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

HLH-2004 Diagnostic Criteria

The diagnosis of HLH can be established if either criterion 1 OR criterion 2 is fulfilled:

1. Molecular diagnosis consistent with HLH (genetic mutations associated with primary HLH)

2. Diagnostic criteria fulfilled (5 of the 8 criteria below):

   • Fever (temperature ≥38.5°C)
   • Splenomegaly
   • 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
   • Hypertriglyceridemia and/or hypofibrinogenemia:
     • Fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL)
     • Fibrinogen ≤1.5 g/L
   • Hemophagocytosis in bone marrow, spleen, or lymph nodes
   • Low or absent NK cell activity
   • Ferritin ≥500 μg/L
   • Soluble IL-2 receptor (sCD25) ≥2400 U/mL

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Alternative Diagnostic Tool: HScore

The HScore is an alternative scoring system that can be particularly useful in adult patients. Parameters and points include:

• Known underlying immunosuppression: 0 (no) or 18 (yes)
• Temperature: 0 (<38.4°C), 33 (38.4-39.4°C), or 49 (>39.4°C)
• Organomegaly: 0 (no), 23 (hepatomegaly or splenomegaly), or 38 (hepatomegaly and splenomegaly)
• Number of cytopenias: 0 (1 lineage), 24 (2 lineages), or 34 (3 lineages)
• Ferritin: 0 (<2000 μg/L), 35 (2000-6000 μg/L), or 50 (>6000 μg/L)
• Triglyceride: 0 (<1.5 mmol/L), 44 (1.5-4 mmol/L), or 64 (>4 mmol/L)
• Fibrinogen: 0 (>2.5 g/L) or 30 (≤2.5 g/L)
• AST: 0 (<30 U/L) or 19 (≥30 U/L)
• Hemophagocytosis on bone marrow aspirate: 0 (no) or 35 (yes)

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Important Diagnostic Considerations

• Ferritin levels are particularly important in HLH diagnosis:

  • Values >7,000-10,000 μg/L strongly suggest HLH in adults
  • Levels >10,000 μg/L are >90% sensitive and specific for HLH in children
  • However, hyperferritinemia is less specific in adults than in children 1, 3

• Soluble IL-2 receptor (sCD25) is a valuable diagnostic marker:

  • Has been reported as an excellent diagnostic test for adult HLH
  • Area under the curve of 0.90 (95% CI, 0.83-0.97) compared to 0.78 for ferritin 1

• Hemophagocytosis may not be present initially:

  • If not proven at presentation, further search for hemophagocytic activity is encouraged
  • Serial bone marrow aspirates may be helpful
  • Material may be obtained from other organs if bone marrow is not conclusive 1, 4

Supportive Diagnostic Findings

Additional findings that provide supportive evidence for HLH diagnosis include:

• Spinal fluid pleocytosis (mononuclear cells)
• Elevated spinal fluid protein
• Liver histology resembling chronic persistent hepatitis
• Cerebromeningeal symptoms
• Lymph node enlargement
• Jaundice, edema, skin rash
• Hepatic enzyme abnormalities
• Hypoproteinemia, hyponatremia
• Elevated VLDL/low HDL 1, 3

Diagnostic Challenges

• The HLH-2004 criteria were developed for children and are not formally validated for adults 1
• Some tests (NK cell activity, sCD25) may not be readily available in all settings, potentially delaying diagnosis 5
• Diagnostic delay can occur as laboratory findings may evolve over time, requiring serial testing 3
• Distinguishing HLH from underlying malignancy can be challenging, especially in older patients where the likelihood of underlying lymphoma increases with age 3, 6
• Many diagnostic features are nonspecific and can overlap with systemic inflammatory response syndrome, infections, or neoplastic diseases 4

Early recognition and diagnosis of HLH are critical for timely initiation of appropriate therapy and improved outcomes, as the condition can rapidly progress to multiorgan failure with high mortality if left untreated.