post-TB Lung Research Articles

Tuberculosis-Associated Respiratory Disability in Children, Adolescents, and Adults: Protocol for a Systematic Review and Individual Participant Data Meta-Analysis.

Approximately 2% of the global population has survived tuberculosis (TB). Increasing evidence indicates that a significant proportion of pulmonary TB survivors develop TB-associated respiratory disability, commonly referred to as post-TB lung disease (PLTD) and marked by impaired respiratory function, persistent symptoms, and activity limitations. However, the prevalence, risk factors, and progression of TB-associated respiratory disability throughout the life course are not well understood. To address these gaps, we will undertake a systematic review and individual participant-level data meta-analysis (IPD-MA) focusing on TB-associated respiratory disability in children, adolescents, and adults successfully treated for pulmonary TB. We will systematically search MEDLINE, Embase, CENTRAL, Global Index Medicus, and medRxiv for original studies investigating TB-associated respiratory disability in people of all ages who have completed treatment for microbiologically confirmed or clinically diagnosed pulmonary TB. Authors of eligible studies will be invited to contribute de-identified data and form a collaborative group. Primary outcomes will be (1) abnormal lung function based on spirometry parameters and (2) chronic respiratory symptoms. We will estimate the overall and subgroup-specific prevalence of each outcome through IPD meta-analysis. Next, we will develop clinical prediction tools assessing the risk of future TB-associated respiratory disability at (i) the start of TB treatment and (ii) end of TB treatment for those without existing signs of disability. Finally, we will use stepwise hierarchical modelling to identify epidemiological determinants of respiratory disability. This study has been approved by the ethics review boards at the Rhode Island Hospital (2138217-2) and the Research Institute of the McGill University Health Centre (2024-10345). Individual study authors will be required to obtain institutional approval prior to sharing data. Results will be disseminated through open-access, peer-reviewed publications and conference presentations. CRD42024529906.

Lung function and health-related quality of life among adult patients following pulmonary TB treatment.

<sec><title>OBJECTIVES</title>Pulmonary TB (PTB) increases the risk of chronic lung complications, which are associated with increased morbidity and mortality. We determined the prevalence and predictors of post-TB lung disease and persistent symptoms in a resource-limited setting.</sec><sec><title>METHODS</title>Adults who completed PTB treatment underwent spirometry and completed the St. George's Respiratory Questionnaire (SGRQ), a questionnaire that assesses quality of life on symptom, activity, and impact. We performed multivariate analyses to calculate the X-adjusted prevalence ratio (PRadj) of abnormal spirometry and identify associated risk factors.</sec><sec><title>RESULTS</title>Among the 162 participants, 89 (54.9%) were male. The median age was 32 years, and 65 (40.1%) had HIV. Overall, 65 participants (40.1%) had abnormal lung function, with spirometric restriction seen in 29.0%, obstruction in 4.9%, and a mixed pattern in 6.2%. Smoking (PRadj 1.88, 95% CI 1.11-3.16; P = 0.02) and female sex (PRadj 1.81, 95% Cl 1.15-2.84; P = 0.01) were independent risk factors for abnormal lung function. The median SGRQ scores were higher in participants with cavitation (P < 0.001) or bilateral consolidation on initial chest X-ray (P = 0.01).</sec><sec><title>CONCLUSIONS</title>Lung function abnormalities, particularly spirometric restriction, are common in patients completing PTB treatment. Female sex and smoking status were associated with lung function abnormalities; therefore, additional studies to understand the underlying mechanistic pathways are warranted.</sec>.

Pathogenesis of Post-Tuberculosis Lung Disease: Defining Knowledge Gaps and Research Priorities at the Second International Post-Tuberculosis Symposium.

Post-tuberculosis (post-TB) lung disease is increasingly recognized as a major contributor to the global burden of chronic lung disease, with recent estimates indicating that over half of TB survivors have impaired lung function after successful completion of TB treatment. However, the pathologic mechanisms that contribute to post-TB lung disease are not well understood, thus limiting the development of therapeutic interventions to improve long-term outcomes after TB. This report summarizes the work of the Pathogenesis and Risk Factors Committee for the Second International Post-Tuberculosis Symposium, which took place in Stellenbosch, South Africa, in April 2023. The committee first identified six areas with high translational potential: 1) tissue matrix destruction, including the role of matrix metalloproteinase dysregulation and neutrophil activity; 2) fibroblasts and profibrotic activity; 3) granuloma fate and cell death pathways; 4) mycobacterial factors, including pathogen burden; 5) animal models; and 6) the impact of key clinical risk factors, including HIV, diabetes, smoking, malnutrition, and alcohol. We share the key findings from a literature review of those areas, highlighting knowledge gaps and areas where further research is needed.

