What is Hemophagocytic Lymphohistiocytosis (HLH)?

What is Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a life-threatening hyperinflammatory disorder caused by excessive, uncontrolled activation of cytotoxic T cells, natural killer (NK) cells, and macrophages, resulting in a cytokine storm that leads to multiorgan damage and high mortality if untreated. 1, 2

Core Pathophysiology

HLH represents a state of aberrant immune activation where the body fails to properly terminate the inflammatory response. 1, 3 The sustained activation of cytotoxic lymphocytes and macrophages produces massive inflammatory cytokine release, creating a self-perpetuating cycle of tissue damage. 3, 4

Classification: Two Distinct Forms

Primary (Genetic) HLH

• Hereditary defects affecting lymphocyte cytotoxicity cause primary HLH, including familial HLH types 2-5 (mutations in perforin, UNC13D, STX11, STXBP2), Griscelli syndrome type 2, and X-linked lymphoproliferative syndromes. 1, 2
• Predominantly occurs in childhood but can present in adolescents and young adults. 1
• Often triggered by infections despite the underlying genetic predisposition. 1, 2

Secondary (Acquired) HLH

• Most common form in adults, arising from immune triggers without primary genetic defects (though some patients may harbor unidentified genetic predispositions). 1, 5
• Infectious triggers are most frequent, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV). 1, 2
• Malignancy-associated HLH occurs especially with T-cell and NK-cell lymphomas, B-cell lymphomas (DLBCL, Hodgkin), and Castleman disease. 2, 5
• Autoimmune/autoinflammatory conditions can trigger HLH (called macrophage activation syndrome or MAS in this context), including systemic juvenile idiopathic arthritis, adult-onset Still's disease, and systemic lupus erythematosus. 1, 5
• Chemotherapy-induced immunosuppression creates vulnerability to infections that trigger HLH. 2
• Iatrogenic causes include CAR T-cell therapy (3.5% incidence) and alemtuzumab treatment. 5, 6

Cardinal Clinical Features

The clinical hallmarks that should immediately raise suspicion for HLH include: 1, 5

• Persistent high fever that is unremitting and unexplained. 5
• Hepatosplenomegaly (though may be absent in some secondary forms). 1, 5
• Bi- or trilineage cytopenias affecting combinations of red cells, white cells, and platelets. 1, 5
• Neurological symptoms including headaches, vision disturbances, altered mental status, seizures, and gait abnormalities. 5
• Rapid progression to multiorgan failure with a sepsis-like presentation. 1, 5

Characteristic Laboratory Abnormalities

The laboratory profile of HLH is distinctive and includes: 1, 2, 5

• Markedly elevated ferritin (typically >5000 ng/mL and rapidly rising). 5
• Hypertriglyceridemia and hypofibrinogenemia. 1, 5
• Elevated soluble CD25 (IL-2 receptor alpha chain). 1, 5
• Elevated transaminases, lactate dehydrogenase, and d-dimers. 1
• Decreased albumin and sodium. 1
• Low or absent NK cell activity. 2, 7

Diagnostic Approach: HLH-2004 Criteria

Diagnosis requires either molecular/genetic confirmation of HLH OR fulfillment of at least 5 of the following 8 criteria: 2, 5, 7

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 μg/L
8. Elevated soluble CD25

Critical diagnostic pitfall: Hemophagocytosis alone is neither sensitive nor specific for HLH and may occur in sepsis and other conditions—the diagnosis depends on the combination, extent, and progression of unexplained clinical and laboratory abnormalities. 7

Why Recognition Matters

• Mortality remains extremely high, especially in adults with malignancy-associated HLH (30-day survival only 56-70%). 7
• Early recognition prevents irreversible organ damage and is essential for survival. 1, 5, 8
• HLH is likely under-recognized because it mimics sepsis and multiple organ dysfunction syndrome. 1, 3
• Delayed diagnosis significantly increases mortality—empirical treatment should not be delayed while waiting for all diagnostic criteria to be met. 5

Key Clinical Pitfalls to Avoid

• Do not dismiss persistent fever with cytopenias and ferritin >5000 ng/mL as simple infection—maintain high suspicion for HLH. 5
• Do not wait for hemophagocytosis to be demonstrated before considering HLH, as it may be absent early or difficult to find. 7
• Do not overlook CNS involvement—perform lumbar puncture if neurological symptoms are present. 5
• Do not apply pediatric protocols directly to adults without dose adjustments and consideration of different clinical contexts. 1, 5