COVID-19, inflammatory response, iron homeostasis and toxicity: a prospective cohort study in the Emergency Department of Piacenza (Italy). COVID19, Iron, Inflammation and Toxicity in ER

Main Article Content

Lorena Duca https://orcid.org/0000-0002-2008-3187
Isabella Nava
Daniele Vallisa
Giovanni Battista Vadacca
Andrea Magnacavallo
Andrea Vercelli
Patrizio Capelli
Giovanna Graziadei
Filippo Banchini

Keywords

COVID-19, Emergency, iron, ferritin, hepcidin, non-transferrin-bound iron

Abstract

Background and aim: Dysregulation of iron metabolism and hyper-inflammation are two key points in the pathogenesis of coronavirus disease 2019 (COVID-19). Since high hepcidin levels and low serum iron can predict COVID-19 severity and mortality, we decided to investigate iron metabolism and inflammatory response in 32 COVID-19 adult patients with a diagnosis of COVID-19 defined by a positive result of RT-PCR nasopharyngeal swab, and admitted to an Italian emergency department for acute respiratory failure at different degree.


Methods: Patients were stratified in 3 groups based on PaO2/FiO2 ratio at admission: 13 (41%) were normoxemic at rest and suffered from exertional dyspnea (group 1); 14 (44%) had a mild respiratory failure (group 2), and 5 (15%) a severe hypoxiemia (group 3).


Results: White blood cells were significantly higher in group 3, while lymphocytes and hemoglobin were significantly reduced. Serum iron, transferrin saturation, non-transferrin-bound iron (NTBI) and ferritin were significantly increased in group 2. All the groups showed high hepcidin levels, but in group 3 this parameter was significantly altered. It is noteworthy that in group 1 inflammatory and oxidative indices were both within the normal range.


Conclusions: We are aware that our study has some limitations, the small number of enrolled patients and the short period of data collection, but few works have been performed in the Emergency Room. However, we strongly believe that our results confirm the pivotal role of both iron metabolism dysregulation and hyper-inflammatory response in the pathogenesis of tissue and organ damage in COVID-19 patients.

