Inflammation and iron metabolism dysregulation as hallmarks of COVID-19 severity

Background: Coronavirus Disease 2019 (COVID-19) can cause severe clinical outcomes by triggering an excessive immune response and systemic inflammation. As disease severity increases, levels of key inflammatory markers rise accordingly. Inflammation is also associated with alterations in iron metabolism, contributing to immune dysfunction. In this study, we investigated the relationship between inflammation, iron metabolism, and COVID-19 severity to identify potential biomarkers and improve understanding of disease mechanisms. We also perform an exploratory analysis to investigate whether these features associated also with long COVID-19 severity. Materials and methods: We conducted a retrospective, multicentre, casecontrol- cross-sectional observational study including 144 COVID-19 hospitalized patients and 139 COVID-19-negative controls (individuals referred for vaccination), enrolled at two hospitals in the Lombardy region, Italy. Patients were divided into four groups according to disease severity. Laboratory parameters included serum markers of inflammation (IL-6, S100A8/A9, and Creactive protein) and iron metabolism (iron, ferritin, hepcidin, total transferrin, and transferrin saturation). Finally, a publicly available peripheral blood mononuclear cell (PBMC) transcriptomic dataset was analyzed to evaluate whether inflammation and iron dysmetabolism associated with long COVID-19 severity. Results: COVID-19 patients exhibited a marked increase in inflammatory markers (IL-6, S100A8/A9, C-reactive protein), as well as ferritin and hepcidin, while serum iron, transferrin levels, and saturated transferrin levels were lower compared to controls. Moreover, increasing COVID-19 severity was associated with higher ferritin, inflammatory markers, white blood cell and neutrophil counts, whereas total transferrin progressively decreased with disease severity. PBMC alterations in iron metabolism and inflammation were observed in patients with severe long COVID-19. Conclusions: Our data indicate a close association between inflammation, altered iron metabolism, and COVID-19 severity, with transcriptomic evidence supporting the persistence of these pathways in severe long COVID-19.