Initial Approach to a Patient with Hemophagocytic Lymphohistiocytosis (HLH) with No Clear Cause
For patients with HLH of unknown cause, initial treatment should include high-dose corticosteroids with etoposide following the HLH-94 protocol framework, while simultaneously pursuing an aggressive diagnostic workup to identify potential triggers. 1
Immediate Assessment and Management
Step 1: Confirm HLH Diagnosis
- Verify diagnosis using HLH-2004 criteria (5 of 8 criteria)
- Look for the "three Fs": fever, falling blood counts, and raised ferritin 2
- Consider HLH in any acutely unwell patient not responding to expected treatment
Step 2: Initial Treatment
Start HLH-directed therapy immediately:
Supportive care:
- Frequent monitoring (at least every 12 hours in critically ill patients) 1
- Monitor ferritin, sCD25, and cell counts to assess treatment response
Step 3: Parallel Diagnostic Workup
Genetic Testing
- Test for HLH-associated mutations, especially in young adults or those with family history 3
- Include testing for PRF1, STXBP2, SH2D1A, UNC13D, and STX11 mutations 3
Search for Malignancy
- Thorough cancer workup with special consideration of lymphoma 3
- Use positron emission tomography-guided imaging
- Consider repetitive tissue sampling
- Consult with a lymphoma reference pathologist
- Pay special attention to Hodgkin lymphoma, T-cell lymphomas, and other lymphoma subtypes strongly associated with HLH 3
- Consider splenectomy in individuals with HLH of unknown cause and splenomegaly to detect hidden lymphomas 3
Infection Screening
- Comprehensive screening for viral infections, especially EBV
- Test for bacterial, fungal, and parasitic infections
- Consider HIV testing due to associated immunodeficiency risk 3
Autoimmune/Rheumatologic Evaluation
- Screen for underlying autoimmune conditions
- Consider testing for macrophage activation syndrome (MAS) in the context of rheumatic diseases
Step 4: Management Based on Clinical Status
For Severe HLH with Organ Failure
- Immediate administration of etoposide is clearly indicated 3
- Full HLH-94 protocol implementation (dexamethasone 10 mg/m², etoposide, cyclosporine A)
For Less Severe Presentation
- Consider modified HLH-94 protocol with reduced etoposide frequency (once weekly instead of twice weekly) 3
- Dose reduction from 150 mg/m² to 50-100 mg/m² in elderly patients or those with comorbidities 3
Additional Therapeutic Considerations
- Consider IV immunoglobulin (up to 1.6 g/kg in split doses over 2-3 days) 3
- Weekly reevaluation of the need for continued etoposide therapy 3
- Consider anakinra for patients with features of MAS 3
Step 5: Infection Prevention
- Implement broad antimicrobial prophylaxis against Pneumocystis jirovecii and fungi 3
- Consider hospitalization in units with HEPA-filtered air 3
- Implement antiviral prophylaxis due to severe T-cell depletion 3
Important Considerations
Treatment Duration
- Many patients with secondary HLH require 8 weeks of etoposide 3
- Patients with residual disease after 8 weeks may benefit from maintenance therapy and possibly allogeneic stem cell transplantation 3
Monitoring Response
- Monitor ferritin levels, cell counts, and clinical status to assess treatment efficacy
- Consider consultation with an HLH reference center whenever possible 1
Pitfalls to Avoid
- Delayed recognition and treatment of HLH significantly increases mortality 1
- Don't overlook signs of hypercytokinemia 4
- Don't wait for all diagnostic criteria to be met before initiating treatment in critically ill patients
- Don't miss hidden lymphoma as a trigger - repeat biopsies may be necessary 3
- Don't forget to adjust etoposide dosing in patients with renal impairment 3