The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis

Abstract

Background Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax . Methods A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. Results In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was − 0.13 g/dL [− 0.27, 0.01] lower at day of nadir ( p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 ( p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration − 0.72 g/dL [− 0.90, − 0.54] lower than patients without recurrence ( p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL. Conclusions Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. Trial registration This trial was registered with PROSPERO: CRD42016053312 . The date of the first registration was 23 December 2016. Electronic supplementary material The online version of this article (10.1186/s12916-019-1386-6) contains supplementary material, which is available to authorized users.

Linking hydroxychloroquine to hemolysis in a ‘suspected’ glucose-6-phosphate dehydrogenase deficient patient with COVID-19 infection – a critical appraisal

“…The presence of confounding factors like COVID-19 infection, suspected DIC with high D-dimer, concurrent administration of lopinavir, along with lack of robust supporting evidence preclude establishing hydroxychloroquine as the sole cause for hemolysis in the patient. To conclude, linking CQ-HCQ with hemolysis in G6PD-deficient subjects based on the present report with above-mentioned confounding factors and inconsistencies is against the established scientific evidence [3][4][5].…”

“…A seminal study by Youngster et al [3] refuted such claims and categorically suggested the lack of evidence of CQ (thus its hydroxy derivative, HCQ) causing hemolysis in patients with G6PD-deficiency. A recent meta-analysis of clinical trials in CQ+/-primaquine, did not demonstrate a significant drop in hemoglobin from baseline in G6PDdeficients on CQ monotherapy [5]. No incidents of hemolysis were observed in 11 G6PD-deficient patients even after >700 months of HCQ exposure as per the largest US study that examined the occurrence of hemolysis with hydroxychloroquine [4].…”

“…It must be considered that CQ-and HCQ are not novel drugs but have been used for the treatment of multiple infectious and inflammatory disorders for more than 50 years. Hemolysis due to administration of CQ-HCQ in patients with G6PD-deficiency has not been conclusively proven in any of the large trials using CQ and HCQ [3][4][5]. The belief of 'antimalarials' causing hemolysis, unfortunately, became engraved in the minds of clinicians by the well-founded evidence on hemolysis by primaquine.…”

Vivax malaria in pregnancy and lactation: a long way to health equity

“…Relapse is the main source of P. vivax infection in areas of low endemicity and contributes to chronic anaemia. A recent metanalysis confirms that, despite short term risk of haemolysis, radical cure with primaquine improves hematologic outcomes in the long term [33]. In most P. vivax-endemic regions, anaemia is a major public health problem, which contributes to maternal mortality [34].…”

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

“…The peripheral blood smear anomalies that are orientated with a G6PD deficiency diagnosis, such as hemi-ghost cells, were increasing from day-4 until day-7 (one day after administration of single large dose of hydroxychloroquine). Based on these factors, one can safely ascertain that hemolysis (and hemolytic parameters) gradually increased from day-1 to reach the peak around 4 As the authors have rightly mentioned, there are no guidelines that recommend baseline G6PD evaluation for hydroxychloroquine prescriptions. 5 The presumed caution on using hydroxychloroquine in G6PD deficients is not supported by clinical evidence, but by drug information resources and drug package inserts.…”