What are the diagnostic steps and treatment options for a patient suspected of having Hemophagocytic Lymphohistiocytosis (HLH)?

Treatment and Diagnosis of Hemophagocytic Lymphohistiocytosis (HLH)

Diagnose HLH using the HLH-2004 criteria, requiring either molecular/genetic confirmation OR 5 of 8 clinical parameters, then immediately initiate the HLH-94 protocol (etoposide + dexamethasone) while simultaneously treating any underlying trigger. 1, 2

Diagnostic Approach

Core Diagnostic Criteria (HLH-2004)

You must document 5 of the following 8 parameters to diagnose HLH 1, 2, 3:

• Fever (typically >39.4°C, prolonged and high) 4
• Splenomegaly (present in majority of cases) 4
• Cytopenias affecting ≥2 cell lines (anemia, thrombocytopenia, neutropenia) 2, 4
• Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL) 2
• Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver 2
• Low or absent NK cell activity 2
• Ferritin ≥500 ng/mL (often markedly elevated, >10,000) 2, 4
• Soluble CD25 ≥2,400 U/mL 2, 4

Critical caveat: Hemophagocytosis alone is neither sensitive nor specific—it can occur in sepsis and other conditions 5, 2. The diagnosis hinges on the combination, extent, and progression of abnormalities that are otherwise unexplained 5.

Essential Diagnostic Workup

Immediate laboratory evaluation 1, 4:

• Complete blood count, ferritin, triglycerides, fibrinogen, soluble CD25, LDH
• Liver enzymes and coagulation studies
• NK cell activity testing

Identify the underlying trigger 5:

• Screen peripheral blood and bone marrow for blasts in all patients 5
• Chest X-ray and CT/ultrasound of abdomen to evaluate for lymphadenopathy and organomegaly 5
• Biopsy suspicious lymph nodes or cutaneous lesions 5
• Consider CT, MRI, or PET imaging in patients with high malignancy likelihood (especially adults >60 years) 5
• Evaluate cerebrospinal fluid for CNS involvement 5
• Infectious workup including EBV, CMV, and other viral serologies 1

Age-dependent malignancy risk 5, 2:

• Adults >60 years: 68% have underlying lymphoma
• Adults 30-59 years: 38% have lymphoma
• Ages 15-29: 10% have lymphoma
• Children <14 years: 0% have lymphoma (8% overall malignancy rate)

Monitoring Disease Activity

Platelets are the most rapid indicator of HLH activity—dropping platelet counts signal disease flares 5. Ferritin rises quickly in active HLH but normalizes slowly after treatment 5. Use temperature, spleen size, blood counts, ferritin, fibrinogen, soluble CD25, and LDH to track treatment response 5.

Treatment Algorithm

Immediate Management Based on Clinical Stability

For deteriorating or unstable patients: Start corticosteroids (dexamethasone) with or without IVIG immediately 1

For stable patients with transient HLH responding to disease-specific treatment: Watchful waiting may be appropriate 1

Standard HLH-94 Protocol (First-Line Treatment)

Core regimen 1, 3:

1. Dexamethasone to suppress inflammatory cytokine production
2. Etoposide (highly effective against T-cell proliferation and cytokine secretion)
3. Cyclosporine A added after 8 weeks (not upfront as in HLH-2004)
4. Intrathecal therapy (methotrexate + corticosteroids) ONLY if progressive neurological symptoms after 2 weeks OR abnormal CSF not improving

Dose modifications for adults and elderly 1:

• Reduce etoposide frequency: once weekly instead of twice weekly
• Reduce etoposide dose: 50-100 mg/m² instead of 150 mg/m² (elderly are vulnerable to end-organ damage)
• Keep cumulative etoposide dose <2-3 g/m² to minimize secondary malignancy risk

Treatment by HLH Subtype

Primary (Genetic) HLH 1, 2:

• Complete HLH-94 protocol
• Allogeneic hematopoietic stem cell transplantation (alloSCT) is mandatory for cure
• Achieve inactive HLH before transplantation—this strongly correlates with better survival

Malignancy-Associated HLH 1, 2:

• Combined approach: HLH-directed AND malignancy-directed therapy simultaneously 1
• Etoposide-containing regimens show superior survival compared to treating malignancy alone 1
• Consider lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate (treat both conditions) 1
• AlloSCT may be considered as consolidation in hematologic malignancy-associated HLH 1, 2
• Strongly consider postponing subsequent chemotherapy blocks except in neoplasm relapse 1
• Rigorous anti-infectious prophylaxis (anti-fungal, Pneumocystis jirovecii) and surveillance (Aspergillus, EBV, CMV) 1

Prognosis is poor 1, 2:

• 30-day survival: 56-70%
• Median overall survival: 36-230 days
• 3-year survival: 18-55%
• T-cell lymphoma-associated HLH has worse prognosis than B-cell lymphoma

Infection-Associated HLH 1:

• Anti-infectious treatment is pivotal
• For EBV-associated HLH: Consider rituximab (anti-B-cell therapy) for highly replicative EBV infection
• Presence of infection does NOT contradict a malignant trigger—both can coexist 5

Autoimmune/Autoinflammatory-Associated HLH 1:

• Anti-interleukin-1 treatment in addition to glucocorticosteroids, cyclosporin A, and etoposide

Refractory/Relapsed HLH Treatment Options 1:

1. Chemotherapy intensification
2. Alemtuzumab (anti-CD52 antibody)
3. Cytokine adsorption using filter columns or plasma exchange
4. Ruxolitinib (JAK2 inhibitor, off-label)
5. Emapalumab (anti-IFN-γ antibody)

Critical Pitfalls to Avoid

HLH can present identically to sepsis or multiple organ dysfunction syndrome 1, 4—maintain high index of suspicion in critically ill patients with unexplained cytopenias and hyperferritinemia.

Do not wait for hemophagocytosis on bone marrow to diagnose HLH—it is neither sensitive nor specific 5, 2.

Do not assume infection excludes malignancy as the underlying trigger—both frequently coexist 5.

Repeat bone marrow aspirate if cytopenias persist to differentiate treatment toxicity from active HLH 5.

The HLH-94 protocol has transformed HLH from uniformly fatal to >50% long-term survival 1—early recognition and prompt treatment initiation are essential for mortality reduction.