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

Primary Diagnostic Approaches

HLH can be diagnosed if either of these criteria is met:

1. A molecular diagnosis consistent with HLH (genetic testing showing mutations in HLH-associated genes) 1

2. At least 5 of the following 8 diagnostic criteria: 1

   • Fever
   • Splenomegaly
   • Cytopenias affecting ≥2 of 3 lineages in peripheral blood:
     • Hemoglobin <90 g/L (<100 g/L in infants <4 weeks)
     • Platelets <100 × 10⁹/L
     • Neutrophils <1.0 × 10⁹/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 without evidence of malignancy
   • Low or absent NK cell activity (according to local laboratory reference)
   • Ferritin ≥500 mg/L
   • Soluble IL-2 receptor (sCD25) ≥2400 U/mL

Important Considerations for Diagnosis

• Clinical judgment is essential: The HLH-2004 criteria were developed for children and are not formally validated in adults, though they remain the standard diagnostic approach 1

• Hyperferritinemia is a key marker: While ferritin ≥500 mg/L is the diagnostic threshold, values >7,000-10,000 mg/L (and sometimes >100,000 mg/L) are more characteristic of HLH in adults 1

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

• Hemophagocytosis may not be present initially: If not found on initial bone marrow examination, further searches in other organs or serial marrow aspirates over time are recommended 1

Alternative Diagnostic Tool: HScore

The HScore is an alternative scoring system developed specifically for adults with suspected secondary HLH: 1, 2

• Parameters scored include:

  • Known underlying immunosuppression
  • Temperature
  • Organomegaly
  • Number of cytopenias
  • Ferritin level
  • Triglyceride level
  • Fibrinogen level
  • AST level
  • Hemophagocytosis on bone marrow aspirate 1

• A cutoff score of 168 provides 100% sensitivity and 94.1% specificity for HLH diagnosis in critically ill patients 2

Supportive Diagnostic Findings

Additional findings that support the diagnosis include: 1

• 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 and low HDL 1

Pitfalls and Caveats

• Do not delay treatment: HLH may be strongly considered, and treatment initiated, even if all 5 criteria are not yet fulfilled 1

• Adult vs. pediatric differences: Hyperferritinemia is less specific for HLH in adults than in children 1

• Underlying triggers: A meticulous search for underlying triggers (infections, malignancies, autoimmune disorders) should be conducted, even during ongoing HLH treatment 1

• Mortality risk factors: The fulfillment status of hypertriglyceridemia and hypofibrinogenemia has been associated with risk of multiple organ dysfunction syndrome and early mortality 3

• Critical illness considerations: In critically ill patients, adjusted cutoffs (ferritin >3000 μg/L and fever >38.2°C) may improve diagnostic accuracy 2