key: cord-0753058-xqeepo0e
authors: Schilling, William H.K.; Bancone, Germana; White, Nicholas J.
title: No evidence that chloroquine or hydroxychloroquine induce hemolysis in G6PD deficiency()
date: 2020-08-07
journal: Blood Cells Mol Dis
DOI: 10.1016/j.bcmd.2020.102484
sha: 43d0ddee6a7c326df553ffb6b0935c0b95426cc5
doc_id: 753058
cord_uid: xqeepo0e

nan

To the Editor, Hydroxychloroquine and chloroquine have come under intense scrutiny over the past six months as they have been proposed as treatments for COVID-19. It is widely quoted and stated that the 4-aminoquinolines chloroquine and hydroxychloroquine cause oxidant hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency, yet there is no convincing evidence for this claim, and there is substantial evidence against it. X-linked G6PD deficiency is the most common human enzymopathy. It affects an estimated 400 million people worldwide with average allelic frequencies of 8-10% in populations living in or originating from tropical areas 1 . Billions of chloroquine treatments have been given in these malaria endemic areas, and millions have received hydroxychloroquine for rheumatological conditions. As a result, hundreds of millions of people with G6PD deficiency have received these drugs. Chloroquine has been used safely, and without evidence of iatrogenic hemolysis for over six decades in both the prevention and the treatment of malaria, even in countries with the most severe G6PD deficiency variants.

The 4-aminoquinolines were developed as antimalarials because they were more effective and less toxic than their predecessors-the 8-aminoquinolines. Notably they lacked hemolytic toxicity. The oxidative and hemolytic effects of the 8-aminoquinolines were apparent in early clinical testing nearly 100 years ago 2,3 . Investigation of primaquine "sensitivity" ultimately led to the discovery of G6PD deficiency in 1956 4 . This provided a common mechanism for hemolytic reactions to different drugs, chemicals and oxidant There are very few case reports suggesting that chloroquine might cause hemolysis in G6PD deficiency. The letter by Sicard in 1978 describing a partially completed study from Laos (where G6PD deficiency prevalence was estimated to be around 13%) is unusual. 'When a single high dose of chloroquine (600 mg) was given routinely to soldiers for malaria prophylaxis, some of them had very severe hemolytic anaemia, with "coca-cola" urine and acute renal failure. 50 such cases were thoroughly investigated. All were G6PD deficient and the alleged diagnosis of blackwater fever could be ruled out' 11 . Nothing else like this has ever been reported since. It may be relevant that at that time a combined chloroquine-J o u r n a l P r e -p r o o f primaquine medication was commonly used by militaries and that later reports of chloroquine-induced hemolysis might have used the same combination 12 . A recent metaanalysis of 3421 chloroquine treated patients with vivax malaria found no evidence for hemolysis above that associated with malaria itself 13 . It is highly unlikely that significant oxidant hemolysis following treatment with chloroquine alone would remained unnoticed in the hundreds of millions of occasions that chloroquine has been given to prevent or treat malaria in patients who were G6PD deficient. Similarly, use of hydroxychloroquine in rheumatological conditions is not associated with hemolysis in G6PD deficient individuals 14 .

Furthermore, hemolysis and methemoglobinemia are not features of chloroquine overdose, even though chloroquine was commonly used in self-poisoning in malaria endemic regions where G6PD deficiency prevalences are high. hours of starting chloroquine in a man with the A-variant of G6PD deficiency 17 . This is not the pattern seen in primaquine or dapsone induced hemolysis in G6PD deficiency in which the fall in hemoglobin is typically delayed by more than one day as residual erythrocytic stores of antioxidants are depleted. The other case reports are also satisfactorily explained by disease rather than drug induced hemolysis 18 . In conclusion, there is no evidence that chloroquine or hydroxychloroquine provoke oxidant hemolysis in G6PD deficient individuals.

Glucose-6-phosphate dehydrogenase deficiency

Die Behandlung der Naturlichen Malaria Infectionen mit Plasmochin. Arch f Schiffs u Trop Hyg

Toxic Effects of Plasmochin

Enzymatic deficiency in primaquine-sensitive erythrocytes

Primaquine sensitivity in patients with favism

Primaquine sensitivity. Glucose-6-phosphate dehydrogenase deficiency: an inborn error of metabolism of medical and biological significance

Clinical spectrum of hemolytic anemia associated with G 6 PD deficiency

Effects of primaquine and chloroquine on oxidative stress parameters in rats

Methemoglobinemia provoked by malarial chemoprophylaxis in Vietnam

Haemoglobinopathies and G6PD. deficiency in Laos

Drug-induced haemolysis and renal failure in children with glucose-6-phosphate dehydrogenase deficiency in Afghanistan

The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis

Hydroxychloroquine Use and Hemolytic Anaemia in G6PDH-Deficient Patients

COVID-19 infection and treatment with hydroxychloroquine cause severe haemolysis crisis in a patient with glucose-6-phosphate dehydrogenase deficiency

Doubtful precipitation of hemolysis by hydroxychloroquine in glucose-6-phosphate dehydrogenase deficient patient with COVID-19 infection

G6PD deficiency-associated hemolysis and methemoglobinemia in a COVID-19 patient treated with chloroquine