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

HLH Diagnostic Criteria

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 protocol, though treatment may be initiated with strong clinical suspicion even if fewer than 5 criteria are met. 1

The 8 HLH-2004 Diagnostic Criteria

The following criteria form the foundation of HLH diagnosis, requiring 5 of 8 to be fulfilled 1, 2:

1. Fever 1

2. Splenomegaly 1

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

   • 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:

   • 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

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

7. Ferritin ≥500 μg/L 1, 2

8. Soluble CD25 (sCD25/soluble IL-2 receptor) ≥2400 U/mL 1, 3

Critical Diagnostic Considerations

Ferritin as a Screening Tool

• Hyperferritinemia should always prompt inclusion of HLH in the differential diagnosis 1
• Ferritin levels of 7,000-10,000 μg/L are characteristic of HLH in adults, and values may rarely exceed 100,000 μg/L 1, 2
• Ferritin ≥500 μg/L has 94.0% sensitivity as a screening marker and should trigger further HLH evaluation 4
• However, hyperferritinemia is less specific in adults than children, requiring integration of other clinical features 1

Soluble CD25 Performance

• sCD25 is superior to ferritin for diagnosing adult HLH, with an area under the curve of 0.90 (95% CI 0.83-0.97) compared to ferritin's 0.78 (95% CI 0.67-0.88) 1, 2, 3
• sCD25 should be obtained in all patients with suspected HLH 3

Hemophagocytosis Findings

• Absence of hemophagocytosis on initial bone marrow aspirate does NOT exclude HLH 2, 3
• If not found initially, pursue serial marrow aspirates over time or examine other organs (spleen, lymph nodes, liver) 1, 2
• Hemophagocytosis often appears late in the disease course 5

Alternative Diagnostic Approach: HScore

For adults with suspected secondary HLH, the HScore provides an alternative validated scoring system with a cut-off of 169 points 2, 4. The HScore includes 1, 2:

• Known underlying immunosuppression (HIV or long-term immunosuppressive therapy)
• Temperature
• Organomegaly (hepatomegaly and/or splenomegaly)
• Number of cytopenias (1,2, or 3 lineages)
• Ferritin level
• Triglyceride level
• Fibrinogen level
• AST level
• Hemophagocytosis on bone marrow aspirate

The HScore demonstrated mean sensitivity of 82.4% and specificity of 87.6% across multiple validation cohorts 4.

Modified Diagnostic Thresholds

Recent multicenter validation suggests 4 fulfilled HLH-2004 criteria (rather than 5) may be sufficient for diagnosis, with mean sensitivity of 86.5% and specificity of 86.1% 4. This lower threshold allows for earlier diagnosis and treatment initiation.

Supportive Diagnostic Findings

Additional findings that strengthen the diagnosis include 1, 2:

• CNS involvement: Spinal fluid pleocytosis (mononuclear cells) and/or elevated CSF protein
• Hepatic findings: Liver biopsy showing chronic persistent hepatitis pattern
• Other laboratory abnormalities: Elevated AST, LDH, D-dimer; low albumin, sodium; elevated VLDL with low HDL
• Clinical features: Cerebromeningeal symptoms, lymphadenopathy, jaundice, edema, skin rash

Critical Pitfalls to Avoid

Do Not Delay Treatment

HLH-directed therapy may be initiated based on strong clinical suspicion even when fewer than 5 criteria are fulfilled 1, 2, 3. The high mortality of untreated HLH justifies empiric treatment in compelling cases.

Recognize HLH Mimics

HLH frequently mimics sepsis, septic shock, or multiple-organ-dysfunction syndrome 2, 3, 6. Maintain high suspicion in critically ill patients with:

• Unexplained hyperinflammation
• Persistent fever despite antibiotics
• Progressive cytopenias
• Hepatosplenomegaly with coagulopathy

Search for Underlying Triggers

A meticulous search for underlying disease must continue despite ongoing HLH treatment 1, 3. In adults, triggers include:

• Infections (most common): EBV, CMV, other viruses
• Malignancies (prevalence increases with age, reaching ~68% in adults >60 years): T-cell/NK-cell lymphomas (35%), B-cell lymphomas (32%), leukemias, Hodgkin lymphoma
• Autoimmune/autoinflammatory disorders: Systemic lupus erythematosus, systemic juvenile idiopathic arthritis

Validation Limitations

The HLH-2004 criteria were developed for pediatric patients and have not been formally validated in adults, though they remain the standard diagnostic framework requiring clinical judgment 1, 2, 3, 7.