Iron deficiency and postcovid syndrome: a clinical case

Postcovid syndrome is a serious public health problem affecting millions of people worldwide. There is a growing body of evidence that people may exhibit symptoms after organ damage developed during the acute phase of COVID‑19, while others experience new symptoms after a mild infection, without any evidence of acquired organ or tissue damage. In this regard, understanding the determinants and regulators of COVID‑19 and postcovid syndrome pathology is an important clinical challenge that will enable better management of future variants and pandemic waves. There is presumably a close relationship between iron homeostasis, COVID‑19, and postcovid syndrome, the pathogenetic aspects of which have yet to be determined. Nevertheless, the available literature already indicates that iron deficiency and iron deficiency anemia (without inflammatory anemia) in patients with postcovid syndrome occur in 30% and 9% of cases, respectively. Given the importance and urgency of this problem and the fact that one in three patients with postcovid syndrome may have iron deficiency, this article presents a case from clinical practice in which a patient with postcovid syndrome was found to have iron deficiency and iron deficiency anemia, and treatment of this condition and disease resulted in improvement in general well-being and regression of symptoms. Thus, the effects of COVID‑19 on iron metabolism exist, and they can be corrected. The use of oral iron preparations, in particular iron sulfate, allows optimal therapeutic and clinical effects in this clinical situation along with a good tolerability and safety profile.

1. Rekomendacii po vedeniyu bol’nyh s koronavirusnoj infekciej COVID 19 v ostroj faze i pri postkovidnom sindrome v ambulatornyh usloviyah / pod red. prof. P.A. Vorob’eva. Problemy standartizacii v zdravoohranenii. 2021;7–8:3–96 (in Russ.). https://doi.org/10.26347/1607–2502202107–08003–096

2. Higgins V, Sohaei D, Diamandis EP, Prassas I. COVID 19: from an acute to chronic disease? Potential long-term health consequences. Crit Rev Clin Lab Sci. 2021;58(5):297–310. https://doi.org/10.1080/10408363.2020.1860895

3. Sudre CH, Murray B, Varsavsky T. et al. Attributes and predictors of long COVID. Nat. Med. 2021;27(4):626–631. https://doi.org/10.1038/s41591–021–01292-y

4. Yong SJ, Liu S. Proposed subtypes of post-COVID 19 syndrome (or long-COVID) and their respective potential therapies. Rev. Med. Virol. 2022;32(4): e2315. https://doi.org/10.1002/rmv.2315

5. Ayoubkhani D, Pawelek P, Gaughan C. Technical article: Updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID 19) in the UK: 26 April 2020 to 1 August 2021. Office for National Statistics. 2021 Sep 16. Available at: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021

6. NICE (National Institute for Health and Care Excellence) Guidance. COVID 19 rapid guideline: managing the long-term effects of COVID 19. Available at: www.nice.org.uk/guidance/NG188

7. WHO (World health Organization). A clinical case definition of post COVID 19 condition by a Delphi consensus, 6 October 2021. (WHO); 2021. Available at: https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1

8. Castanares-Zapatero D, Chalon P, Kohn L. et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med. 2022;54(1):1473–1487. https://doi.org/10.1080/07853890.2022.2076901

9. Long QX, Tang XJ, Shi QL. et al. Clinical and immunological assessment of asymptomatic SARS-CoV 2 infections. Nat. Med. 2020;26(8):1200–1204. https://doi.org/10.1038/s41591–020–0965–6

10. Amenta EM, Spallone A, Rodriguez-Barradas MC, El Sahly HM, Atmar RL, Kulkarni PA. Postacute COVID 19: An Overview and Approach to Classification. Open Forum Infect. Dis. 2020;7(12): ofaa509. https://doi.org/10.1093/ofid/ofaa509

11. Nalbandian A, Sehgal K, Gupta A. et al. Post-acute COVID 19 syndrome. Nat. Med. 2021;27(4):601–615. https://doi.org/10.1038/s41591–021–01283-z

