Invasive scedosporiosis in lung transplant recipients: A nine-year retrospective study in a tertiary care hospital.

BACKGROUND: Scedosporium species and Lomentospora prolificans (Sc/Lp) are emerging molds that cause invasive disease associated with a high mortality rate. After Aspergillus, these molds are the second filamentous fungi recovered in lung transplant (LT) recipients. AIMS: Our objective was to evaluate the incidence, risk factors and outcome of Sc/Lp infections in LT recipients at a tertiary care hospital with a national reference LT program. METHODS: A nine-year retrospective study was conducted. RESULTS: During this period, 395 LT were performed. Positive cultures for Sc/Lp were obtained from twenty-one LT recipients. Twelve patients (incidence 3.04%) developed invasive scedosporiosis (IS). In 66.7% of the patients with IS the invasive infection was defined as a breakthrough one. The main sites of infection were lungs and paranasal sinuses. Most of the patients received combination antifungal therapy. The IS crude mortality rate after 30 days was 16.7%, and 33.3% after a year. CONCLUSIONS: Our study highlights improved survival rates associated with combination antifungal therapy in LT recipients and underlines the risk of breakthrough infections in patients with allograft dysfunction on nebulized lipidic amphotericin B prophylaxis. In addition to pretransplant colonization, acute or chronic organ dysfunctions seem to be the main risk factors for IS.

Tuberculosis Following Lung Transplantation. A 27-Year Spanish Multicenter Experience. Incidence, Presentation, Prevention and Treatment with Rifampicin / Tuberculosis tras trasplante de pulmón. Experiencia multicéntrica de 27 años en España. Incidencia, presentación, prevención y uso de rifampicina en el tratamiento

BACKGROUND: Tuberculosis (TB) represents a diagnostic and therapeutic challenge for solid organ transplant recipients, particularly after lung transplant (LT). Our aim was to determine the impact of TB in LT patients in Spain, considering prevalence, clinical presentation, prevention and therapeutic management. In addition, differences in outcome between rifampicin (RIF) versus non-RIF containing regimens were analyzed. METHODS: Multicenter, observational retrospective study, including all cases of TB diagnosed in recipients after LT, in five pulmonary transplant units in Spain, between January 1990 and December 2017. RESULTS: Among 2962 LT recipients, 45 cases of TB were diagnosed, resulting in a prevalence of 1.52%. Most of them (88.89%) were diagnosed during the first year posttransplantation, 86.67% with pulmonary presentation. Screening for latent TB infection (LTBI) was done in 36 of the 45 patients and LTBI was detected pretransplant in 12 (33.33%). Less than half of the patients with disease (42.22%) received rifampicin (RIF). Lower probability of TB worsening was found in RIF-containing regimens (p = 0.049), as well as longer survival (p = 0.001). RIF use was not associated with an increased risk in rejection (p = 0.99), but doses of calcineurin inhibitors (CNI) had to be raised an average of 215%. CONCLUSIONS: Risk of TB after LT was lower in our series than previously reported. TB should be searched during the first year posttransplant in patients with TB risk factors. Pulmonary presentation was predominant. More sensitive algorithms for detecting LTBI before LT are crucial. It is reasonable to use RIF-containing regimens over non-RIF regimens based on the tendency toward better outcome in our series. RIF regimen requires close monitoring of CNI trough level for 2-3 weeks, until stability is achieved

