Characteristics of each of 5 patients with MAS*
. | A . | B . | C . | D . | E . |
|---|---|---|---|---|---|
| Sex/age | F/4 y | M/4 y | M/14 d | M/1 y | M/2 mo |
| Underlying disorder | Systemic JIA† | Leishmaniasis‡ | Probable primary HLH§ | Short bowel syndrome, chronic parenteral nutrition, EBV infection∥ | Neonatal adenoviral necrotizing hepatitis, HSV 1 hepatitis in transplant liver§ |
| Clinical findings | |||||
| Nonremitting high fever | + | + | + | + | + |
| Hepatosplenomegaly | + | + | + | + | + |
| Coagulopathy | + | − | + | + | + |
| Lymphadenopathy | − | + | − | − | − |
| Multiple organ failure | + | − | − | − | − |
| CNS dysfunction | + | − | − | + | + |
| Biochemistry | |||||
| Hemoglobin, g/L | 84 | 71 | 104 | 75 | 88 |
| Platelets, × 109/L | 46 | 91 | 16 | 20 | 36 |
| White cells (neutrophils), × 109/L | 4.9 (ND) | 2.1 (0.6) | 3.4 (1.3) | 3 (1.1) | 4.4 (2.7) |
| ESR, mm/h | 45 | 64 | ND | 39 | 39 |
| Ferritin, μg/L (15-300)¶ | ND | 645 | 11 619 | 59 240 | 7979 |
| AST/ALT, U/L (<38/40)¶ | 1721/315 | 50/25 | 1130/875 | 802/292 | 2468/2105 |
| Triglycerides, μM/L (<2034)¶ | ND | 2904 | 1141 | 3616 | 622 |
| Fibrinogen, μM/L (5.3-10.6)¶ | ND | 7.41 | 1.0 | 3.82 | 10.0 |
| Sodium, mM/L (135-145)¶ | 127 | 134 | 129 | 130 | 132 |
| Treatment | Resuscitation for overwhelming shock and DIC | High-dose CSTs, CsA, IVIG, amphotericin | High-dose CSTs, CsA, ATG | High-dose CSTs, CsA, OKT3 | CSTs, tacrolimus, azathioprine,# high-dose CSTs, acyclovir, basiliximab |
| Outcome | Rapidly fatal | Remission | Remission of MAS but fatal infection during work-up for allogeneic BMT | Remission | Ongoing MAS and fatal CMV pneumonia |
. | A . | B . | C . | D . | E . |
|---|---|---|---|---|---|
| Sex/age | F/4 y | M/4 y | M/14 d | M/1 y | M/2 mo |
| Underlying disorder | Systemic JIA† | Leishmaniasis‡ | Probable primary HLH§ | Short bowel syndrome, chronic parenteral nutrition, EBV infection∥ | Neonatal adenoviral necrotizing hepatitis, HSV 1 hepatitis in transplant liver§ |
| Clinical findings | |||||
| Nonremitting high fever | + | + | + | + | + |
| Hepatosplenomegaly | + | + | + | + | + |
| Coagulopathy | + | − | + | + | + |
| Lymphadenopathy | − | + | − | − | − |
| Multiple organ failure | + | − | − | − | − |
| CNS dysfunction | + | − | − | + | + |
| Biochemistry | |||||
| Hemoglobin, g/L | 84 | 71 | 104 | 75 | 88 |
| Platelets, × 109/L | 46 | 91 | 16 | 20 | 36 |
| White cells (neutrophils), × 109/L | 4.9 (ND) | 2.1 (0.6) | 3.4 (1.3) | 3 (1.1) | 4.4 (2.7) |
| ESR, mm/h | 45 | 64 | ND | 39 | 39 |
| Ferritin, μg/L (15-300)¶ | ND | 645 | 11 619 | 59 240 | 7979 |
| AST/ALT, U/L (<38/40)¶ | 1721/315 | 50/25 | 1130/875 | 802/292 | 2468/2105 |
| Triglycerides, μM/L (<2034)¶ | ND | 2904 | 1141 | 3616 | 622 |
| Fibrinogen, μM/L (5.3-10.6)¶ | ND | 7.41 | 1.0 | 3.82 | 10.0 |
| Sodium, mM/L (135-145)¶ | 127 | 134 | 129 | 130 | 132 |
| Treatment | Resuscitation for overwhelming shock and DIC | High-dose CSTs, CsA, IVIG, amphotericin | High-dose CSTs, CsA, ATG | High-dose CSTs, CsA, OKT3 | CSTs, tacrolimus, azathioprine,# high-dose CSTs, acyclovir, basiliximab |
| Outcome | Rapidly fatal | Remission | Remission of MAS but fatal infection during work-up for allogeneic BMT | Remission | Ongoing MAS and fatal CMV pneumonia |
EBV indicates Epstein-Barr virus; HSV 1, herpes simplex virus 1; CNS, central nervous system; ESR, erythrocyte sedimentation rate; AST/ALT, aspartate aminotransferase/alanine aminotransferase; +, finding was present; −, finding was absent; ND, not determined; DIC disseminated intravascular coagulation; CSTs, corticosteroid; CsA, cyclosporin A; IVIG, intravenous immunoglobulin; ATG, antithymocyte globulin; OKT3, anti-CD3 monoclonal antibody; BMT, bone marrow transplantation; CMV, cytomegalovirus.
Diagnostic guidelines developed by the Histiocyte Society. The diagnosis of HLH can be established either if a molecular diagnosis consistent with HLH is established, or, if 5 of the 8 diagnostic criteria for HLH are fulfilled: (1) fever; (2) splenomegaly; (3) cytopenias affecting 2 or more of 3 lineages in the peripheral blood (hemoglobin < 90 g/L, platelets < 100 × 109/L, neutrophils < 1.0 × 109/L); (4) hypertriglyceridemia (fasting ≥ 265 mg/dL) and/or hypofibrinogenemia (≤ 1.5 g/L); (5) hemophagocytosis in bone marrow, spleen, or lymph nodes; (6) low or absent NK cell activity; (7) ferritin ≥ 500 μg/L, (8) soluble CD25 ≥ 2400 U/mL. Of note, cerebromeningeal symptoms, hyponatremia, and disturbed liver function are consistent with the diagnosis.
The association with early phase systemic-onset JIA and the presence of severe coagulopathy was considered as supportive evidence for the diagnosis.3,11 The fulminant and fatal course precluded functional NK/CTL testing.
Diagnosed at relapse of MAS.
Family history negative. Fulminant disease course precluded NK/CTL functional testing and genetic investigations.
Family history and mutational analysis of perforin gene negative. Prolonged cytopenia and protracted treatment with cyclosporine precludes NK/CTL functional testing.
Reference ranges for normal values of biochemical parameters are indicated in parentheses.
Immunosuppressive treatment in the context of the recent liver transplantation would have interfered with functional NK/CTL testing.