RESUMEN
Since the early days of clinical lung transplantation the preservation of donor organs has become a fairly standardized procedure and most centers do follow similar processes. This includes the use of low-potassium high dextran flush solutions and static cold storage (SCS) in a cooler filled with ice. Depending on the length of SCS, organs usually arrive at the recipient hospital at a temperature of 0°C-4°C. The question of the optimal storage temperature for donor lung preservation has been revisited as data from large animal experiments demonstrated that organs stored at 10°C experience less mitochondrial damage. Thus, prolonged cold ischemic times can be better tolerated at 10°C-even in pre-damaged organs. The clinical applicability of these findings was demonstrated in an international multi-center observational study including three high-volume lung transplant centers. Total clinical preservation times of up to 24 hrs have been successfully achieved in organs stored at 10°C without hampering primary organ function and short-term outcomes. Currently, a randomized-controlled trial (RCT) is recruiting patients with the aim to compare standard SCS on ice with prolonged SCS protocol at 10°C. If, as anticipated, this RCT confirms data from previous studies, lung transplantation could indeed become a semi-elective procedure.
Asunto(s)
Trasplante de Pulmón , Preservación de Órganos , Animales , Humanos , Frío , Hielo , Pulmón , Trasplante de Pulmón/métodos , Estudios Observacionales como Asunto , Preservación de Órganos/métodos , Perfusión/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Temperatura , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: India has the highest prevalence of multidrug-resistant TB (MDR-TB) globally. Vitamin D deficiency is potentially an important risk factor for MDR-TB.METHODS: We conducted a case-control study of 90 newly diagnosed adult MDR-TB cases, 180 household controls and 82 non-household controls in Mumbai, India. Serum 25-hydroxyvitamin D (25(OH)D), anthropometry, clinical status and history, dietary data and sociodemographic data were collected from each participant. Interferon-gamma release assay (IGRA) was also performed in controls to assess latent TB. Multivariable regression was performed to estimate associations between 25(OH)D vs. case status and IGRA positivity.RESULTS: Mean participant age was 33.8 ± 12.0 years; 72.8% had 25(OH)D <20 ng/ml. Mean 25(OH)D was significantly (P < 0.05) lower in cases (12.5 ± 7.9) than both household (17.5 ± 11.2) and non-household controls (16.4 ± 9.1). In multivariable models, 25(OH)D concentration was inversely associated with MDR-TB case status among cases and household controls (OR 0.95 per 1 ng/ml, 95% CI 0.92-0.99; P = 0.015), and among cases and non-household controls (OR 0.94 per 1 ng/ml, 95% CI 0.89-1.00; P = 0.033); 53.6% of controls were IGRA-positive. 25(OH)D status was not associated with IGRA positivity.CONCLUSION: Vitamin D status was independently associated with MDR-TB case status. Research should evaluate the effectiveness of vitamin D supplementation in prevention and adjunctive treatment of MDR-TB.
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Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis Pulmonar , Deficiencia de Vitamina D , Adulto , Estudios de Casos y Controles , Humanos , Persona de Mediana Edad , Factores de Riesgo , Tuberculosis Resistente a Múltiples Medicamentos/complicaciones , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiología , Vitamina D , Deficiencia de Vitamina D/diagnóstico , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/epidemiología , Adulto JovenRESUMEN
BACKGROUND: We assessed treatment uptake and completion for 6 months of isoniazid (6H) and 3 months of isoniazid plus rifapentine weekly (3HP) in a programmatic setting in Pakistan.METHODS: All household contacts were clinically evaluated to rule out TB disease. 6H was used for TB preventive treatment (TPT) from October 2016 to April 2017; from May to September 2017, 3HP was used for contacts aged ≥2 years. We compared clinical evaluation, TPT uptake and completion rates between contacts aged ≥2 years in the 6H period and in the 3HP period.RESULTS: We identified 3,442 contacts for the 6H regimen. After clinical evaluation, 744/1,036 (72%) started treatment, while 46% completed treatment. In contrast, 3,722 contacts were identified for 3HP. After clinical evaluation, 990/1,366 (72%) started treatment, while 67% completed treatment. Uptake of TPT did not differ significantly between the 6H and 3HP groups (OR 1.03, 95%CI 0.86-1.24). However, people who initiated 3HP had 2.3 times greater odds (95% CI 1.9-2.8) of completing treatment than those who initiated 6H after adjusting for age and sex.CONCLUSION: In programmatic settings in a high-burden country, household contacts of all ages were more likely to complete TPT with shorter weekly regimens, although treatment uptake rate for the two regimens was similar.
