Corticosteroid Use in Severe COVID-19 and Factors Associated with Secondary Infection and Mortality Among Patients Admitted to the Intensive Care Unit

Pelin Kılıç Erol; Ebru Kaya; Ayça Sultan Şahin

doi:10.4274/BMB.galenos.2025.43534

Abstract

Objective

To assess the outcomes of corticosteroid usage in Coronavirus disease-2019 (COVID-19) patients treated in the intensive care unit (ICU) and determine factors associated with secondary infection and mortality.

Method

This retrospective analysis involved data from patients admitted to the ICU for COVID-19 treatment between April 1, 2020, and December 31, 2021. The medical records of 114 patients who received corticosteroids and the records of 94 patients who did not, were comprehensively reviewed, and information about demographic characteristics, clinical features, and laboratory results was recorded.

Results

The 28-day mortality rate was 52.9% (n=110), the overall mortality was 61.5% (n=128), and secondary infection occurred in 52.9% (n=110) of COVID-19 ICU patients. Steroid users had longer ICU stays (p=0.001), longer intubation periods (p<0.001), a higher need for positive inotropic therapy (p<0.001), and higher APACHE II scores (p=0.014). Overall mortality was higher in steroid recipients (p=0.001), while 28-day mortality was similar (p=0.061). The frequency of secondary infections in COVID-19 ICU patients was significantly higher in the steroid group (p=0.003). Multivariable logistic regression analysis indicated that extended ICU stays [odds ratio (OR): 1.174] and prolonged intubation (OR: 1.317) were independently associated with secondary infections. Similarly, older age (OR: 1.079), need for renal replacement therapy (OR: 7.600), need for positive inotropic therapy (OR: 25.627), and high SOFA score (OR: 1.528) were independently associated with mortality.

Conclusion

According to the findings of the study, although corticosteroid use in severe COVID-19 cases does not appear to increase the risk of secondary infections or mortality, the decision to use corticosteroids should be made with careful consideration of the patient’s clinical condition. Additionally, more comprehensive and in-depth studies on the use of corticosteroids in COVID-19 patients are needed.

Keywords:

Anti-inflammatory agents, Coronavirus infections, COVID-19, COVID-19 drug treatment, dexamethasone, methylprednisolone

Introduction

The clinical presentation of Coronavirus disease-2019 (COVID-19) ranges from asymptomatic/mild respiratory disease to severe pneumonia, hypoxemic lung failure, multi-system organ dysfunction, and death (1). Studies performed early in the pandemic demonstrated that acute respiratory distress syndrome (ARDS) occurred in approximately 17-41% of cases (2, 3), while cytokine release syndrome was also implicated in severe COVID-19 (4). Furthermore, postmortem data showed that patients who died due to COVID-19 had high levels of inflammatory cytokines, tissue necrosis and interstitial macrophage and monocyte infiltrations in the lung, heart and gastrointestinal mucosa (5). Even during the initial waves of the pandemic, these data showed the importance of alleviating extreme immune activity in COVID-19, which encouraged trials focusing on anti-inflammatory therapies (4). Various agents have been used for this purpose, including immunoglobulin, colchicine, janus kinase inhibitor inhibitors, interleukin (IL)-6 inhibitors, IL-1 inhibitors, anti-tumor necrosis factor-α agents, and corticosteroids (6).

Corticosteroids, which exert broad anti-inflammatory effects, are potent immunomodulatory medications that alleviate hyperinflammation (7). Initially, the World Health Organization (WHO) and infectious disease authorities had recommended avoiding systemic corticosteroids in COVID-19 patients due to limited improvements in mortality and the fact that prior studies involving patients with severe Middle-East respiratory syndrome (MERS) had shown delayed RNA clearance with glucocorticoids (8, 9). Today, WHO recommends corticosteroids in severe or critical COVID-19 patients, especially in COVID-19 cases requiring respiratory support (10, 11). This shift in guidance emerged as a result of numerous studies and meta-analyses that shared clinical evidence for the benefits of corticotherapy in patients with severe COVID-19 (2, 7, 12, 13). Nonetheless, for the beneficial use of corticosteroids, COVID-19 patients need to be well targeted because patients requiring low-flow oxygen do not appear to experience the same benefits as those receiving ventilation or high-flow oxygen support (14).

