RESUMEN

The clinical significance and treatment strategies for minimal acute rejection (grade A1), the most common form of acute rejection (AR), remain controversial. In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between minimal AR and chronic lung allograft dysfunction (CLAD) and test a novel hypothesis using bronchoalveolar lavage (BAL) CXCL9 concentration during minimal AR as a biomarker of subsequent CLAD development. In univariable and multivariable models adjusted for all histopathologic injury patterns, minimal AR was not associated with CLAD development. However, minimal AR with elevated BAL CXCL9 concentrations markedly increased CLAD risk in a dose-response manner. Minimal AR with CXCL9 concentrations greater than the 25th, 50th, and 75th percentile had adjusted hazard ratios (HRs) for CLAD of 1.1 (95% confidence interval [CI] 0.8-1.6), 1.6 (95% CI 1.1-2.3), and 2.2 (95% CI 1.4-3.4), respectively. Thus we demonstrate the utility of BAL CXCL9 measurement as a prognostic biomarker that allows discrimination of recipients at increased risk of CLAD development after minimal AR. BAL CXCL9 measurement during transbronchial biopsies may provide clinically useful prognostic data and guide treatment decisions for this common form of AR, as a possible strategy to minimize CLAD development.

Asunto(s)

Lesión Pulmonar Aguda/diagnóstico , Biomarcadores/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Quimiocina CXCL9/metabolismo , Rechazo de Injerto/diagnóstico , Trasplante de Pulmón/efectos adversos , Complicaciones Posoperatorias/diagnóstico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Rechazo de Injerto/metabolismo , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/metabolismo , Pronóstico , Estudios Retrospectivos , Trasplante Homólogo

RESUMEN

The impact of allograft injury time of onset on the risk of chronic lung allograft dysfunction (CLAD) remains unknown. We hypothesized that episodes of late-onset (≥6 months) allograft injury would produce an augmented CXCR3/ligand immune response, leading to increased CLAD. In a retrospective single-center study, 1894 transbronchial biopsy samples from 441 lung transplant recipients were reviewed for the presence of acute rejection (AR), lymphocytic bronchiolitis (LB), diffuse alveolar damage (DAD), and organizing pneumonia (OP). The association between the time of onset of each injury pattern and CLAD was assessed by using multivariable Cox models with time-dependent covariates. Bronchoalveolar lavage (BAL) CXCR3 ligand concentrations were compared between early- and late-onset injury patterns using linear mixed-effects models. Late-onset DAD and OP were strongly associated with CLAD: adjusted hazard ratio 2.8 (95% confidence interval 1.5-5.3) and 2.0 (1.1-3.4), respectively. The early-onset form of these injury patterns did not increase CLAD risk. Late-onset LB and acute rejection (AR) predicted CLAD in univariable models but lost significance after multivariable adjustment for late DAD and OP. AR was the only early-onset injury pattern associated with CLAD development. Elevated BAL CXCR3 ligand concentrations during late-onset allograft injury parallel the increase in CLAD risk and support our hypothesis that late allograft injuries result in a more profound CXCR3/ligand immune response.

Asunto(s)

Lesión Pulmonar Aguda/etiología , Rechazo de Injerto/etiología , Trasplante de Pulmón/efectos adversos , Alveolos Pulmonares/patología , Lesión Pulmonar Aguda/diagnóstico , Líquido del Lavado Bronquioalveolar/química , Femenino , Estudios de Seguimiento , Rechazo de Injerto/diagnóstico , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Trasplante Homólogo

