Hospitalised adults with COVID-19 and flu at the same time are at substantially greater risk of severe disease and death compared with patients who have COVID-19 alone or with other viruses, a large UK study in The Lancet shows. They were more than four times more likely to require ventilation support and 2.4 times more likely to die.
Researchers say the findings show the need for greater flu testing of COVID-19 patients in hospital and highlight the importance of full vaccination against both COVID-19 and flu.
The team from the University of Edinburgh, University of Liverpool, Leiden University and Imperial College London, made the findings in a study of more than 305,000 hospitalised patients with COVID-19.
The research, delivered as part of the International Severe Acute Respiratory and emerging Infection Consortium’s (ISARIC) Coronavirus Clinical Characterisation Consortium, is the largest ever study of people with COVID-19 and other endemic respiratory viruses.
ISARIC’s study was set up in 2013 in readiness for a pandemic such as this. The team looked at the data of adults who had been hospitalised with COVID-19 in the UK between 6 February 2020 and 8 December 2021.
Test results for respiratory viral co-infections were recorded for 6,965 patients with COVID-19. Some 227 of these also had the influenza virus, and they experienced significantly more severe outcomes.
Dr Maaike Swets, PhD student at the University of Edinburgh and Leiden University, said: “In the past two years we have frequently witnessed patients with COVID-19 become severely ill, at times leading to an ICU admission and the employment of an artificial ventilator to help with breathing. That an influenza infection could give rise to a similar situation was already known, but less was understood about the outcomes of a double infection of SARS-CoV-2 and other respiratory viruses.”
Professor Kenneth Baillie, professor of Experimental Medicine at the University of Edinburgh, said: “We found that the combination of COVID-19 and flu viruses is particularly dangerous. This will be important as many countries decrease the use of social distancing and containment measures. We expect that COVID-19 will circulate with flu, increasing the chance of co-infections. That is why we should change our testing strategy for COVID patients in hospital and test for flu much more widely.”
Professor Calum Semple, professor of Outbreak Medicine and Child Health at the University of Liverpool, said: “We are seeing a rise in the usual seasonal respiratory viruses as people return to normal mixing. So, we can expect flu to be circulating alongside COVID this winter. We were surprised that the risk of death more than doubled when people were infected by both flu and COVID-19 viruses. It is now very important that people get fully vaccinated and boosted against both viruses, and not leave it until it is too late.”
Dr Geert Groeneveld, doctor at Leiden University Medical Centre’s infectious diseases department, said: “Understanding the consequences of double infections of SARS-CoV-2 and other respiratory viruses is crucial as they have implications for patients, hospitals and ICU capacity during seasons that SARS-CoV-2 and influenza circulate together.”
Professor Peter Openshaw, professor of Experimental Medicine at Imperial College London, said: “Being infected with more than one virus is not very common but it’s important to be aware that co-infections do happen. The vaccines that protect against COVID and flu are different, and people need both. The way that these two infections are treated is also different so it’s important to test for other viruses even when you have a diagnosis in someone who is hospitalised with a respiratory infection. This latest discovery by the ISARIC consortium again adds significantly to improving the way we manage patients.”
The findings were published in The Lancet.
SARS-CoV-2 co-infection with influenza viruses, respiratory syncytial virus, or adenoviruses
Maaike Swets, Clark Russell, Ewen Harrison, Annemarie Docherty, Nazir Lone, Michelle Girvan, Hayley Hardwick, Leonardus Visser, Peter Openshaw, Geert Groeneveld, Malcolm Semple, Kenneth Baillie.
Published in The Lancet on 2022
Measures to reduce transmission of SARS-CoV-2 have also been effective in reducing the transmission of other endemic respiratory viruses.
As many countries decrease the use of such measures, we expect that SARS-CoV-2 will circulate with other respiratory viruses, increasing the probability of co-infections. The clinical outcome of respiratory viral co-infections with SARS-CoV-2 is unknown.
We examined clinical outcomes of co-infection with influenza viruses, respiratory syncytial virus, or adenoviruses in 212 ,466 adults with SARS-CoV-2 infection who were admitted to hospital in the UK between Feb 6, 2020, and Dec 8, 2021, using the International Severe Acute Respiratory and Emerging Infection Consortium–WHO Clinical Characterisation Protocol.
Tests for respiratory viral co-infections were recorded for 6,965 patients with SARS-CoV-2. Viral co-infection was detected in 583 (8·4%) patients: 227 patients had influenza viruses, 220 patients had respiratory syncytial virus, and 136 patients had adenoviruses. Co-infection with influenaza viruses was associated with increased odds of receiving invasive mechanical ventilation compared with SARS-CoV-2 monoinfection. SARS-CoV-2 co-infections with influenza viruses and adenoviruses were each significantly associated with increased odds of death.
To extrapolate these results from the tested population to a representative hospitalised population, we accounted for differences between tested and non-tested patients using inverse probability weighting. In this weighted multivariable regression analysis, influenza virus co-infection significantly increased the odds of receiving invasive mechanical ventilation and the odds of in-hospital mortality.
This study had several strengths. First, it is the largest study of people with COVID-19 undergoing additional testing for endemic respiratory viruses, reporting 583 confirmed co-infections and 6382 confirmed SARS-CoV-2 monoinfections. Second, we recruited patients over an 18-month duration. Finally, we report outcome data for most patients.
The study also has a few limitations. A risk of selection bias exists because tested patients differed from untested patients, particularly in severity of illness: being more unwell increased the probability of testing for co-infections. After correction for these and other differences with inverse probability weighting analysis, influenza virus co-infection remained associated with receipt of invasive mechanical ventilation, with an odds ratio that was larger than in the unweighted analysis but with wider confidence intervals.
As in the unweighted analysis, SARS-CoV-2 co-infection with respiratory syncytial virus or adenoviruses was not significantly associated with receipt of invasive mechanical ventilation. Furthermore, adenoviruses and respiratory syncytial virus co-infections did not have the same effect on the receipt of invasive mechanical ventilation as did influenza virus co-infection, making it unlikely that this association is limited to the tested population rather than the hospital population.
A similar result was seen in the weighted multivariable regression analysis with in-hospital mortality as the outcome variable, with a larger odds ratio in the weighted analysis than in the unweighted analysis. The case report form used for data collection did not collect the date of testing for additional viruses, and testing would probably have been done after admission; therefore community versus nosocomial acquisition cannot be established. As hospital-acquired viral respiratory infection is rare, we assume that viral co-infection was present at the time of hospital admission in most study patients.
Finally, because vaccination data for influenza viruses were not registered in the database, and since most patients were admitted before COVID-19 vaccinations were available, we were unable to establish the effect of influenza viruses or SARS-CoV-2 vaccination on outcome in monoinfected and co-infected patients.
As public health restrictions are lifted, respiratory virus co-infections are more likely to occur during future winters. The marked increase in risk among patients with co-infection has several implications for policy.
First, our results provide further support for vaccination against both SARS-CoV-2 and influenza viruses. Second, they suggest that testing for influenza viruses is important in hospital inpatients with COVID-19 to identify patients at risk and a cohort of patients who might have different responses to immunomodulatory and antiviral therapy.
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