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Treatment with sirolimus ameliorates tacrolimus-induced autoimmune cytopenias after solid organ transplant

Teachey, David T; Jubelirer, Tracey; Baluarte, H Jorge; Wade, Amanda; Manno, Catherine S
The development of autoimmune blood cell cytopenias is a potentially life-threatening complication of solid organ transplantation, resulting from T-cell dysregulation from immunosuppressive medications. Conventional treatment with corticosteroids and IVIgG is often unsuccessful as these therapies are unlikely to overcome the T-cell dysregulation. We describe two patients who developed severe autoimmune cytopenias after solid organ transplantation. They had limited response to conventional medications, but had complete resolution of autoimmunity upon transition of immunosuppression from tacrolimus to sirolimus. Altering the immunosuppressive regimen to modify T-cell dysregulation may be beneficial for patients who develop post-transplant autoimmune disease and allow continued preservation of allograft
PMID: 19621445
ISSN: 1545-5017
CID: 115319

The clinical management of hemophilia and head trauma: a survey of current clinical practice among pediatric hematology/oncology physicians

Witmer, Char M; Manno, Catherine S; Butler, Regina B; Raffini, Leslie J
BACKGROUND: Determining the appropriate evaluation for a pediatric patient with hemophilia and head trauma is a diagnostic challenge with no neuroimaging guidelines and limited clinical evidence to direct care. PROCEDURE: A questionnaire, with two case scenarios, was emailed to members of the American Society of Pediatric Hematology/Oncology. The case scenarios involved asymptomatic toddlers with severe hemophilia who had either fallen from a height (case 1) or from standing (case 2). Respondents were asked to select from six management options. The case scenarios were then altered to include: a large palpable hematoma, prophylactic factor infusion 24 hr prior, the trauma occurred 48 hr prior, wearing a soft helmet, or emesis. RESULTS: The completed response rate was 23% (252/1,077). Computed tomography (CT) was selected by 68.9% (#1) and 56.4% (#2) of respondents. In both case scenarios the presence of a palpable bruise resulted in a statistically significant increase in CT usage to 83.7% and 82.8% (P < 0.001). The use of prophylaxis did not result in a statistically significant decrease in CT usage. Duration of factor replacement was variable ranging from 1 to 4 days. CONCLUSION: Physician self reported management of pediatric patients with hemophilia and head trauma is diverse. The use of CT imaging for mild head trauma in patients without signs or symptoms of intracranial hemorrhage was very common. The use of prophylaxis did not reduce the use of head CT imaging. This variation in clinical practice demonstrates the lack of evidence regarding the management of head trauma in patients with hemophilia
PMID: 19489052
ISSN: 1545-5017
CID: 115320

Incidence of bleeding complications in pediatric patients with type 1 von Willebrand disease undergoing adenotonsillar procedures

Witmer, Char M; Elden, Lisa; Butler, Regina B; Manno, Catherine S; Raffini, Leslie J
OBJECTIVE: To review the incidence of postoperative bleeding in children with type 1 von Willebrand disease (VWD) who were treated with a single institution protocol. STUDY DESIGN: We performed a retrospective study to determine the postoperative hemorrhage rate in pediatric patients with type 1 VWD who were treated via the Children's Hospital of Philadelphia institutional protocol. This protocol utilizes intravenous desmopressin (DDAVP), oral aminocaproic acid, and overnight observation. RESULTS: Between the years of 2000 to 2006, 41 children with type 1 VWD underwent an adenotonsillar procedure and were treated with this protocol. Seven patients (17%) experienced delayed (>24 hours after surgery) postoperative hemorrhage requiring intervention. Five of the 7 patients required cautery to control the bleeding, and the remaining 2 patients responded to DDAVP and aminocaproic acid alone. Older age and lower VW antigen levels were associated with postoperative hemorrhage (P = .05). CONCLUSIONS: Despite therapeutic intervention to decrease the risk of postoperative hemorrhage, the incidence of hemorrhage was higher in pretreated patients with type 1 VWD than in children without bleeding disorders. Further prospective studies are necessary to determine the optimal treatment to reduce bleeding complications in these patients
PMID: 19394040
ISSN: 1097-6833
CID: 115321

Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome

Teachey, David T; Greiner, Robert; Seif, Alix; Attiyeh, Edward; Bleesing, Jack; Choi, John; Manno, Catherine; Rappaport, Eric; Schwabe, Dirk; Sheen, Cecilia; Sullivan, Kathleen E; Zhuang, Hongming; Wechsler, Daniel S; Grupp, Stephan A
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.
PMID: 19208097
ISSN: 1365-2141
CID: 3318402

A prospective observational study of IVC filters in pediatric patients

Raffini, Leslie; Cahill, Anne Marie; Hellinger, Jeffrey; Manno, Catherine
BACKGROUND: The use of inferior vena cava (IVC) filters to prevent pulmonary embolism (PE) has increased with the advent of retrievable filters (Crowther: Am J Med 120: S13-S17, 2007). Both permanent and retrievable filters have been used in the pediatric population, though reports describing such patients and their outcomes are limited. PROCEDURE: Our center has established a longitudinal prospective cohort study of consecutive patients with acute venous thromboembolism (VTE) at our pediatric tertiary care institution. Data collection in this study includes medical history, risk factors, radiologic and laboratory studies, therapy, and follow-up. RESULTS: Two hundred ten patients were enrolled into this cohort from January 2003 to January 2007. IVC filters were percutaneously placed into 11 patients, ranging in age from 6.8 to 23.4 years. The primary reason for filter placement was a VTE and a contraindication to anticoagulation. Nine patients had retrievable filters placed and two received permanent filters. Seven of the nine retrievable filters were removed 21-97 days (median 37 days) after placement. In the remaining two patients, thrombus prevented removal in one, and the filter was electively retained in the other. One patient with a permanent filter died from malignancy. The three patients who are alive and well with IVC filters have had them for 25-60 months. No patient with an IVC filter developed a subsequent PE. CONCLUSIONS: Approximately 5% of patients in this pediatric thrombosis cohort received an IVC filter. The placement and removal of these devices is technically feasible in children
PMID: 18561173
ISSN: 1545-5017
CID: 90491

