Hemophagocytic Lymphohistiocytosis: The Partners Healthcare Experience over the Past 8 Years

Introduction

Hemophagocytic Lymphohistiocytosis (HLH) is a rare disorder of uncontrolled immune activation characterized by clinical and laboratory evidence of severe inflammation. This syndrome can be caused by genetic mutations affecting cytotoxic function (familial HLH) or secondary to infectious, rheumatologic, malignant, or metabolic conditions (acquired HLH). Familial HLH typically presents in childhood and is well described. Less is known about the clinical characteristics, appropriate diagnostic criteria, and optimal treatment in the adult population. The purpose of this study was to characterize the clinical and laboratory features of adults with HLH in a large academic healthcare system.

Methods

Using a centralized clinical data registry, we searched for all patients at Brigham and Women’s Hospital and Massachusetts General Hospital who had been entered under the diagnostic code for “hemophagocytic syndrome” from 2006 through 2013. Subjects <18 years old were excluded. The remaining medical charts were manually curated to identify patients who we determined to have HLH based on the HLH-2004 guidelines.

Results

We identified 50 adults who met the diagnostic criteria for HLH. The mean age was 52 years (range 18-75 years). Thirty-three patients were male (66%) and 17 were female (34%). The racial distribution included 33 White patients (66%), 5 Black (10%), 5 Asian (10%), 4 Hispanic (8%), and 3 of unknown race (6%). The most common clinical and laboratory abnormalities included fever, cytopenia, transaminitis, and elevated ferritin (table 1). Ferritin was ≥500 ng/mL in all patients, with a mean maximum ferritin level of 34,502 ng/mL and median of 19,687 ng/mL. Of the 50 patients identified, 5 were tested for known familial HLH mutations. Of those tested, 1 patient was homozygous for the PRF1 polymorphism A91V. Twenty-one patients had malignancy-associated HLH (42%). Of those with malignancy-associated HLH, all 21 patients had hematologic cancers (100%) including myeloid (n=6), B-lymphoid (n=10), and T-lymphoid (n=5) malignancies. Infection-associated HLH occurred in 13 patients (26%), including those with identified viral (n=7), bacterial (n=2), viral and bacterial (n=2), and fungal (n=1) pathogens. One patient had recurrent HLH flares in the setting of various infections (EBV, CMV, HBV, and C.difficile). The most common infections were EBV (n=3) and CMV (n=3). Five patients (10%) had both malignancy and infection at the time of HLH diagnosis. Ten patients (20%) had a history of an autoimmune disorder, including 4 with infections and 1 with malignancy at the time of HLH diagnosis. Six of these 10 patients had recently received immunosuppression. The most common autoimmune disorders identified were systemic lupus erythematosus (n=2) and rheumatoid arthritis (n=2). Treatment varied depending on the underlying diagnosis. The majority of patients with malignancy received chemotherapy with or without additional immunosuppressives. Patients with a history of autoimmune disorder typically received immunosuppressives without etoposide. Patients without cancer or autoimmune disease were most often treated with a regimen containing steroids and etoposide. Additional treatments including cyclosporine, IVIG, and stem cell transplant were used in select cases.

Discussion

In our adult population, HLH frequently arises in the setting of hematologic malignancy or infection. The different clinical contexts in which HLH occurs in adults suggests a common aberrant immune response to a variety of potential “triggers.” Alternatively, the diagnostic criteria, which were developed for use in the pediatric population, may be less specific and thus require further refinement in the adult population. Further research is necessary to improve the diagnostic criteria and treatment of this frequently fatal disorder.

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