Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory syndrome of inappropriate and excessive immune system activation. It often occurs in the setting of viral, bacterial, fungal, and parasitic infections. HLH associated with malaria is very rare, and literature on this association is limited. Significant overlap exists between these two conditions, which makes the diagnosis of HLH superimposed on malaria difficult. We present a case of a patient who recently traveled from Djibouti and was diagnosed with Plasmodium falciparum malaria. She had a transient improvement in response to antimalarial therapy followed by clinical deterioration. This prompted further investigations that revealed the diagnosis of HLH, which was confirmed by an elevated soluble interleukin-2 receptor CD25 (sCD25) level, a specific marker of HLH. Most patients recover with antimalarial therapy, supportive care, and monitoring, whereas some patients require immunosuppressive therapy. Maintaining a high index of suspicion for HLH-associated malaria in at-risk patients allows for early identification and management.
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