What is the recommended treatment for Hemophagocytic Lymphohistiocytosis (HLH) triggered by an infectious cause?

Treatment of Infection-Associated Hemophagocytic Lymphohistiocytosis

For infection-triggered HLH, treatment intensity must be stratified by disease severity: rapidly deteriorating patients require immediate etoposide-based therapy, while less severe cases can start with corticosteroids ± IVIG, always combined with pathogen-specific antimicrobial therapy. 1

General Principles for Infection-Associated HLH

The fundamental approach differs based on the specific infectious trigger, as viral infections (particularly EBV, HIV, CMV, influenza) are the most common causes of infection-associated HLH in adults. 1 Mortality ranges from 20-88%, primarily from refractory disease, secondary infections, and progression of the underlying trigger. 1, 2

The critical decision point is whether the pathogen targets the monocyte-macrophage system versus other cell types, as this determines whether immunosuppression should be avoided or embraced. 1

Pathogen-Specific Treatment Algorithms

EBV-Associated HLH

For severe or rapidly deteriorating EBV-HLH:

• Initiate etoposide according to HLH-94 protocol immediately without delay 1, 2
• Add dexamethasone 5-10 mg/m² 2
• Add rituximab 375 mg/m² weekly for 2-4 doses to clear the B-cell viral reservoir 1, 2
• Monitor ferritin, sCD25, cell counts, and EBV DNA levels to guide treatment duration 1, 2

For less severe or improving EBV-HLH:

• Start with corticosteroids (prednisolone 1-2 mg/kg or dexamethasone 5-10 mg/m²) with or without IVIG (1.6 g/kg over 2-3 days) 1, 2
• Add rituximab 375 mg/m² weekly until EBV DNA negativity 2
• Escalate to etoposide if clinical deterioration occurs 1

Critical caveat: EBV-HLH frequently involves T-cell/NK-cell infection regardless of ethnicity, so rituximab cannot replace anti-T-cell therapy with corticosteroids ± etoposide. 1, 2 EBV DNA levels >10³ copies/mL are clinically relevant for HLH development. 1, 2 Consider stem cell transplantation for continuously rising or sustained high EBV DNA levels, as in chronic active EBV. 1

HIV-Associated HLH

• Initiate highly active antiretroviral therapy immediately 1
• Aggressively search for lymphomas and opportunistic infections as the actual triggers 1
• Treat with short-course corticosteroids (with or without IVIG) for the inflammatory response 1
• Etoposide was used in approximately half of HIV-HLH cases in large series 1
• Apply virus-specific treatment on a case-by-case basis given the wide spectrum of potential viral triggers 1

Influenza-Associated HLH

• Start antiviral therapy (neuraminidase inhibitors) immediately 3, 4
• Add corticosteroids (prednisolone 1-2 mg/kg or dexamethasone 5-10 mg/m²) to control hyperinflammation 3, 4
• Consider IVIG 1.6 g/kg over 2-3 days for anti-inflammatory effects 3, 4
• Initiate etoposide-based therapy according to HLH-94 protocol for rapidly deteriorating patients or those not responding to initial therapy 3, 4
• Monitor for refractoriness related to persistent viral replication and secondary infections 3

Infections Targeting the Monocyte-Macrophage System

For Leishmania, Rickettsia, and Tuberculosis, avoid HLH-94 immunosuppression as these respond to pathogen-specific antimicrobial therapy alone: 1

• Leishmaniasis: Liposomal amphotericin B cures the infection 1
• Rickettsial disease: Tetracyclines or chloramphenicol 1
• Tuberculosis: Quadruple antibiotic therapy adapted according to resistance testing 1

Monitoring Parameters

Monitor the following at least every 12 hours in critically ill patients to determine need for escalation: 1

• Ferritin levels (often markedly elevated, >5000 ng/mL suggests HLH) 3, 4
• Soluble CD25 (IL-2 receptor) levels 3, 2
• Complete blood counts for cytopenias 3, 2
• Pathogen-specific markers (EBV DNA, viral loads) 1, 2
• Liver function tests 2

Critical Care Considerations

In critically ill patients with persistent fever, cytopenias, organomegaly, particularly with confirmed or presumed sepsis, sepsis-like syndromes, or evolving multiorgan failure, raise suspicion for HLH and initiate testing. 1 HLH, multiorgan dysfunction syndrome, and sepsis can coexist, with sepsis serving as the HLH trigger. 1

Key pitfall: Fever may be masked by frequent antipyretics, continuous renal replacement therapy, or extracorporeal life support. 1 Look for unresponsiveness to vasopressors, need for extracorporeal support, inexplicable cytopenias, and organ failure not responding to appropriate antimicrobial treatment and aggressive supportive care. 1

Refractory Disease Management

For refractory infection-associated HLH, treatment decisions must focus on the most likely triggering cause. 1 Contact with an HLH reference center is strongly recommended. 1, 2 Secondary infections are a major cause of mortality during HLH treatment and require vigilant monitoring. 3, 2