• persistent or intermittent fevers
• hepatosplenomegaly (often manifested initially as isolated splenomegaly)
• thrombocytopenia and anemia that often evolve to severe pancytopenia
• coagulation abnormalities (in particular, hypofibrinogenemia)
• hepatic dysfunction
• all in the absence of other causes of thrombocytopenia and hepatosplenomegaly

Other tests that are helpful are serum ferritin (spectacularly high,eg >1000), and ESR (low, due to low fibrinogen cf underlying JIA).

The underlying problem is the inability to kill infected target cells. The frustrated NK-l and cytotoxic T-cell activity leads to a massive inflammatory cascade, resulting in macrophage activation, dissemination, and organ infiltration. The haemophagocytosis of the name refers to characteristic macrophage/histiocyte consumption of erythrocytes, most evident in the marrow but sometimes seen in the peripheral blood film.  Not always dramatic, not always evident at presentation so serial bone marrow examinations may be required (spleen aspirate?).

There are four categories:

• a familial syndrome (perforin deficiency)
• associated with infection (Epstein-Barr virus, cytomegalovirus, parvovirus B19, bacteria, fungi, mycobacteria, and parasites)
• associated with juvenile idiopathic arthritis (where it is usually called macrophage activation syndrome)
• associated with immunodeficiency 
  • DiGeorge syndrome should be excluded by FISH
  • Lysinuric protein intolerance – hyperammonemia is characteristic
  • the accelerated phases of Chediak-Higashi and Griscelli syndromes (both characterized by albinism,  mutations in LYST or RAB27A genes respectively)

• In male infants, consider X-linked lymphoproliferative disease where natural killer cells are unable to kill Epstein-Barr virus.

Treatment

Henter diagnostic criteria, need 5 of 8 clinical features, but some eg NK activity not routinely available.

HLH2004 regimen  includes dexamethasone, etoposide.

IVIG is an adjunctive therapy.

[NEJM 2004:351]