What is Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome characterized by dysregulated immune activation of cytotoxic T cells, NK cells, and macrophages, leading to severe systemic inflammation, organ damage, and potentially death if not promptly recognized and treated. 1

Definition and Classification

• HLH represents a spectrum of hyperinflammatory disorders resulting in excessive immune activation with characteristic clinical and laboratory findings 1
• HLH is classified into two main types:
  • Primary (genetic/familial) HLH: Caused by genetic mutations affecting lymphocyte cytotoxicity and immune regulation, predominantly occurring in children 1, 2
  • Secondary (acquired) HLH: More common in adults, triggered by infections, malignancies, or autoimmune/autoinflammatory disorders 1
• When secondary HLH occurs in the context of autoimmune/inflammatory disorders, it is often referred to as macrophage activation syndrome (MAS-HLH) 1, 3

Pathophysiology

• Core pathogenic mechanism involves sustained, aberrant activation of cytotoxic CD8+ T cells and macrophages with resultant inflammatory cytokine storm 4
• Impaired function of natural killer (NK) cells and cytotoxic T-cells is characteristic of all forms of HLH 2
• In primary HLH, genetic defects affect perforin/granzyme-mediated cytotoxicity, crucial for both killing infected cells and terminating immune responses 2
• Secondary HLH can be triggered by:
  • Infections (particularly viruses like EBV and CMV) 1
  • Malignancies (especially lymphomas) 1
  • Autoimmune/autoinflammatory conditions 1
  • Immunotherapies (including CAR T-cell therapy) 1

Clinical Manifestations

• Cardinal clinical features include:
  • Persistent high fever (≥38°C) 1, 5
  • Hepatosplenomegaly 1, 5
  • Bi- or trilineage cytopenias 5
  • Neurological symptoms (common) 2
• Laboratory abnormalities include:
  • Elevated ferritin (often markedly high) 1, 5
  • Hypertriglyceridemia 1, 5
  • Hypofibrinogenemia 1, 5
  • Elevated liver enzymes 5
  • Elevated soluble CD25 (IL-2 receptor alpha chain) 1, 2
  • Decreased albumin and sodium levels 1
  • Elevated D-dimers and LDH 1

Diagnosis

• Diagnosis is challenging due to overlap with features of sepsis, malignancies, and multiple organ dysfunction syndrome 1
• The HLH-2004 diagnostic criteria (developed for children but commonly applied in adults) include 1:
  • Molecular diagnosis consistent with HLH OR
  • At least 5 of the following 8 criteria:
    1. Fever ≥38.5°C
    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 μg/L
    8. Elevated soluble CD25 (soluble IL-2 receptor)
• A high index of suspicion is necessary for early diagnosis 5, 6
• Comprehensive diagnostic workup should include evaluation for potential triggers (infections, malignancies, autoimmune conditions) 7

Management

• Treatment approach should be individualized based on HLH subtype, underlying cause, and clinical severity 3
• First-line treatment for most secondary HLH cases includes high-dose corticosteroids (methylprednisolone 1g/day for 3-5 consecutive days) and simultaneous treatment of the underlying cause 3
• For inadequate response to corticosteroids, second-line options include:
  • Cyclosporine A (2-7 mg/kg/day) 3
  • Anakinra (IL-1 blockade, 2-10 mg/kg/day subcutaneously) 3
• Specific management by HLH subtype:
  • MAS-HLH: High-dose corticosteroids first-line, with cyclosporine A, anakinra, or tocilizumab as second-line options 1, 3
  • Malignancy-associated HLH: Treatment directed at the underlying malignancy along with anti-HLH therapy 1, 3
  • Infection-triggered HLH: Rigorous treatment of the infectious trigger is essential 1
• For primary (genetic) HLH, more aggressive therapy with etoposide-based protocols (HLH-94 or HLH-2004) is typically required, followed by hematopoietic stem cell transplantation 2
• Supportive care is crucial, including:
  • Frequent clinical reassessment (at least every 12 hours) 1, 3
  • Monitoring of inflammatory parameters and organ function 3
  • Ventilation, vasopressors, renal replacement therapy, and transfusions as needed 3

Prognosis

• Mortality remains high, especially in adults with malignancy-associated HLH 1, 3
• Factors associated with higher mortality include:
  • Shock at ICU admission 3
  • Platelet count <30 g/L 3
  • HLH associated with T-cell lymphomas (worse prognosis than B-cell lymphoma-associated HLH) 1
• Early recognition and prompt treatment are essential to prevent irreversible organ damage and improve survival 1, 3

Emerging Therapies

• Novel therapies under investigation include:
  • Ruxolitinib (JAK1/2 inhibitor) 1, 3
  • Emapalumab (anti-IFN-γ monoclonal antibody) 1, 3
  • Alemtuzumab 1, 3