Abstract
Background
The impact of steroid treatment on mortality outcomes in patients with coronavirus disease 2019 (COVID-19) has been widely demonstrated, while its effect on secondary infections, such as bloodstream infections (BSIs), is controversial. Recent studies have reported the survival benefits of using steroids for a standard duration compared to extended use, though their impact on the risk of BSIs remains debated. This study investigated whether extended steroid use is associated with the risk of BSIs and mortality in critically ill patients with COVID-19.
Methods
This national multicenter retrospective study conducted at 22 university-affiliated hospitals evaluated the effect of steroid treatment duration in hospitalized patients with COVID-19 treated with more than high-flow nasal cannula therapy. Patients were divided into two groups according to the duration of corticosteroid treatment: extended (> 10 days) and standard (≤ 10 days). Propensity score matching was performed by adjusting for covariates. Baseline characteristics and clinical outcomes were compared between the two groups.
Results
Among 1,114 patients, 378 with a hospital length of stay (LOS) exceeding 10 days were included. Each group of the propensity score–matched cohort had 189 patients, with no significant differences in demographic characteristics between the two groups, except for the incidence of BSIs (extended group vs. standard group, 49.7% vs. 36.0%, P = 0.043). After adjusting for confounding factors, extended use of steroids remained significantly associated with BSIs (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.25–4.04; P = 0.007). The use of a mechanical ventilator, extracorporeal membrane oxygenation, continuous renal replacement therapy, and a longer hospital LOS were associated with BSIs. In-hospital mortality was associated with an older age, higher body mass index, higher sequential organ failure assessment score at admission, and the presence of a BSI (OR, 2.47; 95% CI, 1.50–4.05; P < 0.001). Kaplan-Meier survival analysis demonstrated no significant difference in in-hospital mortality between the extended and standard groups.
Conclusion
Extended steroid therapy was significantly associated with a higher incidence of BSIs in critically ill patients with COVID-19.
Keywords: Coronavirus, Adrenal Cortex Hormones, COVID-19, SARS-CoV-2, Steroids, Bloodstream Infections, Korea
Graphical Abstract
INTRODUCTION
Most patients with coronavirus disease 2019 (COVID-19) experience a mild course of the disease; however, a minority may develop severe pneumonia, leading to life-threatening respiratory failure or acute respiratory distress syndrome. Currently, the standard treatment for COVID-19 is stratified based on the severity of the disease.1
Systemic steroids have been widely administered during the COVID-19 pandemic. In recent studies, such as the RECOVERY trial and several meta-analyses, reduced mortality was observed with steroid treatment in patients with COVID-19, especially in those who required oxygen support with or without a mechanical ventilator.2,3,4 Based on these results, guidelines recommend the use of steroids in hospitalized patients with severe illness who require high-flow nasal cannula oxygen delivery, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).1,4,5 The RECOVERY trial evaluated the administration of 6 mg of dexamethasone once daily for up to 10 days, which is the current recommended dose for hospitalized adults with COVID-19.2 Although there is clear evidence that steroids can benefit some patients with COVID-19 who require oxygen therapy, many unresolved issues remain.
To date, there are no definitive answers regarding the optimal dose and type of steroids, timing of initiation, and duration of administration in patients with severe COVID-19. Furthermore, steroids can cause various adverse effects. Generally, steroid administration is associated with hyperglycemia, steroid-induced neuromyopathy, gastrointestinal bleeding, and secondary infections.6,7,8,9 Critically ill patients are particularly susceptible to secondary infections. This increased vulnerability is due to the frequent performance of invasive procedures, such as mechanical ventilation, and the use of central venous catheters.10,11 Several clinical trials have aimed to investigate secondary infection as an adverse event during steroid treatment in patients with COVID-19; however, most were discontinued after the release of the results of the RECOVERY trial or did not show sufficient statistical power.12,13,14 Additionally, studies addressing the relationship between the duration of steroid use and the risk of bloodstream infection (BSI) in patients with severe COVID-19 are lacking.
In this study, using data from critically ill patients with COVID-19 treated at 22 university-affiliated hospitals across South Korea, we investigated the risk factors for BSI in these patients who received steroid treatment, including the duration of steroid use, and examined the factors influencing their prognosis.
METHODS
Study population
This was a nationwide, multicenter, retrospective observational cohort study using data collected from patients admitted to 22 university-affiliated hospitals between January 2020 and August 2021. The eligible subjects were hospitalized patients with COVID-19 aged ≥ 19 years who had received high-flow nasal cannula oxygen, mechanical ventilation, or ECMO. Patient registration protocols dictated the exclusion of patients who were not hospitalized in the intensive care unit (ICU), did not undergo blood cultures, did not receive oxygen therapy, or received only low-flow oxygen therapy. Among the original cohort, patients with missing values in matching covariants or those with a hospital length of stay (LOS) and ICU LOS shorter than 10 days were excluded from the study.
Data collection and definitions
The following data were collected by trained coordinators at each center: 1) demographic data, including age, sex, body mass index (BMI), laboratory findings, comorbidities, the Clinical Frailty Scale, COVID-19 vaccination status, timing of COVID-19 diagnosis, and sequential organ failure assessment (SOFA) score at hospital admission; 2) initial dose of steroids and duration of steroid treatment; 3) ICU admission treatment and information regarding the use of rescue therapies, including remdesivir, tocilizumab, vasopressors, ECMO, and continuous renal replacement therapy (CRRT); 4) cultured pathogens during hospitalization; and 5) clinical outcomes, such as in-hospital mortality and hospital and ICU LOS.
