key: cord-0922347-5pdh19xe authors: Fazel Nabavi, Seyed; Habtemariam, Solomon; Sureda, Antoni; Banach, Maciej; Berindan-Neagoe, Ioana; Andrei Cismaru, Cosmin; Bagheri, Mahdi; Sadegh Bagheri, Mohammad; Mohammad Nabavi, Seyed title: Glucose-6-phosphate dehydrogenase deficiency and SARS- CoV-2 mortality: Is there a link and what should we do? date: 2020-09-17 journal: Clin Biochem DOI: 10.1016/j.clinbiochem.2020.09.004 sha: 925f03a6f0804dd5eeb012c9d7577f8582c0920a doc_id: 922347 cord_uid: 5pdh19xe nan Glucose-6-phosphate dehydrogenase (G6PD) is an indispensable cytosolic enzyme involved in the production of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). Its deficiency resulting from mutations in the X-linked recessive G6PD gene affects more than 400 million people worldwide [1] . The pathological consequences of G6PD deficiency is severe particularly where oxidative stress is implicated. G6PDknockdown fibroblasts and lung epithelial cells were found to exhibit more susceptibility to coronavirus 229E (HCoV 229E) infection due to increased production of reactive oxygen species (ROS) and/or depletion of the reduced form of glutathione (GSH) [2] . This susceptibility could be abrogated using antioxidant supplementation e.g. by lipoic acid. In G6PD-knockdown airway epithelial (A549) cells with increased susceptibility to HCoV 229E infection, impaired inflammatory responses associated with a decreased phosphorylation of MAPK (p38 and ERK1/2) and nuclear factor kappa B (NF-κB) as well as dysregulated NADPH oxidase signaling were reported [3] . Wu et al. [4] also showed that the human protein HSCARG, a NADPH sensor and negative regulator of NF-κB, was upregulated in G6PD-knockdown cells leading to susceptibility to enterovirus 71 (EV71) infection. Staphylococcus aureus due to their inability to eliminate the increased ROS production [5] . H5N1 virus and SARS-CoV infections can lead to acute lung injury and induce acute respiratory distress syndrome (ARDS) by inducing the oxidative stress machinery, the innate immunity and toll-like receptor-4 signaling via activation of NF-κB [6, 7] . This response results in cytokine storm or overproduction of the proinflammatory interleukins [8] . All these data suggest that G6PD deficiency is associated with oxidative stress and inflammatory response dysregulation (Fig. 1) , and increases susceptibility to severe viral respiratory infections. At the time of writing of this article, the world was battling the unprecedented coronavirus pandemic disease, the so-called COVID-19. The virus (SARS-CoV-2) has rapidly spread across the world from the Wuhan province of China and infected more than 12 million people and caused more than 550,000 deaths [9] . A well-known antimalarial drug chloroquine, its derivative hydroxychloroquine and other antivirals which are known to inhibit viral entry into host cells by increasing endosomal pH have been introduced in an attempt to treat COVID-19 [10] . There are currently 197 clinical trials assessing the role of antimalarials alone or in combination with other agents against COVID-19 infection [12, 13] . Nevertheless, G6PD deficiency is not routinely evaluated for the inclusion in such trials and the use of oxidizing antimalarials in these patients could be associated with poor progress due to extensive hemolysis [11, 14] . These poor results highlight the need to test for G6PD deficiency prior to enrolment in clinical trials evaluating antimalarials and other oxidizing drugs in COVID-19. This is supported by studies involving hydroxycholorine which have been halted at early endpoints for not showing clinical benefits [15] or raising safety signals in the clinical and laboratory findings [16] . Even though the Pharmacovigilance Memorandum document by the US Department of Health and Human Services has noted hemolysis associated with hydroxychloroquine therapy as a potential problem in individuals with G6PD deficiency, the adverse event of methemoglobinemia is not specifically described. G6PD deficiency is not a rare disease, affecting approximately 5% of the global population, and up to 20-30% in various African, Asian, Middle Eastern and other Mediterranean regions [17, 18, 19] . Certainly, many cases of G6PD deficiency go unnoticed in the absence of disease triggers. Infectious diseases are a well-known factor for triggering hemolytic anemia in such individuals due to impaired mechanisms of managing oxidizing stress [14] . As this leads to a reduced tolerance to viral infections [20] , it may be assumed that these individuals are more susceptible to respiratory infections. However there is insufficient available data to support or confirm this assumption and, in the case of the Dengue virus, a non-respiratory pathogen, there was no increased susceptibility in G6PD deficient cases in a cross sectional study on pediatric patients [21] . The extent of the response of G6PD-deficient patients to SARS-CoV-2 viral infections is not yet known but critical assessment of possible differential pathology and therapeutic needs must be considered. Georgakouli et al. [22] demonstrated that lipoic acid supplementation (600 mg/day) improved the redox status in patients with G6PD deficiency. However, adding an acidic drug could favor endosomal acidification needed for viral fusion. Due to the role of oxidative stress in the pathogenesis of severe forms viral lung infections, it may be useful to evaluate in clinical trials the usage of haptoglobin therapy for SARS-CoV-2 patients with G6PD deficiency and/or G6PD deficient healthcare workers (who work in atmospheres with high viral load). Glucose-6-phosphate dehydrogenase deficiency and SARS-CoV-2 mortality: Is there a link and what should we do? Mahdi Bagheri 1 , Mohammad Sadegh Bagheri 1 and Seyed Mohammad Nabavi 1* 1. Baqiyatallah Hospital Department of Functional Sciences The Functional Genomics Department -The Oncology Institute Glucose-6-phosphate dehydrogenase deficiency Glucose-6-Phosphate Dehydrogenase Deficiency Enhances Human Coronavirus 229E Diminished COX-2/PGE2-mediated antiviral response due to impaired NOX/MAPK signaling in G6PD-knockdown lung epithelial cells Glucose-6-phosphate dehydrogenase enhances antiviral response through downregulation of NADPH Sensor HSCARG and upregulation of NF-κB signaling Glucose-6-phosphate dehydrogenase (G6PD)-deficient epithelial cells are less tolerant to infection by Staphylococcus aureus Distinct Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury Pathways in Two Different Nonhuman Primate Species The pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models Coronavirus disease (COVID-19) Situation Report-172 COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression G6PD deficiency Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Search of: antimalarial | COVID -List Results -ClinicalTrials.gov Hemolytic anemias Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection A Randomized Clinical Trial WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19 The global prevalence of glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis Erythrocyte G-6-PD deficiency in blood donors of Oristano Glucose-6-Phosphate Dehydrogenase Deficiency Enhances Human Coronavirus 229E Infection Impact of glucose-6-phosphate dehydrogenase deficiency on dengue infection in Myanmar children Legends: Fig.1. Viral replication in double membrane vesicles (DMVs) leads to oxidative stress with accumulation of reactive oxygen species (ROS). G6PDH deficiency impairs the ability of the cell to form NADPH This project was funded in part by a grant to Dr. A. Sureda from the Spanish government, Instituto de Salud Carlos III (CIBEROBN CB12/03/30038).