Hemophagocytic Lymphohistiocytosis (HLH)
HLH is a severe, potentially life-threatening hyperinflammatory syndrome characterized by excessive and uncontrolled activation of macrophages and cytotoxic T lymphocytes that can rapidly progress to multi-organ failure if not promptly diagnosed and treated. 1
Classification
- Primary (genetic) HLH:
- More common in children
- Caused by mutations affecting lymphocyte cytotoxicity and immune regulation 1
- Secondary (acquired) HLH:
- Predominant in adults
- Triggered by infections, malignancies, autoimmune disorders, or complications of therapies such as CAR-T 1
Diagnostic Criteria (HLH-2004)
Requires molecular diagnosis compatible with HLH OR at least 5 of 8 criteria:
- Fever
- Splenomegaly
- Cytopenias (affecting ≥2 cell lines)
- Hypertriglyceridemia and/or hypofibrinogenemia
- Hemophagocytosis in bone marrow, spleen, or lymph nodes
- Low or absent NK cell activity
- Ferritin ≥500 ng/mL (levels >10,000 μg/L are highly specific in children)
- Elevated soluble CD25 (sCD25 ≥2400 U/mL) 1
Key Laboratory Markers
- Ferritin: Often markedly elevated, though less specific in adults than children 1
- Soluble IL-2 receptor (sCD25): Superior diagnostic performance compared to ferritin (AUC 0.90 vs 0.78) 1
Clinical Course and Prognosis
Without early treatment, HLH is rapidly fatal, with >10% of patients dying within two months of diagnosis. Complications include:
- Visceral organ hemorrhage
- Opportunistic infections due to neutropenia
- Multi-organ failure 1
Treatment Approach
Treatment must be initiated rapidly and includes:
- Treating the underlying trigger
- Controlling hyperinflammation using HLH-94 or HLH-2004 protocols
- Providing supportive care 1
Delay in treatment beyond 6 days is associated with significantly worse outcomes, including higher in-hospital mortality (OR 2.00), circulatory shock, mechanical ventilation requirements, and organ failure 2.