What are the main clinical features, etiology, and management of Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic Lymphohistiocytosis: Clinical Features, Etiology, and Management

Clinical Features

HLH presents as a severe hyperinflammatory syndrome with unremitting fever, cytopenias, hepatosplenomegaly, and markedly elevated ferritin levels, often progressing to multiorgan failure with high mortality if untreated. 1, 2

Cardinal Clinical Manifestations

• Fever: High, persistent, unremitting fever is nearly universal 1, 3
• Organomegaly: Hepatosplenomegaly is characteristic, though may be absent in some secondary forms 1, 4
• Cytopenias: Affecting two or more cell lines (anemia, thrombocytopenia, neutropenia) 1, 3
• Neurologic involvement: Headaches, vision disturbances, gait abnormalities, altered mental status, and seizures 1, 4
• Multiorgan dysfunction: Hepatitis with elevated transaminases and bilirubin, coagulopathy with hypofibrinogenemia, pulmonary edema, renal dysfunction 1, 2

Key Laboratory Abnormalities

• Hyperferritinemia: Rapidly rising ferritin >5000 ng/mL is highly suggestive 1, 2
• Elevated inflammatory markers: CRP, IL-6, INF-γ, sIL-2Ra (soluble CD25) 1, 3
• Coagulopathy: Hypofibrinogenemia, elevated D-dimer 1, 3
• Hypertriglyceridemia: Often >265 mg/dL 4, 3
• Hemophagocytosis: May be found on bone marrow, liver, or lymph node biopsy, though absence does not exclude diagnosis 1, 4

Diagnostic Criteria

Diagnosis requires fulfilling at least 5 of 8 HLH-2004 criteria: fever, splenomegaly, cytopenias (≥2 lineages), hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low NK cell activity, elevated ferritin (≥500 ng/mL), and elevated soluble CD25. 5, 4

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Etiology

Primary (Genetic) HLH

• Familial HLH genes: PRF1, UNC13D, STXBP2, STX11 causing defective cytotoxic lymphocyte function 4, 6
• Granule/pigment abnormalities: RAB27A (Griscelli syndrome), LYST (Chédiak-Higashi), AP3B1 (Hermansky-Pudlak type 2) 4
• X-linked lymphoproliferative diseases: SH2D1A (XLP-1), XIAP (XLP-2) with EBV susceptibility 4, 6
• Other genetic defects: NLRC4, CDC42 4

Secondary HLH

Secondary HLH arises from immune triggers in the absence of primary genetic defects, though some patients may have unidentified genetic predispositions. 1, 4

• Infection-triggered: EBV is most common, but also CMV, HSV, HIV, fungal, parasitic infections 4, 3
• Malignancy-associated: Particularly T-cell and NK-cell lymphomas, B-cell lymphomas, Castleman disease 2, 3
• Autoimmune/autoinflammatory (Macrophage Activation Syndrome): Occurs specifically in systemic juvenile idiopathic arthritis, adult-onset Still's disease, systemic lupus erythematosus 7, 3
• Iatrogenic: CAR T-cell therapy (3.5% incidence), other immunotherapies 1, 6

Important Distinction

MAS should be reserved specifically for HLH occurring in the context of underlying autoimmune/autoinflammatory diseases, not for infection- or malignancy-triggered secondary HLH. 7

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Management

Initial Treatment Algorithm

For most secondary HLH cases, initiate high-dose corticosteroids (methylprednisolone 1g/day IV for 3-5 consecutive days) as first-line therapy while simultaneously treating the underlying trigger. 2, 5

First-Line Treatment

• Corticosteroids: Methylprednisolone 1g/day IV for 3-5 days is the cornerstone 2, 5
• Treat underlying cause: This is essential and must occur concurrently 2, 3
  • Antimicrobials for infection-triggered HLH
  • Chemotherapy for malignancy-associated HLH
  • Disease-modifying therapy for MAS

Second-Line Treatment (for inadequate response within 24-48 hours)

• Cyclosporine A: 2-7 mg/kg/day, particularly effective in MAS 2, 5
• Anakinra: 2-10 mg/kg/day subcutaneously (IL-1 receptor antagonist) 2, 5
• Etoposide: Consider reduced dose of 50-100 mg/m² weekly in adults with comorbidities; particularly effective in malignancy-associated HLH 2

Third-Line and Refractory Cases

• Tocilizumab: Anti-IL-6 therapy, especially for CAR T-cell-induced HLH/MAS 1, 2
• Rituximab: For EBV-triggered HLH 2
• Etoposide: As last resort for refractory cases, though carries significant toxicity 1, 2

Context-Specific Management

CAR T-Cell Therapy-Induced HLH/MAS

Management mirrors CRS treatment with anti-IL-6 therapy (tocilizumab) and aggressive corticosteroids; for tocilizumab-refractory cases, add anakinra. 1

• First-line: Tocilizumab plus corticosteroids 1
• Refractory cases: Corticosteroids plus anakinra 1
• Avoid etoposide due to T-cell toxicity in CAR T setting 1

MAS-HLH (Autoimmune/Autoinflammatory)

High-dose corticosteroids first, then cyclosporine A, anakinra, or tocilizumab as second-line agents targeting autoimmune pathways. 2, 7

Malignancy-Associated HLH

Treatment must target both the HLH and underlying malignancy; etoposide-containing regimens are particularly effective, with better prognosis in B-cell lymphoma and Castleman disease. 2

Primary (Genetic) HLH

Chemotherapy (typically HLH-94 or HLH-2004 protocols with etoposide and dexamethasone) as bridge to allogeneic hematopoietic stem cell transplantation, which is the only curative option. 6, 3

Critical Care Management

Patients with shock at ICU admission, platelet count <30 g/L, grade ≥3 neurotoxicity, or severe organ dysfunction require ICU-level care with frequent reassessment every 12 hours. 2, 5

• Supportive care: Mechanical ventilation, vasopressors, renal replacement therapy, transfusions as needed 2, 5
• Monitoring: Inflammatory parameters (ferritin, CRP), organ function (liver, kidney, coagulation), cytokine levels 2, 5
• Antifungal prophylaxis: Strongly consider in patients receiving prolonged corticosteroids 1

Prognostic Factors

Factors associated with higher mortality include shock at ICU admission, platelet count <30 g/L, and malignancy-associated HLH. 2

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Critical Pitfalls to Avoid

Delayed diagnosis and treatment significantly increases mortality; maintain high index of suspicion in patients with persistent fever, cytopenias, and ferritin >5000 ng/mL. 2, 5

• Do not wait for all HLH-2004 criteria: Treat empirically if clinical suspicion is high with rapidly rising ferritin and cytopenias in context of fever 1, 2
• Do not neglect the underlying trigger: Inadequate antimicrobial therapy when infection is the trigger is a common fatal error 2, 5
• Do not apply pediatric protocols directly to adults: Adult HLH requires dose adjustments and different considerations 2
• Do not overlook CNS involvement: Perform lumbar puncture if grade 3-4 neurotoxicity present (after excluding elevated intracranial pressure) 1
• Do not delay ICU transfer: Patients with grade ≥2 organ dysfunction require intensive monitoring 1, 5