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 diagnostic criteria according to the HLH-2004 guidelines. 1, 2
Primary Diagnostic Criteria (HLH-2004)
The diagnosis of HLH can be established if either criterion 1 or criterion 2 is fulfilled:
Molecular diagnosis consistent with HLH 1, 2
- Genetic testing showing mutations in HLH-associated genes (e.g., PRF1, UNC13D, STX11, STXBP2)
Fulfillment of 5 of the 8 criteria below 1, 2
- Fever 1
- Splenomegaly 1
- Cytopenias affecting ≥2 of 3 lineages in peripheral blood: 1
- 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: 1
- Fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL)
- Fibrinogen ≤1.5 g/L
- Hemophagocytosis in bone marrow, spleen, or lymph nodes without evidence of malignancy 1
- Low or absent NK cell activity (according to local laboratory reference) 1
- Ferritin ≥500 μg/L 1
- Soluble IL-2 receptor (sCD25) ≥2400 U/mL 1
Alternative Diagnostic Tool: HScore
The HScore is an alternative scoring system developed specifically for adults with suspected secondary HLH: 1, 2
| Parameter | Points |
|---|---|
| Known underlying immunosuppression | 0 (no) or 18 (yes) |
| Temperature (°C) | 0 (<38.4), 33 (38.4-39.4), or 49 (>39.4) |
| Organomegaly | 0 (no), 23 (hepatomegaly or splenomegaly), or 38 (both) |
| Cytopenias | 0 (1 lineage), 24 (2 lineages), or 34 (3 lineages) |
| Ferritin (μg/L) | 0 (<2000), 35 (2000-6000), or 50 (>6000) |
| Triglyceride (mmol/L) | 0 (<1.5), 44 (1.5-4), or 64 (>4) |
| Fibrinogen (g/L) | 0 (>2.5) or 30 (≤2.5) |
| AST (U/L) | 0 (<30) or 19 (≥30) |
| Hemophagocytosis on bone marrow aspirate | 0 (no) or 35 (yes) |
- An HScore ≥169 has been validated as suitable to diagnose secondary HLH 3
Important Clinical Considerations
Hyperferritinemia is a key diagnostic marker: 1
Soluble IL-2 receptor (sCD25) has excellent diagnostic accuracy for adult HLH with an area under the curve of 0.90 compared to 0.78 for ferritin 1
Hemophagocytosis may not be present initially: 1
- If initial bone marrow examination is negative, search in other organs or perform serial marrow aspirates
- Hemophagocytosis alone is neither sensitive nor specific for HLH 1
Modified diagnostic approaches: 3, 4
- Recent multicenter validation studies suggest 4 fulfilled HLH-2004 criteria may be sufficient for diagnosis
- In settings where NK cell activity and sCD25 testing are unavailable, adapted HLH-2004 criteria with a cutoff of 4 out of 6 available criteria may be used
Supportive Diagnostic Findings
Additional findings that support the diagnosis include: 1, 2
- Spinal fluid pleocytosis and/or elevated spinal fluid protein
- Liver histology resembling chronic persistent hepatitis
- Cerebromeningeal symptoms
- Lymph node enlargement
- Jaundice, edema, skin rash
- Hepatic enzyme abnormalities
- Hypoproteinemia, hyponatremia
- Elevated VLDL/low HDL
Diagnostic Pitfalls and Caveats
Do not delay treatment if HLH is strongly suspected, even if all criteria are not yet fulfilled 1
HLH-2004 criteria limitations: 5
- Originally developed for pediatric cases
- Not formally validated in adults
- Some common laboratory findings in HLH (hypoalbuminemia, elevated liver enzymes) are not represented
Differential diagnosis challenges: 5, 6
- HLH can mimic systemic inflammatory response syndrome, viral infections, or malignancies
- Careful evaluation for underlying triggers is essential, including infections, malignancies, and autoimmune disorders
Etiology search: Continue searching for underlying triggers (especially malignancies) despite ongoing HLH treatment 1