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Isoniazida , Tuberculosis Latente , Antituberculosos/uso terapéutico , Quimioterapia Combinada , Humanos , Isoniazida/uso terapéutico , Tuberculosis Latente/tratamiento farmacológico , Pakistán/epidemiologíaRESUMEN
BACKGROUND: In Lima, Peru, a mobile TB screening program ("TB Móvil") was implemented in high TB prevalence districts to increase TB screening. Community engagement activities to promote TB Móvil were simultaneously conducted. OBJECTIVE: To describe a structured, theory-driven community engagement strategy to support the uptake of TB Móvil. METHODS: We adapted Popular Opinion Leader (POL), an evidence-based social networking intervention previously used in Peru to promote HIV testing, for TB Móvil. Community health workers, women who run soup kitchens, and motorcycle taxi drivers served as "popular opinion leaders" who disseminated information about TB Móvil in everyday conversations, aided by a multi-media campaign. Performance indicators of POL included the number/characteristics of persons screened; number of multimedia elements; and proportion of persons with abnormal radiographs hearing about TB Móvil before attending. RESULTS: Between February 2019 and January 2020, 63,899 people attended the TB Móvil program at 210 sites; 60.1% were female. The multimedia campaign included 36 videos, 16 audio vignettes, flyers, posters, community murals and "jingles." Among attendees receiving an abnormal chest X-ray suggestive of TB, 48% (6,935/14,563) reported hearing about TB Móvil before attending. CONCLUSIONS: POL promotes the uptake of TB Móvil and should be considered as a strategy for increasing TB screening uptake.
CONTEXTE: À Lima, Pérou, un programme mobile de dépistage de la TB (« TB Móvil ¼) a été mis en place dans les quartiers à forte prévalence de TB afin d'accroître le dépistage de la maladie. Des activités de mobilisation communautaire visant à promouvoir TB Móvil ont été menées en parallèle. L'objectif de ce rapport est de décrire une stratégie structurée de mobilisation communautaire, fondée sur des principes théoriques, afin de soutenir le recours au programme TB Móvil. MÉTHODES: Nous avons adapté à TB Móvil l'intervention factuelle de réseautage social appelée « Popular Opinion Leader (POL; leader d'opinion) ¼, précédemment utilisée au Pérou pour promouvoir le dépistage du VIH. Les agents de santé communautaires, les femmes responsables de la soupe populaire et les chauffeurs de mototaxis étaient des leaders d'opinion. Ils communiquaient des informations sur TB Móvil lors de leurs conversations quotidiennes, qui étaient étayées par une campagne multimédia. Les indicateurs de performance des POL comprenaient le nombre/les caractéristiques des personnes dépistées, le nombre d'éléments multimédias et le pourcentage de personnes avec cliché radiographique anormal qui avaient entendu parler de TB Móvil avant de se faire dépister. RÉSULTATS: Entre février 2019 et janvier 2020, 63 899 personnes ont pris part au programme TB Móvil dans 210 sites ; 60,1% étaient des femmes. La campagne multimédia reposait sur 36 vidéos, 16 vignettes audio, des prospectus, des posters, des peintures murales dans la communauté et des « jingles ¼. Parmi les personnes dont la radiographie pulmonaire était anormale et évocatrice de TB, 48% (6 935/14 563) ont rapporté avoir entendu parler de TB Móvil avant de venir consulter. CONCLUSIONS: L'intervention POL, qui semblait renforcer le recours au programme TB Móvil, peut donc servir d'une stratégie de promotion du dépistage de la TB.
