What is Hemophagocytic Lymphohistiocytosis (HLH)?

What is Hemophagocytic Lymphohistiocytosis (HLH)?

HLH is a life-threatening hyperinflammatory syndrome caused by uncontrolled activation of cytotoxic T cells and macrophages, resulting in a cytokine storm that leads to multi-organ failure and death without immunosuppressive treatment. 1

Core Disease Mechanism

HLH represents a final common pathway of immune dysregulation where the immune system fails to properly terminate its response to triggers, leading to sustained and excessive activation. 1 The pathophysiology centers on:

• Defective cytotoxic function: Either from genetic mutations (primary HLH) or acquired immune dysfunction (secondary HLH), both preventing normal termination of immune responses 1
• Uncontrolled T-cell activation: Aberrantly activated cytotoxic CD8+ T cells drive the inflammatory cascade 2
• Macrophage hyperactivation: Toxic activation of macrophages and other innate immune cells perpetuates tissue damage 3
• Cytokine storm: Massive release of inflammatory cytokines (particularly IFN-γ, IL-6, TNF-α) causes systemic inflammation and organ dysfunction 4

Classification: Two Distinct Origins, One Terminal Pathway

Primary (Genetic) HLH:

• Caused by hereditary defects in lymphocyte cytotoxicity genes (perforin, UNC13D, STX11, STXBP2) 5
• Most common in children, though can present in adolescents and young adults 1, 6
• Includes familial HLH types 2-5, Griscelli syndrome type 2, and X-linked lymphoproliferative syndromes 5

Secondary (Acquired) HLH:

• Far more common in adults, triggered by infections, malignancies, or autoimmune/autoinflammatory disorders 1, 5
• Represents acquired immune dysfunction in response to specific triggers 1
• Key triggers include:
  • Infections: EBV and CMV are most frequent viral triggers; invasive fungi and bacteria in immunosuppressed patients 5
  • Malignancies: T-cell and NK-cell lymphomas most common; also B-cell lymphomas and Hodgkin lymphoma 5
  • Autoimmune disorders: Systemic juvenile idiopathic arthritis, adult-onset Still's disease, systemic lupus erythematosus 6
  • Iatrogenic: CAR T-cell therapy (3.5% incidence) 6

Cardinal Clinical Features

HLH presents with a phenotype often indistinguishable from sepsis or multi-organ dysfunction syndrome, making early recognition challenging. 1 Look for:

• Persistent high fever: Nearly universal, unremitting despite antibiotics 6
• Hepatosplenomegaly: Characteristic finding, though may be absent in some secondary forms 6
• Cytopenias: Affecting ≥2 cell lines (anemia, thrombocytopenia, neutropenia), progressive despite supportive care 6
• Neurologic involvement: Headaches, vision changes, altered mental status, seizures from CNS infiltration by activated lymphocytes 1, 6
• Multi-organ dysfunction: Hepatitis with elevated transaminases/bilirubin, coagulopathy with hypofibrinogenemia, pulmonary edema, renal dysfunction 1, 6

Diagnostic Laboratory Hallmarks

Hyperferritinemia >5,000 ng/mL (especially >10,000 ng/mL) with progressive cytopenias should immediately trigger HLH evaluation. 6 Key laboratory findings:

• Markedly elevated ferritin: Reflects both macrophage activation and hepatocyte damage; rapidly rising levels highly suggestive 1, 6
• Hypertriglyceridemia and hypofibrinogenemia: Disproportionate to liver dysfunction alone 6
• Elevated soluble CD25 (sIL-2Rα): ≥2,400 U/mL provides strong supportive evidence 6
• Other abnormalities: Elevated transaminases, LDH, d-dimers; decreased albumin and sodium 6

Formal Diagnostic Criteria

Diagnosis requires meeting ≥5 of 8 HLH-2004 criteria: 5, 6

1. Fever
2. Splenomegaly
3. Cytopenias (≥2 lineages)
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

Critical caveat: Do not delay empirical treatment while waiting for all criteria to be met if clinical suspicion is high with ferritin >10,000 μg/L and progressive cytopenias. 6

Why HLH is Rapidly Fatal Without Treatment

The uncontrolled inflammatory cascade progresses rapidly through these mechanisms: 1

• Cytokine-mediated tissue damage: Direct toxic effects on multiple organs
• Vascular leak and shock: From endothelial damage
• Coagulopathy: Consumption of clotting factors and platelet destruction
• Bone marrow suppression: From cytokine effects and hemophagocytosis
• CNS inflammation: Cytokine penetration and lymphocyte infiltration
• Terminal multi-organ failure: Without immunosuppression to break the cycle 1

Treatment Principles

Treatment must simultaneously suppress hyperinflammation AND address the underlying trigger. 1, 6

First-line therapy for most secondary HLH:

• High-dose corticosteroids (methylprednisolone 1g/day IV for 3-5 consecutive days) 5, 6
• Simultaneous treatment of trigger: antimicrobials for infections, chemotherapy for malignancies, disease-modifying therapy for autoimmune conditions 1, 6

Second-line options for inadequate corticosteroid response:

• Cyclosporine A, anakinra (IL-1 blockade), or tocilizumab (IL-6 blockade) 5, 6
• Tocilizumab particularly effective in CAR T-cell-induced HLH 6
• Etoposide reserved for refractory cases due to significant toxicity 6

Emapalumab (anti-IFN-γ) is the only FDA-approved targeted therapy, specifically for primary HLH. 4

Critical Pitfalls to Avoid

• Delayed diagnosis kills: Maintain high suspicion in any patient with persistent fever, cytopenias, and ferritin >5,000 ng/mL 6
• Don't wait for complete criteria: Start treatment empirically if clinical picture strongly suggests HLH 6
• Don't neglect the trigger: Immunosuppression alone fails without addressing underlying infection or malignancy 6
• Don't apply pediatric protocols directly to adults: Different dosing and considerations required 6
• Don't delay ICU transfer: Patients with grade ≥2 organ dysfunction require intensive monitoring 6
• Don't overlook CNS involvement: Perform lumbar puncture if grade 3-4 neurotoxicity present 6

Prognosis

Mortality remains high, especially in adults with malignancy-associated HLH. 6 Factors predicting worse outcomes include:

• Shock at ICU admission 6
• Platelet count <30 g/L 6
• T-cell lymphoma-associated HLH 5
• Delayed diagnosis and treatment initiation 6

Early recognition and prompt immunosuppressive treatment are essential to prevent irreversible organ damage and improve survival. 1, 6