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Improving Diagnostic Strategies for Latent Tuberculosis Infection in Populations at Risk for Developing Active Disease

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Improving Diagnostic Strategies for Latent Tuberculosis Infection in Populations at Risk for Developing Active Disease Improving diagnostic strategies for latent tuberculosis infection in populations at risk for developing active disease Laura Muñoz López Aquesta tesi doctoral està subjecta a la llicència Reconeixement 3.0. Espanya de Creative Commons. Esta tesis doctoral está sujeta a la licencia Reconocimiento 3.0. España de Creative Commons. This doctoral thesis is licensed under the Creative Commons Attribution 3.0. Spain License. UNIVERSIDAD DE BARCELONA Facultad de Medicina IMPROVING DIAGNOSTIC STRATEGIES FOR LATENT TUBERCULOSIS INFECTION IN POPULATIONS AT RISK FOR DEVELOPING ACTIVE DISEASE Memoria presentada por LAURA MUÑOZ LOPEZ Para optar al grado de Doctor en Medicina Barcelona, marzo de 2017 El Dr. Miguel Santín, proFesor asociado de la Facultad de Medicina de la Universidad de Barcelona y Médico Adjunto del Servicio de EnFermedades InFecciosas del Hospital Universitario de Bellvitge, hace constar que la tesis titulada “Improving diagnostic strategies For latent tuberculosis infection in populations at risk for developing active disease” que presenta la licenciada Laura Muñoz, ha sido realizada bajo su dirección en el campus de Bellvitge de la Facultad de Medicina, la considera Finalizada y autoriza su presentación para que sea deFendida ante el tribunal que corresponda. En Barcelona, marzo de 2017 Dr. Miguel Santín A mis padres A mi gran Familia The research presented in this thesis has been carried out thanks to the Fondo de Investigaciones Sanitarias Ministerio de Ciencia e Innovación Beca P-FIS 10/00443 AGRADECIMIENTOS Las primeras palabras de agradecimiento son sin duda para el director de esta tesis. Sin las ideas, horas de trabajo y paciencia de Miguel Santín ninguno de los estudios que componen esta tesis, ni por supuesto la propia tesis, hubiesen visto la luz. Las segundas palabras para Lucía y para Charo: sin su trabajo sistemático, ordenado y constante desde el inicio de la Unidad Clínica de Tuberculosis, no podríamos estar hablando de la segunda tesis de este área del Servicio. El tercer puesto de los agradecimientos está discutido… pero probablemente lo merecen los investigadores del OPTIMIST en los doce centros participantes, que han respondido a la primera todas las veces que ha hecho falta, y que han hecho posible llegar a reclutar 870 contactos de tuberculosis en 3 años y medio de periodo de inclusión y dos años de seguimiento. El motivo real de haber escrito la tesis no fue inicialmente el afán por la investigación ni por la docencia. Es difícil explicarlo a los que no conocieron el Servicio de Enfermedades Infecciosas a principio de los años 2000: un Servicio formado por un grupo de profesionales con características muy especiales: buenos clínicos, estudiosos, rigurosos y exigentes, con tradición docente y que mantenían la ilusión por la medicina a pesar del paso de los años (Pedro F-Viladrich y Javier Ariza como máximos representantes de esto último). En ese Servicio por aquel entonces, se alinearon los astros para que coincidieran en el tiempo unos cuantos investigadores “junior”, R- grandes míos a los que yo más admiraba y a quien me quería parecer. Sobre todo a Cristina y a Jaime, por su capacidad de trabajo infinita, el ser capaces de ayudar a los demás aunque ellos fuesen con el agua al cuello, su sonrisa permanente y el no dejar nunca de ir a ver a un paciente ni de resolver los “marrones” que caían en sus manos. Y como quería ser así, seguí el camino que ellos siguieron. Luego supe que otros grandes clínicos del Hospital también habían sido becarios de infecciosas, Bea Rosón, Abelardo, Oscar, Nuria Sabé, Olga C…Personas que ya me habían sorprendido al trabajar con ellas por lo bien ordenada que tenían la cabeza. Pensé que recorriendo sus pasos yo podría también parecerme a ellos. A estos ejemplos del buen hacer les debo también mi agradecimiento. En el proceso, que sin duda es más importante que el resultado final de tener ahora este documento en las manos, ha habido muchos más momentos buenos que malos. Ha habido mucho trabajo pero también mucho espíritu de equipo, mucha estadística pero mucha ayuda para superarla, muchas guardias pero muchas más celebraciones (¡cualquier excusa es buena!). Muchas sesiones clínicas, que eran -y son- la joya del Servicio, donde las opiniones de los Seniors iban modelando el razonamiento de los juniors, donde se aprendía tanta Medicina y tanto sentido común de Carmen Peña, las reflexiones de fondo de Javier Ariza que ponían nervioso al que presentaba el caso, el apunte de la experiencia de Pedro, siempre con espíritu docente para los residentes, el comentario brillante de los Migueles aportando posibles diagnósticos diferenciales, las aclaraciones de la historia clínica de Imma, las