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)§ |
| 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