Background Malaria is a parasitic infection transmitted by the Anopheles mosquito, with Plasmodium falciparum being the most severe species. Initial symptoms include fever, headaches, and nausea, often leading to a robust immune response. Diagnostic challenges arise in non-endemic regions, and cross-reactivity with other tests may occur. Case Presentation A 49-year-old woman traveling from Yemen via Djibouti presented in the Midwest with irregular fluctuating fevers, cough, headache with behavioral changes, and abdominal pain with emesis. Initial workup showed pancytopenia, hemolysis, and significant splenomegaly on CT scan. Blood smear confirmed Plasmodium falciparum malaria, classified as severe due to cerebral involvement and hyperparasitemia. Despite a positive fourth-generation HIV test, confirmatory HIV differentiation test and HIV nucleic acid amplification were negative, indicating a false positive likely due to severe malaria. The patient was successfully treated with three days of artemether-lumefantrine, and symptoms subsided.

Discussion This case highlights the potential for false positive fourth-generation HIV tests in the context of severe malaria. The high sensitivity (99.8%) and specificity (99.5%) of these tests are generally reliable, but cross-reactivity can occur, necessitating confirmatory testing to avoid misdiagnosis. Previous cases have reported similar findings. For instance, a 2019 case report described a tourist returning from West Africa with severe P. falciparum malaria who tested false positive on the fourth-generation HIV test, but confirmatory testing was negative. Another case in 2023 documented a woman with P. malariae presenting a false positive HIV test, which was subsequently negated by differentiation testing. These false positives are thought to occur due to the immune system's response to malaria, which can produce antibodies or immune complexes that cross-react with HIV test antigens. Studies have shown that younger patients with malaria might produce more nonspecific antibodies, leading to higher rates of false positives. Historical enzyme immunoassay tests also reported similar issues, with significant rates of false positives in malaria patients. The unique presentation of our patient shows the necessity of considering false positives in regions where malaria is rare but HIV testing is common. This case reinforces the need for thorough diagnostic evaluations and the importance of reflexive confirmatory testing to prevent misdiagnosis and unnecessary treatment.