In this multicenter retrospective study of 13,781 COVID-19 inpatient encounters, our results demonstrate an increased risk of ICU admission, mechanical ventilation, and in-hospital mortality conferred by COVID-19 bacterial co-infection that substantially exceeds previously described risk factors for severity and mortality (e.g., advanced age, male sex, select comorbidities) . The external validity of this result is enhanced by use of data spanning the two years of the pandemic (2020–2022) across two independent cohorts, as well as a 10-year pre-COVID-19 pandemic comparator cohort (2010–2019). Our investigation identified laboratory trends associated with COVID-19 bacterial co-infection and provide evidence that ≥ 15 NLR, temperature, white blood cell count, and heart rate components of the SIRS criterion can help healthcare providers discriminate COVID-19 bacterial co-infections within 24-h of admission. These results emphasize the role of bacteria in SARS-CoV-2 mortality and highlight the potential for NLR as a rapid and easily available prognostic biomarker of bacterial co-infection, and relatedly, disease severity.
A strength of this study is the use of large, demographically diverse, independent cohorts. The UAB cohort (n = 4075) reflects an academic hospital and level I trauma center servicing five surrounding states. The OLHS cohort (n = 9706) includes encounters from rural, suburban, and academic medical centers across the state of Louisiana. Despite the different clinical settings, both cohorts overall were well matched for patient age, race, sex, and inpatient LOS. Due to sufficiently sized cohorts, all risk factor and outcome modeling performed in this study did not use any form of imputed data. In agreement with previous studies, we found COVID-19 bacterial co-infection to be relatively infrequent in both UAB (2.5%, n = 110) and OLHS cohorts (2.7%, n = 240), with Staphylococcus aureus and Escherichia coli as the most frequent Gram-positive and Gram-negative pathogens recovered from 48-h post-admission blood cultures, respectively .
Prior studies have explored early biomarkers of COVID-19 co-infections including a 2021 multi-cohort study that reported an elevated baseline white blood cell count and stepwise decrease in CRP at two time points (admission and 48–72-h later) were sufficient to exclude COVID-19 bacterial co-infection in 46% of cases . A crucial limitation to this approach is the requirement of 3 laboratory measurements over a 72-h period, in addition to the modest observed exclusion rate. Here, our results confirm both the elevated CRP and white blood cell count findings as indicators of bacterial co-infection in COVID-19. In addition, we found elevated NLR, lactate, creatinine, and procalcitonin at 24-h post-admission, which raises the possibility of a novel co-infection prediction score that could help overcome the clinical lag associated with culture data and sequential (48–72-h later) laboratory values. Further studies will be needed to inform the robustness of elevated NLR for co-infection detection both in the context of COVID-19 and other viral co-infections such as influenza.
Bacterial co-infection is a major source of morbidity and mortality in the context of respiratory viral infections. A recent retrospective study from Lui et al. reported a 6.8% bacterial co-infection rate with influenza A or B viruses, parainfluenza virus, or respiratory syncytial virus with 10–13% 30-day mortality rate . Our results show that COVID-19 patients with confirmed bacteremic co-infections have double the 30-day mortality rate (UAB: 25%, OLHS: 20%) when compared to influenza virus bacterial co-infections . We determined that COVID-19 bacterial co-infections had a profound impact on increased likelihood of in-hospital mortality, ICU admission, and need for mechanical ventilation. Across both cohorts, the odds ratio for in-hospital mortality for COVID-19 co-infection was higher than the reported mortality odds ratio for influenza virus bacterial co-infection and was independent of SARS-CoV-2 variant [17, 28, 29]. Importantly, the 26% and 22% in-hospital mortality rates observed in the UAB and OLHS cohorts were fivefold higher than the community-acquired bacteremia encounters from the UAB pre-COVID-19 pandemic comparator cohort (5.9%) These results strongly suggest an underappreciated interaction between bacterial pathogens and SARS-CoV-2, and their impact on clinical outcomes.
In addition to the blood culture-positive co-infection group, the suspected co-infection population displayed increased odds ratios for markers of severe disease. This is partially explained by the association of increased disease severity at presentation prompting clinicians to manage the possibility of bacterial co-infection with initiation of antibacterial therapy and collection of blood cultures. However, another consideration is that co-infection for this study was strictly defined to pathogens recovered from blood culture. From a physiologic perspective, co-infection includes a broad variety of organisms involving multiple different tissues. However, accurately differentiating relevant pathogens from recovery of incidental or colonizing organisms is inherently difficult, particularly from sites such as the respiratory tract. Further, recovery of pathogens from the blood is influenced by the presence of antimicrobials prior to culture collection, either as an outpatient or shortly after presentation. Despite the restrictiveness of our approach and the low frequency of bacterial co-infection, our observations attribute a massive effect on morbidity and mortality to co-infection when viewed in context of the estimated 4 million hospitalizations for COVID-19 in the United States .
A critical question remains regarding the optimal therapeutic management of high-risk presentations of COVID-19 and potentially other respiratory viral pathogens. Although targeted antimicrobial therapy remains a mainstay of modern management of critically ill patients, results from a 2022 multi-omic study comparing broncho-alveolar lavage samples from influenza virus and COVID-19 co-infections showed that initiation of antimicrobials during COVID-19 co-infection did not alter lung inflammation . Notably, here nearly all patients identified in the co-infected group, and all patients in the suspected co-infection groups, had prompt initiation of antimicrobial treatment. These results suggest that antimicrobials alone may be insufficient to prevent progression to severe disease and worse clinical outcomes in COVID-19 bacterial co-infections. Interestingly, a variety of immune modulators for moderate and severe COVID-19 have been found to improve clinical outcomes, with limited evidence for secondary infections [24, 32,33,34,35]. Collectively, these observations suggest the possibility that targeted immune suppression may be beneficial in managing severe COVID-19 even in the setting of co-infection. Future multicenter studies focused on determining immunological correlates for disease severity and bacterial co-infection are warranted for COVID-19 and other respiratory viral pathogens.
This study has limitations. By applying a strict definition of bacterial co-infection based on blood cultures taken within 48-h of admission, our study deliberately decreased sensitivity for bacterial co-infection overall, and excluded other types of pathogens. We eliminated culture results from bacterial species likely to represent contaminant or colonizer species unlikely to represent active infection (Additional file 1: eFigs. 2–3). Another limitation in our analyses was poor coverage of vaccination status at time of presentation from both cohorts. This prevented inclusion of vaccination as a model variable for all outcome models, although our analysis that SARS-CoV-2 variant did not impact our findings, suggests that vaccination status did not drive our observations.
In conclusion, this retrospective multicenter analysis identified COVID-19 bacterial co-infections in independent cohorts using 48-h blood culture results. Our results show elevated neutrophil-to-lymphocyte ratio and components of the SIRS criteria as early, unambiguous, biomarkers of COVID-19 bacterial co-infections. Finally, we assessed the clinical impact of COVID-19 co-infection and found increased likelihood of ICU admission, mechanical ventilation, and in-hospital mortality compared to COVID-19 infection alone.