What is the treatment approach for Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic Lymphohistiocytosis (HLH): Symptoms, Diagnosis, and Treatment

Clinical Presentation

HLH presents with a constellation of hyperinflammatory symptoms that require immediate recognition to prevent mortality from multiorgan failure. 1

Key Clinical Features

• Persistent fever unresponsive to antibiotics (often masked by antipyretics or renal replacement therapy) 1
• Cytopenias affecting multiple cell lines (particularly platelets <30 g/L, which predicts mortality) 2
• Hepatosplenomegaly with liver dysfunction and elevated transaminases 1
• Neurologic symptoms including altered mental status, seizures, or focal deficits 3
• Rash and lymphadenopathy in some cases 3
• Multiorgan dysfunction with shock, respiratory failure, and renal impairment 2

Red Flags for Deterioration

• Rapidly rising ferritin (>5000 ng/mL) with worsening cytopenias 4
• Unresponsiveness to vasopressors despite adequate fluid resuscitation 1
• Need for extracorporeal life support 1
• Disproportionate inflammatory response to the clinical trigger 1

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Diagnosis

Diagnosis requires 5 of 8 HLH-2004 criteria, though clinical judgment should guide treatment initiation before all criteria are met in deteriorating patients. 1

HLH-2004 Diagnostic Criteria

1. Fever ≥38.5°C 1
2. Splenomegaly 1
3. Cytopenias (affecting ≥2 cell lines): hemoglobin <9 g/dL, platelets <100 × 10⁹/L, neutrophils <1.0 × 10⁹/L 1
4. Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL) 1
5. Hemophagocytosis in bone marrow, spleen, or lymph nodes 1
6. Low or absent NK cell activity 1
7. Ferritin ≥500 ng/mL (typically >5000 ng/mL in severe cases) 1, 4
8. Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL 1

Essential Workup

• Complete blood count with differential 5
• Ferritin and soluble CD25 levels 5, 4
• Triglycerides and fibrinogen 1
• Liver and renal function tests 5
• Bone marrow examination to identify hemophagocytosis and rule out malignancy 1
• Genetic testing for familial HLH mutations in young adults or those with family history 1
• Trigger identification: infectious workup (EBV, CMV, HIV, malaria, tuberculosis), malignancy screening, rheumatologic evaluation 1, 5

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Treatment Approach

Treatment intensity must be graded based on disease severity, with immediate etoposide reserved for patients with imminent organ failure, while less severe cases may respond to corticosteroids alone. 1

Treatment Algorithm by Severity

Mild-to-Moderate HLH (No Organ Failure)

1. Treat the underlying trigger aggressively 1

   • Antimicrobials for infection-associated HLH 1
   • Disease-specific therapy for malignancy-associated HLH 1
   • Optimize rheumatologic disease control for MAS-HLH 1

2. Corticosteroids as first-line immunosuppression 1

   • Dexamethasone 10 mg/m² daily OR 1
   • Prednisolone 1-2 mg/kg daily 1
   • For MAS-HLH: High-dose pulse methylprednisolone 1 g/day for 3-5 days 1

3. Consider IVIG 1.6 g/kg divided over 2-3 days for anti-inflammatory effects 1, 5

4. Weekly reassessment to determine need for escalation 1

Severe HLH (Organ Failure, Shock, or Rapid Deterioration)

1. Immediate etoposide-based therapy (modified HLH-94 protocol) 1, 4

   • Dexamethasone 10 mg/m² daily PLUS 1
   • Etoposide with modified dosing based on severity 1
   • Dose reduction required if renal impairment present 1, 5
   • No dose reduction for isolated hyperbilirubinemia or elevated transaminases 1

2. Duration: Many patients require 8 weeks of etoposide 1

   • Weekly reevaluation to assess need for continuation 1, 5
   • Keep cumulative dose below 2-3 g/m² to minimize secondary malignancy risk 1

3. Consider adding cyclosporine A (CSA) 2-7 mg/kg/day (or tacrolimus) with careful drug level monitoring 1

MAS-HLH Specific Modifications

MAS-HLH requires a different approach due to distinct pathogenesis. 1

1. First-line: High-dose pulse methylprednisolone 1 g/day × 3-5 days 1
2. Second-line (insufficient response):
   • Add CSA 2-7 mg/kg/day 1
   • OR Anakinra 2-10 mg/kg/day subcutaneously in divided doses 1
3. Alternative: Tocilizumab (anti-IL-6) with increasing experience 1
4. Avoid etoposide unless life-threatening, as bone marrow recovery is essential 1