RESUMEN

Primary graft dysfunction (PGD) is a possible risk factor for bronchiolitis obliterans syndrome (BOS) following lung transplantation; however, the mechanism for any such association is poorly understood. Based on the association of TGF-ß with acute and chronic inflammatory disorders, we hypothesized that it might play a role in the continuum between PGD and BOS. Thus, the association between PGD and BOS was assessed in a single-center cohort of lung transplant recipients. Bronchoalveolar lavage fluid concentrations of TGF-ß and procollagen collected within 24 h of transplantation were compared across the spectrum of PGD, and incorporated into Cox models of BOS. Immunohistochemistry localized expression of TGF-ß and its receptor in early lung biopsies posttransplant. We found an association between PGD and BOS in both bilateral and single lung recipients with a hazard ratio of 3.07 (95% CI 1.76-5.38) for the most severe form of PGD. TGF-ß and procollagen concentrations were elevated during PGD (p < 0.01), and associated with increased rates of BOS. Expression of TGF-ß and its receptor localized to allograft infiltrating mononuclear and stromal cells, and the airway epithelium. These findings validate the association between PGD and the subsequent development of BOS, and suggest that this association may be mediated by receptor/TGF-ß biology.

Asunto(s)

Biomarcadores/metabolismo , Bronquiolitis Obliterante/diagnóstico , Rechazo de Injerto/diagnóstico , Trasplante de Pulmón/efectos adversos , Disfunción Primaria del Injerto/diagnóstico , Factor de Crecimiento Transformador beta/metabolismo , Anciano , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/metabolismo , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Rechazo de Injerto/sangre , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Técnicas para Inmunoenzimas , Enfermedades Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Disfunción Primaria del Injerto/etiología , Disfunción Primaria del Injerto/metabolismo , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad

RESUMEN

Despite the adoption of antifungal prophylaxis, fungal infections remain a significant concern in lung transplant recipients. Indeed, some concern exists that such prophylaxis may increase the risk of infection with drug-resistant fungal organisms. Here, we describe a case of disseminated Scedosporium prolificans infection, presenting as pericarditis, which developed in a lung transplant patient receiving prophylactic voriconazole for 8 months. The epidemiology and clinical presentation of S. prolificans infections are reviewed, and controversies surrounding antifungal prophylaxis and the development of resistant infections are discussed.

Asunto(s)

Aneurisma Infectado/microbiología , Aneurisma de la Aorta/microbiología , Trasplante de Pulmón , Micosis/microbiología , Pericarditis/microbiología , Pirimidinas/uso terapéutico , Scedosporium/aislamiento & purificación , Triazoles/uso terapéutico , Anciano , Aneurisma Infectado/diagnóstico , Aneurisma Infectado/prevención & control , Antifúngicos/uso terapéutico , Aneurisma de la Aorta/diagnóstico , Aneurisma de la Aorta/prevención & control , Farmacorresistencia Fúngica/efectos de los fármacos , Femenino , Humanos , Micosis/diagnóstico , Micosis/prevención & control , Pericarditis/diagnóstico , Pericarditis/prevención & control , Voriconazol

RESUMEN

A genetic screen using mice was performed to identify dominant loci affecting behavior. Mice were mutagenized with ENU, then bred to examine their G1 offspring for behavioral abnormalities. Potentially mutant G1 pups were screened through a variety of behavioral assays, including tests of learning and memory, sensorimotor gating, fear and anxiety, nociception (pain perception) and locomotor activity. Mice falling outside the normal performance distribution in these tests were considered potential behavioral mutants and were bred for further analysis. Outliers included both animals with very discrete defects and animals with abnormal performance across a range of tests. To date, we have identified two confirmed mutants affecting sensorimotor gating. These results provide further impetus for the use of random mutagenesis screens as a tool for dissecting the genetic basis of brain and behavior.

Asunto(s)

Conducta Animal/fisiología , Pruebas Genéticas/métodos , Ratones Mutantes Neurológicos/genética , Actividad Motora/genética , Umbral del Dolor/fisiología , Alquilantes , Animales , Condicionamiento Psicológico/fisiología , Etilnitrosourea , Conducta Exploratoria/fisiología , Miedo , Femenino , Locomoción/fisiología , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Mutagénesis/genética , Reflejo de Sobresalto/genética , Esquizofrenia/genética , Cola (estructura animal)