Tuberculosis in Liver Transplant Recipients: A Report of Eight Cases During a Five Year Period.

INTRODUCTION: Tuberculosis incidence in Portugal ranged from 20 to 22 cases per 100 000 inhabitants between 2010 and 2014. Tuberculosis incidence in liver transplant recipients is not precisely known, but it is estimated to be higher than among the general population. Tuberculosis in liver transplant recipients is particularly challenging because of the atypical clinical presentation and side effects of the antibacillary drugs and their potential interactions with immunosuppressive therapies. MATERIAL AND METHODS: We retrospectively reviewed the clinical records of liver transplant recipients with post-transplant tuberculosis occurring from January 2010 to December 2014 at a liver transplantation unit in Lisbon, Portugal. Demographic data, baseline and clinical features, as well as treatment regimen, toxicities and outcomes, were analyzed. RESULTS: Among 1005 recipients, active tuberculosis was diagnosed in eight patients between January 2010 and December 2014 (frequency = 0.8%). Late onset tuberculosis was more frequent than early tuberculosis. Mycobacterium tuberculosis complex was isolated from cultures in almost every case (7; 87.5%). Extra-pulmonary involvement and disseminated tuberculosis were frequent. Two patients developed rejection without allograft loss. Crude mortality was 37.5%, with 2 deaths being related to tuberculosis. DISCUSSION: Despite the uncertainty regarding treatment duration in liver transplant recipients, disease severity, as well as number of active drugs against TB infection, should be taken into account. There was a need for a rifampin-free regimen and immunosuppression adjustment in patients who experienced acute graf rejection. CONCLUSION: Although the number of cases of tuberculosis is low, its post-transplant frequency is significant and the observed mortality rate is not to be neglected. The cases of hepatotoxicity and graft rejection seen in this case series demonstrate the challenges associated with tuberculosis diagnosis in liver transplant recipients and management of the interactions between immunosuppressors and rifampin. This study strengthens the recommendation of latent tuberculosis infection screening and treatment in liver transplant candidates or recipients.

Introdução: A incidência de tuberculose em Portugal entre 2010 - 2014 foi de 20 a 22 casos por 100 000 habitantes. A incidência de tuberculose em transplantados hepáticos não é conhecida, estimando-se que seja mais elevada do que a da população em geral. O manejo da tuberculose em transplantados hepáticos constitui um desafio, não só pela apresentação clínica frequentemente atípica, mas também pelos efeitos secundários da terapêutica antibacilar e suas interações farmacológicas com a medicação imunossupressora, necessária no período pós-transplante. Material e Métodos: Os autores fizeram uma revisão retrospetiva dos casos de doentes transplantados hepáticos com tuberculose pós- transplante diagnosticada durante o período entre janeiro 2010 e dezembro 2014 num centro de transplantação hepática em Lisboa, Portugal. Foram analisados os dados demográficos, características clínicas, a par do regime antibacilar, toxicidade e evolução. Resultados: Num total de 1005 transplantados foi diagnosticada tuberculose ativa em oito doentes entre janeiro de 2010 e dezembro de 2014 (frequência de 0,8%). O desenvolvimento de tuberculose tardia foi mais frequente do que a doença precoce. Foi isolado Mycobacterium tuberculosis complex no exame cultural de sete doentes (87,5%). Foram frequentes a presença de envolvimento extrapulmonar, assim como doença tuberculosa disseminada. Dois doentes desenvolveram rejeição aguda, sem perda de enxerto. A taxa de mortalidade global foi de 37,5%, com duas mortes directamente atribuíveis à tuberculose. Discussão: Apesar da incerteza quanto à duração do tratamento da tuberculose em transplantados hepáticos, deverão ser tidos em conta a gravidade da doença, assim como o número de fármacos com actividade antibacilar. Nesta série, os doentes que desenvolveram rejeição aguda necessitaram da utilização de um regime sem rifampicina, e ajuste da terapêutica imunossupressora. Conclusão: Apesar do baixo número de casos de tuberculose, a sua frequência pós-transplante é significativa e a mortalidade associada não é negligenciável. Os casos de hepatotoxicidade e rejeição de enxerto demonstram os desafios no diagnóstico da tuberculose em transplantados hepáticos e a dificuldade do manejo das interações entre imunossupressores e a rifampicina. Este estudo reforça a recomendação de rastreio e tratamento de tuberculose latente em transplantados ou candidatos a transplante hepático.

European ring exercise on water toxicity using different bioluminescence inhibition tests based on Vibrio fischeri, in support to the implementation of the water framework directive.

An inter-laboratory comparison exercise was conducted under the European Union funded project entitled: Screening Methods for Water Data Information in Support of the Implementation of the Water Framework Directive (SWIFT-WFD) and coordinated by the Consejo Superior de Investigaciones Científicas (CSIC), in order to evaluate the reproducibility of different toxicity tests based on the bioluminescence inhibition of Vibrio fischeri, for the rapid water toxicity assessment. For the first time, this type of exercise has been organized in Europe, and using different tests based on the same principle. In this exercise, 10 laboratories from 8 countries (Austria, Cyprus, Germany, Greece, Italy, Portugal, Romania, and Spain) took place, and a total number of 360 samples were distributed. During the exercise, six series of six samples were analyzed along 5 months. Every batch of samples was composed by three real samples and three standard solutions. The real samples were: a raw influent and the effluent of a wastewater treatment plant (WWTP), and a sample from a first settlement of the WWTP spiked with a mixture of toxicant standards. A final number of 330 (91.7%) samples was analyzed, 3300 values in duplicate were collected, and the results for each sample were expressed as the 50% effective concentration (EC(50)) values calculated through five points of dilution inhibition curves, after 5 and 15min of incubation times. A statistical study was initiated using 660 results. The mean values, standard deviations (sigma), variances (sigma(2)), and upper and lower warning limits (UWL and LWL) were obtained, using the EC(50) values calculated with the result from the participating laboratories. The main objectives of this toxicity ring study were to evaluate the repeatability (r) and reproducibility (R) when different laboratories conduct the test, the influence of complex matrix samples, the variability between different tests based on the same principle, and to determine the rate at which participating laboratories successfully completed tests initiated. In this exercise, the 3.93% toxicity values were outliers according with the Z-score values and the Dixon test. The samples with the greater number of outliers were those with the smallest variability coefficient, corresponding to the greater and the smaller toxicity level. No relation was found through the cluster analysis, between the final results and the different commercial devices involved. Testing by multiple commercial devices did not appear to reduce the precision of the results, and the variability coefficient for the exercise was nearby to the average value for past editions carried out at national level, where the different participants used the same commercial device. Stability of samples was also followed during the exercise. While statistical significance differences were not found for the greater part of samples, for the sample from the WWTP influent, a significant decrease of the toxicity value was found along this study. Nevertheless, this was a type of sample with a high toxicity level during all the exercise. On the other hand, in order to obtain the chemical characterization of real samples, those were analyzed by chromatographic techniques, using different sequential solid phase extraction (SSPE) procedures, followed by liquid chromatography coupled with mass spectrometry (LC-MS), and gas chromatography-mass spectrometry (GC-MS). Good agreement was found between the chemical analysis results and the toxicity level of the samples.