Prior tuberculosis, radiographic lung abnormalities and prevalent diabetes in rural South Africa

BackgroundGrowing evidence suggests that chronic inflammation caused by tuberculosis (TB) may increase the incidence of diabetes. However, the relationship between post-TB pulmonary abnormalities and diabetes has not been well characterized.MethodsWe analyzed data from a cross-sectional study in KwaZulu-Natal, South Africa, of people 15 years and older who underwent chest X-ray and diabetes screening with hemoglobin A1c testing. The analytic sample was restricted to persons with prior TB, defined by either (1) a self-reported history of TB treatment, (2) radiologist-confirmed prior TB on chest radiography, and (3) a negative sputum culture and GeneXpert. Chest X-rays of all participants were evaluated by the study radiologist to determine the presence of TB lung abnormalities. To assess the relationships between our outcome of interest, prevalent diabetes (HBA1c ≥6.5%), and our exposure of interest, chest X-ray abnormalities, we fitted logistic regression models adjusted for potential clinical and demographic confounders. In secondary analyses, we used the computer-aided detection system CAD4TB, which scores X-rays from 10 to 100 for detection of TB disease, as our exposure interest, and repeated analyses with a comparator group that had no history of TB disease.ResultsIn the analytic cohort of people with prior TB (n = 3,276), approximately two-thirds (64.9%) were women, and the average age was 50.8 years (SD 17.4). The prevalence of diabetes was 10.9%, and 53.0% of people were living with HIV. In univariate analyses, there was no association between diabetes prevalence and radiologist chest X-ray abnormalities (OR 1.23, 95%CI 0.95–1.58). In multivariate analyses, the presence of pulmonary abnormalities was associated with an 29% reduction in the odds of prevalent diabetes (aOR 0.71, 95%CI 0.53–0.97, p = 0.030). A similar inverse relationship was observed for diabetes with each 10-unit increase in the CAD4TB chest X-ray scores among people with prior TB (aOR 0.92, 95%CI 0.87–0.97; p = 0.002), but this relationship was less pronounced in the no TB comparator group (aOR 0.96, 95%CI 0.94–0.99).ConclusionsAmong people with prior TB, pulmonary abnormalities on digital chest X-ray are inversely associated with prevalent diabetes. The severity of radiographic post-TB lung disease does not appear to be a determinant of diabetes in this South African population.

Scoping review of post-TB pulmonary vascular disease: Proceedings from the 2nd International Post-Tuberculosis Symposium.

Tuberculosis (TB) may cause significant long-term cardiorespiratory complications, of which pulmonary vascular disease is most under-recognized. TB is rarely listed as a cause of pulmonary hypertension (PH) in most PH guidelines, yet PH may develop at various stages in the time course of TB, from active infection through to the post-TB period. Predisposing risk factors for the development of PH are likely multifactorial, involving active TB disease and post-TB lung disease (PTLD), host-related and environment-related factors. Moreover, post-TB PH should likely be classified in Group 3 PH, with the pathogenesis similarly complex and multifactorial as other Group 3 PH causes. Identifying risk factors that predispose to post-TB PH may aid in developing risk stratification criteria for early identification and referral for confirmatory diagnostic tests. Given that universal screening for PH in TB survivors may be impractical and unfeasible, a targeted screening approach for high-risk individuals would be sensible. In this scoping review of post-TB PH, resulting from the proceedings of the 2nd International Post-Tuberculosis Symposium, we aim to describe the epidemiology, risk factors, and pathophysiology of post-TB PH. We emphasize diagnosing PH with an alternative set of diagnostic guidelines in resource-constrained settings where right heart catheterization may not be feasible. Research to describe the burden and distribution of post-TB PH should be prioritized as there is a current gap in knowledge regarding the prevalence and incidence of post-TB PH among persons with TB.

A mouse model of TB-associated lung fibrosis reveals persistent inflammatory macrophage populations during treatment.

