The U-shaped association of serum iron level with disease severity in adult hospitalized patients with COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that leads to severe respiratory failure (RF). It is known that host exposure to viral infection triggers an iron-lowering response to mitigate pathogenic load and tissue damage. However, the association between host iron-lowering response and COVID-19 severity is not clear. This two-center observational study of 136 adult hospitalized COVID-19 patients analyzed the association between disease severity and initial serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels. Serum iron levels were significantly lower in patients with mild RF than in the non-RF group; however, there were no significant differences in iron levels between the non-RF and severe RF groups, depicting a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron and TSAT levels were independently associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.

Iron and iron-related proteins in COVID-19

“…It was speculated that lower serum iron and higher serum ferritin in male patients would be associated with more severe disease in male patients [ 13 ]. However, another study reported lower levels of serum iron and transferrin saturation in female patients than male patients [ 15 ]. Besides gender, age is another factor to consider in COVID-19.…”

Iron status and the risk of sepsis and severe COVID-19: A two-sample Mendelian randomization study

“…We assessed sex specific summary-level data on iron status and COVID-19 outcomes and showed that there was some tendency that the effect of serum iron and TSAT was more pronounced among women compared with men. Another study looking at iron status at time of hospitalization for COVID-19 identified sex differences where female patients had significantly lower serum iron, TSAT and ferritin levels and higher TIBC levels compared to men, whereas the association with severity between serum iron and TSAT was observed in both sexes (15).…”

“…Genetically-predicted iron status may not perfectly reflect this time-varying exposure (51). The U-shaped risk relationship that has been proposed for the extremes of iron status (10, 15) might cause an attenuated association when evaluated in a linear model as in the two-sample MR methods. Non-linear MR methods could be more suitable to explore this U-shaped relationship but requires large GWAS with both measurements of iron biomarkers as well as the outcomes of interest (37).…”

“…Few studies have evaluated sex differences in iron status at time of infection. In a small study iron status were lower in female patients when measured at hospitalization due to COVID-19 (15).…”

“…On the other hand, excess serum iron, TSAT and lower TIBC (i.e. indication of iron overload) and hyperferritinemia have been associated with critical illness from COVID-19 (14, 15). In a study examining nutritional status in European populations, there were indications of low iron status linked to higher mortality from COVID-19 (16).…”