Profilaxis de la infección por Aspergillus con anfotericina B nebulizada en pacientes transplantados pulmonares

Consultable des del TDXTítol obtingut de la portada digitalitzadaEsta tesis se compone de dos articulos: 1. Profilaxis con anfotericina B nebulizada contra la infección por Aspergillus en el trasplante de pulmón: Estudio de factores de riesgo. J Heart Lung Transplant 2001;20: 1274-1281. Introducción: La infección por Aspergillus spp. permanece como una causa importante de morbilidad y mortalidad en el trasplante de pulmón (TP). Algunas estrategias de profilaxis han sido ensayadas. Una de ellas es la anfotericina B nebulizada (nAB). Sin embargo, la eficacia de esta profilaxis no ha sido claramente demostradas. El objetivo de este estudio fue determinar si la profilaxis con nAB puede proteger contra la infección por Aspergillus spp. en los receptores de TP. Pacientes y métodos: Un estudio de factores de riesgo fue realizado en 55 pacientes con TP. 22 potenciales factores de riesgo fueron analizados. En 44 (80%) de los pacientes la nAB fue indicada como profilaxis. Se realizó un estudio multivariante utilizando regresión logística. Resultados: Dieciocho de 55 pacientes (33%) desalloraron infección por Aspergillus spp. El análisis multivariante mostró que la nAB es un factor protector (odds ratio: 0,13; intervalo de confianza (IC) 95%: 0,02-0,69; p< 0,05) y la enfermedad por citomegalovirus (CMV) fue un factor independiente de riesgo para desarrollar infeccion por Aspergillus spp. (odds ratio:5,1; CI95%: 1,35-19,17; p<0,05). Sólo un paciente requirió suspensión de la profilaxis por broncoespasmo. La profilaxis con nAB fue bien tolerada en el resto de los pacientes con sólo pocos, ligeros y fácilmente controlables efectos adversos. Conclusiones: Los resultados demuestran que la profilaxis con nAB puede ser eficiente y segura en la prevención de la infección por Aspergillus spp. en pacientes con TP, y que la enfermedad por citomegalovirus incrementa la probabilidad de esta infección. 2. Concentración y distribución de la anfotericina B nebulizada en el tracto respiratorio de pacientes con trasplante de pulmón. Transplantation 2003;75:1571-1574. Introducción: El problema de utilizar anfotericina B nebulizada (nAB) como profilaxis contra la infección por Aspergillus spp. después del trasplante de pulmón (TP) es el escaso conocimiento de su farmacocinética y distribución en el pulmón. El objetivo de este estudio fue determinar la concentración y distribución de la nAB en el tracto respiratorio de pacientes con TP. Método: En el estudio de concentración del fármaco, 120 broncoscopias fue realizadas en 39 pacientes con TP después de la administración de 6 mg de nAB/día durante un mínimo de 7 días. La media de las concentraciones de nAB en las secreciones bronquiales aspiradas (BAS) y en el lavado broncoalveolar (BAL) fueron determinadas a las 4, 12, 24 y 48 horas post-nebulización. En el estudio de distribución, 17 pacientes inhalaron 6 mg de anfotericina B marcada con Tecnecio99m(nAB-99mTc) y la distribución fue medida utilizando una gamma cámara. La perfusión pulmonar también fue determinada. Ambas pruebas fueron cualitativamente evaluadas. Resultados: En el estudio de concentración del fármaco, la media de concentraciones alcanzada a las 4 horas post-nebulización fue de 1,46 g/mL en BAS y 15,75g/mL en BAL. A las 24 horas las concentraciones fueron 0,37 g/mL y 11,02 g/mL en BAS y BAL respectivamente. En el estudio de distribución, la distribución de nAB-99mTc fue uniforme en 12 de 13 injertos sin Síndrome de bronquiolitis obliterante (BOS) y en uno de 4 injertos con BOS. Una cercana correlación fue observada entre la distribución regional del fármaco y la perfusión (r= 0,82, p< 0,01). Conclusiones: Las concentraciones de nAB permanecen elevadas durante las primeras 24 horas en BAL y durante menos tiempo en el BAS. La distribución del fármaco es uniforme en pacientes sin BOS. Además, los estudios de perfusión pulmonar parecen ser útiles para determinar la distribución de la nAB en pacientes que recibieron un TP.Esta tesis se compone de dos artículos: 1. J Heart Lung Transplant. 