ABSTRACT
Background: Several risk factors for Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) infection are well established, including advanced age, male gender, strong inflammatory response, neutropenia and lymphopenia, and more recently hypoferremia. Hepcidin, the liver peptide hormone whose role is to regulate plasma iron concentration, is at the crossroad between iron metabolism and inflammation, being positively regulated by iron itself and proinflammatory cytokines. However, its role as potential biomarker of COVID-19 severity has not been explored in depth. Aims: Aim of the study is to investigate whether plasma hepcidin, measured at admission, can be considered a marker of COVID-19 severity and mortality. Methods: Plasma hepcidin and iron levels were analyzed in a well-characterized cohort of 111 Italian COVID-19 patients hospitalized between March 18th and May 5th, 2020 at San Raffaele University Hospital (UH), in Milan, Italy, one regional COVID-19 reference hospital. Diagnosis of COVID-19 was based on a positive real-time reverse-transcriptase polymerase chain reaction (RT-PCR) from a nasal and/or throat swab together with signs, symptoms, and/or radiological findings suggestive of COVID-19. The cohort had a median age of 57.6 (48.5-66.3) years, and included prevalently males (64%). Blood samples were obtained at admission, plasma immediately retrieved and frozen until analyzed for the concentration of iron, hepcidin (ELISA kit from Intrinsic LifeSciences), proinflammatory markers as C-reactive protein (CRP) and ferritin, and cytokines with a role in hepcidin modulation, as interleukin IL6, IL1b, TNFa and Interferon gamma (IFNg). Results: In this cohort of COVID-19 patients, iron concentration was below normal range in 93.7% of patients, whereas hepcidin levels were significantly increased in 61.3% of patients. However, considering that hypoferremia suppresses hepcidin expression, even normal hepcidin is inappropriately high in most cases. Patients with higher hepcidin levels were significantly older and had higher concentrations of markers of inflammation (CRP and ferritin) and cell damage (AST and LDH). Negative correlations were observed with the severity of respiratory failure, as reflected by the PaO2/FiO2 ratio. The role of hepcidin is strengthened by the Kaplan-Meier survival curve (Figure 1A) and confirmed by the Regression Tree analysis, which identified hepcidin as the most important predictor of death among the others recognized predictors. On the other hand, iron levels do not affect survival, likely because of the uniformly low levels in all patients (Figure 1B). Interestingly, limiting the analysis to critical patients in ICU, high hepcidin predicts mortality (Figure 1C), independently of age lung function, inflammation and tissue damage. Summary/Conclusion: Overall our data suggest that hepcidin can be considered a marker of morbidity and outcome of COVID-19, of special value for severely compromised patients in ICU (Nai et al., AJH 2021). Further studies are needed to verify whether targeting the hepcidin axis may influence the disease outcome.