Diagnostic Criteria for Secondary HLH
The diagnosis of secondary HLH should be based on the HLH-2004 criteria, requiring 5 of 8 clinical and laboratory parameters to be fulfilled, though treatment may be initiated even when fewer than 5 criteria are met if clinical suspicion is high. 1
HLH-2004 Diagnostic Criteria (5 of 8 Required)
The following 8 criteria form the diagnostic framework, with at least 5 needed for diagnosis 1:
Clinical Criteria:
- Fever (present in 99% of cases)
- Splenomegaly (present in 77-84% of cases)
Laboratory Criteria:
Cytopenias affecting ≥2 of 3 lineages:
- Hemoglobin <90 g/L (<100 g/L in infants <4 weeks)
- Platelets <100 × 10⁹/L
- Neutrophils <1.0 × 10⁹/L
Hypertriglyceridemia and/or hypofibrinogenemia:
- Fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL)
- Fibrinogen ≤1.5 g/L
Hemophagocytosis in bone marrow, spleen, or lymph nodes (no evidence of malignancy)
Low or absent NK cell activity (according to local laboratory reference)
Ferritin ≥500 μg/L (though levels of 7,000-10,000 μg/L are more characteristic in adults; >10,000 μg/L has >90% sensitivity and specificity) 1
Soluble CD25 (sCD25/soluble IL-2 receptor) ≥2,400 U/mL (has excellent diagnostic performance with AUC 0.90, superior to ferritin) 1
Key Diagnostic Nuances
Important Caveats:
- The HLH-2004 criteria were developed for children and are not formally validated for adults, though they remain the standard based on expert consensus 1
- Clinical judgment must be integrated with the criteria—treatment should not be delayed if strong clinical suspicion exists, even without meeting 5 criteria 1
- A recent multicenter validation study suggests that 4 fulfilled HLH-2004 criteria may be sufficient for diagnosis in adults (mean sensitivity 86.5%, specificity 86.1%) 2
Screening and Supportive Markers:
- Ferritin ≥500 μg/L has 94% sensitivity as a screening marker—hyperferritinemia should always prompt HLH evaluation 2
- sCD25 is the single best diagnostic test with superior performance to ferritin (AUC 0.90 vs 0.78), with >90% sensitivity and 80% specificity 1, 3
Alternative Diagnostic Tool - HScore:
The HScore is a validated probability calculator that can estimate HLH likelihood 1. An HScore ≥169 has 82.4% sensitivity and 87.6% specificity for secondary HLH 2. The HScore incorporates:
- Known immunosuppression (18 points)
- Temperature (0-49 points)
- Organomegaly (0-38 points)
- Number of cytopenias (0-34 points)
- Ferritin level (0-50 points)
- Triglycerides (0-64 points)
- Fibrinogen (0-30 points)
- AST elevation (0-19 points)
- Hemophagocytosis on bone marrow (0-35 points)
Additional Supportive Findings
While not part of the formal criteria, these findings strengthen the diagnosis 1:
- CSF pleocytosis (mononuclear cells) and/or elevated CSF protein
- Hepatic histology resembling chronic persistent hepatitis
- Lymphadenopathy (84% of cases)
- Hepatomegaly (66% of cases)
- Hepatic enzyme abnormalities (AST, ALT, LDH elevation—very common)
- Hypoalbuminemia, hyponatremia
- Elevated VLDL/decreased HDL
- Respiratory system involvement (>50% of cases)
- CNS involvement (23% of cases)
Critical Diagnostic Pitfall
Do not wait for hemophagocytosis to be demonstrated—it may be absent early in disease or difficult to identify 1. If initial bone marrow is non-diagnostic, serial aspirates or biopsies from other organs (liver, lymph nodes, spleen) should be pursued, but treatment should not be delayed while awaiting histologic confirmation if other criteria are met.
Trigger Identification
A meticulous search for underlying triggers must be conducted and continued despite ongoing treatment 1. In adults, the most common triggers are:
- Infections (78% in pediatric series; most common overall): EBV is the leading viral trigger (57% of infection-associated cases) 1, 3
- Malignancies (particularly with increasing age): T/NK-cell lymphomas (35%), B-cell lymphomas (32%), leukemias (6%), Hodgkin lymphoma (6%) 1
- Autoimmune/autoinflammatory diseases (termed MAS-HLH when associated with Still's disease, lupus, vasculitis)