What is the recommended diagnosis and treatment approach for a patient suspected of having Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic Lymphohistiocytosis (HLH): Diagnosis and Treatment

Diagnostic Approach

Diagnose HLH using the HLH-2004 criteria, which requires either molecular diagnosis consistent with HLH or fulfillment of 5 of 8 criteria: fever, splenomegaly, cytopenias (affecting ≥2 cell lines), hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow/spleen/lymph nodes, low or absent NK cell activity, ferritin ≥500 μg/L, and elevated soluble CD25 (sIL-2 receptor). 1

Key Diagnostic Considerations

• Ferritin is the most practical screening parameter when HLH is suspected in patients presenting with the triad of fever, cytopenia, and organomegaly, though it must be interpreted in clinical context 2

• Hemophagocytosis itself is neither sensitive nor specific for HLH and may be present in sepsis and other conditions, so do not rely on this finding alone 1

• HLH presents with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome, making it a critical differential diagnosis in deteriorating ICU patients who fail to respond to standard sepsis management 1, 2

• In male patients with lymphoma and EBV-driven HLH, strongly consider genetic or flow cytometric analysis for X-linked lymphoproliferative syndrome 1 (XLP1), which is characterized by HLH at primary EBV infection, hypogammaglobulinemia, and lymphoma 3

Classification That Guides Treatment

• Primary (genetic) HLH is caused by mutations affecting lymphocyte cytotoxicity and immune regulation, most common in children but can occur in adolescents and young adults 1

• Secondary (acquired) HLH is most common in adults and triggered by infections (especially EBV, CMV), malignancies (particularly T-cell lymphomas), autoimmune/autoinflammatory disorders, or immunotherapies 1

Treatment Algorithm

Immediate Management Based on Clinical Stability

For rapidly deteriorating or unstable patients: Start corticosteroids (dexamethasone 10 mg/m²/day or methylprednisolone) immediately with or without IVIG, and initiate etoposide 150 mg/m² twice weekly for 2 weeks then weekly. 1, 4

For stable patients with transient HLH responding to disease-specific treatment: Watchful waiting may be appropriate, but maintain a low threshold to initiate full protocol if deterioration occurs. 1, 4

Standard HLH-94 Protocol Components

The HLH-94 protocol remains the recommended standard treatment, consisting of: 1

• Dexamethasone 10 mg/m²/day to suppress inflammatory cytokine production 1, 4

• Etoposide 150 mg/m² twice weekly for 2 weeks, then weekly - highly effective against T-cell proliferation and cytokine secretion 1, 4

• Cyclosporine A (2-7 mg/kg/day) added after 8 weeks in HLH-94 (or upfront in HLH-2004 protocol) 1, 4

• Intrathecal therapy only for progressive neurological symptoms after 2 weeks of therapy or if abnormal cerebrospinal fluid has not improved 1

Critical Dosing Modifications for Adults

In adult patients, especially elderly: Reduce etoposide frequency to once weekly instead of twice weekly and/or reduce dosing to 50-100 mg/m² instead of 150 mg/m² due to vulnerability to end-organ damage. 1

Keep cumulative etoposide dose below 2-3 g/m² to minimize risk of secondary malignancies, particularly in non-malignancy associated HLH. 1, 4

Treatment Based on HLH Subtype

Primary (Genetic) HLH

Complete the full HLH-94 protocol followed by allogeneic hematopoietic stem cell transplantation (alloSCT), as this is the only curative approach. 1

• Achieving inactive HLH before transplantation strongly correlates with better survival 1

Malignancy-Associated HLH

Use a combined approach with simultaneous HLH-directed and malignancy-directed therapy, as etoposide-containing regimens show better survival compared to treating the underlying malignancy alone. 3, 1, 4

• Consider lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate (such as CHOEP), as these agents may treat both HLH and the underlying neoplasm in murine models 3, 1

• AlloSCT may be considered as consolidation in patients with HLH in the context of hematologic malignancy 1

• Strongly consider postponing subsequent chemotherapy blocks or interrupting maintenance therapy except in cases of neoplasm relapse 1

• Implement rigorous anti-infectious prophylaxis (anti-fungal, pneumocystis jiroveci) and regular surveillance for secondary infections (aspergillus, EBV, CMV) 1

Infection-Associated HLH (Especially EBV)

Anti-infectious treatment is pivotal and must be initiated immediately alongside HLH-directed therapy. 1, 4

For EBV-associated HLH: Add rituximab 375 mg/m² once weekly for 2-4 doses to clear the viral reservoir, with monitoring of EBV DNA levels, ferritin, and soluble CD25 to guide the number of doses needed. 5, 4

• Consider IVIG at 1.6 g/kg over 2-3 days for its anti-inflammatory effects 5

• For patients with continuously increasing or sustained high levels of EBV DNA, consider hematopoietic stem cell transplantation 5

Autoimmune/Autoinflammatory-Associated HLH (Macrophage Activation Syndrome)

Use anti-interleukin-1 treatment in addition to glucocorticosteroids, cyclosporin A, and etoposide. 3, 1

Refractory or Relapsed Disease

If inadequate response within 24-48 hours to initial therapy, consider treatment intensification with: 1, 4

• Alemtuzumab (anti-CD52 antibody) as salvage therapy 1, 4

• Ruxolitinib (JAK2 inhibitor) - off-label use 1, 4

• Emapalumab (anti-IFN-γ antibody) for refractory cases 1, 4

• Cytokine adsorption using filter columns or plasma exchange 1

Critical Pitfalls to Avoid

Do not mistake HLH for refractory sepsis - if a patient with "sepsis" deteriorates despite standard care with fever, cytopenia, and organomegaly, immediately check ferritin and consider HLH 2

Do not wait for bone marrow hemophagocytosis to diagnose HLH - this finding is neither sensitive nor specific and delays treatment 1

Do not treat with immunosuppression alone without addressing the underlying trigger - simultaneous treatment of both HLH and its cause is essential 1, 4

Do not use standard sepsis protocols for HLH - treatment is fundamentally different and requires immunosuppression rather than immune support 2

Prognostic Factors

Malignancy-associated HLH carries the worst prognosis with 30-day survival of 56-70%, median overall survival of 36-230 days, and 3-year survival of 18-55% depending on subtype. 1

The HLH-94 protocol has improved survival from nearly uniformly fatal to >50% long-term survival in primary HLH. 1

Factors associated with higher mortality include: shock at ICU admission, platelet count <30 g/L, malignancy-associated HLH (particularly T-cell lymphoma), and secondary infections 1, 5