How to manage secondary Hemophagocytic Lymphohistiocytosis (HLH) due to infection?

Management of Secondary HLH Due to Infection

Treat the underlying infection aggressively while simultaneously initiating immunomodulatory therapy with corticosteroids, and escalate to etoposide-based regimens for rapidly deteriorating patients or those failing initial therapy. 1

Initial Management Framework

Immediate Antimicrobial Therapy

• Initiate pathogen-directed treatment immediately upon identifying the infectious trigger (antiviral for viral infections, antimalarial for malaria, antibiotics for bacterial infections) 2, 3
• For EBV-HLH specifically, consider adding rituximab (375 mg/m² once weekly for 2-4 doses) to clear the viral reservoir in B cells 1
• Viral infections, particularly EBV, HIV, cytomegalovirus, and influenza, are the most common triggers of infection-associated HLH 1

Risk-Stratified Immunomodulatory Approach

For Less Severe or Improving Disease:

• Start with corticosteroids alone: prednisolone 1-2 mg/kg or dexamethasone 5-10 mg/m² 1, 2
• Add IVIG 1.6 g/kg divided over 2-3 days for anti-inflammatory effects 1, 2
• This conservative approach is justified when clinical manifestations are improving or disease severity is moderate 1

For Rapidly Deteriorating Patients or Treatment-Naive EBV Cases:

• Initiate etoposide-based therapy (HLH-94 protocol) without delay 1, 2
• Do not wait for response to corticosteroids if the patient shows rapid clinical deterioration 1
• Many patients with secondary HLH require the full 8-week course of etoposide 1
• Perform weekly reevaluation of the need for continued etoposide therapy, though patients may continue the full course in the absence of major toxicities 1, 3

Alternative and Adjunctive Therapies

• Cyclosporine A may be added to the regimen, with careful drug level monitoring 1
• Anakinra (IL-1 inhibition) may reduce mortality in patients with MAS features and can be considered for refractory cases 1, 2
• For severe refractory cases, consider emapalumab (anti-IFN-γ monoclonal antibody) to avoid secondary malignancy risk from etoposide 4

Monitoring Treatment Response

Key Parameters to Track

• Monitor ferritin, soluble CD25 (sCD25), complete blood counts, and pathogen-specific markers (e.g., EBV DNA levels) 1, 3
• EBV DNA levels >10³ copies/mL are relevant for development of EBV-HLH 1
• These parameters guide treatment intensity and duration decisions 1, 3

Critical Infection Prevention Measures

Prophylaxis Requirements

• Administer broad antimicrobial prophylaxis against Pneumocystis jirovecii and fungi for all patients requiring HLH-directed immunosuppressive treatment 1, 3
• Provide antiviral prophylaxis due to severe T-cell depletion from HLH therapy 1
• Consider hospitalization in units with high-efficiency particulate air (HEPA)-filtered air 1
• Implement surveillance screening for aspergillus, EBV, and CMV 1

Recognition of Secondary Infections

• Secondary infections are a major cause of fatality during HLH treatment 1, 3
• Suspect HLH recurrence when cytopenia is unduly prolonged after chemotherapy, fever persists despite antibiotics, and other HLH parameters are present 1

Special Considerations by Infection Type

EBV-HLH Specifics

• The prognosis for EBV-HLH has improved greatly with prompt HLH-94 protocol treatment 1
• Variable severity demands graded intensity and length of treatment 1
• Rituximab addition is particularly effective for clearing the B-cell viral reservoir 1

Non-EBV Viral HLH

• Appropriate antiviral treatment followed by immunomodulatory agents (corticosteroids, IVIG, or cyclosporine A) is usually successful 4
• Recent SARS-CoV-2-related HLH may become life-threatening despite this approach 4

Malaria-Associated HLH

• Appears to have better prognosis compared to other infection-triggered HLH 3
• Some cases resolve without HLH-specific treatment once antimalarial therapy is administered 3
• Still requires corticosteroids for hyperinflammation control 3

Common Pitfalls to Avoid

Delayed Etoposide Initiation

• Do not delay etoposide in rapidly deteriorating patients, particularly treatment-naive EBV-infected patients 1, 2
• The variable severity of infection-associated HLH should not lead to universal conservative management 1

Etoposide Use in Profoundly Cytopenic Patients

• In "HLH during chemotherapy" (occurring during treatment of malignancy), etoposide should be used sparingly because bone marrow recovery is central for immune reconstitution 1
• For these patients, the positive effect of immunosuppression must be weighed against negative effects on infection treatment 1

Diagnostic Confusion

• HLH symptoms may overlap with severe sepsis or cytokine release syndrome, leading to delayed diagnosis 2
• Suspect HLH in patients with rapidly rising ferritin (>5000 ng/mL) with cytopenias, fever, and organ dysfunction 2

Prognosis and Long-Term Management

• Mortality in adult HLH ranges from 20% to 88%, primarily from refractory HLH, secondary infections, and progression of underlying disease 1, 2
• Patients with residual disease after 8 weeks may benefit from maintenance therapy and possibly allogeneic stem cell transplantation 1
• Refractory EBV-HLH cases may require hematopoietic stem cell transplantation 4