Tuesday, September 22, 2020

PHE Study: Co-Infection With COVID-19 & Seasonal Influenza



Last year's Northern Hemisphere flu season ended early and abruptly with the arrival of COVID-19, and this year's Southern Hemisphere flu season never really materialized, leaving us with a paucity of information on the interactions (including co-infections) between the SARS-COV-2 pandemic virus and seasonal influenza. 

We did see a few early reports of some co-infections with COVID-19 (see last April's IDCases: Co-infection With SARS-CoV-2), but the sampling size was too small to gauge the impact, other than  to establish that co-infection with other respiratory viruses (influenza, parainfluenza, etc.) was possible. 

In the past, co-infection with different flu viruses has been a concern due to influenza's ability to swap genetic material (reassortment), and potentially produce a hybrid offspring (see MMWR: Seasonal H3N2 & H1N1pdm09 Reassortant Infection — Idaho, 2019). Fortunately, this is not a concern with COVID-19, as it is structurally quite different from influenza, making reassortment impossible. 

But the potential health impact on an individual simultaneously infected with COVID-19 and seasonal flu is well understood.  

Overnight the British press has been filled with headlines of a PHE (Public Health England) study that warns that being co-infected with influenza and COVID doubles the risk of death over having COVID alone.  A few examples:

Warning over dire consequences of Covid and flu ‘co-infection’

The source of these media reports is a study - published on a the medRxiv pre-print server - portions of which I've excerpted below.  

As we've discussed previously (see When Epidemic Viruses Collide), this study found evidence of viral interference, meaning that if you already have influenza, you are (at least temporarily) less likely to be infected with SARS-CoV-2. 

This effect was also seen during the 2009 H1N1 pandemic, as some countries that reported rampant rhinovirus outbreaks in the fall of 2009 saw far less H1N1 activity than expected (see 2009 New Scientist article Common cold may hold off swine flu).

But - based on a relatively small sample (n=58) of UK co-infections last spring -  for those unlucky enough to be infected by both influenza and SARS-CoV-2 (COVID-19), the risk of severe illness and/or death appears to increase substantially. 

You'll want to follow the link to read it in its entirety.  I'll have a brief postscript when you return.

Interactions between SARS-CoV-2 and Influenza and the impact of coinfection on disease severity: A test negative design


Corresponding author: Dr Jamie Lopez Bernal

Public Health England 61 Colindale Ave, London NW9 5EQ, London England

Jamie.LopezBernal2@phe.gov.uk Tel: 0208 3276528



The potential impact of COVID-19 alongside influenza on morbidity, mortality and health service capacity is a major concern as the Northern Hemisphere winter approaches. This study investigates the interaction between influenza and COVID-19 during the latter part of the 2019-20 influenza season in England.


Individuals tested for influenza and SARS-CoV-2 were extracted from national surveillance systems between 20/01/2020 and 25/04/2020. To estimate influenza infection on the risk of SARS-CoV-2 infection, univariable and multivariable analyses on the odds of SARS-CoV-2 in those who tested positive for influenza compared to those who tested negative for influenza. To assess whether a coinfection was associated with severe SARS-CoV-2 outcome, univariable and multivariable analyses on the odds of death adjusted for age, sex, ethnicity, comorbidity and coinfection status.


The risk of testing positive for SARS-CoV-2 was 68% lower among influenza positive cases, suggesting possible pathogenic competition between the two viruses. Patients with a coinfection had a risk of death of 5.92 (95% CI, 3.21-10.91) times greater than among those with neither influenza nor SARS-CoV-2 suggesting possible synergistic effects in coinfected individuals. The odds of ventilator use or death and ICU admission or death was greatest among coinfection patients showing strong evidence of an interaction effect compared to SARS-CoV-2/influenza acting independently.


Cocirculation of these viruses could have a significant impact on morbidity, mortality and health service demand. Testing for influenza alongside SARS-CoV-2 and maximising influenza vaccine uptake should be prioritised to mitigate these risks.

Funding: This study was funded by Public Health England


We found that influenza infection was associated with a lower risk of SARS-CoV-2 infection, suggesting that there may be pathogenic competition between these two viruses. We also found strong evidence that coinfection with influenza and SARS-CoV-2 was associated with an increased risk of death or severe disease and that this appears to be beyond the additive effect of the two viruses acting independently.
The risk of testing positive for SARS-CoV-2 was 68% lower among influenza positive cases. This is consistent with recent descriptive evidence from New York where < 3% of those testing positive for SARS-CoV-2 had coinfection with influenza whereas 13% of those testing negative for SARS-CoV-2 were influenza positive 22 . It is also consistent with existing evidence on the interaction between influenza and seasonal coronavirus and rhinovirus 3-5,23 . There are biologically plausible mechanisms for such an effect, including stimulation of non-specific immune responses by the first infectious agent, such as the induction of a refractory state in bystander cells as a result of the antiviral effect of interferon induced as part of an innate immune response to an RNA viral infection.

The results from this study indicate that the risk of death was nearly six times greater among individuals with a SARS-CoV-2 and influenza coinfection than those with neither influenza nor SARS-CoV-2 and that this effect is significantly higher than the risk associated with SARS-CoV-2 infection alone
Similarly, the combined outcomes of ventilator use or death and ICU admission or death gave similar results. These findings suggest a possible synergistic effect between SARS-CoV-2 and influenza once an individual is coinfected. The high mortality rate is consistent with case reports of severe outcomes in coinfected patients 12,13,29 . Conversely, some case series have not seen increased severity with influenza and SARS-CoV-2 co-infection, where the outcomes have been similar to cases with SARS-CoV-2 only 30,31 . Synergistic effects have previously been reported between influenza and other respiratory viruses, for example by facilitating cell to cell spread 32 .  

         (Continue . . .) 

While we don't know to what extent seasonal flu will return this winter - the UK's plan to `maximize' the flu vaccine uptake this winter makes sense - as it should make it easier to triage and differentiate between flu and COVID cases, will hopefully reduce the number of flu beds the NHS will need this winter, and should prevent some of these serious co-infections. 

Ironically, however, increased flu vaccination could also reduce the amount of `viral interference' caused by this year's influenza season, and that could marginally increase the number of COVID cases. 

As a practical matter, any immunity due to influenza infection is almost certainly short-lived, lasting a matter of weeks or a few months.  In the grand scheme of things, I doubt it will make much difference to the attack rate of COVID-19.  

Even so, I worry the anti-vaccination contingent will try to use this as `proof' that getting the flu vaccine increases your chances of getting COVID-19.

While there is no perfect solution for flu or our COVID pandemic, I will be rolling up my sleeve again this month, and getting the flu vaccine.  As we've seen time and time again (see CDC: Another Study Linking Severe Influenza To Heart Damage) the benefits of the flu vaccine  - even accepting its moderate protection - far exceed the risks.