Can iron chelation as an adjunct treatment of COVID-19 improve the clinical outcome? (original) (raw)

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A recent bioinformatic study showed that one of the important pathogenic effects of coronavirus disease 2019 (COVID-19) is through the direct damage of haemoglobin molecules by the novel coronavirus (SARS-CoV-2) [[1](/article/10.1007/s00228-020-02942-9#ref-CR1 "Wenzhong L, Hualan L (2020) COVID-19: attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. [cited 2020 Apr 10]; Available from: https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173

            . Accessed 10 April 2020")\]. The haemoglobin molecule consists of four globulin subunits: two beta chains and two alpha chains \[[1](/article/10.1007/s00228-020-02942-9#ref-CR1 "Wenzhong L, Hualan L (2020) COVID-19: attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. [cited 2020 Apr 10]; Available from: 
              https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173
              
            . Accessed 10 April 2020")\]. Each subunit attaches to heme which has two main components: iron and porphyrin \[[1](/article/10.1007/s00228-020-02942-9#ref-CR1 "Wenzhong L, Hualan L (2020) COVID-19: attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. [cited 2020 Apr 10]; Available from: 
              https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173
              
            . Accessed 10 April 2020")\]. SARS-CoV-2 attacks one of the beta chains of the haemoglobulin which leads to dissociation of iron from heme \[[1](/article/10.1007/s00228-020-02942-9#ref-CR1 "Wenzhong L, Hualan L (2020) COVID-19: attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. [cited 2020 Apr 10]; Available from: 
              https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173
              
            . Accessed 10 April 2020")\]. This leads to increased free iron level in the body, which could explain why most patients with COVID-19 have very high ferritin level \[[2](/article/10.1007/s00228-020-02942-9#ref-CR2 "Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J', Yu T, Zhang X, Zhang L (2020) Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395(10223):507–513")\]. Although the result of this study has not been fully validated, it might explain multiple aspects of the pathogenesis of COVID-19\. Increased iron level in the body generates reactive oxygen species which causes oxidative stress and damage to the lung, leading to subsequent lung fibrosis and decline in the lung function \[[3](/article/10.1007/s00228-020-02942-9#ref-CR3 "Turi JL, Yang F, Garrick MD, Piantadosi CA, Ghio AJ (2004) The iron cycle and oxidative stress in the lung. Free Radic Biol Med 36(7):850–857"), [4](/article/10.1007/s00228-020-02942-9#ref-CR4 "Ali M, Kim R, Brown A, Donovan C, Vanka K, Mayall J et al (2020) Critical role for iron accumulation in the pathogenesis of fibrotic lung disease. J Pathol 251(1):49–62")\]. There is evidence shows that iron overload increases viral replication, which might have a role in the severity of the infection \[[5](/article/10.1007/s00228-020-02942-9#ref-CR5 "Drakesmith H, Prentice A (2008) Viral infection and iron metabolism. Nat Rev Microbiol 6(7):541–552")\]. Infection with SARS-CoV-2 causes diffuse endothelial inflammation which leads to widespread microvascular thrombosis, organ ischemia and multi-organ failure \[[6](/article/10.1007/s00228-020-02942-9#ref-CR6 "Varga Z, Flammer A, Steiger P, Haberecker M, Andermatt R, Zinkernagel A et al (2020) Endothelial cell infection and endotheliitis in COVID-19. Lancet 395(10234):1417–1418")\]. Interestingly, an in vitro study showed that iron had a similar effect by inducing the release of endothelial inflammatory cytokines, such as IL-6 \[[7](/article/10.1007/s00228-020-02942-9#ref-CR7 "Visseren F, Verkerk M, van der Bruggen T, Marx J, van Asbeck B, Diepersloot R (2002) Iron chelation and hydroxyl radical scavenging reduce the inflammatory response of endothelial cells after infection with Chlamydia pneumoniae or influenza A. Eur J Clin Investig 32(s1):84–90")\]. Through its iron chelation effect, deferoxamine reduces iron availability in serum and body tissue which could prevent lung injury and fibrosis following COVID-19 infection. An in vitro study showed that deferoxamine decreased the level of viral replication of some RNA viruses, such as HIV-1\. Moreover, when it was combined with an antiviral drug, it led to a synergistic effect on reducing the viral replication cycle \[[8](/article/10.1007/s00228-020-02942-9#ref-CR8 "Georgiou N, van der Bruggen T, Oudshoorn M, Nottet H, Marx J, van Asbeck B (2000) Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin. J Infect Dis 181(2):484–490")\]. This might suggest that deferoxamine could be beneficial in adjunction with anti-viral drugs to treat Covid-19\. In addition, deferoxamine decreased the level of IL-6 and endothelial inflammation in vitro, which could reduce the severity of COVID-19 infection as endothelial inflammation is one of the important factors which leads to multi-organ damage and failure \[[7](/article/10.1007/s00228-020-02942-9#ref-CR7 "Visseren F, Verkerk M, van der Bruggen T, Marx J, van Asbeck B, Diepersloot R (2002) Iron chelation and hydroxyl radical scavenging reduce the inflammatory response of endothelial cells after infection with Chlamydia pneumoniae or influenza A. Eur J Clin Investig 32(s1):84–90")\]. Interestingly, deferoxamine has immunomodulatory effect. It improved the immune response against enteroviral infection in infected mice by inducing upregulation of B cells and increasing the level of neutralising antibody titre \[[9](/article/10.1007/s00228-020-02942-9#ref-CR9 "Yang Y, Ma J, Xiu J, Bai L, Guan F, Zhang L, Liu J, Zhang L (2014) Deferoxamine compensates for decreases in B cell counts and reduces mortality in enterovirus 71-infected mice. Marine Drugs 12(7):4086–4095")\]. Therefore, deferoxamine could ameliorate the pathogenic effect of COVID-19 caused by viral-induced lymphopenia.