RESUMEN
BACKGROUND: Evaluation of the joint clinical and economic impacts of lung transplant and associated technologies is crucial for evidence-informed decision-making and wise allocation of scarce healthcare resources. We performed a scoping review to summarize and categorize the available evidence of the costs and cost-effectiveness of lung transplantation. METHODS: A systematic search of MEDLINE, EMBASE, NHS EED, and EconLit was performed to identify studies involving lung transplantation for adults that measured costs, cost-effectiveness, or which described themselves as economic evaluations. A scoping review was performed in adherence to the framework described by Arksey & O'Malley. Risk of bias was assessed in included studies using the ECOBIAS and CHEC-list tools. RESULTS: In total, 324 studies were identified, of which 28 met inclusion criteria. Cost-utility estimates of lung transplant versus waitlist, from the healthcare payer perspective and a time-horizon of at least 10-years ranged between $42,459 and $154,051 per quality-adjusted life year. Common topics of study included lung transplant versus waitlist care, immunosuppression, organ retrieval and allocation, and mechanical life support. CONCLUSIONS: Sources of variation in costs-assessments and economic evaluations included differences in the type of study performed, payer perspective adopted, study time horizon, and variation in clinical practice. The best available cost-utility estimates for lung transplant versus waitlist may represent cost-effectiveness under some circumstances, but high-quality evidence is lacking. Further cost-utility analyses, with sufficient methodologic rigour, are required to overcome the observed variation in results and confirm cost-effectiveness of the current standard of care in lung transplantation.
Asunto(s)
Trasplante de Pulmón/economía , Obtención de Tejidos y Órganos/economía , Costos y Análisis de Costo , HumanosAsunto(s)
Tuberculosis Resistente a Múltiples Medicamentos , Antituberculosos/uso terapéutico , Humanos , Población Rural , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/prevención & controlRESUMEN
The development of de novo donor-specific HLA antibodies (dnDSA) after transplantation is associated with graft failure, mortality, and cost. There is no effective therapeutic intervention to prevent dnDSA or ameliorate associated injury. The aims of this study were to identify specific HLA factors associated with dnDSA development and to propose primary prevention strategies that could reduce the incidence of dnDSA without prohibitively limiting access to transplant. The investigation cohort included heart transplant recipients from 2008 to 2015 (n = 265). HLA typing was performed and HLA antibody testing was undertaken before and after transplantation. HLAMatchmaker analysis was performed for persistent dnDSA to identify potentially more immunogenic eplet differences. Validation was performed in recipients of lung transplants from 2008 to 2013 (n = 433). The majority of recipients with dnDSA had antibodies to identical eplet positions on DQ2 and DQ7. A high-risk epitope mismatch (found in DQA1*05 + DQB1*02/DQB1*03:01(7)) was associated with a 4.2- and 4.9-fold increased risk of dnDSA in heart and lung recipients respectively. HLA electrostatic potential modeling provided a plausible explanation for this observed immunogenicity. A theoretical allocation algorithm avoiding high-risk epitope mismatches was generated and predicted to reduce dnDSA by up to 72% without additional testing, eplet analysis, or cost.
Asunto(s)
Epítopos/inmunología , Rechazo de Injerto/etiología , Supervivencia de Injerto/inmunología , Antígenos HLA/inmunología , Trasplante de Corazón/efectos adversos , Isoanticuerpos/efectos adversos , Trasplante de Pulmón/efectos adversos , Estudios de Cohortes , Estudios de Seguimiento , Prueba de Histocompatibilidad , Humanos , Complicaciones Posoperatorias , Pronóstico , Asignación de Recursos , Factores de Riesgo , Donantes de TejidosRESUMEN
OBJECTIVES: Exhaled breath condensate (EBC) is a noninvasive means of sampling the airways that has shown significant promise in the diagnosis of many disorders. There have been no reports of its usefulness in the detection of galactomannan (GM), a component of the cell wall of Aspergillus. The suitability of EBC for the detection of GM for the diagnosis of invasive aspergillosis (IA) using the Platelia Aspergillus enzyme-linked immunosorbent assay was investigated. METHODS: Prospective, cross-sectional study of lung transplant recipient and haemotologic malignancy patients at a university centre. EBC samples were compared to concomitant bronchoalveolar lavage (BAL) samples among lung transplant recipients and healthy controls. EBC was collected over 10 minutes using a refrigerated condenser according to the European Respiratory Society/American Thoracic Society recommendations, with the BAL performed immediately thereafter. RESULTS: A total of 476 EBC specimens with 444 matched BAL specimens collected from lung transplant recipients (n = 197) or haemotologic malignancy patients (n = 133) were examined. Both diluted and untreated EBC optical density (OD) values (0.0830, interquartile range (IQR) 0.0680-0.1040; and 0.1130, IQR 0.0940-0.1383), respectively, from all patients regardless of clinical syndrome were significantly higher than OD values in healthy control EBCs (0.0508, IQR 0.0597-0.0652; p < 0.0001). However, the OD index values did not correlate with the diagnosis of IA (44 samples were associated with IA). Furthermore, no significant correlation was found between EBC GM and the matched BAL specimen. CONCLUSIONS: GM is detectable in EBC; however, no correlation between OD index values and IA was noted in lung transplant recipients.
