Iron homeostasis in Sars-CoV-2 infection: insights from a cohort of hospitalized patients

Iron plays a vital role in various biological functions such as energy production and oxygen transport. Systemic iron regulation is mainly controlled by the hormone hepcidin, which is secreted by the liver in response to high serum iron levels and promotes the degradation of ferroportin, the body’s only iron exporter. Beyond its metabolic roles, iron is crucial for immune function. During infections, hepcidin levels are known to increase in response to inflammatory cytokines like IL-6 to limit iron availability to pathogens. The COVID-19 pandemic has highlighted the role of iron homeostasis in infections, especially in severe cases where uncontrolled inflammation, driven by cytokines like IL-6, TNF-α, and IL-8, can lead to acute respiratory distress syndrome (ARDS), multi-organ failure, and ultimately, increased mortality. This excessive immune response exacerbates iron dysregulation and can lead to a vicious cycle of inflammation and impaired iron metabolism, contributing to disease severity. In COVID-19 patients, iron-related parameters typically show significant deviations from the norm, with a progressive worsening as disease severity increases. However, conflicting results have been reported regarding hepcidin levels. To better elucidate the relationships between inflammatory components and iron metabolism in severe COVID-19, blood samples of 392 patients hospitalized for COVID-19 pneumonia were taken at three time points (48 hours, 7 days and 14 days after hospital admission). Various assays, including cytokine analysis, hepcidin, erythroferrone (ERFE), and soluble transferrin receptor (sTfR) quantifications, were performed. Statistical analysis, including t-tests, non-parametric tests, and correlation assessments, was conducted to evaluate associations with disease severity. A score was built that takes into consideration the possible evolution of the disease, with a strong focus on oxygen demand, to divide the population according to disease severity. The population primarily comprised mainly older male patients. The cytokine profile of the high severity group showed significantly higher levels of IL-6, IL-10 and IL-8, together with higher hepcidin and ferritin levels, when compared to low/medium severity group. No statistically significant difference was found in serum iron, ERFE and sTfR between the two severity groups. Hepcidin strongly and positively correlated with IL-6 levels. Serum Iron negatively correlated with markers of inflammation and cytokines, especially in milder cases. Multivariate analysis linked ferritin, IL-1RA, IL10, and sTfR to serum iron and N/L (Neutrophils over Lymphocytes ratio), ferritin, IL-1R-A, IL-8, and IL-6 to hepcidin. Logistic regression identified the neutrophil to N/L ratio, CRP, P/F and hepcidin as the most important and independent predictors of COVID-19 severity. Across different time points, CRP and lymphocytes levels decreased significantly. Cytokine levels, including IL-6, IL-8, and IL-10, initially predicted severity but showed no significant differences between groups at T2. Ferritin levels were elevated in the high-severity group and decreased over time in the non-severe group. Serum iron levels did not differ significantly between severity groups, but showed a U-pattern, with significant changes between T0 and T1. Overall hepcidin levels remained higher than normal range, but with a decreasing trend over time. This suggests that hepcidin may play a role in regulating iron metabolism during COVID-19, and that its levels are influenced by the disease progression and treatment.