Vikas Bansal ¹ Nitesh K Jain ² Amos Lal ¹ Anwar Khedr ² Aysun Tekin ¹ Abbas B. Jama ² Noura Attallah ² Esraa Hassan ² Hisham Mushtaq ² Sara K. Robinson ² Marjan Jahani Kondori ² Thoyaja Koritala ² Donna Lee Armaignac ³ Amy B. Christie ⁴ Umamaheswara Raju ⁵ Ashish Khanna ⁶ Rodrigo Cartin-Ceba ⁷ Devang Sanghavi ⁸ Abigail T La Nou ⁹ Karen Boman ¹⁰ Vishakha Kumar ¹⁰ Allan J Walkey ¹¹ Juan Pablo Domecq ^1,2 Rahul Kashyap ^1,12 Syed Anjum Khan ^2*

• ¹ Mayo Clinic, Rochester, United States
• ² Mayo Clinic Health System, Mankato, MN, United States
• ³ Center for Advanced Analytics, Baptist Health South Florida, Miami, FL, United States
• ⁴ Department of Trauma Critical Care, The Medical Center Navicent Health, Mercer University School of Medicine,, Macon, GA,, United States
• ⁵ Gandhi Medical College and Hospital, Hyderabad, India
• ⁶ Wake Forest University, Winston-Salem, North Carolina, United States
• ⁷ Mayo Clinic Arizona, Scottsdale, Arizona, United States
• ⁸ Mayo Clinic Florida, Jacksonville, Florida, United States
• ⁹ Mayo Clinic Health System, Eau Claire, Wisconsin, United States
• ¹⁰ Society of Critical Care Medicine, Mount Prospect, Illinois, United States
• ¹¹ Department of Medicine, School of Medicine, Boston University, Boston, Massachusetts, United States
• ¹² WellSpan Health, York, Pennsylvania, United States

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 hours 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).Conclusions: 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.