Patients were divided into two groups according to the duration of steroid treatment: extended (> 10 days) and standard (≤ 10 days). BSI development was defined as a positive blood culture for one or more bacterial or fungal organisms occurring at least 48 hours after ICU admission, and multiple infections in one individual were counted as one BSI case. Polymicrobial infections were not separately specified. Data were reviewed by two separate investigators to determine whether the organism was clinically significant or a contaminant. Isolates from blood cultures were excluded if they were considered contaminants and not true causes of BSI, based on clinical and microbiological data, and in accordance with CDC criteria.15,16 In cases of disagreement between the two investigators, the discordant cases were discussed with an infectious disease specialist, and a final decision was made. The initial steroid dose was defined as the dexamethasone-equivalent dose.
Propensity score matching
Propensity score matching was performed to mitigate the potential bias caused by confounding variables, acknowledging the likelihood of uneven baseline patient characteristics between the extended and standard groups. After excluding patients with missing values in the matching covariates, propensity score matching was performed using the nearest-neighbor method to produce balanced cohorts and evaluate the effects of steroid duration. Patients were matched 1:1 by propensity score using the covariates of age, sex, BMI, COVID-19 vaccination status, comorbidities such as diabetes mellitus, cardiovascular disease, chronic lung disease, chronic neurological disease, an immunocompromised state, connective tissue disease, hematologic malignancy and solid tumor, absolute neutrophil count, partial pressure of oxygen (PaO2), fraction of inspired oxygen (FiO2), SOFA score at admission, Clinical Frailty Scale score at admission, hospital LOS, use of mechanical ventilation, use of ECMO, use of CRRT, tocilizumab treatment, and initial dose of steroids as the confounding factors.
Statistical analysis
Continuous variables are expressed as medians and interquartile ranges and categorical variables as numbers and percentages. Baseline characteristics were compared using the χ2 test or Fisher’s exact test for categorical variables and the t-test or Mann-Whitney U test for continuous variables. Multivariate logistic regression analyses were performed to investigate the association between patient characteristics and in-hospital mortality or the presence of BSI. In addition to the duration of steroid use, the model included clinically meaningful variables (age, BMI, initial steroid dose, PaO2/FiO2 ratio, SOFA score, use of mechanical ventilation, ECMO use, CRRT use, and hospital LOS). Clinical parameters with a P value of 0.05 in the univariate logistic regression were included in the multivariate logistic regression. To evaluate the goodness-of-fit of the logistic regression model, we used the Hosmer-Lemeshow test.17 The test results indicated an adequate fit between the model and the observed data. The goodness-of-fit was computed to assess the relevance of the logistic regression model. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. The probabilities of in-hospital survival for each group were estimated using the Kaplan-Meier method and compared using the log-rank test. All tests were two-sided, and P values < 0.05 were considered statistically significant. All statistical analyses were performed using R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria).
Ethics statement
This study was conducted in accordance with the relevant legislation and the protocol was approved by the Ethics Committee of Seoul St. Mary’s Hospital (KC23RIDI0860). The study complies with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines, and the requirement for informed consent was waived due to the retrospective design of the study.
RESULTS
Baseline characteristics
Among 1,114 patients with COVID-19, 166 were excluded. A total of 948 patients were included in the final study (Fig. 1). The baseline patient characteristics are presented in Table 1. All the patients included in this study were prescribed steroids. The median duration of steroid use was 13.0 days (10.0–22.0) and the initial dexamethasone-equivalent dose was 6 mg (6.0–10.0). BSI occurred in 192 cases, with ICU and in-hospital mortality observed in 205 (21.6%) and 236 cases (24.9%), respectively.
Fig. 1. Study flow diagram.
COVID-19 = coronavirus disease 2019, ICU = intensive care unit, LOS = length of stay.
Table 1. Baseline characteristics of the overall study population.