2001 Dec;20(12):1274-81. Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors. Monforte V, Roman A, Gavaldà J, Bravo C, Tenorio L, Ferrer A, Maestre J, Morell F. BACKGROUND: Aspergillus infection remains a major cause of morbidity and mortality after lung transplantation. Therefore, some strategies have been attempted, one of which is nebulized amphotericin B (nAB); however, the efficacy of this prophylaxis has not been shown clearly. The aim is to study whether nAB can protect against Aspergillus infection in lung transplant recipients. PATIENTS AND METHODS: A study of risk factors was conducted in 55 consecutive lung allograft recipients. Twenty-three potential risk factors were analyzed. In 44 (80%) patients, nAB was indicated as prophylaxis. Multivariate analysis using logistic regression was performed. RESULTS: Eighteen of the 55 patients (33%) developed infection due to Aspergillus spp. Multivariate analysis showed nAB to be a preventive factor (odds ratio: 0.13; 95% confidence interval [CI] 0.02-0.69; p < 0.05) and cytomegalovirus (CMV) disease was an independent risk factor for developing Aspergillus infection (odds ratio: 5.1; 95% CI 1.35-19.17; p < 0.05). Only 1 patient required withdrawal of the prophylaxis owing to bronchospasm. nAB was well-tolerated in the remaining patients with only a few, mild, easily controlled side effects. CONCLUSIONS: The present results show that nAB prophylaxis may be efficient and safe in preventing Aspergillus infection in lung-transplanted patients, and CMV disease increases the probability of Aspergillus infection. 2. Transplantation. 2003 May 15;75(9):1571-4. Nebulized amphotericin B concentration and distribution in the respiratory tract of lung-transplanted patients. Monforte V, Roman A, Gavaldà J, López R, Pou L, Simó M, Aguadé S, Soriano B, Bravo C, Morell F. BACKGROUND: A criticism of using nebulized amphotericin B (nAB) as prophylaxis against Aspergillus infection after lung transplantation is the lack of knowledge of its pharmacokinetics and distribution in the lung. The aim of this study was to ascertain the concentrations and distribution of nAB in the respiratory tract of patients receiving lung transplantations. METHODS: In the drug-concentration study, 120 bronchoscopies were performed in 39 patients receiving lung transplantions after administration of 6 mg of nAB once daily for a minimum of 7 days. Mean nAB concentration in bronchial aspirated secretions (BAS) and bronchoalveolar lavage (BAL) was determined at 4, 12, 24, and 48 hours postnebulization. In the distribution study, 17 patients inhaled 6 mg of 99m technetium-labeled AB, and pulmonary distribution was measured using a gamma camera. Pulmonary perfusion was also measured. Both tests were quantitatively evaluated. RESULTS: In the drug-concentration study, mean concentrations of 1.46 microg/mL in BAS and 15.75 microg/mL in BAL were reached at 4 hours. At 24 hours, concentrations were 0.37 microg/m and 11.02 microg/mL in BAS and BAL, respectively. In the distribution study, 99m technetium-labeled AB distribution was uniform in 12 of 13 allografts without bronchiolitis obliterans syndrome (BOS) and in 1 of 4 allografts with BOS. A close correlation was observed between regional drug distribution and regional perfusion (r=0.82, P<0.01). CONCLUSIONS: nAB concentrations remained high for the first 24 hours in BAL and for less time in BAS, with distribution of the drug being uniform in patients without BOS. Furthermore, lung-perfusion studies appear to be useful to ascertain nAB distribution in patients receiving lung transplantions

