Hypoferremia Predicts Hospitalization and Oxygen Demand in COVID-19 Patients

Background: Disease severity in COVID-19 patients is associated with cytokine release syndrome (CRS). Understanding factors linked to disease severity and identifying early markers that are predictive for the need of hospitalization or oxygen supplementation are highly relevant. Therefore we assessed iron metabolism markers in COVID-19 patients for their ability to predict disease severity. Methods: Patients tested positive for SARS-CoV-2 referred to the Heidelberg University Hospital were retrospectively analyzed. Patients were divided into outpatients never admitted to hospital (cohort A, n=204), inpatients (cohort B,n=81), and outpatients later admitted to hospital because of health deterioration (cohort C,n=23). Findings: Iron metabolism parameters were severely altered in patients of cohort B and C compared to cohort A. In multivariate regression analysis including age, gender, CRP and iron-related parameters only serum iron and ferritin were significantly associated with hospitalization. ROC analysis revealed an AUC for serum iron of 0.894 and an iron concentration <6µmol/l as the best cutoff-point predicting hospitalization. When stratifying inpatients in a low- and high oxygen demand group serum iron level differed significantly between these two groups and showed a high negative correlation with the inflammatory parameters IL-6, procalcitonin, and CRP. Unexpectedly, serum iron levels poorly correlate with the hepcidin. In addition, we analyzed the effect of immunomodulatory therapies on serum iron levels and observed a 1.8-, 2.0-, and 2.3-fold increase one day after treatment with anakinra, tocilizumab, and immunoglobulins, respectively. Interpretation: We conclude that measurement of serum iron can help predicting the severity of COVID-19. The differences in serum iron availability observed between the low and high oxygen demand group suggest that disturbed iron metabolism likely plays a causal role in the pathophysiology leading to lung injury. Funding Statement: MUM acknowledges funding from the Deutsche Forschungsgemeinschaft (SFB1036, SFB1118) and from the Federal Ministry of Education and Research (NephrESA project Nr 031L0191C). Declaration of Interests: There are no potential conflicts of interest. Ethics Approval Statement: The study was approved by the local ethics committee in Heidelberg (ethics approval number S148/2020) and was conducted in accordance with the Declaration of Helsinki.