Utility of computed tomography of the head following head trauma in boys with haemophilia

Witmer, C M; Raffini, L J; Manno, C S
The most serious site of bleeding for patients with haemophilia is the central nervous system. Intracranial haemorrhage (ICH) in patients with haemophilia can occur spontaneously or following mild head trauma however no guidelines exist for the approach to these patients. The goal of this review was to determine the utility of screening computed tomography (CT) of the head for patients with haemophilia who experience head trauma and to determine if the use of clinical criteria could allow a selective approach to radiographic imaging. In a retrospective study we reviewed the management of head trauma in a cohort of paediatric patients with haemophilia in a single institution. The cohort included males, ages birth to 18 years with haemophilia A or B who were followed at the haemophilia treatment center at The Children's Hospital of Philadelphia from 1994 to 2005. Between the years of 1994 and 2005, 97 patients were evaluated for head trauma for a total of 374 emergency department visits. There were 295 head CT scans performed to identify 9 (3%) episodes of intracranial bleeding. Fifty-six per cent of the patients with intracranial bleeding had no clinical signs or symptoms. The clinical outcome was excellent in all cases with no deaths or reported morbidity. In this cohort, a lack of symptoms and a normal neurological exam did not exclude ICH, especially in patients with severe haemophilia who were evaluated soon after a mild head trauma event suggesting the utility of early head CT imaging
PMID: 17880444
ISSN: 1351-8216
CID: 87023

CD8(+) T-cell responses to adeno-associated virus capsid in humans

Mingozzi, Federico; Maus, Marcela V; Hui, Daniel J; Sabatino, Denise E; Murphy, Samuel L; Rasko, John E J; Ragni, Margaret V; Manno, Catherine S; Sommer, Jurg; Jiang, Haiyan; Pierce, Glenn F; Ertl, Hildegund C J; High, Katherine A
Hepatic adeno-associated virus (AAV)-serotype 2 mediated gene transfer results in transgene product expression that is sustained in experimental animals but not in human subjects. We hypothesize that this is caused by rejection of transduced hepatocytes by AAV capsid-specific memory CD8(+) T cells reactivated by AAV vectors. Here we show that healthy subjects carry AAV capsid-specific CD8(+) T cells and that AAV-mediated gene transfer results in their expansion. No such expansion occurs in mice after AAV-mediated gene transfer. In addition, we show that AAV-2 induced human T cells proliferate upon exposure to alternate AAV serotypes, indicating that other serotypes are unlikely to evade capsid-specific immune responses
PMID: 17369837
ISSN: 1078-8956
CID: 87024

Modern management of haemophilic arthropathy

Raffini, Leslie; Manno, Catherine
Currently available factor concentrates for treatment of patients with haemophilia are virally inactivated or are made by recombinant technology and their broad use in developed nations has resulted in the dramatic elimination of the treatment-related viral illnesses that decimated the haemophilia community in the late 20th century. The major morbidity experienced by patients with haemophilia today is joint disease, a result of repeated bleeding episodes into joint spaces. Although administration of factor concentrates to prevent bleeding has been demonstrated to prevent haemophilic joint disease when applied assiduously, repeated bleeding episodes induce synovitis that is irreversible and may progress despite subsequent prophylaxis. Surgical and nuclear medicine interventions are available to reduce the pain of haemophilic arthropathy and to reduce further bleeding episodes. Patients with high titre inhibitors are at great risk for the development of joint disease and present the greatest therapeutic challenges when joint surgery is needed.
PMID: 17341263
ISSN: 0007-1048
CID: 3318392

May-Thurner syndrome (iliac vein compression) and thrombosis in adolescents [Case Report]

Raffini, Leslie; Raybagkar, Deepti; Cahill, Anne Marie; Kaye, Robin; Blumenstein, Marilyn; Manno, Catherine
May-Thurner syndrome refers to anatomic compression of the left iliofemoral vein by the overriding right iliac artery. We report three adolescents who presented to our pediatric hospital with iliac vein thrombosis and were diagnosed with May-Thurner syndrome. Each received catheter-directed thrombolysis followed by balloon angioplasty to restore flow. Two patients had endovascular stents placed. The procedures were well tolerated, without major complications. Additional thrombophilic risk factors were identified in each patient. Though uncommon, pediatric hematologists should consider May-Thurner syndrome in adolescents who present with a left lower extremity thrombosis. Aggressive therapy may be warranted due to the risk of post-thrombotic syndrome.
PMID: 16365865
ISSN: 1545-5009
CID: 3318382

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)

Teachey, David T; Obzut, Dana A; Axsom, Kelly; Choi, John K; Goldsmith, Kelly C; Hall, Junior; Hulitt, Jessica; Manno, Catherine S; Maris, John M; Rhodin, Nicholas; Sullivan, Kathleen E; Brown, Valerie I; Grupp, Stephan A
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans
PMCID:1895548
PMID: 16757690
ISSN: 0006-4971
CID: 87026