Impact of Lung Function Decline on Mortality in Lung Transplant Recipients: Long-Term Results From the L-CsA-i Study for the Prevention of Bronchiolitis Obliterans Syndrome

Cyclosporine (CsA); Chronic rejection; Lung transplantationCiclosporina (CsA); Rechazo crónico; Trasplante de pulmónCiclosporina (CsA); Rebuig crònic; Trasplantament de pulmóBackground: Chronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx). Methods: 10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis. Results: A total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality (p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk. Conclusion: Based on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions.This study was funded by Zambon S.p.A., Milan, Italy

A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation

Bronchiolitis obliterans; Clinical research; Lung transplantationBronquiolitis obliterante; Investigación clínica; Trasplante de pulmónBronquiolitis obliterant; Recerca clínica; Trasplantament de pulmóLong-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6–32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients.The study was funded by PARI Pharma GmbH. Open access funding enabled and organized by ProjektDEAL

Efficacy and safety of the combination of reduced duration prophylaxis followed by immuno-guided prophylaxis to prevent cytomegalovirus disease in lung transplant recipients (CYTOCOR STUDY): an open-label, randomised, non-inferiority clinical trial

Cytomegalovirus; Immuno-guided prophylaxis; Lung transplantationCitomegalovirus; Profilaxis inmunoguiada; Trasplante de pulmónCitomegalovirus; Profilaxi immuno-guiada; Trasplantament de pulmóINTRODUCTION: Prolonged use of antivirals to prevent the development of cytomegalovirus (CMV) disease in lung transplant patients has been shown to have significant side effects, for which alternatives are being sought to reduce their use. The monitoring of cell immunity against CMV could be an alternative as it has shown to be useful in identifying transplant patients at low risk of infection, who could benefit from shorter prophylaxis. The aim of the CYTOCOR study is to demonstrate that the combination of a reduced prophylaxis strategy with subsequent CMV-specific immunological monitoring would allow CMV infection to be controlled in lung transplant patients as effectively as the usual strategy (prophylaxis followed by pre-emptive therapy), while reducing the side effects of antivirals due to the shorter duration of prophylaxis. METHODS AND ANALYSIS: Phase III randomised, open, multicentre, parallel, non-inferiority clinical trial to study the efficacy and safety of the combination of a prophylaxis strategy up to month +3 post-transplant followed by immuno-guided prophylaxis using the QuantiFERON-CMV technique up to month +12 post-transplant to prevent CMV disease in CMV-seropositive lung transplant recipients. This strategy will be compared with a combination of a usual prophylaxis strategy up to month +6 post-transplant followed by pre-emptive therapy up to month +12. To study the incidence of CMV disease, patients will be followed up to 18 months post-transplantation. A total of 150 patients are expected to be recruited for the study. ETHICS AND PUBLIC DISSEMINATION: The clinical trial has been approved by the Research Ethics Committees and authorised by the Spanish Agency of Medicines and Medical Devices (AEMPS).If the hypothesis of this clinical trial is verified, the dissemination of the results could change clinical practice by increasing knowledge about the safety and efficacy of discontinuing valganciclovir prophylaxis in lung transplant recipients.We would like to acknowledge the support of the Spanish Network for Research in Infectious Disease (REIPI, RD16/0016), the Group for the Study of Infections in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and SCReN (Spanish Clinical Research Network) funded by the ISCIII-Sub-Directorate General for Research Assessment and Promotion through project PT13/0002/0010-PT17/0017/0012 and PT17/0017/0032

Impact of Lung Function Decline on Mortality in Lung Transplant Recipients: Long-Term Results From the L-CsA-i Study for the Prevention of Bronchiolitis Obliterans Syndrome

BackgroundChronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx). Methods10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis. ResultsA total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality (p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk. ConclusionBased on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions

Transcriptomic analysis of a near-isogenic line of melon with high fruit flesh firmness during ripening

This is the peer reviewed version of the following article: Zarid, M., García-Carpintero, V., Esteras, C., Esteva, J., Bueso, M.C., Cañizares, J., Picó, M.B., Monforte, A.J. and Fernández-Trujillo, J.P. (2021), Transcriptomic analysis of a near-isogenic line of melon with high fruit flesh firmness during ripening. J Sci Food Agric, 101: 754-777, which has been published in final form at https://doi.org/10.1002/jsfa.10688. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] BACKGROUND A near-isogenic line (NIL) of melon (SC10-2) with introgression in linkage group X was studied from harvest (at firm-ripe stage of maturity) until day 18 of postharvest storage at 20.5 degrees C together with its parental control ('Piel de Sapo', PS). RESULTS SC10-2 showed higher flesh firmness and whole fruit hardness but lower juiciness than its parental. SC10-2 showed a decrease in respiration rate accompanied by a decrease in ethylene production during ripening, both of which fell to a greater extent than in PS. The introgression affected 11 volatile organic compounds (VOCs), the levels of which during ripening were generally higher in SC10-2 than in PS. Transcriptomic analysis from RNA-Seq revealed differentially expressed genes (DEGs) associated with the effects studied. For example, 909 DEGs were exclusive to the introgression, and only 23 DEGs were exclusive to postharvest ripening time. Major functions of the DEGs associated with introgression or ripening time were identified by cluster analysis. About 37 genes directly and/or indirectly affected the delay in ripening of SC10-2 compared with PS in general and, more particularly, the physiological and quality traits measured and, probably, the differential non-climacteric response. Of the former genes, we studied in more detail at least five that mapped in the introgression in linkage group (LG) X, and 32 outside it. CONCLUSION There is an apparent control of textural changes, VOCs and fruit ripening by an expression quantitative trait locus located in LG X together with a direct control on them due to genes presented in the introgression (CmTrpD,CmNADH1,CmTCP15,CmGDSL esterase/lipase, andCmHK4-like) and CmNAC18.This work was funded by grants 11784/PI/09 (Seneca Foundation, Region of Murcia) and Ministry of Economy and Innovation (AGL2010-20858). M Zarid acknowledges an UE-Erasmus predoctoral fellowship, a program coordinated by the University of Murcia in the framework of CMN. Thanks are due to Semillas Fitó SA (Barcelona, Spain), for providing seeds of PS melons and IRTACRAG for the seeds of SC10-2. We acknowledge the assistance of P Varó and his team in CIFEA-Torre Pacheco for crop management, to N Dos-Santos, M Medina, M García-Gutiérrez, A Hakmaoui, E Cuadros, I Canales and AA Escudero (UPCT) for sampling and technical assistance, to SAIT-UPCT for GC-MS analysis, to AG Sifres (COMAV) for RNA extraction, and to CNAG (Barcelona) for professional assistance in RNA-Seq. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Zarid, M.; García-Carpintero, V.; Esteras Gómez, C.; Esteva, J.; Bueso, MC.; Cañizares Sales, J.; Picó Sirvent, MB.... (2021). Transcriptomic analysis of a near-isogenic line of melon with high fruit flesh firmness during ripening. Journal of the Science of Food and Agriculture. 101(2):754-777. https://doi.org/10.1002/jsfa.10688S7547771012Ríos, P., Argyris, J., Vegas, J., Leida, C., Kenigswald, M., Tzuri, G., … Garcia-Mas, J. (2017). 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Polimorfismos en genes candidatos a la composición de ácidos grasos y su efecto en carne Wagyu-Cross

