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.

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.

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

FAMILIAL HLH

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

ACQUIRED HLH/MAS

Acquired HLH occurs in children without the described genetic mutations associated with familial HLH and is often triggered by infection, especially EBV. Children with some degree of acquired or iatrogenic immunocompromise, including those taking immunosuppressive drugs, infected with human immunodeficiency virus (HIV), or status-post stem-cell transplant, are at risk for developing HLH.⁴

Acquired HLH in the setting of autoimmune disease, most commonly soJIA and adult-onset Still disease, is known as MAS. Approximately 10% of patients with soJIA develop MAS, though as many as 30% to 50% of these patients have subclinical HLH.^6,7

Several models seek to explain the manner in which known triggers interact with immunologic or inflammatory conditions to precipitate acquired HLH. The first parallels the model proposed for FHL in which the dysfunction of cytotoxic cells leads to the persistence of stimulated CD8⁺ T cells, driving interferon-gamma production and attendant cytokine-mediated toxicity. However, not all patients with MAS have defects in these cytotoxicity pathways, leading to hypotheses that alternative pathways may also lead to HLH, including repeated stimulation of Toll-like receptors and decreased production of IL-10.⁸ In both the acquired and familial forms of HLH, self-sustaining feedback of numerous proinflammatory substances, including cytokines and chemokines, leads to a dysregulated immune response and the characteristic clinical presentation.^4,9

The diagnosis of HLH/MAS begins with considering hemophagocytosis as the cause of persistent fever in a very ill child with organomegaly, systemic inflammation, cytopenias, liver function abnormalities, or neurologic symptoms such as seizures, meningismus, or cranial nerve palsies. In addition, while many of these findings are nonspecific and can be associated with other disease processes, HLH and MAS are characterized by the severe and persistent nature of these findings. While most pediatric cases of FHL are diagnosed within the first year of life, new understanding of the spectrum of disease has led to diagnoses later in life.^4,10 In addition, in the case of acquired HLH/MAS the presentation may be delayed and may occur in the context of a known autoimmune disease or may be the presenting event.