Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19 – Nature.com

A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021 (WHO, 2021).

Al-Aly, Z., Xie, Y. & Bowe, B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature 594, 259264 (2021).

Article ADS CAS PubMed Google Scholar

Taquet, M. et al. Incidence, co-occurrence, and evolution of long-COVID features: a 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLoS Med. 18, e1003773 (2021).

Article CAS PubMed PubMed Central Google Scholar

Group, P.-C. C. Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study. Lancet Respir. Med. 10, 761775 (2022).

Article Google Scholar

Huang, L. et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet 398, 747758 (2021).

Article CAS PubMed PubMed Central Google Scholar

Augustin, M. et al. Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study. Lancet Reg. Health Eur. 6, 100122 (2021).

Article PubMed PubMed Central Google Scholar

Garcia-Abellan, J. et al. Antibody response to SARS-CoV-2 is associated with long-term clinical outcome in patients with COVID-19: a longitudinal study. J. Clin. Immunol. 41, 14901501 (2021).

Article CAS PubMed PubMed Central Google Scholar

Sudre, C. H. et al. Attributes and predictors of long COVID. Nat. Med. 27, 626631 (2021).

Article CAS PubMed PubMed Central Google Scholar

Tleyjeh, I. M. et al. Long term predictors of breathlessness, exercise intolerance, chronic fatigue and well-being in hospitalized patients with COVID-19: a cohort study with 4months median follow-up. J. Infect. Public Health 15, 2128 (2022).

Article PubMed Google Scholar

Lui, D. T. W. et al. Long COVID in patients with mild to moderate disease: do thyroid function and autoimmunity play a role? Endocr. Pract. 27, 894902 (2021).

Article PubMed PubMed Central Google Scholar

Munipalli, B. et al. Risk factors for post-acute sequelae of COVID-19: survey results from a tertiary care hospital. J. Investig. Med. 71, 896906 (2023).

Article PubMed Google Scholar

Vasilevskaya, A. et al. Sex and age affect acute and persisting COVID-19 illness. Sci. Rep. 13, 6029 (2023).

Article ADS CAS PubMed PubMed Central Google Scholar

Grossa, S. et al. Long COVID 1year after hospitalisation for COVID-19: a prospective bicentric cohort study. Swiss Med. Wkly https://doi.org/10.4414/SMW.w30091 (2021).

Su, Y. et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell 881895 (2022).

Peluso, M. J. et al. Chronic viral coinfections differentially affect the likelihood of developing long COVID. J. Clin. Invest. https://doi.org/10.1172/JCI163669 (2023).

Ryan, F. J. et al. Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection. BMC Med. 20, 26 (2022).

Article CAS PubMed PubMed Central Google Scholar

Shuwa, H. A. et al. Alterations in T and B cell function persist in convalescent COVID-19 patients. Med 2, 720735 (2021).

Article CAS PubMed Google Scholar

Phetsouphanh, C. et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat. Immunol. 23, 210216 (2022).

Cheong, J. G. et al. Epigenetic memory of coronavirus infection in innate immune cells and their progenitors. Cell 186, 38823902 (2023).

Article CAS PubMed Google Scholar

Bergamaschi, L. et al. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity 54, 12571275 (2021).

Article CAS PubMed PubMed Central Google Scholar

Bellmann-Weiler, R. et al. Prevalence and predictive value of anemia and dysregulated iron homeostasis in patients with COVID-19 infection. J. Clin. Med. https://doi.org/10.3390/jcm9082429 (2020).

Bergamaschi, G. et al. Anemia in patients with COVID-19: pathogenesis and clinical significance. Clin. Exp. Med. 21, 239246 (2021).

Article CAS PubMed PubMed Central Google Scholar

Hippchen, T., Altamura, S., Muckenthaler, M. U. & Merle, U. Hypoferremia is associated with increased hospitalization and oxygen demand in COVID-19 patients. Hemasphere 4, e492 (2020).

Article PubMed PubMed Central Google Scholar

Shah, A. et al. Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19. Crit. Care 24, 320 (2020).

Article PubMed PubMed Central Google Scholar

Nemeth, E. et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 12711276 (2004).

Article CAS PubMed PubMed Central Google Scholar

Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 20902093 (2004).

Article ADS CAS PubMed Google Scholar

Weiss, G., Ganz, T. & Goodnough, L. T. Anemia of inflammation. Blood 133, 4050 (2019).

Article CAS PubMed PubMed Central Google Scholar

Ganz, T. Anemia of inflammation. N. Engl. J. Med. 381, 11481157 (2019).

Article CAS PubMed Google Scholar

Morceau, F., Dicato, M. & Diederich, M. Pro-inflammatory cytokine-mediated anemia: regarding molecular mechanisms of erythropoiesis. Mediators Inflamm. 2009, 405016 (2009).

