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.

尽管 COVID-19 急性后遗症 (PASC) 的驱动因素尚不清楚，但 SARS-CoV-2 感染后持续症状的报道越来越多。在这里，我们评估了 214 名感染 SARS-CoV-2 的个体，这些个体的疾病严重程度各不相同，从 COVID-19 症状出现起一年内，以确定 PASC 的早期相关性。疾病两周后检测到的多变量特征，包括未解决的炎症、贫血、低血清铁、铁稳态基因表达改变和新出现的应激性红细胞生成；无论 COVID-19 的严重程度如何，都区分了几个月后报告 PASC 的人。全血血红素代谢特征在发病后 1-3 个月的住院患者中丰富，与明显的缺铁网织红细胞增多症同时发生。PASC 患者持续出现淋巴细胞减少和树突状细胞数量减少，单细胞分析报告铁分布不良，表明单核细胞铁负荷和增殖淋巴细胞铁需求增加。因此，COVID-19 导致的铁稳态缺陷、红细胞生成失调和免疫功能障碍可能导致氧运输效率低下、炎症不平衡和持续症状，并且可能在治疗上是可以控制的。