Infection-Associated HLH

• Pathogen-specific antimicrobials are paramount 1, 5
• Leishmania: Liposomal amphotericin B 1
• Rickettsial disease: Tetracyclines or chloramphenicol 1
• Tuberculosis: Quadruple antibiotic therapy 1
• Malaria: Appropriate antimalarial therapy based on species and resistance patterns 5
• Some cases resolve without HLH-specific treatment, particularly infection-associated HLH 1, 5

Malignancy-Associated HLH (Mal-HLH)

Mal-HLH has the worst prognosis and requires distinguishing between two subtypes. 1

1. "Malignancy-triggered HLH" (at diagnosis or relapse):

   • Treat underlying malignancy with disease-specific protocols 1
   • Add HLH-directed therapy as needed 1

2. "HLH during chemotherapy" (infection-induced):

   • Corticosteroids (prednisolone 1-2 mg/kg or dexamethasone 5-10 mg/m²) 1
   • IVIG 1.6 g/kg over 2-3 days 1
   • Use etoposide sparingly to allow bone marrow recovery 1

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Critical Care Management

Patients requiring ICU admission need aggressive supportive care combined with HLH-directed therapy, with reevaluation at least every 12 hours. 1

Supportive Measures

• Mechanical ventilation for respiratory failure 2
• Vasopressor support for shock 2
• Renal replacement therapy for acute kidney injury 2
• Extracorporeal life support when indicated 1

Infection Prophylaxis (Essential)

Secondary infections are a major cause of mortality during HLH treatment. 1, 4

• Pneumocystis jirovecii prophylaxis (mandatory) 1
• Antifungal prophylaxis 1
• Antiviral prophylaxis due to severe T-cell depletion 1
• HEPA-filtered air hospitalization when possible 1

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Allogeneic Stem Cell Transplantation

Patients with primary (genetic) HLH require allogeneic SCT for cure after achieving disease control. 1

Indications

• Confirmed genetic HLH mutations 1
• Refractory disease after 8 weeks of therapy 1
• Residual disease requiring maintenance therapy 1

Conditioning Regimen

• Reduced-intensity conditioning (RIC) for primary HLH and nonmalignant secondary HLH 1
• Myeloablative conditioning (MAC) for malignancy-associated HLH per disease-specific protocols 1
• Inactive HLH before transplant strongly associated with better survival 1

Pre-Transplant Bridging

• HLH-94 maintenance therapy (dexamethasone + CSA) often recommended after initial 8 weeks 1
• Screen HLA-matched relatives for same genetic mutations to avoid affected donors 1

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Novel and Emerging Therapies

Several targeted agents show promise for refractory HLH, though evidence remains limited. 1

• Ruxolitinib (JAK1/2 inhibitor) in clinical trials 1
• Anakinra (IL-1 blockade) may reduce mortality in sepsis-associated MAS 1
• Emapalumab (anti-IFN-γ antibody) under investigation 1
• Alemtuzumab (anti-CD52) in trials 1

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Common Pitfalls and Caveats

Diagnostic Challenges

• HLH overlaps with severe sepsis and cytokine release syndrome, leading to delayed diagnosis 4
• Fever may be masked by antipyretics, continuous renal replacement therapy, or extracorporeal support 1
• Bone marrow hemophagocytosis may be absent early in disease course 3

Treatment Considerations

• Do not delay etoposide in rapidly deteriorating patients with organ failure 1, 4
• Avoid HLH-94 protocol in patients with pathogens targeting the monocyte-macrophage system (Leishmania, Rickettsia, tuberculosis) until specific antimicrobial therapy is initiated 1
• Etoposide dose reduction mandatory for renal impairment but not for liver dysfunction alone 1, 5
• Monitor for secondary infections vigilantly as they cause significant mortality 1, 4

Prognostic Factors

• Shock at ICU admission and platelets <30 g/L predict mortality 2
• B-cell lymphoma and Castleman's disease associated with better survival 2
• Malignancy-associated HLH has worst prognosis overall 1
• Adult HLH mortality ranges 20-88% depending on underlying cause 4