| Characteristics | Values (N = 948) | ||
|---|---|---|---|
| Age, yr | 69.0 (60.0–77.0) | ||
| Sex, male | 573 (60.4) | ||
| BMI, kg/m2 | 24.6 (22.2–27.1) | ||
| COVID-19 variant surge | |||
| Pre-delta dominant period (2020.1.20–2021.7.24) | 786 (82.9) | ||
| Delta dominant period (2021.7.25–2022.1.15) | 161 (17.0) | ||
| Omicron dominant period (2022.1.16–2022.9.3) | 1 (0.1) | ||
| History of COVID-19 vaccination (n = 847) | 45 (5.3) | ||
| Underlying diseases | |||
| Hypertension | 516 (54.4) | ||
| Diabetes | 317 (33.4) | ||
| Cardiovascular disease | 108 (11.4) | ||
| Chronic lung disease | 75 (7.9) | ||
| Chronic neurological disease | 121 (12.8) | ||
| Chronic kidney disease | 68 (7.2) | ||
| Chronic liver disease | 27 (2.8) | ||
| Immunocompromised | 25 (2.6) | ||
| Connective tissue disease | 13 (1.4) | ||
| Hematologic malignancies | 14 (1.5) | ||
| Solid tumor | 67 (7.1) | ||
| Clinical Frailty Scale score at admission | 3.0 (2.0–4.0) | ||
| Treatment | |||
| Remdesivir | 713 (75.2) | ||
| Tocilizumab | 85 (9.0) | ||
| Steroids | 948 (100.0) | ||
| Duration of steroid use, days | 13.0 (10.0–22.0) | ||
| Initial dose of steroids (dexamethasone-equivalent), mg | 6.0 (6.0–10.0) | ||
| Vital signs | |||
| Systolic blood pressure, mmHg | 132.0 (119.0–146.0) | ||
| Diastolic blood pressure, mmHg | 75.0 (67.0–85.0) | ||
| Heart rate, beats/min | 80.0 (70.0–92.0) | ||
| Respiratory rate, breaths/min | 22.0 (20.0–26.0) | ||
| Body temperature, ℃ | 36.8 (36.4–37.4) | ||
| Glasgow Coma Scale score | 15.0 (15.0–15.0) | ||
| PaO2/FiO2 ratio | 140.0 (92.9–201.7) | ||
| SOFA score | 4.0 (3.0–5.0) | ||
| Life-supporting interventions | |||
| High-flow nasal cannula therapy | 772 (81.4) | ||
| Mechanical ventilation | 576 (60.8) | ||
| Extracorporeal membrane oxygenation | 116 (12.2) | ||
| Renal replacement therapy | 110 (11.6) | ||
| Outcomes | |||
| Blood stream infection | 192 (20.3) | ||
| ICU length of stay, days | 16.0 (10.0–29.0) | ||
| Hospital length of stay, days | 23.0 (15.5–40.0) | ||
| ICU mortality | 205 (21.6) | ||
| In-hospital mortality | 236 (24.9) | ||
Data are presented as number (percentage) or median (interquartile range).
BMI = body mass index, COVID-19 = coronavirus disease 2019, SOFA = sequential organ failure assessment, ICU = intensive care unit, PaO2 = partial pressure of oxygen, FiO2 = fraction of inspired oxygen.
Clinical characteristics and outcomes before and after propensity score matching according to duration of steroid treatment
The clinical characteristics and outcomes of the short and extended steroid treatment groups are shown in Table 2. In this study, 608 patients (64.1%) were treated with steroids for more than 10 days. The proportion of patients with cardiovascular disease and hematological malignancy in the extended group was higher than that in the standard group (13.5% vs. 7.6%, P = 0.009 and 2.3% vs. 0.0%, P = 0.011, respectively). Additionally, the extended group exhibited a higher proportion of patients who received tocilizumab (10.7% vs. 5.9%, P = 0.019) and a higher initial steroid dosage (6.0 mg [6.0–11.7] vs. 6.0 mg [6.0–6.0], P < 0.001). The PaO2/FiO2 ratio was lower (131.2 [91.0–196.8] vs. 147.5 [101.3–241.1], P = 0.004) and the SOFA score was higher (4.0 [3.0–6.0] vs. 4.0 [3.0–5.0], P = 0.007) in the extended group. Moreover, a greater percentage of patients in the extended group required mechanical ventilation (66.6% vs. 50.3%, P < 0.001) and there was a higher incidence of BSI (23.2% vs. 15.0%, P = 0.003). Furthermore, both ICU LOS (17.0 days [11.0–34.0] vs. 14.0 [10.0–24.0], P < 0.001) and hospital LOS (25.0 days [17.0–46.0] vs. 20.0 [13.0–29.5], P < 0.001) were significantly longer in the extended group.
Table 2. Baseline characteristics and outcomes before and after propensity score matching.
| Characteristics | Unmatched (N = 948) | Matched (N = 378) | ||||||
|---|---|---|---|---|---|---|---|---|
| Extended (n = 608) | Standard (n = 340) | P value | Extended (n = 189) | Standard (n = 189) | P value | |||
| Age, yr | 69.0 (60.0–77.0) | 70.0 (60.0–78.0) | 0.562 | 72.0 (64.0–79.0) | 71.0 (63.0–79.0) | 0.614 | ||
| Sex, male, n (%) | 363 (59.7) | 210 (61.8) | 0.580 | 81 (42.9) | 75 (39.7) | 0.601 | ||
| Body mass index, kg/m2 | 24.8 (27.2–27.3) | 24.4 (22.3–26.8) | 0.446 | 24.8 (22.0–27.4) | 24.4 (22.2–26.5) | 0.326 | ||
| History of COVID-19 vaccination, n (%) | 26 (5.0) | 19 (5.8) | 0.736 | 4 (2.1) | 7 (3.7) | 0.541 | ||
| COVID-19 variant surge,a n (%) | 0.594 | 0.601 | ||||||
| Pre-delta dominant period | 509 (83.7) | 276 (81.4) | 166 (87.8) | 159 (84.1) | ||||
