TABLE 1.

Diagnostic criteria used for the HLH2004 trial and relevance for clinical diagnosis

HLH2004 entry criteria	Comment
A. Molecular diagnosis consistent with HLH: Pathologic mutations of PRF1, UNC13D, STXBP2, Rab27a, STX11, SH2D1A, or XIAP or	In a patient with known genetic defects, treatment before full development of HLH may be appropriate, but genetic studies usually just help to define HLH recurrence risk, not the presence of an active disease state.
B. Five of the eight criteria listed below are fulfilled
1. Fever ≥38.3°C	Nearly universal in untreated HLH.
2. Splenomegaly	While splenomegaly and hepatomegaly are very common in HLH, adenopathy is not.
3. Cytopenias (affecting at least two of three lineages in the peripheral blood): Hemoglobin <9 g/dL (in infants <4 weeks: hemoglobin <10 g/dL) Platelets <100 × 103/mL Neutrophils < 1 × 103/mL	Cytopenias are ubiquitous in HLH. Lack of cytopenias should make one doubt a diagnosis of HLH, except in the special case of isolated, CNS-only disease.
4. Hypertriglyceridemia (>265 mg/dL) and/or hypofibrinogenemia (<150 mg/dL)	Low fibrinogen in the context of inflammation is paradoxical and one of the more distinctive features of HLH.
5. Hemophagocytosis in bone marrow or spleen or lymph nodes or liver	Not specific to HLH, or essential for the diagnosis, but helpful as a disease marker. Of note, it is often not evident early after disease onset.
6. Low or absent NK-cell activity	More modern and robust assays measuring perforin levels and its degranulation should replace this assay for reliable diagnosis of HLH. This assay is not specific for primary HLH.
7. Ferritin >500 ng/mL	Most patients have much higher levels than this threshold suggests.
8. Elevated Soluble CD25 (soluble IL-2 receptor alpha)	As HLH is a T-cell driven disease, this assay is extremely informative for diagnosis and response to therapy. See Section 3 for more information.