Article CAS PubMed Google Scholar

Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 10601072 (2012).

Article CAS PubMed PubMed Central Google Scholar

Yang, W. S. & Stockwell, B. R. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 26, 165176 (2016).

Article CAS PubMed Google Scholar

Hin, N., Newman, M., Pederson, S. & Lardelli, M. Iron responsive element-mediated responses to iron dyshomeostasis in Alzheimers disease. J. Alzheimers Dis. 84, 15971630 (2021).

Article CAS Google Scholar

Hanspers, K., Willighagen, E., Slenter, D., Hu, F. & Lupascu, D.-A. Ferroptosis (WP4313) https://www.wikipathways.org/instance/WP4313 (WikiPathways, 2021).

Zhou, Z. D. & Tan, E. K. Iron regulatory protein (IRP)iron responsive element (IRE) signaling pathway in human neurodegenerative diseases. Mol. Neurodegener. 12, 75 (2017).

Article PubMed PubMed Central Google Scholar

Muckenthaler, M. U., Galy, B. & Hentze, M. W. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu. Rev. Nutr. 28, 197213 (2008).

Article CAS PubMed Google Scholar

Potts, M. et al. Proteomic analysis of circulating immune cells identifies cellular phenotypes associated with COVID-19 severity. Cell Rep. 42, 112613 (2023).

Stephenson, E. et al. Single-cell multi-omics analysis of the immune response in COVID-19. Nat. Med. 27, 904916 (2021).

Article CAS PubMed PubMed Central Google Scholar

Chicault, C. et al. Iron-related transcriptomic variations in CaCo-2 cells, an in vitro model of intestinal absorptive cells. Physiol. Genomics 26, 5567 (2006).

Article CAS PubMed Google Scholar

Haschka, D. et al. Classical and intermediate monocytes scavenge non-transferrin-bound iron and damaged erythrocytes. JCI Insight https://doi.org/10.1172/jci.insight.98867 (2019).

Schulte-Schrepping, J. et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell 182, 14191440 (2020).

Article CAS PubMed PubMed Central Google Scholar

Peluso, M. J. & Deeks, S. G. Early clues regarding the pathogenesis of long-COVID. Trends Immunol. 43, 268270 (2022).

Haase, V. H. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 27, 4153 (2013).

Article CAS PubMed PubMed Central Google Scholar

Hadjadj, J. et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369, 718724 (2020).

Article ADS CAS PubMed PubMed Central Google Scholar

Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science https://doi.org/10.1126/science.abd4585 (2020).

Lanser, L. et al. Dynamics in anemia development and dysregulation of iron homeostasis in hospitalized patients with COVID-19. Metabolites https://doi.org/10.3390/metabo11100653 (2021).

Maccio, A. et al. The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study. Haematologica 100, 124132 (2015).

Article CAS PubMed PubMed Central Google Scholar

Wilson, A., Yu, H. T., Goodnough, L. T. & Nissenson, A. R. Prevalence and outcomes of anemia in rheumatoid arthritis: a systematic review of the literature. Am. J. Med. 116, 50S57S (2004).

Article PubMed Google Scholar

Rodriguez, R. et al. Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6. Infect. Immun. 82, 745752 (2014).

Article PubMed PubMed Central Google Scholar

Drakesmith, H., Nemeth, E. & Ganz, T. Ironing out ferroportin. Cell Metab. 22, 777787 (2015).

Article CAS PubMed PubMed Central Google Scholar

Drakesmith, H. & Prentice, A. Viral infection and iron metabolism. Nat. Rev. Microbiol. 6, 541552 (2008).

Article CAS PubMed Google Scholar

Erslev, A. Humoral regulation of red cell production. Blood 8, 349357 (1953).

Article CAS PubMed Google Scholar

Dulmovits, B. M. et al. HMGB1-mediated restriction of EPO signaling contributes to anemia of inflammation. Blood 139, 31813193 (2022).

Article CAS PubMed PubMed Central Google Scholar

Khalil, S. et al. Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor. J. Exp. Med. 215, 661679 (2018).

Article CAS PubMed PubMed Central Google Scholar

Libregts, S. F. et al. Chronic IFN- production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis. Blood 118, 25782588 (2011).

Article CAS PubMed Google Scholar

Bennett, L. F. et al. Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C. Sci. Signal. 12, eaap7336 (2019).

Article CAS PubMed PubMed Central Google Scholar

Jackson, A., Nanton, M. R., ODonnell, H., Akue, A. D. & McSorley, S. J. Innate immune activation during Salmonella infection initiates extramedullary erythropoiesis and splenomegaly. J. Immunol. 185, 61986204 (2010).

Article CAS PubMed Google Scholar

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