ANTECEDENTES: La tuberculosis (TB) representa un reto diagnóstico y terapéutico para los receptores de trasplantes de órgano sólido, en particular tras un trasplante de pulmón (TP). Nuestro objetivo fue determinar el impacto de la TB en los pacientes con TP en España, tomando en consideración su prevalencia, presentación clínica, prevención y manejo terapéutico. Además, se analizaron las diferencias en los resultados finales entre los tratamientos que incluían rifampicina (RIF) frente a aquellos que no la incluían. MÉTODOS: Estudio multicéntrico, observacional y retrospectivo que incluía todos los casos de TB diagnosticados en pacientes receptores de TP, en 5 unidades de trasplante pulmonar en España, entre enero de 1990 y diciembre de 2017. RESULTADOS: Entre los 2.962 pacientes receptores de TP, se diagnosticaron 45 casos de TB, siendo esta una prevalencia del 1,52%. La mayoría (el 88,89%) se diagnosticaron durante el primer año postrasplante; el 86,67% de ellos fue con presentación pulmonar. Se realizó cribado en busca de infección tuberculosa latente (ITBL) en 36 de los 45 pacientes y se detectó ITBL pretrasplante en 12 de ellos (33,33%). Menos de la mitad de los pacientes con la enfermedad (42,22%) recibieron tratamiento con RIF. Se halló una menor probabilidad de empeoramiento de la TB en los tratamientos que incluían RIF (p = 0,049), así como mayor supervivencia (p = 0,001). El uso de RIF no se asoció a un aumento en el riesgo de rechazo (p = 0,99), pero fue necesario aumentar en una media del 215% las dosis de inhibidores de calcineurina (ICN). CONCLUSIONES: El riesgo de TB tras un TP fue menor en nuestra serie que lo referido previamente. Debería investigarse la TB durante el primer año postrasplante en aquellos pacientes con factores de riesgo para TB. La presentación pulmonar fue la predominante. Es crucial elaborar algoritmos con mayor sensibilidad para detectar ITBL antes del TP. Es razonable utilizar tratamientos que incluyan RIF frente a aquellos que no la incluyen basándonos en la tendencia a un resultado final más favorable en nuestra serie de casos. Los tratamientos con RIF requieren un seguimiento minucioso de los niveles de ICN durante 2-3 semanas hasta que se alcance una situación estable

Tuberculosis Following Lung Transplantation. A 27-Year Spanish Multicenter Experience. Incidence, Presentation, Prevention and Treatment with Rifampicin.

BACKGROUND: Tuberculosis (TB) represents a diagnostic and therapeutic challenge for solid organ transplant recipients, particularly after lung transplant (LT). Our aim was to determine the impact of TB in LT patients in Spain, considering prevalence, clinical presentation, prevention and therapeutic management. In addition, differences in outcome between rifampicin (RIF) versus non-RIF containing regimens were analyzed. METHODS: Multicenter, observational retrospective study, including all cases of TB diagnosed in recipients after LT, in five pulmonary transplant units in Spain, between January 1990 and December 2017. RESULTS: Among 2962 LT recipients, 45 cases of TB were diagnosed, resulting in a prevalence of 1.52%. Most of them (88.89%) were diagnosed during the first year posttransplantation, 86.67% with pulmonary presentation. Screening for latent TB infection (LTBI) was done in 36 of the 45 patients and LTBI was detected pretransplant in 12 (33.33%). Less than half of the patients with disease (42.22%) received rifampicin (RIF). Lower probability of TB worsening was found in RIF-containing regimens (p=0.049), as well as longer survival (p=0.001). RIF use was not associated with an increased risk in rejection (p=0.99), but doses of calcineurin inhibitors (CNI) had to be raised an average of 215%. CONCLUSIONS: Risk of TB after LT was lower in our series than previously reported. TB should be searched during the first year posttransplant in patients with TB risk factors. Pulmonary presentation was predominant. More sensitive algorithms for detecting LTBI before LT are crucial. It is reasonable to use RIF-containing regimens over non-RIF regimens based on the tendency toward better outcome in our series. RIF regimen requires close monitoring of CNI trough level for 2-3 weeks, until stability is achieved.

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.

INTRODUCTION: 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. TRIAL REGISTRATION NUMBER: NCT03699254.

Post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation.

Post-transplant lymphoproliferative disorders (PTLD) are a rare complication after both solid organ (SOT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this single center retrospective study, we compared clinical, biological, and histological features, and outcomes of PTLD after both types of transplant. We identified 82 PTLD (61 after SOT and 21 after allo-HSCT). The presence of B symptoms, Waldeyer ring, spleen, central nervous system, and liver involvement, and advanced Ann-Arbor stage were more frequent in allo-HSCT recipients. PTLD had an earlier onset in allo-HSCT than in SOT cohort (4 vs. 64 months, p < .0001). PTLD was EBV-positive in 100% of allo-HSCT, in contrast to 47% of SOT (p = .0002). Four years after PTLD diagnosis, median overall survival was 32% (95% CI, 22-48) and 10% (95% CI, 2-49) in SOT and allo-HSCT recipients, respectively (p = .002). In conclusion, the clinical presentation and the outcome of PTLD varies greatly depending on the type of transplant.

Risk factors, survival, and impact of prophylaxis length in cytomegalovirus-seropositive lung transplant recipients: A prospective, observational, multicenter study.

