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 clinical and laboratory criteria from the HLH-2004 guidelines, though clinical judgment should guide initiation of treatment even before all criteria are met. 1

The HLH-2004 Diagnostic Criteria

The diagnosis is established if either of the following is present:

Criterion 1: Molecular Diagnosis

• Genetic testing demonstrating mutations in HLH-associated genes (perforin, UNC13D, STX11, STXBP2, or genes associated with Griscelli syndrome, Chediak-Higashi syndrome, or X-linked lymphoproliferative syndromes) 1

Criterion 2: Five of Eight Clinical/Laboratory Parameters

The 8 diagnostic criteria are: 1, 2, 3

1. Fever - Prolonged high fever, often >39.4°C 3

2. Splenomegaly - Clinically detectable enlarged spleen 1

3. Cytopenias affecting ≥2 of 3 lineages in peripheral blood:

   • Hemoglobin <90 g/L (or <100 g/L in infants <4 weeks)
   • Platelets <100 × 10⁹/L
   • Neutrophils <1.0 × 10⁹/L 1

4. Hypertriglyceridemia and/or hypofibrinogenemia:

   • Fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL)
   • Fibrinogen ≤1.5 g/L 1

5. Hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy 1

6. Low or absent NK cell activity according to local laboratory reference 1

7. Ferritin ≥500 μg/L 1, 2

8. Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL 1, 2

Critical Diagnostic Considerations

Hyperferritinemia as a Key Marker

• Ferritin levels >7,000-10,000 μg/L are highly characteristic of HLH in adults, with values occasionally exceeding 100,000 μg/L 1, 2
• Ferritin ≥500 μg/L has 94.0% sensitivity as a screening marker and should always prompt inclusion of HLH in the differential diagnosis 1, 4
• However, hyperferritinemia is less specific in adults than children and requires integration of other clinical features 1

Soluble IL-2 Receptor Performance

• Soluble CD25 (sCD25) has superior diagnostic performance compared to ferritin, with an area under the curve of 0.90 versus 0.78 for ferritin 2

Hemophagocytosis Limitations

• Hemophagocytosis is neither sensitive nor specific for HLH and may be absent at initial presentation 1
• If not found initially, serial bone marrow aspirates over time or examination of other organs (liver, spleen, lymph nodes) should be pursued 1, 2
• Hemophagocytosis can occur in other conditions including septicemia and malignancies 1

Alternative Diagnostic Tool: HScore

For adults with suspected secondary HLH, the HScore provides a validated alternative approach: 2

• The HScore includes parameters such as known immunosuppression, organomegaly, number of cytopenias, ferritin level, triglyceride level, fibrinogen level, AST level, and hemophagocytosis 2
• An HScore ≥169 has 82.4% mean sensitivity and 87.6% mean specificity for diagnosing secondary HLH 4
• This scoring system was developed specifically for adults, unlike HLH-2004 criteria which were designed for pediatric patients 2

Modified Diagnostic Thresholds Based on Recent Validation

Recent multicenter validation suggests lowering the threshold for HLH-2004 criteria: 4

• Four fulfilled HLH-2004 criteria (instead of 5) achieved 86.5% mean sensitivity and 86.1% mean specificity across 13 validation cohorts 4
• Revised HLH-2004 criteria with NK cell activity removed (4 of 7 criteria) showed 83.8% sensitivity and 87.8% specificity 4

Supportive Diagnostic Findings

Additional findings that strengthen the diagnosis include: 1, 2

• Cerebrospinal fluid pleocytosis (mononuclear cells) and/or elevated CSF protein
• Liver histology resembling chronic persistent hepatitis
• Cerebromeningeal symptoms
• Lymph node enlargement
• Jaundice and edema
• Skin rash
• Hepatic enzyme abnormalities
• Hypoproteinemia and hyponatremia
• Elevated VLDL with low HDL

Critical Pitfalls and Caveats

Do Not Delay Treatment

• HLH-directed therapy may be initiated even when fewer than 5 criteria are fulfilled if clinical suspicion is high 1, 2
• The combination, extent, and progression of clinical and laboratory abnormalities must be judged as unusual, unexpected, and otherwise unexplained 1

Differentiation from Sepsis

• HLH can present identically to sepsis, septic shock, or multiple organ dysfunction syndrome in critically ill patients 3, 5
• A high index of suspicion is essential, as many diagnostic features are nonspecific 5, 6

Search for Underlying Triggers

• A meticulous search for underlying disease (infections, malignancies particularly lymphomas, autoimmune disorders) must continue despite ongoing HLH treatment 1
• In adults, malignancies (especially T-cell/NK-cell lymphomas and B-cell lymphomas) are major triggers, with increasing prevalence with age 1
• In male patients with lymphoma and EBV-driven HLH, genetic or flow cytometric analysis for X-linked lymphoproliferative syndrome should be strongly considered 1

Age-Related Considerations

• The likelihood of malignancy-associated HLH increases dramatically with age: 68% in adults >60 years versus 0% in children <14 years 3