Association between disease severity and co-detection of respiratory pathogens in infants with RSV infection
Authors: Lin Gu-Lung , Drysdale Simon B , Snape Matthew D , O’Connor Daniel , Brown Anthony , MacIntyre-Cockett George , Mellado-Gomez Esther , de Cesare Mariateresa , Ansari M Azim , Bonsall David , Bray James E , Jolley Keith A , Bowden Rory , Aerssens Jeroen , Bont Louis , Openshaw Peter J M , Martinon-Torres Federico , Nair Harish , Golubchik Tanya , Pollard Andrew J 
Published: February 2023

AbstractBACKGROUNDRespiratory syncytial virus (RSV) is the leading cause of hospitalisation associated with acute respiratory infection in infants and young children, with substantial disease burden globally. The impact of additional respiratory pathogens on RSV disease severity is not completely understood.OBJECTIVESThe objective of this study was to explore the associations between RSV disease severity and the presence of other respiratory pathogens.METHODSNasopharyngeal swabs were prospectively collected from two infant cohorts: a prospective longitudinal birth cohort study and an infant cross-sectional study recruiting infants <1 year of age with RSV infection in Spain, the UK, and the Netherlands during 2017–20 [part of the REspiratory Syncytial virus Consortium in EUrope (RESCEU) project]. The samples were sequenced using targeted metagenomic sequencing with a probe set optimised for high-resolution capture of sequences of over 100 pathogens, including all common respiratory viruses and bacteria. Viral genomes and bacterial genetic sequences were reconstructed. Associations between clinical severity and presence of other pathogens were evaluated after adjusting for potential confounders, including age, gestational age, RSV viral load, and presence of comorbidities.RESULTSRSV was detected in 433 infants. Nearly one in four of the infants (24%) harboured at least one additional non-RSV respiratory virus, with human rhinovirus being the most frequently detected (15% of the infants), followed by seasonal coronaviruses (4%). In this cohort, RSV-infected infants harbouring any other virus tended to be older (median age: 4.3 vs. 3.7 months) and were more likely to require intensive care and mechanical ventilation than those who did not.Moraxella, Streptococcus, andHaemophilusspecies were the most frequently identified target bacteria, together found in 392 (91%) of the 433 infants (S. pneumoniaein 51% of the infants andH. influenzaein 38%). The strongest contributors to severity of presentation were younger age and the co-detection ofHaemophilusspecies alongside RSV. Across all age groups in both cohorts, detection ofHaemophilusspecies was associated with higher overall severity, as captured by ReSVinet scores, and specifically with increased rates of hospitalisation and respiratory distress. In contrast, presence ofMoraxellaspecies was associated with lower ReSVinet scores and reduced need for intensive care and mechanical ventilation. Infants with and withoutStreptococcusspecies (orS. pneumoniaein particular) had similar clinical outcomes. No specific RSV strain was associated with co-detection of other pathogens.CONCLUSIONOur findings provide strong evidence for associations between RSV disease severity and the presence of additional respiratory viruses and bacteria. The associations, while not indicating causation, are of potential clinical relevance. Awareness of coexisting microorganisms could inform therapeutic and preventive measures to improve the management and outcome of RSV-infected infants.