Worldwide, more than 10 million people fell ill with tuberculosis (TB) every year, and a total of 1.25 million people died from TB in 2023. However, TB is preventable and curable; with current recommended treatments, more than 85% of people with TB can be cured. In 2020, it was estimated that there were 155 million TB survivors still alive globally.1

After treatment completion, up to 50% of patients (and more than 70% of those with multidrug resistant TB) develop post-TB lung disease (PTLD), defined as “evidence of chronic respiratory abnormality, with or without symptoms, attributable at least in part to previous (pulmonary) TB.”2,3 The most frequently reported sequelae of pulmonary TB include radiological findings (cavities, bronchiectasis, fibrosis), chronic obstructive pulmonary disease (COPD), spirometry abnormalities (obstruction, restriction, and mixed patterns), in addition to psychosocial challenges, and reduced health-related quality of life.4–6 It has been estimated that substantial patients’ suffering happens after the completion of anti-TB treatment: out of 122 million Disability Adjusted Life Years (DALYs) due to incident TB disease estimated in 2019, 58 million DALYs have been attributed to PTLD, representing 47% of the total burden estimate.7

According to World Health Organization (WHO)’s policy,5 rehabilitation is an essential health service and should be available for people affected by TB-associated disability. Pulmonary rehabilitation (PR) has been proven to be helpful in patients with other chronic respiratory diseases, such as COPD. Although some evidence exists on the effectiveness of rehabilitation in PTLD patients, the present guidance6,8,9 was based on small cohorts from a single center (with a sample size not exceeding 20–30 cases, often not evaluating all recommended variables before and after rehabilitation) and assuming analogies with the efficacy/effectiveness of rehabilitation observed in COPD patients.10–15 Furthermore, no previous study had a control Group of non-rehabilitated patients and was able to analyze the effectiveness of rehabilitation separately for PTLD with and without COPD (and, in COPD patients, by COPD severity), given that COPD is common among these patients.8

Therefore, taking advantage of the recently published national PTLD management guidelines6 and of the availability of both a large cohort of rehabilitated PTLD patients (evaluated for all the recommended variables) and of a comparable control cohort, the objectives of this study were, in a large collaborating multicentre study conducted in reference centers in Brazil, Italy and France, to evaluate if patients with PTLD had benefits from PR in comparison with non-rehabilitated patients, and to evaluate efficiency/effectiveness of rehabilitation in PTLD patients with and without COPD.

Eighty-five patients were included in Group 1 and 96 patients were included in Group 2. No participants were excluded or withdrawn from the study during the PRP. Table 1 shows the patients’ characteristics. The frequency of coughing was higher in Group 1 (83.5%) than in Group 2 (60.4%) (p=0.001). There were no differences between the groups in all the other variables. In Group 1, three patients were unable to perform 6MWT and 5 patients were unable to perform ABG analysis.

Table 2 shows the comparison of pulmonary function tests between Groups 1 (rehabilitation) and 2 (no rehabilitation), and between initial and final evaluation. Several functional parameters improved after rehabilitation: forced expiratory volume in one second (FEV1) post-bronchodilator (BD), forced vital capacity (FVC) post-BD, DLCO, distance walked in 6MWT, initial SaO2 at 6MWT, and the final SaO2 at 6MWT. The median increase in 6-minute walk distance (6MWD) was 60m (Q1;Q3: 0m; 107.5m); 54/81 (66.7%) had an improvement greater than 25m. There was no statistically significant difference in the increase in 6MWD comparing patients with COPD (52.5m [Q1;Q3: −7.3m; 119.3m]) and without COPD (68.0m [Q1;Q3: 6.5m; 99.5m]) (p=0.963).

On the other hand, several functional parameters decreased after 3 months in Group 2, including: FEV1 post-BD (L), FEV1 post-BD (%), FVC post-BD (L), FVC post-BD (%), FEV1/FVC post-BD, DLCO, DLCO (%), and distance walked in 6MWT (Table 2).

