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 clinical and laboratory criteria from the HLH-2004 diagnostic guidelines, though clinical judgment should guide the decision to initiate treatment even before all criteria are met. 1, 2

The HLH-2004 Diagnostic Criteria

The diagnosis is established if 5 of the following 8 criteria are present: 1, 2, 3

• Fever (prolonged, often >39.4°C) 1, 3
• Splenomegaly 1, 2, 3
• Cytopenias affecting ≥2 of 3 lineages in peripheral blood: 1, 2, 3
  • Hemoglobin <90 g/L (or <100 g/L in infants <4 weeks)
  • Platelets <100 × 10⁹/L
  • Neutrophils <1.0 × 10⁹/L
• Hypertriglyceridemia and/or hypofibrinogenemia: 1, 2, 3
  • Fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL)
  • Fibrinogen ≤1.5 g/L
• Hemophagocytosis in bone marrow, spleen, or lymph nodes (with no evidence of malignancy) 1, 2
• Low or absent NK cell activity (according to local laboratory reference) 1, 2, 3
• Ferritin ≥500 μg/L 1, 2, 3
• Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL 1, 2, 3

Alternative Diagnostic Pathway

A molecular diagnosis consistent with HLH (genetic testing showing mutations in HLH-associated genes) can establish the diagnosis without requiring the clinical criteria. 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 >10,000 μg/L is >90% sensitive and specific for HLH in children, though less specific in adults. 1
• Hyperferritinemia should always prompt inclusion of HLH in the differential diagnosis. 1

Soluble IL-2 Receptor (sCD25)

• sCD25 has superior diagnostic performance in adults with an area under the curve of 0.90, compared to 0.78 for ferritin. 2

Hemophagocytosis Limitations

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

Alternative Scoring System: HScore

The HScore is an alternative diagnostic tool developed specifically for adults with suspected secondary HLH, incorporating: 2

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

Supportive Diagnostic Findings

Additional findings that strengthen the diagnosis include: 1, 2

• Spinal fluid pleocytosis (mononuclear cells) and/or elevated CSF protein
• Liver histology resembling chronic persistent hepatitis
• Cerebromeningeal symptoms
• Lymph node enlargement
• Jaundice
• Edema and skin rash
• Hepatic enzyme abnormalities
• Hypoproteinemia and hyponatremia
• Elevated VLDL/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, as the syndrome is rapidly progressive and potentially fatal. 1, 2

Diagnostic Challenges in Context

• In malignancy-associated HLH, several diagnostic features (fever, organomegaly, cytopenias, elevated LDH, coagulation disturbances) may be caused by either HLH or the underlying neoplasm. 1
• HLH can present identically to sepsis or multiple organ dysfunction syndrome, making differentiation extremely challenging in critically ill patients. 3, 4
• The key is assessing whether the combination, extent, and progression of clinical and laboratory abnormalities are unusual, unexpected, and otherwise unexplained. 1

Age-Related Considerations

The likelihood of malignancy-associated HLH increases with age: 68% of cases in adults >60 years are triggered by lymphoma, compared to 38% in ages 30-59,10% in ages 15-29, and 0% under age 14. 3

Ongoing Trigger Search

A meticulous search for underlying triggers (infections, malignancies, autoimmune disorders) must continue despite ongoing HLH treatment, as occult malignancies (particularly lymphomas) are a major cause in adults. 1, 2