Hemophagocytic lymphohistiocytosis: review of etiologies and management

George, Melissa R

Both sporadic and familial cases of HLH can be initiated by infectious causes; however, it is important to distinguish between primary, genetic cases versus secondary, as treatment of the underlying condition may be attempted in the latter. All patients who meet the criteria should be tested for a precipitating infection, including culture of blood and urine, chest radiography, and screening for EBV, cytomegalovirus, parvovirus B19, human immunodeficiency virus (HIV), and human herpes virus-6. Throat and rectal swabs for viral culture may also prove useful. HLH has also been linked to HIV-associated infections such as pneumocystosis and histoplasmosis, so appropriate screening of infected patients should be considered. It is also recommended that patients with a travel history be screened for relevant infections. 36 The possible role of infectious diseases in causing HLH was first elucidated in 1979 in a case series describing renal transplant patients with a viral-associated HLH (viral-associated hemophagocytic syndrome). 4 EBV, a DNA (deoxyribonucleic acid) virus and member of the Herpesviridae family has been the most consistently reported virus associated with HLH. [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] The majority of EBV-associated HLH cases have been reported in Asia, with limited information on the incidence elsewhere in the world. A Japanese study estimated the annual incidence of HLH at 1 in 800,000 persons per year, with 90% of these cases being secondary and one-third of these secondary cases being related to EBV. This leads to an estimated annual incidence of 0.4 cases of EBV-associated HLH per million persons. Some have theorized that the higher rates of EBV-associated HLH in Asian countries may be due to a more pathogenic strain of EBV. 53 Several studies have performed sequence analysis of the EBV nuclear antigen 2 (EBNA-2) gene and latent membrane protein-1 (lmp-1). These studies have demonstrated that no single sub-strain of EBV has been linked to HLH as of yet. [54] [55] [56] It appears that new infection as well as reactivation of latent EBV infection may predispose individuals to HLH. Quantitative determination of EBV genome copy numbers in peripheral blood may be useful in predicting prognosis and effectiveness of therapy. 57, 58 Interestingly, male patients with EBV-associated HLH may have mutations in the SH2D1A gene, which is traditionally associated with X-linked lymphoproliferative syndrome (XLPS). XLPS is characterized by immunodeficiency to EBV. A Japanese study performed genetic analysis of the SH2D1A gene in 40 male patients presenting with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and chronic EBV infection, finding mutations in a quarter of these patients. Given this strong association, it is recommended that male patients with EBV-associated HLH be screened for XLPS. 59 While fulminant infectious mononucleosis may overlap with EBV-associated HLH, higher viral loads are seen in EBV-associated HLH. 54 While not as commonly reported nor as well defined as EBV, many other viruses may be associated with HLH. These can be best organized by DNA or RNA (ribonucleic acid) and, subsequently, by virus family, as listed in Table 2 .