What is the management of Hemophagocytic Lymphohistiocytosis (HLH)?

Management of Hemophagocytic Lymphohistiocytosis (HLH)

Treatment of HLH must be individualized according to subtype and underlying cause, with corticosteroids as first-line treatment for most cases and additional specific therapies based on clinical response and HLH type. 1

Initial Assessment and Diagnosis

• Suspect HLH in patients with persistent fever, cytopenias, organomegaly, particularly in cases of sepsis or evolving multiorgan failure 2
• Diagnostic workup should follow HLH-2004 criteria, including assessment for fever, hepatosplenomegaly, cytopenias, and evidence of hemophagocytosis in bone marrow or organs 3
• Monitor ferritin, sCD25, complete blood counts, liver function, and renal function to assess disease activity and treatment response 3

Treatment Algorithm by HLH Subtype

First-Line Treatment for Most HLH Cases:

• High-dose corticosteroids: methylprednisolone 1g/day for 3-5 consecutive days 1
• Simultaneously identify and treat the underlying cause (infection, malignancy, autoimmune disease) 1
• For patients not responding to corticosteroids within 24-48 hours, add etoposide (consider reduced dose of 50-100 mg/m² weekly in adults with comorbidities) 1

Secondary HLH Management by Trigger:

1. MAS-HLH (Rheumatic Disease-Associated):

   • First-line: High-dose pulse methylprednisolone (1 g/day for 3-5 consecutive days) 2
   • Second-line for inadequate response:
     • Cyclosporine A (2-7 mg/kg per day) 2
     • Anakinra (2-10 mg/kg per day SC in divided doses) 2
     • Consider tocilizumab for IL-6 blockade in selected cases 2

2. Malignancy-Associated HLH:

   • Treatment directed at both the underlying malignancy and HLH 1
   • Etoposide-containing regimens are particularly effective 1
   • Better prognosis in HLH associated with B-cell lymphoma and Castleman disease 4

3. Infection-Associated HLH:

   • Pathogen-specific antimicrobial therapy is essential 2
   • For EBV-triggered HLH, consider adding rituximab (anti-CD20 antibody) 1
   • Leishmania: (liposomal) amphotericin B 2
   • Rickettsial disease: tetracyclines or chloramphenicol 2
   • Tuberculosis: quadruple antibiotic treatment with adaptation according to resistance testing 2

4. Immune Effector Cell-Associated HLH-like Syndrome:

   • High-dose corticosteroids as initial treatment 3
   • Consider tocilizumab (use cautiously with neurologic involvement) 3
   • Monitor every 12 hours to guide therapy 3

5. Primary/Familial HLH:

   • Consider allogeneic hematopoietic stem cell transplantation 1, 5

Management in Critical Care Setting

• Frequent clinical reassessment (at least every 12 hours) 2, 1
• Provide supportive care including ventilation, vasopressors, renal replacement therapy, and transfusions as needed 1
• Be aware that fever may be masked by antipyretics, continuous renal replacement therapy, and extracorporeal life support 2
• Poor prognostic factors include shock at ICU admission and platelet count <30 g/L 4

Emerging and Alternative Therapies

• JAK inhibitors (ruxolitinib) show promise in recent studies 1, 6
• Anti-IFN-γ monoclonal antibody (emapalumab) is under investigation 1
• Intravenous immunoglobulins may be considered in selected cases 2

Common Pitfalls to Avoid

• Delayed diagnosis and treatment significantly increases mortality 1
• Inadequate use of antimicrobials when infection is the primary trigger 3
• Direct application of pediatric protocols without adjustments for adults 3
• Failure to recognize that HLH, multi-organ dysfunction syndrome, and sepsis can coexist 2
• Insufficient monitoring of treatment response (should be at least every 12 hours) 2