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Aspergillus/química , Líquido del Lavado Bronquioalveolar/química , Neoplasias Hematológicas/microbiología , Aspergilosis Pulmonar Invasiva/diagnóstico , Mananos/aislamiento & purificación , Anciano , Aspergillus/aislamiento & purificación , Pruebas Respiratorias , Líquido del Lavado Bronquioalveolar/microbiología , Estudios de Casos y Controles , Pared Celular/química , Estudios Transversales , Espiración , Femenino , Galactosa/análogos & derivados , Humanos , Huésped Inmunocomprometido , Aspergilosis Pulmonar Invasiva/microbiología , Trasplante de Pulmón , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Cystic fibrosis (CF) affects multiple organs including the lung, liver, and pancreas. Lung transplant, liver transplant, and combined lung-liver transplant have become well-established therapies for CF patients with end-stage organ failure. Thus far, however, there has been limited experience with pancreas transplantation in CF. In this report, we detail the clinical history, transplant procedure, and post-operative recovery of a patient who underwent combined lung-liver-pancreas transplant for advanced CF.
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Fibrosis Quística , Trasplante de Hígado/métodos , Trasplante de Pulmón/métodos , Trasplante de Páncreas/métodos , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Fibrosis Quística/fisiopatología , Fibrosis Quística/cirugía , Progresión de la Enfermedad , Humanos , Hígado/fisiopatología , Hígado/cirugía , Pulmón/fisiopatología , Pulmón/cirugía , Masculino , Páncreas/fisiopatología , Páncreas/cirugía , Atención Perioperativa/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
Ex vivo lung perfusion (EVLP) enables assessment of marginal donor lungs for transplantation. We aimed to discover biomarkers in EVLP perfusate that could predict development of primary graft dysfunction (PGD). From September 2008 to August 2013, 100 clinical EVLPs were performed. Eleven patients developed PGD grade 3 within 72 h after transplant. The non-PGD group consisted of 34 patients without PGD grade 3. Nonbilateral lung transplants or transplant after extracorporeal life support were excluded from analyses. Soluble intercellular adhesion molecule 1 (sICAM-1), soluble VCAM-1 (sVCAM-1), and soluble E selectin (sE-selectin) levels, as markers of endothelial activation, were measured in the perfusate of EVLP by enzyme-linked immunosorbent assay and were correlated with clinical outcome. Levels of sICAM-1 at 1 h and sVCAM-1 at 1 and 4 h were significantly higher in the PGD group compared with the non-PGD group. The sE selectin levels were not statistically different between the study groups. Higher levels of sVCAM-1 at 1 and 4 h were statistically significantly associated with PGD either alone or after adjustment for other PGD risk factors. These adhesion molecules may help identify donor lungs at higher risk of PGD during EVLP.
Asunto(s)
Biomarcadores/metabolismo , Trasplante de Pulmón/efectos adversos , Complicaciones Posoperatorias/diagnóstico , Disfunción Primaria del Injerto/diagnóstico , Donantes de Tejidos , Adulto , Selectina E/metabolismo , Circulación Extracorporea , Femenino , Estudios de Seguimiento , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Persona de Mediana Edad , Perfusión , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/metabolismo , Disfunción Primaria del Injerto/etiología , Disfunción Primaria del Injerto/metabolismo , Pronóstico , Estudios Retrospectivos , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
Lung transplantation using RNA+ hepatitis C (HCV+) donors to seronegative recipients is not currently performed due to the very high risk of transmission. Previous reports have shown poor survival when this practice was applied. The emergence of new direct-acting antiviral drugs (DAA) suggests a high chance of sustained virologic response in immunocompetent patients. We report here successful transplantation of lungs from HCV+ donor to HCV- recipient. The recipient was an HCV- patient with chronic lung allograft dysfunction. Viral transmission occurred early posttransplant but excellent clinical outcomes were observed including elimination of HCV after 12 weeks of treatment using DAAs.
