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 recent multicenter validation suggests that 4 out of 8 criteria may be sufficient for secondary HLH in adults. 1, 2

The 8 HLH-2004 Diagnostic Criteria

The following parameters must be assessed when HLH is suspected 1, 3:

1. Fever - typically prolonged and often >39.4°C 1, 4

2. Splenomegaly 1, 3

3. Cytopenias affecting ≥2 of 3 lineages in peripheral blood 1, 3:

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

4. Hypertriglyceridemia and/or hypofibrinogenemia 1, 3:

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

5. Hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy 1, 3

6. Low or absent NK cell activity (according to local laboratory reference) 1, 3

7. Ferritin ≥500 μg/L 1, 3

8. Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL 1, 3

Critical Diagnostic Considerations

Ferritin as a Screening Tool

• Ferritin ≥500 μg/L has 94% sensitivity across validation cohorts and should always prompt inclusion of HLH in the differential diagnosis 2
• In adults, ferritin values of 7,000-10,000 μg/L are more characteristic of HLH, and levels may rarely exceed 100,000 μg/L 1, 3
• Ferritin >10,000 μg/L is >90% sensitive and specific for HLH in children, though less specific in adults 1

Soluble IL-2 Receptor Performance

• Soluble CD25 (sCD25) has an area under the curve of 0.90 for diagnosing adult HLH, compared to 0.78 for ferritin, making it an excellent diagnostic test 3

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 (spleen, lymph nodes, liver) should be pursued 1, 3
• Hemophagocytosis can occur in septicemia and other conditions related to malignancies 1

Alternative Diagnostic Approach: HScore

For adults with suspected secondary HLH, the HScore (cut-off ≥169) performs comparably to HLH-2004 criteria with 82.4% mean sensitivity and 87.6% mean specificity 2, 3. The HScore includes 3:

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

Validated Modifications for Secondary HLH

Recent multicenter validation demonstrates that 4 fulfilled HLH-2004 criteria (rather than 5) achieves 86.5% mean sensitivity and 86.1% mean specificity for secondary HLH 2. Removing NK cell activity from the criteria (revised HLH-2004) maintains 83.8% sensitivity and 87.8% specificity with a cut-off of 4 criteria 2.

Supportive Diagnostic Findings

Additional findings that strengthen the diagnosis include 1, 3:

• Spinal 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/low HDL

Essential Clinical Judgment Points

When to Initiate Treatment

HLH-directed therapy may be initiated even when 5 criteria are not yet fulfilled if clinical suspicion is high, as the diagnosis should be based on HLH-2004 criteria in conjunction with clinical judgment and patient history 1, 3. The combination, extent, and progression of clinical and laboratory abnormalities must be judged as unusual, unexpected, and otherwise unexplained 1.

Age-Related Considerations

• In adults, particularly with increasing age, malignancies (primarily lymphomas) are a major cause of HLH 1
• The likelihood of malignancy-associated HLH increases dramatically with age: 68% in adults >60 years versus 38% in ages 30-59 years 4
• Mean age at HLH onset in adults is 49 years 1

Critical Pitfalls to Avoid

Diagnostic Confusion with Sepsis

HLH can present identically to sepsis or multiple organ dysfunction syndrome, making differentiation extremely challenging in critically ill patients 4, 5. Many diagnostic features are nonspecific and can meet criteria for systemic inflammatory response syndrome 6.

Context-Dependent Interpretation

In the context of malignancy, several HLH criteria (fever, organomegaly, cytopenias, elevated LDH, coagulation disturbances) may be caused by either HLH or the underlying neoplasm 1. Hyperferritinemia must be differentiated from transfusion-related iron overload 1.

Underlying Trigger Identification

A meticulous search for underlying disease triggers (infections, malignancies, autoimmune disorders) must be continued despite ongoing HLH treatment 1, 3. This includes screening peripheral blood and bone marrow for blasts, chest X-ray, abdominal ultrasound/CT, and biopsy of suspicious lymph nodes 1.