BACKGROUND: The optimal length of cytomegalovirus (CMV) prophylaxis in lung transplantation according to CMV serostatus is not well established. METHODS: We have performed a prospective, observational, multicenter study to determine the incidence of CMV infection and disease in 92 CMV-seropositive lung transplant recipients (LTR), their related outcomes and risk factors, and the impact of prophylaxis length. RESULTS: At 18 months post transplantation, 37 patients (40%) developed CMV infection (23 [25%]) or disease (14 [15.2%]). Overall mortality was higher in patients with CMV disease (64.3% vs 10.2%; P<.001), but only one patient died from CMV disease. In the multivariate analysis, CMV disease was an independent death risk factor (odds ratio [OR] 18.214, 95% confidence interval [CI] 4.120-80.527; P<.001). CMV disease incidence was higher in patients with 90-day prophylaxis than in those with 180-day prophylaxis (31.3% vs 11.8%; P=.049). Prophylaxis length was an independent risk factor for CMV disease (OR 4.974, 95% CI 1.231-20.094; P=.024). Sixteen patients withdrew from prophylaxis because of adverse events. CONCLUSION: CMV infection and disease in CMV-seropositive LTR remain frequent despite current prophylaxis. CMV disease increases mortality, whereas 180-day prophylaxis reduces the incidence of CMV disease.

Patient-reported symptoms and functioning as indicators of mortality in advanced cystic fibrosis: A new tool for referral and selection for lung transplantation.

BACKGROUND: Despite well-known risk factors and predictive survival models, many patients with cystic fibrosis (CF) die while on the waiting list for lung transplant. We evaluated whether specific Cystic Fibrosis Questionnaire (CFQ-R) scales provide additional benefit to conventional tools in identifying referral timing and waitlist mortality. METHODS: From January 2010 to January 2015, 152 patients (34% on the waitlist) were evaluated with the CFQ-R and standard protocol quarterly. Data were used to explore the prognostic association of health-related quality of life. RESULTS: The Physical Functioning domain (PFD) of the CFQ-R predicted mortality in advanced CF disease better than habitual parameters (p = 0.005). For patients with the same forced expiratory volume in 1 sec (FEV1), a low score categorized patients with an increased risk of death. For patients with CF and FEV1 <30% predicted and a low Physical score, mortality rate was ~35% at 2 years. The best model for probability of inclusion on the waitlist was FEV1 % (p < 0.001, hazard ratio [HR] = 0.94; 95% confidence interval [CI] [0.90, 0.97]) and Physical Functioning (p = 0.013, HR = 0.96; 95% CI [0.95, 0.99]). The best model for probability of death similarly included FEV1 % (p = 0.09, HR = 0.97; 95% CI [0.94, 1.00]) and CFQ-R Physical Functioning score (p = 0.005, HR = 0.97; 95% CI [0.95, 0.99]). The Health Perception score showed similar results. A low Health Perception score combined with a high resting heart rate showed a trend for mortality. CONCLUSIONS: The CFQ-R may be an additional tool for guiding decisions to place a patient with CF on the waiting list for lung transplantation. The CFQ-R Physical Functioning and Health Perception scales were more accurate than conventional tools in predicting death before transplant.

Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation.

Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 and CYP3A5 genes with tacrolimus (Tac) and ABCC2, UGT1A9 and SLCO1B1 genes with mycophenolic acid (MPA), during the first six months after lung transplantation (51 patients). The genotype was correlated to the trough blood drug concentrations corrected for dose and body weight (C0/Dc). The ABCB1 variant in rs1045642 was associated with significantly higher Tac concentration, at six months post-transplantation (CT vs. CC). In the MPA analysis, CT patients in ABCC2 rs3740066 presented significantly lower blood concentrations than CC or TT, three months after transplantation. Other tendencies, confirming previously expected results, were found associated with the rest of studied SNPs. An interesting trend was recorded for the incidence of acute rejection according to NOD2/CARD15 rs2066844 (CT: 27.9%; CC: 12.5%). Relevant SNPs related to Tac and MPA in other solid organ transplants also seem to be related to the efficacy and safety of treatment in the complex setting of lung transplantation.

Genotype and allele frequencies of drug-metabolizing enzymes and drug transporter genes affecting immunosuppressants in the Spanish white population.

