Case Presentation: A 31-year-old male with a past medical history significant for treated syphilis presented with a three-month history of recurrent fevers. Despite close outpatient follow-up and extensive workup, his symptoms persisted prompting him to go to the ED.On presentation, the patient was febrile, hypotensive, and tachycardic. He was admitted for sepsis and was started on broad-spectrum antibiotics. Initial workup revealed pancytopenia, transaminitis (AST 669U/L, ALT 188U/L, Alkaline Phosphatase 420 U/L), hyperferritinemia (6920ng/mL), and hypofibrinogenemia (95mg/dL). Splenomegaly was noted on imaging. Extensive infectious workup was notable for chronic active EBV infection. However, this was not deemed to explain his whole clinical picture so further workup was pursued. Moreover, despite treatment for sepsis, there was no clinical improvement. Peripheral smear showed schistocytes for which Hematology was consulted. Upon further review of the case, they recommended a workup for HLH.The patient was diagnosed with EBV-HLH after meeting 6 out of 8 criteria, i.e. fever, splenomegaly, cytopenia, hyperferritinemia, hypofibrinogenemia, and elevated soluble CD25. Once HLH was suspected, IVIG and dexamethasone were initiated following the HLH-2004 protocol. Clinical and serological improvements were noted, including resolution of fever. Etoposide was added per treatment protocol for EBV-HLH, which led to further improvement. On his first post hospitalization follow up, the patient reported continued improvement of symptoms with most of his labs, including ferritin, fibrinogen, and liver function tests, returning to normal levels.
Discussion: Hemophagocytic Lymphohistiocytosis (HLH) is a rare but fatal syndrome secondary to the absence of downregulation of activated macrophages and cytotoxic T cells. This leads to excessive yet ineffective immune response causing tissue destruction and organ damage. Traditionally, Secondary HLH was thought to be the predominant type in adults, with viruses and malignancy as common triggers. More recently, an increase in incidence of HLH in adults, including Primary HLH, has been observed.HLH usually presents similarly to sepsis or other systemic inflammatory conditions, making it difficult for clinicians to diagnose at the time of presentation. Its rarity, variable presentation, and lack of a single serology to confirm diagnosis also pose challenges to clinicians causing it to be underrecognized. Key features to note include the triad of fever, cytopenia, and splenomegaly along with hyperferritinemia and unexplained transaminitis. If workup for common inflammatory response causes is inconclusive, HLH should be considered. Diagnosis requires patients to meet at least 5 out of the 8 HLH-2004 diagnostic criteria. Cytopenia, hypofibrinogenemia, and hypertriglyceridemia differentiate it from sepsis. Once HLH is suspected, prompt treatment to prevent irreversible organ damage from hyperinflammation should be started. Determining the trigger is also essential as an etiology-guided treatment for HLH leads to a better prognosis.
Conclusions: Since prompt diagnosis and initiation of treatment of HLH has shown improved clinical outcomes, the case highlights the importance of early suspicion for HLH in patients initially meeting sepsis criteria but with unrevealing workup. The case also demonstrates that tailored treatment regimens can have a significant impact on preventing the progression of organ damage and further clinical deterioration.