| Delta dominant period | 98 (16.1) | 63 (18.6) | 23 (12.2) | 30 (15.9) | ||||
| Omicron dominant period | 1 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | ||||
| Underlying diseases, n (%) | ||||||||
| Hypertension | 335 (54.8) | 183 (53.8) | 0.832 | 106 (56.1) | 115 (60.8) | 0.404 | ||
| Diabetes | 210 (34.5) | 107 (31.5) | 0.374 | 70 (37.0) | 67 (35.4) | 0.831 | ||
| Cardiovascular disease | 82 (13.5) | 26 (7.6) | 0.009 | 18 (9.5) | 14 (7.4) | 0.579 | ||
| Chronic lung disease | 49 (8.1) | 26 (7.6) | 0.920 | 9 (4.8) | 12 (6.3) | 0.653 | ||
| Chronic neurological disease | 81 (13.3) | 40 (11.8) | 0.557 | 26 (13.8) | 23 (!2.2) | 0.759 | ||
| Chronic kidney disease | 50 (8.2) | 18 (5.3) | 0.122 | 8 (4.2) | 9 (4.8) | 1.000 | ||
| Chronic liver disease | 20 (3.3) | 7 (2.1) | 0.374 | 4 (2.1) | 3 (1.6) | 1.000 | ||
| Immunocompromised | 21 (3.5) | 4 (1.2) | 0.059 | 4 (2.1) | 3 (1.6) | 1.000 | ||
| Connective tissue disease | 11 (1.8) | 2 (0.6) | 0.152 | 2 (1.1) | 2 (1.1) | 1.000 | ||
| Hematologic malignancies | 14 (2.3) | 0 (0.0) | 0.011 | 0 (0.0) | 0 (0.0) | 1.000 | ||
| Solid tumor | 45 (7.4) | 22 (6.5) | 0.686 | 12 (6.3) | 12 (6.3) | 1.000 | ||
| Clinical Frailty Scale score at admission | 3.0 (2.0–4.0) | 3.0 (2.0–4.0) | 0.432 | 3.0 (2.0–4.0) | 3.0 (2.0–4.0) | 0.238 | ||
| Treatment, n (%) | ||||||||
| Remdesivir | 445 (73.2) | 268 (78.8) | 0.065 | 144 (76.2) | 146 (77.2) | 0.903 | ||
| Tocilizumab | 65 (10.7) | 20 (5.9) | 0.019 | 9 (4.8) | 8 (4.2) | 1.000 | ||
| Steroids | ||||||||
| Duration of steroid use, days | 19.0 (14.0–29.5) | 10.0 (7.0–10.0) | < 0.001 | 19.0 (14.0–29.0) | 10.0 (7.0–10.0) | < 0.001 | ||
| Initial dose of steroids, mgb | 6.0 (6.0–11.7) | 6.0 (6.0–6.0) | < 0.001 | 6.0 (6.0–6.0) | 6.0 (6.0–6.0) | 0.413 | ||
| Vital signs | ||||||||
| Systolic blood pressure, mmHg | 132 (120.0–146.0) | 130.0 (116.0–145.0) | 0.046 | 134 (122.0–147.0) | 130.0 (112.0–144.0) | 0.032 | ||
| Diastolic blood pressure, mmHg | 76.0 (67.0–85.0) | 74.0 (65.0–83.5) | 0.021 | 75.1 ± 13.7 | 74.0 ± 13.3 | 0.437 | ||
| Heart rate, beats/min | 81.0 (70.0–94.0) | 78.0 (68.0–90.0) | 0.013 | 79.0 (68.0–92.0) | 80.0 (69.0–91.0) | 0.931 | ||
| Glasgow Coma Scale score | 15.0 (14.0–15.0) | 15.0 (15.0–15.0) | 0.033 | 15.0 (14.0–15.0) | 15.0 (14.0–15.0) | 0.410 | ||
| Laboratory findings | ||||||||
| White blood cell count, × 109 cells/L | 7.5 (5.5–11.0) | 7.5 (5.1–10.8) | 0.501 | 7.7 (5.8–10.9) | 7.9 (5.3–11.6) | 0.944 | ||
| ANC, × 109 cells/L | 6.5 (4.4–9.9) | 6.2 (3.7–9.1) | 0.094 | 6.7 (4.7–10.1) | 6.7 (4.0–10.2) | 0.891 | ||
| Platelet count, × 109 cells/L | 187.5 (136.5–240.5) | 189.0 (135.0–238.0) | 0.889 | 181.0 (133.0–230.0) | 180.0 (130.0–238.0) | 0.646 | ||
| ALC, × 109 cells/L | 0.7 (0.5–1.0) | 0.7 (0.5–1.0) | 0.075 | 0.7 (0.5–0.9) | 0.7 (0.5–0.9) | 0.998 | ||
| PaO2/FiO2 ratio | 131.2 (91.0–196.8) | 147.5 (101.3–214.1) | 0.004 | 138.2 (94.0–205.0) | 141.1 (97.8–197.5) | 0.462 | ||
| SOFA score | 4.0 (3.0–6.0) | 4.0 (3.0–5.0) | 0.007 | 4.0 (3.0–5.0) | 4.0 (3.0–6.0) | 0.568 | ||
| Life-supporting interventions, n (%) | ||||||||
| High-flow nasal cannula therapy | 480 (78.9) | 292 (85.9) | 0.011 | 148 (78.3) | 155 (82.0) | 0.439 | ||
| Mechanical ventilation | 405 (66.6) | 171 (50.3) | < 0.001 | 148 (78.3) | 138 (73.0) | 0.281 | ||
| Extracorporeal membrane oxygenation | 74 (12.2) | 42 (12.4) | 1.000 | 28 (14.8) | 39 (20.6) | 0.178 | ||
| Renal replacement therapy | 68 (11.2) | 42 (12.4) | 0.653 | 33 (17.5) | 34 (18.0) | 1.000 | ||
| Outcomes, n (%) | ||||||||
| Blood stream infection | 141 (23.2) | 51 (15.0) | 0.003 | 68 (36.0) | 39 (20.6) | 0.001 | ||
| ICU length of stay, days | 17.0 (11.0–34.0) | 14.0 (10.0–24.0) | < 0.001 | 21.0 (16.0–37.0) | 22.0 (15.0–31.0) | 0.518 | ||
| Hospital length of stay, days | 25.0 (17.0–46.0) | 20.0 (13.0–29.5) | < 0.001 | 28.0 (19.0–45.0) | 26.0 (18.0–41.0) | 0.221 | ||
| ICU mortality | 129 (21.2) | 76 (22.4) | 0.745 | 55 (29.1) | 61 (32.3) | 0.577 | ||
| Hospital mortality | 150 (24.7) | 86 (25.3) | 0.893 | 58 (30.7) | 68 (36.0) | 0.326 | ||
Matched covariates: age, sex, body mass index, COVID-19 vaccination, diabetes, cardiovascular disease, chronic lung disease, chronic neurological disease, immunocompromised status, connective tissue disease, hematological malignancy, solid tumor, treatment with tocilizumab, ANC, PaO2, FiO2, SOFA score, hospital length of stay, Clinical Frailty Scale score at admission, use of mechanical ventilation, use of extracorporeal membrane oxygenation, use of continuous renal replacement therapy, and initial dose of steroids.