Post-TB lung disease (PTLD) causes a significant burden of global disease. Fibrosis is a central component of many clinical features of PTLD. To date, we have a limited understanding of the mechanisms of TB-associated fibrosis and how these mechanisms are similar to or dissimilar from other fibrotic lung pathologies. We have adapted a mouse model of TB infection to facilitate the mechanistic study of TB-associated lung fibrosis. We find that the morphologies of fibrosis that develop in the mouse model are similar to the morphologies of fibrosis observed in human tissue samples. Using Second Harmonic Generation (SHG) microscopy, we are able to quantify a major component of fibrosis, fibrillar collagen, over time and with treatment. Inflammatory macrophage subpopulations persist during treatment; matrix remodeling enzymes and inflammatory gene signatures remain elevated. Our mouse model suggests that there is a therapeutic window during which adjunctive therapies could change matrix remodeling or inflammatory drivers of tissue pathology to improve functional outcomes after treatment for TB infection.

Accuracy of chest x-ray screening of silica-exposed miners for tuberculosis.

The World Health Organization recommends systematic chest X-ray (CXR) screening for tuberculosis (TB) in silica-exposed workers. However, evidence on the accuracy of CXR screening in such populations is lacking. To measure the accuracy of CXR screening for active TB in silica-exposed miners, in a population with a high prevalence of silicosis, post-TB lung disease and HIV. A secondary analysis of data from a miner screening programme in Lesotho was undertaken. We measured the performance of CXR (in participants with and without cough) for 'abnormalities suggestive of TB' against Xpert MTB/RIF (Xpert). The sample size was 2572 and positive Xpert prevalence was 3%. CXR alone had high sensitivity (0.93, 95% confidence interval [CI] 0.87-0.99), but low specificity (0.41, 95% CI 0.39-0.42). Requiring cough and a positive CXR increased specificity (0.79, 95% CI 0.77-0.81), resulting in reduced sensitivity (0.41, 95% CI 0.30-0.52). There was no difference in CXR accuracy by HIV status. However, specificity was markedly reduced in the presence of silicosis (from 0.70, 95% CI 0.68-0.72, to 0.03, 95% CI 0.02-0.04) or past TB history (from 0.59, 95% CI 0.56-0.62 to 0.27, 95% CI 0.25-0.29). Throughout, positive predictive value remained very low (5%) and negative predictive value very high (99%). CXR screening accurately identifies TB-negative CXRs in this population, but post-TB lung disease and silicosis would result in a high proportion of Xpert-negative referrals and an increased risk of unneeded empirical treatment. Adapted screening algorithms, practitioner training and digital access to previous mining CXRs are needed.

Multidrug-resistant tuberculosis.

Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level.

Perspectives from the 2nd International Post-Tuberculosis Symposium: mobilising advocacy and research for improved outcomes.

In 2020, it was estimated that there were 155 million survivors of TB alive, all at risk of possible post TB disability. The 2nd International Post-Tuberculosis Symposium (Stellenbosch, South Africa) was held to increase global awareness and empower TB-affected communities to play an active role in driving the agenda. We aimed to update knowledge on post-TB life and illness, identify research priorities, build research collaborations and highlight the need to embed lung health outcomes in clinical TB trials and programmatic TB care services. The symposium was a multidisciplinary meeting that included clinicians, researchers, TB survivors, funders and policy makers. Ten academic working groups set their own goals and covered the following thematic areas: 1) patient engagement and perspectives; 2) epidemiology and modelling; 3) pathogenesis of post-TB sequelae; 4) post-TB lung disease; 5) cardiovascular and pulmonary vascular complications; 6) neuromuscular & skeletal complications; 7) paediatric complications; 8) economic-social and psychological (ESP) consequences; 9) prevention, treatment and management; 10) advocacy, policy and stakeholder engagement. The working groups provided important updates for their respective fields, highlighted research priorities, and made progress towards the standardisation and alignment of post-TB outcomes and definitions.

Post-TB lung disease: keep going beyond TB!

Post-TB lung disease: keep going beyond TB!

Interventions to prevent post-tuberculosis sequelae: a systematic review and meta-analysis

