Fig. 1.

Intersections between iron metabolism and severe COVID-19, according to suggestions from studies described and referenced in the text. Marked hypoferremia has been consistently reported in severe COVID-19, and might play a substantial role as contributing factor to a worsening clinical course. Hypoferremia is associated to the marked increase of pro-inflammatory cytokines, including IL-6 which is a major stimulator of hepcidin production by the liver. Hepcidin contribute to hypoferremia by inhibiting iron export from macrophages due to ferroportin internalization and degradation. Other still unknown mechanisms could contribute to hepcidin-independent hypoferremia. Activation of macrophages can mimic hemophagocytic syndromes with marked hyperferritinemia and further contribute to the cytokine storm. The functional iron deficiency in turn is a major determinant of the anemia of inflammation, and can alter either oxygen sensing and lymphocyte function. Altogether these mechanisms could contribute to disease severity.