Letters to the Editor / Cartas al Editor
COVID-19 - G6PD DEFICIENCY AND HYDROXYCHLOROQUINE
Vitorino Modesto dos Santos1, Laura Campos Modesto2,
Julia Campos Modesto3
Department of Medicine, Armed Forces Hospital, Catholic University of Brasília,
2Medical Course, University Center of Brasília-DF,
3Medical Course, Catholic University of Brasília, Brazil
Rev Electron Biomed / Electron J Biomed 2019;3:54-57.
G6PD deficiency increased in interest during the Covid-19 pandemic, due to the hydroxychloroquine (HCQ) utilization for early treatment1-8. Mutations in the g6pdx gene of the X chromosome are sex-linked and hemizygous males can have the condition, and females are rarely symptomatic carriers, or heterozygous G6PD deficient 1. G6PD acts in processing of antioxidants and glutathione reduction, and its deficiency increase oxidative damage to red blood cells (RBCs).
Manifestations follow trigger mechanisms: fava beans, quinine derivatives, and infections1. Deficiency degrees are variable, the diagnosis is confirmed by enzymatic activity and molecular analysis, and the best management is avoiding exposure to oxidative stressors1.
Afra et al. evaluated the linking of HCQ to hemolysis in COVID-19, focusing on inconsistency, lack of clarity, and controversies detected in reviewed reports2. They commented that HCQ has been utilized for more than 50 years and hemolysis due to this drug in people with G6PD deficiency has not been conclusively proven in any of the reported large trials. Hemolysis did not occur in 11 deficient patients in more than 700 months of exposure. Besides, there is evidence of a complement-mediated procoagulant state, a prerequisite for atypical hemolytic-uremic syndrome in patients with COVID-19. They concluded that lacks evidence to establishing HCQ as the sole cause of hemolysis2.
Aguilar et al. reported potential risks of HCQ for COVID-19 outweighing their benefits3. A 51-year-old man with comorbidities had COVID-19 and community pneumonia treated with levofloxacin, and required hemodialysis before admission. He underwent HCQ (400 mg twice daily on day 1, and 400 mg once daily on days 2-4). The G6PD deficiency was confirmed one day after completion of HCQ therapy. There was low hemoglobin 8.4 g/dL, reticulocytosis, and elevated lactic dehydrogenase on admission. The hemolytic anemia improved with RBCs transfusion3. They stressed the lack of HCQ-induced hemolysis in the literature and the high dose of 800 mg in the COVID-19 pneumonia protocol twice the normal dose of HCQ in Rheumatology. The hemolysis was before the HCQ use, the patient had kidney failure; and COVID-19 can trigger hemolysis in G6PD deficient3
Mastroianni et al. reviewed hemolytic anemia and the use of HCQ in G6PD-deficient patients4. A 32-year-old male had COVID-19 and bilateral interstitial pneumonia. He used HCQ (400 mg twice daily on day 1, and 200 mg twice daily from day 2 to day 5). He had low hemoglobin 7.7 g/dl on day 2 and hemolysis without schistocytes or reticulocytosis, and G6PD deficiency, and improved with transfusion of RBCs. The authors commented on a study of 18 G6PD-deficient patients using HCQ without hemolysis, reinforcing the lack of evidence that this drug causes hemolytic anemia. Viral infections can promote oxidative stress, and hemolysis was reported in G6PD-deficient patients with COVID-19, but who did not undergo the HCQ4.
Onori et al. reviewed the G6PD-deficiency and HCQ in COVID-19, and commented the well tolerated antiviral effect against SARS, Zika, rabies, Ebola, poliovirus, HIV, influenza A and B, hepatitis A and C, Chikungunya, and Dengue5. In a case with moderate deficiency, a single dose of HCQ was taken on day 6, but he had hemolysis on day 5. In a case with severe deficiency, HCQ started on admission and the hemoglobin dropped (13.3 to 11.8 g/dl) on day 2 and the drug seemed to be the "culprit". In other case of deficiency HCQ started on admission, the drop in hemoglobin occurred 48 h after, and HCQ was considered the "culprit". In a fourth case with severe deficiency, HCQ administration started on admission and was stopped after 3 doses. Hemoglobin dropped from 12.2 to 9.1 g/dl over 10 days, but the patient had hemoglobin D disease. In another case with moderate deficiency, HCQ started 48 h after admission. Hemoglobin dropped from 12.4 to 6.6 g/dl on day 8, and HCQ seemed to be the "culprit". Finally, in a case of severe deficiency, HCQ started on admission, hemoglobin dropped from 10 to 7.7 g/dl on day 2, and the drug seemed to be the "culprit". They concluded that the deficiency affects redox homeostasis and immune responses, enhancing viral infection and hemolysis can occur in COVID-19. The use usually effective, safe, and well-tolerated of HCQ in G6PD-deficient people can be argued in COVID-19. HCQ acts as a trigger in earlier modified scenery, not as an "innocent" bystander5.
