What are the diagnostic criteria for Hemophagocytic Lymphohistiocytosis (HLH)?

Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis (HLH)

The diagnosis of HLH requires either a molecular diagnosis consistent with HLH or fulfillment of 5 out of 8 specific diagnostic criteria according to the HLH-2004 guidelines. 1, 2

HLH-2004 Diagnostic Criteria

HLH can be diagnosed if either of the following is fulfilled:

1. Molecular diagnosis consistent with HLH 1, 2

   • Genetic testing showing mutations in HLH-associated genes

2. OR 5 of the 8 following criteria 1, 2:

   • Fever 1
   • Splenomegaly 1
   • Cytopenias affecting ≥2 of 3 lineages in peripheral blood:
     • Hemoglobin <90 g/L (<100 g/L in infants <4 weeks)
     • Platelets <100 × 10^9/L
     • Neutrophils <1.0 × 10^9/L 1
   • Hypertriglyceridemia and/or hypofibrinogenemia:
     • Fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL)
     • Fibrinogen ≤1.5 g/L 1
   • Hemophagocytosis in bone marrow, spleen, or lymph nodes without evidence of malignancy 1
   • Low or absent NK cell activity (according to local laboratory reference) 1
   • Ferritin ≥500 μg/L 1
   • Soluble IL-2 receptor (sCD25) ≥2400 U/mL 1

Important Clinical Considerations

• Hyperferritinemia is a key marker for HLH diagnosis:

  • In adults, ferritin levels are often >7,000-10,000 μg/L and may exceed 100,000 μg/L 1
  • Ferritin >10,000 μg/L has been reported to be 90% sensitive and 96% specific for HLH in children 3
  • Ferritin ≥500 μg/L has 94% mean sensitivity across multiple cohorts and serves as a reliable screening marker 4, 5

• Soluble IL-2 receptor (sCD25) is an excellent diagnostic test for adult HLH with an area under the curve of 0.90 compared to 0.78 for ferritin 1

• Despite the name, hemophagocytosis is neither sensitive nor specific for HLH and may not be present initially 1

  • If not found on initial examination, further searches in other organs or serial bone marrow aspirates are recommended 1

Alternative Diagnostic Tool: HScore

• The HScore is an alternative scoring system developed specifically for adults with suspected secondary HLH 2
• Parameters included in the HScore:
  • Known underlying immunosuppression (0 or 18 points)
  • Temperature (0,33, or 49 points based on range)
  • Organomegaly (0,23, or 38 points)
  • Number of cytopenias (0,24, or 34 points)
  • Ferritin level (0,35, or 50 points)
  • Triglyceride level (0,44, or 64 points)
  • Fibrinogen level (0 or 30 points)
  • AST level (0 or 19 points)
  • Hemophagocytosis on bone marrow aspirate (0 or 35 points) 1
• An HScore cutoff of 169 has shown mean sensitivity of 82.4% and specificity of 87.6% across multiple cohorts 4

Supportive Diagnostic Findings

Additional findings that support the diagnosis of HLH include:

• Spinal fluid pleocytosis and/or elevated spinal fluid protein 1
• Liver histology resembling chronic persistent hepatitis 1
• Cerebromeningeal symptoms, lymph node enlargement, jaundice, edema, skin rash 1
• Hepatic enzyme abnormalities, hypoproteinemia, hyponatremia 1
• Elevated VLDL and low HDL 1

Diagnostic Pitfalls and Caveats

• The HLH-2004 criteria were developed for children and are not formally validated in adults, though they remain the standard diagnostic approach 1, 6
• Treatment should not be delayed if HLH is strongly suspected, even if all 5 criteria are not yet fulfilled 1
• In resource-limited settings where NK cell activity and sCD25 testing are unavailable, modified criteria with a cutoff of 4 out of 6 available criteria may be used 5
• A comprehensive search for underlying triggers (infections, malignancies, autoimmune disorders) should be conducted even during ongoing HLH treatment 1
• Ferritin >6,000 μg/L has been identified as an independent prognostic factor for inferior survival 5