Journal Article

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

Pelly, Victoria S., Mulè, Matthew P., Hess, Christoph, Ruffieux, Hélène, Drakesmith, Hal, Bradley, John R., Mescia, Federica, Kotagiri, Prasanti, Göttgens, Berthold, Hanson, Aimee L., Turner, Lorinda, Smith, Kenneth G. C., Bergamaschi, Laura, Gleadall, Nicholas, Lyons, Paul A., Nathan, James A.

2024

Overview

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. Smith and colleagues find that a multivariate signature of unresolved inflammation and altered iron homeostasis detected beyond 2 weeks following acute COVID-19 onset was the strongest early differentiator of those who report long COVID symptoms at 3–10 months.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/232/1473 / 631/250/255/2514 / 631/250/256/2515 / 692/420/254 / 692/699/255/2514 / Biomedical and Life Sciences / Biomedicine / Complications / COVID-19 / Dendritic cells / Disease Progression / Erythropoiesis / Gene expression / Homeostasis / Humans / Immunology / Infectious Diseases / Inflammation / Iron / Iron deficiency / Long COVID / Lymphocytes / Lymphopenia / Monocytes / Research Personnel / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2