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2.
J Allergy Clin Immunol Pract ; 7(3): 848-855, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.

3.
EBioMedicine ; 28: 114-119, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29339099

RESUMO

Human adenoviruses (HAdV) are a major cause of morbidity and mortality in pediatric human stem cell transplant (HSCT) recipients. Our previous studies identified the gastrointestinal tract as a site of HAdV persistence, but the role of intestinal virus shedding pre-transplant for the risk of ensuing invasive infection has not been entirely elucidated. Molecular HAdV monitoring of serial stool samples using RQ-PCR was performed in 304 children undergoing allogeneic HSCT. Analysis of stool and peripheral blood specimens was performed pre-transplant and at short intervals until day 100 post-HSCT. The virus was detected in the stool of 129 patients (42%), and 42 tested positive already before HSCT. The patients displaying HAdV shedding pre-transplant showed a significantly earlier increase of intestinal HAdV levels above the critical threshold associated with high risk of invasive infection (p<0.01). In this subset of patients, the occurrence of invasive infection characterized by viremia was significantly higher than in patients without HAdV shedding before HSCT (33% vs 7%; p<0.0001). The data demonstrate that intestinal HAdV shedding before HSCT confers a greatly increased risk for invasive infection and disseminated disease post-transplant, and highlights the need for timely HAdV monitoring and pre-emptive therapeutic considerations in HSCT recipients.


Assuntos
Adenovírus Humanos/fisiologia , Doenças Transmissíveis/virologia , Intestinos/virologia , Transplante de Células-Tronco/efeitos adversos , Eliminação de Partículas Virais , Fezes/virologia , Humanos , Incidência , Cinética , Análise Multivariada , Fatores de Risco , Especificidade da Espécie , Fatores de Tempo , Transplante Homólogo , Viremia/epidemiologia
4.
Clin Infect Dis ; 65(11): 1819-1828, 2017 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-29020364

RESUMO

Background: This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). Methods: GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas ß-lactams (noncarbapenems), carbapenems, and multidrug resistance. Results: Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and ß-lactam/ß-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on ß-lactam/ß-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria. Conclusions: Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial. Clinical Trials Registration: NCT02257931.


Assuntos
Antibacterianos/farmacologia , Bacteriemia/microbiologia , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/microbiologia , Transplante de Células-Tronco Hematopoéticas , Transplantados , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/epidemiologia , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/epidemiologia , Humanos , Lactente , Internacionalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Transplantados/estatística & dados numéricos , Adulto Jovem
6.
Br J Haematol ; 169(5): 711-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25817915

RESUMO

Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Histiocitose de Células de Langerhans/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histiocitose de Células de Langerhans/mortalidade , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
7.
Clin Infect Dis ; 57(6): 794-802, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23771985

RESUMO

BACKGROUND: The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting. METHODS: A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease. RESULTS: One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extralymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0-1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival. CONCLUSIONS: More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Fatores Imunológicos/uso terapêutico , Transtornos Linfoproliferativos/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , DNA Viral/sangue , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/cirurgia , Infecções por Vírus Epstein-Barr/virologia , Europa (Continente)/epidemiologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Lactente , Estimativa de Kaplan-Meier , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/cirurgia , Transtornos Linfoproliferativos/virologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Rituximab , Carga Viral
8.
PLoS One ; 8(4): e59592, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23630567

RESUMO

Adenoviral infections are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. Adoptive transfer of donor-derived human adenovirus (HAdV)-specific T-cells represents a promising treatment option. However, the difficulty in identifying and selecting rare HAdV-specific T-cells, and the short time span between patients at high risk for invasive infection and viremia are major limitations. We therefore developed an IL-15-driven 6 to 12 day short-term protocol for in vitro detection of HAdV-specific T cells, as revealed by known MHC class I multimers and a newly identified adenoviral CD8 T-cell epitope derived from the E1A protein for the frequent HLA-type A*02∶01 and IFN-γ. Using this novel and improved diagnostic approach we observed a correlation between adenoviral load and reconstitution of CD8(+) and CD4(+) HAdV-specific T-cells including central memory cells in HSCT-patients. Adaption of the 12-day protocol to good manufacturing practice conditions resulted in a 2.6-log (mean) expansion of HAdV-specific T-cells displaying high cytolytic activity (4-fold) compared to controls and low or absent alloreactivity. Similar protocols successfully identified and rapidly expanded CMV-, EBV-, and BKV-specific T-cells. Our approach provides a powerful clinical-grade convertible tool for rapid and cost-effective detection and enrichment of multiple virus-specific T-cells that may facilitate broad clinical application.


Assuntos
Adenoviridae/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Infecções por Adenoviridae/imunologia , Infecções por Adenoviridae/virologia , Antígenos Virais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cultura de Células/economia , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Citotoxicidade Imunológica , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Fenótipo , Transplante Homólogo , Cultura de Vírus/economia , Adulto Jovem
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