Case Presentation: A 63-year-old female with past medical history significant for myasthenia gravis managed with azathioprine (AZA) presented with recurrent fevers, shortness of breath, malaise and night sweats for one week after attending a funeral in Pennsylvania. She denied any sick contacts, hiking, animal exposure, tick bites, or rashes. She was seen outpatient and her workup was unremarkable. She was prescribed Augmentin empirically, however her symptoms worsened, prompting her visit to the emergency department. She was found to be tachycardic, otherwise vitals were unremarkable. Initial labs were significant for pancytopenia. CT pulmonary embolism study showed splenomegaly with an ill-defined lucency within, which was again seen on CT abdomen/pelvis.Her CMV IgM and IgG titers were positive, with a CMV viral load of 370,000 copies/ml. Other labs were significant for LDH 452 U/L, ferritin 2260 ng/ml, hypofibrinogen, and hypertriglyceridemia. Hematology-oncology was consulted due to concern for HLH given the six of eight HLH-2004 criteria she met. She underwent a bone marrow (BM) biopsy, and was started on ganciclovir. Her BM biopsy showed reactive findings consistent with CMV with possible early HLH; NK cell activity was very low (<1) with high soluble IL-2Ra (sCD25), consistent with HLH. She was started on dexamethasone however, etoposide was held due to uncontrolled CMV infection, development of disseminated intravascular coagulopathy (DIC) and transaminitis. Once her liver failure improved, she was started on etoposide. Her fibrinogen and ferritin levels and CMV titers improved however, her cytopenias worsened after 1 dose of etoposide, thus was further held. Her hospital course was complicated by development of acute respiratory distress syndrome (ARDS), acute renal failure, bacteremia, candidemia, and hemodynamic instability despite multiple vasopressors. Given her grim prognosis, her family opted for comfort measures, and the patient unfortunately passed away.
Discussion: HLH is a rare, underdiagnosed disease characterized by hyperinflammation and cytokine dysregulation, and can be associated with numerous conditions, such as neoplastic, infectious, autoimmune, or hereditary diseases. The HLH-2004 diagnostic criteria for acquired HLH include fever; splenomegaly; cytopenias; hyperferritinemia; hypertriglyceridemia and/or hypofibrinogenemia; hemophagocytosis in the bone marrow, spleen or lymph nodes; low or absent NK-cell activity, and high levels of sCD25; five of eight criteria are required for diagnosis. Despite the nonspecific findings and criteria of HLH, making a timely diagnosis is imperative to initiate early therapy. The aim of HLH therapy is to suppress the dysregulated immune response using corticosteroids, etoposide, and cyclosporine A as induction therapy for eight weeks. The overall reported mortality for acquired HLH exceeds 50%; among the viruses associated with HLH, EBV carries the worst prognosis.
Conclusions: HLH is an underdiagnosed disease associated with high mortality, making a timely diagnosis imperative. CMV-induced HLH in immunocompromised adults is a rare disease and few cases have been reported to date. Our patient with CMV disease fulfilled all eight of the HLH-2004 diagnostic criteria. Clinicians should consider HLH as a differential diagnosis for sepsis as early treatment may reduce mortality associated with this disease.