Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory disorder affecting macrophages and cytotoxic lymphocytes. Primary HLH is typically caused by genetic mutations, whereas secondary HLH is typically triggered by infections or malignancy. Due to high mortality despite the current proposed diagnostic and treatment guidelines, a high index of suspicion is vital to expedite testing and determine the underlying trigger.
We present the case of a 13-month-old Native American female who was transferred to our facility with recurrent fever, cough, rash, oral sores, and seizure-like activity. Her clinical symptoms were complicated by multilineage cytopenias, transaminitis, and elevated inflammatory markers. A bone marrow biopsy was obtained with mildly hypercellular marrow with trilineage hematopoiesis, no hemophagocytosis, and no evidence of malignancy. Her ferritin was >10,000 mcg/L, which raised suspicion for HLH. Further testing demonstrated coagulopathy, hypofibrinogenemia, and elevated sIL2R and CXCL9levels. EBV quantitative PCR was extremely elevated at >300,000 IU/mL, raising suspicion that EBV triggered HLH. Immune evaluation was unremarkable. Rapid whole-exome sequence was obtained and did not reveal a candidate gene. Though the patient was well-appearing and afebrile after the bone marrow biopsy, she did meet the criteria for HLH. HLH-specific therapy was initiated with partial response to dexamethasone and emapalumab and minimal improvement in EBV viremia. EBV PCR was repeated on sorted lymphocytes which demonstrated T cell tropism, so nivolumab was added with gradual resolution of EBV viremia. Further genetic testing including an HLH gene panel did not demonstrate an underlying defect. The patient’s ethnicity remained her only potential risk factor for the development of HLH.
HLH is a rare disorder that can be precipitated by inborn errors of immunity, infection, malignancy, and rheumatic disease. Identification of the underlying trigger is necessary to prevent recurrence by controlling the underlying disease. This case demonstrates the importance of considering other risk factors, such as our patient’s T cell tropism and potentially her Native American ethnicity, when no other etiology can be identified.
