Table 1.

Diagnostic criteria for HLH used in the HLH-2004 trial^*

The diagnosis of HLH† may be established:
A. Molecular diagnosis consistent with HLH: pathologic mutations of PRF1, UNC13D, Munc18-2, Rab27a, STX11, SH2D1A, or BIRC4
or
B. Five of the 8 criteria listed below are fulfilled:
1. Fever ≥ 38.5°C
2. Splenomegaly
3. Cytopenias (affecting at least 2 of 3 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
4. Hypertriglyceridemia (fasting, > 265 mg/dL) and/or hypofibrinogenemia (< 150 mg/dL)
5. Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver
6. Low or absent NK-cell activity
7. Ferritin > 500 ng/mL‡
8. Elevated sCD25 (α-chain of sIL-2 receptor)§

^*Adapted from Henter et al.⁷

^†In addition, in the case of familial HLH, no evidence of malignancy should be apparent.

^‡Although the HLH-2004 protocol uses ferritin > 500 ng/mL, we generally view ferritin > 3000 ng/mL as concerning for HLH and ferritin > 10 000 as highly suspicious.⁸

^§Elevations above age-adjusted, laboratory-specific normal levels (defined as > 2 SD from the mean) appear more meaningful than the original designation of > 2400 U/mL because of variations between laboratories.¹⁷