COVID-19 = coronavirus disease 2019, ANC = absolute neutrophil count, ALC = absolute lymphocyte count, PaO2 = partial pressure of oxygen, FiO2 = fraction of inspired oxygen, SOFA = sequential organ failure assessment, ICU = intensive care unit.
aPre-delta dominant period, 2020.1.20–2021.7.24; Delta dominant period, 2021.7.25–2022.1.15; Omicron dominant period, 2022.1.16–2022.9.3.
bDexamethasone-equivalent.
After 1:1 propensity score matching of 378 patients using the nearest-neighbor method (189 each in the extended and standard groups), the study groups were well-balanced in terms of baseline characteristics and disease severity (Table 2, Fig. 2). After matching, the median duration of steroid treatment in the extended group was significantly longer at 19.0 days (14.0–29.0) compared to 10.0 days (7.0–10.0) in the standard group (P < 0.001). There were no significant differences in demographic characteristics, comorbidities, or initial disease severity represented by vital signs, except for systolic blood pressure, laboratory data, SOFA score, PaO2/FiO2 ratio, and COVID-19 treatments such as remdesivir and tocilizumab (Table 2). Regarding clinical outcomes, there were no significant differences in ICU and hospital LOS, ICU mortality, or in-hospital mortality between the two groups. However, the rate of BSI development was higher in the extended group than in the standard group (36.0% vs. 20.6%, P = 0.001).
Fig. 2. Distribution before (A) and after (B) PSM between the standard and extended steroid treatment group. (C) Region of common support between the standard and extended steroid treatment group.
PSM = propensity score matching.
BSI
The characteristics of the identified BSI pathogens are listed in Table 3. In the propensity score-matched cohort, bacteria constituted the largest portion of BSI in both the extended and standard groups (89.7% and 75.0%, respectively). Gram-positive cocci were the most frequently identified bacteria, followed by Gram-negative bacteria. Candida spp. accounted for the majority of the fungi. Although fungemia was more frequent in the extended group, it was not statistically significant (30.0% vs. 16.2%, P = 0.231).
Table 3. Identified pathogen of blood stream infection.
| Variables | Unmatched | Matched | ||||
|---|---|---|---|---|---|---|
| Extended | Standard | Extended | Standard | |||
| Bacteria, n (%) | 121 (85.8) | 40 (76.9) | 61 (89.7) | 30 (75.0) | ||
| Gram-positive cocci | 86 | 29 | 41 | 22 | ||
| Staphylococcus aureus | 7 | 2 | 1 | 1 | ||
| Coagulase negative staphylococcus | 61 | 21 | 31 | 15 | ||
| Streptococci species | 2 | 0 | 0 | 0 | ||
| Enterococci species | 21 | 8 | 11 | 8 | ||
| Gram-negative bacteria | 42 | 14 | 27 | 14 | ||
| Klebsiella pneumoniae | 16 | 4 | 13 | 4 | ||
| Escherichia coli | 6 | 1 | 4 | 1 | ||
| Pseudomonas aeruginosa | 4 | 0 | 2 | 0 | ||
| Othersa | 17 | 9 | 9 | 9 | ||
| Other gram-positive bacteria | 10 | 5 | 4 | 2 | ||
| Fungus, n (%) | 20 (14.2) | 12 (23.1) | 11 (16.2) | 12 (30.0) | ||
| Candida species | 17 | 12 | 9 | 12 | ||
| Other fungi | 3 | 0 | 2 | 0 | ||
Data are presented as number (percentage). Percentages represent the proportion of patients in whom a specific pathogen was identified among those who developed bloodstream infections.
aOthers: Acinetobacter baumannii (25), Burkholderia cepacia (2), Clostridium perfringens (2).
