The interactions of SARS-CoV-2 with co-circulating pathogens: Epidemiological implications and current knowledge gaps

Despite the availability of effective vaccines, the persistence of SARS-CoV-2 suggests that co-circulation with other pathogens and resulting multi-epidemics -- such as twindemics of COVID-19 and influenza -- will become increasingly frequent. To better forecast and control the risk of such multi-epidemics, it is essential to elucidate the potential interactions of SARS-CoV- 2 with other pathogens; these interactions, however, remain poorly defined. Here, we aimed to review the current body of evidence about SARS-CoV-2 interactions. To study pathogen interactions in a systematic way, we first developed a general framework to capture their major components - namely, sign, strength, symmetry, duration, and mechanism. We then reviewed the experimental evidence from animal models about SARS-CoV-2 interactions. The studies identified demonstrated that SARS-CoV-2 and influenza A virus co-infection increased disease severity compared with mono-infection. By contrast, the effect of previous or co-infection on viral load of either virus was inconsistent across studies. Next, we reviewed the epidemiological evidence about SARS-CoV-2 interactions in human populations. Although numerous studies were identified, only few were specifically designed to infer interaction and many were prone to bias and confounding. Nevertheless, their results suggested that influenza and pneumococcal conjugate vaccinations were associated with reduced risk, and earlier influenza infection with increased risk, of SARS-CoV-2 infection and severe COVID-19. Finally, we formulated simple transmission models of SARS-CoV-2 co-circulation with a virus or a bacterium, showing how they can naturally incorporate the proposed framework. More generally, we propose that such models, when designed with an integrative and multidisciplinary perspective, will be invaluable tools in studying SARS-CoV-2 interactions with other pathogens.