COVID-19: Stay Cool toward Corticosteroids.

Due to the global COVID-19 pandemic, intensive care units and general wards are packed with infected patients whose conditions are often complicated by sepsis, acute respiratory failure, or acute respiratory distress syndrome (ARDS). Under the current circumstances, in which no established drugs are available, clinicians have been attempting to treat patients with a wide range of existing drugs, including low-to-high doses of corticosteroids, particularly for critically ill patients. Corticosteroid administration often lowers fever and decreases laboratory indices of inflammation; however, these short-term clinical improvements do not necessarily lead to improved long-term outcomes. Because corticosteroids produce a broad spectrum of anti-inflammatory and immunosuppressive effects,1,2 we should be cautious before initiating corticosteroid treatment, especially at a high dose, without the coadministration of antimicrobials for such acute infections. Over the past two decades, corticosteroids have been used to a significant extent to treat patients during epidemics of severe acute respiratory syndrome (SARS)coronavirus (CoV), Middle East respiratory syndrome (MERS)-CoV, and H1N1 influenza. In the initial phase of the SARS epidemic, even high-dose pulse therapy with methylprednisolone (≥500 mg/day) was suggested to be effective.3 However, the efficacy of corticosteroids remains unproven, and an increase in viral load was observed in SARS patients.4,5 With regard to acute respiratory failure or ARDS associated with H1N1 influenza, the efficacy of low-to-moderate dose corticosteroids in combination with oseltamivir was suggested in early reports,6,7 but later larger studies and systematic reviews showed either no efficacy or harmfulness for H1N1 infection and H1N1-associated ARDS.8–10 Corticosteroids were also administered to MERS-CoV patients, but its ineffectiveness and resultant delayed viral clearance were revealed in a recent large-scale multicenter study.11 There are conflicting results regarding COVID-19. A singlecenter retrospective study reported the possible efficacy of corticosteroids for COVID-19-associated ARDS by unadjusted Kaplan–Meier analysis.12 In contrast, another larger single-center cohort study suggested the harmfulness of high-dose corticosteroids by Cox proportional hazards analysis, although the definition of high dose was not clear.13 In a recently published systematic review of coronavirus infection, corticosteroid use was associated with higher mortality.14 COVID-19 infections are often associated with sepsis and ARDS, and the efficacy of corticosteroids for these critical conditions has been assessed by multiple randomized controlled trials. High-dose methylprednisolone treatments using either 30 mg/kg/6 h four times or an initial dose of 30 mg/kg followed by 5 mg/kg/h for 9 h were proven ineffective for both sepsis and ARDS.15–18 Although low-dose hydrocortisone is effective for the reversal of shock, its efficacy in improving long-term outcomes has not been established.19,20 Regarding ARDS, the administration of a moderate dose of methylprednisolone over a long period has been tried, but its effectiveness has not been established.21 The recently published positive results of dexamethasone treatment for ARDS patients require further assessment.22 Furthermore, it must be kept in mind that sepsis and ARDS are syndromes with a broad spectrum of clinical manifestations and that their pathophysiologies are heterogeneous. In fact, atypical features of COVID-19-induced ARDS have been noted.23 Thus, we cannot merely extrapolate the abovementioned results in sepsis and ARDS associated with other illnesses to similar conditions induced by COVID-19. In recently published studies, the blood levels of proinflammatory cytokines in patients with COVID-19, even in those with severe infections, were relatively low compared with those in patients with bacterial infections. These findings do not support the “cytokine storm” hypothesis, which is often cited as the basis for high-dose corticosteroid use.12,24 In summary, routine use or high doses of corticosteroids are not recommended for treating COVID-19 infection. So as not to reduce each patient’s chance of spontaneous recovery, the indication, timing, dosage, and treatment duration of corticosteroids should be assessed cautiously and on an individual basis while considering each patient’s clinical, inflammatory, and immunological conditions and whether putative antiviral drugs are being coadministered. High-dose corticosteroids, in particular, are not recommended. Preferably, steroids should be