Fig. 3 shows the results of the multivariate analysis of the clinical factors associated with the occurrence of BSI, presented on a logarithmic scale to accommodate the asymmetric CIs. According to the analysis, the usage of steroids for more than 10 days was significantly associated with the occurrence of BSI (OR, 2.77; 95% CI, 1.59–4.80; P < 0.001). Other independent risk factors for the occurrence of BSI were the use of mechanical ventilation (OR, 2.81; 95% CI, 1.11–7.13; P = 0.029), use of ECMO (OR, 2.80; 95% CI, 1.44–5.45; P = 0.002), use of CRRT (OR, 4.04; 95% CI, 2.09–7.84; P < 0.001), and hospital LOS (OR, 1.02; 95% CI, 1.01–1.03; P < 0.001).
Fig. 3. Multivariable analysis of factors independently associated with blood stream infection among critically ill patients with coronavirus disease 2019.
MV = mechanical ventilation, ECMO = extracorporeal membrane oxygenation, CRRT = continuous renal replacement therapy, LOS = length of stay, CI = confidence interval.
Risk factors for in-hospital mortality
Table 4 shows the clinical characteristics based on in-hospital mortality in the propensity score–matched cohort. Notably, the proportion of patients with BSI (41.3% vs. 21.8%, P < 0.001), median age (70.0 years [61.0–78.0] vs. 74.0 years [66.0–81.0], P = 0.001), prevalence of chronic kidney disease (2.8% vs. 7.9%, P = 0.044), white blood cell counts (7.4 [5.4–10.7] vs. 8.6 [6.3–13.9] × 109 cells/L, P = 0.007), absolute neutrophil counts (6.2 [4.1–9.1] vs. 7.5 [5.2–12.1] × 109 cells/L, P = 0.004), SOFA score (4.0 [3.0–5.0] vs. 5.0 [3.0–7.0], P < 0.001), use of mechanical ventilation (96.8% vs. 65.1%, P < 0.001), use of ECMO (38.1% vs. 7.5%, P < 0.001), use of CRRT (43.7% vs. 4.8%, P < 0.001), and ICU LOS (26.0 days [18.0–42.0] vs. 20.0 days [15.0–29.0], P < 0.001) were significantly higher among the deceased patients. In contrast, the Glasgow Coma Scale score (15.0 [15.0–15.0] vs. 15.0 [13.0–15.0], P = 0.002) and PaO2/FiO2 ratio (144.2 [101.8–208.2] vs. 130.2 [79.0–171.3], P = 0.004) were notably lower in patients who did not survive.
Table 4. Clinical characteristics according to in-hospital mortality in propensity score-matched cohort.
| Characteristics | Matched (N = 378) | ||||
|---|---|---|---|---|---|
| Survived (n = 252) | Died (n = 126) | P value | |||
| Age, yr | 70.0 (61.0–78.0) | 74.0 (66.0–81.0) | 0.001 | ||
| Sex, male, n (%) | 148 (58.7) | 74 (58.7) | 1.000 | ||
| Body mass index, kg/m2 | 24.6 (22.1–27.1) | 24.5 (22.0–27.1) | 0.866 | ||
| History of COVID-19 vaccination, n (%) | 10 (4.0) | 1 (0.8) | 0.160 | ||
| Underlying diseases, n (%) | |||||
| Hypertension | 140 (55.6) | 81 (64.3) | 0.130 | ||
| Diabetes | 94 (37.3) | 43 (34.1) | 0.623 | ||
| Cardiovascular disease | 18 (7.1) | 14 (11.1) | 0.267 | ||
| Chronic lung disease | 15 (6.0) | 6 (4.8) | 0.812 | ||
| Chronic neurological disease | 30 (11.9) | 19 (15.1) | 0.482 | ||
| Chronic kidney disease | 7 (2.8) | 10 (7.9) | 0.044 | ||
| Chronic liver disease | 5 (2.0) | 2 (1.6) | 1.000 | ||
| Immunocompromised | 5 (2.0) | 2 (1.6) | 1.000 | ||
| Connective tissue disease | 3 (1.2) | 1 (0.8) | 1.000 | ||
| Hematologic malignancies | 0 (0.0) | 0 (0.0) | |||
| Solid tumor | 12 (4.8) | 12 (9.5) | 0.117 | ||
| Clinical Frailty Scale score at admission | 3.0 (2.0–4.0) | 3.0 (2.0–4.0) | 0.196 | ||
| Treatment, n (%) | |||||
| Remdesivir | 198 (78.6) | 92 (73.0) | 0.282 | ||
| Tocilizumab | 10 (4.0) | 7 (5.6) | 0.661 | ||
| Steroids | |||||
| Duration of steroid use, days | 11.0 (10.0–19.0) | 10.0 (10.0–20.0) | 0.518 | ||
| Initial dose of steroids, mga | 6.0 (6.0–6.0) | 6.0 (6.0–6.0) | 0.670 | ||
| Vital signs | |||||
| Systolic blood pressure, mmHg | 131.5 (120.0–146.0) | 132.5 (118.0–145.0) | 0.705 | ||
| Diastolic blood pressure, mmHg | 75.2 ± 13.7 | 73.1 ± 13.1 | 0.139 | ||
| Heart rate, beats/min | 94.4 ± 14.9 | 92.6 ± 14.9 | 0.262 | ||
