Management of Persistent Fever on Day 18 of Emapalumab Treatment in HLH
Persistent fever on day 18 of emapalumab requires immediate investigation for secondary infection as the primary concern, followed by assessment of HLH disease activity, because secondary infections are a major cause of fatality during HLH treatment and emapalumab-induced T-cell depletion creates profound immunosuppression. 1
Immediate Diagnostic Workup
Initiate comprehensive infectious workup immediately:
- Obtain blood cultures (bacterial and fungal), respiratory viral panel, urine culture, and chest imaging within 2 hours 1
- Measure EBV DNA viral load, CMV PCR, and other viral studies if not recently checked 1
- Check inflammatory markers: ferritin, sCD25, triglycerides, fibrinogen, and complete blood counts to assess HLH disease activity 2, 3
- Perform lumbar puncture if any neurologic symptoms are present, as CNS involvement can manifest as fever 4
Critical Decision Point: Infection vs. Refractory HLH
The distinction between infection-driven fever and inadequate HLH control determines management:
If Infection is Identified or Suspected:
- Start broad-spectrum antimicrobials immediately (antipseudomonal beta-lactam plus vancomycin, plus antifungal coverage with voriconazole or liposomal amphotericin B) given the severe immunosuppression from emapalumab 1
- Continue emapalumab at current dosing while treating the infection, as discontinuation risks HLH flare 2, 5
- Add IVIG 1.6 g/kg divided over 2-3 days for additional anti-inflammatory and immune support 1
- Monitor for clinical improvement within 48-72 hours with antimicrobial therapy 6
If HLH Disease Activity is Inadequate (Rising Ferritin, Worsening Cytopenias, No Infection Found):
- Increase emapalumab dosing or shorten dosing interval, as the pivotal trial demonstrated dose escalation was safe and effective for inadequate response 2, 5
- Add high-dose corticosteroids (methylprednisolone 1g/day IV for 3-5 days) if not already on adequate steroid dosing 7, 4, 3
- Consider adding etoposide 50-100 mg/m² weekly for refractory disease, though use cautiously given existing immunosuppression 1, 7, 3
Monitoring Protocol During Fever Evaluation
Reassess every 12 hours with:
- Temperature trends, hemodynamic stability, and organ function 1, 4
- Serial ferritin, sCD25, triglycerides, fibrinogen, and complete blood counts 2, 3
- Repeat cultures if fever persists beyond 48 hours on antimicrobials 1
- CXCL9 levels if available, as normalization indicates emapalumab efficacy 2
Antimicrobial Prophylaxis Assessment
Verify the patient is receiving appropriate prophylaxis:
- Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole or alternative) is mandatory 1
- Antifungal prophylaxis should be strongly considered given prolonged immunosuppression 4
- Antiviral prophylaxis (acyclovir or valacyclovir) for HSV/VZV reactivation 1
Common Pitfalls to Avoid
Do not attribute fever solely to HLH disease activity without ruling out infection first, as secondary infections during HLH treatment carry mortality rates of 20-88% and are the leading cause of death 1
Do not discontinue emapalumab abruptly for fever alone, as this risks HLH rebound; instead, treat concurrent infection while continuing targeted HLH therapy 2, 5
Do not delay antimicrobial therapy while awaiting culture results in a febrile, immunosuppressed HLH patient on day 18 of treatment, as empiric broad-spectrum coverage is life-saving 1, 3
Do not overlook fungal infections, particularly invasive aspergillosis or candidiasis, which are common in patients receiving prolonged immunosuppression and may present with persistent fever despite antibacterial therapy 1, 4
Transplant Readiness Consideration
If fever resolves and HLH parameters normalize, reassess transplant eligibility, as 91.3% of emapalumab-treated patients in real-world data were considered transplant-eligible, with 90.5% pretransplant survival 2