Haemophagocytic Lymphohistiocytosis
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Direct answer
Haemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome in which activated macrophages engulf blood cells. Diagnosis rests on HLH-2004 criteria, either a molecular diagnosis or at least five of eight features, including fever, splenomegaly, cytopenias, raised ferritin and low natural killer cell activity. Familial forms present in infancy and need transplantation, whereas secondary forms follow infection, malignancy or autoimmune disease and are treated by addressing the trigger.
What you must remember
- Diagnostic threshold: HLH-2004 requires a molecular diagnosis or at least five of eight criteria, so a single high value never establishes the diagnosis.
- Fever and splenomegaly: fever of at least 38.5 degrees Celsius and splenomegaly are among the commonest presenting features.
- Cytopenias: at least two of three lineages must be affected, with haemoglobin below 9 g/dL, platelets below 100 × 10^9/L or neutrophils below 1.0 × 10^9/L.
- Lipids and fibrinogen: fasting triglycerides of at least 265 mg/dL and/or fibrinogen of at most 150 mg/dL count as criteria.
- Ferritin and sCD25: ferritin of at least 500 ng/mL and soluble CD25 of at least 2400 U/mL are criteria, though ferritin is also raised in sepsis and liver disease.
- Familial forms: autosomal recessive defects in cytotoxic granule genes such as PRF1, UNC13D, STX11 and STXBP2 present in infancy and need haematopoietic transplantation.
- Secondary forms: Epstein-Barr virus is the commonest infectious trigger, while malignancy and autoimmune disease such as systemic lupus erythematosus also trigger the syndrome.
- Treatment: the HLH-2004 backbone is dexamethasone, etoposide and cyclosporine, with emapalumab used for refractory primary disease in some centres.
A pathway from fever to a diagnosis
An infant with fever, hepatosplenomegaly and falling counts needs early HLH screening rather than a wait for the classic picture.
- Suspect early: unexplained fever with hepatosplenomegaly and two or more cytopenias justifies HLH screening before any marrow review.
- Measure the markers: ferritin, triglycerides, fibrinogen, soluble CD25 and natural killer cell activity complete the criteria picture.
- Look for haemophagocytosis: marrow, spleen, lymph node or liver biopsy may show macrophages engulfing blood cells, though its absence does not exclude the diagnosis.
- Search for a trigger: EBV PCR, cultures, malignancy screening and autoimmune serology identify a secondary cause.
- Consider familial disease: infancy, an affected sibling or parental consanguinity prompts genetic testing for granule-related genes.
- Control the inflammation: dexamethasone, etoposide and cyclosporine follow the HLH-2004 protocol, with emapalumab in refractory primary disease.
- Plan the cure: familial disease needs haematopoietic stem cell transplantation, while secondary disease is managed by treating the trigger alongside immunosuppression.
Where the exam tries to catch you
Questions usually turn on separating familial from secondary disease and on reading ferritin in context.
- Trap: labelling every raised ferritin as HLH. Correct: ferritin rises in sepsis, liver disease and many inflammatory states, so it counts only as one of the HLH-2004 criteria.
- Trap: assuming bone marrow haemophagocytosis is mandatory. Correct: it is only one of eight criteria, so five other features can establish the diagnosis without it.
- Trap: treating familial HLH by trigger removal alone. Correct: familial disease progresses without transplantation, so the search for a trigger never replaces transplant planning.
Frequently asked questions
Which HLH-2004 criteria are needed for diagnosis without a molecular test?
Haemophagocytic lymphohistiocytosis is diagnosed without a molecular test when at least five of the eight HLH-2004 criteria are met. These include fever, splenomegaly, cytopenias affecting two or more lineages, raised triglycerides or low fibrinogen, haemophagocytosis, low natural killer cell activity, raised ferritin and raised soluble CD25.
Which infection most commonly triggers secondary haemophagocytic lymphohistiocytosis?
Epstein-Barr virus is the commonest infectious trigger of secondary haemophagocytic lymphohistiocytosis, particularly in older children and adolescents. Malignancy and autoimmune diseases such as systemic lupus erythematosus can also trigger the syndrome.
Why is serum ferritin alone insufficient to diagnose haemophagocytic lymphohistiocytosis?
Serum ferritin is raised in sepsis, liver disease and many inflammatory states, so a high value does not establish haemophagocytic lymphohistiocytosis on its own. Ferritin must be interpreted within the HLH-2004 criteria alongside other features.
What distinguishes familial from secondary haemophagocytic lymphohistiocytosis in an infant?
Familial haemophagocytic lymphohistiocytosis is genetic, usually autosomal recessive, presents in infancy and needs transplantation for cure. Secondary disease is triggered by infection, malignancy or autoimmune illness and tends to appear in older children, although the boundary is not always clear.