What is Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome characterized by dysregulated hyperinflammation of the immune system that leads to uncontrolled activation of cytotoxic T lymphocytes, natural killer cells, and macrophages, resulting in a cytokine storm that can cause multi-organ damage and death if not promptly diagnosed and treated. 1, 2

Types and Pathophysiology

HLH presents in two main forms:

1. Primary (Familial) HLH:

   • Caused by genetic mutations affecting T-cell and NK-cell function
   • Typically presents in early childhood
   • Requires hematopoietic stem cell transplantation for definitive treatment

2. Secondary (Acquired) HLH:

   • Triggered by:
     • Infections (particularly EBV)
     • Malignancies (especially lymphomas)
     • Autoimmune/inflammatory disorders (called macrophage activation syndrome or MAS in this context)
     • Immunosuppression
     • Therapies like CAR T-cell therapy 3, 1

The core pathophysiology involves impaired cytotoxic function leading to persistent immune activation and excessive cytokine production, creating a destructive inflammatory cascade 2, 4.

Diagnostic Criteria

HLH diagnosis is based on the HLH-2004 protocol criteria, requiring either:

1. Molecular diagnosis consistent with HLH, or
2. At least 5 of these 8 criteria 1, 2:

Criteria	Description
1	Fever
2	Splenomegaly
3	Cytopenias (affecting ≥2 cell lines)
4	Hypertriglyceridemia and/or hypofibrinogenemia
5	Hemophagocytosis in bone marrow, spleen, or lymph nodes
6	Low or absent NK cell activity
7	Ferritin ≥500 ng/mL (often much higher)
8	Elevated soluble CD25 (IL-2 receptor)

Clinical Presentation

HLH often presents as a sepsis-like syndrome with:

• Persistent high fever
• Hepatosplenomegaly
• Multi-organ dysfunction:
  • Liver dysfunction (elevated transaminases)
  • Renal impairment
  • Respiratory failure (pulmonary edema, ARDS)
  • Neurological manifestations
  • Coagulopathy
  • Severe cytopenias 1, 2, 4

Treatment Approach

Treatment must be initiated rapidly and consists of three key components:

1. Treat the underlying trigger:

   • Aggressive antimicrobial therapy for infections
   • Chemotherapy for malignancy-associated HLH
   • Interruption of immunosuppressive therapy in iatrogenic cases 3, 1

2. Control hyperinflammation:

   • HLH-specific protocols (HLH-94 or HLH-2004) using:
     • Etoposide
     • Dexamethasone
     • Cyclosporine A
   • For MAS: glucocorticoids, IL-1 blockade, cyclosporine A 1, 4

3. Supportive care:

   • Management of cytopenias
   • Treatment of infections
   • Neurological support
   • Respiratory support as needed 1

Prognosis and Monitoring

Without early treatment, HLH can be rapidly fatal, with >10% of patients dying within two months of diagnosis 1. Prognosis varies by subtype:

• Malignancy-triggered HLH has poorer outcomes (especially T-cell lymphoma-associated)
• 30-day survival: 56-70%
• Median overall survival: 36-230 days
• 3-year survival: 18-55% depending on subtype 3

Important Clinical Considerations

• Diagnostic challenges: HLH can be difficult to diagnose due to diverse clinical manifestations and overlap with sepsis and other critical illnesses 2, 4
• Adult vs. pediatric presentation: While diagnostic criteria were developed for pediatric patients, they are still used in adults despite not being formally validated 2
• CAR T-cell therapy: HLH occurs in approximately 3.5% of patients receiving CAR T-cell therapy and may overlap with cytokine release syndrome 3, 1
• Malignancy screening: Aggressive search for underlying malignancies is essential, as occult malignancies (particularly lymphomas) can trigger HLH 5
• Infection surveillance: Regular monitoring for secondary infections or reactivations (aspergillus, EBV, CMV) is strongly recommended 3

Early recognition and aggressive treatment are crucial for improving outcomes in this potentially fatal syndrome.