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.