LAUSR

INTRODUCTION H emophagocytic lymphohistiocytosis (HLH) is a rare immune disorder that is life threatening if not promptly diagnosed and treated. Its identification, however, remains a diagnostic challenge for clinicians, given the large overlap in presenting symptoms with other conditions, including autoimmune disease and infection. Further adding to the complexity is that HLH encompasses 2 separate forms of disease (Figure1): primary or familial HLH (FHL), and secondary HLH (sHLH), which is often referred to as macrophage activation syndrome (MAS) when associated with rheumatological disease and which can occur in response to robust immunological activation. Hemophagocytic lymphohistiocytosis syndrome is characterized by persistent fever, hepatosplenomegaly, and cytopenias. Laboratory abnormalities include hyperferritinemia, hypertriglyceridemia, coagulopathy with hypofibrinoginemia, and hepatic dysfunction. Histopathology classically demonstrates hemophagocytosis in bone marrow and other involved tissues. However, histologic evidence of hemophagocytosis is detected in only a small proportion of cases at presentation, and its identification is neither sensitive nor specific for the diagnosis of HLH. Revised HLH diagnostic criteria state that the presence of 5 of the following 8 features can be considered diagnostic: (i) fever, (ii) splenomegaly, (iii) cytopenia involving 2 of 3 lineages, (iv) hypertriglyceridemia and/or hypofibrinogenemia, (v)) hemophagocytosis in bone marrow, spleen, or lymph nodes, (vi)) reduced or absent natural killer (NK) cell activity, (vii) hyperferritinemia, and (viii) elevated soluble interleukin-2 (IL-2) receptor. However, these diagnostic criteria do not need to be fulfilled if a genetic diagnosis of HLH is made. Primary HLH or FHL is a group of autosomal recessive immune disorders with an estimated incidence of 0.12 per 100,000 children per year. Nearly 70% of patients with FHL develop disease within the first year of life, with high mortality if unrecognized, and family history can often be negative. The various genetic defects associated with FHL have been linked to pathways involved in perforin-mediated cytolysis, which is central to the effector functions of cell-mediated immunity. Under physiologic conditions, cytotoxic cells, including NK cells and CD8þ T lymphocytes, engage virus-infected or tumor-transformed cells to induce apoptosis in these targets. Within the synapse formed between immune cells and target cells, lytic granules are released, which contain perforin and granzymes. Perforin is a key protein that forms pores in the target cell membrane, allowing for the entry of granzymes, which ultimately trigger programmed cell death. Genetic mutations in these cytolytic pathways lead to impaired cell-mediated cytotoxicity, and in HLH may lead to inappropriate survival of antigen-presenting target cells and subsequent persistent activation of effector cells with overproduction of proinflammatory cytokines or cytokine storm. Another proposed mechanism contributing to the overall immune activating state in HLH is based on the observation that perforin is involved in downregulating CD8þ T cells following an immune response. Therefore, abnormalities in this pathway may also result in failed suppression of activated cytotoxic T lymphocytes and prolonged proinflammatory cytokine production, macrophage activation, and hemophagocytosis. In contrast to primary HLH, sHLH occurs in all age groups and can be acquired in response to various immune system triggers, including infection, malignancy, and autoimmune disease. Secondary HLH presents with a clinical syndrome similar to that of primary HLH, but