Saturday, October 17, 2020

PrePrint: Sequential Infection with Influenza A virus Followed by SARS-CoV-2 (In a Mouse Model)


Three weeks ago, in PHE Study: Co-Infection With COVID-19 & Seasonal Influenzawe looked at a Public Health England study that warned that being co-infected with influenza and COVID more than doubles the risk of death over having COVID alone.

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


While being infected with Influenza lowered the risk of contracting SARS-CoV-2 (likely due to `viral interference'), among those who did contract both, they determined `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.'

In an attempt to better understand the mechanisms behind their increased mortality rate linked to dual infections, researchers at  University of Liverpool, Liverpool School of Tropical Medicine and the University of Zurich sequentially infected mice with influenza A and SARS-CoV-2 and then monitored the course of their illness.

They found that mice co-infected fared significantly worse than those infected with either Influenza A or SARS-CoV-2. While obviously bad news for mice, this also raises concerns for this year's flu season in humans. 

First the link abstract from the Pre-print study, followed by excerpts from a press release published by the University of Liverpool.   You'll of course want to read both in their entirety.

Jordan J. Clark, Rebekah Penrice-Randal, Parul Sharma, Anja Kipar, Xiaofeng Dong, Andrew Davidson, Maia Kavanagh Williamson, View ORCID ProfileDavid A. Matthews, Lance Turtle, Tessa Prince, View ORCID ProfileGrant L. Hughes, Edward I. Patterson, Ghada Shawli, Krishanthi Subramaniam, Jo Sharp, Lynn McLaughlin, En-Min Zhou, Joseph D. Turner, Amy E. Marriott, Stefano Colombo, Shaun H. Pennington, Giancarlo Biagini, Andrew Owen, Julian A. Hiscox, View ORCID ProfileJames P. Stewart


COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2, a recently emerged coronavirus that has rapidly caused a pandemic. Coalescence of a second wave of this virus with seasonal respiratory viruses, particularly influenza virus is a possible global health concern. To investigate this, transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) were first infected with IAV followed by SARS-CoV-2.

 The host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 only. Infection of mice with each individual virus resulted in a disease phenotype compared to control mice. Although, SARS-CoV-2 RNA synthesis appeared significantly reduced in the sequentially infected mice, these mice had a more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to singly infected or control mice. 
The sequential infection also exacerbated the extrapulmonary manifestations associated with SARS-CoV-2. This included a more severe encephalitis. Taken together, the data suggest that the concept of “twinfection” is deleterious and mitigation steps should be instituted as part of a comprehensive public health response to the COVID-19 pandemic.

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Study highlights risks associated with the sequential infection of influenza followed by COVID-19

A Liverpool-led study* provides evidence that the ‘twinfection’ of influenza and COVID-19 may exacerbate the health risk associated with COVID-19.

When multiple pathogens are in circulation at the same time this can lead to cooperative or competitive forms of pathogen-pathogen interactions. This concept of co-infection was evident during the outbreak of the Spanish flu in 1918 with secondary bacterial pneumonia co-infecting many patients suffering from the influenza A virus and causing a more severe outcome.

Recently there have been several case reports of coinfections with influenza and SARS-Cov-2 in humans with COVID-19. One study from the UK reported that patients with a coinfection exhibited up to six times higher risk of death.


To ascertain the health risks associated with the ‘twinfection’ researchers from the University of Liverpool, Liverpool School of Tropical Medicine and the University of Zurich sequentially co-infected mice with influenza and SARS-CoV-2. The work was led by Professor James Stewart and Professor Julian Hiscox from the University of Liverpool’s Institute of Infection, Ecological and Veterinary Sciences.

Infected mice mirror many features of severe COVID-19 infection in humans and are a model used to develop understanding of lung disease and to test pharmacological interventions. Animal models of COVID-19 present critical tools to fill knowledge gaps for the disease in humans and for screening therapeutic or prophylactic interventions. While animal models can’t predict with total accuracy the consequences of coinfection in humans, the data presented will have implications for development of successful pre-emptive interventions for SARS-CoV-2 and the clinical management of COVID-19.

Results – ‘Important implications’

The researchers found that the infection of mice with these viruses resulted in disease and then recovery. However, sequential infection with influenza virus and then SARS-CoV-2 displayed overt clinical symptoms that were worse than the individual infections.

Interestingly in the sequentially infected mice, whilst the replication of SARS-CoV-2 was diminished compared to mice infected with this virus alone, there was an enhanced inflammatory response. This is a key driver for severe COVID-19 infection in humans and plays a significant role in mortality.

Reflecting this, sequentially infected mice exhibited significantly more rapid mortality compared with mice infected with either virus alone. These results suggest that infection with both viruses leads to an exacerbation of pathological processes.

This evidence highlights important implications for the ongoing pandemic. As countries across the globe come out of a period of lockdown, the rate of infection of SARS-CoV-2 is likely to increase and as many countries head toward flu season, attention should be focussed not only slowing the transmission of SARS-CoV-2 but also reducing influenza infections as part of a comprehensive public health response to mitigate the effects of co-infection.

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While it isn't known yet how much of a factor influenza A will be this winter in the Northern Hemisphere (it was practically a no-show in the Southern Hemisphere this year) - or how effective this year's flu shot will be against circulating strains - early coinfection reports from the PHE and this latest study suggest you really want to avoid having a double whammy this year. 

While mask wearing, hand hygiene, and social distancing will certainly help, getting the flu shot this fall makes a lot of sense.  I got mine (and the pneumonia vax) in late September, and I'm urging others to consider doing the same. 

For more on vaccine protection this winter, you may wish to revisit:

The Conversation: Until a Coronavirus Vaccine Is Ready, Pneumonia Vaccines May Reduce Deaths From COVID-19