12. Suriawinata E, Mehta KJ. Iron and iron-related proteins in COVID 19. Clin. Exp. Med. 2022;1–23. https://doi.org/10.1007/s10238–022–00851-y

13. Sonnweber T, Grubwieser P, Sahanic S. et al. The Impact of Iron Dyshomeostasis and Anaemia on Long-Term Pulmonary Recovery and Persisting Symptom Burden after COVID 19: A Prospective Observational Cohort Study. Metabolites. 2022;12(6):546. https://doi.org/10.3390/metabo12060546

14. Litton E, Lim J. Iron Metabolism: An Emerging Therapeutic Target in Critical Illness. Crit Care. 2019;23(1):81. https://doi.org/10.1186/s13054–019–2373–1

15. Ali MK, Kim RY, Brown AC. et al. Critical role for iron accumulation in the pathogenesis of fibrotic lung disease. J. Pathol. 2020;251(1):49–62. https://doi.org/10.1002/path.5401

16. Carota G, Ronsisvalle S, Panarello F, Tibullo D, Nicolosi A, Li Volti G. Role of Iron Chelation and Protease Inhibition of Natural Products on COVID 19 Infection. J. Clin. Med. 2021;10(11):2306. https://doi.org/10.3390/jcm10112306

17. Brigham EP, McCormack MC, Takemoto CM, Matsui EC. Iron status is associated with asthma and lung function in US women. PLoS One. 2015;10(2): e0117545. https://doi.org/10.1371/journal.pone.0117545

18. Zhao K, Huang J, Dai D, Feng Y, Liu L, Nie S. Serum Iron Level as a Potential Predictor of Coronavirus Disease 2019 Severity and Mortality: A Retrospective Study. Open Forum Infect. Dis. 2020;7(7): ofaa250. https://doi.org/10.1093/ofid/ofaa250

19. Nai A, Lorè NI, Pagani A, et al. Hepcidin levels predict Covid 19 severity and mortality in a cohort of hospitalized Italian patients. Am. J. Hematol. 2021;96(1): E32–E35. https://doi.org/10.1002/ajh.26027

20. Sonnweber T, Boehm A, Sahanic S. et al. Persisting alterations of iron homeostasis in COVID 19 are associated with non-resolving lung pathologies and poor patients’ performance: a prospective observational cohort study. Respir Res. 2020;21(1):276. https://doi.org/10.1186/s12931–020–01546–2

21. Profilaktika, diagnostika i lechenie novoj koronavirusnoj infekcii (COVID 19). Vremennye metodicheskie rekomendacii, utverzhdennye Minzdravom RF. Versiya 16 (18.08.2022) (in Russ.). Режим доступа: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/060/193/original/%D0%92%D0%9C%D0%A0_COVID-19_V16.pdf

22. ZHelezodeficitnaya anemiya. Klinicheskie rekomendacii, utverzhdennye Nauchno-prakticheskim sovetom Minzdrava RF, 2021 (in Russ.). Режим доступа: https://cr.minzdrav.gov.ru/recomend/669_1

23. Bellmann-Weiler R, Lanser L, Barket R. et al. Prevalence and Predictive Value of Anemia and Dysregulated Iron Homeostasis in Patients with COVID 19 Infection. J. Clin. Med. 2020;9(8):2429. https://doi.org/10.3390/jcm9082429

24. Wrighting DM, Andrews NC. Interleukin 6 induces hepcidin expression through STAT3. Blood. 2006;108(9):3204–3209. https://doi.org/10.1182/blood-2006–06–027631

25. Girelli D, Marchi G, Busti F, Vianello A. Iron metabolism in infections: Focus on COVID 19. Semin Hematol. 2021;58(3):182–187. https://doi.org/10.1053/j.seminhematol.2021.07.001

26. Liu T, Zhang J, Yang Y. et al. The role of interleukin 6 in monitoring severe case of coronavirus disease 2019. EMBO Mol. Med. 2020;12(7): e12421. https://doi.org/10.15252/emmm.202012421

