No abstract

No abstract

Summary We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second‐line therapy for patients with steroid‐refractory disease.

No abstract

In a double-blind study, we compared the postoperative (post-op) blood loss in 161 children undergoing open heart surgery with cardiopulmonary bypass whose immediate post-op transfusion requirements were met with either very fresh whole blood (VFWB), 24- to 48-hour-old whole blood or reconstituted whole blood (packed red blood cells, fresh frozen plasma [FFP], and platelets). Assignment to treatment groups was not strictly random but dependent, in part, on the ability of families to provide directed donors for fresh blood. The three patient groups were comparable with respect to patient age, pre-op coagulation profiles (bleeding time, prothrombin time, activated partial thromboplastin time, platelet count, fibrin split products, fibrinogen, and platelet aggregation tests) difficulty of operative procedures and time spent on CPB. Mean 24-hour post-op blood loss in milliliters per kilogram was 50.9 +/- 9.3 in the VFWB group, 44.8 +/- 6.0 in the 24- to 48-hour-old group, and 74.2 +/- 8.9 in the reconstituted group (p = .03). When blood loss was compared in the 93 children less than 2 years of age, mean blood loss was 52.3 +/- 10.8 in the VFWB group, 51.7 +/- 7.4 in the 24- to 48-hour-old group, and 96.2 +/- 10.7 in the reconstituted group (P = .001). For subjects who had received reconstituted blood, 30- minute and 3-hour post-op platelet aggregation responses to adenosine diphosphate (10 mumol/L) and 30-minute aggregation response to epinephrine (2.5 mumol/L) were more depressed than in the VFWB and 24- to 48-hour groups (P less than .001, P = .005, and P = .02). Comparison of other post-op coagulation tests could not explain the increased blood loss in the reconstituted group. We conclude that the transfusion of less than 48 hours old whole blood is associated with significantly less post-op blood loss than the transfusion of packed red blood cells, FFP, and platelets in children under 2 years old who underwent complex cardiac surgery. The blood losses associated with the transfusion of VFWB and 24- to 48-hour-old blood are comparable and may be, in part, due to better functioning platelets.

No abstract

ALPS is a recently described disorder of disrupted lymphocyte homeostasis. Patients with ALPS have mutations in the Fas apoptotic pathway, leading to abnormal lymphocyte survival. Clinical manifestations in patients with ALPS vary but typically include autoimmune cytopenias, organomegaly, lymphadenopathy, and increased risk of development of lymphoma and certain leukemias. A similar constellation of findings can be seen in Evans Syndrome (ES), a hematologic disorder defined by autoimmune destruction of at least two hematologic cell types. We hypothesized that a subset of patients diagnosed with ES may have ALPS. We have designed a study to screen children with the diagnosis of ES syndrome for ALPS with a three tiered approach. First, a retrospective chart review was performed on all patients treated at CHOP in the past five years for ES who are still followed by the Division of Hematology. Next, patients with a clinical diagnosis of ES without another underlying diagnosis were screened for ALPS by flow cytometric analysis for double negative T cells (DNTs) (CD3+, CD4−, CD8−, TCRαβ+). DNTs are elevated in patients with ALPS and may provide the best current screening assay for this disease. DNTs analysis is easy to perform at low cost. Finally, patients were tested for ALPS by the gold standard test, defective in-vitro Fas mediated apoptosis. This test is labor intensive and not clinically available. 21 patients met entry criteria for the study, and, of these, 19 consented to enrollment. 16/19 had immune mediated destruction of all three hematologic cell lines. 2/19 had only had destruction of two cell types and 1 patient had immune thrombocytopenia with a positive DAT but no hemolysis or neutropenia. 14/19 had chronic disease with frequent hematologic exacerbations. The other 5 had occasional flares with illness. 10/19 had significant lymphadenopathy and 11/19 had organomegaly at some point in their history. 14/19 had either lymphadenopathy or organomegaly. 17/19 patients were screened for DNTs and 10 had elevated DNTs. Thus far, 7 patients have been tested for defective Fas mediated apoptosis. Every patient was tested in tandem with a normal control who demonstrated normal Fas mediated apoptosis. Five of the patients, all of whom had elevated DNTs, had defective Fas mediated apoptosis, confirming the diagnosis of ALPS. The other two patients did not have defective Fas mediated apoptosis: one did not have elevated DNTs and the other had a borderline result (2.7%; upper limit normal 2.6%). One of the patients with defective Fas mediated apoptosis and elevated DNTs had no history of lymphadenopathy or organomegaly. The lack of clinically identifiable lymphoproliferation in a patient with defective apoptosis is an unexpected finding, in apparent contradiction of the accepted NIH definition of ALPS which lists lymphoproliferation as a mandatory diagnostic criterion. This patient is three years old and may develop clinically identifiable lymphoproliferation with age. In summary, in the group of 17 ES patients screened to date, 59% had elevated DNTs suggestive of ALPS, with functional confirmation in 5/5 tested. Our data suggest that DNTs may be a sensitive first line-screening test and may serve as a marker that identifies patients who require definitive testing. Our preliminary findings suggest a high prevalence of ALPS among ES patients, a novel finding with important implications.

No abstract