dudas razonables y razonadas de Núria y el aporte histórico de Carmen C. Me siento afortunada de haber participado en esas conversaciones. A las generaciones sucesivas de becarios, sobre todo a Marta y Iván: este periodo ha sido mágico en parte por vosotros; nos hemos hecho fuertes juntos, y estos años nos han unido para siempre de una manera especial. Quizá con los que vinieron después no haya coincidido tanto, pero sé que Silvia, Alba, Anto, Isa, Aina, Sara y Cris han manteniendo el pabellón bien alto dentro y fuera del Aula Rufí. Esta “concentración del saber” no estaba localizada únicamente en la planta 12 del Hospital. Muchos grandes profesionales de todos los Servicios me han ayudado con su ejemplo y su dedicación a aprender el oficio de ser médico. No los puedo nombrar a todos porque la lectura sería farragosa… Muchos estaban concentrados también en la planta 7: Tuve la suerte de rotar con Joan Mañá en los tres primeros meses de planta de Medicina siendo R3. Me enseñó mucho. Muchísima medicina. Olga y Bea me enseñaron eficacia y rapidez de decisión en las guardias y en la planta: nunca se les han caído los anillos cuando se tenía que sacar adelante una guardia mala. Con “House” Vidaller descubrí la manera de buscar pistas para diagnosticar y tratar los casos que desde toda “la casa” le venían a consultar: ¡hay que estudiar, nena!. Maestros en las rotaciones: Juana Barthe, Ignacio Martínez-Ballarín, Fede Manresa, Carme Baliellas, Xavier Xiol, Manolo P-Maraver, Charlie Villabona, Joan Torras, Luisa Corral, MºJesús Ferrer, Rosario Cañizares (q.e.p.d), Mar Marín, Joan Guillamon en el HaD, Pere Cardona, Sergio Martínez-Yélamos, y maestros en Urgencias: Xavi y Javi, Ana Álvarez y Ferran Llopis; y compañeros/ hermanos de Urgencias con el pool de la saga Iglesias- Muñoz- Castellví- Muñoz- Pelegrín- Santo- Roset- Oriol- Martín- Boix- Cos- Giménez- Camprubí. Muy agradecida tengo que estar al soporte extra-hospitalario de estos largos años. A todas las personas que me han aguantado en los momentos de hundimiento antes de un deadline o cuando me rechazaban un artículo: las ciudadanas de las capitales francesa y griega, saben a quienes me refiero: especialmente a Anna B, María Ll, Marta S, Ció, Guille y Teresa por el número de años y la intensidad de los mismos. En los últimos dos años he tenido la suerte de conocer y después formar parte de un equipo de grandes profesionales en Servicio de M. Interna en el Parc Sanitari Sant Joan de Déu. Los minions han hecho todo lo posible para que sacase tiempo para acabar la tesis: Gemma y MºJosé porque ya habían pasado por lo mismo, Xoel porque está en mismo trance, y Elisabet, Amara y Gilsy que han endulzado este último periodo: literalmente con chuches y chocolate, y echándome una mano o un brazo entero con mis pacientes de planta. Y por último, y no por eso menos importante, a mis padres y hermanos que nunca han dudado en que este proyecto acabaría con éxito algún día, y a mis sobrinos Nacho María y Ana, que acaban sus años de grado universitario, habiéndolos empezado cuando yo ya era becaria… Creo que han podido comprobar que “el que la sigue, la consigue”. Ahora acabamos -o casi- los cuatro juntos para empezar otra etapa. Ellos tampoco han dudado y siempre me han animado. A Pablo y a Blanca que todavía les queda un trecho… espero que estén a tiempo de pensar si quieren hacer un doctorado o no después de esta experiencia vivida en cabeza ajena... Y a Jaime, que por lo menos tiene claro que no quiere estudiar Medicina. RESUMEN INTRODUCCIÓN La tuberculosis (TB) es una de las enfermedades más antiguas y devastadoras que ha acompañado al ser humano desde hace cientos de años. A pesar de ser una enfermedad tratable y prevenible desde el descubrimiento de los fármacos activos frente a su agente causal Mycobacterium tuberculosis (Mtb), la TB sigue siendo una de las diez causas de mortalidad más frecuentes en el mundo. En 2014 se declararon 1.5 millones de muertes por esta causa, concentrándose el 80% de casos en 22 países en vías de desarrollo. A pesar de esta distribución, la TB no es exclusiva de los países pobres: Mtb no conoce fronteras y ningún país ha logrado nunca eliminar esta enfermedad. El reservorio de Mtb es casi exclusivamente humano, aunque antaño y todavía ahora en países del tercer mundo, ha existido transmisión zoonótica a través de la ingesta de leche no pasteurizada de ganado vacuno enfermo. El paciente enfermo de TB es fuente de contagio para el resto de personas: al toser o al hablar está dispersando secreciones respiratorias microscópicas que contienen Mtb. Se sabe que este bacilo puede mantener su viabilidad varios días expuesto al ambiente, lo que hace que el contagio sea extremadamente difícil de prevenir. Al ser inhalado y alcanzar el espacio alveolar, Mtb se enfrenta a los macrófagos, la primera barrera que le presenta el sistema inmunitario. Tras un complejo sistema de citoquinas estimuladoras e inhibidoras de otros grupos celulares, se organizará el granuloma.
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