What are the key findings to diagnose Hemophagocytic Lymphohistiocytosis (HLH)?

How to Recognize Hemophagocytic Lymphohistiocytosis (HLH)

Diagnose HLH using the HLH-2004 criteria: you need 5 out of 8 specific parameters, or a molecular diagnosis consistent with HLH, combined with clinical judgment about whether the combination, extent, and progression of findings are unusual and otherwise unexplained. 1

The 8 HLH-2004 Diagnostic Parameters

You must identify 5 of the following 8 criteria to diagnose HLH: 1

• Fever (persistent, often >39.4°C) 1, 2
• Splenomegaly (hepatomegaly may also be present) 1, 2
• Cytopenias affecting ≥2 of 3 lineages:
  • Hemoglobin <90 g/L (or <100 g/L in infants <4 weeks) 1
  • Platelets <100 × 10⁹/L 1
  • Neutrophils <1.0 × 10⁹/L 1
• Hypertriglyceridemia and/or hypofibrinogenemia:
  • Fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL) 1
  • Fibrinogen ≤1.5 g/L 1
• 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 CD25 (soluble IL-2 receptor) ≥2400 U/mL 1

Key Clinical Recognition Points

The Ferritin Red Flag

Hyperferritinemia should always prompt inclusion of HLH in your differential diagnosis. 1 Ferritin levels characteristic of HLH in adults are often 7,000-10,000 μg/L, and rarely may exceed 100,000 μg/L. 1 While ferritin >10,000 μg/L is >90% sensitive and specific for HLH in children, it is less specific in adults, requiring integration of other clinical features. 1

Critical Clinical Judgment Required

You must judge whether the combination, extent, and progression of clinical and laboratory abnormalities are unusual, unexpected, and otherwise unexplained. 1 This is particularly crucial in the context of malignancy, where many HLH features (fever, organomegaly, cytopenias, elevated LDH, coagulation disturbances) may overlap with the underlying neoplasm. 1

Hemophagocytosis Is NOT Required

Despite the name, hemophagocytosis is neither sensitive nor specific for HLH and may be present in septicemia and other conditions related to malignancies. 1 If not initially present, serial bone marrow aspirates over time or examination of other organs (liver, lymph nodes) may reveal it. 1

Additional Supportive Findings

Beyond the 8 core criteria, look for: 1

• CNS involvement: CSF pleocytosis (mononuclear cells), elevated CSF protein, neurological symptoms (headaches, trouble walking, vision disturbances, weakness) 1, 2
• Hepatic findings: Liver biopsy resembling chronic persistent hepatitis, elevated liver enzymes 1
• Other features: Lymphadenopathy, jaundice, edema, skin rash, hypoproteinemia, hyponatremia, elevated VLDL/low HDL 1, 2

The HScore Alternative

The HScore is a validated diagnostic tool (area under the curve 0.90) that uses weighted features to predict HLH likelihood. 1 It incorporates temperature, organomegaly, number of cytopenias, ferritin levels, triglycerides, fibrinogen, AST, hemophagocytosis, and immunosuppression status with specific point values. 1

Age-Related Malignancy Risk

The likelihood of underlying malignancy increases dramatically with age: 1

• 68% in patients >60 years (usually lymphoma) 1
• 38% in ages 30-59 years 1
• 10% in ages 15-29 years 1
• 0% under age 14 years 1

In any patient with HLH, malignancy should be considered as a possible underlying disease. 1

Common Pitfall: HLH Mimics Sepsis

HLH can present identically to sepsis or multiple organ dysfunction syndrome, making differentiation extremely challenging in critically ill patients. 2 A high index of suspicion is essential when patients have persistent fever, worsening cytopenias, and progressive organ dysfunction despite appropriate antimicrobial therapy. 2

Diagnostic Workup When HLH Is Suspected

Obtain the following tests immediately: 1, 2

• Complete blood count with differential 2
• Ferritin 1, 2
• Triglycerides (fasting preferred) 1, 2
• Fibrinogen 1, 2
• Soluble CD25 (soluble IL-2 receptor) 1, 2
• Liver enzymes 2
• Coagulation studies 2
• Bone marrow aspirate and biopsy 1
• NK cell activity testing 1

When to Initiate Treatment Before Full Criteria Met

On occasion, HLH-directed therapy may be initiated even though 5 criteria are not fulfilled, if clinical suspicion is high and the patient is deteriorating. 1 This is particularly relevant when dealing with a known HLH trigger (like Ehrlichia infection) and progressive hyperinflammation despite treating the underlying cause. 3

Soluble CD25 as a Diagnostic Tool

Soluble CD25 (soluble IL-2 receptor) has been reported as a good to excellent low-cost diagnostic test for adult HLH with superior performance (area under the curve 0.90) compared to ferritin alone (area under the curve 0.78). 1