The core of the current project is a prospective cohort of up to 1600 patients across four countries (Mozambique, Tanzania, South Africa and The Gambia), enrolled at the time of TB diagnosis, and followed up for at least 2 years. The overall goal of the cohort is to describe the evolution of pulmonary symptoms and functional lung impairment as well as risk factors (clinical, immunological, microbiological, etc.) contributing to the lung outcome.
The TB cohort facilitates the conduct of the other Research Tasks by providing the required data and samples. Data and information derived from the cohort will be analyzed and refurbished to inform a broader research community as well as local, national and supranational authorities about the relevant findings and new insights.
The majority of TB studies to date have focussed on diagnosis and treatment responses without considering the implications of sustained loss of lung function and subsequent long-term sequelae. The aims of this research task are to understand the pathophysiology and identify confounders for exacerbated lung damage leading to long-term clinical sequelae within the TB core cohorts and to define pre- or early-treatment biomarkers in blood/sputum that may predict treatment response and pulmonary outcome.
This state of the art project will bring together a leading team of researchers to elucidate inflammatory pathways that could be targeted for host-adjunctive therapies to potentially limit lung pathology and avoid long-term damage.
Host factors and environmental factors are widely accepted as major determinants driving the course of infection and outcome of treatment. The potential influence of pathogen diversity is less well understood. The overall objective of this research task is to describe the genetic characteristics, metabolic state, dynamic of bacterial load before and during treatment, and to assess the impact of these factors on transmission, treatment outcome and long term sequelae of TB disease, for all patients enrolled into the TB cohort.
There is growing consensus that progress in tuberculosis (TB) control in the low- and middle-income countries will require not only investment in strengthening diagnostics and treatment but also actions on the socio-economic determinants and consequences of TB, as well as measures to improve patients’ quality of life and well-being after suffering TB disease.
The published literature contains surprisingly little evidence about the costs to the health systems of treating TB and the impact of TB and TB treatment on patients’ quality of life, economic well-being, and productivity. The main goal of the Socio-Economic Research Task is to evaluate the health-related quality of life impacts of TB and TB treatment and assess the economic cost to patients and to the health system of pulmonary TB and the treatment in four countries in Africa. The information generated by the study will help policy makers budget for TB care and treatment and provide evidence for investment in new drug regimens, TB control, and household interventions.
Delayed eradication of infection and resolution of inflammation are common in tuberculosis despite eventual microbiologic cure. Prolonged and intense inflammation in the lung in TB results in depletion of glutathione (GSH), leaving the lung susceptible to damage by reactive oxygen species (ROS). This study will conduct a randomized, controlled phase 2 trial of adjunctive N-acetylcysteine (NAC) in TB patients.
In this RT we are proposing the continuation of the existing TB Sequel cohort of nearly 1,560 recruited (between 2017 and 2019) and clinically, micro-biologically, socio-economically, genetically, spatially, and immunologically well-described former TB patients to prospectively study the association between PTLD and long-term morbidity and mortality. About 40% of cohort participants had moderate to severe lung impairment in spirometry 24 months after TB treatment initiation, which we consider as clinically relevant PTLD.
TB Sequel II would be the only cohort worldwide that provides prospective TB- and PTLD- outcome data from a relevant number of patients for up to 8-10 years after TB diagnosis. Therefore, the expected data will be extremely useful to researchers and stakeholders to develop (post-) TB interventions aiming at reducing TB-related morbidity burden as well as to prioritise national health policies and research agendas especially in high TB burden countries with limited resources.
Most TB patients are left with impaired lung function and shortened survival despite microbiologic cure. Means to treat or prevent these outcomes do not presently exist. Oxidative injury is a common final pathway for tissue damage in TB. NAC is a dietary supplement and WHO essential medicine to replenish glutathione (GSH), a key cellular anti-oxidant. The NAC-TB sub-study of TB Sequel found: 1) GSH is markedly depleted at TB diagnosis; 2) NAC rapidly increases GSH; and, 3) in patients with severe lung impairment at baseline, NAC promotes recovery of lung function. This RT will con-firm and extend these findings by optimizing NAC therapy to treat and prevent PTLD.
The host immune-response against Mtb infection and related inflammatory processes most likely play a dominant role in the development of PTLD. The clinical data and samples collected from the TB Sequel I-cohort were ideal for studying the inflammatory pathways of PTLD during and directly after TB treatment, including the host-pathogen-interaction of distinct clinical PTLD phenotypes. In TB Sequel II, our PTLD-research will expand to the study of the inflammatory processes in the lungs and the role of specific pathogens that are associated with PTLD-progression, cardio-respiratory exacerbations and other adverse clinical outcomes. In addition, we will analyse the host and pathogen interactions during a therapeutic intervention trial, exploring NAC-treatment for both prevention and treatment of PTLD.
While there has been much interest recently in the long-term pulmonary outcomes following micro-biological cure, there is limited evidence on the full spectrum of socio-economic complications experienced after treatment completion. Evidence suggests that the negative impact of TB may continue for up to 5 years post-TB treatment. TB Sequel II will provide an opportunity to continue following TB survivors prospectively to describe the long-term socio-economic consequences of pulmonary TB and identify individuals who may benefit from more frequent monitoring during follow-up and from socio-economic interventions to mitigate these consequences.
PTLD contributes to a significant morbidity burden in African countries; however, there is a lack of evidence-based, context-specific and acceptable strategies for screening, management and treatment of PTLD. The overarching aim of this work is to support the development of a clinical pathway to diagnosis and management of PTLD through strengthening capacities of National TB Programs (NTPs) and health care providers (HCPs) and piloting context-adapted tools and interventions.