What is the next best step in managing a patient with suspected Hemophagocytic Lymphohistiocytosis (HLH) and elevated ferritin level?

Management of Suspected HLH with Elevated Ferritin

The next best step is to complete the HLH-2004 diagnostic workup immediately while simultaneously conducting an aggressive search for the underlying trigger, particularly focusing on viral serologies (EBV, CMV), malignancy screening, and obtaining additional diagnostic criteria including triglycerides, fibrinogen, soluble IL-2 receptor (sCD25), and NK cell activity. 1

Immediate Diagnostic Workup Required

Complete the HLH-2004 Criteria Assessment

You need 5 of 8 criteria to diagnose HLH, and this patient already has several 1, 2:

• Fever - Present 1
• Splenomegaly - Present 1
• Cytopenias (≥2 lineages) - Present 1
• Ferritin ≥500 ng/mL - Present (>1000 ng/mL) 1

Still need to obtain:

• Fasting triglycerides (≥3.0 mmol/L or ≥265 mg/dL) and fibrinogen (≤1.5 g/L) 1, 2
• Soluble IL-2 receptor (sCD25) (≥2400 U/mL) - This has superior diagnostic performance compared to ferritin (AUC 0.90 vs 0.78) 1, 2
• NK cell activity (low or absent) 1, 2
• Bone marrow aspirate to look for hemophagocytosis (though absence does not exclude HLH) 1, 2

Critical Context About Your Ferritin Level

While ferritin >1000 ng/mL raises concern, ferritin levels characteristic of HLH in adults are typically 7,000-10,000 ng/mL or higher 1, 2. In pediatric studies, ferritin >10,000 ng/mL was 90% sensitive and 96% specific for HLH 3. Your patient's ferritin >1000 ng/mL is concerning but not yet in the highly specific range for HLH 1, 3. This means hyperferritinemia is less specific in adults and requires integration with other clinical features 1.

Parallel Search for Underlying Trigger

Do not delay this workup - it must continue even during HLH treatment if initiated 1:

Infectious Triggers (Most Common in Adults)

• EBV serologies (VCA IgM, VCA IgG, EBNA, EBV PCR) - EBV is the most common viral trigger 1
• CMV PCR and serology 1
• Parvovirus B19 PCR 1
• HIV, hepatitis panel 1

Malignancy Screening (Critical in Adults)

In adults, malignancy triggers nearly half of HLH cases, with risk increasing with age 1:

• CT chest/abdomen/pelvis to evaluate for lymphoma 1
• Peripheral blood flow cytometry for T-cell and NK-cell lymphomas 1
• LDH, uric acid as markers of lymphoproliferative disease 1
• In Western countries, diffuse large B-cell lymphoma (DLBCL) is the predominant trigger (32% of cases), while T-cell/NK-cell lymphomas account for 35% 1

Rheumatologic Triggers

• ANA, RF, anti-CCP if considering macrophage activation syndrome (MAS) in context of Still's disease or systemic lupus 1

Daily Monitoring Strategy

Serial monitoring is essential to track disease activity and guide treatment decisions 1:

• Daily CBC - Platelets are the most sensitive marker of HLH activity and drop rapidly with flares 1
• Daily ferritin - Rises rapidly in active HLH but normalizes slowly after resolution 1
• Fibrinogen and triglycerides every 1-2 days 1
• LDH, AST/ALT, bilirubin to monitor organ toxicity 1

When to Initiate Treatment

HLH-directed therapy may be initiated even if 5 criteria are not yet fulfilled if clinical suspicion is high 1, 2. However, do not start treatment until you have:

1. Obtained baseline samples for sCD25, NK cell activity, and genetic testing 1
2. Sent viral serologies and malignancy workup 1
3. Documented trend in ferritin and platelets over 24-48 hours 1

Hematology Consultation

Obtain urgent hematology consultation now - This is a complex diagnosis requiring subspecialty expertise, particularly given the need to differentiate HLH from:

• Severe viral marrow suppression 1
• Drug-induced cytopenias 1
• Underlying MDS with acute inflammatory trigger 1
• Malignancy-associated HLH 1

Common Pitfalls to Avoid

• Do not assume infection alone explains the presentation - The combination of fever, cytopenias, splenomegaly, and hyperferritinemia demands HLH evaluation 1, 4
• Do not wait for hemophagocytosis on bone marrow - It may be absent initially and requires serial aspirates or evaluation of other organs 1, 2
• Do not stop the trigger search once HLH is diagnosed - Identifying and treating the underlying cause is essential for survival 1
• Do not use tocilizumab if neurotoxicity develops - It does not treat HLH-associated neurologic symptoms and may worsen them 1