Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19

Abstract

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1–3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.

The effects of iron deficient and high iron diets on SARS-CoV-2 lung infection and disease

“…A limitation of this study is that we have not investigated the responses over the long-term, with a role for iron status in increasing the severity of long-COVID suggested by several studies [12, 19, 173]. However, whether mouse models [174] can faithfully recapitulate pathological or immunopathological features of human long-COVID remains to be established [175], with underlying co-morbidities [176] clearly absent in genetically identical, specific pathogen free, laboratory mice.…”

“…Viral infections, including COVID-19, can result in significant damage to RBC [80,81], with COVID-19 also able to infect RBC progenitors [82]. Erythropoiesis is thus stimulated [12], with erythroblasts adapting to iron deficient conditions by modulating gene expression [83][84][85], with such modulation likely giving rise to these erythroblast annotations.…”

“…COVID-19 is often associated with a 'cytokine storm' and the life threatening, acute respiratory distress syndrome (ARDS). The severity of COVID-19 is influenced by a range of comorbidities [4][5][6], with a large body of literature suggesting that iron deficiency and iron overload may also contribute to disease severity [7][8][9][10][11][12][13][14][15][16][17][18][19].…”

“…Whether anemia arising from an iron deficient diet, or the comorbidity giving rise to the anemia, is responsible for the increase in COVID-19 severity remains unclear [45][46][47][48][49]. Iron dysregulation and inflammatory stress erythropoiesis have also been associated with long-COVID [12]. However, cause and affect are again difficult to verify, as increased iron dysregulation and stress erythropoiesis may be the result of more severe SARS-CoV-2 infections [38,50], which then predispose to more pronounced long-COVID [51,52].…”

Hemoglobin and Its Relationship with Fatigue in Long-COVID Patients Three to Six Months after SARS-CoV-2 Infection

“…For example, in an analysis of 214 ex-COVID-19 patients, where all aforementioned variables were included, patients who reported Long-COVID Syndrome months after the acute phase were distinguished by inflammation and abnormal iron homeostasis that lasted longer than two weeks after the onset of symptoms. This led the researchers to conclude that the effects of inflammatory iron dysregulation on erythropoiesis and blood oxygen transportation may be partially responsible for several of the characteristics of Long-COVID [ 51 ]. Alternately this might suggest that factors other than inflammation have a more significant role.…”