COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy

Abstract

SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.

Keywords: Adult-onset Still’s disease; Anti-viral; COVID-19; Catastrophic antiphospholipid syndrome; Deferoxamine; Hemophagocytic lymphohistiocytosis; Hyperferritinemic; Iron; Iron depletion therapy; Macrophage activation syndrome; SARS-CoV-2.

Fig. 1

Iron chelation therapy in SARS-CoV-2 infection. SARS-CoV-2, likely through inflammasome activation, leads to stimulation of infiltrating macrophages that can promote hyperinflammation, characterized by increased levels of IL-6, TNF-α, IL-1β, ferritin and subsequent possible lung fibrotic complications. The increased ferritin production allows adequate storage of iron and deprives the pathogen of iron. Labile iron in the cell contributes to the formation of reactive oxygen species that further promote tissue damage and fibrosis. Iron accumulates in the reticuloendothelial macrophages and the shedding of CD163 is the marker of macrophage activation. Iron chelation therapy can interrupt these steps. (a) Deferoxamine (DFO) has a direct effect on ferritin since promotes ferritin degradation in lysosomes by inducing autophagy. Both deferiprone and deferasirox are likely to chelate cytosolic iron and iron which is extracted from ferritin prior to ferritin degradation by proteasomes. (b) DFO can induce an up-regulation of IFN-γR2 expression on the cell surface on activated T cells thus restoring T cell response to SARS-CoV-2 infection. (c) Deferasirox and DFO reduce fibrosis-inhibiting the production of free radicals, macrophage tissue infiltration and cause a remarkable decrease of IL-6 levels