biostudies-literatureHanson ALRCUK | MRC | Medical Research FoundationMedical Research CouncilEC | Horizon 2020 Framework ProgrammeWellcome TrustNIGMS NIH HHS471-482https://www.ebi.ac.uk/biostudies/studies/S-EPMC10907301biostudies-literatureUnknown25(3)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.Nature immunologyIron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19.PMC10907301T32 GM008719MC_UU_00008/10MC_UU_00036/4MR/L019027/1200871/Z/16/ZMC_PC_17230733100MR/W018861/1Bradley JRHess CNathan JAHanson ALMule MPGottgens BDrakesmith HCambridge Institute of Therapeutic Immunology and Infectious Disease–National Institute for Health Research (CITIID–NIHR) COVID BioResource CollaborationKotagiri PPelly VSGleadall NLyons PASmith KGCMescia FBergamaschi LTurner LRuffieux HfalseIron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19.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.2024-01-01T00:00:00Z2024 Mar2026-06-11T06:13:23.033Z2026-06-11T03:13:03.423ZS-EPMC109073013842945810.1038/s41590-024-01754-8