Diagnosis and Treatment of Hemophagocytic Lymphohistiocytosis (HLH)
Early recognition and prompt treatment of HLH with a combination of corticosteroids, immunosuppressants, and targeted therapy against underlying triggers is essential to prevent irreversible organ damage and death. 1
Diagnostic Criteria
HLH is diagnosed using the HLH-2004 criteria, which requires either:
- Molecular diagnosis consistent with HLH (genetic testing) OR
- Fulfillment of 5 of the 8 following criteria 2:
- Fever (≥38.5°C) 2
- Splenomegaly 2
- Cytopenias affecting ≥2 cell lines:
- Hemoglobin <9 g/dL
- Platelets <100,000/μL
- Neutrophils <1,000/μL 2
- Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL) 2
- Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver 2
- Low or absent NK cell activity 2
- Ferritin ≥500 ng/mL (often much higher) 2
- Elevated soluble CD25 (≥2400 U/mL) 2
Important Diagnostic Considerations
- Hemophagocytosis alone is neither sensitive nor specific for HLH and may be present in other conditions like sepsis 2
- HLH can present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome 1
- Meticulous search for underlying triggers, including occult malignancies, is essential 1
Classification of HLH
HLH is classified into two main types:
Primary (genetic) HLH:
Secondary (acquired) HLH:
Treatment Approach
General Principles
- Treat the underlying cause while simultaneously initiating HLH-directed therapy 4
- First-line treatment: High-dose corticosteroids (methylprednisolone 1g/day for 3-5 consecutive days) 4
- Second-line treatment: Based on clinical response and HLH subtype 4
Treatment by HLH Subtype
Primary HLH
- Etoposide-based protocols (HLH-94 or HLH-2004) 3, 5
- Hematopoietic stem cell transplantation (HSCT) is essential for cure 3
Malignancy-Associated HLH
- Combined approach with HLH-directed and malignancy-directed therapy 1
- Etoposide-containing regimens show better survival compared to treatment directed only at underlying pathology 1
- Consider stem cell transplantation as consolidation 1
- T-cell lymphoma-associated HLH has worse prognosis than B-cell lymphoma-associated HLH 1, 2
MAS-HLH (Autoimmune/Autoinflammatory)
- High-dose pulse methylprednisolone (1 g/day for 3-5 consecutive days) 1
- Add cyclosporine A (2-7 mg/kg/day) for insufficient response 1
- IL-1 blocking therapy with anakinra (2-10 mg/kg/day SC in divided doses) 1, 4
- Anti-IL-6 blockade with tocilizumab may be considered 1
HLH During Chemotherapy
- Postpone subsequent chemotherapy blocks or interrupt maintenance therapy 1
- Rigorously treat infectious triggers 1
- Anti-infectious prophylaxis (anti-fungal, pneumocystis jiroveci) 1
- Regular surveillance for secondary infections or reactivations (aspergillus, EBV, CMV) 1
Emerging Therapies
- Ruxolitinib (JAK1/2 inhibitor) 1, 4
- Emapalumab (anti-IFN-γ monoclonal antibody) 1, 4
- Alemtuzumab (anti-CD52) 1, 4
Prognosis and Monitoring
- Frequent clinical reassessment (at least every 12 hours) and monitoring of inflammatory parameters and organ function 4
- Malignancy-associated HLH has poor prognosis:
- Factors associated with higher mortality:
Common Pitfalls to Avoid
- Delayed diagnosis and treatment significantly increases mortality 4
- Direct application of pediatric protocols without adjustments for adults 1
- Inadequate treatment of underlying triggers 4
- Overreliance on hemophagocytosis as a diagnostic criterion 2
- Failure to consider HLH in patients presenting with sepsis-like syndrome 1