What is Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome characterized by excessive immune activation of cytotoxic T cells, natural killer cells, and macrophages, resulting in fever, hepatosplenomegaly, cytopenias, and a distinctive pattern of laboratory abnormalities. 1

Classification and Etiology

HLH presents in two main forms:

1. Primary (Hereditary) HLH:

   • Genetic disorders including familial HLH 2-5, Griscelli syndrome type II, and X-linked lymphoproliferative syndromes
   • Predominantly occurs in children
   • Often triggered by infections

2. Secondary (Acquired) HLH:

   • Triggered by various conditions:
     • Infections (particularly viral infections like EBV, CMV)
     • Malignancies (can be malignancy-triggered or occur during chemotherapy)
     • Autoimmune/autoinflammatory disorders
     • Post-transplantation

Clinical Manifestations

Key clinical features include:

• Fever (persistent, high-grade)
• Hepatosplenomegaly
• Cytopenias (affecting 2 or more cell lines)
• Neurological symptoms (in some cases)

Laboratory Findings

Characteristic laboratory abnormalities:

• Elevated ferritin (often markedly high >10,000 ng/mL)
• Hypertriglyceridemia
• Hypofibrinogenemia
• Elevated soluble CD25 (IL-2 receptor)
• Elevated liver enzymes (transaminases, LDH)
• Elevated D-dimers
• Decreased albumin and sodium
• Hemophagocytosis in bone marrow, spleen, or lymph nodes (though not required for diagnosis)

Pathophysiology

HLH results from dysregulated immune activation with:

• Excessive activation of cytotoxic T cells and NK cells
• Impaired cytotoxic function leading to persistent immune stimulation
• Hypercytokinemia ("cytokine storm")
• Macrophage activation and hemophagocytosis
• Tissue infiltration by activated lymphocytes and macrophages 1, 2

Diagnosis

Diagnosis is challenging due to:

• Rarity of the condition
• Variable presentation
• Overlap with features of triggering conditions (especially malignancies)
• Time required for diagnostic testing 1, 3

The HLH-2004 diagnostic criteria are commonly used, requiring either:

1. Molecular diagnosis consistent with HLH, or
2. At least 5 of 8 clinical and laboratory 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
   • Elevated soluble CD25 (IL-2 receptor)

Special Considerations

Malignancy-Associated HLH

Two distinct scenarios:

1. Malignancy-Triggered HLH: Occurs at onset or relapse of malignancy
2. HLH During Chemotherapy: Occurs during treatment, often with infectious triggers 1

CAR T Cell Therapy-Related HLH

Can occur as a complication of CAR T cell therapy, requiring specific management approaches 1

Treatment

Treatment must be initiated promptly and includes:

1. Treating the underlying trigger:

   • Antimicrobials for infections
   • Chemotherapy for malignancies
   • Immunosuppression for autoimmune triggers

2. Controlling hyperinflammation:

   • HLH-specific protocols (HLH-94 or HLH-2004) including:
     • Etoposide
     • Dexamethasone
     • Cyclosporine A (in some cases)

3. Supportive care:

   • Management of cytopenias
   • Treatment of infections
   • Neurological support if CNS involvement

Prognosis

Without prompt treatment, HLH is frequently fatal due to:

• Multi-organ failure
• Severe infections
• Bleeding complications
• Neurological deterioration

Early recognition and aggressive treatment are essential for survival. Mortality remains high, particularly in secondary HLH in adults with malignancy triggers.

Key Challenges

• Delayed diagnosis due to nonspecific initial presentation
• Distinguishing HLH features from those of underlying conditions
• Balancing immunosuppressive therapy with treatment of triggers
• Managing treatment-related complications

Expert consultation is strongly recommended for suspected cases to guide diagnostic workup and treatment decisions 2.