How to manage Hemophagocytic Lymphohistiocytosis (HLH) with false-positive viral tests?

False-Positive Viral Tests in HLH: Clinical Significance and Management

False-positive viral tests in HLH are not a clinically significant problem; rather, the challenge is distinguishing true viral triggers from incidental viral detection in patients with hyperinflammation, and treatment decisions should never be delayed while awaiting viral test results. 1

Understanding Viral Testing in HLH Context

The concept of "false-positive" viral tests in HLH is somewhat misleading—the real clinical challenge involves interpreting positive viral tests in the context of severe hyperinflammation:

• Viral infections, particularly EBV, CMV, HIV, and influenza, are the most common triggers of secondary HLH in adults, accounting for the majority of infection-associated cases 1
• The hyperinflammatory state in HLH can reactivate latent viruses (particularly EBV and CMV), making it difficult to determine whether the virus is the primary trigger or a secondary phenomenon 2
• Pending viral test results must not delay the clinical decision to treat HLH, as mortality ranges from 20-88% without prompt treatment 1

Distinguishing True Viral Triggers from Incidental Detection

EBV-Specific Considerations

• EBV DNA levels >10³ copies per milliliter are clinically relevant for the development of EBV-HLH, helping distinguish true triggers from incidental detection 1, 3
• Monitor EBV DNA levels serially—a decrease of at least 1 log₁₀ in the first week of treatment indicates response to therapy 3
• EBV-HLH can involve infection of T cells and/or NK cells (not just B cells), which affects treatment decisions 1, 3

CMV and Other Viral Triggers

• CMV viremia in the context of HLH criteria (particularly with impressive hyperferritinemia >10,000 ng/mL) suggests true viral triggering rather than incidental detection 4
• Treatment of the presumptive viral trigger can lead to resolution of HLH without requiring full HLH-directed chemotherapy 4

Treatment Algorithm Based on Viral Test Results

When Viral Tests Are Positive

For all patients with confirmed viral HLH:

• Initiate virus-specific treatment immediately (antivirals for CMV/influenza; note that antivirals are NOT effective for EBV) 1, 3
• Start corticosteroids (dexamethasone 5-10 mg/m² or prednisolone 1-2 mg/kg) in all cases 3
• Consider IVIG (1.6 g/kg over 2-3 days) for anti-inflammatory effects 3, 5

For EBV-HLH specifically:

• Add rituximab 375 mg/m² weekly (1-4 doses) to clear the B-cell viral reservoir, even though T-cell/NK-cell involvement may predominate 1, 3
• For rapidly deteriorating patients or treatment-naive EBV cases, initiate etoposide according to HLH-94 protocol without delay 1, 3
• For less severe disease with improving manifestations, a conservative approach with corticosteroids ± IVIG is justified 1, 3

Monitoring to Confirm True Viral Trigger

• Serial monitoring of ferritin, soluble CD25, cell counts, and viral DNA levels (for EBV/CMV) guides treatment decisions 1, 3
• Resolution of HLH parameters with virus-specific treatment alone confirms the virus as the true trigger 4
• Persistent or worsening HLH despite viral treatment suggests either refractory disease or an alternative underlying trigger (particularly malignancy) 1

Critical Pitfalls to Avoid

Do Not Delay Treatment for Test Results

• The clinical decision to treat HLH should never be delayed pending viral test results or genetic testing 1
• Initiate HLH-directed therapy based on clinical criteria while awaiting confirmatory tests 1

Do Not Miss Hidden Malignancy

• 40-70% of adult HLH cases are malignancy-associated, with lymphoma being the most common underlying trigger 1
• Positive viral tests do not exclude malignancy—immunosuppression from malignancy or chemotherapy can lead to viral reactivation 1
• Use PET-guided imaging, repetitive tissue sampling, and consultation with lymphoma reference pathologists when HLH etiology remains unclear 1
• An elevated sCD25/ferritin ratio has been reported in lymphoma-associated HLH 1

Recognize Pathogens Requiring Specific Treatment

• Patients with pathogens targeting the monocyte-macrophage system (Leishmania, Rickettsia, tuberculosis, malaria) should receive specific antimicrobial treatment rather than immunosuppression 1, 5
• These patients typically respond well to pathogen-directed therapy without requiring full HLH-94 protocols 1, 5
• Malaria-associated HLH has better prognosis and may resolve without HLH-specific treatment in some cases 5

When to Escalate or Modify Treatment

• For refractory cases with persistently elevated or increasing viral DNA levels despite initial therapy, consider stem cell transplantation (particularly for chronic active EBV) 1
• Contact an HLH reference center for complex cases with unclear viral significance or refractory disease 1, 3
• Weekly reevaluation of the need for continued etoposide therapy is essential to allow bone marrow recovery 3, 6