As the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus continues to mutate over time, the possible role of glucocorticoids in different virus mutations will remain a topic of interest [15). Reviewing evidence to offer insights into the efficacy and safety of corticosteroids in the evolving landscape of COVID-19 can provide valuable guidance for future clinical interventions. In this study, we aimed to investigate the relationship between corticosteroids and clinical outcomes in patients followed up in the intensive care unit (ICU) due to COVID-19.

Materials and Methods

The medical records of patients diagnosed with COVID-19 who were admitted to the ICU of our Anesthesia Department, between 1 April 2020 and 31 December 2021, were examined. Inclusion criteria were: Having at least one positive SARS-CoV-2 polymerase chain reaction test in nasopharyngeal or oropharyngeal swab samples; being followed up in the ICU; and being 18 years of age or older. Exclusion criteria were pregnancy, malignancy, immunodeficiency, chronic organ failure, being in the postoperative period, receiving immunosuppressive/anti-cytokine therapy, secondary infection before treatment, culture growth in the ICU, ICU stay of less than 48 hours, and age younger than 18 years. The study plan was approved by the University of Health Sciences Turkey, Kanuni Sultan Süleyman Training and Research Hospital, Clinical Research Ethics Committee (date/number: February 2022/#2022/34).

The medical records of the patients were examined in detail, and information on demographic characteristics, clinical features, and laboratory results relative to patients with and without corticosteroid therapy in addition to standard treatment were recorded. Baseline values of laboratory measurements (IL-6, D-dimer, ferritin, fibrinogen) were recorded and longitudinal samples were assessed to determine the lowest, highest, and average values for several inflammatory parameters [C-reactive protein (CRP), procalcitonin, complete blood count parameters]. The emergence of secondary infection and mortality (28-day mortality and total mortality) was recorded as outcomes of interest.

All patients included in the study received the standard care specified in the COVID-19 treatment guideline published by the Ministry of Health, and the COVID-19 anticytokine, anti-inflammatory treatment guideline. Favipiravir, as antiviral treatment, and low molecular weight heparin as deep vein thrombosis prophylaxis were administered to all patients without contraindications. Corticosteroid treatment was initiated in patients with ARDS whose clinical condition worsened and whose oxygen demand or acute phase reactants had increased. The standardized daily therapy was 300 mg methylprednisolone or 56.3 mg dexamethasone (equivalent to 1500 mg hydrocortisone). According to respiratory symptoms and peripheral partial oxygen saturation values, patients were given oxygen support with a face mask, reservoir mask, or high-flow nasal cannula. When these interventions were inadequate, patients received non-invasive or invasive mechanical ventilation support. Fluid therapy was administered according to the fluid status of the patient, and vasopressor support was initiated in patients who did not respond to fluid therapy. Blood, urine, tracheal aspirate, and, if necessary, wound site cultures were obtained when there were findings suggestive of secondary infection (new onset fever, leukocyte count of ≥12,000, procalcitonin value of ≥0.5). The results of these cultures were recorded, and the patients received empirical antibiotic therapy to cover detected or possible microorganisms.

APACHE II Score

The APACHE II score developed by Knaus et al. (16) is widely used to assess disease severity and mortality in patients hospitalized in intensive care units. A total score is calculated using the acute physiologic score, age, and parameters indicating chronic disease status. Although the theoretical maximum score is 71, it is rarely seen above 50. An increase in the total score indicates a negative change in health status and is associated with an increased risk of mortality (16).

Sequential Organ Failure Assessment (SOFA)

SOFA was developed by the European Society of Intensive Care Medicine in 1996 to assess the acute morbidity of critical illness by defining the degree of organ failure due to sepsis. A total score can be calculated by summing the scores given to six organ systems (respiratory, cardiovascular, central nervous system, renal, coagulation, and liver) ranging from 0 to 4. The total score can be up to 24, and mortality increases as the score increases (17).

Statistical Analysis

Two-tailed p-values of less than 0.05 were considered statistically significant. SPSS version 25.0 (IBM, Armonk, NY, USA) was used for statistical analysis. The Kolmogorov-Smirnov test was used to examine the conformity of the variables to normal distribution. Descriptive statistics were presented using median (25^th-75^th percentile) for non-normally distributed continuous variables and frequency (percentage) for categorical variables. Due to non-normal distributions, continuous variables were analyzed with the Mann-Whitney U test. Categorical variables were analyzed with the Pearson chi-square test or Fisher’s Exact test. Logistic regression analyses were performed to determine significant factors independently associated with secondary infection or mortality. Variables were analyzed using univariable logistic regression , and statistically significant variables were included in multivariable logistic regression.

