The association between early corticosteroid use and the risk of secondary infections in hospitalized patients with COVID-19: a double-edged sword. Results from the international SCCM discovery viral infection and respiratory illness universal study (VIRUS) COVID-19 registry

Abstract

Background:

Corticosteroids improve survival in hospitalized COVID-19 patients needing supplemental oxygen. However, concern exists about increased risk of secondary infections. This study investigated the impact of early corticosteroids use on these infections.

Methods:

Data from the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS): COVID-19 registry were analyzed for adult patients, stratified by early corticosteroid use (within 48 h of admission). The primary outcome was documented secondary infections, including bacteremia, bacterial pneumonia, empyema, meningitis/encephalitis, septic shock, and ventilator-associated pneumonia. Univariate and multivariable logistic regression models were used to assess the association between early corticosteroids and these outcomes.

Results:

Among 17,092 eligible patients, with 13.5% developed at least one secondary bacterial infection during hospitalization. Patients receiving early corticosteroids were older (median 63 years) compared to those who did not (median 60 years), with a similar gender distribution (42.5% vs. 44.2% female). Unadjusted analysis revealed a higher risk for any secondary infection (OR 1.93, 95% CI 1.76–2.12). This association persisted for specific infections including bacteremia (OR 2.0, 95% CI 1.58–2.54), bacterial pneumonia (OR 1.5, 95% CI 1.27–1.77), and septic shock (OR 1.67, 95% CI 1.44–1.93). However, the effect on meningitis/encephalitis (OR 0.62, 95% CI 0.24–1.57) and ventilator-associated pneumonia (VAP; OR 1.08, 95% CI 0.75–1.57) was non-significant. Adjusted analysis maintained significance for any secondary infection (OR 1.15, 95% CI 1.02–1.29), bacteremia (OR 1.43, 95% CI 1.09–1.88), and infections with unknown sources (OR 1.63, 95% CI 1.31–2.02). Notably, the association weakened and became non-significant for bacterial pneumonia (OR 0.98, 95% CI 0.81–1.20) and septic shock (OR 0.94, 95% CI 0.79–1.11), while it became significant for meningitis/encephalitis (OR 0.26, 95% CI 0.08–0.82). VAP remained non-significant (OR 0.87, 95% CI 0.56–1.34).

Conclusion:

Early use of corticosteroids increased overall secondary infection risk in hospitalized COVID-19 patients, but the impact varied. Risk of bacteremia was notably increased, while the association with bacterial pneumonia and septic shock weakened after adjustment becoming non-significant and surprisingly reduced meningitis/encephalitis risk was noted suggesting the complexity of corticosteroid effects. Further research is needed to understand how corticosteroids influence specific secondary infections, and thereby optimize the treatment strategies.

Introduction

COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had far reaching social, political, and economic impact since it was first reported in November 2019. It has led to significant morbidity and mortality with a high rate of hospitalization. Multiple risk factors are involved in the disease prognosis, and patients infected with SARS-CoV-2 display a spectrum of clinical presentations that range from asymptomatic to life-threatening manifestation (1–7). For this multi-system disorder (8–12) different therapeutic strategies have been tested since the disease’s inception (13–18). The Mayo Clinic and Society of Critical Care (SCCM) Discovery Network created a global Viral Infection and Respiratory Illness Universal Study (VIRUS): COVID-19 registry for the collection of high-quality data in real-time (19) and for the study of COVID-19 treatments and related outcomes (20–22).

Historically pandemics such as influenza have had a high rate of mortality attributed to co-infections (23). Co-infections occur when a patient is infected with two or more pathogens (viruses, bacteria) at the same time (24). In contrast, the co-infection rate in COVID-19 patients was also noted, but much lower (around 3–8%) compared to historical influenza outbreaks (25, 26). However, occurrence of secondary infections, which develop after the initial COVID-19 infection (24), was noted to be above 40%, a rate much higher than the non-COVID-19 patients (27–33). A number of factors contributed to this secondary infection burden such as prolonged hospitalization, high device utilization rates such as central line and urinary catheter use, invasive mechanical ventilation, pandemic surge overwhelming healthcare capacity, high burn out rate, high comorbidity rate, and immunocompromised state of patients (33–36).

Corticosteroids have been used as therapeutic agents in viral pneumonia and Adult respiratory distress syndrome (ARDS) for many decades (37–39). However, their therapeutic benefit or harm was not well defined with contradictory results in ARDS studies and lack of benefit or even harm in Influenza pneumonia and Middle East Respiratory Syndrome (MERS) (40–42). Given this uncertainty and amidst the chaos of the COVID-19 pandemic, corticosteroids were shown to improve survival in patients with severe COVID-19 requiring supplemental oxygen and respiratory assist devices (40, 43–45). Indeed, the survival effect was more pronounced in critically ill patients needing invasive mechanical ventilation (40, 44, 46). However, the possibility of corticosteroids causing harm when used in patients with ARDS secondary to prolonged viral shedding, hyperglycemia secondary to use of corticosteroids, immunosuppression of the host and therefore increasing the risk of secondary infection remained unsettled (34, 36, 40, 47).

