Commentary
Corticosteroids are anti-inflammatory and vasoconstrictive medications that have long been used in intensive care units for the treatment of acute respiratory distress syndrome and septic shock. However, the therapeutic role of corticosteroids for treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was uncertain at the outset of the COVID-19 pandemic due to concerns that this class of medications may cause an impaired immune response in the setting of a life-threatening SARS-CoV-2 infection. Evidence supporting this notion included prior studies showing that corticosteroid therapy was associated with delayed viral clearance of Middle East respiratory syndrome or a higher viral load of SARS-CoV.2,3 The uncertainty surrounding the therapeutic use of corticosteroids in treating COVID-19 led to a simultaneous global effort to conduct randomized controlled trials to urgently examine this important clinical question. The open-label Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, conducted in the UK, was the first large-scale randomized clinical trial that reported the clinical benefit of corticosteroids in treating patients hospitalized with COVID-19. Specifically, it showed that low-dose dexamethasone (6 mg/day) administered orally or IV for up to 10 days resulted in a 2.8% absolute reduction in 28-day mortality, with the greatest benefit, an absolute risk reduction of 12.1%, conferred to patients who were receiving invasive mechanical ventilation at the time of randomization.4 In response to these findings, the National Institutes of Health COVID-19 Treatment Guidelines Panel recommended the use of dexamethasone in patients with COVID-19 who are on mechanical ventilation or who require supplemental oxygen, and recommended against the use of dexamethasone for those not requiring supplemental oxygen.5
The meta-analysis discussed in this commentary, conducted by the WHO REACT Working Group, has replicated initial findings from the RECOVERY trial. This prospective meta-analysis pooled data from 7 randomized controlled trials of corticosteroid therapy in 1703 critically ill patients hospitalized with COVID-19. Similar to findings from the RECOVERY trial, corticosteroids were associated with lower all-cause mortality at 28 days after randomization, and this benefit was observed both in critically ill patients who were receiving mechanical ventilation or supplemental oxygen without mechanical ventilation. Interestingly, while the OR estimates were imprecise, the reduction in mortality rates was similar between patients who were administered dexamethasone and hydrocortisone, which may suggest a general drug class effect. In addition, the mortality benefit of corticosteroids appeared similar for those aged ≤ 60 years and those aged > 60 years, between female and male patients, and those who were symptomatic for ≤ 7 days or > 7 days before randomization. Moreover, the administration of corticosteroids did not appear to increase the risk of SAEs. While more data are needed, results from the RECOVERY trial and this prospective meta-analysis indicate that corticosteroids should be an essential pharmacologic treatment for COVID-19, and suggest its potential role as a standard of care for critically ill patients with COVID-19.
This study has several limitations. First, not all trials systematically identified participated in the meta-analysis. Second, long-term outcomes after hospital discharge were not captured, and thus the effect of corticosteroids on long-term mortality and other adverse outcomes, such as hospital readmission, remain unknown. Third, because children were excluded from study participation, the effect of corticosteroids on pediatric COVID-19 patients is unknown. Fourth, the RECOVERY trial contributed more than 50% of patients in the current analysis, although there was little inconsistency in the effects of corticosteroids on mortality between individual trials. Last, the meta-analysis was unable to establish the optimal dose or duration of corticosteroid intervention in critically ill COVID-19 patients, or determine its efficacy in patients with mild-to-moderate COVID-19, all of which are key clinical questions that will need to be addressed with further clinical investigations.
The development of effective treatments for COVID-19 is critical to mitigating the devastating consequences of SARS-CoV-2 infection. Several recent COVID-19 clinical trials have shown promise in this endeavor. For instance, the Adaptive COVID-19 Treatment Trial (ACCT-1) found that intravenous remdesivir, as compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.6 Moreover, there is some evidence to suggest that convalescent plasma and aerosol inhalation of IFN-κ may have beneficial effects in treating COVID-19.7,8 Thus, clinical trials designed to investigate combination therapy approaches including corticosteroids, remdesivir, convalescent plasma, and others are urgently needed to help identify interventions that most effectively treat COVID-19.
Applications for Clinical Practice
The use of corticosteroids in critically ill patients with COVID-19 reduces overall mortality. This treatment is inexpensive and available in most care settings, including low-resource regions, and provides hope for better outcomes in the COVID-19 pandemic.
Katerina Oikonomou, MD, PhD
General Hospital of Larissa, Larissa, Greece
Fred Ko, MD, MS