Evaluation of perturbed iron-homeostasis in a prospective cohort of patients with COVID-19

Abstract

Background: Marked reductions in serum iron concentrations are commonly induced during the acute phase of infection. This phenomenon, termed hypoferremia of inflammation, leads to inflammatory anemia, but could also have broader pathophysiological implications. In patients with coronavirus disease 2019 (COVID-19), hypoferremia is associated with disease severity and poorer outcomes, although there are few reported cohorts. Methods: In this study, we leverage a well characterised prospective cohort of hospitalised COVID-19 patients and perform a set of analyses focussing on iron and related biomarkers and both acute severity of COVID-19 and longer-term symptomatology. Results: We observed no associations between acute serum iron and long-term outcomes (including fatigue, breathlessness or quality of life); however, lower haemoglobin was associated with poorer quality of life. We also quantified iron homeostasis associated parameters, demonstrating that among 50 circulating mediators of inflammation IL-6 concentrations were strongly associated with serum iron, consistent with its central role in inflammatory control of iron homeostasis. Surprisingly, we observed no association between serum hepcidin and serum iron concentrations. We also observed elevated erythroferrone concentrations in COVID-19 patients with anaemia of inflammation. Conclusions: These results enhance our understanding of the regulation and pathophysiological consequences of disturbed iron homeostasis during SARS-CoV-2 infection.

Comparison of Standard and New Iron Status Biomarkers: A Prospective Cohort Study in Sepsis Patients

“…A moderate negative correlation was found between iron, Hepc, and TSAT and Hepc in the IDWA sepsis patients [ 21 ]. Our results are similar to the results in the cohort of novel coronavirus disease (COVID-19) patients in whom the negative correlation between serum iron and Hepc was weak (r = −0.24, p = 0.04) [ 25 ]. This is quite striking as an infection is known to cause hypoferremia of inflammation, which in turn leads to anemia of inflammation [ 25 ].…”

“…Our results are similar to the results in the cohort of novel coronavirus disease (COVID-19) patients in whom the negative correlation between serum iron and Hepc was weak (r = −0.24, p = 0.04) [ 25 ]. This is quite striking as an infection is known to cause hypoferremia of inflammation, which in turn leads to anemia of inflammation [ 25 ]. The study by Frost et al showed that an increased inflammatory response, resulting mainly from interleukin 6 influencing the increase of hepcidin concentration, should not be associated with low serum iron.…”

Hepcidin and ferritin levels as markers of immune cell activation during septic shock, severe COVID-19 and sterile inflammation

“…Meanwhile, in severe respiratory infections such as COVID-19, profound dysregulation of the immune system drives mortality (29, 30), and intense research efforts are ongoing to establish immunerelated biomarkers for the severity and prognosis of COVID-19. These comprise both cellular (31) and humoral markers including the role of iron homeostasis (32). The objective of this study was to investigate the expression dynamics of ferritin and hepcidin as potential stratification markers in patients with septic shock or COVID-19, with emphasis on the possible immunomodulatory roles of these proteins in the context of long-term immunological exhaustion (e.g., long-term COVID-19 and post-sepsis syndrome).…”

“…The role of hepcidin and the predictive ability of its circulating concentrations during COVID-19 and septic shock remain controversial. An analysis of biomarkers in COVID-19 patients showed that serum iron levels were strongly associated with IL-6 and other inflammatory components, but no correlation was observed with COVID-19 recovery or even hepcidin levels (32). Conversely, other groups have associated higher levels of hepcidin or iron with the severity of COVID-19 (38)(39)(40)(41) or sepsis (22), though studies in mice have reported that high hepcidin levels play a beneficial role in sepsis models (42-44).…”

“…This condition, where sterile inflammation or systemic inflammatory response syndrome (SIRS)like occurs early after surgery, helped us to determine whether the observed changes in hepcidin levels were pathogen-dependent or -independent. The role of iron homeostasis in COVID-19 has recently been investigated (32), with a significant strong association found between decreased iron levels and COVID-19 progression. We have also previously shown that survival of fulminant septic shock can be associated with the specific proteomic profile of neutrophils (35).…”