A study of 214 individuals infected with SARS-CoV-2 found that persistent symptoms following infection, known as post-acute sequelae (PASC) or 'long COVID', are associated with early signs of inflammation, iron dysregulation, and stress erythropoiesis. These factors were detected beyond two weeks of disease and were linked to the development of PASC months later, regardless of the severity of the initial infection. The study identified a whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1–3 post-onset, which coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis revealed iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. These findings suggest that defects in iron homeostasis, dysregulated erythropoiesis, and immune dysfunction due to COVID-19 may contribute to inefficient oxygen transport, inflammatory disequilibrium, and persistent symptomatology, and may be therapeutically tractable. The study also found that iron dysregulation and inflammatory anemia are associated with prolonged symptoms in patients with moderate to severe COVID-19. Inflammation and disrupted iron homeostasis occur in hospitalized patients with COVID-19, and the levels of inflammatory markers such as CRP, IL-6, IL-1β, and TNF-α were elevated in groups C–E compared with healthy controls (HCs). The iron-regulating hormone hepcidin, which blocks the release of iron from cells, was elevated in the serum of groups C–E at day 0–14 compared with HCs. The levels of iron, the iron transport protein transferrin, and transferrin iron saturation (TSAT) were markedly reduced in the serum of groups C–E at day 0–14 compared with HCs, and serum iron and TSAT remained significantly lower in group E at day 181–270 post onset. Low iron in combination with increased ferritin and hepcidin in the serum is a characteristic of inflammatory anemia, which is associated with dysregulated iron trafficking and disrupted erythropoiesis in the context of systemic inflammation. The study also found that iron availability is essential for cellular metabolism and regulates the function and proliferative capacity of leukocytes. However, iron overload increases susceptibility to ROS-induced ferroptotic cell death. Consistent with hepcidin-mediated iron redistribution, the study observed transcriptional signatures of iron accumulation in circulating CD16⁺ classical and CD14⁺ nonclassical monocytes, potentially predisposing them to cellular dysfunction through ROS-mediated damage and contributing to tissue and organ pathology in patients with COVID-19. Iron-laden macrophages are detectable in post-mortem bone marrow samplesA study of 214 individuals infected with SARS-CoV-2 found that persistent symptoms following infection, known as post-acute sequelae (PASC) or 'long COVID', are associated with early signs of inflammation, iron dysregulation, and stress erythropoiesis. These factors were detected beyond two weeks of disease and were linked to the development of PASC months later, regardless of the severity of the initial infection. The study identified a whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1–3 post-onset, which coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis revealed iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. These findings suggest that defects in iron homeostasis, dysregulated erythropoiesis, and immune dysfunction due to COVID-19 may contribute to inefficient oxygen transport, inflammatory disequilibrium, and persistent symptomatology, and may be therapeutically tractable. The study also found that iron dysregulation and inflammatory anemia are associated with prolonged symptoms in patients with moderate to severe COVID-19. Inflammation and disrupted iron homeostasis occur in hospitalized patients with COVID-19, and the levels of inflammatory markers such as CRP, IL-6, IL-1β, and TNF-α were elevated in groups C–E compared with healthy controls (HCs). The iron-regulating hormone hepcidin, which blocks the release of iron from cells, was elevated in the serum of groups C–E at day 0–14 compared with HCs. The levels of iron, the iron transport protein transferrin, and transferrin iron saturation (TSAT) were markedly reduced in the serum of groups C–E at day 0–14 compared with HCs, and serum iron and TSAT remained significantly lower in group E at day 181–270 post onset. Low iron in combination with increased ferritin and hepcidin in the serum is a characteristic of inflammatory anemia, which is associated with dysregulated iron trafficking and disrupted erythropoiesis in the context of systemic inflammation. The study also found that iron availability is essential for cellular metabolism and regulates the function and proliferative capacity of leukocytes. However, iron overload increases susceptibility to ROS-induced ferroptotic cell death. Consistent with hepcidin-mediated iron redistribution, the study observed transcriptional signatures of iron accumulation in circulating CD16⁺ classical and CD14⁺ nonclassical monocytes, potentially predisposing them to cellular dysfunction through ROS-mediated damage and contributing to tissue and organ pathology in patients with COVID-19. Iron-laden macrophages are detectable in post-mortem bone marrow samples