After the “Dexamethasone in Hospitalized Patients with COVID-19” (The RECOVERY collaborative group) (44), corticosteroids became a mainstay of treatment for treating hospitalized patients with severe COVID-19 requiring supplementation oxygen and respiratory assist devices. However, this landmark trial was not powered to detect the differences between the groups with regards to the secondary infection rate, a side effect profile of corticosteroid uses in COVID-19 patients (44). Many other randomized control trials which suspended recruitment post “Dexamethasone in Hospitalized Patients with COVID-19” reported a very small number of patients with secondary infection, which left this question unanswered (48, 49). Observational studies with their inherent confounding limitations reported conflicting results of corticosteroids being a risk for of secondary infections (27, 34–36, 42). There are several mechanisms on how corticosteroids might cause harm when used in patients with severe COVID-19. Prolonged viral shedding, steroid induced hyperglycemia, and immunosuppression are among the most accepted mechanism on how steroids might increase the risk of secondary infections, but still this important question remains unsettled (34, 36, 40, 47).

Considering the existing evidence of corticosteroid-induced immunosuppression and the high prevalence of secondary infections in hospitalized COVID-19 patients, this study aims to investigate the potential association between early corticosteroid use and secondary infection rates within a large, multicenter. Multinational SCCM Discovery VIRUS COVID-19 registry, a rich repository of demographics, treatment details, healthcare processes, hospital outcomes, and documented complications for hospitalized COVID-19 patients from 183 hospitals across 24 countries.

Methods

Overview of the VIRUS COVID-19 registry

Our analysis utilized data from the SCCM Discovery VIRUS COVID-19 registry, a comprehensive collection of clinical information for hospitalized patients of all ages confirmed to have SARS-CoV-2 infection (by PCR or similar methods) across 183 hospitals in 24 countries from March 1, 2020. The registry was established through the Society of Critical Care Medicine (SCCM) Discovery Network. Established in early 2020, the registry served as a consolidated international repository for ongoing COVID-19 related clinical research. Details of registry design, data management, process of resolution of qualitative and quantitative data related issues have been described elsewhere (20–22), and initial findings from the registry have been previously reported (2, 50).

The registry included patients from both intensive care units and general medical wards, encompassing a diverse spectrum of respiratory support needs. These needs ranged from supplemental oxygen to more advanced interventions like high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, proning, neuromuscular paralysis, and extracorporeal membrane oxygenation (ECMO). Patient were followed up until discharge or death, whichever occurred first. This registry received exempt status from human participant research review by the Mayo Clinic Institutional Review Board (IRB#: 20-002610) and is registered on Clinicaltrials.gov (NCT04323787). All participating investigative sites obtained local ethical approval and a data use agreement before data collection commenced. As stipulated in the approved protocol, informed consent was waived under Common Rule 45 CFR 46.116, and individual study sites signed a data use agreement to acquire permission for de-identified data extraction and entry into registry case report forms (CRFs). The case report forms were adapted from the World Health Organization templates (51) and modified for an ICU-specific context through rapid, iterative editing to balance feasibility, efficiency, and comprehensiveness, with input from multiple clinical specialties and adding pertinent data for clinical research.

Study design and data source

This ancillary study utilizes data from the “SCCM Viral Infection and Respiratory Illness Universal Study (VIRUS) – COVID-19 registry.” We focused on adult patients aged 18 years and older, adhering to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (52). Our primary exposure of interest was early administration of systemic corticosteroids within 48 h of hospital admission. Patients were categorized into two groups: those receiving early corticosteroids and those who did not. While complete corticosteroid treatment details (duration and type of corticosteroid formulation) were not captured, relevant elements like COVID-19 diagnosis confirmation, patient demographics, comorbid conditions, COVID-19 disease severity, early corticosteroid use, pre-hospital and in-hospital medications, hospital complications and pertinent clinical outcomes were collected from the VIRUS CRF.

Exclusion criteria

Patients were excluded if:

• Hospitalization was less than 48 h

• They had a secondary or co-infection diagnosed within the first 48 h of hospitalization

• Data was missing on medication use on days 0–2 and

• Microbiology results or complications during hospitalization were missing.

Infection classification

Admission diagnoses of bacteremia, bacterial pneumonia, meningitis/encephalitis, or positive microbiological findings within 48 h were classified as community-acquired infections and considered co-infections. Complications of bacteremia, empyema, endocarditis, lung abscess, septic shock, ventilator-associated pneumonia, and positive microbiological findings after 48 h were classified as hospital-acquired infections and considered as secondary infections.

Primary outcome

The study’s primary focus was the occurrence of any documented secondary infection. This included infections like bacteremia, bacterial pneumonia, empyema, meningitis/encephalitis, septic shock, ventilator-associated pneumonia (VAP) and those with an unknown source.

