What are the HLH‑2004 diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH)?

HLH-2004 Diagnostic Criteria

The diagnosis of hemophagocytic lymphohistiocytosis requires either molecular confirmation of HLH-associated genetic mutations OR fulfillment of 5 out of 8 clinical and laboratory criteria. 1, 2

The 8 HLH-2004 Criteria (5 of 8 Required)

1. Fever – Persistent high temperature 1, 2

2. Splenomegaly – Enlarged spleen on physical examination or imaging 1, 2

3. Cytopenias (≥2 of 3 lineages) 1, 2

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

4. Hypertriglyceridemia and/or Hypofibrinogenemia 1, 2

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

5. Hemophagocytosis – Evidence in bone marrow, spleen, or lymph nodes without malignancy 1, 2

6. Low or absent NK-cell activity – According to local laboratory reference 1, 2

7. Ferritin ≥ 500 µg/L 1, 2

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

Critical Diagnostic Considerations

Start Treatment on Strong Clinical Suspicion

Do not delay HLH-directed therapy while waiting to fulfill all 5 criteria if clinical suspicion is high, as untreated HLH carries extremely high mortality. 2, 3 Treatment may be initiated with fewer than 5 criteria when the overall clinical picture is compelling. 2

Most Valuable Diagnostic Markers in Adults

• Soluble CD25 (sCD25) is superior to ferritin for adult HLH diagnosis, with an area under the ROC curve of 0.90 (95% CI 0.83–0.97) versus ferritin's 0.78 (95% CI 0.67–0.88). 1, 4 This marker should be obtained in all patients with suspected HLH. 2, 4

• Ferritin levels in adult HLH typically range 7,000–10,000 µg/L and can exceed 100,000 µg/L, far higher than the diagnostic threshold of 500 µg/L. 2 Rapidly rising ferritin indicates active disease. 3

• Fever (98.96%), elevated ferritin (94.27%), elevated sCD25 (94.79%), and low/absent NK-cell activity (94.27%) are the most sensitive criteria, while hemophagocytosis (74.48%), hypofibrinogenemia (50.52%), and hypertriglyceridemia (37.50%) are less consistently present. 5

Hemophagocytosis Is Neither Sensitive Nor Specific

Absence of hemophagocytosis on initial bone marrow aspirate does NOT exclude HLH. 1, 3 Serial marrow aspirates or examination of other tissues (spleen, lymph nodes, liver) should be pursued if suspicion persists, as hemophagocytosis often appears later in the disease course. 1, 2

Alternative Scoring System: HScore (for Adults)

In critically ill adults, an HScore ≥ 168 provides 100% sensitivity and 94.1% specificity, slightly outperforming the HLH-2004 criteria. 6 The HScore incorporates 9 weighted parameters: 1

• Known underlying immunosuppression (HIV or long-term immunosuppressive therapy)
• Temperature (< 38.4°C, 38.4–39.4°C, or > 39.4°C)
• Organomegaly (none, hepatomegaly or splenomegaly, or both)
• Number of cytopenias (1,2, or 3 lineages; defined as Hgb ≤ 9.2 g/dL, WBC ≤ 5 × 10⁹/L, or PLT ≤ 110 × 10⁹/L)
• Ferritin (< 2000–6000, or > 6000 µg/L)
• Triglycerides (< 1.5,1.5–4, or > 4 mmol/L)
• Fibrinogen (> 2.5 or ≤ 2.5 g/L)
• AST (< 30 or ≥ 30 U/L)
• Hemophagocytosis on bone marrow aspirate (yes/no)

Validation Limitations and Clinical Judgment

The HLH-2004 criteria were developed for pediatric patients and have never been formally validated in adults, yet they remain the standard diagnostic framework. 1, 2, 7 Various adult case series have used modified criteria. 1 Clinical judgment is essential when applying these criteria to adults, particularly in critically ill patients where HLH can mimic sepsis or multiple organ dysfunction syndrome. 3, 8

For critically ill adults, consider lowering the diagnostic threshold to 4 fulfilled HLH-2004 criteria (95.0% sensitivity, 93.6% specificity), or adjust cutoffs to ferritin ≥ 3000 µg/L and fever ≥ 38.2°C (97.5% sensitivity, 96.1% specificity). 6

Supportive Findings (Not Part of Formal Criteria)

Additional findings that strengthen the diagnosis include: 1, 3

• Spinal fluid pleocytosis or elevated CSF protein
• Liver histology resembling chronic persistent hepatitis
• Cerebromeningeal symptoms, lymphadenopathy, jaundice, edema, skin rash
• Hepatic enzyme abnormalities (present in 94.27% of cases) 5
• Hypoproteinemia, hyponatremia
• Elevated VLDL/low HDL
• Coagulopathy (present in 75.52% of cases) 5

Mandatory Trigger Identification

In adults, nearly half of HLH cases are triggered by malignancy, with the proportion rising to 68% in patients > 60 years (35% T-cell/NK-cell lymphomas, 32% B-cell lymphomas). 2 In younger adults (30–59 years), malignancy accounts for 38% of cases. 3 Infection (especially EBV and CMV) is the second most common trigger. 2, 5

Mandatory screening includes: 3

• Peripheral blood and bone marrow evaluation for blasts
• Chest X-ray
• CT or ultrasound of abdomen and enlarged lymph nodes
• Biopsy of suspicious lymph nodes or cutaneous lesions