27. Nemeth E, Ganz T. Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. Int J. Mol. Sci. 2021;22(12):6493. https://doi.org/10.3390/ijms22126493

28. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133(1):40–50. https://doi.org/10.1182/blood-2018–06–856500

29. Lanser L, Burkert FR, Bellmann-Weiler R. et al. Dynamics in Anemia Development and Dysregulation of Iron Homeostasis in Hospitalized Patients with COVID 19. Metabolites. 2021;11(10):653. https://doi.org/10.3390/metabo11100653

30. Kilercik M, Ucal Y, Serdar M, Serteser M, Ozpinar A, Schweigert FJ. Zinc protoporphyrin levels in COVID 19 are indicative of iron deficiency and potential predictor of disease severity. PLoS One. 2022;17(2): e0262487. https://doi.org/10.1371/journal.pone.0262487

31. Koskenkorva-Frank TS, Weiss G, Koppenol WH, Burckhardt S. The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress. Free Radic. Biol. Med. 2013;65:1174–1194. https://doi.org/10.1016/j.freeradbiomed.2013.09.001

32. Gupta Y, Maciorowski D, Medernach B. et al. Iron dysregulation in COVID 19 and reciprocal evolution of SARS-CoV 2: Natura nihil frustra facit. J. Cell. Biochem. 2022;123(3):601–619. https://doi.org/10.1002/jcb.30207

33. Baier MJ, Wagner S, Hupf J. et al. Cardiac iron overload promotes cardiac injury in patients with severe COVID 19. Infection. 2022;50(2):547–552. https://doi.org/10.1007/s15010–021–01722–6

34. Chen G, Wu D, Guo W. et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 2020;130(5):2620–2629. https://doi.org/10.1172/JCI137244

35. Hippchen T, Altamura S, Muckenthaler MU, Merle U. Hypoferremia is Associated With Increased Hospitalization and Oxygen Demand in COVID 19 Patients. Hemasphere. 2020;4(6): e492. https://doi.org/10.1097/HS9.0000000000000492

36. Mahroum N, Alghory A, Kiyak Z. et al. Ferritin – from iron, through inflammation and autoimmunity, to COVID 19. J. Autoimmun. 2022;126:102778. https://doi.org/10.1016/j.jaut.2021.102778

37. Kronstein-Wiedemann R, Stadtmüller M, Traikov S, et al. SARS-CoV 2 Infects Red Blood Cell Progenitors and Dysregulates Hemoglobin and Iron Metabolism. Stem. Cell. Rev. Rep. 2022;18(5):1809–1821. https://doi.org/10.1007/s12015–021–10322–8

38. Mancilha EMB, Oliveira JSR. SARS-CoV 2 association with hemoglobin and iron metabolism. Rev. Assoc. Med. Bras. (1992). 2021;67(9):1349–1352. https://doi.org/10.1590/1806–9282.20210555

39. Kim YM, Shin EC. Type I and III interferon responses in SARS-CoV 2 infection. Exp. Mol. Med. 2021;53(5):750–760. https://doi.org/10.1038/s12276–021–00592–0

40. Pachlopnik Schmid J, Ho CH, Chrétien F. et al. Neutralization of IFNgamma defeats haemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice. EMBO Mol. Med. 2009;1(2):112–124. https://doi.org/10.1002/emmm.200900009

41. 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(4):748–773. https://doi.org/10.1039/c3mt00347g

42. Banchini F, Cattaneo GM, Capelli P. Serum ferritin levels in inflammation: a retrospective comparative analysis between COVID 19 and emergency surgical nonCOVID 19 patients. World J. Emerg. Surg. 2021;16(1):9. https://doi.org/10.1186/s13017–021–00354–3

43. Haschka D, Tymoszuk P, Petzer V. et al. Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation. JCI Insight. 2021;6(13): e141760. https://doi.org/10.1172/jci.insight.141760