Statistical analysis

Continuous variables with normal distributions were summarized using means and standard deviations (SD). For non-normal continuous variables, medians, and interquartile ranges (IQRs) were reported, indicating the 25th and 75th percentiles. Categorical variables were presented as frequencies and percentages. Differences between groups for categorical variables were assessed using Pearson’s Chi-squared tests. To compare non-parametric continuous variables, a Kruskal-Wallis ANOVA was employed with subsequent Mann–Whitney U tests for pairwise comparisons. All analyses were conducted on available data, with the number of observations reported for each variable. Missing data was not imputed. We investigated the association between early in-hospital administration of systemic corticosteroids and these outcomes using both univariate and multivariable logistic regression models. We used existing literature and our univariate analysis to find certain patient characteristics and comorbidities associated with our outcomes of interest. These predictor variables were included into the multivariable model, after evaluating for collinearity. The multivariable logistic regression model adjusted for potential confounding factors, including age, gender, race, ethnicity, body mass index (BMI), ICU admission during index hospitalization, various comorbidities such as coronary artery disease (CAD), hypertension, heart failure, chronic obstructive pulmonary disease (COPD), asthma, chronic kidney disease, diabetes (DM), stroke/other neurological disorders, and dyslipidemia, the highest documented COVID-19 severity as per the WHO Ordinal scale during hospitalization, length of hospital stay, concurrent medication use (including tocilizumab, baricitinib), and antibacterials exposure within the first 48 h of admission. Finally, we compared the frequency of these outcomes between those who received early corticosteroids and those who did not. Diagnoses of these infections were based on the VIRUS registry records and were evaluated and documented as “yes” or “no” in the case report forms. All analyses were conducted using JMP® Software, version Pro 14 (SAS Institute Inc., Cary, NC, USA).

Results

Patient population and baseline characteristics

A total of 17,092 patients met eligibility criteria between March 1, 2020, and March 14, 2023, and were included in the analysis (Figure 1). Of these, 9,641 received early inpatient systemic corticosteroids (Figure 1). Table 1 presents a comparison of baseline demographics between the early corticosteroid and control groups. Notably, the median age of patients receiving early corticosteroids was 63 years (IQR 51–75) with 42.5% female, compared to 60 years (IQR 45–74) with 44.2% female in the control group. Table 2 further details the patient characteristics of the index hospitalization based on early steroid use within 48 h of admission.

Figure 1

Secondary infection rates and association with corticosteroids

Overall, 13.5% of patients developed at least one of the studied secondary bacterial infections during their hospitalization. Unadjusted analysis (Table 3) revealed that early corticosteroid administration significantly increased the odds of any secondary infection (OR 1.93, 95% CI 1.76–2.12; p-value <0.001). This association remained significant for specific infections like bacteremia (OR 2.0, 95% CI 1.58–2.54; p-value <0.001), bacterial pneumonia (OR 1.5, 95% CI 1.27–1.77; p-value <0.001), septic shock (OR 1.67, 95% CI 1.44–1.93; p-value <0.001), and secondary infection from unknown source (OR 2.72, 95% CI 2.26–3.26, p-value <0.001).

After adjusting for potential confounding factors, the association between early corticosteroid use and secondary infections persisted for some but not all outcomes. The adjusted odds of developing any secondary infection (OR 1.15, 95% CI 1.02–1.29; p-value = 0.023), bacteremia (OR 1.43, 95% CI 1.09–1.88; p-value = 0.010), meningitis/encephalitis (OR 0.26, 95% CI 0.08–0.82; p-value = 0.021), and secondary infection from unknown source (OR 1.63, 95% CI 1.31–2.02, p-value <0.001) remained statistically significant. However, the association with bacterial pneumonia and septic shock did not reach statistical significance in the adjusted model (OR 0.94, 95% CI 0.79–1.11, p-value = 0.468).

Discussion

The administration of corticosteroids early in the course of hospitalization for COVID-19 significantly increased the overall risk of secondary infections. However, the effects on specific infection types were heterogeneous. Bacteremia risk was substantially elevated, while the associations with bacterial pneumonia and septic shock became less evident after controlling for potential confounding factors. Notably, meningitis/encephalitis exhibited a surprising trend toward decreased risk.

The overall rate of secondary infection in our study was 13.5% with the early corticosteroid group having a rate of 16.6% and non-corticosteroid group a rate of 9.4%. This secondary rate of infection in our study was consistent with other reported studies in literature elsewhere (53, 54). The rate of secondary infections in COVID-19 has been found to be higher than in the pre COVID-19 time period (34, 53, 54). As noted previously, this has been attributed to a number of causes unique to the pandemic such as excessive use of antibiotics, lax infection control measures during pandemic, prolonged hospitalization especially in critically ill patients associated with increased device utilization rates, and ventilator associated pneumonia amongst others (34, 53, 54).