Objetivo. Comparar la composición de ácidos grasos (FA) en la carne Wagyu y sus cruzas con Angus, Beefmaster, Brangus y Hereford, y analizar su relación con marcadores genéticos del metabolismo lipídico. Materiales y metodos. Se colectaron 111 muestras de Longissimus dorsi, las cuales se agruparon por grupo genético, se cuantificaron los FA (cromatografía de gases líquidos) y se tipificaron marcadores de ADN asociados teóricamente a FA. Se examinó el equilibrio de Hardy-Weinberg y desequilibrio de ligamiento de los marcadores y se estimó el efecto de las cruzas y el efecto de los genotipos. Resultados. Las cruzas no mostraron diferencias substanciales en la composición de FA con respecto a Wagyu. Nueve SNPs mostraron asociación con la composición de FA, y se encontró un efecto importante en el marcador SLC2A4 ss62538460, el cual influyó sobre SFA, MUFA y MUFA/SFA. Los marcadores, PLTP ss77832104 y IGF2R ss77831885 influyeron sobre C16:0, MYOZ1 ss77832104 sobre C17:1 y PPARGC1A c.1892+19 sobre C18:2. Además, se comprobaron efectos previamente descritos de MEF2C ss38329156 y SCD c.878. Conclusiones. Los presentes resultados representan una de las primeras evidencias sobre la deposición de FA en ganado Wagyu y sus cruzas y propone algunos loci en genes candidatos con posibilidad de implementación en estrategias de mejoramiento asistido

Long-term results of sirolimus treatment in lymphangioleiomyomatosis: a single referral centre experience

There are few published data on long-term treatment with sirolimus in lymphangioleiomyomatosis (LAM). The objective of this study was to describe the long-term effect of sirolimus in a series of LAM patients followed up in a referral centre, focusing on pulmonary function. We retrospectively reviewed a series of 48 patients with LAM diagnosed, followed up and treated with sirolimus in a single centre. Response to sirolimus was evaluated at 1 and 5 years. A negative sirolimus response was defined as an FEV1 decline greater than - 75 ml/year. A mixed-effects model was used to estimate the longitudinal changes in FEV1 (average slope), both as absolute (ml/year) and as predicted values (%predicted/year). From a total of 48 patients, 9 patients underwent lung transplantation and 4 died during the study. Mean (95% CI) FEV1 slope over 5 years was - 0.14 (- 26.13 to 25.85) ml/year in the whole LAM group, 42.55 (14.87 to 70.22) ml/year in the responder group, - 54.00 (- 71.60 to - 36.39) ml/year in the partial responder group and - 84.19 (- 113.5 to - 54.0) ml/year in the non-responder group. After 5 years of sirolimus treatment 59% had a positive response, 30% had a partial response and 11% had a negative response. Our study found that sirolimus treatment had a positive long-term effect on most LAM patients