Anemia and iron metabolism in patients with sars-cov-2 infection: The role of inflammation and hypoxia
Authors: D. Maira, L. Duca, E. Di Pierro, D. Consonni, G. Grasselli, M. Proietti, R. Lombardi, L. Valenti, M. D. Cappellini, I. Motta
Journal: HemaSphere (2021)

Background: Coronavirus Disease (COVID-19) could be considered as a human model of marked inflammation combined with severe hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction. In patients with SARS-CoV-2 infection, Hb levels tend to be relatively high even in the context of severe disease and marked inflammation. A better understanding of erythropoiesis and iron metabolism in COVID-19 could contribute to elucidate the relationship between hypoxia and inflammation on erythropoietic control. Aims: To investigate the prevalence of anemia, the alterations of iron homeostasis,and the relationship between inflammation,hypoxia and erythropoiesis in a cohort of COVID-19 patients admitted both to medical wards and intensive care unit (ICU). Methods: We retrospectively analyzed data of 303 patients with COVID- 19 (178 subjects admitted to medical wards and 125 subjects admitted to the ICU). Biochemical parameters were collected on admission (T0), after 7 days of hospitalization (T1) and at discharge/death (T2). Results: The median age of the patients was 62 years (53-71) and 72% were males. ICU patients had lower mean Hb levels compared to non- ICU patients (11.3±1.8 vs 12.8±1.8 g/dL at T0, 10.2±1.6 vs 12.2±1.9 g/ dL at T1, 10±1.4 vs 12±1.7 g/dL at T2;p<0.001). Mean Hb concentration did not fall under 12 g/dl in the non-ICU group and under 10 g/ dl in the ICU group during hospitalization. Hb decreased by approximately 1 g/dl in both cohorts during the first 7 days of hospitalization, then remained stable until discharge. ICU patients also showed increased inflammatory markers and ferritin levels (1401 vs 839 mcg/l at T0, p<0.001;913 vs 832 mcg/L at T1, p ns;764 vs 651 mcg/L at T2, p ns). There were no significant differences in other iron parameters between groups. Hypoxia was a prominent feature of ICU patients (P/F ratio 91 vs 224, p<0.001). Patients who were anemic on admission maintained relatively constant Hb concentrations from T0 to T2 (10.8 g/dL at T0, 10.2 g/dL at T1 and 10.4 g/dL at T2), thus remaining in a range of mild to moderate anemia. Conversely, the non-anemic group displayed a greater reduction of Hb levels (13.7 g/dl at T0, 12.7 g/dl at T1, 12 g/dl at T2). Anemic subjects were more hypoxic than non-anemic patients (P/F 151 vs 292 at T0, p<0.001) and showed significantly higher levels of CRP (10.8 vs 6.6 mg/dL), IL-6 (60.3 vs 47.7 ng/L) and leukocyte count (7290 vs 6130 x109/L). Ferritin was higher in anemic patients at T0 and T1 (1220 vs 926 mcg/L and 852 vs 896 mcg/L, p ns), decreasing more at T2 (655 vs 763 mcg/L, p ns). Median hepcidin levels, which were available for a limited subset of non- ICU patients, were elevated during the whole period: 233 ng/mL at T0, 95 ng/mL at T1 and 60 ng/mL at T2. Summary/Conclusion: In patients with SARS-CoV-2 infection, two main factors influence erythropoiesis and iron homeostasis: systemic inflammation and profound hypoxia. Markedly high ferritin and hepcidin levels reflect a strong inflammatory response. However, COVID-19 patients tend to have disproportionately high Hb levels in the contest of the inflammatory milieu. The absolute reduction in Hb levels is more prominent in patients who displayed normal Hb on admission. Conversely, anemic and profoundly hypoxic subjects show constant mean Hb levels over time. Thus, we can hypothesize that the erythropoietic drive provided by hypoxia could counterbalance the effect of inflammation on hepcidin regulation, preventing Hb levels from falling dramatically during hospitalization.