Ramirez et al. evaluated the prevalence of variants in G6PD gene in African descents, and suggested that these variations can play a role in adverse effects of HCQ treatment for COVID-196. They commented that G6PD enzyme acts in the production of nicotinamide adenine dinucleotide phosphate (NADPH) required in the glutathione mediated detoxification of reactive oxygen species; and low NADPH may not be sufficient to neutralize the reactive oxygen species induced by HCQ6. Although yet not known about SARS-Cov-2 virus, they commented that G6PD-deficient cells are more vulnerable to alphacoronavirus 229E infection in vitro, related to high oxidant production6.
Sgherza et al. reported a 61-year-old Caucasian man with G6PD deficiency and COVID-19 treated by HCQ (200 mg, thrice daily), darunavir (800 mg, once a day), and azithromycin (500 mg, once a day) for 7 days, without hemolysis. There was a decrease in the hemoglobin without hemolysis. They commented on the use of HCQ in G6PD deficiency, and the variables influencing hemolysis risk that should be investigated to discriminate patients who may have benefits of this drug7.
Youssef et al. reviewed the severity of pneumonia in 17 patients with COVID-19 needing supplemental oxygen, six (35%) with G6PD deficiency, and 11 (65%) normal controls 8. The main differences of severity were the G6PD levels (12.2 vs. 5.6), PaO2/FiO2 ratio (159 vs. 108), days on mechanical ventilation (10.25 vs. 21), hemoglobin level (10 vs. 8.1), and hematocrit (32 vs. 26). Only one G6PD-deficient died. They emphasized the role of deficiency in viral proliferation8.
Although HCQ utilized in COVID-19 might trigger hemolysis in some G6PD-deficient patients, it can also represent an "innocent bystander" and one must compare risks with benefits.
1.- Ravikumar N, Greenfield G. Glucose-6-phosphate dehydrogenase deficiency: a review. Int J Med Students 2020;8(3):281-287.
2.- Abramova I, Park K, Hosny C, Tuladhar S, Yao Q, Patnaik A. A study on the relevance of glucose-6-phosphate dehydrogenase level screening in patients with rheumatic diseases prior to initiating treatment with hydroxychloroquine. Cureus 2020;12(8):e9519.
3.- Aguilar J, Averbukh Y. Hemolytic anemia in a glucose-6-phosphate dehydrogenase-deficient patient receiving hydroxychloroquine for COVID-19: a case report. Perm J 2020;24:20.158.
4.- Mastroianni F, Colombie V, Claes G, et al. Hydroxychloroquine in a G6PD-deficient patient with covid-19 complicated by haemolytic anaemia: culprit or innocent bystander? Eur J Case Rep Intern Med 2020;7(9):001875.
5.- Onori ME, Ricciardi Tenore C, Urbani A, Minucci A. Glucose-6-phosphate dehydrogenase deficiency and hydroxychloroquine in the COVID-19 era: a mini review. Mol Biol Rep 2021;48(3):2973-2978.
6.- Ramirez de Oleo IE, Mejia Saldarriaga M, Johnson BK. Association of hydroxychloroquine use and hemolytic anemia in patients with low levels of glucose-6-phosphate dehydrogenase. J Clin Rheumatol 2020 Sep 18. doi: 10.1097/RHU.0000000000001571.
7.- Sgherza N, Dalfino L, Palma A, et al. "Hemolysis, or not hemolysis, that is the question". Use of hydroxychloroquine in a patient with COVID-19 infection and G6PD deficiency. Mediterr J Hematol Infect Dis 2020;12(1):e2020076.
8.- Youssef JG, Zahiruddin F, Youssef G, Padmanabhan S, Ensor J, Pingali SR, Zu Y, Sahay S, Iyer SP. G6PD deficiency and severity of COVID19 pneumonia and acute respiratory distress syndrome: tip of the iceberg? Ann Hematol 2021;100(3):667-673.
CONFLICT OF INTEREST: The authors have no conflicts of interest to declare.
Vitorino Modesto dos Santos
Department of Medicine, Armed Forces Hospital,
Estrada do Contorno do Bosque s/n,
Cruzeiro Novo, CEP: 70658-900,
Email: vitorinomodesto @ gmail.com