Interpatient variability in drug response can be widely explained by genetically determined differences in metabolizing enzymes, drug transporters, and drug targets, leading to different pharmacokinetic and/or pharmacodynamic behaviors of drugs. Genetic variations affect or do not affect drug responses depending on their influence on protein activity and the relevance of such proteins in the pathway of the drug. Also, the frequency of such genetic variations differs among populations, so the clinical relevance of a specific variation is not the same in all of them. In this study, a panel of 33 single nucleotide polymorphisms in 14 different genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, MTHFR, NOD2/CARD15, SLCO1A2, SLCO1B1, TPMT, and UGT1A9), encoding for the most relevant metabolizing enzymes and drug transporters relating to immunosuppressant agents, was analyzed to determine the genotype profile and allele frequencies in comparison with HapMap data. A total of 570 Spanish white recipients and donors of solid organ transplants were included. In 24 single nucleotide polymorphisms, statistically significant differences in allele frequency were observed. The largest differences (>100%) occurred in ABCB1 rs2229109, ABCG2 rs2231137, CYP3A5 rs776746, NOD2/CARD15 rs2066844, TPMT rs1800462, and UGT1A9 rs72551330. In conclusion, differences were recorded between the Spanish and other white populations in terms of allele frequency and genotypic distribution. Such differences may have implications in relation to dose requirements and drug-induced toxicity. These data are important for further research to help explain interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.

[Lung transplantation for cystic fibrosis: infectious events]. / Transplante pulmonar en la fibrosis quística: complicaciones infecciosas.

BACKGROUND AND OBJECTIVE: Lung transplantation is the only treatment for end-stage lung disease in patients with cystic fibrosis (CF). The presence of pathogens in the airways prior to transplantation is a risk factor for infections in the post-transplantation period; in fact, infections account for 80% of deaths within the first year. Our goal was to analyze the incidence of infectious complications in patients who underwent a lung transplantation due to cystic fibrosis. PATIENTS AND METHOD: Descriptive transversal study of CF transplanted lung patients since the beginning of the transplantation programme (1991 to September 2004). We evaluated data regarding opportunistic infections, demographical information, lung function, mortality causes and survival. We used descriptive statistics and Kaplan Meier for survival. RESULTS: 267 lung transplants were done, 57 were due to CF, 30 men and 27 women, with an average age of 21 years (7.8 years. The average time on waiting list was 96 days (range 1-407). 57 bilateral lung transplants, 3 heart-lung transplants and one combined liver-lung transplant were performed. All patients received triple immunosuppression (tacrolimus/cyclosporine, azathioprine and prednisone). 16 patients (28%) died: 4 in early postoperative period (7%), 5 at 6 months after transplantation, and the remaining 7 patients died several years post transplantation. Survival was 82% at one year, 76% at three years, and 65% at five years; 75% of our patients survived a mean of 3.56 years. Cytomegalovirus (CMV) infections occurred in 26% of patients and were associated with chronic rejection (p < 0.05). Purulent bronchitis was the most frequent bacterial infection: 59% of cases were caused by multiresistant pathogens. There was a 8.77% cases of B cepacia infection with 2 patients dying because of it. There were 7 cases of airway infection due to Aspergillus fumigatus, and 5 fungal invasive forms that were associated with chronic rejection (p < 0.05). Two cases of tuberculosis (Mycobacterium tuberculosis) were registered, 1 case of M. abcessus lung disease and 1 case of visceral leishmaniosis. Infectious diseases accounted for 19% of early and 12% of late mortality. CONCLUSIONS: Although serious infections were seen after transplantation in our series, infectious events did not represent a high risk of postoperative mortality rate. Fungal disease was the only late relevant infectious complication, mainly associated with chronic rejections. Close CMV monitoring, and even pre-emptive antifungal therapy, are recommended for patients with chronic rejection.

Trasplante pulmonar en la fibrosis quística: complicaciones infecciosas / Lung transplantation for cystic fibrosis: infectious events