Our study demonstrated increased secondary infection rate, bacteremia, and secondary infection from an after unknown source after adjustment, whereas no difference was noted in bacterial pneumonia, VAP, and septic shock. This increased rate of infection is remarkably similar to other reported retrospective large series such as the ESICM UNITE-COVID study (34). Furthermore, a study on mechanically ventilated patients also reported an increased risk of bacterial pneumonia and fungal infections with dexamethasone, emphasizing superinfections in critically ill patients (55). Similarly, another study focused on ICU patients found that prolonged corticosteroid use significantly raised the risk of bloodstream infections, consistent with our observation of increased bacteremia risk (56). It is noteworthy that the early steroid group had an increased incidence of acute hypoxic respiratory failure at admission and a higher COVID-19 disease severity scale. Interestingly, the early steroid group had a higher incidence of severe illness at admission, indicated by increased acute hypoxic respiratory failure scores and higher COVID-19 disease severity scales. This likely explains the association with a greater use and duration of respiratory support devices, including invasive mechanical ventilation (IMV) in the early steroid group. Additionally, the early steroid group had a higher ICU admission rate, longer ICU and hospital lengths of stay, and increased hospital mortality, but not ICU mortality. It is important to note that our study covered a period of nearly 3 years, encompassing both the pre and post-RECOVERY trial period. The RECOVERY trial (44) established the survival benefits of corticosteroids in COVID-19, likely leading to the widespread adoption of dexamethasone during the latter part of the study timeframe. This shift in standard care practices might explain why most patients requiring respiratory support received dexamethasone in the later stages of our study. However, the widespread adoption of corticosteroids as standard care after this trial makes it difficult to disentangle the independent effect of corticosteroids on infection rates. Similar to the ESICM UNITE-COVID study (34), we did not observe an overall ICU mortality benefit, but a trend toward increased mortality in the entire hospitalized population receiving early steroids. While our study was not designed to assess mortality definitively, this could be due to the higher acuity of illness in the group receiving early corticosteroids.

However, our results differ from other studies, such as the Mount Sinai COVID Informatics Center (MSCIC) analysis, which reported a lower coinfection rate in patients receiving corticosteroids (57). The MSCIC data consisted of more than 4,000 patients but also was reported early in the pandemic (54). Similarly, a study of critically ill patients found no significant association between corticosteroid use and secondary infections, contrasting with our findings of increased overall risk (58). This study focused on critically ill ICU patients with severe COVID-19, who were receiving intensive care and mechanical ventilation. In contrast to both studies our study consists of patients both from the general medical ward and ICU, spread out over a three-year period, during which time care for COVID-19 patients gradually became more standardized with hospitals only experiencing periods of intermittent surge. Thus, our results are more generalizable, more reflective of and applicable to real world with less bias.

Our study explores the link between corticosteroids and secondary infections in COVID-19 patients. While our data hints at fewer cases of meningitis/encephalitis with steroid use, the small group (18 people) limits firm conclusions. COVID-19 itself can cause this complication, as shown by a study of 32 cases by Huo et al. (59). The same study mentions individual cases where meningitis/encephalitis patients improved after getting steroids. This suggests that the benefit we observed might not be entirely due to steroids alone. It highlights the need to explore how these complications arise and how steroids influence their development. In hospitalized COVID-19 patients, meningitis and encephalitis are less often linked to secondary bacterial infections. Instead, they are usually caused by immune-driven inflammation in the brain or the virus directly invading the nervous system (59). Corticosteroids like dexamethasone help reduce cytokine storms and brain inflammation, which might explain the lower risk of these complications with steroid use (60). However, our preliminary finding of decreased incidence needs further research with larger groups and stronger methods to definitively assess this, confirm or refute our findings, uncover the underlying mechanisms, and thereby guide optimal clinical management.

Our study investigates the complex relationship between early corticosteroid use and secondary infections in COVID-19, offering several key strengths. This large-scale, international registry study (20–22) encompasses data from diverse hospitals across the globe, providing a robust and generalizable perspective on this critical relationship. Focusing on real-world data from actual clinical settings directly translates our findings to everyday patient care, enhancing their relevance and applicability. Furthermore, the comprehensive analysis of a wide range of secondary infections provides a clear picture of the potential risks associated with early corticosteroids. Importantly, we adjusted for various potential confounders, strengthening the validity and reliability of our observed associations. Finally, the consistency of our results with other large studies further reinforces the credibility and reproducibility of this association (53).

However, it is crucial to acknowledge the study’s limitations, which necessitate further research. While this observational study offers valuable real-world insights, it cannot definitively prove causality, and the retrospective design may limit the accuracy and completeness of data, especially when it comes to secondary infections like VAP and bacteremia. Additionally, variations in treatment regimes, patient populations across hospitals, and viral strains during different surge periods could have influenced our findings, which could not be adjusted in our study. Notably, different corticosteroid formulations, doses, and durations were employed based on local practices, and although this is unlikely to significantly impact our secondary infection results given the consistent effect observed in previous studies (43, 61), it warrants further investigation. Similarly, the determination of secondary infections relied on investigator judgment and reporting across multiple sites, introducing potential bias due to non-standardization. This is unavoidable given the geographic spread of hospitals and the multitude of investigators involved. The analysis of microbiological data also faces limitations. Firstly, data collection depends on what researchers recorded, potentially introducing bias, particularly for free-text information like antimicrobial use. Secondly, we cannot directly link microbiological findings to clinical outcomes. Thirdly, excluding patients with missing data may overestimate infection rates, as missing data is more likely for negative cultures. Additionally, for bloodstream and urinary tract infections, it is difficult to distinguish catheter-related infections. Finally, evaluating multi-bacterial culture positivity and microorganism susceptibility presents challenges. Despite these limitations, the consistency of our findings with other large studies is reassuring (34).

