Case Presentation: A 23-year-old male presented to the emergency department after experiencing three nocturnal fevers over the preceding week. On further examination, he was febrile (38.5°C) and exhibited mild thrombocytopenia, lymphopenia, and hyperbilirubinemia. The patient had emigrated from the Democratic Republic of Congo three years earlier and had not traveled outside the United States since his arrival. His medical history was notable for malaria, which was treated at age 19. Upon admission, a contract-enhanced CT of the chest, abdomen, and pelvis revealed no lymphadenopathy. Given the concern for tick-borne infection, he was started on empiric doxycycline while awaiting further diagnostic results. A blood smear revealed Malaria, consistent with Plasmodium vivax and < 1% parasitemia, and he was initiated on artemether-lumefantrine. A qualitative Glucose-6-Phosphate Dehydrogenase (G6PD) assay showed absent enzyme activity. After discussing two treatment options, the patient was ultimately discharged on Chloroquine once weekly for 52 weeks.
Discussion: Malaria is a parasitic, vector-borne illness that affects approximately 500 million people each year. The presentation of this patient is consistent with uncomplicated malaria; however, his lack of recent travel – having been in the U.S. for three years – does not align with the 1,773 cases reported annually in the U.S., nearly all of which occur in recent travelers. As such, this case highlights a delayed malaria relapse, which occurs when latent forms of the parasite are reactivated. This phenomenon is unique to two of the five Plasmodium species that cause malaria, P. vivax and P. ovale, which have a distinct phase in their life cycle during which they may produce hypnozoites – dormant liver forms that may go untreated or unrecognized, only to reemerge years later. The recent onset of malaria symptoms in this individual is presumptively the result of a relapsing infection, enabled by inadequate treatment in the past. To ensure eradication of Plasmodium vivax, treatment must address both the active and latent forms of the parasite. The CDC recommends chloroquine or artemisinin-based therapies for active infection, in addition to primaquine to target liver hypnozoites. However, primaquine is a potent oxidant and can cause severe hemolytic anemia in G6PD-deficient patients, such as this one. The mutation is disproportionately common in regions where malaria is endemic, likely due to a selective advantage it provides by making G6PD-deficient cells more resistant to malaria infection. While primaquine is contraindicated in those with completely absent G6PD activity, it can be used cautiously in those with mild deficiency, provided extended dosing intervals and close monitoring are implemented. Given this patient’s preference for prompt discharge and reluctance to undergo further G6PD testing, a 52-week prophylactic course of chloroquine was chosen as the only safe option. Although this treatment does not guarantee a cure, it prevents most relapses, as reactivation typically occurs within the first year of infection.
Conclusions: Malaria should be considered in all patients with fever of unknown origin, particularly those with history of recent travel or previous malaria. Plasmodium vivax can remain dormant in the liver, leading to reemergence years after the initial infection. Treatment must be tailored to G6PD status and should include therapy targeting liver hypnozoites to prevent relapse, or prophylaxis to prevent clinical manifestations.