Iron Dysregulation and Inflammatory Stress Erythropoiesis Associate with Long-term Outcome of COVID-19

A recent research published in Nature Immunology investigates the impact of iron dysregulation and inflammatory stress erythropoiesis in determining the long-term consequences of COVID-19. Kenneth G. C. Smith and colleagues investigated the complicated syndrome known as post-acute sequelae of SARS-CoV-2 infection (PASC) or “long COVID.” Chronic viral illness (CVID-19) symptoms persist or emerge more than three months after infection. 

The health outcomes of 214 people with proven SARS-CoV-2 infection were thoroughly investigated, ranging from those who had no symptoms to those who needed mechanical breathing. The researchers methodically evaluated immunological, clinical, hematological, and transcriptomic data for up to a year after infection. The findings revealed that inflammation-induced iron dysregulation, which lasted more than two weeks after infection, particularly in hospitalized patients, had a physiological effect on erythropoiesis (red blood cell formation) and iron homeostasis. This dysregulation, an influential early predictor of PASC, was identified after over three months. 

According to the study, PASC offers a therapeutic challenge and a significant cost to healthcare systems worldwide due to its diverse and, at times, non-specific symptoms. Thirty percent of infected persons and eighty percent of hospitalized patients had no SARS-CoV-2 symptoms for at least three to six months after infection. These symptoms include trouble breathing, extreme weariness, weak muscles, and mental fogginess. The study found that patients with severe COVID-19, whether hospitalized or not, can have these long-term health consequences. 

The researchers concluded that months of immune-cell abnormalities following a mild to severe COVID-19 infection indicated long-term immunological damage. Inflammatory anemia is distinguished by low iron levels and high hepcidin and ferritin levels, especially in patients with this illness. The study also revealed that those with moderate to severe COVID-19 had a reduced capacity to deal with anemia, as seen by low iron levels for hemoglobin synthesis and poor stress erythropoiesis. 

Furthermore, the study’s gene-set enrichment analysis (GSEA) revealed that the whole blood transcriptome of patients with moderate to severe COVID-19 had the highest level of HALLMARK genes associated with heme metabolism between days 31 and 90 after infection. This implies that the development of reticulocytes, the cells responsible for generating heme, is delayed in these individuals, which explains their apparent late-stage heme metabolism profile. 

The findings of this study indicate that more excellent research into the dynamics of COVID-19, particularly the factors that contribute to PASC, is essential. Early indicators of poor outcomes, such as iron dysregulation and inadequate stress erythropoiesis, can be exploited to develop possible customized therapeutics to mitigate the long-term effects of COVID-19 on patients’ health. 

Journal Reference – Hanson, A. L., Mulè, M. P., Ruffieux, H., Mescia, F., Bergamaschi, L., Pelly, V. S., … Smith, K. G. C. (2024). Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19. Retrieved from https://www.nature.com/articles/s41590-024-01754-8