Hemophagocytic lymphohistiocytosis in adults

Dear Sir, I read with interest a recent article by Antonodimitrakis and colleagues in your journal presenting a case of acquired hemophagocytic lymphohistiocytosis (HLH) in a 60-year-old woman suffering from diabetes mellitus type 2 (1). The reported patient developed a life-threatening HLH associated with a reactivation of an Epstein–Barr virus (EBV) infection and was successfully treated by means of corticosteroids alone. Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of an exaggerated inflammatory reaction triggered by various inherited and/or acquired factors (2). The literature on the topic of HLH in adults is limited; however, acquired (i.e. secondary) forms of HLH (e.g. infection-associated HLH, I-HLH; autoimmune-associated HLH, A-HLH; malignancy-associated HLH, M-HLH) are the most prevalent. Antonodimitrakis et al. wrote in their article that ‘the patient’s age showed that a familial form of HLH was unlikely’ (1). Familial forms of HLH (FHL) are autosomal recessive disorders related to different mutations in genes encoding proteins required for lymphocyte cytotoxicity (i.e. PRF1, UNC13D, STX11, STXBP2) (2). Although FHL usually arises in infants and the vast majority of HLH cases in adults are acquired, it should be stressed that, albeit rarely, FHL can occur in adulthood, including older individuals (so-called late-onset FHL) (3–5). Therefore, the possibility of late-onset FHL in adults with HLH cannot be univocally excluded before tests of NK/T cell degranulation and activity, as well as genetic testing, have been performed. A retrospective study from Japan revealed that the frequency of different forms of HLH in adults varied depending on the age bracket (6). Among HLH patients aged 15–29 years, I-HLH was the most common (68% of cases). It was caused in equal parts by EBV-HLH (34%) and I-HLH other than EBVHLH (34%). In this age group, the second most common cause of HLH was A-HLH (22%), followed by M-HLH (10%). In the group of patients aged 30–59 years, M-HLH occurred only slightly less frequently than I-HLH (37% and 47%, respectively), followed by A-HLH (9%) and HLH after hematopoietic stem cell transplantation (7%). In the group of patients aged ‡60 years, however, malignancy was the most frequent cause of HLH (68%), followed by I-HLH (26%) and A-HLH (6%) (6). A recent, retrospective, population-based study from our group showed the annual incidence of MHLH in adults to be 1:280,000 per year, or 0.36/ 100,000 individuals per year (7). The results of this study were limited by the small population of the Swedish region of northern Halland but were strengthened by the long observation period of over 14 years. Although M-HLH in East Asia is most often associated with NK/T cell lymphoproliferative malignancies, M-HLH in Europe tends to develop more frequently in the course of the hematological malignancies (6,7). Importantly, it is worth to remember that M-HLH can occur before or during the treatment of known malignancy, or as the first manifestation of an occult malignancy (7,8). Therefore an episode of HLH with unclear etiology in the older individual should always serve as a warning signal for a yet undiagnosed malignancy, leading to further careful cancer diagnostics and follow-up, as was