Hemophagocytic Lymphohistiocytosis: Truly On the Rise or Simply On the Radar?.

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disorder of the immune system that appears to be increasing in incidence. HLH induces a hyperinflammatory state that mimics sepsis with stimulated and unregulated proliferation of T lymphocytes, macrophages, and cytokines. While first described in infants and children, the incidence now appears to be increasing in adults, as evident by the increase of case series and reports currently in the literature. Given the rarity of HLH, there is little clinical data to guide treatment decisions but the disease is uniformly fatal without treatment. Our study aims to define the incidence of HLH at our institution, characterize its course, and identify strategies to improve outcomes.

In this single-center retrospective case series, following IRB approval, all documented cases of HLH diagnosed or treated at Beth Israel Deaconess Medical Center between 1997 and 2011 were analyzed. Cases were identified by a query of all inpatient and outpatient visits using ICD-9 billing code 288.4, hematopathology record review and review of cases from the hematologic malignancy clinical service. Forty-two patients were identified and 18 were included in the final analysis. Twenty-three were excluded due to alternative diagnoses and 1 was excluded due to the date of diagnosis being outside the study time period. Vital statistics, demographics and clinical data were collected on all eligible patients.

The key findings from our case series are highlighted below in Table 1.

Our study illustrates several interesting points. First, there were no identifiable cases of HLH at our institution before 2005 but multiple cases have been diagnosed annually since 2007. This rise may represent an increase in diagnosis due to greater awareness of the disease or may point to a new environmental trigger or exposure resulting in a true increase in incidence. Interestingly, 89% of patients diagnosed with HLH in our series were from rural areas with a spike in incidence in 2009, the year of the H1N1 pandemic. Information about patients' influenza status was not available for this analysis but raises the question if this strain of influenza may have triggered a rise in incidence in HLH at our institution. The second observation is that only 39% of our patients met the suggested clinical criteria for a diagnosis of HLH, yet all were clinically managed as HLH (Henter et al, Pediatr Blood Cancer 2007). This highlights the difficulty in diagnosing patients as several of the diagnostic labs are not easy to obtain. Our last observation is that this remains a highly lethal disease with a mortality of 78% in our population. In following the HLH-2004 treatment protocol (Henter et al, Pediatr Blood Cancer 2007), 100% of patients received steroids but only 72% received an immunosuppressant and only half received etoposide. One-third of treated patients attained remission but there were only four survivors in this case series. Three of the survivors had secondary HLH due to lymphoma, rheumatoid arthiritis (RA) and CMV infection. Only one survivor had primary HLH. The patient with RA was treated with the HLH-2004 protocol initially but was then switched to alemtuzumab due to persistent disease. He remains in remission 8 months after his last dose of alemtuzumab. In conclusion, there has been an increase in HLH incidence at our institution of unclear etiology. The majority of patients die of HLH despite efforts to use the HLH-2004 protocol, and many patients are unable to receive the full protocol. Further investigation is needed to determine the etiology of its increased incidence and to develop better treatment strategies in the adult population.

Off Label Use: Alemtuzumab was used as a second-line therapy for a patient with secondary HLH in an off-label fashion.