COVID-19 Bacteremic Co-infection Is a Major Risk Factor for Mortality, ICU Admission, and Mechanical Ventilation

Michael John Patton; Carlos J. Orihuela; Kevin S. Harrod; Mohammad A. N. Bhuiyan; Paari Dominic; Christopher G. Kevil; Daniel Fort; Vincent X. Liu; Maha Farhat; Jonathan L. Koff; Charitharth V. Lal; Anuj Gaggar; Robert P. Richter; Nathaniel Erdmann; Matthew Might; Amit Gaggar


Crit Care. 2023;27(34) 

In This Article

Abstract and Introduction


Background: Recent single-center reports have suggested that community-acquired bacteremic co-infection in the context of Coronavirus disease 2019 (COVID-19) may be an important driver of mortality; however, these reports have not been validated with a multicenter, demographically diverse, cohort study with data spanning the pandemic.

Methods: In this multicenter, retrospective cohort study, inpatient encounters were assessed for COVID-19 with community-acquired bacteremic co-infection using 48-h post-admission blood cultures and grouped by: (1) confirmed co-infection [recovery of bacterial pathogen], (2) suspected co-infection [negative culture with ≥ 2 antimicrobials administered], and (3) no evidence of co-infection [no culture]. The primary outcomes were in-hospital mortality, ICU admission, and mechanical ventilation. COVID-19 bacterial co-infection risk factors and impact on primary outcomes were determined using multivariate logistic regressions and expressed as adjusted odds ratios with 95% confidence intervals (Cohort, OR 95% CI, Wald test p value).

Results: The studied cohorts included 13,781 COVID-19 inpatient encounters from 2020 to 2022 in the University of Alabama at Birmingham (UAB, n = 4075) and Ochsner Louisiana State University Health—Shreveport (OLHS, n = 9706) cohorts with confirmed (2.5%), suspected (46%), or no community-acquired bacterial co-infection (51.5%) and a comparison cohort consisting of 99,170 inpatient encounters from 2010 to 2019 (UAB pre-COVID-19 pandemic cohort). Significantly increased likelihood of COVID-19 bacterial co-infection was observed in patients with elevated ≥ 15 neutrophil-to-lymphocyte ratio (UAB: 1.95 [1.21–3.07]; OLHS: 3.65 [2.66–5.05], p < 0.001 for both) within 48-h of hospital admission. Bacterial co-infection was found to confer the greatest increased risk for in-hospital mortality (UAB: 3.07 [2.42–5.46]; OLHS: 4.05 [2.29–6.97], p < 0.001 for both), ICU admission (UAB: 4.47 [2.87–7.09], OLHS: 2.65 [2.00–3.48], p < 0.001 for both), and mechanical ventilation (UAB: 3.84 [2.21–6.12]; OLHS: 2.75 [1.87–3.92], p < 0.001 for both) across both cohorts, as compared to other risk factors for severe disease. Observed mortality in COVID-19 bacterial co-infection (24%) dramatically exceeds the mortality rate associated with community-acquired bacteremia in pre-COVID-19 pandemic inpatients (5.9%) and was consistent across alpha, delta, and omicron SARS-CoV-2 variants.

Conclusions: Elevated neutrophil-to-lymphocyte ratio is a prognostic indicator of COVID-19 bacterial co-infection within 48-h of admission. Community-acquired bacterial co-infection, as defined by blood culture-positive results, confers greater increased risk of in-hospital mortality, ICU admission, and mechanical ventilation than previously described risk factors (advanced age, select comorbidities, male sex) for COVID-19 mortality, and is independent of SARS-CoV-2 variant.


Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of Coronavirus disease 2019 (COVID-19), has resulted in over 6.3 million deaths worldwide.[1] Studies conducted in the first year of the pandemic identified advanced age, select comorbidities, male sex, leukopenia, neutrophilia, and several small nucleotide polymorphisms as major risk factors for disease severity and post-infection mortality.[2–4] Bacterial co-infection in COVID-19 was initially reported to have low prevalence with limited contribution to overall severity and mortality.[5–16] Despite these early reports, recent evidence suggests that bacterial co-infection in COVID-19 may influence mortality, although large-scale multicenter studies have not validated this hypothesis.[17]

Reported COVID-19 co-infection rates have ranged from 2 to 8% but consistently appear less than the influenza co-infection rates as reported in the 1918 pandemic and the estimated 34% co-infection rate of the 2009 influenza A (H1N1) pandemic.[6,7,18–20] Mortality rates from COVID-19 co-infection have varied widely from twofold compared to non-co-infected COVID-19 patients, to having no effect on mortality among co-infected ICU patients.[5,8,17,21] Several issues confound a reliable determination of co-infection prevalence and associated morbidity, notably inconsistent definitions of co-infection, limited sample size without independent multicenter cohorts, and inclusion of outpatient encounters in co-infection event rate calculations.[5,7] Here, we defined bacterial co-infection as the presence of a pathogenic isolate from a sterile site, blood, as determined by positive blood cultures taken within 48-h of admission. This approach provides an analysis that discriminates true pathogens from incidental or colonizing organisms, enabling a consistent assessment of co-infection across cohorts and their impact on clinical outcomes.

The primary aims of this retrospective study were to define: (1) the prevalence of COVID-19 co-infections, (2) the impact of COVID-19 co-infection and SARS-CoV-2 variant strain on clinical outcomes including ICU admission, need for invasive mechanical ventilation, and in-hospital mortality utilizing two independent cohorts, and (3) early biomarkers associated with bacterial co-infection. We hypothesized that bacterial co-infection contributes to poor clinical outcomes in COVID-19 subjects irrespective of SARS-CoV-2 variant, and that early recognition of co-infection is possible with routinely gathered laboratory and vital sign measurements.