Asunto(s)
Supervivencia de Injerto , Hepatitis C/prevención & control , Trasplante de Pulmón/métodos , Donantes de Tejidos , Obtención de Tejidos y Órganos , Receptores de Trasplantes , Adulto , Hepacivirus/fisiología , Hepatitis C/transmisión , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
In regard to tuberculosis (TB) and other major global epidemics, the use of new diagnostic tests is increasing dramatically, including in resource-limited countries. Although there has never been as much digital information generated, this data source has not been exploited to its full potential. In this opinion paper, we discuss lessons learned from the global scale-up of these laboratory devices and the pathway to tapping the potential of laboratory-generated information in the field of TB by using connectivity. Responding to the demand for connectivity, innovative third-party players have proposed solutions that have been widely adopted by field users of the Xpert(®) MTB/RIF assay. The experience associated with the utilisation of these systems, which facilitate the monitoring of wide laboratory networks, stressed the need for a more global and comprehensive approach to diagnostic connectivity. In addition to facilitating the reporting of test results, the mobility of digital information allows the sharing of information generated in programme settings. When they become easily accessible, these data can be used to improve patient care, disease surveillance and drug discovery. They should therefore be considered as a public health good. We list several examples of concrete initiatives that should allow data sources to be combined to improve the understanding of the epidemic, support the operational response and, finally, accelerate TB elimination. With the many opportunities that the pooling of data associated with the TB epidemic can provide, pooling of this information at an international level has become an absolute priority.
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Pruebas Diagnósticas de Rutina , Registros Electrónicos de Salud , Registro Médico Coordinado , Técnicas de Diagnóstico Molecular , Juego de Reactivos para Diagnóstico , Tuberculosis/diagnóstico , Tuberculosis/prevención & control , Acceso a la Información , Pruebas Diagnósticas de Rutina/tendencias , Registros Electrónicos de Salud/tendencias , Epidemias , Predicción , Humanos , Almacenamiento y Recuperación de la Información , Técnicas de Diagnóstico Molecular/tendencias , Valor Predictivo de las Pruebas , Pronóstico , Juego de Reactivos para Diagnóstico/tendencias , Factores de Tiempo , Tuberculosis/epidemiología , Tuberculosis/transmisiónRESUMEN
SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a growing global health threat that often requires presumptive treatment in the absence of drug susceptibility testing (DST) results. OBJECTIVE: To compare two approaches to the treatment of MDR-TB contacts with no DST results who develop TB disease. DESIGN: We conducted a retrospective cohort study of adults treated for TB disease who were contacts of patients living with MDR-TB. Subjects had been treated according to one of two presumptive treatment strategies: 1) regimens containing exclusively first-line drugs, and 2) regimens that included both first- and second-line drugs that were adjusted if and when DST results became available. The primary endpoint was a composite of death and treatment failure. RESULTS: Household contacts of MDR-TB patients who developed TB disease and were treated with first-line regimens were significantly more likely to experience unfavorable end-of-treatment outcomes than those treated with presumptive MDR-TB regimens (RR 2.88, 95%CI 1.24-6.68). CONCLUSION: Household contacts of MDR-TB patients who develop TB disease but have no DST results should receive regimens containing second-line drugs selected based on the infecting strain of the index patient. Regimens containing only first-line anti-tuberculosis drugs significantly increase the risk of unfavorable outcomes.
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Antituberculosos/uso terapéutico , Composición Familiar , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto , Farmacorresistencia Bacteriana Múltiple , Determinación de Punto Final , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Proyectos Piloto , Estudios Retrospectivos , Factores de Riesgo , Esputo/microbiología , Resultado del Tratamiento , Adulto JovenRESUMEN
Ex vivo lung perfusion (EVLP) is a platform to treat infected donor lungs with antibiotic therapy before lung transplantation. Human donor lungs that were rejected for transplantation because of clinical concern regarding infection were randomly assigned to two groups. In the antibiotic group (n = 8), lungs underwent EVLP for 12 h with high-dose antibiotics (ciprofloxacin 400 mg or azithromycin 500 mg, vancomycin 15 mg/kg, and meropenem 2 g). In the control group (n = 7), lungs underwent EVLP for 12 h without antibiotics. A quantitative decrease in bacterial counts in bronchoalveolar lavage (BAL) was found in all antibiotic-treated cases but in only two control cases. Perfusate endotoxin levels at 12 h were significantly lower in the antibiotic group compared with the control group. EVLP with broad-spectrum antibiotic therapy significantly improved pulmonary oxygenation and compliance and reduced pulmonary vascular resistance. Perfusate endotoxin levels at 12 h were strongly correlated with levels of perfusates tumor necrosis factor α, IL-1ß and macrophage inflammatory proteins 1α and 1ß at 12 h. In conclusion, EVLP treatment of infected donor lungs with broad-spectrum antibiotics significantly reduced BAL bacterial counts and endotoxin levels and improved donor lung function.
