Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis

Abstract

Little is known about the relationship between the specific airway microbiota composition and severity of bronchiolitis. We aimed to identify nasopharyngeal microbiota profiles and link these profiles to acute severity in infants hospitalised for bronchiolitis.We conducted a multicentre prospective cohort study of 1005 infants (age <1 year) hospitalised for bronchiolitis over three winters, 2011-2014. By applying a 16S rRNA gene sequence and clustering approach to the nasopharyngeal aspirates collected within 24 h of hospitalisation, we determined nasopharyngeal microbiota profiles and their association with bronchiolitis severity. The primary outcome was intensive care use, i.e. admission to an intensive care unit or use of mechanical ventilation.We identified four nasopharyngeal microbiota profiles: three profiles were dominated by one of Haemophilus, Moraxella or Streptococcus, while the fourth profile had the highest bacterial richness. The rate of intensive care use was highest in infants with a Haemophilus-dominant profile and lowest in those with a Moraxella-dominant profile (20.2% versus 12.3%; unadjusted OR 1.81, 95% CI 1.07-3.11, p=0.03). After adjusting for 11 patient-level confounders, the rate remained significantly higher in infants with Haemophilus-dominant profiles (OR 1.98, 95% CI 1.08-3.62, p=0.03). These findings were externally validated in a separate cohort of 307 children hospitalised for bronchiolitis.

Figure 1. Clustering and Composition in Nasopharyngeal Microbiota of 1005 Infants Hospitalized for Bronchiolitis, MARC-35

All nasopharyngeal microbiota profiles of infants were clustered using partitioning around medoids clustering method with weighted UniFrac distance. Colored bars indicate 4 microbiota profiles: Haemophilus-dominant profile (green), Moraxella-dominant profile (red), Streptococcus-dominant profile (yellow), and mixed profile (blue). The optimal number of clusters was identified by the Silhouette index. To obtain further information about the bacterial composition of samples within microbiota profiles, the 10 most abundant genera present in an adjacent heatmap were displayed. The taxonomy depicted is on the genus level because each genus was dominated by one operational taxonomic unit. HDP = Haemophilus-dominant profile; MDP = Moraxella-dominant profile; SDP = Streptococcus-dominant profile; MP = mixed profile.

Figure 2. Independent Association of Relative Abundance of Haemophilus Genus with the Rate of Severity Outcomes in Infants Hospitalized for Bronchiolitis, MARC-35

Two-level mixed-effects models were constructed to account for patient clustering at the hospital level. The models adjusted for 11 patient-level variables (i.e., age, sex, race/ethnicity, gestational age, history of breathing problems, daycare attendance, siblings at home, lifetime history of antibiotic use, history of corticosteroid use, use of antibiotics during the pre-hospitalization visit, and respiratory viruses detected by PCR). A) There was a positive linear association between relative abundance of Haemophilus genus and the rate of intensive care use (adjusted OR, 1.07 [per 0.1 increase in the relative abundance of Haemophilus]; 95%CI, 1.01-1.13; P=0.03). B) There was a positive linear association between relative abundance of Haemophilus genus and the rate of a hospital length-of-stay of ≥3days (adjusted OR, 1.11 [per 0.1 increase in the relative abundance of Haemophilus]; 95%CI, 1.06-1.17; P<0.001).