Downloads

Download data is not yet available.
Abstract 71 | PDF Downloads 50

References

1. Zhu J, Zhong Z, Ji P, Li H, Li B, Pang J, et al. Clinicopathological characteristics of 8697 patients with COVID-19 in China: a meta-analysis. Fam Med Community health 2020; https://doi.org/10.1136/fmch-2020-000406.
2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z 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. https://doi.org/10.1016/ S0140-6736(20)30566-3.
3. Channappanavar R, & Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin immunopathol. 2017; 39(5): 529–39. https://doi.org/10.1007/s00281-017-0629-x.
4. Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, & Chiumello D. COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 2020; 201(10):1299–300. https://doi.org/10.1164/rccm.202003-0817LE.
5. Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med 2020; https://doi.org/10.1016/j.clinbiochem..05.012.
6. Zhang Y, Li J, Zhan Y, Wu L, Yu X, Zhang W, et al. Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect Immun 2004; 72(8):4410–5. https://doi.org/10.1128/IAI.72.8.4410-4415.2004.
7. Lee P, Peng H, Gelbart T, Wang L, & Beutler E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA 2005; 102(6):1906–10. https://doi.org/10.1073/pnas.0409808102.
8. Pathan N, Hemingway CA, Alizadeh AA, Stephens AC, Boldrick JC, Oragui EE et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet 2004; 363:203-9. https://doi.org/10.1016/S0140-6736(03)15326-3.
9. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8(4):420-2. https://doi.org/10.1016/S2213-2600(20)30076-X.
10. Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica 2020; 105(2):260-72. https://doi.org/10.3324/haematol.2019.232124.
11. Nemeth E, Valore E V, Territo M, Schiller G, Lichtenstein A, & Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003; 101(7), 2461–3. https://doi.org/10.1182/blood-2002-10-3235.
12. Pagani A, Nai A, Silvestri L, & Camaschella C. Hepcidin and Anemia: A Tight Relationship. Front Physiol 2019; 10, 1294. https://doi.org/10.3389/fphys.2019.01294.
13. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood 2019; 133(1):40-50. https://doi.org/ 10.1182/blood-2018-06-856500.
14. Girelli D, Marchi G, Camaschella C. Anemia in the Elderly. Hemasphere 2018; 2(3):e40. https://doi.org/10.1097/HS9.0000000000000040.
15. Poggiali E, Migone De Amicis M, Motta I. Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. Eur J Intern Med 2014; 25(1):12-7. https://doi.org/10.1016/j.ejim.2013.07.011.
16. Taneri PE, Gómez-Ochoa SA, Llanaj E, Raguindin PF, Rojas LZ, Roa-Díaz ZM et al. Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis. Eur J Epidemiol 2020; 35(8):763-73. https://doi.org/10.1007/s10654-020-00678-5.
17. Drakesmith H, & Prentice A. Viral infection and iron metabolism. Nat Rev Microbiol 2008; 6(7): 541–52. https://doi.org/10.1038/nrmicro1930
18. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276(11):7806-10. https://doi.org/10.1074/jbc.M008922200.
19. Banchini F, Vallisa D, Maniscalco P, Capelli P. Iron overload and Hepcidin overexpression could play a key role in COVID infection, and may explain vulnerability in elderly, diabetics, and obese patients. Acta Biomed 2020; 91(3):e2020013. https://doi.org/ 10.23750/abm.v91i3.9826.
20. Nai A, Lorè NI, Pagani A, De Lorenzo R, Di Modica S, Saliu F 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. https://doi.org/10.1002/ajh.26027.
21. Roghi A, Poggiali E, Duca L, Mafrici A, Pedrotti P, Paccagnini S, et al. Role of Non-Transferrin-Bound Iron in the pathogenesis of cardiotoxicity in patients with ST-elevation myocardial infarction assessed by Cardiac Magnetic Resonance Imaging. Int J Cardiol 2015; 199:326-32. https://doi.org/10.1016/j.ijcard.2015.07.056.
22. Knutson MD. Non-transferrin-bound iron transporters. Free Radic Biol Med 2019; 133:101-11. https://doi.org/10.1016/j.freeradbiomed.2018.10.413.
23. Ito S, Ikuta K, Kato D, Lynda A, Shibusa K, Niizeki N, et al. In vivo behavior of NTBI revealed by automated quantification system. Int J Hematol 2016; 104(2):175-81. https://doi.org/10.1007/s12185-016-2002-6.
24. Shah A, Frost JN, Aaron L, Donovan K, Drakesmith H. Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19. Crit Care 2020; 24(1):320. https://doi.org/10.1186/s13054-020-03051-w.
25. Sonnweber T, Boehm A, Sahanic S, Pizzini A, Aichner M, Sonnweber B 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.
26. Banchini F, Cattaneo GM, Capelli P. Serum ferritin levels in inflammation: a retrospective comparative analysis between COVID-19 and emergency surgical non-COVID-19 patients. World J Emerg Surg 2021; 16:19. https://doi.org/10.1186/s13017-021-00354-3.
27. Liu B, Li M, Zhou Z, Guan X, Xiang Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun 2020; 111:102452. https://doi.org/10.1016/j.jaut.2020.102452.
28. Campochiaro C, Della-Torre E, Cavalli G, De Luca G, Ripa M, Boffini N, et al. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med 2000; 76:43–9. https://doi.org/10.1016/j.ejim.2020.05.021.
29. Dalamaga M, Karampela I, Mantzoros CS. Commentary: Could iron chelators prove to be useful as an adjunct to COVID-19 Treatment Regimens? Metabolism 2020; 108:154260. https://doi.org/10.1016/j.metabol.2020.154260.
30. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell El, Fan E et al. Acute respiratory distress syndrome:the Berlin Definition. JAMA 2012; 307:2526-33. https://doi.org/10.1001/jama.2012.5669.
31. Porter JB, Abeysinghe RD, Marshall L, Hider RC, Singh S. Kinetics of removal and reappearance of non-transferrin-bound plasma iron with deferoxamine therapy. Blood 1996; 88:705-13.
32. Hollak CE, van Weely S, van Oers MH, Aerts JM. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 1994; 93(3):1288-92.
33. Via G, Storti E, Gulati G, Neri L, Mojoli F, Braschi A. Lung ultrasound in the ICU: from diagnostic instrument to respiratory monitoring tool. Minerva Anestesiol 2012; 78(11):1282–96.
34. Manivel V, Lesnewski A, Shamim S, Carbonatto G, Govindan T. CLUE: COVID-19 lung ultrasound in emergency department. Emerg Med Australas 2020; 32(4):694-6. https://doi.org/10.1111/1742-6723.13546.
35. Colombi D, Bodini FC, Petrini M, Maffi G, Morelli N, Milanese G et al. Well-aerated Lung on Admitting Chest CT to Predict Adverse Outcome in COVID-19 Pneumonia. Radiology 2020; 296(2):E86-96. https://doi.org/ 10.1148/radiol.2020201433.
36. Ozdemir H, Çiftçi E, Ince EU, Ertem M, Ince E, Doğru U. Hemophagocytic lymphohistiocytosis associated with 2009 pandemic influenza A (H1N1) virus infection. J Pediatr Hematol Oncol 2011;33(2):135-7.https://doi.org/10.1097/MPH.0b013e3181f46baf.
37. Pechlaner R, Kiechl S, Mayr M, Santer P, Weger S, Haschka D et al. Correlates of serum hepcidin levels and its association with cardiovascular disease in an elderly general population. Clin Chem Lab Med 2016; 54(1):151-61. https://doi.org/10.1515/cclm-2015-0068.
38. Poggiali E, Zaino D, Immovilli P, Rovero L, Losi G, Dacrema A et al. Lactate dehydrogenase and C-reactive proteina s predictors of respiratory failure in COVID-19 patients. Clin Chem Acta 2020; 509:135-8. https://doi.org/10.1016/j.cca.2020.06.012.

Most read articles by the same author(s)

1 2 > >>