What are the symptoms and diagnostic criteria for Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic Lymphohistiocytosis: Symptoms and Diagnosis

HLH should be diagnosed using the HLH-2004 criteria, which requires either a molecular diagnosis consistent with HLH or fulfillment of 5 out of 8 specific clinical and laboratory parameters, though clinical judgment may warrant treatment initiation even when fewer than 5 criteria are met. 1

Cardinal Clinical Symptoms

The hallmark clinical presentations include:

• Prolonged high fever (often >39.4°C), which is one of the most consistent features 1, 2
• Hepatosplenomegaly (enlargement of liver and/or spleen), present in the majority of cases 1, 2
• Cytopenias affecting two or more cell lines (anemia, thrombocytopenia, neutropenia) 1, 2
• Central nervous system symptoms including altered mental status, seizures, or focal neurological deficits, which are common and may indicate CNS involvement 1, 2

Additional clinical features that provide supportive evidence include lymph node enlargement, jaundice, edema, skin rash, and cerebromeningeal symptoms 1.

Diagnostic Criteria (HLH-2004)

Diagnosis is established if EITHER criterion is fulfilled:

Criterion 1: Molecular diagnosis consistent with HLH

• Genetic mutations in PRF1, UNC13D, STX11, or other HLH-associated genes 1

Criterion 2: Five of the following 8 parameters

1. Fever (persistent, high-grade) 1

2. Splenomegaly (with or without hepatomegaly) 1

3. Cytopenias affecting ≥2 of 3 lineages:

   • Hemoglobin <90 g/L (<100 g/L in infants <4 weeks)
   • Platelets <100 × 10⁹/L
   • Neutrophils <1.0 × 10⁹/L 1

4. Hypertriglyceridemia and/or hypofibrinogenemia:

   • Fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL)
   • Fibrinogen ≤1.5 g/L 1

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

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

Critical Diagnostic Considerations

Hyperferritinemia is a key diagnostic clue: Ferritin levels of 7,000-10,000 μg/L are characteristic of HLH in adults, and levels >10,000 μg/L are >90% sensitive and specific in children, though less specific in adults. 1

Soluble CD25 (sCD25) is highly valuable: Recent data shows sCD25 has superior diagnostic performance compared to ferritin, with an area under the curve of 0.90 versus 0.78 for ferritin. 1

Hemophagocytosis is neither sensitive nor specific: Despite the name, hemophagocytosis may be absent initially and can occur in other conditions like septicemia. If not present initially, serial bone marrow aspirates or examination of other organs (liver, lymph nodes) may be helpful. 1, 3

Diagnostic Workup Algorithm

When HLH is suspected, the following systematic approach should be followed:

Laboratory evaluation:

• Complete blood count with differential 1
• Ferritin, triglycerides, fibrinogen 1
• Soluble CD25 (sCD25/soluble IL-2 receptor) 1
• Liver enzymes (AST, ALT), LDH 1
• Coagulation studies 1
• NK cell function testing 1

Bone marrow examination:

• Screen for hemophagocytosis and blasts 1
• Consider serial aspirates if initial examination is non-diagnostic 1

Imaging studies:

• Chest X-ray 1
• Ultrasound and/or CT of abdomen and enlarged lymph nodes 1
• Consider CT, MRI, or PET scan in patients with elevated likelihood of malignancy 1

CNS evaluation (if neurological symptoms present or elevated CSF protein/cell count):

• Cerebrospinal fluid analysis for protein, cell count, and hemophagocytosis 1
• Brain MRI 1

Trigger identification:

• Screen for infections (EBV, CMV, aspergillus) 1
• Evaluate for underlying malignancy, particularly lymphoma in adults 1
• Consider genetic testing in younger patients or those with family history 1

Age-Related Diagnostic Considerations

The likelihood of malignancy-associated HLH increases with age: In adults over 60 years, 68% of HLH cases are triggered by lymphoma, compared to 38% in ages 30-59,10% in ages 15-29, and 0% under age 14. 1 Therefore, more extensive malignancy workup (including biopsy of suspicious lymph nodes or cutaneous lesions) is warranted in older adults. 1

Common Diagnostic Pitfalls

In the context of malignancy or chemotherapy: Many HLH features (fever, organomegaly, cytopenias, elevated LDH, coagulation disturbances) overlap with manifestations of the neoplasm itself or treatment toxicity. The key is assessing whether the combination, extent, and progression of abnormalities are unusual, unexpected, and otherwise unexplained. 1

Ferritin elevation must be differentiated from transfusion-related iron overload in patients receiving multiple transfusions. 1

HLH can present identically to sepsis or multiple organ dysfunction syndrome, making differentiation challenging in critically ill patients. A high index of suspicion is essential. 3, 4