It is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines.

[citation needed] The onset of HLH occurs before the age of one year in approximately 70 percent of cases.

Therefore, HLH should be included in the differential diagnosis of intensive care unit patients with cytopenia and hyperferritinemia.

[citation needed] Primary HLH is caused by high-penetrance variants in genes associated with the syndrome, and thus is part of the phenotype of several inborn errors of immunity (IEI).

[7] Secondary HLH (sHLH) is associated with, and thought to be promoted by, malignant and non-malignant diseases that likewise weaken the ability of the immune system to attack EBV-infected cells.

[9][10][11] Secondary HLH may also result from iatrogenic causes such as bone marrow or other organ transplantations; chemotherapy; or therapy with immunosuppressing agents.

[citation needed] The five subtypes of FHL[14] are each associated with a specific gene: Nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations.

[15] The underlying causes, either inherited or acquired, lead to an unchecked immune response when exposed to triggers.

[citation needed] The serum C reactive protein, erythrocyte sedimentation rate, and ferritin level are markedly elevated.

[21] Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and haematologic alterations and death in the absence of treatment.

[citation needed] A subtype of primary HLH where the inflammation is limited to the central nervous system has been described.

This is a rare autosomal recessive disorder characterized by partial albinism, hepatosplenomegaly, pancytopenia, hepatitis, immunologic abnormalities, and lymphohistiocytosis.

It can be dangerous to infer a genetic impairment of granule-mediated cytotoxicity in patients, especially older children and adults, who meet any of the various criteria for HLH.

Thus, like shock, one must simultaneously manage both the acute physiologic changes associated with HLH (like systemic inflammation, DIC, hepatitis, etc.)

[citation needed] The International Histiocyte Society has collected the published consensus management documents for the many contexts in which HLH occurs and they host full-text versions.

[citation needed] On 20 November 2018, the FDA approved the anti-IFN-gamma monoclonal antibody emapalumab (proprietary name Gamifant) for the treatment of pediatric and adult primary HLH.

[32] Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only).

However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the central nervous system (brain and/or spinal cord).

[34] A systematic review recently reported the pooled proportion are fever 97.2%, hepatomegaly 70.2%, splenomegaly 78.4%, thrombocytopenia 90.1%, anemia 76.0%, and serum ferritin ≥500 μg/L 97.1%.