Haemophagocytic syndrome

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Haemophagocytic syndrome (haemophagocytic lymphohistiocytosis, HLH, macrophage activation syndrome is a life-threatening hyperinflammatory syndrome, mediated by cytokines, triggered by ineffective but highly activated immune processes.

The underlying cause is congenital or acquired defects in T- or NK-cell function. The inability to kill infected target cells (which may include activated macrophages), results in release of pro-inflammatory cytokines with unwanted macrophage activation, dissemination and organ infiltration.

LogoKeyPointsBox.pngHenter[1] diagnostic criteria requires 5 out of 8:
  1. Fever
  2. Splenomegaly
  3. Hyperferritinaemia
    • This is one of the rare causes of very high ferritin levels
  4. Hypertriglyceridaemia/hypofibrinogenaemia
  5. 2 or more cytopenias
  6. Reduced NK cell activity (not easy to measure routinely)
  7. High levels of sCD25
  8. Haemophagocytosis in bone marrow, lymph nodes or CSF

It is characterised by:

  • Persistent or intermittent fevers
  • Organomegaly, typically hepatosplenomegaly (often manifested initially as isolated splenomegaly)
  • Cytopenias, typically thrombocytopenia and anaemia that often evolves to severe pancytopenia
  • Coagulation abnormalities (in particular, hypofibrinogenemia)
  • Hepatic dysfunction

All in the absence of other causes of thrombocytopenia and hepatosplenomegaly. The diagnostic criteria evolved largely from paediatric experience (about 60% of cases are in children) and may be less applicable to adults (see box on right).

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. Sub-classification 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 some categories:

Contents

Familial haemophagocytic lymphohistiocytosis

Familial haemophagocytic lymphohistiocytosis (familial HLH) is a rare autosomal recessive disorder with usual onset in infancy of haemophagocytic syndrome which is more commonly associated with infections or systemic disease. The known subtypes are:

  1. FHL1 due to mutations at 9q21.3-q22 (the so called HPLH1 or FHL1 genes as yet uncharacterised)[2]
  2. FHL2 due to mutations of the PRF1 gene at 10q22 that codes for perforin-1 a component of cytolytic granules
  3. FHL3 due to mutations of the UNC13D gene at 17q25.1 that codes for unc-13 homolog D involved in exocytosis
  4. FHL4 due to mutations if the STX11 gene at 6q24 that codes for syntaxin-11 involved in targetting/fusion of transport vesicles
  5. FHL5 due to mutations of the STXBP2 gene at 19p13.3-p13.2 which codes for syntaxin-binding protein-2 that interacts with syntaxin-11.

It is now distinguished from Omenn syndrome (familial reticuloendotheliosis with eosinophilia) which is due to mutations of the RAG1 or RAG2 genes at 11p and Faisalabad histiocytosis mapped to 11q25.

Haemophagocytic syndromes associated with infections

Haemophagocytic syndromes associated with juvenile idiopathic arthritis

  • ESR may be low, due to low fibrinogen cf underlying (JIA).

Haemophagocytic syndromes 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).

Haemophagocytic syndromes associated with medicines

Diagnosis

LogoKeyPointsBox.pngVery 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

HLH 1994 regimen,[4] subsequently refined by further work in 2004[5] consists of etoposide, dexamethasone and ciclosporin. This is weaned or stopped at the end of 8 weeks, if there is a response. Allogeneic bone marrow transplant if not responding.

References