Hemophagocytic Lymphohistiocytosis in Adults: A Case Series of 30 Patients At a U.S. Tertiary Care Center

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by overwhelming immune activation that results in excessive inflammation, phagocytosis of blood cells by macrophages, and end-organ damage. Both familial forms (“primary HLH”), often presenting in childhood, and sporadic forms (“secondary HLH”), often presenting in adults, have been recognized. While pediatric HLH is well characterized, only limited data is available on the diagnosis and treatment of HLH in adults. This study, the largest single center case series of adult HLH to date, characterizes cases treated at the University of Washington since 2000 to further our understanding of the clinical characteristics and treatment outcomes of HLH in the adult population.

Potential cases of HLH were identified by searching hospital billing records for the appropriate ICD-9 code (288.4). Information available from the electronic medical records was used for disease confirmation according to the HLH-2004 criteria, and to obtain relevant information on demographics as well as patient- and disease-related characteristics (including laboratory data, treatment, and outcome.

Among the 30 cases who met HLH-2004 diagnostic criteria, the median age was 42 (range: 19 – 76) years. The most common signs and symptoms were fever (100%), splenomegaly (80%), hepatomegaly (40%), lymphadenopathy (40%), and rash (37%). The most common laboratory abnormalities during hospitalization were hyperferritinemia (100%), hepatitis (100%), pancytopenia (93%), elevated creatinine (73%), elevated triglycerides (60%), and low fibrinogen (57%). The presumed causes of HLH were: 30% viral (EBV [n=9], HSV [n=1]), 23% malignancies (B-cell lymphoma [n=4], NK/T-cell lymphoma [n=2], acute lymphoblastic leukemia [n=1]), 20% rheumatologic (Still's disease [n=2], lupus-like syndrome [n=2], Stevens-Johnson syndrome [n=1], dermatomyositis [n=1]), 17% EBV-driven lymphoma (Hodgkin's disease [n=2], NK/T-cell lymphoma [n=1], post-transplant lymphoproliferative disorder-like syndrome [n=1]), 3% bacterial sepsis, and 6% idiopathic. Genetic testing was performed in only 4 patients, without identification of mutations. For treatment, corticosteroids were frequently used; fewer than half the patients received cyclosporine, etoposide, intravenous immunoglobulins, rituximab, interleukin-1 receptor antagonist, or intrathecal therapy. Two patients were retreated after relapse, and one received an allogeneic hematopoietic cell transplant. Two patients received no treatment: one died before therapy was initiated; in the other, treatment was withheld due to pregnancy, and symptoms resolved post-partum. The in-hospital mortality rate was 50%, with most patients dying of multi-organ failure.

In univariate analysis, factors associated with in-hospital mortality were older age (49 vs 35 years; p=0.025), lower hemoglobin nadir (6.4 vs 7.3 g/dL; p=0.020), lower triglycerides (284 vs 447 mg/dL; p=0.027), and higher total bilirubin (15.0 vs 6.4 mg/dL; p=0.019); gender, ethnicity, number of co-morbid conditions, symptoms, latency to treatment, and treatment used were not significantly associated. The best outcomes were seen in patients with EBV-driven lymphoma (80% survival, n=5), while the worst outcomes were seen in patients with non-EBV-driven hematologic malignancies (29% survival, n= 7). Patients with EBV-driven disease were more likely to be treated with etoposide (75 vs 11%); those with malignancy were less likely to be treated with cyclosporine (25 vs 65%).

A high index of suspicion for HLH should be maintained for adults who present with fever, splenomegaly, cytopenias, and hepatitis. HLH is associated with high mortality, particularly when occurring in older patients, those with anemia and hyperbilirubinemia, and those with non-EBV-driven hematologic malignancies. Further studies from this and other cohorts are needed to develop and refine prognostic criteria for outcomes in adult HLH.

No relevant conflicts of interest to declare.