| Glasgow Coma Scale score | 15.0 (15.0–15.0) | 15.0 (13.0–15.0) | 0.002 | ||
| Laboratory findings | |||||
| White blood cell count, × 109 cells/L | 7.4 (5.4–10.7) | 8.6 (6.3–13.9) | 0.007 | ||
| ANC, × 109 cells/L | 6.2 (4.1–9.1) | 7.5 (5.2–12.1) | 0.004 | ||
| Platelet, × 109 cells/L | 187.0 (133.5–239.5) | 177.5 (128.0–226.0) | 0.132 | ||
| ALC, × 109 cells/L | 0.7 (0.5–0.9) | 0.7 (0.4–0.9) | 0.209 | ||
| PaO2/FiO2 ratio | 144.2 (101.8–208.2) | 130.2 (79.0–171.3) | 0.004 | ||
| SOFA score | 4.0 (3.0–5.0) | 5.0 (3.0–7.0) | < 0.001 | ||
| Life-supporting interventions, n (%) | |||||
| High-flow nasal cannula therapy | 213 (84.5) | 90 (71.4) | 0.004 | ||
| Mechanical ventilation | 164 (65.1) | 122 (96.8) | < 0.001 | ||
| Extracorporeal membrane oxygenation | 19 (7.5) | 48 (38.1) | < 0.001 | ||
| Renal replacement therapy | 12 (4.8) | 55 (43.7) | < 0.001 | ||
| Blood stream infection, n (%) | 55 (21.8) | 52 (41.3) | < 0.001 | ||
| ICU length of stay, days | 20.0 (15.0–29.0) | 26.0 (18.0–42.0) | < 0.001 | ||
| Hospital length of stay, days | 26.0 (18.5–45.0) | 27.0 (19.0–44.0) | 0.732 | ||
COVID-19 = coronavirus disease 2019, ANC = absolute neutrophil count, ALC = absolute lymphocyte count, PaO2 = partial pressure of oxygen, FiO2 = fraction of inspired oxygen, SOFA = sequential organ failure assessment, ICU = intensive care unit.
aDexamethasone-equivalent.
The occurrence of BSI was independently associated with in-hospital mortality (adjusted OR, 2.47; 95% CI, 1.50–4.05; P < 0.001) in the multivariate logistic regression analysis after adjusting for potential confounding factors (Table 5). Other independent risk factors for in-hospital mortality included an older age (adjusted OR, 1.04; 95% CI, 1.01–1.06; P < 0.001), higher BMI (adjusted OR, 1.06; 95% CI, 1.00–1.12, P = 0.044), and higher SOFA score (adjusted OR, 1.18; 95% CI, 1.08–1.29; P < 0.001).
Table 5. Multivariable logistic regression analysis of risk factors for in-hospital mortality.
| Risk factors | Univariable analysis | Multivariable analysis | ||
|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Age | 1.03 (1.01–1.05) | < 0.001 | 1.04 (1.01–1.06) | < 0.001 |
| Body mass index | 1.02 (0.97–1.08) | 0.425 | 1.06 (1.00–1.12) | 0.044 |
| Chronic kidney disease | 3.02 (1.12–8.13) | 0.029 | ||
| Clinical Frailty Scale score at admission | 1.07 (0.95–1.21) | 0.268 | ||
| White blood cell count | 1.04 (1.01–1.09) | 0.023 | ||
| Absolute neutrophil count | 1.03 (1.00–1.06) | 0.035 | 1.02 (1.00–1.05) | 0.076 |
| PaO2/FiO2 ratio | 1.00 (0.99–1.00) | 0.007 | ||
| SOFA score | 1.23 (1.13–1.33) | < 0.001 | 1.18 (1.08–1.29) | < 0.001 |
| Occurrence of blood stream infection | 2.52 (1.58–4.00) | < 0.001 | 2.47 (1.50–4.05) | < 0.001 |
OR = odds ratio, CI = confidence interval, PaO2 = partial pressure of oxygen, FiO2 = fraction of inspired oxygen, SOFA = sequential organ failure assessment.
Finally, Kaplan-Meier survival analysis demonstrated no significant difference in the in-hospital mortality rate between the extended and standard groups (log-rank test, P = 0.121) (Fig. 4).
Fig. 4. Kaplan-Meier survival analysis plot for in-hospital mortality between the standard and extended steroid treatment group.
DISCUSSION
In this nationwide multicenter propensity score–matched study, we evaluated the effects of prolonged steroid therapy on the outcomes of critically ill patients with COVID-19. Our results indicate that extended steroid use, which is commonly prescribed but does not enhance in-hospital survival, is associated with the occurrence of BSI. Furthermore, BSI occurrence was significantly correlated with increased in-hospital mortality among these patients, even after adjusting for various clinical and laboratory parameters. To the best of our knowledge, this is the first multicenter investigation focusing on the adverse effects of extended steroid treatment in this patient group.