Results

A total of 208 COVID-19 patients treated in the ICU were included in this study. One hundred-fourteen (54.8%) had received steroid treatment and 94 (45.2%) had not received steroid treatment. Overall, 59.1% were male, 40.9% were female, and the median age was 68 (55-76) (range: 27-89) years. The 28-day mortality rate was 52.9% (n=110), the overall mortality was 61.5% (n=128), and the secondary infection rate was 52.9% (n=110). Length of ICU stay and intubation were 12 (2-57) days and 6 (0-57) days, respectively. Age (p=0.788) and sex distribution (p=0.653) were similar in the steroid and non-steroid groups. The frequency of comorbidities (p=0.029), especially neurological disease (p=0.020), was higher in the non-steroid group. The length of ICU stay (p=0.001), the length of intubation (p<0.001), and the frequency of needing positive inotropic therapy (p<0.001) were higher in steroid users. While the overall mortality rate was significantly higher in the steroid group (p=0.001), the groups were similar in terms of 28-day mortality rate (p=0.061). APACHE II score, was significantly higher in the steroid group (p=0.014), while there was no difference in terms of SOFA score (p=0.968). There was no difference between the groups in terms of baseline values for CRP (0.393), procalcitonin (p=0.338), leukocyte count (p=0.965), neutrophil count (p=0.390), IL-6 (p=0.313), D-dimer (p=0.501), ferritin (p=0.071) and fibrinogen (p=0.096). Baseline lymphocyte (p=0.001) and monocyte counts (p<0.001) were lower in the steroid group (Table 1).

The frequency of secondary infection was significantly higher in the steroid group (p=0.003). There was no difference between the groups in terms of blood culture positivity (p=0.169), but urine culture positivity (p=0.035) and Klebsiella pneumoniae in urine culture (p=0.001) were more common in steroid recipients. The frequency of tracheal culture positivity (p=0.001) and Klebsiella pneumoniae presence in tracheal cultures (p<0.001) was significantly higher in steroid recipients (Table 2).

Multivariable logistic regression revealed that longer stay in the ICU [odds ratio (OR): 1.174, 95% confidence interval (CI): 1.070-1.287, p=0.001] and longer intubation duration (OR: 1.317, 95% CI: 1.150-1.509, p<0.001) were independently associated with secondary infection likelihood. In the univariate analysis, corticosteroid use was found to be associated with an increased risk of secondary infections, while in the multivariate analysis, no significant relationship was observed between corticosteroid use and the risk of secondary infections (OR: 0.828, 95% CI: 0.329-2.084, p=0.689) (Table 3).

Multivariable logistic regression revealed that higher age (OR: 1.079, 95% CI: 1.027-1.134, p=0.003), need for renal replacement therapy (OR: 7.600, 95% CI: 1.380-41.843, p=0.020), need for positive inotropic therapy (OR: 25.627, 95% CI: 6.261-104.902, p<0.001), and high SOFA score (OR: 1.528, 95% CI: 1.098-2.125, p=0.012) were independently associated with mortality likelihood. While corticosteroid use was found to increase mortality in the univariate analysis, it was not identified as one of the factors influencing mortality in the multivariate analysis (OR: 2.005, 95% CI: 0.579-6.944, p=0.272) (Table 4).

Discussion

The COVID-19 pandemic has placed an unforeseen burden on the global health system, requiring the world to react quickly to find different solutions, both for preventive and therapeutic purposes. One of the agents used for this purpose is a corticosteroid, which has strong anti-inflammatory properties (18). Systemic glucocorticoids are not routinely indicated in COVID-19, and their use is limited to cases with severe complications such as ARDS or the so-called “cytokine storm” (19). In this study, we examined a group of patients who were admitted for severe COVID-19 and received steroids (or not) based on available guidelines. We also investigated factors associated with mortality and secondary infections. Our data showed that steroid recipients had longer ICU stay and intubation periods, as well as higher APACHE II scores and increased inflammatory parameters. Notably, steroid recipients also had higher frequencies of positivity for urine and tracheal cultures - largely as a result of increased Klebsiella pneumoniae prevalence. Finally, the multivariate analyses revealed that steroid use was not independently associated with the development of secondary infections or mortality.

