Case Discussion:
Primaquine is a well-established treatment for Plasmodium vivax but is known to carry a risk of hemolytic anemia, particularly in patients with G6PD deficiency. The World Health Organization (WHO) recommends screening for G6PD deficiency before starting primaquine therapy(3). Previous studies have reported a small risk of hemolysis in patients with normal G6PD levels, with one study documenting a 0.3% (1/389) incidence of clinically significant hemolysis(11). While there have been reports of hemolytic anemia in patients who tested negative for G6PD deficiency using rapid diagnostic tests (RDTs), this case is unique in that the patient’s G6PD levels were quantitatively within the normal range(12). This finding challenges the reliability of current laboratory screening methods and suggests that clinicians should exercise caution even when G6PD test results suggest a lower risk(11).
This case represents the first known instance of significant hemolytic anemia induced by primaquine in a patient with a normal quantitative G6PD analysis. Detailed monitoring was possible due to the patient being admitted to a tertiary care center. Daily hemoglobin levels were measured, allowing for the early identification of hemolysis and the timely discontinuation of primaquine after three doses. The occurrence of hemolytic anemia in this patient, despite a normal quantitative G6PD analysis, suggests that current screening methods may not be foolproof. It cannot be assumed that any G6PD field test has perfect sensitivity even in optimal laboratory settings(13). Possible causes could include operator error during sample preparation and processing, cold chain issues that compromised the integrity of the sample or screening kit, or a lack of adequate climate control to ensure that tests were conducted under appropriate conditions.
The delay in recognizing hemolysis in this case, due to the hemoglobin levels initially being within the expected range for anti-malaria treatment, further emphasizes the need for better early markers of hemolytic anemia(11). Identifying such markers could enable clinicians to make more informed decisions regarding the continuation of primaquine treatment quickly, thereby reducing the risk of severe hemolytic crises. The patient didn’t show any physical signs and symptoms, and his urine color was normal even when his Hb dipped by almost 25% on day 4. Such absence of clinical sign and symptoms despite the significant decrease in hemoglobin suggests that there would be substantial risk of delayed presentation to the hospital if this case was managed on an outpatient basis without proper follow-up.
The National Malaria Treatment Protocol 2019 of Nepal encourages G6PD screening prior to 14-day PQ regimen but they aren’t done routinely because of lack of necessary infrastructure, fears of additional costs, and very low incidence of PQ-induced severe hemolysis for a low-dose PQ regimen provided over an extended period(10,14). This case shows that exposing patients to PQ treatment even after quantitative G6PD testing exposes patients to an increased risk of hemolysis. It underscores the need for clinicians to remain vigilant when prescribing primaquine at all levels of G6PD. It highlights the limitations of current G6PD testing and the importance of close monitoring for signs of hemolytic anemia. In settings where daily monitoring is not feasible, such as outpatient care in low-resource environments, the risk of late presentation and severe anemia increases.