Corticosteroids, COVID-19 pneumonia, and acute respiratory distress syndrome

Abstract

Although corticosteroids dampen the dysregulated immune system and sometimes are prescribed as an adjunctive treatment for pneumonia, their effectiveness in the treatment of coronavirus disease 2019 (COVID-19) remains controversial. In this issue of the JCI, Liu and Zhang et al. evaluated corticosteroid treatment in more than 400 patients with severe COVID-19. The authors assessed subjects retrospectively for cardiac and liver injury, shock, ventilation, mortality, and viral clearance. Corticosteroids in severe COVID-19-related acute respiratory distress syndrome (ARDS) were associated with increased mortality and delayed viral clearance. Here, we consider how to reconcile the negative effects of corticosteroids revealed by Liu and Zhang et al. with the favorable effects (reduced mortality) that were described in the RECOVERY trial. We posit that treatment timing, dosage, and COVID-19 severity determine immune response and viral outcome. Patients with moderate-to-severe COVID-19 pneumonia are likely to benefit from moderate-dose corticosteroid treatment when administered relatively late in the disease course.

Figure 1. Model for deleterious or beneficial effects of corticosteroids in the treatment of COVID-19.

(A) In asymptomatic or mild cases and in the absence of treatment, SARS–CoV-2 induces transcriptional upregulation of interferons (IFNs) and NF-κB activation, which promote cytokine production and activation of macrophages as well as demargination of PMNs. Antigens are presented to T cells and a targeted cytotoxic response ensues. (B) In worsening illness, corticosteroid treatment can delay pathogen recognition and control. Dampened danger signaling leads to impaired IFN release, unchecked viral replication, and consequent alveolar and lung damage. (C) In severe illness with COVID-19 without corticosteroid treatment, viral propagation to the alveoli amplifies danger signals and worsens alveolar epithelial and endothelial damage. Persistent damage leads to exuberant NF-κB activation and inflammation worsens even as viral load decreases. (D) In severe cases of COVID-19 corticosteroid treatment may decrease proinflammatory cytokine burden and help resolution. Corticosteroids promote a proresolving macrophage phenotype that can clear cellular debris. Corticosteroids also reduce capillary permeability and increase alveolar edema fluid clearance, resulting in improved barrier function.