Large-scale prevention of respiratory syncytial virus (RSV) infection may have ecological consequences for co-circulating pathogens, including influenza. We assessed if and for how long RSV infection alters the risk for subsequent influenza infection.

We analysed a prospective longitudinal cohort study conducted in South Africa between 2016 and 2018. For participating households, nasopharyngeal samples were taken twice weekly, irrespective of symptoms, across three respiratory virus seasons, and real-time polymerase chain reaction (PCR) was used to identify infection with RSV and/or influenza. We fitted an individual-level hidden markov transmission model in order to estimate RSV and influenza infection rates and their interdependence.

Of a total of 122113 samples collected, 1265 (1.0%) were positive for influenza and 1002 (0.8%) positive for RSV, with 15 (0.01%) samples from 12 individuals positive for both influenza and RSV. We observed 2.25-fold higher incidence of co-infection than expected if assuming infections were unrelated. We estimated that infection with influenza is 2.13 (95% CI 0.97 - 4.69) times more likely when already infected with, and for a week following, RSV infection, adjusted for age. This equates to 1.4% of influenza infections that may be attributable to RSV in this population. Due to the local seasonality (RSV season precedes the influenza season), we were unable to estimate changes in RSV infection risk following influenza infection.

RSV infection was associated with an increased risk for influenza infection for a short period after infection. However, the impact on population-level transmission dynamics of this individual-level synergistic effect was not measurable in this setting.

Evidence before this study We searched PubMed titles and abstracts for the terms “influenza”, “RSV” or “Respiratory syncytial virus” and “interaction”, “competition” or “enhancement” resulting in 56 articles, excluding reviews. Evidence for the potential interaction of influenza and RSV originates from analyses of viral surveillance and experimental non-human studies, or isolated mathematical models. Most such studies suggest potential competitive exclusion of RSV and Influenza but are prone to potential confounding and unable to test the links between biological mechanisms and population level impacts.

Added value of this study This longitudinal study with frequent testing of participants for colonisation with RSV and Influenza allows sufficient resolution to analyse direct evidence for interaction of both viruses on colonisation. In contrast to evidence insofar we find that the effect of RSV colonisation on the risk for influenza acquisition is short lived and synergistic, but unlikely to substantially effect influenza epidemiology on population level.

Implications of all the available evidence RSV infections are likely to have limited impact on influenza circulation.

The authors have declared no competing interest.

The study was funded through a cooperative agreement with the United States Centers for Disease Control and Prevention (CDC) (grant number 1U01IP001048). Testing for RSV was supported by the Bill and Melinda Gates Foundation (Grant number: OPP1164778). The data analyses were supported by Germanys Innovation Fund of the Joint Federal Committee (grant no. 01VSF18015).

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The ethics committee of London School of Hygiene and Tropical Medicine gave ethical approval for this work. The ethics committee of the University of Witwatersrand gave ethical approval for this work

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