Improving diagnostic strategies for latent tuberculosis infection in populations at risk for developing active disease

Abstract

BACKGROUND Latent tuberculosis infection (LTBI) management is a crucial component of tuberculosis prevention in high-risk individuals. A global approach including diagnosis and treatment completion ensures good outcomes.T-cell-based interferon-gamma release assays (IGRAs) were first developed a decade ago, at which time they represented a promising alternative to the tuberculin skin test (TST); however, they too are limited by their poor ability to predict future active TB, being only slightly better than TST at best. Since the implementation of IGRAs, several cross-sectional studies showed the comparison of TST and IGRAs results in populations at risk for developing active tuberculosis, with still not enough evidence based on longitudinal cohorts and properly designed clinical trials to date.

HYPOTHESIS 1. In immunosuppressed individuals: The addition of an IGRA test might benefit the diagnostic strategy in order to maximize TST sensitivity. 2. In recently infected individuals (contact tracing studies): Implementing the use of IGRAs could narrow the proportion of preventive therapy in individuals at risk of developing active tuberculosis, without increasing its risk.

OBJETIVES 1. Immunosuppressed individuals: 1.1 To assess whether a comprehensive latent tuberculosis screening and treatment program includind an IGRA can prevent anti-TNF–associated tuberculosis. 1.2. To assess the usefulness of QFT-GIT in predicting the development of active tuberculosis in comparison to the TST in patients undergoing liver transplant and hematopoietic stem cell transplant.

2. Contact tracing studies 2.1 To ascertain whether using IGRA, either in place of TST or to confirm a positive TST, might reduce the number of people considered for preventive treatment, without leading to a significant increase in the risk of subsequent active tuberculosis. 2.2 To determine whether the use of QFT-GIT as a confirmatory test of the TST to target preventive therapy in tuberculosis contacts might reduce the number of individuals receiving treatment without an increased risk of subsequent active tuberculosis, as compared to a TST-based strategy.

METHODS The clinical studies included in this thesis comprise three longitudinal cohort studies, a systematic review and a clinical trial. The three observational studies are retrospective analyses of prospectively gathered data, recorded as part of the clinical assistance in the Tuberculosis Unit at Bellvitge University Hospital. The research ethics committee approved them all. The statistical analyses were made with the SPSS (Statistical Package for the Social Sciences) software (version 17 and 22). The level of significance was fixed at α = 5%, and confidence intervals (CIs) for differences in proportions were estimated using OpenEpi software version 2.3.1.122.

RESULTS 1. Immunosuppressed individuals: 1.1 First, although anti-TNF–associated tuberculosis can be greatly reduced, a certain risk remains during the first year of treatment. Second, the 2-step TST approach for LTBI screening prior to anti-TNF therapy is no longer justified. Third, systematic periodic retesting for LTBI in patients with negative test results prior to anti-TNF therapy is not required. 1.2 The rate of post-transplant TB among QFT- GT-positive patients was both low and comparable to that of the TST in this cohort of liver transplant and Hematopoietic Stem Cell Transplant recipients.

2. Contact tracing studies In low-incidence settings of TB, using QFT-GIT to confirm positive TST reactors allows a significant reduction of TB infection diagnoses and preventive therapy prescriptions without increasing the risk of active disease.

ANTECEDENTES: Desde la implementación de los IGRAs (Interferon Gamma Release Assays) se ha generado poca evidencia científica fundamentada en ensayos clínicos o en el seguimiento longitudinal de cohortes.

HIPÓTESIS: 1. La implementación de los IGRAs en el cribado de infección tuberculosa latente (ITL) en pacientes inmunodeprimidos puede mejorar la rentabilidad diagnóstica. 2. Los IGRAs pueden optimizar la selección de pacientes candidatos a recibir tratamiento de ITL en el estudio de contactos (EC), reduciendo su número, sin aumentar el riesgo de tuberculosis activa (TB).

OBJETIVOS: 1. Demostrar la eficacia de un protocolo sistemático de prevención de TB que incluye un IGRA en los candidatos a anti-TNF. 2. Calcular los valores predictivos (VP) para el desarrollo de TB de la prueba de la tuberculina (PT) y un IGRA en pacientes candidatos a trasplante hepático (TH) o de progenitores hematopoyéticos (PH). 3. Demostrar que basar la indicación del tratamiento para ITL en el resultado de un IGRA disminuye la proporción de candidatos a tratamiento en comparación con PT, sin que por ello aumente el riesgo de TB.

MÉTODOS: La tesis responde a los objetivos mediante un ensayo clínico multicéntrico y tres estudios prospectivos aprobados por el Comité de Ética del Hospital de Bellvitge, así como una revisión sistemática.

RESULTADOS: 1. En candidatos a agentes anti-TNF se ha demostrado la eficacia del protocolo sistemático para la prevención de TB. El cese de PT en dos tiempos ha supuesto una disminución significativa en la proporción de diagnósticos y tratamientos de ITL sin aumentar del riesgo de TB ulterior. No es necesario repetir el cribado sistemáticamente tras un resultado negativo inicial. 2. En los candidatos a TH y de PH, el VP positivo para el desarrollo de TB del IGRA ha sido comparable a PT, siendo bajo, y por tanto no útil para predecir el desarrollo de TB. El VP negativo ha sido elevado en ambas pruebas. 3. La estrategia diagnóstica que confirma con un IGRA los resultados positivos de la PT ha demostrado ser no inferior a la estrategia basada únicamente en PT para la prevención de tuberculosis en el EC, permitiendo reducir significativamente el número de candidatos a tratamiento preventivo.