Hemophagocytic lymphohistiocytosis (HLH)

Diagnostic criteria for hemophagocytic lymphohistocytosis (HLH)

HLH can be diagnosed if either of the following two are met:

  1. A gene mutation consistent with familial HLH is present (these include mutations of PRF, UNC13D and STX11), OR
  2. At least five out of the eight following diagnostic criteria for HLH are fulfilled:
    • Fever
    • Splenomegaly
    • Cytopenia affecting ≥ 2 of 3 lineages: Hemoglobin < 90 g/L (in infants under four weeks, hemoglobin < 100 g/L); Platelets < 100 x109/L; Neutrophils < 1.0  x109/L
    • Hypertriglyceridemia and/or hypofibrinogenemia: Fasting triglycerides ≥ 3.0 mmol/L (≥ 265 mg/dl), OR fibrinogen ≤ 1.5 g/L
    • Hemophagocytosis in bone marrow, spleen or lymph nodes
    • Low or absent NK-cell activity (using local laboratory reference ranges)
    • Ferritin ≥ 500 ug/L
    • Soluble CD25 (i.e., soluble IL-2 receptor) ≥ 2,400 U/ml

Notes:

  1. If hemophagocytic activity is not found at presentation, further search for hemophagocytic activity is encouraged. If the bone marrow is inconclusive, consider biopsies of other organs or serial bone marrow aspirates may also be helpful.
  2. The following findings may provide supportive evidence for HLH:
    • spinal fluid pleocytosis (mononuclear cells) and/or elevated CSF protein
    • liver histology resembling chronic persistent hepatitis
  3. Other findings consistent with HLH are:
    • cerebromeningeal symptoms
    • lymphadenopathy
    • jaundice
    • edema
    • rash
    • liver enzyme abnormalities
    • hypoproteinemia
    • hyponatremia
    • raised VLDL
    • lowered HDL

These criteria for the diagnosis of hemophagocytic lymphohistiocytosis (HLH), also referred to as macrophage activation syndrome, were published by the Histiocyte Society, alongside the HLH-2004 treatment protocol, in 2007.1