TABLE II.
Diagnostic criteria for hemophagocytic lymphohistiocytosis
| Patient ID | Fever | Splenomegaly | Hemoglobin (g/dL) minimal | Platelet count, minimal | Leukocytes, maximal | Hemophagocytosis | Hyperferritinemia (≥500 mg/L) | Hypertriglyceridemia (fasting level: ≥3.0 mmol/L) or hypofibrinogenemia (≤1.5 g/L) | Elevated soluble CD25 level (≥2400 U/mL) | Low NK and/or T-cell cytotoxicity | NK cell degranulation | Perforin/SAP/XIAP expression | HLH criteria fulfilled | HLH according to an assessment by the attending physicians assessment (age at onset [y]) | HLH trigger |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| P1.1 | NA | NA | low | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | No HLH | Not applicable |
| P1.2 | Yes | No | 6.8 | 245-425 (age 8-14 y) | 9.2 | NA | Yes (553, age 14 y) | No Fib: 1.99-6.47, age 8-14 y TG 1.2 age 9 y |
NA | NA | NA | NA | NA (2/5; NA: 3)) | No HLH | Not applicable |
| P1.3 | Yes | Yes | 7.1 | 29 | 17.4 | Not in bone marrow (age 11 mo) | Yes (4,511) | Yes TG: 3,32, coagulation defect |
Yes; 3,957 | Normal | Normal CD107 expression | NA | Yes (6/8) | HLH (6 mo) | Rotavirus and norovirus |
| P2.1 | NA | NA | 14.7 | 213 | 9 | NA | No (68) | Yes TG: 4.9 Fib level normal |
NA | Not done | Not done | NA | NA (1/3; NA: 5) | No HLH | Not applicable |
| P2.2 | Yes | Yes | 6.0 | 6 | 25.58 | NA | Yes (34,616) | No Fib: 1.9 TG 0.8 |
NA | Not done | Not done | NA | NA (4/5; NA: 3) | HLH-like (3 mo) | Influenza A |
| P3.1 | NA | NA | NA | low | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | Not applicable |
| P3.2 | Yes | No | 8.8 | 34 | 9.12 | NA | No (220) | No Fib 1.55 |
No; 2,122 | Not done | Not done | NA | No (2/6; NA: 2) | HLH-like (1 y) | HHV6 |
| P4.1 | No | Yes | 6.7 | 15 | 33 | In liver (autopsy) | Yes (4,890) | Yes TG: 9.8 Fib not decreased: 5.4 |
No | Normal | Normal CD107 expression | Normal | Yes (5/8) | HLH (7 mo) | ADV |
| P4.2 | Yes | Yes | 7.5 | 62 | 23.8 | No | No (141) | Yes TG: 5.8 Fib not decreased: 4.9 |
NA | Normal | Normal CD107 expression | Normal | NA (4/7; NA: 1) | HLH-like (22 mo) | ADV, Parainfluenza |
| P5.1 | Yes | No | 7.5 | 54 | 36.6 | No (CSF analyzed) | Yes (82,148) | Yes Fib: 0.78 TG not increased: 1.2 |
Yes; 3,185 | Not done | Normal CD107 expression | 13% in NK cells (ref >5%)* | Yes (5/8) | HLH (2 mo) | HHV6, low-level CMV viremia |
| P5.2 | Yes | Yes | 6.8 | 14 | 36.7 | Yes (in BM) | Yes (37,474) | Yes Fib: 1.3 TG 5.5 |
Yes; 12,000 | Not done | Normal CD107 expression | 20% in NK cells (ref >5%)* | Yes (7/8) | HLH (9 mo) | HHV6 |
| P6.1 | Yes | Yes | 9.1 | 63 | 17.3 | NA | NA | NA | NA | NA | NA | NA | NA (3/3; NA:5) | No HLH | Not applicable |
| P7.1 | Yes | Yes | low | 42 | 50 | NA | Yes (12,000) | No | No | Normal NK cytotoxicity | Normal CD107a expression | NA (4/7; NA:1) | HLH-like (5 mo) | ||
| Yes | Yes | 7.5 | 20 | >50 | Yes (BM) | Yes (23,000) | No | NA | Yes (5/7; NA:1) | HLH (1 y) | Vaccine strain measles and low-level EBV viremia | ||||
| Yes | Yes | low | low | high | No (CSF) | Yes (2,546) | No | NA | † | NA (4/7; NA:1) | HLH-like (2 y 9 mo) | Influenza B and Staphylococcus aureus | |||
| P8.1 | Yes | Yes | 5.5 | 25 | Low (0.2) | No | Yes (6,000) | Yes TG 11.82 mmol/L |
Yes; 14,682 | Normal | NA | ND | Yes 6/8 | HLH (8 y) | No infectious agent found |
| P8.2 | No | Yes | 5.2 | 18 | No (BM) | Yes (2,805) | No | Yes (2,534) | Reduced NK cytotoxicity but tested with low NK cell number | NA | NA | NA (4/6, NA:2) | HLH-like (2 mo) | No infectious agent found | |
| Yes | Yes | 6.5 | 95 | NA | Yes (582) | No | No (1,164) | NA | NA | No (4/8) | HLH-like (6 y) | Influenza A |
ADV, Adenovirus; BM, bone marrow; CMV, cytomegalovirus; CSF, cerebrospinal fluid; Fib, Fibrinogen level; HHV6, human herpes virus type 6; HLH, hemophagocytic lymphohistiocytosis; ID, identifier; NA, not available; NK, natural killer; ref, reference; SAP, SLAM-associated protein; TG, triglycerides (fasting level).
Diagnostic criteria for hemophagocytic lymphohistiocytosis; according to the HLH-2004 study group’s criteria (Henter et al9).
Perforin expression was in the lower normal range in P5.1 and P5.2; this was probably due to the concomitant presence of a heterozygous p.Ala91Val variant in PRF1, which was also carried by the healthy father (data not shown). In the (male) patient P5.1, SAP and XIAP expression was measured by flow cytometry and was normal.
An abnormally low percentage of perforin-expressing NK cells, although this might reflect the relative expansion of a CD56 bright NK cell population. The sample was collected during a period of acute illness, when the NK cell count was low (in a context of viral infection/HLH). It is noteworthy that the NK cell count subsequently normalized but perforin release was not retested.