COVID-19 bacteremic co-infection is a major risk factor for mortality, ICU admission, and mechanical ventilation

Abstract

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.

Fig. 1

Accrual of COVID-19 bacterial co-infection encounters from the UAB and OLHS cohorts

Fig. 2

Elevated neutrophil-to-lymphocyte ratio (≥ 15) in COVID-19 bacterial co-infection patients is independent of dexamethasone treatment within 48-h of hospital admission. Post-admission laboratory trends for COVID-19 inpatient encounters pooled from both the UAB and OLHS cohorts and stratified by confirmed, suspected, and no bacterial co-infection and 48-h dexamethasone treatment. Mean laboratory values with standard error bars from day of admission (day 0) to 4 days post-admission are shown for patients with A dexamethasone treatment within 48-h (solid lines) and B no dexamethasone treatment within 48-h (dashed line), all stratified by COVID-19 co-infection status. Statistical significance was assessed using Bonferroni corrected t-tests: (p < 0.0001 = ****/####, p < 0.001 = ***/###, p < 0.01 = **/##, p < 0.05 = */#). Reference group (red): Confirmed co-infection 48-h post-admission blood culture (+). Comparison group 1 (light blue, *): No co-infection. Comparison group 2 (dark blue; #): Suspected co-infection 48-h post-admission blood culture (−). UAB, University of Alabama at Birmingham cohort; OLHS, Ochsner Louisiana State University Health—Shreveport cohort

Fig. 3

Elevated neutrophil-to-lymphocyte ratio (≥ 15) and select SIRS score components are prognostic indicators of COVID-19 bacterial co-infection. Adjusted odds ratios and 95% CIs for COVID-19 bacterial co-infection post-admission risk factors are shown for the UAB (green) and OLHS (purple) cohorts. Accompanying co-infection rates and Wald test statistical significance are reported for each model variable. SIRS components were restricted to the first reading within 24-h of admission. Neutrophil-to-lymphocyte ratio was computed with first complete blood count measurement taken within 24-h of admission. n, total inpatient encounters; C, Celsius temperature; SIRS, systemic inflammatory response syndrome; CI, Confidence interval; OR, adjusted odds ratio; UAB, University of Alabama at Birmingham cohort; OLHS, Ochsner Louisiana State University Health—Shreveport cohort

Fig. 4

COVID-19 bacterial co-infection confers greater increased risk for in-hospital mortality, mechanical ventilation, and ICU admission than previously identified COVID-19 severity risk factors. Multivariable logistic regression models show confirmed COVID-19 co-infection is the greatest contributor to increased likelihood of in-hospital mortality (red), mechanical ventilation (green), and ICU admission (dark gray). Model variables included culture status within 48-h of admission (reference*: no 48-h blood culture), age ≥ 65 (reference*: age < 65), male sex (reference*: female sex), 24-h post-admission SIRS score ≥ 2 (reference*: 24-h post-admission SIRS score < 2), diabetic history, COPD history, heart failure or MI history, renal disease history (reference*: no pre-admission history of respective comorbidity). For model details see Additional file 1: eTables 2–4. Reference*, reference not shown; SIRS, severe inflammatory response syndrome score; MI, myocardial infarction; COPD, chronic obstructive pulmonary disease; UAB, University of Alabama at Birmingham cohort; OLHS, Ochsner Louisiana State University Health—Shreveport cohort