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
Core Pathophysiology
HLH represents a final common pathway of immune dysregulation where the immune system fails to adequately restrict its response to various triggers, leading to sustained but ineffective immune activation. 1, 2 The disease mechanism involves:
Defective cytotoxic function: In primary HLH, genetic mutations impair the ability of NK cells and cytotoxic T lymphocytes to kill target cells and terminate immune responses, while in secondary HLH, acquired immune dysfunction produces similar effects. 1, 3
Hypercytokinemia: The aberrant activation drives excessive release of inflammatory cytokines (particularly IFN-γ, IL-6, IL-18, TNF-α), creating a self-perpetuating cytokine storm. 1, 4
Macrophage activation: Activated macrophages proliferate throughout the reticuloendothelial system and phagocytose blood cells (hemophagocytosis), though this finding is neither sensitive nor specific for diagnosis. 5, 1
Classification: Two Distinct Forms
Primary (Genetic) HLH
- Hereditary defects in genes controlling lymphocyte cytotoxicity, including familial HLH types 2-5 (mutations in PRF1, UNC13D, STX11, STXBP2), Griscelli syndrome type 2, and X-linked lymphoproliferative syndromes. 3
- Predominantly pediatric, though can present in adolescents and young adults with hypomorphic mutations. 1, 3
- Requires hematopoietic stem cell transplantation for cure after initial disease control. 6
Secondary (Acquired) HLH
- Most common in adults, triggered by infections (especially EBV, CMV), malignancies (particularly T-cell/NK-cell lymphomas), autoimmune diseases (macrophage activation syndrome in Still's disease, systemic JIA, SLE), or iatrogenic causes (CAR T-cell therapy). 5, 3, 7
- Does not require genetic defects, though some patients may harbor unidentified genetic predispositions. 7
- Treatment focuses on suppressing hyperinflammation while simultaneously addressing the underlying trigger. 7
Cardinal Clinical Features
The syndrome presents with a constellation of findings that overlap significantly with sepsis and multi-organ dysfunction, making diagnosis challenging:
- Persistent high fever: Nearly universal, characterized by unremitting high-grade fever unresponsive to antibiotics. 7, 8
- Hepatosplenomegaly: Characteristic but may be absent in some secondary forms. 5, 7
- Cytopenias: Affecting two or more cell lines (anemia, thrombocytopenia, neutropenia). 7, 8
- Neurologic involvement: Headaches, altered mental status, seizures, gait abnormalities, vision disturbances from CNS infiltration by activated lymphocytes. 1, 7
- Multi-organ dysfunction: Hepatitis with elevated transaminases, coagulopathy with hypofibrinogenemia, pulmonary edema, renal dysfunction progressing to terminal organ failure. 1, 7
Diagnostic Laboratory Hallmarks
- Hyperferritinemia: Rapidly rising ferritin >5000 ng/mL is highly suggestive; reflects both macrophage activation and hepatocyte damage. 1, 7
- Hypertriglyceridemia and hypofibrinogenemia: Result from cytokine-mediated metabolic derangements and consumptive coagulopathy. 7, 8
- Elevated soluble CD25 (sIL-2Rα): Marker of T-cell activation. 5, 7
- Decreased NK cell activity: Functional assay demonstrating impaired cytotoxicity. 5
- Elevated inflammatory markers: CRP, IL-6, IFN-γ commonly elevated. 7
Formal Diagnostic Criteria (HLH-2004)
Diagnosis requires either molecular diagnosis consistent with HLH OR fulfillment of at least 5 of 8 criteria: 3, 7
- Fever ≥38.5°C
- Splenomegaly
- Cytopenias affecting ≥2 lineages (hemoglobin <9 g/dL, platelets <100×10⁹/L, neutrophils <1.0×10⁹/L)
- Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
- Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver
- Low or absent NK cell activity
- Ferritin ≥500 μg/L (though >5000 μg/L is more specific)
- Elevated soluble CD25 ≥2400 U/mL
Critical Clinical Implications
The pathophysiology explains why HLH mimics sepsis or multi-organ dysfunction syndrome, creating diagnostic delays that significantly increase mortality. 1, 7 Key points:
Rapid progression: The uncontrolled inflammatory cascade advances quickly, and early recognition prevents irreversible organ damage and death. 1, 7
High mortality: Especially in adults with malignancy-associated HLH, with shock at ICU admission, platelet count <30 g/L, and T-cell lymphoma association being particularly ominous prognostic factors. 3, 7
Dual treatment imperative: Therapy must simultaneously target the hyperinflammation (with immunosuppression) and the underlying trigger (antimicrobials for infection, chemotherapy for malignancy, disease-modifying therapy for autoimmune disease). 1, 7
Do not delay empirical treatment while waiting for all diagnostic criteria to be met if clinical suspicion is high based on persistent fever, progressive cytopenias, and ferritin >5000 ng/mL. 7
Common Pitfalls to Avoid
Attributing all findings to sepsis alone when a patient with infection continues deteriorating despite appropriate antimicrobials—consider concurrent HLH. 3
Waiting for hemophagocytosis on bone marrow biopsy, which may be absent early in disease and is neither sensitive nor specific. 5, 2
Overlooking CNS involvement—perform lumbar puncture if grade 3-4 neurotoxicity present. 7
Applying pediatric protocols directly to adults—adult secondary HLH has different triggers, organ reserve, and clinical presentations requiring modified approaches. 1
Neglecting the underlying trigger while treating hyperinflammation—both must be addressed simultaneously for survival. 7