Haemophagocytic syndrome

From Ganfyd

Haemophagocytic syndrome (haemophagocytic lymphohistiocytosis, HLH, macrophage activation syndrome is a group of disorders, characterized by :

• Persistent or intermittent fevers
• Hepatosplenomegaly (often manifested initially as isolated splenomegaly)
• Thrombocytopenia and anaemia that often evolve to severe pancytopenia
• Coagulation abnormalities (in particular, hypofibrinogenemia)
• Hepatic dysfunction

All in the absence of other causes of thrombocytopenia and hepatosplenomegaly.

Henter[1] diagnostic criteria: Splenomegaly Hyperferritinaemia This is one of the rare causes of very high ferritin levels Hypertriglyceridaemia High levels of sCD25 and bone marrow haemophagocytosis

The common factor is the inability to kill infected target cells. The resulting sustained natural-killer-cell and cytotoxic T-cell activity leads via inflammatory cytokines to macrophage activation, dissemination, and organ infiltration. Haemophagocytosis in the marrow is not always evident at presentation so serial bone marrow examinations may be required. A spleen aspirate may be an alternative to marrow. Subclassification in the literature tends to be confusing, which is not surprising as full diagnosis may be quite an intellectual and technical challenge, while the imperative of treatment is usually far more important.

It can be regarded as primary (genetic) or secondary. Alternatively there are four categories:

1. Familial haemophagocytic lymphohistiocytosis (perforin deficiency)
2. Haemophagocytic syndromes associated with infections (Epstein-Barr virus, cytomegalovirus, parvovirus B19, influenza, bacteria, fungi, mycobacteria, and parasites)
3. Associated with juvenile idiopathic arthritis (ESR may be low, due to low fibrinogen cf underlying (JIA).
4. Associated with immunodeficiency states:
   • DiGeorge syndrome should be excluded by FISH
   • Lysinuric protein intolerance - hyperammonaemia is characteristic
   • Chediak-Higashi and Griscelli syndromes: the accelerated phases are both characterized by albinism - mutations in the LYST or RAB27A gene, respectively, will confirm the diagnosis.
   • X-linked lymphoproliferative disease (susceptibility to kill Epstein-Barr virus).

Diagnosis

Very high ferritin and pancytopenia is extremely suggestive

• Think of it and check ferritin
• Bone marrow may show the haemophagocytes. This is not always the case early.

Prognosis

This is somewhat better for the familial forms that tend to present in childhood. Epstein-Barr virus associated haemophagocytic syndrome is known to have a very high mortality, as is that associated with lymphomas.

Treatment

HLH94 regimen of etoposide and dexamethasone and then if no self limiting underlying condition like a viral initiating factor, ciclosporin for control, bone marrow transplant for cure.

References