Discussion

In this systematic review and meta-analysis, we included 955 laboratory-confirmed COVID-19 patients coinfected with influenza or RSV and 6907 patients infected with SARS-CoV-2 alone from 12 retrospective observational studies. We found that co-infection with influenza was associated with a 2-fold increase in the risk for ICU admission and for mechanical ventilation among COVID-19 patients whereas evidence was limited on the role of RSV co-infection. Co-infection with influenza did not seem to increase the risk of death in COVID-19 patients.
The 2-fold increase in the risk of ICU admission and receiving mechanical ventilation in COVID-19 patients coinfected with influenza could have important implications for the clinical management. COVID-19 patients who received influenza positive tests before or upon admission might benefit from early interventions that could prevent or slow disease deterioration. This also highlights the importance of influenza vaccination program that might have been suspended because of the COVID-19 pandemic28.
Earlier systematic reviews that compared co-infections of any viruses (rather than co-infection of influenza as used in this study) with mono-infection among COVID-19 patients did not observe any statistical differences in ICU admission between the co-infection and mono-infection groups 29–31. This suggests that the increased risk of ICU admission in the co-infection group observed in our study was likely to be influenza-specific. One of the possible explanations is that influenza co-infection could predispose patients to secondary bacterial infections, which could lead to more severe clinical outcomes32,33. This explanation is supported by a recently published study in Israel that observed substantial reductions in pneumococcal diseases in young children during the COVID-19 pandemic; the authors showed that the reductions in pneumococcal and pneumococcus-associated diseases were not predominantly related to reduced pneumococcal carriage and density but were strongly associated with the disappearance of specific respiratory viruses such as influenza34. The role of influenza co-infection in the increased severity of COVID-19 patients was also supported by influenza probe studies. In a large Brazilian cohort study of over 53,000 COVID-19 patients, those who received a recent influenza vaccine had 7% lower risks of requiring intensive care treatment (95% CI: 2% to 13%) and 17% lower risks of requiring invasive respiratory support (95% CI: 12% to 23%)35. Moreover, a recently published animal model study found that simultaneous or sequential co-infection by SARS-CoV-2 and the influenza A(H1N1)pdm09 strain caused more severe disease than mono-infection by either virus in hamsters 36.
However and interestingly, a systematic review and meta-analysis by Guan and colleagues reported that influenza co-infection lowered the risk for critical outcomes (composite outcomes including any of shock, being admitted to ICU and requiring ventilatory support), with the pooled OR of 0.64 (0.43 to 0.97) based on five studies 37. As this was contrary to the findings of our study, we closely compared the methodology and the extractions between our study and that by Guan and colleagues; in addition to the use of the composite outcomes as mentioned above that differed from our study, the meta-estimate by Guan and colleagues was largely driven by a preprint that only had univariate OR available for extraction. Moreover, there seemed to be a discrepancy in the extracted OR in the study by Guan and colleagues — one of the included studies, by Stowe and colleagues, 19 reported that COVID-19 patients with influenza co-infection were around twice as likely to be ventilated (OR 2.15, 1.20 to 3.84) or to be admitted to ICU (OR 2.08, 1.17 to 3.70) through multivariate analysis whereas the OR was extracted as 0.91 (0.41 to 2.02) in the report by Guan and colleagues. After removing the preprint and correcting the extraction above from the included studies by Guan and colleagues, the updated OR in their study reversed — 1.76 (1.06 to 2.92), which re-confirmed the robustness of the meta-estimates in our study (details are provided in Figure S4).
Our meta-analysis revealed that co-infection with SARS-CoV-2 and influenza had no observable effects on the overall mortality in both the main and the two sensitivity analyses (i.e., excluding studies with small sample size and excluding low-quality studies). Nonetheless, these findings did not yet indicate that co-infection of influenza did not increase the risks of mortality. We could not rule out type II error (i.e., false negative) due to the limited statistical power; most studies had less than 50 COVID-19 patients with co-infections and the median number of deaths is 1 (IQR: 0-4). Moreover, the point estimates from the main and sensitivity analyses were consistently above 1, favouring the association between influenza co-infection and mortality.
Similar to influenza co-infection, no effects on the overall mortality were observed for RSV co-infection but this was only based on three small studies. Our review highlighted the gaps in the knowledge on the role of RSV co-infection in COVID-19 disease severity. A retrospective study among six children’s hospitals in the United States revealed that one in six COVID-19 inpatients under 18 years old had viral co-infections, with two thirds of viral co-infections being RSV co-infections; the proportion of viral co-infections was even higher in infants under one year — one in three infants hospitalized for COVID-19 had viral co-infections, with almost three quarters of them having RSV co-infections 38. The substantial proportion of RSV co-infection among paediatric COVID-19 patients calls for further research on the possible synergistic effects of the RSV and SARS-CoV-2 in this vulnerable age group.
At the time of writing of this manuscript, a large-scale study from the UK (including about 7000 COVID-19 patients) was published, which reported that that influenza co-infection was associated with increased odds of receiving invasive mechanical ventilation among COVID-19 patients (OR: 4.1, 2.0 to 8.5) in a multivariable regression analysis, further confirming the findings of our study39. The authors of that study did not find any significant associations for co-infection with other viruses including adenovirus and RSV, confirming our speculation that the association on viral co-infection and COVID-19 clinical severity is specific to influenza. Ad-hoc inclusion of the estimates from that study did not substantially change our meta-estimates (Table S2).
We acknowledge some limitations of this study. Several factors could contribute to heterogeneity in the findings of the studies, such as study population (including age and sex), case definition, laboratory method and statistical method; we were unable to explicitly account for these variations. In the present review, there were only four studies applying multivariate analyses to adjust for common confounders between co-infections and severity outcomes. Although restricting to these high-quality studies did not substantially change any of our findings, this highlighted the lack of high-quality studies on the role of co-infections and COVID-19 disease severity. We were also unable to account for bacterial co-infection in the analysis due to the absence of data that had reliable laboratory confirmation on viral and bacterial infections. Compared with other outcomes, mortality as the proxy for disease severity was more likely to be affected by variations in clinical treatment, which could confound the estimates if treatment differed by status of co-infection. All of the included studies were conducted in 2020 when the activity of influenza and RSV was on the course to gradual reduction; it remains unknown whether the resurgence of influenza and RSV could modify the association reported in this review.
Despite these limitations, this systematic review and meta-analysis includes a comprehensive summary with extensive literature search, and critical appraisal and synthesis of existing evidence on the role of influenza and RSV co-infection in the clinical severity of COVID-19 patients. While our study highlights the gaps in research on this topic particularly for RSV, existing evidence suggests that influenza co-infection could increase the disease severity of COVID-19 patients, which could have important implications for clinical management as well as influenza vaccination campaign in the context of resurgence of influenza among other respiratory viruses in the post-COVID-19 era.
Competing interests: YL reported grants from the World Health Organization and Wellcome Trust, outside the submitted work. All other authors declared that they have no competing interests.
Funding: This work receive1234-d support from the Nanjing Medical University Talents Start-up Grants (NMUR20210008).
Access to data: The study data are available from the corresponding author upon reasonable request.
Authorship contribution: BC – led data extraction, analysis and interpretation and wrote the manuscript;SD ­– contributed to data extraction and quality assessment; XW ­– contributed to interpretation and critically reviewed the manuscript; YL – conceptualised the study, provided critical oversight to data extraction, analysis and interpretation and critically reviewed the manuscript. The corresponding author (YL) had full access to all the data in the study and was responsible for the decision to submit the manuscript for publication.