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BACKGROUND

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Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are clinically related life-threatening immune dysregulatory processes characterized by fever, systemic inflammation, organomegaly, coagulopathy, and hematologic cytopenias. Both conditions may also include neurologic symptoms, often accompanied by cerebrospinal fluid and brain imaging abnormalities. HLH and MAS are defined histologically by the phagocytosis of hematopoietic cells by normal-appearing macrophages. This hemophagocytosis is most typically seen on samples from bone marrow aspirates, but it can also be seen in the spleen and in other lymphatic tissue.

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HLH may be inherited, as in the case of familial hemophagocytic lymphocytosis (FHL), or acquired. FHL is caused by genetic defects in proteins that mediate cytotoxicity in natural killer (NK) cells and cytotoxic T cells. These abnormalities lead to the impaired functioning of these cells, triggering cytokine storm and often cardiovascular collapse. Acquired HLH is typically triggered by viral infections, but it may also be associated with malignancies, acquired immunodeficiencies, and rheumatologic disorders. Historically, the diagnosis of FHL was made in infancy based on clinical criteria. With the discovery of several genetic mutations that lead to familial HLH, however, cases have been identified in older children and even adults,1-3 suggesting that HLH presenting at any age may be due to both inherited and acquired factors. This finding may have important implications for treatment.

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MAS typically exists in the context of severe rheumatologic diseases, most commonly systemic-onset juvenile idiopathic arthritis (soJIA). Systemic lupus erythematosis (SLE) and Kawasaki disease may also permit the development of MAS, though at times MAS may be the presenting manifestation of the underlying rheumatologic disorder, greatly complicating diagnosis. MAS is considered a form of acquired HLH occurring in a specific population, and the term rheumatologic disease–associated HLH has been proposed, though the strict diagnostic criteria for HLH may not be met.4 The diagnosis of either HLH or MAS should be considered in an ill child with prolonged fever, organomegaly, elevated inflammatory markers, cytopenias, coagulopathy, neurologic symptoms, and/or evidence of liver dysfunction. A significantly elevated ferritin greater than 10,000 μg L–1 has been demonstrated to be a sensitive and specific marker of these hemophagocytic processes.5

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PATHOPHYSIOLOGY

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FAMILIAL HLH

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To date, four FHL-associated genetic mutations have been identified. These mutations (Table 151-1) all affect the ability of cytotoxic cells, such as NK cells and cytotoxic T lymphocytes, to carry out the effective killing of target cells. Mutations in perforin vitiate the cytotoxic granules of cytotoxic cells, while the other genes associated with FHL affect cytotoxic granule exocytosis. Of note, HLH has also been associated with heritable primary immunodeficiencies, including Griscelli syndrome, Chediak-Higashi syndrome, X-linked lymphoproliferative syndrome (XLP), and mutations in the ITK gene. HLH associated with XLP and ITK mutations is often triggered by Epstein-Barr virus (EBV) infection.4

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