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

Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis (HLH)

The diagnosis of HLH should be based on the HLH-2004 diagnostic criteria, which requires fulfillment of either a molecular diagnosis consistent with HLH or at least 5 of 8 specific clinical and laboratory criteria. 1

HLH-2004 Diagnostic Criteria

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

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

OR

1. At least 5 of these 8 diagnostic criteria:

• Fever (≥38.5°C)
• Splenomegaly
• Cytopenias affecting ≥2 of 3 lineages:
  • 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, lymph nodes, or liver
• Low or absent NK cell activity
• Ferritin ≥500 μg/L
• Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL

Key Diagnostic Considerations

Ferritin as a Critical Marker

• Hyperferritinemia should always prompt consideration of HLH in the differential diagnosis 1
• In adults, ferritin levels >7,000-10,000 μg/L strongly suggest HLH, though values can rarely exceed 100,000 μg/L 1, 2
• While ferritin >10,000 μg/L is >90% sensitive and specific for HLH in children, it is less specific in adults and requires integration with other clinical features 1

Hemophagocytosis

• If hemophagocytosis is not evident on initial bone marrow examination, further investigation is recommended 1
• Serial marrow aspirates may be necessary as this finding can develop over time 1
• Samples from other organs (spleen, lymph nodes, liver) may demonstrate hemophagocytosis if bone marrow is inconclusive 1

Alternative Scoring System: HScore

The HScore is an alternative diagnostic tool that includes:

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

A recent validation study showed HScore ≥169 has better sensitivity (96%) but reduced specificity (71%) compared to HLH-2004 criteria, while HScore ≥200 performs comparably to HLH-2004 3

Additional Supportive Findings

The following findings provide strong supportive evidence for HLH diagnosis:

• Cerebrospinal fluid pleocytosis (mononuclear cells)
• Elevated CSF protein
• Liver histology resembling chronic persistent hepatitis
• Other findings: cerebromeningeal symptoms, lymphadenopathy, jaundice, edema, skin rash, hepatic enzyme abnormalities, hypoproteinemia, hyponatremia, elevated VLDL, and decreased HDL 1, 2

Special Considerations in Adults

• The HLH-2004 criteria were originally developed for pediatric cases but are recommended for adult diagnosis as well 1, 4
• In adults, particularly with increasing age, underlying malignancies (especially lymphomas) are a major trigger of HLH 1
• The likelihood of underlying malignancy increases with age:

  • 60 years: 68% have lymphoma

  • 30-59 years: 38% have lymphoma
  • 15-29 years: 10% have lymphoma 2

Diagnostic Challenges and Pitfalls

1. Incomplete criteria fulfillment: HLH may be strongly suspected and treatment initiated even when fewer than 5 criteria are met, based on clinical judgment 1

2. Evolving laboratory findings: Serial testing may be necessary as laboratory abnormalities can develop over time 2

3. Diagnostic delay: Waiting for specialized tests like NK cell activity or sCD25 can delay diagnosis; consider adapted criteria (using 4 of 6 available criteria) when these specialized tests are unavailable 5

4. Malignancy masking: HLH can obscure underlying malignancies, potentially delaying curative treatment 6

5. Confounding conditions: Many HLH features overlap with systemic inflammatory response syndrome, infections, or neoplastic diseases 4

Diagnostic Algorithm

1. Initial screening:

   • Complete blood count to identify cytopenias
   • Ferritin level (values >7,000-10,000 μg/L highly suspicious)
   • Liver function tests
   • Triglycerides and fibrinogen

2. If initial screening suggests HLH:

   • Bone marrow examination for hemophagocytosis
   • NK cell activity testing
   • Soluble CD25 (IL-2 receptor) measurement
   • Imaging for hepatosplenomegaly
   • Coagulation studies

3. Search for underlying triggers:

   • Infection workup
   • Malignancy evaluation (especially lymphoma)
   • Autoimmune disease assessment

4. Consider genetic testing for primary HLH, particularly in younger patients or those with family history

The diagnosis of HLH requires high clinical suspicion and prompt evaluation, as early diagnosis and treatment significantly impact mortality and morbidity outcomes.