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Published in: Respiratory Research 1/2020

Open Access 01-12-2020 | Computed Tomography | Research

Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients’ performance: a prospective observational cohort study

Authors: Thomas Sonnweber, Anna Boehm, Sabina Sahanic, Alex Pizzini, Magdalena Aichner, Bettina Sonnweber, Katharina Kurz, Sabine Koppelstätter, David Haschka, Verena Petzer, Richard Hilbe, Markus Theurl, Daniela Lehner, Manfred Nairz, Bernhard Puchner, Anna Luger, Christoph Schwabl, Rosa Bellmann-Weiler, Ewald Wöll, Gerlig Widmann, Ivan Tancevski, Judith-Löffler-Ragg, Günter Weiss

Published in: Respiratory Research | Issue 1/2020

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Abstract

Background

Severe coronavirus disease 2019 (COVID-19) is frequently associated with hyperinflammation and hyperferritinemia. The latter is related to increased mortality in COVID-19. Still, it is not clear if iron dysmetabolism is mechanistically linked to COVID-19 pathobiology.

Methods

We herein present data from the ongoing prospective, multicentre, observational CovILD cohort study (ClinicalTrials.gov number, NCT04416100), which systematically follows up patients after COVID-19. 109 participants were evaluated 60 days after onset of first COVID-19 symptoms including clinical examination, chest computed tomography and laboratory testing.

Results

We investigated subjects with mild to critical COVID-19, of which the majority received hospital treatment. 60 days after disease onset, 30% of subjects still presented with iron deficiency and 9% had anemia, mostly categorized as anemia of inflammation. Anemic patients had increased levels of inflammation markers such as interleukin-6 and C-reactive protein and survived a more severe course of COVID-19. Hyperferritinemia was still present in 38% of all individuals and was more frequent in subjects with preceding severe or critical COVID-19. Analysis of the mRNA expression of peripheral blood mononuclear cells demonstrated a correlation of increased ferritin and cytokine mRNA expression in these patients. Finally, persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status as compared to patients without hyperferritinemia.

Discussion

Alterations of iron homeostasis can persist for at least two months after the onset of COVID-19 and are closely associated with non-resolving lung pathologies and impaired physical performance. Determination of serum iron parameters may thus be a easy to access measure to monitor the resolution of COVID-19.