Future research and recommendations

While our study has provided valuable information on how early corticosteroid use, COVID-19 itself, and secondary infections are linked, there are still unanswered questions. We need to understand better how exactly early steroids affect the risk of secondary infections; especially why different types of infections are impacted differently. Additionally, figuring out the exact role of COVID-19 versus corticosteroids in causing secondary infections requires studies that look closely at the types of pathogens involved and potentially treatments aimed at specific parts of the immune system. Investigating specific pathogens and their susceptibility to corticosteroids could provide more refined understanding of the risk profile. To improve patient outcomes, future research should explore the possibility of personalized corticosteroid plans based on individual risk factors for secondary infections and tailored to different types of COVID-19. Additionally, investigating additional treatments that could reduce the increased risk of secondary infections associated with early corticosteroids could be helpful in clinical practice. By addressing these remaining questions thorough research, we can get a clear picture of the complex relationship between COVID-19, corticosteroids, and secondary infections, ultimately leading to better treatment options and improved patient outcomes.

Conclusion

Our study suggests that early in-hospital corticosteroids use significantly increased the risk of any secondary infection in patients with COVID-19, but their effect on specific infections varied significantly. While bacteremia risk substantially increased, associations with bacterial pneumonia and septic shock was weakened upon adjusting for confounding factors. Notably, meningitis/encephalitis showed a surprising decreased incidence, highlighting a critical knowledge gap in the existing data. This is particularly concerning considering that existing data from trials like the RECOVERY collaboration group and others did not report on secondary infections. This emphasizes the urgent need for careful consideration of both potential benefits and risks when using corticosteroids in this setting. Future randomized controlled trials should explicitly address the potential risk of secondary infections as an outcome to fully assess the risk–benefit profile of corticosteroid therapy so as to guide optimal clinical management.

From the society of critical care medicine (SCCM) discovery viral infection and respiratory illness universal study (VIRUS): COVID-19 registry investigator group

SCCM Discovery VIRUS investigators collaborative co-author list is in the Acknowledgements section. The journal is requested to PubMed index the list of VIRUS: COVID-19 Registry Investigator Group as collaborative co-authors submitted along with this manuscript.

References

• 1.

  Shah A Kashyap R Tosh P Sampathkumar P O'Horo JC . Guide to understanding the 2019 novel coronavirus. Mayo Clin Proc. (2020) 95:646–52. doi: 10.1016/j.mayocp.2020.02.003

  • CrossRef
  • Google Scholar

• 2.

  Domecq JP Lal A Sheldrick CR Kumar VK Boman K Bolesta S et al . Outcomes of patients with coronavirus disease 2019 receiving organ support therapies: the international viral infection and respiratory illness universal study registry. Crit Care Med. (2021) 49:437–48. doi: 10.1097/CCM.0000000000004879

  • CrossRef
  • Google Scholar

• 3.

  Bhalala US Gist KM Tripathi S Boman K Kumar VK Retford L et al . Characterization and outcomes of hospitalized children with coronavirus disease 2019: a report from a multicenter, viral infection and respiratory illness universal study (coronavirus disease 2019) registry. Crit Care Med. (2022) 50:e40–51. doi: 10.1097/CCM.0000000000005232

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4.

  Deo N Tekin A Bansal V Koritala T Mullen B Armaignac DL et al . Cutaneous manifestations of hospitalized COVID-19 patients in the VIRUS COVID-19 registry. Int J Dermatol. (2022) 61:623–5. doi: 10.1111/ijd.16134

  • CrossRef
  • Google Scholar

• 5.

  Tripathi S Gist KM Bjornstad EC Kashyap R Boman K Chiotos K et al . Coronavirus disease 2019-associated PICU admissions: a report from the society of critical care medicine discovery network viral infection and respiratory illness universal study registry. Pediatr Crit Care Med. (2021) 22:603–15. doi: 10.1097/PCC.0000000000002760

  • CrossRef
  • Google Scholar

• 6.

  Tripathi S Sayed IA Dapul H McGarvey JS Bandy JA Boman K et al . Risk factors for critical coronavirus disease 2019 and mortality in hospitalized young adults: an analysis of the Society of Critical Care Medicine discovery viral infection and respiratory illness universal study (VIRUS) coronavirus disease 2019 registry. Crit Care Explor. (2021) 3:e 0514. doi: 10.1097/CCE.0000000000000514

  • CrossRef
  • Google Scholar

• 7.

  Singh R Rathore SS Khan H Karale S Chawla Y Iqbal K et al . Association of obesity with COVID-19 severity and mortality: an updated systemic review, meta-analysis, and meta-regression. Front Endocrinol. (2022) 13:780872. doi: 10.3389/fendo.2022.780872

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8.

  Razonable RR Pennington KM Meehan AM Wilson JW Froemming AT Bennett CE et al . A collaborative multidisciplinary approach to the management of coronavirus disease 2019 in the hospital setting. Mayo Clin Proc. (2020) 95:1467–81. doi: 10.1016/j.mayocp.2020.05.010

  • CrossRef
  • Google Scholar

• 9.

  Sheraton M Deo N Kashyap R Surani S . A review of neurological complications of COVID-19. Cureus. (2020) 12:e8192. doi: 10.7759/cureus.8192

  • CrossRef
  • Google Scholar

• 10.