A meta-analysis of 20,197 patients reported that findings from both observational studies and randomized controlled trials confirmed the beneficial effect of corticosteroids on reducing the need for mechanical ventilation (12). Despite the presence of several large studies and meta-analyses on the topic, there are various studies with notable outcomes and notable findings. Tomazini et al. (20) reported that there was no difference in the duration of mechanical ventilation at 28 days with dexamethasone use among COVID-19 patients with moderate/severe ARDS. Sarkar et al. (21) reported that systemic steroid treatment was not effective in reducing the length of hospital stay. In a study conducted by Emgin et al. (22) with COVID-19 patients in the ICU, the length of stay was reported to be longer in patients who received dexamethasone treatment. In the present study, ICU stay, intubation duration, need for positive inotropic therapy, and APACHE-II score were higher in steroid-treated patients. These relationships are not surprising as the present study included patients who had severe COVID-19 (admitted to the ICU) and steroid recipients were those who required advanced treatment due to their clinical and laboratory prognosis.

Secondary bacteremia is an important complication that can lead to a poor prognosis in COVID-19 patients and requires an appropriate treatment strategy, especially for patients with concomitant predisposing factors. Given that steroids can frequently obscure infection indicators by reducing body temperature and levels of acute phase proteins like CRP, it is essential to be cautious about potential secondary infections and conduct thorough assessments when employing steroid treatment for COVID-19 (23). Contrary to the results of a previous study evaluating the follow-up of MERS coronavirus infection in the ICU (8), no increased risk of bacterial infection or delayed viral clearance was reported when using corticosteroids in managing COVID-19 patients requiring oxygen support (7, 19). Corticosteroids are reported to be important options in criticallyill COVID-19 patients, particularly since they have been suggested to have no impact on secondary infection (24). Similarly, Abelenda-Alonso et al. (25) reported that there was no association between steroid use and the development of nosocomial bloodstream infections in patients with severe COVID-19 pneumonia. In a study evaluating the outcomes of COVID-19 patients admitted to the ICU in two different hospitals, it was reported that immunosuppressive treatments such as steroids and tocilizumab were not associated with an increased risk of bacteremia. In addition, it was reported that those who developed bacteremia among COVID-19 patients in the ICU had a higher SOFA score, were intubated more frequently and for longer durations, stayed in the ICU longer, and had higher mortality (26). In the present study, although the prevalence of secondary infection was found to be higher in steroid recipients compared to non-recipients, in multivariable analysis, we found that this increase in secondary infection was independently associated with longer ICU stay and longer intubation. There was no independent relationship between steroid use and the risk of secondary infection. Our results are consistent with the information in the literature. However, this does not change the fact that the decision to use corticosteroids should be made cautiously to prevent the risk of secondary infections. This is because there are also studies in the literature reporting opposite results. In a study evaluating COVID-19 patients admitted to an ICU, dexamethasone treatment was associated with a threefold increase in the risk of pulmonary aspergillosis (27). In a retrospective study, it was reported that steroid treatment increased the risk of non-respiratory nosocomial bacterial infections, while male sex, advanced age, and ICU need were found to be risk factors for bacteremia (23). Of note, both studies centered around specific pathogens (23, 27) which may explain the differences in results. In addition, prophylactic antimicrobial treatment protocols can vary from institution to institution, and it is possible that other factors contributed to these conflicting findings, including drug access, management guidelines, and antibiotic resistance patterns.

