Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients' performance: a prospective observational cohort study

Abstract

Background: Severe coronavirus disease 2019 (COVID-19) is frequently associated with hyperinflammation and hyperferritinemia. The latter is related to increased mortality in COVID-19. Still, it is not clear if iron dysmetabolism is mechanistically linked to COVID-19 pathobiology.

Methods: We herein present data from the ongoing prospective, multicentre, observational CovILD cohort study (ClinicalTrials.gov number, NCT04416100), which systematically follows up patients after COVID-19. 109 participants were evaluated 60 days after onset of first COVID-19 symptoms including clinical examination, chest computed tomography and laboratory testing.

Results: We investigated subjects with mild to critical COVID-19, of which the majority received hospital treatment. 60 days after disease onset, 30% of subjects still presented with iron deficiency and 9% had anemia, mostly categorized as anemia of inflammation. Anemic patients had increased levels of inflammation markers such as interleukin-6 and C-reactive protein and survived a more severe course of COVID-19. Hyperferritinemia was still present in 38% of all individuals and was more frequent in subjects with preceding severe or critical COVID-19. Analysis of the mRNA expression of peripheral blood mononuclear cells demonstrated a correlation of increased ferritin and cytokine mRNA expression in these patients. Finally, persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status as compared to patients without hyperferritinemia.

Discussion: Alterations of iron homeostasis can persist for at least two months after the onset of COVID-19 and are closely associated with non-resolving lung pathologies and impaired physical performance. Determination of serum iron parameters may thus be a easy to access measure to monitor the resolution of COVID-19.

Trial registration: ClinicalTrials.gov number: NCT04416100.

Keywords: COVID-19; Hepcidin; Hyperferritinemia; Iron metabolism; SARS-CoV-2.

Fig. 1

Serum markers of iron homeostasis in post-acute COVID-19 according to disease severity. Correlations of a hepcidin-25, b soluble transferrin receptor (sTFR), c C-reactive protein (CRP) and d interleukin-6 (IL6) with serum ferritin are shown. ρ indicates the correlation coefficient as calculated with Spearman-rank test

Fig. 2

Post-acute mRNA expression of key modulators of iron homeostases and monocyte-derived cytokines in peripheral blood mononuclear cells of COVID-19 patients. Relative ΔΔCT mRNA expression as compared to levels in patients with mild to moderate COVID-19 are shown. Disease severity was categorized according to the need of medical treatment: mild to moderate, outward treatment or inward treatment without respiratory support; severe to critical, inward treatment with the need for respiratory support (oxygen supply or mechanical ventilation). p values depict significant differences between severity groups as calculated with Mann–Whitney U test, error bars indicate 1 standard error; N = 109. TFR1 transferrin receptor 1, DMT1 divalent metal transporter 1, FPN1 ferroportin-1, IL6 interleukin 6, IL10 interleukin 10, TNF tumor necrosis factor, HAMP hepcidin antimicrobial peptide, n.s. not significant

Fig. 3

Association of post-acute hyperferritinemia with COVID-19 severity. a Serum concentrations of ferritin according to disease severity (mild: outward treatment; N = 22; moderate: inward treatment without respiratory support, N = 34; sever: inward treatment with additional respiratory support or intensive care unit admission, N = 53). b Frequency of lung pathologies detected with computed tomography (CT) scan 60 days after disease onset in patients with (N = 41) or without (N = 68) hyperferritinemia. c The severity of pathological CT findings according to the evaluation by two independent experts. The severity of lung involvement detected by CT was graded for each lung lobe and a sum score for the total lung was calculated (0–25 points). N = 109. d Six-minute walking distance in patients with (N = 12) or without (N = 11) hyperferritinemia. p values are reported according to the Kruskal–Wallis test (a) or the Mann–Whitney U test (c, d)

Fig. 4

Representative CT scans of COVID-19 patients with or without hyperferritinemia. When comparing lung pathologies in CT scans 60 days after COVID-19 onset, patients with persisting hyperferritinemia presented with significantly more severe lung pathologies. A representative CT scan of two individuals without (a) and with (b) hyperferritinemia are shown