  Khan H Sabzposh H Deshpande S Kashyap R . Pregnancy during COVID-19 pandemic - maternal and neonatal outcomes: a concise review. Int J Acad Med. (2020) 6:287–93. doi: 10.4103/Ijam.Ijam_94_20

  • CrossRef
  • Google Scholar

• 11.

  Shah K Mann S Singh R Bangar R Kulkarni R . Impact of COVID-19 on the mental health of children and adolescents. Cureus. (2020) 12:e10051. doi: 10.7759/cureus.10051

  • CrossRef
  • Google Scholar

• 12.

  Sheraton M Deo N Dutt T Surani S Hall-Flavin D Kashyap R . Psychological effects of the COVID 19 pandemic on healthcare workers globally: a systematic review. Psychiatry Res. (2020) 292:113360. doi: 10.1016/j.psychres.2020.113360

  • CrossRef
  • Google Scholar

• 13.

  Md Insiat Islam R . Current drugs with potential for treatment of COVID-19: a literature review. J Pharm Pharm Sci. (2020) 23:58–64. doi: 10.18433/jpps31002

  • CrossRef
  • Google Scholar

• 14.

  Gilzad-Kohan H Jamali F . Anti-inflammatory properties of drugs used to control COVID-19 and their effects on the renin-angiotensin system and angiotensin-converting Enzyme-2. J Pharm Pharm Sci. (2020) 23:259–77. doi: 10.18433/jpps31346

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15.

  Bansal V Mahapure KS Bhurwal A Gupta I Hassanain S Makadia J et al . Mortality benefit of Remdesivir in COVID-19: a systematic review and Meta-analysis. Front Med. (2020) 7:606429. doi: 10.3389/fmed.2020.606429

  • CrossRef
  • Google Scholar

• 16.

  Bansal V Mahapure KS Mehra I Bhurwal A Tekin A Singh R et al . Mortality benefit of convalescent plasma in COVID-19: a systematic review and Meta-analysis. Front Med. (2021) 8:624924. doi: 10.3389/fmed.2021.624924

  • CrossRef
  • Google Scholar

• 17.

  Singh R Rathore SS Khan H Bhurwal A Sheraton M Ghosh P et al . Mortality and severity in COVID-19 patients on ACEIs and ARBs-A systematic review, Meta-analysis, and Meta-regression analysis. Front Med. (2021) 8:703661. doi: 10.3389/fmed.2021.703661

  • CrossRef
  • Google Scholar

• 18.

  Garcia MA Johnson SW Bosch NA et al . Variation in use of repurposed medications among patients with coronavirus disease 2019. From the Society of Critical Care Medicine discovery viral infection and respiratory illness universal study: coronavirus disease 2019 registry Investigator Group. Criti Care Explorat. (2021) 3:p e0566. doi: 10.1097/CCE.0000000000000566

  • CrossRef
  • Google Scholar

• 19.

  The Society of Critical Care Medicine, Lyntek Medical Technologies Inc . VIRUS COVID-19 registry dashboard: a COVID-19 registry of current ICU and hospital care patterns. Available at: https://sccmcovid19.org/

• 20.

  Walkey AJ Kumar VK Harhay MO Bolesta S Bansal V Gajic O et al . The viral infection and respiratory illness universal study (VIRUS): an international registry of coronavirus 2019-related critical illness. Crit Care Explor. (2020) 2:e0113. doi: 10.1097/CCE.0000000000000113

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21.

  Walkey AJ Sheldrick RC Kashyap R Kumar VK Boman K Bolesta S et al . Guiding principles for the conduct of observational critical care research for coronavirus disease 2019 pandemics and beyond: the Society of Critical Care Medicine discovery viral infection and respiratory illness universal study registry. Crit Care Med. (2020) 48:e1038–44. doi: 10.1097/CCM.0000000000004572

  • CrossRef
  • Google Scholar

• 22.

  Turek JR Bansal V Tekin A Singh S Deo N Sharma M et al . Lessons from a rapid project management exercise in the time of pandemic: methodology for a global covid-19 virus registry database. JMIR Res Protoc. (2022) 11:e27921. doi: 10.2196/27921

  • CrossRef
  • Google Scholar

• 23.

  Brundage JF Shanks GD . Deaths from bacterial pneumonia during 1918-19 influenza pandemic. Emerg Infect Dis. (2008) 14:1193–9. doi: 10.3201/eid1408.071313

  • CrossRef
  • Google Scholar

• 24.

  Feldman C Anderson R . The role of co-infections and secondary infections in patients with COVID-19. Pneumonia. (2021) 13:5. doi: 10.1186/s41479-021-00083-w

  • CrossRef
  • Google Scholar

• 25.

  Centers for Disease C, Prevention . Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) - United States, May-August 2009. MMWR Morb Mortal Wkly Rep. (2009) 58:1071–4.

  • Google Scholar

• 26.

  Echenique IA Chan PA Chapin KC Andrea SB Fava JL Mermel LA . Clinical characteristics and outcomes in hospitalized patients with respiratory viral co-infection during the 2009 H1N1 influenza pandemic. PLoS One. (2013) 8:e60845. doi: 10.1371/journal.pone.0060845

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27.

