Our findings show that development of SI in critically ill patients with a viral pneumonia was not different between our COVID-19 and influenza cohorts. In our cohort, the development of SI in COVID-19 patients was associated with significant morbidity and healthcare resource use.

The incidence of SI was greater than 50% in both the COVID-19 and influenza cohorts. The adjusted OR relating the risk of SI to viral infection type was 1.0, but the 95% CI for the OR included values consistent with both a two-fold increase and a 50% decrease with COVID-19 compared with influenza. The sites of infection and causative pathogens were not different between groups. The SI rate that we describe is higher than that reported in the previous influenza cohort studies,6,22 which may relate to the critically ill nature of our cohort. In our COVID-19 cohort, the rate of SI (55%) is also higher than previously reported, even in the critically ill population,17,18,19 although admittedly the range previously reported is broad. We speculate this could be due to the extremely sick nature of our cohort, including patients who either received or were assessed for ECMO. The pathogens responsible for SI in the COVID-19 cohort were typical of organisms commonly associated with SI in other viral pneumonias or hospital-acquired infections.

These findings highlight the magnitude of SI among patients with viral pneumonia and associated significant implications at both patient and healthcare system levels. As the global pandemic continues to place enormous strain on local and national healthcare resources, any modifiable factors that may reduce the burden of COVID-19 should be explored. Our study supports the implementation and continuation of systems of care directed at preventing nosocomial infection.

Our findings are consistent with the previous reports20 indicating that SI are likely to happen upwards of a week after hospital admission. These results should be used to inform decision-making when initiating empiric antibiotherapy when SI is clinically suspected. The ability to minimize unnecessary antibiotic exposures is required to prevent development of antibiotic-resistant organisms and promote antibiotic stewardship.

In the COVID-19 cohort, patients with SI showed significantly longer hospital and ICU stays and greater duration of mechanical ventilation compared with patients who did not develop SI (Table 6). Increased morbidity and mortality in ICU patients with COVID-19 and SI have also been shown in other studies focused on this population.12,13

There are two plausible mechanisms explaining the association of increased length of stay of critically ill patients with COVID-19 and SI in both the hospital and ICU: SI extends recovery from COVID-19, but also an extended hospital and ICU course predisposes to higher frequency of SI. The observational design of our study means we cannot differentiate between these mechanisms.

Steroid use was associated with SI in the COVID-19 cohort. Our study occurred before the results of RECOVERY were published,23 when the use of steroid therapy in COVID-19 patients was not standard of care. Steroids were prescribed at the discretion of the treating clinician and possibly for various indications—viral pneumonia, shock, and treatment of cryptogenic organizing pneumonia. Although we have showed an association of steroids and SI, we cannot infer causality because of the observational nature of the study. In addition, the relatively low use of steroids in our study (21% of all COVID-19 patients; 20 patients total) makes it challenging to associate steroid use with specific infections. Nevertheless, a significant strength of our study is the possibility (because of the timing of data collection) to compare the incidence of SI in those receiving steroids with that of a control group who did not receive steroids—this quickly became impossible with publication of the RECOVERY trial. Therefore, despite the small sample size, this is a unique and interesting finding (Table 7).

In this historical cohort study, we are unable to differentiate between association and causation of SI and increased morbidity among our COVID-19 cohort. It may be that SI did not cause an increase in morbidity and that this subset of COVID-19 patients were more critically ill from the outset and therefore more likely to have longer hospital and ICU stays and extended mechanical ventilation. Interestingly, there was a higher prevalence of chronic lung disease and immunosuppression among the influenza cohort, which would be expected to predispose to worse clinical outcomes if they had developed a SI, but this was not seen. This speaks to COVID-19’s broad mechanisms in causing severe illness and thus, despite the rate of SI not being statistically different, clinical outcomes in this population were worse.

Another limitation of this study is the subjective nature of diagnosing bacterial infections and potential difficulty differentiating infection from colonization (in pneumonia for example). Nevertheless, we used CDC definitions for bacterial infections and if there was any disagreement between the authors a full discussion was had and consensus reached.

While the relatively smaller size of our comparison cohort is a drawback, we feel that the 2018–2019 influenza season was the best control group to use considering the severity and high level of critical illness locally during this influenza season. The 47 patients with influenza were all the patients admitted to the TGH and TWH ICUs that season, so it was not possible to increase this sample size. A consequence is that the CI for the OR relating risk of SI to COVID-19 is wide and cannot rule out what may be important increases or decreases in risk. A case-matched retrospective study may have addressed this limitation although would mean not all available COVID-19 patient data would be used. We do, however, feel that the comparison of the COVID-19 with the influenza cohort in an identical clinical setting is a unique strength of this study. The diversity of our population is also a unique strength of this study.

Finally, we recognize that much has changed since the initial wave of the pandemic in terms of therapeutic options. In particular, the use of steroids and other immunomodulators (e.g., IL6 receptor antagonist, tocilizumab) is now standard of care in critically ill patients.23,24 The impact of these therapies on SI has not been extensively studied, but mechanistically, they should increase rates of SI because of their immunomodulatory role. The multivariate analysis of our COVID-19 cohort receiving steroids showed significantly higher rates of SI, although number of patients analyzed was small. It is also feasible that effective therapeutic treatments may shorten the course of critical illness making patients less prone to nosocomial illness.23,24,25 Our study, because of its timing in early 2020, provides a unique comparison between critically ill patients who received steroids and those who did not.

Many previous studies of SI lacked sufficient detail to allow application to specific patient groups with major limitations being failure to differentiate between healthcare settings (critically ill vs not), lack of granular detail on SI, and their risk factors.26

We addressed gaps in the literature by focusing on ICU patients, extracting extensive detail from available data, and having a control group—a critically ill influenza cohort—with influenza having a known association with SI.

Finally, our study includes a clinically diverse critically ill population with both patients referred to TGH from across the province and patients directly admitted via the emergency department to TWH and TGH.