86 Chapter 4 co-infection shows, 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 using in-hospital mortality as the outcome variable, with a larger OR in the weighted analysis compared to the unweighted analysis (2.49 vs 1.61, respectively). The case report form used for data collection did not collect the date of testing for additional viruses and it is likely testing would have been done after admission and therefore community versus nosocomial acquisition cannot be determined. As hospital acquired viral respiratory infection is rare30, we assume that viral co-infection was present at hospital admission in the majority of our study patients. Lastly, because influenza vaccination data were not registered in the database and since most patients were admitted before COVID-19 vaccinations were available, we were unable to determine the impact of influenza or SARS-CoV-2 vaccination on outcome in mono- and co-infected patients. Influenza virus and SARS-CoV-2 can both cause severe damage in the lungs and lead to ARDS2,18.In a comparison of plasma samples from fatal H1N1 influenza A virus infection and SARS-CoV-2, we have previously demonstrated that in comparison to COVID-19, influenza is associated with a comparatively greater elevation in concentrations of some pro-inflammatory cytokines (IL-18, IL-1β) and pro-thrombotic mediators (vWF-A2, tissue factor, thrombomodulin), and equivalent concentrations of IL-631. In contrast, elevated GM-CSF is a distinct feature of COVID-19. It is plausible that co-infection with influenza viruses and SARS-CoV-2 could ‘synergise’ activation of innate immunity and exacerbate immunopathology, increasing pulmonary damage and progression to ARDS2. Testing this hypothesis in samples from co-infected patients is an important research goal. Although respiratory viral co-infections were uncommon during the first two years of the pandemic, as public health guidance changes and social mixing increases, cocirculation of additional respiratory viruses will also increase leading to more coinfections. Concerningly, we report an association between influenza co-infection and receipt of IMV and in-hospital mortality, in addition to adenovirus and in-hospital mortality. This emphasises the importance of preventive measures to reduce the disease burden associated with these viruses, in particular influenza vaccination. The adoption of more widespread testing would facilitate identification of hospital inpatients at high risk of deterioration and death, and may identify patients in whom different therapeutic strategies may be more effective.
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