  Bardi T Pintado V Gomez-Rojo M Escudero-Sanchez R Azzam Lopez A Diez-Remesal Y et al . Nosocomial infections associated to COVID-19 in the intensive care unit: clinical characteristics and outcome. Eur J Clin Microbiol Infect Dis. (2021) 40:495–502. doi: 10.1007/s10096-020-04142-w

  • CrossRef
  • Google Scholar

• 28.

  Bassetti M Kollef MH Timsit JF . Bacterial and fungal superinfections in critically ill patients with COVID-19. Intensive Care Med. (2020) 46:2071–4. doi: 10.1007/s00134-020-06219-8

  • CrossRef
  • Google Scholar

• 29.

  Maes M Higginson E Pereira-Dias J Curran MD Parmar S Khokhar F et al . Ventilator-associated pneumonia in critically ill patients with COVID-19. Crit Care. (2021) 25:25. doi: 10.1186/s13054-021-03460-5

  • CrossRef
  • Google Scholar

• 30.

  Pickens CO Gao CA Cuttica MJ Smith SB Pesce LL Grant RA et al . Bacterial superinfection pneumonia in patients mechanically ventilated for COVID-19 pneumonia. Am J Respir Crit Care Med. (2021) 204:921–32. doi: 10.1164/rccm.202106-1354OC

  • CrossRef
  • Google Scholar

• 31.

  Rouze A Martin-Loeches I Povoa P Makris D Artigas A Bouchereau M et al . Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: a European multicenter cohort study. Intensive Care Med. (2021) 47:188–98. doi: 10.1007/s00134-020-06323-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32.

  Wang D Hu B Hu C Zhu F Liu X Zhang J et al . Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. (2020) 323:1061–9. doi: 10.1001/jama.2020.1585

  • CrossRef
  • Google Scholar

• 33.

  Weiner-Lastinger LM Pattabiraman V Konnor RY Patel PR Wong E Xu SY et al . The impact of coronavirus disease 2019 (COVID-19) on healthcare-associated infections in 2020: a summary of data reported to the National Healthcare Safety Network. Infect Control Hosp Epidemiol. (2022) 43:12–25. doi: 10.1017/ice.2021.362

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34.

  Conway Morris A Kohler K De Corte T Ercole A De Grooth HJ De Elbers PWG et al . Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set. Crit Care. (2022) 26:236. doi: 10.1186/s13054-022-04108-8

  • CrossRef
  • Google Scholar

• 35.

  Kubin CJ McConville TH Dietz D Zucker J May M Nelson B et al . Characterization of bacterial and fungal infections in hospitalized patients with coronavirus disease 2019 and factors associated with health care-associated infections. Open Forum Infect Dis. (2021) 8:ofab201. doi: 10.1093/ofid/ofab201

  • CrossRef
  • Google Scholar

• 36.

  Ritter LA Britton N Heil EL Teeter WA Murthi SB Chow JH et al . The impact of corticosteroids on secondary infection and mortality in critically ill COVID-19 patients. J Intensive Care Med. (2021) 36:1201–8. doi: 10.1177/08850666211032175

  • CrossRef
  • Google Scholar

• 37.

  Landolf KM Lemieux SM Rose C Johnston JP Adams CD Altshuler J et al . Corticosteroid use in ARDS and its application to evolving therapeutics for coronavirus disease 2019 (COVID-19): a systematic review. Pharmacotherapy. (2022) 42:71–90. doi: 10.1002/phar.2637

  • CrossRef
  • Google Scholar

• 38.

  Khilnani GC Hadda V . Corticosteroids and ARDS: a review of treatment and prevention evidence. Lung India. (2011) 28:114–9. doi: 10.4103/0970-2113.80324

  • CrossRef
  • Google Scholar

• 39.

  Briel M Spoorenberg SMC Snijders D Torres A Fernandez-Serrano S Meduri GU et al . Corticosteroids in patients hospitalized with community-acquired pneumonia: systematic review and individual patient data meta-analysis. Clin Infect Dis. (2018) 66:346–54. doi: 10.1093/cid/cix801

  • CrossRef
  • Google Scholar

• 40.

  Prescott HC Rice TW . Corticosteroids in COVID-19 ARDS: evidence and hope during the pandemic. JAMA. (2020) 324:1292–5. doi: 10.1001/jama.2020.16747

  • CrossRef
  • Google Scholar

• 41.

  Tsai MJ Yang KY Chan MC Kao KC Wang HC Perng WC et al . Impact of corticosteroid treatment on clinical outcomes of influenza-associated ARDS: a nationwide multicenter study. Ann Intensive Care. (2020) 10:26. doi: 10.1186/s13613-020-0642-4

  • CrossRef
  • Google Scholar

• 42.

  Ni YN Chen G Sun J Liang BM Liang ZA . The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Crit Care. (2019) 23:99. doi: 10.1186/s13054-019-2395-8

  • CrossRef
  • Google Scholar

• 43.

  WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group Sterne JAC Murthy S Diaz JV Slutsky AS Villar J et al . Association between Administration of Systemic Corticosteroids and Mortality among Critically ill Patients with COVID-19: a Meta-analysis. JAMA. (2020) 324:1330–41. doi: 10.1001/jama.2020.17023

  • CrossRef
  • Google Scholar

• 44.

