei; Jartti, Tuomas; Bochkov, Yury A et al. (2018) Rhinovirus Species in Children with Severe Bronchiolitis: Multicenter Cohort Studies in the US and Finland. Pediatr Infect Dis J :
Stewart, Christopher J; Hasegawa, Kohei; Wong, Matthew C et al. (2018) Respiratory Syncytial Virus and Rhinovirus Bronchiolitis Are Associated With Distinct Metabolic Pathways. J Infect Dis 217:1160-1169
Luna, Pamela N; Hasegawa, Kohei; Ajami, Nadim J et al. (2018) The association between anterior nares and nasopharyngeal microbiota in infants hospitalized for bronchiolitis. Microbiome 6:2
Hasegawa, Kohei; Pérez-Losada, Marcos; Hoptay, Claire E et al. (2018) RSV vs. rhinovirus bronchiolitis: difference in nasal airway microRNA profiles and NF?B signaling. Pediatr Res 83:606-614
Hasegawa, K; Piedra, P A; Bauer, C S et al. (2018) Nasopharyngeal CCL5 in infants with severe bronchiolitis and risk of recurrent wheezing: A multi-center prospective cohort study. Clin Exp Allergy 48:1063-1067
Petrosino, Joseph F (2018) The microbiome in precision medicine: the way forward. Genome Med 10:12
Dumas, Orianne; Hasegawa, Kohei; Mansbach, Jonathan M et al. (2018) Severe bronchiolitis profiles and risk of recurrent wheeze by age 3 years. J Allergy Clin Immunol :
Hasegawa, Kohei; Stewart, Christopher J; Mansbach, Jonathan M et al. (2017) Sphingolipid metabolism potential in fecal microbiome and bronchiolitis in infants: a case-control study. BMC Res Notes 10:325
Hasegawa, Kohei; Linnemann, Rachel W; Mansbach, Jonathan M et al. (2017) Nasal Airway Microbiota Profile and Severe Bronchiolitis in Infants: A Case-control Study. Pediatr Infect Dis J 36:1044-1051
Stewart, Christopher J; Mansbach, Jonathan M; Wong, Matthew C et al. (2017) Associations of Nasopharyngeal Metabolome and Microbiome with Severity among Infants with Bronchiolitis. A Multiomic Analysis. Am J Respir Crit Care Med 196:882-891

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