Case Presentation: A 70-year-old man with PMH of chronic lymphocytic leukemia (with good hematologic response to Ibrutinib, stopped three months ago due to persistent fevers of unknown etiology), nephrolithiasis (with recent ureteral stent placement), presented with fever to 40.5 degrees Celsius. Patient was found to have E. coli bacteremia due to urinary tract infection and was treated with ertapenem. After a week, high-grade fevers persisted reaching 40 degrees Celsius, even though, patient had clinically improved and cultures had cleared. Treatment was switched to meropenem and micafungin and repeat CT Chest/Abdomen/Pelvis and Indium scan were performed, which did not reveal a source of infection. Hematology recommended restarting treatment for patient’s leukemia and gave a dose of Rituxan and prednisone. Work-up was expanded and patient was found to have ferritin >31,000ng/mL, which raised suspicion for hemophagocytic lymphohistiocytosis (HLH). Further lab work revealed patient had hypofibrinogenemia, hypertriglyceridemia, anemia, thrombocytopenia, high soluble interleuken-2 receptor alpha, which along with the fever and greatly elevated ferritin levels were diagnostic for HLH. Of note, bone marrow biopsy performed prior to hospitalization had not revealed hemophagocytosis. Patient was transferred to a tertiary care center where he was treated with Etoposide and dexamethasone. However, patient continued to deteriorate with worsening pancytopenia and eventually expired after an acute ischemic stroke had hemorrhagic conversion.
Discussion: Hemophagocytic lymphohistiocytosis is a rare, aggressive immune activation syndrome that causes multi-organ failure through greatly excessive cytokine production dubbed “a cytokine storm.” The more common, genetic form typically presents in childhood, while older adults diagnosed with HLH generally have the secondary variant, which can be triggered by infection, malignancy, or rheumatologic conditions. Lymphocytic leukemias have higher incidence of association with HLH and also carry a worse prognosis. Diagnosis is based on meeting 5 out of 8 criteria (the five listed above that our patient exhibited, along with the remaining three of splenomegaly, low or absent NK cell activity, and hemophagocytosis on biopsy). Treatment regimens vary on type of HLH and disease severity, but the more acutely ill patients are treated with dexamethasone and Etoposide for induction, followed by hematopoietic cell transplant. Patients with central nervous system involvement are also given intrathecal Methotrexate and hydrocortisone. Median survival with current treatment modalities is ~50%, but is significantly lower in high-risk cases like leukemia-associated HLH.
Conclusions: Hemophagocytic lymphohistiocytosis has high mortality even with treatment, but is much more devastating without appropriate care. One of the greatest barriers to treatment is delayed diagnosis, which often results from lack of knowledge of the syndrome. Our patient had had intermittent high-grade fevers for a few months as an inpatient and outpatient, which were likely erroneously attributed to various infections, or to his leukemia. It is critical to raise awareness in order to avoid missing or delaying the diagnosis and to thus give patients the greatest chance of survival.