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, NK cells, and macrophages, resulting in a cytokine storm that leads to multi-organ failure and death without immunosuppressive treatment. 1, 2

Core Pathophysiology

HLH represents a final common pathway of excessive immune activation that converges from two distinct origins 1:

• Primary (Genetic) HLH: Results from inherited defects in lymphocyte cytotoxicity, including mutations in perforin (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), as well as Griscelli syndrome type 2 and X-linked lymphoproliferative syndromes 3
• Secondary (Acquired) HLH: Represents immune system failure to restrict inflammatory responses to various triggers without primary genetic defects, though some patients may harbor unidentified genetic predispositions 1, 4

The pathogenic mechanism involves defective cytotoxic function leading to sustained antigen presentation, persistent T-cell activation, and uncontrolled release of inflammatory cytokines (particularly IFN-γ, IL-6, IL-18, TNF-α), which drives macrophage activation and the characteristic hyperinflammatory state 1, 5

Clinical Presentation

HLH manifests as a constellation of clinical and laboratory features 4:

Cardinal Clinical Features:

• Persistent high fever (nearly universal, unremitting) 4
• Hepatosplenomegaly (characteristic but may be absent in some secondary forms) 4
• Bi- or trilineage cytopenias (anemia, thrombocytopenia, neutropenia) 4
• Neurologic involvement (headaches, vision disturbances, altered mental status, seizures, gait abnormalities) 4
• Progressive multi-organ dysfunction (hepatitis with elevated transaminases/bilirubin, coagulopathy with hypofibrinogenemia, pulmonary edema, renal dysfunction) 4

Characteristic Laboratory Abnormalities:

• Hyperferritinemia (rapidly rising ferritin >5000 ng/mL is highly suggestive) 4
• Hypertriglyceridemia 6
• Hypofibrinogenemia 6
• Elevated soluble CD25 (IL-2 receptor alpha chain) 6
• Elevated transaminases, LDH, d-dimers 6
• Decreased albumin and sodium 6

Triggers and Associations

Secondary HLH is triggered by 3, 4:

• Infections: Viral infections (particularly EBV and CMV) are the most frequent triggers; invasive fungi and bacterial infections also occur, especially with chemotherapy-induced immunosuppression 3
• Malignancies: T-cell and NK-cell lymphomas/leukemias are most common; also DLBCL, Hodgkin lymphoma, and Castleman disease 3, 4
• Autoimmune/Autoinflammatory Disorders: Systemic juvenile idiopathic arthritis, adult-onset Still's disease, systemic lupus erythematosus 4
• Iatrogenic: CAR T-cell therapy (3.5% incidence) 4

Diagnostic Criteria

Diagnosis requires fulfilling at least 5 of 8 HLH-2004 criteria 3, 4:

1. Fever
2. Splenomegaly
3. Cytopenias affecting ≥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 diagnostic pitfall: The syndrome can present identically to sepsis or multiple organ dysfunction syndrome, making recognition challenging 1. A high index of suspicion is essential in patients with persistent fever, cytopenias, and ferritin >5000 ng/mL 4.

Age-Related Differences

• Primary HLH: Most common in children, though can occur in adolescents and young adults 1
• Secondary HLH: By far most common in adults, with different triggers, organ reserve, and clinical presentations compared to pediatric patients 1, 2

Prognosis Without Treatment

Without immunosuppressive therapy to control the hyperactive immune system, the uncontrolled inflammatory cascade progresses rapidly to terminal multiple organ failure and death 1. Mortality remains high even with treatment, especially in adults with malignancy-associated HLH 4. Factors associated with higher mortality include shock at ICU admission, platelet count <30 g/L, and T-cell lymphoma-associated HLH 4.

Why Early Recognition Matters

The pathophysiology explains why early recognition and prompt treatment are essential to prevent irreversible organ damage and improve survival 1, 4. The hyperferritinemia reflects both macrophage activation and hepatocyte damage from the inflammatory cascade 1. Tissue damage occurs through CNS infiltration by activated lymphocytes, cytokine-mediated inflammation, and direct organ injury from the cytokine storm 1.