key: cord-281686-edpyn8fd authors: Dalamaga, Maria; Karampela, Irene; Mantzoros, Christos S. title: 19 treatment regimens? date: 2020-05-08 journal: Metabolism DOI: 10.1016/j.metabol.2020.154260 sha: doc_id: 281686 cord_uid: edpyn8fd The pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant threat to global health. Currently, no specific prophylactic and therapeutic treatment is available. No evidence from randomized clinical trials (RCTs) that a treatment may ameliorate the clinical outcome of patients with COVID-19 exists with the only exception of preliminary evidence from remdesivir trials. Here, we present evidence from the literature and a compelling hypothesis on the potential immunomodulatory, iron chelating and anti-oxidant effects of iron chelators in the treatment of COVID-19 and its complications. Interestingly, iron chelation has been shown in vitro to suppress endothelial inflammation in viral infection, which is the main pathophysiologic mechanism behind systemic organ involvement induced by SARS-CoV-2, by inhibiting IL-6 synthesis through decreasing NF-kB. Iron chelators exhibit iron chelating, antiviral and immunomodulatory effects in vitro and in vivo, particularly against RNA viruses. These agents could attenuate ARDS and help control SARS-CoV-2 via multiple mechanisms including: 1) inhibition of viral replication; 2) decrease of iron availability; 3) upregulation of B cells; 4) improvement of the neutralizing anti-viral antibody titer; 5) inhibition of endothelial inflammation and 6) prevention of pulmonary fibrosis and lung decline via reduction of pulmonary iron accumulation. Both retrospective analyses of data in electronic health records, as well as proof of concept studies in humans and large RCTs are needed to fully elucidate the efficacy and safety of iron chelating agents in the therapeutic armamentarium of COVID-19, probably as an adjunctive treatment. The pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant threat to global health. Currently, no specific prophylactic and therapeutic treatment is available. No evidence from randomized clinical trials (RCTs) that a treatment may ameliorate the clinical outcome of patients with COVID-19 exists with the only exception of preliminary evidence from remdesivir trials. Here, we present evidence from the literature and a compelling hypothesis on the potential immunomodulatory, iron chelating and anti-oxidant effects of iron chelators in the treatment of COVID-19 and its complications. Interestingly, iron chelation has been shown in vitro to suppress endothelial inflammation in viral infection, which is the main pathophysiologic mechanism behind systemic organ involvement induced by SARS-CoV-2, by inhibiting IL-6 synthesis through decreasing NF-kB. After a median incubation period of approximately 5 days (range: 2-14 days) (4), the majority of cases present mild symptoms, mainly from the respiratory tract, while some progress to viral pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure or death. While ARDS is associated with a high mortality rate of 30-40% (5-6), evidence suggests that COVID-19 related ARDS may have a worse outcome (7) (8) (9) . Indeed, DFO treatment has been shown to decrease the mortality and relieve the symptoms of Enterovirus 71-infected mice (29) . More importantly, B cell levels of the infected mice were upregulated while the neutralizing antibody titer was also improved (29) . COVID-19 is characterized by lymphopenia (30) (31) . We hypothesize that iron chelators may improve both lymphopenia observed in COVID-19 by upregulating lymphocytes, particularly B cells, as well as the neutralizing antibody titers against SARS-CoV-2. It could also be reasonable to speculate that iron chelators may prevent the development of pulmonary fibrosis and lung function decline following COVID-19 infection. Increased iron levels and/or dysregulated iron homeostasis occur in several lung diseases, including pulmonary fibrosis (21) . More than 20% of survivors of the 2003 outbreak of SARS developed residual pulmonary fibrosis one year after infection (38) (39) (40) . Of note, fibrotic changes have also been reported in more than 17% of patients during the acute phase of COVID-19 (41) . In animal models, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis (21) . Furthermore, iron accumulation is elevated in lung sections from patients with idiopathic pulmonary fibrosis where human lung fibroblasts exhibit higher proliferation and cytokine and J o u r n a l P r e -p r o o f 8 extracellular matrix responses when exposed to higher iron levels. In experimental pulmonary fibrosis, intranasal treatment with the iron chelator DFO has been shown to prevent pulmonary fibrosis and decline in lung function presenting also immunomodulatory properties (21) . Iron is also implicated in endothelial inflammation induced by viral infections through induction of reactive oxygen species leading to nuclear factor kB (NF-kB) activation and subsequent upregulation of proinflammatory mediators such as IL-1β, IL-6 and TNF-α. Iron chelation by DFO has been shown to suppress endothelial inflammation induced by influenza A infection in vitro by inhibiting IL-6 synthesis through decreasing NF-kB (42) . Emerging evidence suggests that endothelial inflammation is the main pathophysiologic mechanism behind the multiorgan involvement and failure induced by SARS-CoV-2 infection. Therefore, we believe that iron chelating agents might prove useful to ameliorate the systemic manifestations of COVID-19. In conclusion, iron chelating agents exhibit iron chelating, antiviral and immunomodulatory A new coronavirus associated with human respiratory disease in China China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China Coronavirus Update (Live): 3,138,097 Cases and 217,968 Deaths from COVID-19 Virus Outbreak-Worldometer. Available from: www.worldometers.info. Retrieved The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application Acute respiratory distress syndrome: the Berlin Definition LUNG SAFE Investigators; ESICM Trials Group. 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