Case Series of Primaquine-Induced Haemolytic Events in Controlled Trials with G6PD Screening

Abstract

Primaquine for radical cure of Plasmodium vivax malaria poses a potentially life-threatening risk of haemolysis in G6PD-deficient patients. Herein, we review five events of acute haemolytic anaemia following the administration of primaquine in four malaria trials from Indonesia, the Solomon Islands, and Vietnam. Five males aged 9 to 48 years were improperly classified as G6PD-normal by various screening procedures and included as subjects in trials of anti-relapse therapy with daily primaquine. Routine safety monitoring by physical examination, urine inspection, and blood haemoglobin (Hb) assessment were performed in all those trials. Early signs of acute haemolysis, i.e., dark urine and haemoglobin drop >20%, occurred only after day 3 and as late as day 8 of primaquine dosing. All patients were hospitalized and fully recovered, all but one following blood transfusion rescue. Hb nadir was 4.7 to 7.9 g/dL. Hospitalization was for 1 to 7 days. Hb levels returned to baseline values 3 to 10 days after transfusion. Failed G6PD screening procedures in these trials led G6PD-deficient patients to suffer harmful exposures to primaquine. The safe application of primaquine anti-relapse therapy requires G6PD screening and anticipation of its failure with a means of prompt detection and rescue from the typically abrupt haemolytic crisis.

Keywords: G6PD deficiency; G6PD screening; acute haemolytic anaemia; primaquine; randomized controlled trials.

Figure 1

Subject’s urine macroscopic result. Dark urine colour suggesting haemolysis (Hillmen scale = 5) was shown on the day 5 of treatment (A). On the following day (day 6 of treatment), the colour was less dark (Hillmen scale = 4 and 2 in the morning (B) and afternoon (C), respectively).

Figure 2

Graphical display of the clinical progression and temporal changes of haemoglobin and urine Hillmen score during primaquine administration and 1–8 days following its cessation. In all cases but one, clinical symptoms had been observed 1–3 days before the onset, along with the slight decline of Hb. Of note, steady increase of Hillmen as the Hb dropped was observed in Case 1 and 4, in which daily urine inspection were performed. In all cases, primaquine was interrupted at the same day of the onset of the haemolysis. In Case 1 and 4, the crisis continued with further blood loss leading to transfusion. In Case 3 and 5, the anaemia was severe (Hb 5–6 g/dL); the patients were given transfusion promptly after haemolysis was suspected. Case 2 became the only case where blood transfusion was not indicated.

Figure 2

Graphical display of the clinical progression and temporal changes of haemoglobin and urine Hillmen score during primaquine administration and 1–8 days following its cessation. In all cases but one, clinical symptoms had been observed 1–3 days before the onset, along with the slight decline of Hb. Of note, steady increase of Hillmen as the Hb dropped was observed in Case 1 and 4, in which daily urine inspection were performed. In all cases, primaquine was interrupted at the same day of the onset of the haemolysis. In Case 1 and 4, the crisis continued with further blood loss leading to transfusion. In Case 3 and 5, the anaemia was severe (Hb 5–6 g/dL); the patients were given transfusion promptly after haemolysis was suspected. Case 2 became the only case where blood transfusion was not indicated.

Figure 2

Graphical display of the clinical progression and temporal changes of haemoglobin and urine Hillmen score during primaquine administration and 1–8 days following its cessation. In all cases but one, clinical symptoms had been observed 1–3 days before the onset, along with the slight decline of Hb. Of note, steady increase of Hillmen as the Hb dropped was observed in Case 1 and 4, in which daily urine inspection were performed. In all cases, primaquine was interrupted at the same day of the onset of the haemolysis. In Case 1 and 4, the crisis continued with further blood loss leading to transfusion. In Case 3 and 5, the anaemia was severe (Hb 5–6 g/dL); the patients were given transfusion promptly after haemolysis was suspected. Case 2 became the only case where blood transfusion was not indicated.