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Abstract
Background Bronchiolitis is the leading cause of hospitalisation of US infants and an important risk factor for childhood asthma. Recent evidence suggests that bronchiolitis is clinically heterogeneous. We sought to derive bronchiolitis endotypes by integrating clinical, virus and lipidomics data and to examine their relationship with subsequent asthma risk.
Methods This is a multicentre prospective cohort study of infants (age <12 months) hospitalised for bronchiolitis. We identified endotypes by applying clustering approaches to clinical, virus and nasopharyngeal airway lipidomic data measured at hospitalisation. We then determined their longitudinal association with the risk for developing asthma by age 6 years by fitting a mixed-effects logistic regression model. To account for multiple comparisons of the lipidomics data, we computed the false discovery rate (FDR). To understand the underlying biological mechanism of the endotypes, we also applied pathway analyses to the lipidomics data.
Results Of 917 infants with bronchiolitis (median age, 3 months), we identified clinically and biologically meaningful lipidomic endotypes: (A) cinicalclassiclipidmixed (n=263), (B) clinicalseverelipidsphingolipids-high (n=281), (C) clinicalmoderatelipidphospholipids-high (n=212) and (D) clinicalatopiclipidsphingolipids-low (n=161). Endotype A infants were characterised by ‘classic’ clinical presentation of bronchiolitis. Profile D infants were characterised by a higher proportion of parental asthma, IgE sensitisation and rhinovirus infection and low sphingolipids (eg, sphingomyelins, ceramides). Compared with endotype A, profile D infants had a significantly higher risk of asthma (22% vs 50%; unadjusted OR, 3.60; 95% CI 2.31 to 5.62; p<0.001). Additionally, endotype D had a significantly lower abundance of polyunsaturated fatty acids (eg, docosahexaenoic acid; FDR=0.01). The pathway analysis revealed that sphingolipid metabolism pathway was differentially expressed in endotype D (FDR=0.048).
Conclusions In this multicentre prospective cohort study of infants with bronchiolitis, integrated clustering of clinical, virus and lipidomic data identified clinically and biologically distinct endotypes that have a significantly differential risk for developing asthma.Delete
- asthma
- paediatric asthma
Data availability statement
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Data availability statement
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Footnotes
Contributors MF carried out the main statistical analysis, drafted the initial manuscript and approved the final manuscript as submitted. ZZ, YR and TO assisted statistical analysis, reviewed the manuscript and approved the final manuscript. JCCC collected the data, reviewed and revised the manuscript, and approved the final manuscript as submitted. RF conducted specimen processing, supervised RNA sequencing and data generation, reviewed and revised the manuscript, and approved the final manuscript as submitted. CAC conceptualised and designed the study, obtained funding, collected the data, supervised the conduct of study and the analysis, critically reviewed and revised the initial manuscript, and approved the final manuscript as submitted. KH conceptualised and designed the study, obtained funding, supervised the statistical analysis, reviewed and revised the initial manuscript, approved the final manuscript as submitted, and is the guarantor of this publication.
Funding This study was supported by grants from the National Institutes of Health (Bethesda, MD): U01 AI-087881, R01 AI-114552, R01 AI-108588, R01 AI-134940, and UG3/UH3 OD-023253.
Competing interests JCCC has received research materials from Pharmavite (vitamin D and placebo capsules) and GSK and Merck (inhaled steroids) to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work.
Provenance and peer review Not commissioned; externally peer reviewed.
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