What are the diagnostic criteria and treatment options for a patient with suspected Hemophagocytic Lymphohistiocytosis (HLH), presenting with persistent fever, hepatosplenomegaly, and cytopenias, possibly triggered by a recent infection, autoimmune disorder, or malignancy?

Diagnosis of Hemophagocytic Lymphohistiocytosis (HLH)

Diagnose HLH using the HLH-2004 criteria, which requires either a molecular diagnosis consistent with HLH or fulfillment of at least 5 out of 8 specific clinical and laboratory parameters. 1

HLH-2004 Diagnostic Criteria

The 8 parameters include: 1, 2

1. Fever (prolonged, high-grade, often >39.4°C)
2. Splenomegaly
3. Cytopenias (affecting ≥2 cell lines: hemoglobin <9 g/dL, platelets <100,000/μL, neutrophils <1,000/μL)
4. Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
5. Hemophagocytosis in bone marrow, spleen, or lymph nodes
6. Low or absent NK cell activity
7. Ferritin ≥500 μg/L (though levels >5,000-10,000 μg/L are highly suggestive)
8. Soluble CD25 (sIL-2Rα) ≥2,400 U/mL

Critical Diagnostic Approach

Do not delay empirical treatment while waiting for all 5 criteria to be met if clinical suspicion is high. 3 The key is to assess whether the combination, extent, and progression of clinical and laboratory abnormalities are unusual, unexpected, and otherwise unexplained. 4

High-Suspicion Clinical Scenarios

Consider HLH immediately when you encounter: 3

• Persistent fever with cytopenias and ferritin >5,000 ng/mL (especially >10,000 μg/L)
• Progressive cytopenias affecting ≥2 cell lines despite supportive care
• Hepatosplenomegaly with multiorgan dysfunction
• Hypertriglyceridemia and hypofibrinogenemia disproportionate to other explanations

Diagnostic Pitfalls to Avoid

HLH can present identically to sepsis or multiple organ dysfunction syndrome, making differentiation extremely challenging in critically ill patients. 1 Both conditions can coexist simultaneously. 5 A high index of suspicion is essential when patients have persistent fever, cytopenias, and markedly elevated ferritin despite appropriate antimicrobial therapy. 3

Hemophagocytosis itself is neither sensitive nor specific—it may be absent on initial bone marrow examination and can occur in sepsis, malignancy, and other conditions. 4 Do not rule out HLH based solely on absence of hemophagocytosis. 6

Essential Diagnostic Workup

Initial Laboratory Evaluation

Obtain the following tests when HLH is suspected: 1, 3

• Complete blood count (assess for bi- or trilineage cytopenias)
• Ferritin (rapidly rising levels indicate active disease)
• Triglycerides and fibrinogen
• Soluble CD25 (sIL-2Rα)
• Liver enzymes (AST, ALT, bilirubin)
• Coagulation studies (PT, PTT, D-dimer)
• LDH

Bone Marrow Examination

Perform bone marrow aspiration and biopsy to: 4

• Screen for hemophagocytosis (though may be absent initially)
• Evaluate for underlying malignancy (screen for blasts, lymphoma involvement)
• Differentiate treatment toxicity from active HLH if cytopenias persist

Trigger Identification

In any patient with HLH, malignancy should be considered as a possible underlying disease. 4 The likelihood of malignancy-associated HLH increases dramatically with age: 68% in patients >60 years, 38% in ages 30-59,10% in ages 15-29, and 0% under age 14. 4

Mandatory Malignancy Screening: 4

• Peripheral blood and bone marrow screening for blasts
• Chest X-ray
• CT or ultrasound of abdomen and enlarged lymph nodes
• Biopsy of suspicious lymph nodes or cutaneous lesions
• Consider PET scan, MRI in patients with elevated malignancy likelihood (especially adults >30 years)

Infectious Workup: 2

• Viral studies: EBV, CMV (most common triggers), HIV, hepatitis panel
• Bacterial cultures: blood, urine, other sites as indicated
• Fungal studies if immunosuppressed
• Parasitic studies if travel history or endemic exposure

Autoimmune/Autoinflammatory Evaluation: 2

• ANA, RF, anti-dsDNA if systemic lupus erythematosus suspected
• Consider adult-onset Still's disease (especially with salmon-colored rash, arthritis)
• Evaluate for systemic juvenile idiopathic arthritis in younger patients

CNS Evaluation

Perform lumbar puncture if neurological symptoms are present (headaches, altered mental status, seizures, vision disturbances, gait abnormalities). 4 Screen cerebrospinal fluid for malignant cells and infections. 3

Monitoring Disease Activity

Platelets rapidly reflect HLH activity—a drop in platelet count indicates disease flares. 4 Monitor the following parameters every 12-24 hours to assess treatment response: 3

• Ferritin (increases rapidly in active HLH but normalizes slowly)
• Triglycerides and fibrinogen
• Complete blood counts
• Liver function tests
• Temperature and spleen size

Age-Related Considerations

In adults, nearly half of published HLH cases are triggered by neoplasm. 4 In children and adolescents, malignant context has a reported prevalence of only 8%. 4 Primary (genetic) HLH is most common in children but can occur in adolescents and young adults. 3

Special Considerations

The presence of an infection should not be regarded as contradictory to a malignant trigger—co-triggers are common, with viral infections often acting as co-triggers in malignancy-associated HLH. 4, 2 It is often difficult to differentiate between malignancy-triggered HLH and HLH during chemotherapy when both malignancy reactivation and infection coexist. 2

In male patients with lymphoma and EBV-driven HLH, strongly consider genetic or flow cytometric analysis for X-linked lymphoproliferative syndrome type 1 (XLP1), as 24% of XLP1 patients develop malignancy, usually Hodgkin lymphoma. 2