Corticosteroids for Severe Coronavirus Disease 2019: High Time for High Dose Clinical Trials?

Over 3 million deaths into the COVID-19 pandemic, low dose corticosteroids are still the chief therapeutic intervention to decrease mortality in critically ill COVID-19 patients. However, the persistently high mortality rate (approximately 30%) and the global surge in cases in 2021 associated with new more contagious variants of SARS-CoV-2 underscore the urgent need to evaluate whether the current corticosteroid regimens achieve the best possible outcomes. Our review of clinical, virological, and immunological data suggest that corticosteroids reduce COVID-19 mortality more when initiated in the second or third weeks after symptom onset, after viral infectivity has waned and SARS-CoV-2 immunopathology is maximal. At this time, clinical deterioration is driven by aberrant hyperinflammation. To counteract the hyperinflammation, we present credible arguments that high dose corticosteroids, defined in this Perspective as intravenous (i.v.) methylprednisolone 500-1000 mg/day for 3-7 days or the equivalent doses of other corticosteroids, can be administered with little or no risk of worsening viral replication and with expected benefits that greatly outweigh potential harm. Since the 1970s, the strategy of administering supraphysiologic doses of i.v. methylprednisolone (termed ‘pulse’ therapy) over a short period to enhance therapeutic benefit while decreasing harmful effects has become an accepted standard of care to effectively suppress inflammation in many autoimmune and immune-mediated disorders. It is particularly useful in conditions requiring rapid immunosuppression and anti-inflammatory effect and has recently been used to control inflammation in SARS-CoV-2 related complications, including multisystem inflammatory syndrome in children (MIS-C) and organizing pneumonia. In aggregate, awareness of the need for more aggressive immunosuppression and lessons learned over a half-century from the successful treatment of various inflammatory disorders, provide a sound scientific and ethics rationale for expeditiously conducting high dose corticosteroid randomized clinical trials (RCTs) in critically ill patients with COVID-19.