Haemophagocytic Lymphohistiocytosis Triggered by Visceral Leishmaniasis Masquerading as Epstein-Barr Virus (EBV)-Associated Haemophagocytic Lymphohistiocytosis in Rheumatoid Arthritis: A Case Report and Literature Review

Abstract

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by uncontrolled immune activation. In adults, it is usually secondary to an underlying condition, such as infection, malignancy, or autoimmune disease. Identifying this trigger is essential, as treatment depends on the cause. Visceral leishmaniasis (VL) is a systemic parasitic infection that may mimic or trigger HLH, particularly in immunosuppressed patients. We report a 59-year-old man with seropositive rheumatoid arthritis, for which he received immunosuppressive treatment with methotrexate and etanercept. For eosinophilic asthma, he was treated with benralizumab. Four months after travelling to the Valencia region in Spain, the patient presented with high fever, marked splenomegaly and pancytopenia. Further laboratory findings showed progressive hyperferritinaemia, hypofibrinogenaemia, and hypertriglyceridaemia, together with haemophagocytosis on bone marrow examination, which supported the diagnosis of secondary HLH. Because Epstein-Barr virus (EBV) DNA was detected in peripheral blood, EBV-associated HLH was initially suspected, and treatment was started with rituximab, targeting potentially EBV-infected B cells, and dexamethasone to suppress the hyperinflammatory response. Further infectious work-up, however, revealed a strongly positive Leishmania serology. Leishmania polymerase chain reaction on the original bone marrow sample subsequently confirmed VL, despite the absence of amastigotes on Giemsa-stained microscopy. Treatment was redirected to liposomal amphotericin B; further HLH-directed immunosuppressive therapy was withheld, and corticosteroids were tapered. The patient became afebrile and showed progressive recovery of cytopenias and inflammatory markers. Detectable EBV DNA should not preclude investigation for alternative infectious triggers of HLH. In immunosuppressed patients with compatible epidemiological exposure, VL should remain in the differential diagnosis even when bone marrow microscopy is negative, as serology and molecular testing may be required for diagnosis.