Hypoferremia is Associated With Increased Hospitalization and Oxygen Demand in COVID-19 Patients

Abstract

Iron metabolism might play a crucial role in cytokine release syndrome in COVID-19 patients. Therefore, we assessed iron metabolism markers in COVID-19 patients for their ability to predict disease severity. COVID-19 patients referred to the Heidelberg University Hospital were retrospectively analyzed. Patients were divided into outpatients (cohort A, n = 204), inpatients (cohort B, n = 81), and outpatients later admitted to hospital because of health deterioration (cohort C, n = 23). 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 <6 μmol/l as the best cutoff-point predicting hospitalization with a sensitivity of 94.7% and a specificity of 67.9%. When stratifying inpatients in a low- and high oxygen demand group serum iron levels 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 hepcidin. 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.

Figure 1

A: ROC curve for cohort A and B for predicting hospitalization for iron, transferrin and TfSat with AUCs of 0.894, 0.735, and 0.863, respectively (and confidence intervals of 0.858–0.931, 0.676–0.795, and 0.824–0.903, respectively). B: ROC curve for cohort A and B for predicting hospitalization for ferritin and CRP with AUCs of 0.725 (CI 0.667–0.784), and 0.838 (CI 0.790–0.886), respectively. C: Course of iron pre-hospitalization for cohort C. Data are presented as boxplot (median ± interquartile range).

Figure 2

Course of iron and inflammatory parameters in inpatients during the disease course. Serum iron, transferrin, transferrin saturation, hepcidin, hemoglobin (Hgb), and IL-6 have been measured at the time of admission (d0) and for 6 following days (d1-d6). Box and whiskers plot represent median with 25th and 75th percentiles (boxes) together with 10th and 90th percentiles (whiskers). Statistical analysis was performed with the Mann-Whitney U test and the p value has been corrected for multiple comparisons with the Holm method. ns = not significant; ^∗p < 0.05; ^∗∗p < 0.01; ^∗∗∗p < 0.001; ^∗∗∗∗p < 0.0001.

Figure 3

Heatmap of the Spearman's r correlation analysis of iron, transferrin and IL-6 with the parameters indicated. White boxes indicate a lack of correlation (p > 0.05) while in red and blue are reported statistically significant direct and indirect correlations, respectively. The intensity of the color indicates the –log10 (p value).

Figure 4

Iron metabolism parameters and CRP before (day 0) and in the days after administration of immunomodulatory medication. Displayed are the courses of serum iron, TfSat, ferritin, CRP, and IL-6 for each individual patient under the three different therapies: Anakinra (n = 6 patients); Tocilizumab (n = 4 patients); intravenous immunoglobulins (IVIG) (n = 6 patients). Data are represented as mean ± s.e.m.