HLH is a rare disorder. Vaguely, it is a hyperinflammatory condition characterised by deregulated activity of natural killer (NK) cells, CD8+ lymphocytes, and macrophages leading to phagocytic activity and ultimately widespread tissue damage. Mortality statistics are lacking but it often causes death. It is one of the cytokine storm syndromes.
This note will deal primarily with secondary HLH (sHLH), which develops in response to some kind of inflammatory stimulus. Primary HLH (pHLH) is a result of mutated genes that govern normal macrophage and cytoxic cell function, it usually present in the paediatric population. In patient with sHLH, there is some evidence of abnormalities in the pHLH associated genes which may predispose to development of the condition.
Mechanism
Dysregulation of normal immune cell signalling leads to failure to clear activated macrophages through perforin mediated cytotoxicity. This causes an escalating inflammatory response as the body can not clear the offending antigen. A cytokine storm ensues with recruitment of cytotoxic T lymphocytes and NK cells. Not much more is known.
Genetic mutations in several genes have been identified in connection with pHLH. These defective genes impair immune cell interaction precipitating HLH.
The haemophagocytosis that is the hallmark of the condition can be seen on biopsy. It is not pathognomonic nor required for diagnosis. It does, however, contribute to the cytopenias seen in HLH.
Signs and symptoms
The old diagnostic criteria was a pentad of fever, cytopenia (in two or more cell lines), splenomegaly, hypertrigliceridaemia with or without hypofibrinogenaemia, and biopsy proven haemphagocytosis. As of 2024, diagnosis can be made when five of the below criteria are met:
- Fever ≥38.5° C
- Splenomegaly ≥2 cm below the costal margin
- Cytopenias ≥2 of the following
- Hemoglobin <90 g/L (<100 g/L in neonates)
- Platelets <100 x 109/L
- Neutrophils <109/L
- Hypofibrinogenemia or hypertriglyceridemia ≥1 of the following:
- Fibrinogen ≤1.5 g/L
- Triglycerides ≥3.0 mmol/L
- Hyperferritinemia ≥500 microg/L
- Hemophagocytosis (in bone marrow or other tissues)
- Elevated soluble CD25 (also called soluble interleukin 2 receptor alpha) ≥2400 units/mL
Management
Mainstays of treatment with immunosupression and cytotoxic therapy with dexamothasone and etoposide come form the HLH protocol from the 90s; CNS involvement warrants intrathecal methotrexate. The newer protocol also utilises cyclophosphamide. Cytotoxic medicines should generally be avoided in the septic patient. Management of HLH is complex and difficult and should probably be left up to haematologist.
Stem cell transplant is indicated in some patients, usually where there is homozygosity for defective alleles or no residual NK cell function.
Further reading:
- Probably OpenEvidence… Information is fragmented across the literature.