Is elevated soluble Interleukin 2 (IL2)/CD25 specific for Hemophagocytic Lymphohistiocytosis (HLH)?

Specificity of Elevated Soluble IL2/CD25 for HLH

Elevated soluble IL-2 receptor (sCD25) is a good diagnostic marker for HLH but is not specific to this condition alone, as it can be elevated in various inflammatory and malignant conditions. 1

Diagnostic Value of sCD25 in HLH

Soluble IL-2 receptor (sCD25) is one of the eight diagnostic criteria in the HLH-2004 guidelines, with levels ≥ 2400 U/mL supporting the diagnosis of HLH. Recent evidence suggests that sCD25 is a valuable diagnostic test for adult HLH with:

• Area under the curve of 0.90 (95% CI, 0.83-0.97) 1
• Superior diagnostic performance compared to ferritin, which has an area under the curve of 0.78 (95% CI, 0.67-0.88) 1

Limitations of sCD25 as a Specific Marker for HLH

Despite its diagnostic value, sCD25 is not specific to HLH alone:

• sCD25 can be elevated in other conditions characterized by T-cell activation and inflammation 2
• Elevated levels may be seen in:
  • Malignancies (particularly lymphomas and leukemias)
  • Severe infections
  • Autoimmune disorders
  • Post-transplant states
  • Other inflammatory conditions 3

Role in HLH Pathophysiology

The elevation of sCD25 in HLH has pathophysiological significance:

• It reflects excessive CD8+ T-cell activation, a hallmark of HLH 3
• Secretion of soluble CD25 by activated CD8+ T-cells can compete with regulatory T-cells for IL-2, contributing to immune dysregulation 3
• This competition for IL-2 may create a feed-forward inflammatory loop that perpetuates HLH 3

Clinical Application of sCD25 Testing

When interpreting sCD25 levels:

1. Consider sCD25 as part of the complete HLH-2004 diagnostic criteria (requiring 5 of 8 criteria) 1, 2
2. Remember that a single elevated marker is insufficient for diagnosis
3. Integrate with other clinical and laboratory findings:
   • Fever
   • Splenomegaly
   • Cytopenias
   • Hypertriglyceridemia and/or hypofibrinogenemia
   • Hemophagocytosis in bone marrow/spleen/lymph nodes
   • Low/absent NK cell activity
   • Ferritin ≥ 500 mg/L 1

Comparison with Other HLH Markers

While sCD25 is valuable, it should be compared with other markers:

• Ferritin: While levels >10,000 μg/L are >90% sensitive and specific for HLH in children, hyperferritinemia is less specific in adults 1, 4
• A retrospective analysis found marked hyperferritinemia (>50,000 μg/L) in adults with various conditions including renal failure, hepatocellular injury, infections, and hematologic malignancies 4

Clinical Pearls and Pitfalls

• Don't rely solely on sCD25 for HLH diagnosis; consider the complete clinical picture
• sCD25 may be mildly elevated in some conditions but markedly elevated in HLH
• Serial measurements of sCD25 may help monitor disease activity and response to treatment 5
• Consider testing sCD25 when other features of HLH are present, even if the full diagnostic criteria are not yet met 1
• In transplant recipients, elevated sCD25 should raise suspicion for HLH, especially in the context of infections 6

In summary, while elevated sCD25 is a valuable diagnostic marker for HLH with good sensitivity, it lacks specificity as a standalone test and must be interpreted within the complete clinical and laboratory context of the patient.