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Antiinfecciosos/administración & dosificación , Trasplante de Pulmón/normas , Pulmón/microbiología , Perfusión/métodos , Obtención de Tejidos y Órganos/normas , Adulto , Antiinfecciosos/farmacología , Carga Bacteriana , Líquido del Lavado Bronquioalveolar/microbiología , Bronconeumonía/tratamiento farmacológico , Bronconeumonía/microbiología , Bronconeumonía/patología , Estudios de Casos y Controles , Circulación Extracorporea , Femenino , Estudios de Seguimiento , Humanos , Pulmón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Pronóstico , Donantes de TejidosRESUMEN
Chronic lung allograft dysfunction, the major cause of death following lung transplantation, usually manifests as irreversible airflow obstruction associated with obliterative bronchiolitis (OB), a lesion characterized by chronic inflammation, lymphoid neogenesis, fibroproliferation and small airway obliteration. Spleen tyrosine kinase (Syk), a tyrosine kinase that regulates B cell function and innate immunity, has been implicated in the pathogenesis of chronic inflammation and tissue repair. This study evaluated the role of Syk in development of OB, using an intrapulmonary tracheal transplant model of OB with the conditional Syk-knockout Syk(flox/flox) //rosa26-CreER(T2) mice and a Syk-selective inhibitor, GSK2230413. BALB/c trachea allografts were transplanted into Syk-knockout (Syk(del/del) ) mice or wild-type C57BL/6 recipients treated with GSK2230413. At day 28, histological analysis revealed that in the Syk(del/del) and GSK2230413-treated C57BL/6 recipients, the graft lumen remained open compared with allografts transplanted into Syk-expressing (Syk(flox/flox) ) and placebo control-treated C57BL/6 recipients. Immunofluorescence showed lymphoid neogenesis with distinct B and T cell zones in control mice. In contrast, lymphoid neogenesis was absent and few B or T cells were found in Syk(del/del) and GSK2230413-treated mice. These observations suggest that inhibition of Syk may be a potential therapeutic strategy for the management of OB following lung transplantation.
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Bronquiolitis Obliterante/etiología , Rechazo de Injerto/inmunología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Trasplante de Pulmón/efectos adversos , Tejido Linfoide/inmunología , Proteínas Tirosina Quinasas/fisiología , Bazo/enzimología , Animales , Linfocitos B/inmunología , Western Blotting , Células Cultivadas , Fibrosis/etiología , Fibrosis/patología , Citometría de Flujo , Supervivencia de Injerto/inmunología , Inmunidad Innata/inmunología , Técnicas para Inmunoenzimas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Complicaciones Posoperatorias , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/inmunología , Quinasa Syk , Linfocitos T/inmunología , Tráquea/trasplante , Trasplante HomólogoAsunto(s)
Agonistas del Receptor de Adenosina A2/farmacología , Frío , Trasplante de Pulmón , Pulmón/efectos de los fármacos , Pulmón/cirugía , Soluciones Preservantes de Órganos/farmacología , Receptor de Adenosina A2A/efectos de los fármacos , Daño por Reperfusión/prevención & control , Conservación de Tejido/métodos , Animales , Femenino , MasculinoRESUMEN
Ischemia-reperfusion (IR)-induced lung injury is one of the major contributing factors of morbidity and mortality after lung transplantation. To determine the IR-induced molecular changes in lung epithelial cells, we developed a cell-culture model that simulates lung preservation and transplantation. Six hours of cold ischemic time (CIT) and reperfusion elicited production of multiple inflammatory cytokines and chemokines and increased expression of endoplasmic reticulum (ER) proteins. Prolonged hypothermic condition (18 h CIT) reduced ER stress protein levels, and induced apoptosis and necrosis (via mechanisms related to mitochondrial permeability transition pore opening). Protein kinase C (PKCδ) was activated during CIT, and its downregulation via small interference (si) (in siRNA) RNA reduced IR-induced cytokine production and apoptotic cell death. δV1-1, a PKCδ peptide inhibitor, reduced translocation of PKCδ and p53 to the mitochondria after 18 h CIT, rescued ER stress protein expression, and converted the major mode of cell death from necrosis to apoptosis. Administration of δV1-1 effectively reduced lung transplantation and IR-induced pulmonary injury in rats. Therefore, inhibition of PKCδ by δV1-1 could be an effective strategy to ameliorate IR-induced lung injury by inhibiting the signaling pathways leading to necrosis.
