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Comment & Response
August 3, 2020

The Uncertain Role of Corticosteroids in the Treatment of COVID-19

Author Affiliations
  • 1Adult Cystic Fibrosis Center at the University of Utah, Salt Lake City
  • 2Center for Quantitative Biology, University of Utah, Salt Lake City
  • 3Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City
  • 4Department of Mathematics, University of Utah College of Science, Salt Lake City
  • 5University of Utah College of Biological Sciences, Salt Lake City
JAMA Intern Med. 2021;181(1):139-140. doi:10.1001/jamainternmed.2020.2438

To the Editor Infection with coronavirus disease 2019 (COVID-19) causes exuberant lung inflammation leading to respiratory failure, acute respiratory distress syndrome (ARDS), and death. Wu et al1 present early experience and retrospective analysis highlighting potential mortality reduction of COVID-19–associated ARDS using corticosteroids to reduce inflammation. However, despite a novel cause, the clinical syndrome resembles that of older diseases, and the analysis faces statistical challenges that have been encountered previously.

Prior studies in ARDS reveal variable steroid effects potentially related to different causes and resulting pathophysiologies invisible at the bedside.2 Different studies have found corticosteroid effects ranging from harmful to beneficial. Within 3 cohort studies of influenza A (H1N1) during the 2009 pandemic, as cited,2 steroid use appeared either ineffective or harmful. Other cohort studies and randomized clinical trials for treatment of ARDS wrestled with artifacts due to indication and survivor bias. The former bias is a familiar issue3 created when unblinded clinicians treat individuals with more serious illness more aggressively, in this case using steroids to prevent or mitigate ARDS. The latter bias arises in 2 ways, either by missing patients unable to survive long enough to receive steroids or failing to follow up with patients long enough to record late deaths due to secondary infections or other steroid-associated complications.

Wu et al1 found that steroid therapy had a low hazard ratio for death for patients receiving steroids for ARDS. However, the result is at odds with results suggesting harm caused by steroids used to prevent ARDS1 and is at odds with another recent report4 using a potentially overlapping patient cohort that found no steroid association with mortality. Wu et al1 suggest that because indication bias usually erroneously suggests harm from a therapy, a beneficial hazard ratio for steroid treatment of ARDS should be believed. However, this assumes that other biases are inconsequential, such as survivor bias due to rapid disease progression compounded by health care resource exhaustion. We note that the Kaplan-Meier curves presented in the original article1 show that substantial numbers of patients were censored, follow-up was substantially shorter than needed to observe steroid adverse reactions, the last observed Kaplan-Meier survival data points of the 2 groups were not statistically different, and, finally, use of steroids was not statistically different between survivors and nonsurvivors of ARDS (Table 3).1

Thus, we urge caution before using steroids for ARDS due to COVID-19. Meticulous observation as performed by Wu et al1 should continue; however, a rigorous blinded randomized clinical trial is needed to discover the benefit or harm of this therapy with confidence.5

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Article Information

Corresponding Author: Theodore G. Liou, MD, Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, 26 N Mario Capecchi Way, Salt Lake City, UT 84132 (ted.liou@utah.edu).

Published Online: August 3, 2020. doi:10.1001/jamainternmed.2020.2438

Conflict of Interest Disclosures: Dr Liou reported grants from the National Institutes of Health, the National Heart, Lung, and Blood Institute, the Cystic Fibrosis Foundation, the Iris M. and Ben B. Margolis Foundation, the Claudia Ruth Goodrich Stevens Endowment Fund, AbbVie, the Cystic Fibrosis Foundation Therapeutics Lab, Corbus Pharmaceuticals, Laurent Pharmaceuticals, Nivalis Therapeutics, Proteostasis Therapeutics, Savara, and Vertex Pharmaceuticals. No other disclosures were reported.

Wu  C, Chen  X, Cai  Y,  et al.  Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.   JAMA Intern Med. Published online March 13, 2020. doi:10.1001/jamainternmed.2020.0994PubMedGoogle Scholar
Ruan  S-Y, Lin  H-H, Huang  C-T, Kuo  P-H, Wu  H-D, Yu  C-J.  Exploring the heterogeneity of effects of corticosteroids on acute respiratory distress syndrome: a systematic review and meta-analysis.   Crit Care. 2014;18(2):R63. doi:10.1186/cc13819PubMedGoogle ScholarCrossref
Bosco  JLF, Silliman  RA, Thwin  SS,  et al.  A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies.   J Clin Epidemiol. 2010;63(1):64-74. doi:10.1016/j.jclinepi.2009.03.001PubMedGoogle ScholarCrossref
Zhou  F, Yu  T, Du  R,  et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.   Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3PubMedGoogle ScholarCrossref
Collins  R, Bowman  L, Landray  M, Peto  R.  The magic of randomization versus the myth of real-world evidence.   N Engl J Med. 2020;382(7):674-678. doi:10.1056/NEJMsb1901642PubMedGoogle ScholarCrossref
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