Preprint: Counterintuitive Effect of Antiviral Therapy on Influenza A & SARS-CoV-2 Coinfection Due to Viral Interference

When Epidemic Viruses Collide

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The hope over the past couple of years has been that COVID would eventually join the panoply of seasonal respiratory viruses - like seasonal influenza, RSV, Adenoviruses, and human coronaviruses - and transition to becoming less of a threat to public health.  

Between vaccines and boosters, acquired immunity, and a series of less virulent Omicron variants, we appear to be moving in that direction. 

This winter saw COVID co-circulate with influenza without apparent increased morbidity and mortality due to co-infections, and at a lower level than last year. 

While both are encouraging signs, we've previously seen indications that influenza and other respiratory infections can have a dampening effect on COVID transmission (see EID Journal Perspective: Viral Interference Between Respiratory Viruses), meaning we'll have to wait to see if we get a COVID rebound after our regular winter respiratory seasons ends. 

Viral interference refers to the impact infection by one virus might have on a concurrent or sequential infection by another (see Study: Human Rhinovirus Infection Blocks SARS-CoV-2 Replication Within the Respiratory Epithelium). 

In 2017's PLoS Comp. Bio.: Spring & Early Summer Most Likely Time For A Pandemic, researchers used `viral interference' and/or temporary immunity hypothesis as plausible explanations why historically pandemics almost always emerge in the spring or early summer; after the end of regular flu season.

This hypothesis may also help explain why the Flu Vaccination May Offer Some Protection Against COVID Infection. 

But the truth is, the interactions between multiple viruses, available therapeutics, and our own (only partially understood) immune systems, are far more complex than we imagine.  

All of which brings us to a preprint - published this week by researchers at the Yale School of Medicine - that finds that an existing influenza A infection dramatically inhibits the replication of SARS-CoV-2 viruses in human airway epithelium cells.

The authors found:

• Infection with IAV three days prior to SARS-CoV-2 led to more than 10,000-fold suppression of SARS-CoV-2 replication by 72 hr post-infection (Fig 1B, center)

• Simultaneous infection with SARS-CoV-2 and IAV also led to a significant decrease in SARS-CoV-2 viral load by day three post infection (Fig 1B, right)

• Conversely, SARS-CoV-2 co-infection under these conditions did not suppress IAV replication (Fig S1)

Counterintuitively, taking an antiviral like oseltamivir - which suppresses influenza virus replication - can revive SARS-CoV-2 replication, which may limit treatment options for co-infections. 

The abstract, and some excerpts from the preprint, follow:

Counterintuitive effect of antiviral therapy on influenza A-SARS-CoV-2 coinfection due to viral interference

Nagarjuna R. Cheemarla, Valia T. Mihaylova, Timothy A. Watkins, View ORCID ProfileEllen F. Foxman

doi: https://doi.org/10.1101/2023.02.07.527372

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Abstract

The resurgence of influenza and continued circulation of SARS-CoV-2 raise the question of how these viruses interact in a co-exposed host. Here we studied virus-virus and host-virus interactions during influenza A virus (IAV) -SARS-CoV-2 coinfection using differentiated cultures of the human airway epithelium. Coexposure to IAV enhanced the tissue antiviral response during SARS-CoV-2 infection and suppressed SARS-CoV-2 replication.

Oseltamivir, an antiviral targeting influenza, reduced IAV replication during coinfection but also reduced the antiviral response and paradoxically restored SARS-CoV-2 replication. These results highlight the importance of diagnosing coinfections and compel further study of how coinfections impact the outcome of antiviral therapy.

         (SNIP)

While the extent to which viral interference operates during coinfections in human subjects is still unknown, if this does occur, this study indicates important implications for therapy. Rapid point-of-care tests and antiviral drugs are available for both influenza A and SARS-CoV-2. While multiplex virology testing has gained traction over the past several years, it is still common practice for patients to undergo testing for one virus at a time and receive therapy if the test is positive. 

However, the results presented here indicate that in the case of an undiagnosed coinfection, treating only one virus could have the unanticipated consequence of increasing replication of the other. A clinical implication is that even when a point of care test for one of these viruses is positive, testing for coinfection may be advisable prior to treatment. 

Further studies in both animal models and human subjects are needed to fully understand the range of IAV-SARS-CoV-2 coinfection outcomes. However, this study contributes to growing evidence of the potential for interference between these viruses, illustrates that antiviral therapy during coinfection can have the unexpected outcome of promoting infection with the un-targeted virus due to viral interference.

As seasonal respiratory viruses increase in prevalence to pre-pandemic levels, these results highlight the importance of diagnosing coinfections and compel further study of how coinfections impact the outcome of antiviral therapy.

         (Continue . . . )

Somewhat surprisingly, while Influenza suppresses SARS-CoV-2 infection and replication, SARS-CoV-2 does not appear to have the same dampening effect on influenza. 

All of which suggests we still have a lot to learn about how these viruses will interact going forward.