  Recovery Collaborative Group Horby P Lim WS Emberson JR Mafham M Bell JL et al . Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. (2021) 384:693–704. doi: 10.1056/NEJMoa2021436

  • CrossRef
  • Google Scholar

• 45.

  Mehra I Mahapure K Armaly P Madas N Shah V Gupta I et al . 146: controversial role of corticosteroids on mortality in COVID-19: systematic review and Meta-analysis. Crit Care Med. (2021) 49:58. doi: 10.1097/01.ccm.0000726472.05866.e3

  • CrossRef
  • Google Scholar

• 46.

  Fang F Zhang Y Tang J Lunsford LD Li T Tang R et al . Association of Corticosteroid Treatment with Outcomes in adult patients with Sepsis: a systematic review and Meta-analysis. JAMA Intern Med. (2019) 179:213–23. doi: 10.1001/jamainternmed.2018.5849

  • CrossRef
  • Google Scholar

• 47.

  Steinberg KP Hudson LD Goodman RB Hough CL Lanken PN Hyzy R et al . Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. (2006) 354:1671–84. doi: 10.1056/NEJMoa051693

  • CrossRef
  • Google Scholar

• 48.

  Angus DC Derde L Al-Beidh F Annane D Arabi Y Beane A et al . Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. (2020) 324:1317–29. doi: 10.1001/jama.2020.17022

  • CrossRef
  • Google Scholar

• 49.

  Dequin PF Heming N Meziani F Plantefève G Voiriot G Badié J et al . Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. (2020) 324:1298–306. doi: 10.1001/jama.2020.16761

  • CrossRef
  • Google Scholar

• 50.

  Lal A Garces JPD Bansal V Tekin A Zec S Khanna AK et al . Pre-hospital aspirin use and patient outcomes in COVID-19: results from the international viral infection and respiratory illness universal study (VIRUS). Arch Bronconeumol. (2022) 58:746–53. doi: 10.1016/j.arbres.2022.07.017

  • CrossRef
  • Google Scholar

• 51.

  WHO ISARIC COVID-19 Clinical Research Resources . (2020). Available at:https://isaric.tghn.org/covid-19-clinical-research-resources/ (Accessed March 31, 2020).

  • Google Scholar

• 52.

  Vandenbroucke JP von Elm E Altman DG Gøtzsche PC Mulrow CD Pocock SJ et al . Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Int J Surg. (2014) 12:1500–24. doi: 10.1016/j.ijsu.2014.07.014

  • CrossRef
  • Google Scholar

• 53.

  Langford BJ So M Raybardhan S Leung V Westwood D MacFadden DR et al . Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect. (2020) 26:1622–9. doi: 10.1016/j.cmi.2020.07.016

  • CrossRef
  • Google Scholar

• 54.

  Markovskaya Y Gavioli EM Cusumano JA Glatt AE . Coronavirus disease 2019 (COVID-19): secondary bacterial infections and the impact on antimicrobial resistance during the COVID-19 pandemic. Antimicrob Steward Healthc Epidemiol. (2022) 2:e114. doi: 10.1017/ash.2022.253

  • CrossRef
  • Google Scholar

• 55.

  Sovik S Barrat-Due A Kasine T Olasveengen T Strand MW Tveita AA et al . Corticosteroids and superinfections in COVID-19 patients on invasive mechanical ventilation. J Infect. (2022) 85:57–63. doi: 10.1016/j.jinf.2022.05.015

  • CrossRef
  • Google Scholar

• 56.

  Dupper AC Malik Y Cusumano JA Nadkarni D Banga J Berbel Caban A et al . Longer steroid treatment increases secondary bloodstream infection risk among patients with COVID-19 requiring intensive care. Infect Dis Clin Pract. (2022) 30. doi: 10.1097/IPC.0000000000001188

  • CrossRef
  • Google Scholar

• 57.

  Ho KS Narasimhan B Difabrizio L Rogers L Bose S Li L et al . Impact of corticosteroids in hospitalised COVID-19 patients. BMJ Open Respir Res. (2021) 8:e000766. doi: 10.1136/bmjresp-2020-000766

  • CrossRef
  • Google Scholar

• 58.

  Pearce AK Zawaydeh Q McGuire WC Husain A Ayoub C Sweeney DA et al . Secondary infections in critically ill patients with COVID-19 receiving steroid therapy. Sci Prog. (2023) 106:368504231207209. doi: 10.1177/00368504231207209

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59.

  Huo L Xu KL Wang H . Clinical features of SARS-CoV-2-associated encephalitis and meningitis amid COVID-19 pandemic. World J Clin Cases. (2021) 9:1058–78. doi: 10.12998/wjcc.v9.i5.1058

  • CrossRef
  • Google Scholar

• 60.

  Hodzic E Hasbun R Granillo A Tröscher AR Wagner H von Oertzen TJ et al . Steroids for the treatment of viral encephalitis: a systematic literature review and meta-analysis. J Neurol. (2023) 270:3603–15. doi: 10.1007/s00415-023-11715-0

  • CrossRef
  • Google Scholar

• 61.

  Tomazini BM Maia IS Cavalcanti AB Berwanger O Rosa RG Veiga VC et al . Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. (2020) 324:1307–16. doi: 10.1001/jama.2020.17021

  • CrossRef
  • Google Scholar