Tuberculosis (TB) remains a global public health challenge, causing substantial mortality and morbidity. While TB treatment has made significant progress, it often leaves survivors with post-TB sequelae, resulting in long-term health issues. Current healthcare systems and guidelines lack comprehensive strategies to address post-TB sequelae, primarily due to insufficient evidence. This systematic review and meta-analysis aimed to identify effective interventions for preventing post-TB sequelae. A systematic search was conducted across four databases including PubMed, SCOPUS, Web of Science, and Cochrane Central Register of Controlled Trials from inception to September 22, 2023. Eligible studies reported interventions designed to prevent post-TB sequelae were included. A random effect meta-analysis was conducted where applicable, and heterogeneity between studies was evaluated visually using forest plots and quantitatively using an index of heterogeneity (I2). This study is registered with PROSPERO (CRD42023464392). From the 2525 unique records screened, 25 studies involving 10,592 participants were included. Different interventions were evaluated for different outcomes. However, only a few interventions were effective in preventing post-TB sequelae. Rehabilitation programs significantly improved lung function (Hedges's g=0.21; 95% confidence interval (CI): 0.03, 0.39) and prevented neurological sequelae (relative risk (RR)=0.10; 95% CI: 0.02, 0.42). Comprehensive interventions and cognitive-behavioural therapy significantly reduced the risk of mental health disorders among TB survivors (Hedges's g=-1.89; 95% CI:-3.77,-0.01). In contrast, interventions targeting post-TB liver sequelae, such as vitamin A and vitamin D supplementation and hepatoprotective agents, did not show significant reductions in sequelae (RR=0.90; 95% CI: 0.52, 1.57). Moreover, adjunctive therapies did not show a significant effect in preventing post-TB neurological sequelae (RR=0.62, 95% CI: 0.31, 1.24). Rehabilitation programs prevented post-TB lung, neurologic and mental health sequelae, while adjuvant therapies and other interventions require further investigation. Healy Medical Research Raine Foundation, Curtin School of Population Health and the Australian National Health and Medical Research Council.

Emphasis on post-TB lung disease and other sequelae of TB is good but a public health approach to TB is morally ambitious???

Emphasis on post-TB lung disease and other sequelae of TB is good but a public health approach to TB is morally ambitious???

The potential for vaccines to aid the treatment of post-TB lung disease.

The potential for vaccines to aid the treatment of post-TB lung disease.

A call to invest in post-TB lung disease to halt TB transmission in communities.

A call to invest in post-TB lung disease to halt TB transmission in communities.

Screening for post-TB lung disease at TB treatment completion: Are symptoms sufficient?

Pulmonary TB survivors face a high burden of post-TB lung disease (PTLD) after TB treatment completion. In this secondary data analysis we investigate the performance of parameters measured at TB treatment completion in predicting morbidity over the subsequent year, to inform programmatic approaches to PTLD screening in low-resource settings. Cohort data from urban Blantyre, Malawi were used to construct regression models for five morbidity outcomes (chronic respiratory symptoms or functional limitation, ongoing health seeking, spirometry decline, self-reported financial impact of TB disease, and death) in the year after PTB treatment, using three modelling approaches: logistic regression; penalised regression with pre-selected predictors; elastic net penalised regression using the full parent dataset. Predictors included demographic, clinical, symptom, spirometry and chest x-ray variables. The predictive performance of models were examined using the area under the receiver-operator curve (ROC AUC) values. Key predictors were identified, and their positive and negative predictive values (NPV) determined. The presence of respiratory symptoms at TB treatment completion was the strongest predictor of morbidity outcomes. TB survivors reporting breathlessness had higher odds of spirometry decline (aOR 20.5, 95%CI:3-199.1), health seeking (aOR 10.2, 2.4-50), and symptoms or functional limitation at 1-year (aOR 16.7, 3.3-133.4). Those reporting activity limitation were more likely to report symptoms or functional limitation at 1-year (aOR 4.2, 1.8-10.3), or severe financial impact of TB disease (aOR2.3, 1.0-5.0). Models were not significantly improved by including spirometry or imaging parameters. ROC AUCs were between 0.65-0.77 for the morbidity outcomes. Activity limitation at treatment completion had a NPV value of 78-98% for adverse outcomes. Our data suggest that whilst challenging to predict the development of post-TB morbidity, the use of symptom screening tools at TB treatment completion to prioritise post-TB care should be explored. We identified little benefit from the additional use of spirometry or CXR imaging.

The Tuberculosis Sentinel Research Network (TB-SRN) of the International epidemiology Databases to Evaluate AIDS (IeDEA): protocol for a prospective cohort study in Africa, Southeast Asia and Latin America

IntroductionTuberculosis (TB) is a leading infectious cause of death globally. It is the most common opportunistic infection in people living with HIV, and the most common cause of their morbidity...

The obstructive phenotype of chronic posttuberculosis disease - is there a role for the occupational exposure?

