BACKGROUND/RATIONALE:
Emerging data suggest that glucocorticoids (steroids) may mitigate severity and improve outcomes of patients with SARS-CoV-2 (SARS2) infection and disease (COVID-19). Concerns raised early in the pandemic against the use of systemic steroids included that steroids could prolong viral shedding based on studies in other viral respiratory infections. Then, observational studies and now randomized controlled trials (RCTs) in patients with COVID-19 suggested potential benefit in shortening course of illness and decreasing mortality. However, steroids are often given with several other immunomodulatory agents and antiviral therapy, making interpretation challenging, and an understanding of potential side effects of steroids and the balance of benefits and harms ranging across the severity of COVID-19 remains incompletely understood. Given a limited evidence base, controversies remain in terms of the overall benefit of steroids in COVID-19 patients particularly amongst those who are not critically ill.

OBJECTIVE(S):
To help address these questions, we proposed an observational cohort study of hospitalized Veterans who tested positive for SARS2 to determine associations between exposure to steroids and outcomes from COVID-19. We achieved the following aims:

Aim 1: Determine associations between steroid exposure in hospitalized COVID-19 patients with risk of 90-day mortality. We compared mortality in those exposed versus not exposed to steroids, including all systemic steroids and also restricted to dexamethasone, using propensity-score weighting approaches to control for confounding by severity of illness.

Aim 2: Compare incidence of complications, including secondary infections, delirium, hyperglycemia and gastrointestinal bleeding, in hospitalized COVID-19 patients exposed and unexposed to steroids, considering duration of steroid exposure and controlling for severity of illness.

METHODS:
We conducted an observational study of patients admitted to a Veterans Affairs Medical Center between June 7, 2020-December 5, 2020 within 14-days after SARS-CoV-2 positive test, excluding those receiving prior systemic corticosteroids. We stratified patients by highest level of respiratory support during the initial 48 hours of hospitalization: 1) no oxygen support; 2) supplemental low-flow oxygen via nasal cannula (NC) that was not identified as a high-flow delivery device; 3) other supplemental oxygen/non-invasive ventilation (NIV), inclusive of oxygen by face mask, non-rebreather mask, NIV, or other forms of oxygen delivery not identifiable as low-flow NC or high-flow; 4) high-flow oxygen (abbreviated as high flow nasal cannula [HFNC]); and 5) invasive mechanical ventilation (IMV). Because nearly all patients on HFNC or IMV received corticosteroids, as well as greater clinical equipoise, we focused our analyses on those not on intensive respiratory support (IRS). Amongst patients on only low-flow nasal cannula (NC) or no oxygen support (i.e., not on IRS) during initial 48 hours of admission, we compared 90-day all-cause mortality between those receiving and not receiving oral/parenteral corticosteroids within 48 hours with inverse probability weighted Cox proportional hazards models.

FINDINGS/RESULTS:
Of 9,058 total patients (95% men, median age 71 years, 27% black), 6,825 (75%) were not on IRS within 48 hours. Among 3,025 patients without oxygen, 598 (20%) received corticosteroids and 283 (9%) died; of 3,800 patients on NC, 2,808 (74%) received corticosteroids and 514 (13%) died. In stratified models comparing those who did and did not receive corticosteroids, patients not on oxygen experienced an 89% increased risk for 90-day mortality (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.33-2.68); there was weak evidence of increased mortality among patients on NC (HR 1.21, 95% CI 0.94-1.57). In sensitivity analyses, we evaluated the average treatment effect among the treated (ATT) population that received corticosteroids in weighted Cox proportional hazards models and also constructed unweighted, but multivariable adjusted models for all primary and subgroup analyses. Results were similar in all subgroup analyses restricting corticosteroids to dexamethasone, excluding patients who were admitted to the ICU within the first 48 hours, and restricting the population to those age 70 and over. All findings were again consistent using ATT or multivariable Cox models.

IMPACT:
Our findings suggest that the harms of corticosteroids may outweigh benefits in hospitalized patients with COVID-19 not on IRS, particularly those who require no oxygen within 48 hours of admission. These differences in mortality became more apparent after 20 days of follow-up and may be underestimated in studies where outcomes were assessed at 30-days and did not extend follow-up to 90-days. Our findings raise a note of caution when considering potential "indication creep" in the real world for use of corticosteroids in patients who do not have moderate-severe COVID-19 requiring IRS.

PUBLICATIONS:

Journal Articles

1. Crothers K, DeFaccio R, Tate J, Alba PR, Goetz MB, Jones B, King JT, Marconi V, Ohl ME, Rentsch CT, Rodriguez-Barradas MC, Shahrir S, Justice AC, Akgün KM, Veterans Aging Cohort Study Clinical COVID-19 Working Group. Dexamethasone in hospitalised COVID-19 patients not on intensive respiratory support. The European respiratory journal. 2022 Jul 1; 60(1). [view]
2. Rentsch CT, Kidwai-Khan F, Tate JP, Park LS, King JT, Skanderson M, Hauser RG, Schultze A, Jarvis CI, Holodniy M, Lo Re V, Akgün KM, Crothers K, Taddei TH, Freiberg MS, Justice AC. Patterns of COVID-19 testing and mortality by race and ethnicity among United States veterans: A nationwide cohort study. PLoS Medicine. 2020 Sep 1; 17(9):e1003379. [view]
3. Datta R, Barrett A, Burk M, Salone C, Au A, Cunningham F, Fisher A, Dembry LM, Akgün KM. Surveillance of adverse drug events associated with tocilizumab in hospitalized veterans with coronavirus disease 2019 (COVID-19) to inform patient safety and pandemic preparedness. Infection control and hospital epidemiology. 2022 Oct 1; 43(10):1488-1491. [view]

JPRE

1. Crothers K, DeFaccio R, Tate J, Alba PR, Goetz M, Jones B, King Jr JT, Marconi V, Ohl ME, Rentsch CT, Rodriguez-Barradas MC, Shahrir S, Justice AC, Akgun KM, Veterans Aging Cohort Study Clinical COVID-19 Working Group -. Early initiation of corticosteroids in patients hospitalized with COVID-19 not requiring intensive respiratory support: cohort study. medRxiv : the preprint server for health sciences [Preprint]. 2021 Jul 8; https://doi.org/10.1101/2021.07.06.21259982. [view]