Hepcidin, the Main Regulator of Iron Homeostasis, is a Marker of COVID-19 Severity and Mortality in a Cohort of Hospitalised Italian Patients - European Medical Journal

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Hepcidin, the Main Regulator of Iron Homeostasis, is a Marker of COVID-19 Severity and Mortality in a Cohort of Hospitalised Italian Patients

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Hematology
Hematology 9.1 Journal feature image
Authors:
Antonella Nai,1,2 Nicola Ivan Lorè,3 Alessia Pagani,1 Rebecca De Lorenzo,2 Simona Di Modica,1 Fabio Saliu,3 Daniela Maria Cirillo,3 Patrizia Rovere-Querini,2,4 Angelo Manfredi,2,5 *Laura Silvestri1,2

1. Regulation of Iron Metabolism Unit-Div. Genetics & Cell Biology-IRCCS San Raffaele Scientific Institute, Milano, Italy
2. San Raffaele Vita-Salute University, Milano, Italy
3. Emerging Bacterial Pathogens Unit-IRCCS San Raffaele Scientific Institute, Milano, Italy
4. Division of Immunology, Transplantation and Infectious Diseases-IRCCS San Raffaele Scientific Institute, Milano, Italy
5. Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele
*Correspondence to [email protected]

Disclosure:

The authors have declared no conflicts of interest.

Acknowledgements:

This work was supported by a COVID-19 programme project grant from the IRCCS San Raffaele Hospital and by the grant COVID-2020-12371617 from the Italian Ministero della Salute. The authors would like to thank the patients for their generous collaboration to our research projects; and Clara Camaschella for valuable criticism and advice. The authors are indebted to Fabio Ciceri, responsible for the San Raffaele Biobank; and would like to thank Cristina Tresoldi and all people working at the Institutional Biobank, whose generous support made it possible to carry out these studies. The contribution of the “Biob angels” of the San Raffaele in the recovery and transport of biological samples is also recognised with gratitude.

Citation:
EMJ Hematol. ;9[1]:38-39. Abstract Review.
Keywords:
COVID-19, hepcidin, inflammation, iron.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIMS

The clinical spectrum of severe COVID-19, the recently described systemic disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) infection, is characterised by the acute activation of the innate immune system accompanied by a prothrombotic state, and ranges from asymptomatic cases to respiratory failure. Unfortunately, precise biomarkers that predict COVID-19 outcome are still lacking. Several risk factors for SARS-CoV-2 infection are well established, including advanced age, male sex, strong inflammatory response, neutropenia and lymphopenia, and more recently hypoferraemia. At present, few data are available on the possible contribution of deranged iron homeostasis on COVID-19. In a retrospective study serum iron was found to be extremely low in most COVID-19 cases and a predictor of mortality.1 In addition, decreased serum iron was associated with hypoxaemia in patients with severe COVID-19 in the intensive care unit (ICU).2 More recently, hypoferraemia was associated with increased hospitalisation and oxygen demand in German patients with COVID-19.3

Hepcidin, the liver peptide hormone that regulates plasma iron concentration by blocking ferroportin function,4 is at the crossroad between iron metabolism and inflammation, being positively regulated by iron itself and proinflammatory cytokines,5 and may represent the link between iron deficiency and COVID-19 severity. However, its role as a potential biomarker of COVID-19 severity has not been explored in depth.

The aim of this study was to investigate whether plasma hepcidin, measured at admission, could be considered a marker of COVID-19 severity and mortality.6

MATERIALS AND Methods

Plasma hepcidin and iron levels were analysed in a well-characterised cohort of 111 Italian patients with COVID-19 hospitalised between 18th March and 5th May, 2020, at San Raffaele University Hospital in Milan, Italy, one regional COVID-19 reference hospital. Diagnosis of COVID-19 was based on a positive real-time reverse-transcriptase PCR (RT-PCR) from a nasal and/or throat swab together with signs, symptoms, and/or radiological findings suggestive of COVID-19. The present study was part of a more extensive monocentric observational cohort study, the Covid-BioB study, implemented at San Raffaele University Hospital.7 The cohort had a median age of 57.6 (48.5–66.3) years, and included predominantly males (64%). Blood samples were obtained at admission, and plasma was immediately retrieved and frozen until analysed for the concentration of iron, hepcidin (ELISA kit from Intrinsic LifeSciences), proinflammatory markers as C-reactive protein (CRP) and ferritin, and cytokines with a role in hepcidin modulation, as IL-6, IL-1b, TNFα and IFN-γ.6

RESULTS

In this cohort of patients with COVID-19, iron concentration was below normal range in 93.7% of patients, whereas hepcidin levels were significantly increased in 61.3% of patients. However, considering that hypoferraemia suppresses hepcidin expression, even normal hepcidin is inappropriately high in most cases. Patients with higher hepcidin levels were significantly older and had higher concentrations of markers of inflammation (CRP and ferritin) and cell damage (AST and LDH). Negative correlations were observed with the severity of respiratory failure, as reflected by the PaO2/FiO2 ratio. The role of high hepcidin levels is strengthened by the Kaplan–Meier survival curve and confirmed by the regression tree analysis, which identified hepcidin as the most important predictor of death among the others recognised predictors. On the other hand, iron levels do not affect survival, likely because of the uniformly low levels in all patients. Interestingly, limiting the analysis to critical patients in ICU, high hepcidin predicts mortality, independently of age, lung function, inflammation, and tissue damage.6

CONCLUSION

Overall, these data suggest that hepcidin can be considered a marker of morbidity and outcome of COVID-19, of special value for severely compromised patients in ICU.6 Further studies are needed to verify whether targeting the hepcidin axis may influence the disease outcome.

References
Zhao K et al. 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. Shah A et al. Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19. Crit Care. 2020;24:320. Hippchen T et al. Hypoferremia is associated with increased hospitalization and oxygen demand in COVID-19 patients. Hemasphere. 2020;4(6):e492. Nemeth E et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-3. Ganz T. Anemia of inflammation. N Engl J Med. 2019;381(12):1148-57. Nai A et al. Hepcidin levels predict COVID-19 severity and mortality in a cohort of hospitalized Italian patients. Am J Hematol. 2021;96(1):E32-5. Università Vita-Salute San Raffaele. Study to Characterize Patients With SARS-Cov-2 Infection and to Create a Biobank to Identify Predictors of Disease Severity, Mortality and Treatment Response. NCT04318366. https://www.clinicaltrials.gov/ct2/show/NCT04318366

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