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Lesión Pulmonar/prevención & control , Trasplante de Pulmón/efectos adversos , Mitocondrias/metabolismo , Oligopéptidos/farmacología , Proteína Quinasa C-delta/antagonistas & inhibidores , Daño por Reperfusión/fisiopatología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Citocinas/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Inflamación/etiología , Inflamación/patología , Inflamación/prevención & control , Lesión Pulmonar/etiología , Lesión Pulmonar/patología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Necrosis , Proteína Quinasa C-delta/genética , Proteína Quinasa C-delta/metabolismo , ARN Interferente Pequeño/genética , RatasRESUMEN
BACKGROUND: The lack of published information about children with multidrug-resistant tuberculosis (MDR-TB) is an obstacle to efforts to advocate for better diagnostics and treatment. OBJECTIVE: To describe the lack of recognition in the published literature of MDR-TB and extensively drug-resistant TB (XDR-TB) in children. DESIGN: We conducted a systematic search of the literature published in countries that reported any MDR- or XDR-TB case by 2012 to identify MDR- or XDR-TB cases in adults and in children. RESULTS: Of 184 countries and territories that reported any case of MDR-TB during 2005-2012, we identified adult MDR-TB cases in the published literature in 143 (78%) countries and pediatric MDR-TB cases in 78 (42%) countries. Of the 92 countries that reported any case of XDR-TB, we identified adult XDR-TB cases in the published literature in 55 (60%) countries and pediatric XDR-TB cases for 9 (10%) countries. CONCLUSION: The absence of publications documenting child MDR- and XDR-TB cases in settings where MDR- and XDR-TB in adults have been reported indicates both exclusion of childhood disease from the public discourse on drug-resistant TB and likely underdetection of sick children. Our results highlight a large-scale lack of awareness about children with MDR- and XDR-TB.
Cadre : La pénurie d'informations publiées sur la tuberculose multirésistante (TB-MDR) de l'enfant entrave les efforts visant à en améliorer le diagnostic et le traitement.Objectif : Décrire le manque de reconnaissance de la TB-MDR et de la TB ultra-résistante (TB-XDR) de l'enfant dans la littérature publiée.Schéma : Nous avons réalisé une recherche systématique de la littérature publiée dans les pays qui ont déclaré au moins un cas de TB-MDR ou -XDR avant 2012 afin d'identifier des cas de TB-MDR ou -XDR chez des adultes et des enfants.Résultats : Sur les 184 pays et territoires qui ont déclaré des cas de TB-MDR entre 2005 et 2012, nous avons identifié des cas de TB-MDR de l'adulte dans la littérature dans 143 (78%) pays et des cas de TB-MDR pédiatrique dans 78 (42%) pays. Sur les pays qui ont déclaré des cas de TB-XDR, nous avons identifié des cas adultes dans la littérature dans 55 (60%) pays et des cas pédiatriques dans 9 (10%) pays.Conclusion : L'absence de publications documentant les cas de TB-MDR et -XDR chez l'enfant dans des régions où la TB-MDR et la TB-XDR ont été déclarées chez les adultes témoigne à la fois d'une exclusion de la maladie de l'enfant du discours public sur la TB pharmacorésistante et probablement d'une sous-détection des enfants malades. Nos résultats mettent en évidence un manque de connaissance à grande échelle de la TB-MDR et de la TB-XDR de l'enfant.