In conclusion, iron chelation drugs, such as deferoxamine, can be used as a supportive treatment to improve the clinical outcome and to reduce the severity of COVID-19 infection. However, multiple randomised control studies are required to test their efficacy and safety.

References

  1. Wenzhong L, Hualan L (2020) COVID-19: attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. [cited 2020 Apr 10]; Available from: https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173. Accessed 10 April 2020
  2. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J', Yu T, Zhang X, Zhang L (2020) Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395(10223):507–513
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  3. Turi JL, Yang F, Garrick MD, Piantadosi CA, Ghio AJ (2004) The iron cycle and oxidative stress in the lung. Free Radic Biol Med 36(7):850–857
    Article CAS PubMed Google Scholar
  4. Ali M, Kim R, Brown A, Donovan C, Vanka K, Mayall J et al (2020) Critical role for iron accumulation in the pathogenesis of fibrotic lung disease. J Pathol 251(1):49–62
    Article CAS PubMed Google Scholar
  5. Drakesmith H, Prentice A (2008) Viral infection and iron metabolism. Nat Rev Microbiol 6(7):541–552
    Article CAS PubMed Google Scholar
  6. Varga Z, Flammer A, Steiger P, Haberecker M, Andermatt R, Zinkernagel A et al (2020) Endothelial cell infection and endotheliitis in COVID-19. Lancet 395(10234):1417–1418
    Article CAS PubMed PubMed Central Google Scholar
  7. Visseren F, Verkerk M, van der Bruggen T, Marx J, van Asbeck B, Diepersloot R (2002) Iron chelation and hydroxyl radical scavenging reduce the inflammatory response of endothelial cells after infection with Chlamydia pneumoniae or influenza A. Eur J Clin Investig 32(s1):84–90
    Article CAS Google Scholar
  8. Georgiou N, van der Bruggen T, Oudshoorn M, Nottet H, Marx J, van Asbeck B (2000) Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin. J Infect Dis 181(2):484–490
    Article CAS PubMed Google Scholar
  9. Yang Y, Ma J, Xiu J, Bai L, Guan F, Zhang L, Liu J, Zhang L (2014) Deferoxamine compensates for decreases in B cell counts and reduces mortality in enterovirus 71-infected mice. Marine Drugs 12(7):4086–4095
    Article CAS PubMed PubMed Central Google Scholar

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  1. Spire Fylde Coast Hospital, St Walburgas road, Blackpool, FY3 8BP, UK
    Anis Abobaker

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Abobaker, A. Can iron chelation as an adjunct treatment of COVID-19 improve the clinical outcome?.Eur J Clin Pharmacol 76, 1619–1620 (2020). https://doi.org/10.1007/s00228-020-02942-9

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