Abstract Tuberculosis (TB) disease is treatable, but the postTB lung disease in previously treated patients is a reality which must not be ignored. A case report of a 52-year-old male patient, heavy smoker (50 pack-years), alcoholic, with occupational exposure to chemical hazards (such as gaz oil vapors, distillate fuels and industrial solvents), physical hazards (thermal extremes, noise, vibration, UV radiation), ergonomic hazards (manual handling activities); and psychosocial hazards (e.g. overload, isoloation from family and friends), was delayed diagnosed with severe extensive cavitary pulmonary TB disease in 1999, treated till 2001. The assessment of lung function was neglected before or after antiTB therapy ended, so COPD was ignored till 2009, when the patient was admitted in a Pneumology Hospital. Other long term postTB disorders, as left fibrothorax, bronchiectasis, cavitary open healling syndrome, were also identified. Chronic postTB lung disease (PTLD), centered on COPD, had unfavorable progressive evolution till September 2022, when premature death occured. In conclusion, the obstructive phenotype of PTLD was delayed diagnosed and had multiple risk factors as tobacco smoking, occupational exposure and severe TB disease itself. A protocol for monitoring obstructive lung disorders among workers in oil industry, especially those diagnosed with TB disease, should be properly adapted through a collaborative approach between the occupational and the chest physician.

Post-tuberculosis Sequelae in Children.

Tuberculosis (TB) is a global health problem especially in the Indian subcontinent imposing significant physical, psychosocial and economic burden on the society. Most national programs define TB cure as completion of treatment with improvement in clinical symptoms, microbiological and radiological clearance. However, follow up these patients for long-term sequelae or complications has not got adequate attention. Post-TB lung disease, neurological deficits and spinal deformities are some of the post-TB sequelae reported in adults, with scanty data available for children. With this review authors attempt to discuss various post-TB disease manifestations and the risk factors associated with their development in children. They address the need to create awareness amongst physicians involved in managing children with TB and obtain more scientific data in this field.

Childhood TB sequel: evaluating respiratory function after treatment for pulmonary tuberculosis in a prospective cohort of Gambian children – a study protocol

Background1.2 million children under 15 years are estimated to have developed tuberculosis (TB) in 2021. 85% of paediatric patients achieve successful treatment outcomes if treated for the first episode of TB. However, despite so-called successful treatment, TB leaves many survivors with permanently destroyed or damaged lungs. Data from prospective paediatric cohorts to establish the burden and evolution of post-TB lung disease (PTLD) are still absent. The Childhood TB Sequel study aims to describe respiratory consequences associated with pulmonary TB in Gambian children, describe the evolution of these sequelae, and determine associated epidemiological risk factors.MethodsWe aim to recruit up to 80 subjects aged 19 years and below who have recently completed treatment for pulmonary TB. Recruitment started in April 2022 and is expected to continue until June 2024. Clinical assessment, chest X-ray, and comprehensive lung function assessment are carried out at treatment completion and again six and 12 months later.DiscussionThe Childhood TB Sequel study will address existing research gaps to enhance our knowledge and understanding of the burden of PTLD in Gambian children. The study will also contribute to formulating a plan for post-TB evaluation and long-term follow-up strategies.Trial registrationClinicalTrials.gov: NCT05325125, April 13, 2022.

Prevalence of pulmonary arterial hypertension in post-tuberculosis lung fibrosis patients: A cross-sectional observational study

Introduction: Post-tuberculosis (TB) lung fibrosis is an infrequently reported cause of Pulmonary arterial hypertension (PAH). Pulmonary TB still being an important global health problem, especially in developing countries, PAH developing after pulmonary TB deserves attention. This study was undertaken to know the prevalence of PAH among patients with post-TB lung fibrosis. Methods: A cross-sectional observational study was carried out in two tertiary care hospitals in Kolkata over a period of 1 year. Sixty adult post-TB lung fibrosis patients without any cardiovascular or other pulmonary comorbidities were included in this study. Results: Out of the 60 patients with varying degrees of lung fibrosis confirmed radiologically, eight patients were found to have PAH (13.33% of the study population). Among the eight cases, six were males and two were females. Five of the males were smokers with a mean of 17.6 pack years of smoking. Out of the eight diagnosed PAH cases, three were mild PAH, four were moderate, and one case had severe PAH (grading based on 2D echocardiography findings). Pulmonary function test (PFT) revealed obstructive pattern in three cases, restrictive pattern in three cases, and mixed in two cases. On PFT, smokers with PAH exhibited obstructive pattern and mixed pattern, whereas the nonsmoker PAH cases exhibited restrictive pattern. Conclusion: All post-TB lung fibrosis cases must be followed up at regular intervals and screened to rule out PAH. Early diagnosis and prompt treatment of the cases will help to reduce morbidity and mortality of the disease which otherwise has a poor prognosis.