Fundamento y objetivo: El trasplante pulmonar es la única alternativa terapéutica en los pacientes con fibrosis quística (FQ) en estadio avanzado. La presencia de patógenos colonizadores en la vía respiratoria pretrasplante es un factor de riesgo que favorece las infecciones en el postrasplante, y éstos son la causa del 80% de las muertes que ocurren durante el primer año. El objetivo de este trabajo fue determinar la incidencia de infecciones en pacientes trasplantados de pulmón por FQ. Pacientes y método: Estudio transversal descriptivo de una cohorte de pacientes trasplantados de pulmón por FQ desde el comienzo del programa de trasplante en el año 1991 hasta septiembre de 2004. Se ha evaluado las infecciones oportunistas, los datos demográficos, la evolución funcional después del trasplante, las causas de mortalidad y la supervivencia. Se ha empleado una estadística descriptiva y el método actuarial de Kaplan Meier para la supervivencia. Resultados: Se realizó un total de 267 trasplantes pulmonares de los que 57 se hicieron por FQ, 30 eran varones y 27 mujeres y la edad media era de 21 años (desviación típica 7,8). El tiempo medio en lista de espera fue de 96 días (extremos 1-407). Se efectuó un trasplante bipulmonar secuencial en 53 pacientes, en 3 casos un trasplante cardiopulmonar y en 1 caso un trasplante hepatopulmonar. Todos recibieron triple inmunodepresión (tacrolimus/ciclosporina, azatioprina y prednisona). La mortalidad global fue de 16 pacientes (28%). Cuatro (7%) murieron en el postoperatorio inmediato, 5 (9%) en los primeros 6 meses postrasplante, y 7, en un tiempo superior a los 6 meses, llegando hasta los 13 años postrasplante. La supervivencia fue del 82, 76 y 65% a 1, 3 y 5 años, respectivamente; el 75% de la serie sobrevivió 3,26 años. Las infecciones por citomegalovirus (CMV) oscilaron en un 26% y se asociaron significativamente con rechazo crónico (p < 0,05). Las bronquitis purulentas fueron las complicaciones bacterianas más frecuentes. De éstas, los gérmenes multirresistentes ocasionaron un 59%. Hubo 5/57 casos de infección por Burkholderia cepacia, con resultado de muerte en 2 pacientes. Se registraron 7 problemas de la vía respiratoria en relación con Aspergillus fumigatus y cinco formas fúngicas invasivas pulmonares que se asociaron a rechazo crónico (p < 0,05). Se produjeron 2 casos de tuberculosis (Mycobacterium tuberculosis), así como 1 caso diseminado por M. abcessus y 1 caso de leishmaniasis visceral. Las infecciones supusieron un 19% (3/16) de la mortalidad temprana y el 12% de la tardía (2/16). Conclusiones: A pesar de las infecciones graves que tuvieron lugar, en nuestra serie no supusieron la principal causa de mortalidad a corto y medio plazo. A largo plazo, las infecciones fúngicas supusieron la única complicación infecciosa más grave, principalmente asociadas a rechazo crónico. Se aconseja extremar la vigilancia y/o el tratamiento anticipado de la infección fúngica y por CMV en los pacientes trasplantados de pulmón con rechazo crónico

Background and objective: Lung transplantation is the only treatment for end-stage lung disease in patients with cystic fibrosis (CF). The presence of pathogens in the airways prior to transplantation is a risk factor for infections in the post-transplantation period; in fact, infections account for 80% of deaths within the first year. Our goal was to analyze the incidence of infectious complications in patients who underwent a lung transplantation due to cystic fibrosis. Patients and method: Descriptive transversal study of CF transplanted lung patients since the beginning of the transplantation programme (1991 to September 2004). We evaluated data regarding opportunistic infections, demographical information, lung function, mortality causes and survival. We used descriptive statistics and Kaplan Meier for survival. Results: 267 lung transplants were done, 57 were due to CF, 30 men and 27 women, with an average age of 21 years (7.8 years. The average time on waiting list was 96 days (range 1-407). 53 bilateral lung transplants, 3 heart-lung transplants and one combined liver- lung transplant were performed. All patients received triple immunosuppression (tacrolimus/cyclosporine, azathioprine and prednisone). 16 patients (28%) died: 4 in the early postoperative period (7%), 5 at 6 months after transplantation, and the remaining 7 patients died several years post transplantation. Survival was 82% at one year, 76% at three years, and 65% at five years; 75% of our patients survived a mean of 3.26 years. Cytomegalovirus (CMV) infections occurred in 26% of patients and were associated with chronic rejection (p < 0.05). Purulent bronchitis was the most frequent bacterial infection: 59% of cases were caused by multiresistant pathogens. There was a 8.77% cases of B cepacia infection with 2 patients dying because of it. There were 7 cases of airway infection due to Aspergillus fumigatus, and 5 fungal invasive forms that were associated with chronic rejection (p < 0.05). Two cases of tuberculosis (Mycobacterium tuberculosis) were registered, 1 case of M. abcessus lung disease and 1 case of visceral leishmaniosis. Infectious diseases accounted for 19% of early and 12% of late mortality. Conclusions: Although serious infections were seen after transplantation in our series, infectious events did not represent a high risk of postoperative mortality rate. Fungal disease was the only late relevant infectious complication, mainly associated with chronic rejections. Close CMV monitoring, and even pre-emptive antifungal therapy, are recommended for patients with chronic rejection