In this study, the occurrence of BSI was associated with extended steroid use. Furthermore, it was also significantly correlated with increased in-hospital mortality. Secondary infections commonly occur as complications in patients with acute respiratory failure or acute respiratory distress syndrome caused by viral infections.18,19 Critically ill patients are susceptible to secondary infections due to immunosuppression associated with severe illness, the use of invasive life support devices, and prolonged hospitalization.20,21,22 Secondary infections occur in approximately 5–40% of critically ill patients with COVID-19.13,23,24 Recent studies have shown that the overall rate of BSI in patients with COVID-19 varies from 5.3% to 43.6%.25,26,27 In some patients with COVID-19, however, there has been no clear evidence on steroid-causing BSI. Buetti et al.28 have reported that while the use of agents such as tocilizumab and anakinra in patients with COVID-19 was associated with the occurrence of BSI, steroid use did not influence the occurrence of BSI. However, another multicenter retrospective study has reported an association between the occurrence of BSI and a combination of steroid and tocilizumab therapy.25 Additionally, the use of steroids increases the odds of any secondary infection in critically ill patients with COVID-19,29,30 and another single-center retrospective study has reported findings consistent with our research, indicating that the extended use of steroids is associated with the occurrence of BSI.31 BSIs induce a critical complication of sepsis and septic shock. Previous studies have also reported the significant impact of BSI on morbidity and mortality in critically ill patients with COVID-19.10,25 Our study supports these findings and expands upon the aforementioned results.
In this study, extended steroid use did not reduce in-hospital mortality. The use of steroids has shown benefits in the treatment of critically ill patients with COVID-19 and has been widely adopted, with current guidelines recommending use for up to 10 days.1,4 However, real-world applications often involve longer treatment,32 as seen in the present study. Despite this, there is limited systematic research on the consequences of prolonged steroid use that might increase the risk of adverse events, such as delayed viral clearance, particularly in critically ill patients with COVID-19.33 Although the study did not exclusively focus on critically ill patients, a recent meta-analysis indicated that using steroids for > 7 days did not offer a survival benefit in hospitalized patients with COVID-19.34 Given these findings, it is crucial to consider the potential risks of extended steroid use, necessitating further targeted research to optimize the therapies for critically ill patients.
The present study has some limitations. First, it was a secondary analysis of a retrospective cohort study. Therefore, the reasons for the prolonged use of steroids have not been properly determined. Some patients may have been deliberately treated with extended steroids, whereas others may have received extended steroids for therapeutic immunomodulation under different conditions. These differences may have influenced the patient outcomes. Secondly, we did not consider the cumulative dose of steroids administered. However, in patients with COVID-19, where immunosuppression over a certain period is necessary to prevent immune-mediated inflammation, the duration of steroid treatment can affect outcomes independently of the cumulative dosage. Third, this study focused only on BSIs. Our findings did not include other secondary infections, such as ventilator-associated pneumonia or urinary tract infections. Fourth, there might be a potential bias for patients who, owing to their severe condition and subsequent rapid deterioration after admission, either did not have the opportunity to be treated with steroids or were administered steroids for an insufficient duration. However, we endeavored to address this by only including patients who were hospitalized in the ICU for 10 days or more in our study.
In this study, the extended use of steroids was associated with an increased risk of BSI in critically ill patients with COVID-19. In addition, the presence of BSIs was associated with a higher mortality risk. However, no correlation was observed between extended steroid use and in-hospital mortality. These findings have important clinical implications, as they suggest that clinicians should be cautious about prolonged steroid use in critically ill COVID-19 patients and closely monitor for signs of BSI. Further prospective studies are required to clarify the effect of prolonged steroid use in critically ill patients with COVID-19.
ACKNOWLEDGMENTS
Members of The Korean Intensive Care Study Group, excluding the authors: Jin-Won Huh (Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine), Sang-Min Lee (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine), Chi Ryang Chung (Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine), Jung Soo Kim (Division of Critical Care Medicine, Department of Hospital Medicine, Inha Collage of Medicine), Sung Yoon Lim (Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University Bundang Hospital), Ae-Rin Baek (Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital), Jung-Wan Yoo (Department of Internal Medicine, Gyeongsang National University Hospital), Ho Cheol Kim (Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University School of Medicine), Eun Young Choi (Division of Pulmonology and Allergy, Department of Internal Medicine, College of Medicine, Yeungnam University and Regional Center for Respiratory Diseases, Yeungnam University Medical Center), Chul Park (Division of Pulmonology and Critical Care Medicine, Wonkwang University Hospital), Tae-Ok Kim (Division of Pulmonary, and Critical Care Medicine, Department of Internal Medicine, Chonnam National University Hospital), Do Sik Moon (Department of Pulmonology and Critical Care Medicine, Chosun University Hospital), Song-I Lee (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungnam National University School of Medicine, Chungnam National University Hospital), Jae Young Moon (Department of Internal Medicine, Chungnam National University College of Medicine, Chungnam National University Sejong Hospital), Sun Jung Kwon (Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Konyang University Hospital), Gil Myeong Seong (Department of Internal Medicine, Jeju National University Hospital, Jeju National University School of Medicine), Won Jai Jung (Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Anam Hospital), Moon Seong Baek (Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine).
Footnotes
Funding: This study was supported by a grant (KATRD-S-2021-2) from the Korean Academy of Tuberculosis and Respiratory Diseases.
Disclosure: The authors have no potential conflicts of interest to disclose.
- Conceptualization: Kim S, Lee J.
- Data curation: Ryoo J, Cho HJ, Kim SC, Park S, Lee SH, Park O, Kim T, Yeo HJ, Cho WH, Lee J.
- Writing - original draft: Kim S, Lee J.
- Writing - review & editing: Kim S, Lee J.
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