Trial registration

ClinicalTrials.gov number: NCT04416100.
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Literature
1.
go back to reference Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. Hlh across speciality Collaboration UK: COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–4.CrossRef Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. Hlh across speciality Collaboration UK: COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–4.CrossRef
2.
go back to reference Arosio P, Ingrassia R, Cavadini P. Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta. 2009;1790:589–99.CrossRef Arosio P, Ingrassia R, Cavadini P. Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta. 2009;1790:589–99.CrossRef
3.
go back to reference Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6:748–73.CrossRef Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6:748–73.CrossRef
4.
go back to reference Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–6.CrossRef Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–6.CrossRef
5.
go back to reference Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823:1434–43.CrossRef Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823:1434–43.CrossRef
6.
go back to reference Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009;113:5277–86.CrossRef Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009;113:5277–86.CrossRef
7.
go back to reference Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133:40–50.CrossRef Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133:40–50.CrossRef
8.
go back to reference Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science. 2012;338:768–72.CrossRef Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science. 2012;338:768–72.CrossRef
10.
go back to reference Weinberg ED. Iron availability and infection. Biochim Biophys Acta. 2009;1790:600–5.CrossRef Weinberg ED. Iron availability and infection. Biochim Biophys Acta. 2009;1790:600–5.CrossRef
11.
go back to reference Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell. 2017;168:344–61.CrossRef Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell. 2017;168:344–61.CrossRef
12.
go back to reference Soares MP, Weiss G. The iron age of host-microbe interactions. EMBO Rep. 2015;16:1482–500.CrossRef Soares MP, Weiss G. The iron age of host-microbe interactions. EMBO Rep. 2015;16:1482–500.CrossRef
13.
go back to reference Skaar EP, Raffatellu M. Metals in infectious diseases and nutritional immunity. Metallomics. 2015;7:926–8.CrossRef Skaar EP, Raffatellu M. Metals in infectious diseases and nutritional immunity. Metallomics. 2015;7:926–8.CrossRef
15.
go back to reference Edeas M, Saleh J, Peyssonnaux C. Iron: innocent bystander or vicious culprit in COVID-19 pathogenesis? Int J Infect Dis. 2020;97:303–5.CrossRef Edeas M, Saleh J, Peyssonnaux C. Iron: innocent bystander or vicious culprit in COVID-19 pathogenesis? Int J Infect Dis. 2020;97:303–5.CrossRef
16.
go back to reference Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract. 2020;10:1271.CrossRef Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract. 2020;10:1271.CrossRef
17.
go back to reference Ruddell RG, Hoang-Le D, Barwood JM, Rutherford PS, Piva TJ, Watters DJ, Santambrogio P, Arosio P, Ramm GA. Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology. 2009;49:887–900.CrossRef Ruddell RG, Hoang-Le D, Barwood JM, Rutherford PS, Piva TJ, Watters DJ, Santambrogio P, Arosio P, Ramm GA. Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology. 2009;49:887–900.CrossRef
18.
go back to reference Sonnweber T, Theurl I, Seifert M, Schroll A, Eder S, Mayer G, Weiss G. Impact of iron treatment on immune effector function and cellular iron status of circulating monocytes in dialysis patients. Nephrol Dial Transplant. 2011;26:977–87.CrossRef Sonnweber T, Theurl I, Seifert M, Schroll A, Eder S, Mayer G, Weiss G. Impact of iron treatment on immune effector function and cellular iron status of circulating monocytes in dialysis patients. Nephrol Dial Transplant. 2011;26:977–87.CrossRef
19.
go back to reference Sonnweber T, Nairz M, Theurl I, Petzer V, Tymoszuk P, Haschka D, Rieger E, Kaessmann B, Deri M, Watzinger K, et al. The crucial impact of iron deficiency definition for the course of precapillary pulmonary hypertension. PLoS ONE. 2018;13:e0203396.CrossRef Sonnweber T, Nairz M, Theurl I, Petzer V, Tymoszuk P, Haschka D, Rieger E, Kaessmann B, Deri M, Watzinger K, et al. The crucial impact of iron deficiency definition for the course of precapillary pulmonary hypertension. PLoS ONE. 2018;13:e0203396.CrossRef
21.
go back to reference Pfeiffer CM, Looker AC. Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges. Am J Clin Nutr. 2017;106:1606S-1614S.CrossRef Pfeiffer CM, Looker AC. Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges. Am J Clin Nutr. 2017;106:1606S-1614S.CrossRef
22.
go back to reference Weiss G. Anemia of chronic disorders: new diagnostic tools and new treatment strategies. Semin Hematol. 2015;52:313–20.CrossRef Weiss G. Anemia of chronic disorders: new diagnostic tools and new treatment strategies. Semin Hematol. 2015;52:313–20.CrossRef