Marco de referencia: La falta de información publicada sobre los niños con tuberculosis multidrogo-resistente (TB-MDR) es un obstáculo a los esfuerzos para abogar por mejores diagnósticos y tratamientos.Objetivos: Describir la falta de reconocimiento en la literatura publicada de la TB-MDR y la TB extremadamente resistente (TB-XDR) en los niños.Métodos: Para los países que hasta 2012 habían informado de algún caso de TB-MDR o TB-XDR, realizamos una búsqueda sistemática de la literatura publicada para identificar casos de TB-MDR o TB-XDR en adultos y en niños.Resultados: De los 184 países y territorios que informaron algún caso de TB-MDR durante 20052012, encontramos reportes de casos de TB-MDR en adultos en la literatura publicada para 143 (78%) países, y reportes de casos de TB-MDR pediátricos para 78 (42%) países. De los 92 países que informaron algún caso de TB-XDR, encontramos reportes de casos de TB-XDR en adultos en la literatura publicada para 55 (60%) países y reportes de casos de TB-XDR pediátricos para 9 (10%) países.Conclusión: La ausencia de publicaciones que documentan casos de TB-MDR y TB-XDR pediátricos en lugares donde casos de TB-MDR y TB-XDR en adultos han sido reportados indica tanto la exclusión de enfermedad infantil del discurso público sobre la TB drogo-resistente y la probable sub-detección de niños enfermos. Nuestros resultados recalcan la falta de reconocimiento a gran escala de los niños con TB-MDR y TB-XDR.
RESUMEN
Chronic lung allograft dysfunction (CLAD) remains a major problem after lung transplantation with no definitive treatment except redo lung transplantation (re-LTx) in selected candidates. However, CLAD is not a homogeneous entity and different phenotypes exist. Therefore, we aimed to evaluate the effect of CLAD phenotypes on survival after re-LTx for CLAD. Patients who underwent re-LTx for respiratory failure secondary to CLAD in four LTx centers between 2003 and 2013 were included in this retrospective analysis. Bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD) were distinguished using pulmonary function, radiology and explant lung histopathology. Patient variables pre- and post-re-LTx were collected and analyzed. A total of 143 patients underwent re-LTx for CLAD resulting in 94 BOS (66%) and 49 rCLAD (34%) patients. Unadjusted and adjusted survival after re-LTx for rCLAD was worse compared to BOS (HR = 2.60, 1.59-4.24; p < 0.0001 and HR = 2.61, 1.51-4.51; p = 0.0006, respectively). Patients waiting at home prior to re-LTx experienced better survival compared to hospitalized patients (HR 0.40; 0.23-0.72; p = 0.0022). Patients with rCLAD redeveloped CLAD earlier and were more likely to redevelop rCLAD. Survival after re-LTx for rCLAD is worse compared to BOS. Consequently, re-LTx for rCLAD should be critically discussed, particularly when additional peri-operative risk factors are present.
Asunto(s)
Trasplante de Pulmón , Disfunción Primaria del Injerto , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Tasa de Supervivencia , Adulto JovenRESUMEN
SETTING: Tomsk, Russia, where multidrug-resistant tuberculosis (MDR-TB) is prevalent. OBJECTIVES: To report rates of recurrence following successful treatment of MDR-TB in a program providing individualized treatment regimens designed according to the current global standard of care. DESIGN: A retrospective cohort study of 408 adults successfully treated for pulmonary MDR-TB from 10 September 2000 to 1 November 2004, and followed for up to 6 years post-treatment. We used Poisson regression with generalized estimating equations to assess whether recurrence rates changed significantly with time. RESULTS: We analyzed 399 (97.5%) patients with at least one follow-up visit (15 850 person-months of observation [PMO]). Baseline resistance to second-line drugs was common (65.2%); 398 patients (99.7%) were human immunodeficiency virus (HIV) negative. In the first year of post-treatment follow-up, there were six episodes of recurrence (1.4/1000 PMO, 95%CI 0.5-3.0). After the first post-treatment year, there were 21 episodes of recurrence (1.8/1000 PMO, 95%CI 1.1-2.8). The rate did not change significantly with time. CONCLUSION: Individualized regimens designed according to the current global standard of care achieved low rates of MDR-TB recurrence among non-HIV-infected persons treated in a programmatic setting.