In COVID-19, corticosteroids (dexamethasone, hydrocortisone or methylprednisolone) have been reported to increase the chances of survival (7). The RECOVERY study was the first to evaluate the effect of dexamethasone treatment on mortality in COVID-19 patients who required oxygen therapy or mechanical ventilation. The authors reported that 28-day mortality was lower with dexamethasone (6 mg once daily for up to 10 days) in patients who received invasive mechanical ventilation or oxygen support; but no difference was found in patients without respiratory support (2). In a prospective meta-analysis by the WHO Rapid Evidence Assessment for COVID-19 Treatments Working Group, evaluating data from 12 countries from February 26, 2020 to June 9, 2020, it was reported that systemic corticosteroids were associated with lower 28-day all-cause mortality in patients with critical COVID-19 compared to usual care or placebo (13). In another retrospective study of COVID-19 patients in the ICU, corticosteroid administration was found to significantly reduce the likelihood of 28-day mortality (24). A recent meta-analysis evaluating the results of fifteen randomized controlled trials reported that in patients with severe and critical COVID-19, glucocorticoid therapy reduced the risk of all-cause mortality compared to conventional therapy, but no difference was found in those with mild disease (15). In another meta-analysis, mortality was shown to be significantly reduced with the use of corticosteroids (12). In the present study, mortality was higher in severe COVID-19 cases with steroid use in univariate analyses. However, in the multivariable model, this significance disappeared, and the use of steroids in treatment was not one of the factors independently affecting the risk of mortality. Factors identified included higher age, higher SOFA score, need for positive inotropic drugs, and need for renal replacement therapy. There are other studies reporting similar results. In a meta-analysis evaluating the efficacy and safety of steroids in COVID-19 (with data from randomized controlled trials and cohorts), there was no association between systemic glucocorticoid use and mortality in COVID-19 patients (21). Tomazini et al. (20) reported no difference in 28-day mortality among recipients and non-recipients of dexamethasone therapy after being diagnosed with moderate or severe ARDS. In contrast, a previous meta-analysis reported that overall mortality increased with the use of glucocorticoids in hospitalized patients who did not need respiratory support (28). Despite varying levels of evidence and partially conflicting results, it is evident that corticosteroids should not be used in COVID-19 cases that do not require respiratory support, but this therapy must be considered in patients requiring respiratory support. In patients requiring respiratory support, particularly those with advanced age, renal replacement therapy, positive inotropic therapy, and high SOFA scores, the decision to use corticosteroids should be made with caution. The variables included in the model used for the analyses may have influenced the results obtained in the study. Additionally, differences in the type, dose, and duration of corticosteroid protocols may further explain the heterogeneity in the reported evidence.When reviewing the existing literature regarding the use of steroids in COVID-19 cases, it is clear that physicians must exercise caution when making decisions about steroid utilization. The primary determining factor for initiating corticosteroid therapy in COVID-19 appears to be the requirement for respiratory support and overall clinical condition. Nonetheless, the decision for corticosteroid treatment should not be solely based on the severity of disease, but should also include consideration of the benefits and risks on a case-by-case basis (19). Although corticosteroids are currently widely used in the treatment of severe COVID-19 patients on respiratory support, many aspects of their use, such as the preferred agent, optimal dose and duration of treatment, are yet to be clarified (7). In addition, we believe that it is important to continuously update the information on this issue. It should be noted that the use of steroids in this population may have negative effects on both mortality and secondary infections. To better prepare for future outbreaks and reduce mortality among COVID-19 patients, a global effort is essential to develop novel treatments targeting both the clinical aspects of COVID-19 and the hyperinflammatory response triggered by the infection.

Study Limitations

This study has notable limitations, including its retrospective and single-center design, which restricts the generalization of results. A significant constraint is the absence of specific data regarding the decision to administer steroids to COVID-19 ICU patients. The variation in clinical severity between patient groups may have influenced the findings. Additionally, the study did not investigate different types, doses, or durations of corticosteroid treatment. The study also did not consider various SARS-CoV-2 variants. Despite these limitations, the data provide valuable insights into corticosteroid use in treating severe COVID-19 cases.

Conclusion

Our results demonstrated that while corticosteroid use in critically ill COVID-19 patients was associated with increased mortality and secondary infections in univariate analyses, this association was not confirmed in multivariate analyses. The primary independent factors contributing to an increased risk of secondary infections were identified as prolonged ICU stay and extended duration of intubation. Furthermore, advanced age, the need for renal replacement therapy, the requirement for positive inotropic support, and a high SOFA score were determined to be independent predictors of increased mortality. In this context, it can be concluded that decisions regarding the use of corticosteroids in severe COVID-19 cases should be made with careful consideration of the individual clinical condition of each patient. To assess whether the effects of corticosteroid use are influenced by SARS-CoV-2 variants or other factors, broader and more comprehensive prospective studies involving various viral variants are needed.

Ethics

Ethics Committee Approval: The study plan was approved by the University of Health Sciences Turkey, Kanuni Sultan Süleyman Training and Research Hospital, Clinical Research Ethics Committee (date/number: February 2022/#2022/34).

Informed Consent: Retrospective study.

Authorship Contributions

Surgical and Medical Practices: P.K.E., E.K., A.S.Ş., Concept: A.S.Ş., Design: A.S.Ş., Data Collection or Processing: P.K.E., Analysis or Interpretation: P.K.E., A.S.Ş., Literature Search: P.K.E., Writing: P.K.E., E.K., A.S.Ş.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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