The Role of Ferritin in Assessing COVID-19 Severity

Ferritin is one of the biomarkers requiring special attention; its blood level increases significantly especially in the severe course of COVID-19. Information on the effect of hyperferritinemia on the disease outcome is very contradictory as are the ideas about the causes of its development.

The objective: to study the effect of hyperferritinemia on the disease outcome and analyse the possible causes of its development in severe COVID-19.

Subjects and Methods. Data on 479 patients with severe course of coronavirus infection treated in intensive care units (ICU) were retrospectively analyzed. Of them, the proportion of patients with a favorable outcome (Group 1) was 51.0% (n = 241), and with an unfavorable outcome 
(Group 2) - 49.0% (n = 235). The following parameters were assessed: the levels of ferritin, C-reactive protein, fibrinogen, IL-6, IL-10, IL-18, procalcitonin, complement C5a, total, direct and indirect bilirubin, ALT, AST, and the blood level of lactate dehydrogenase (LDH). The changes of erythrocyte count and hemoglobin blood level were also monitored. In order to form a clear view of iron metabolism, free iron, transferrin, and myoglobin levels were assessed in several patients with high ferritin values (more than 1,500 pg/L).

Results. In the unfavorable outcome, ferritin levels increase very significantly, reaching maximum by day 6 of patients' stay in ICU. The difference in the level of ferritin between the groups of survivors and deceased during this period is clear and significant (p = 0.0013). The association of ferritin values with the outcome is detected as early as day 1, but by day 4 it becomes highly significant (the cut-off point is 1,080 pg/l). No data have been obtained that would indicate the association of hyperferritinemia with impaired iron metabolism, the development of hepatic dysfunction, or cellular destruction. In contrast to survivors, those who died on day 6 had elevated IL-6 while C5a level remained unchanged. 

Conclusions. The rapid increase in ferritin blood levels to 1,000 pg/L or higher is an unfavorable prognostic sign indicating a high probability of a lethal outcome. When assessing genesis of hyperferritinemia in COVID-19, the crucial significance should be attributed to the cytokine storm rather than disorders of iron metabolism or hemotoxic effects of the virus. The persistent increase of ferritin level in blood during 4-6 days of stay in ICU should be considered as a reason to intensify anticytokine therapy.

1. Gudima G.O., Khaitov R.M., Kudlay DA., Khaitov M.R. Molecular immunological aspects of diagnosis, prevention and treatment of coronavirus infection. Immunologiya, 2021, vol. 42, no. 3, pp. 198210. (In Russ.) https://doi.org/10.33029/0206-4952-2021-42-3-198-210.

2. Kuznetsov IA., Potievskaya VI., Kachanov I.V et al. The role of ferritin in human biological media. Sovremennye Problemy Nauki i Obrazovaniya (Elektronny Journal), 2017, no. 5. (In Russ.) https://science-education.ru/ru/article/view?id=27102.

3. Lodyagin А.N., Batotsyrenov B.V., Shikalova IA . et al. Acidosis and toxic hemolysis are the goals of the pathogenetic treatment of multiple organ pathology in COVID-19. Vestnik Vosstanovitelnoy Meditsiny, 2020, vol. 97, no. 3, pp. 25-30. (In Russ.) https://doi.org/10.38025/ 2078-1962-2020-97-3-25-3.

4. Mamaev А.N., Kudlay D. A. Statisticheskiye metody v meditsine.[Statistical methods in medicine]. Moscow, Prakticheskaya Meditsina Publ., 2021. 136 p.

5. Orlov Yu.P., Dolgikh V.T., Vereschagin E.I. et al. Is there a connection between iron exchange and COVID-19? Messenger of Anesthesiology and Resuscitation, 2020, vol. 17, no. 4, pp. 6-13. (In Russ.) https://doi.org/10.21292/2078-5658-2020-17-4-6-13.

6. Orlov Yu.P., Ivanov А.У., Dolgikh V.T. Disorders of iron metabolism in the pathogenesis of critical conditions. Obschaya Reanimatologiya, 2011, vol. VII, no. 5, pp. 15-19. (In Russ.) https://doi.org/10.15360/1813-9779-2011-5-15.

7. Cheng L., Li H., Li L. et al. Ferritin in the coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. J. Clin. Lab. Anal., 2020, no. 34, pp. e23618. https://doi.org/10.1002/jcla.23618.

8. Colafrancesco S., Alessandri C., Conti F. et al. COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? Autoimmun Rev., 2020, no. 19, pp. 102573. https://doi.org/10.1016/j.autrev.2020.102573.

9. Diao Bo, Wang Ch., Wang R. et al. Human kidney is a target for novel severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). Infection. medRxiv, 2020. https://doi.org/10.1101/2020.03.04.20031120.

10. Feld J., Tremblay D., Thibaud S. et al. Ferritin levels in patients with COVID-19: A poor predictor of mortality and hemophagocytic lymphohistiocytosis. Int. J. Lab. Hematol., 2020, no. 42, pp. 773-779. https://doi.org/10.1111/ijlh.13309.

11. Habib H.M., Ibrahim H.S., Wissam A.Z. et al. The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators. Biomedicine & Pharmacotherapy, 2021, vol. 136, pp. 111228. https://doi.org/10.1016/j.biopha.2021.111228.

12. Kappert K., Jahic A., Tauber R. Assessment of serum ferritin as a biomarker in COVID-19: bystander or participant? Insights by comparison with other infectious and non-infectious diseases. Biomarkers, 2020, https://doi.org/10.1080/1354750X.2020.1797880.

13. Malkova A., Kudlay D., Kudryavtsev I., Starshinova A., Yablonskiy P., Shoenfeld, Y. Immunogenetic Predictors of Severe COVID-19. Vaccines, 2021, no. 9, pp. 211. https://doi.org/doi.org/10.3390/vaccines9030211.

14. Pastoraa J.G., Weiganda M., Kim J. et al. Hyperferritinemia in critically ill COVID-19 patients - Is ferritin the product of inflammation or a pathogenic mediator? Clin. Chim. Acta., 2020, no. 509, pp. 249-251. https://doi.org/10.1016/j.cca.2020.06.033.

15. Perricone C., Bartoloni E., Bursi R. et al. COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy. Immunol. Res., 2020, no. 68, pp. 213-224. https://doi.org/10.1007/s12026-020-09145-5.

16. Rosario C., Z andm an-G oddard G., M eyron-H oltz E.G. et al. The hyperferritinemic syndrome: macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med., 2013, no. 11, pp. 185. https://doi.org/10.1186/1741-7015-11-185.

17. Ruan Q., Yang K., Wang W. et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intens. Care Med., 2020, no. 46, pp. 846-848. https://doi.org/10.1007/s00134-020-05991-x.

18.