23.
go back to reference Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood. 1997;89:1052–7.CrossRef Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood. 1997;89:1052–7.CrossRef
24.
go back to reference Sonnweber T, Pizzini A, Tancevski I, Loffler-Ragg J, Weiss G. Anaemia, iron homeostasis and pulmonary hypertension: a review. Intern Emerg Med. 2020;15:573–85.CrossRef Sonnweber T, Pizzini A, Tancevski I, Loffler-Ragg J, Weiss G. Anaemia, iron homeostasis and pulmonary hypertension: a review. Intern Emerg Med. 2020;15:573–85.CrossRef
25.
go back to reference Cullis JO, Fitzsimons EJ, Griffiths WJ, Tsochatzis E, Thomas DW, British Society for H. Investigation and management of a raised serum ferritin. Br J Haematol. 2018;181:331–40.CrossRef Cullis JO, Fitzsimons EJ, Griffiths WJ, Tsochatzis E, Thomas DW, British Society for H. Investigation and management of a raised serum ferritin. Br J Haematol. 2018;181:331–40.CrossRef
26.
go back to reference Hansell DM, Bankier AA, MacMahon H, McLoud TC, Muller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008;246:697–722.CrossRef Hansell DM, Bankier AA, MacMahon H, McLoud TC, Muller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008;246:697–722.CrossRef
27.
go back to reference Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–62.CrossRef Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–62.CrossRef
28.
go back to reference Phua J, Weng L, Ling L, Egi M, Lim CM, Divatia JV, Shrestha BR, Arabi YM, Ng J, Gomersall CD, et al. Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Respir Med. 2020;8:506–17.CrossRef Phua J, Weng L, Ling L, Egi M, Lim CM, Divatia JV, Shrestha BR, Arabi YM, Ng J, Gomersall CD, et al. Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Respir Med. 2020;8:506–17.CrossRef
29.
go back to reference Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, Xu S, Gao Y, Chen X, Sui X, Li G. The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 2020;127:110108.CrossRef Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, Xu S, Gao Y, Chen X, Sui X, Li G. The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 2020;127:110108.CrossRef
30.
go back to reference Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radic Biol Med. 2020;152:175–85.CrossRef Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radic Biol Med. 2020;152:175–85.CrossRef
31.
go back to reference Oexle H, Gnaiger E, Weiss G. Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim Biophys Acta. 1999;1413:99–107.CrossRef Oexle H, Gnaiger E, Weiss G. Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim Biophys Acta. 1999;1413:99–107.CrossRef
32.
go back to reference Feelders RA, Vreugdenhil G, Eggermont AM, Kuiper-Kramer PA, van Eijk HG, Swaak AJ. Regulation of iron metabolism in the acute-phase response: interferon gamma and tumour necrosis factor alpha induce hypoferraemia, ferritin production and a decrease in circulating transferrin receptors in cancer patients. Eur J Clin Invest. 1998;28:520–7.CrossRef Feelders RA, Vreugdenhil G, Eggermont AM, Kuiper-Kramer PA, van Eijk HG, Swaak AJ. Regulation of iron metabolism in the acute-phase response: interferon gamma and tumour necrosis factor alpha induce hypoferraemia, ferritin production and a decrease in circulating transferrin receptors in cancer patients. Eur J Clin Invest. 1998;28:520–7.CrossRef
33.
go back to reference Tilg H, Ulmer H, Kaser A, Weiss G. Role of IL-10 for induction of anemia during inflammation. J Immunol. 2002;169:2204–9.CrossRef Tilg H, Ulmer H, Kaser A, Weiss G. Role of IL-10 for induction of anemia during inflammation. J Immunol. 2002;169:2204–9.CrossRef
34.
go back to reference Nairz M, Theurl I, Swirski FK, Weiss G. “Pumping iron”-how macrophages handle iron at the systemic, microenvironmental, and cellular levels. Pflugers Arch. 2017;469:397–418.CrossRef Nairz M, Theurl I, Swirski FK, Weiss G. “Pumping iron”-how macrophages handle iron at the systemic, microenvironmental, and cellular levels. Pflugers Arch. 2017;469:397–418.CrossRef
35.
go back to reference Drakesmith H, Prentice A. Viral infection and iron metabolism. Nat Rev Microbiol. 2008;6:541–52.CrossRef Drakesmith H, Prentice A. Viral infection and iron metabolism. Nat Rev Microbiol. 2008;6:541–52.CrossRef
Metadata
Title
Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients’ performance: a prospective observational cohort study
Authors
Thomas Sonnweber
Anna Boehm
Sabina Sahanic
Alex Pizzini
Magdalena Aichner
Bettina Sonnweber
Katharina Kurz
Sabine Koppelstätter
David Haschka
Verena Petzer
Richard Hilbe
Markus Theurl
Daniela Lehner
Manfred Nairz
Bernhard Puchner
Anna Luger
Christoph Schwabl
Rosa Bellmann-Weiler
Ewald Wöll
Gerlig Widmann
Ivan Tancevski
Judith-Löffler-Ragg
Günter Weiss
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2020
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-020-01546-2

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