Table 3 shows the comparison of pulmonary function tests pre- and post-PR, among patients with and without COPD. In COPD patients, several functional parameters increased after rehabilitation, such as FEV1 post-BD (L), FEV1 post-BD (%), FVC post-BD (L), FVC post-BD (%), FEV1/FVC post-BD, DLCO, distance walked in 6MWT, and initial/final SpO2 at 6MWT. In non-COPD patients, only FEV1 post-BD (L) and distance walked in 6MWT improved after rehabilitation.

Table 4 shows the comparison of pulmonary function tests between COPD and no COPD patients who did not underwent rehabilitation. In both COPD and non-COPD patients, there was a decline in several lung function parameters after 3 months.

Table 5 shows the comparison of pulmonary function tests according to COPD severity in Groups 1 and 2. Patients with severe and very severe COPD who underwent rehabilitation showed improvements in more lung function parameters, compared with patients with mild and moderate COPD who underwent rehabilitation. Among patients who did not undergo rehabilitation, both patients with mild to moderate COPD and those with severe and very severe COPD showed worsening of some lung function parameters.

In this study, we demonstrated that PR significantly improved lung volumes and flows measured during forced expiratory maneuvers (specifically FVC and FEV1) and pulmonary gas exchange (DLCO), that might account for improved exercise capacity (measured by the distance walked in the 6MWT) in patients with PTLD in a large multicentre cohort of PTLD patients. TLC, RV, and arterial blood gas analysis (PaO2 and SaO2) were not statistically different before and after PR. On the other hand, patients with PTLD who did not undergo PR worsened their lung function and exercise capacity when assessed 3 months after the initial evaluation (Table 2). In a subgroup analysis, it was observed that the number of lung function parameters which were improved after PR was much higher in COPD patients when compared with patients without COPD. Yet, the increase in post-BD FEV1 (L) and in the distance walked in the 6MWT after PR in non-COPD patients are consistent with preexisting bronchial obstruction and impaired exercise capacity in milder form of lung disease and suggest potential benefit of PR in all PTLD patients.

The first consensus-based set of Clinical Standards for PTLD, published in 2021,8 stated that former TB patients with functional, clinical, and/or radiological findings consistent with PTLD should be evaluated for PR. This important document was followed by the “Brazilian Thoracic Association recommendations for the management of PTLD”6 – the first national society to produce a document on this subject – which also recommended PR for patients with PTLD. A PRP for PTLD patients should take into consideration the local organization of health services, and it is suggested that evaluation of effectiveness of PR be done by comparing the core variables before and after rehabilitation.6,8

In the present study, FEV1, FVC, and DLCO improved significantly after PR. Some authors11,12,14 previously demonstrated similar findings. Visca et al.11 retrospectively investigated if patients with TB sequelae had any benefits from PR in Italy. After a 3-week PRP, 34 subjects with impaired lung function showed a significant improvement in FEV1 and FVC, although several details of their pre-rehabilitation TB history were not available. A group of authors in Japan evaluated the effectiveness of PR for a mean period of 3.9 weeks in 37 in-patients with pulmonary TB sequelae.12 In South Africa, a single-blinded randomized controlled study14 was conducted to assess the effects of a six-week home-based PRP in a group of 34 patients. They found improvements in FEV1 and FVC, although statistical significance was not reached at the end of the program. As expected, the improvement in lung function parameters after PR was greater in patients with PTLD and COPD (especially in those with severe to very severe COPD), in comparison with patients without COPD).

Improvement between pre- and post-rehabilitation moments was remarkably greater (and statistically significant) in more variables among patients with COPD (greater baseline functional impairment) than in patients without COPD or with less severe COPD (lower baseline functional impairment). This suggests that those with greater baseline functional impairment have more room for improvement with PR.

The distance walked in the 6MWT also showed improvement after PR in our study. This is in agreement with previous studies.12,13,15 In a PRP performed in Japan, the distance walked in 6MWT increased from 303m to 339m.12 In Colombia, a study13 including eight participants demonstrated an increase of 63.6m in distance walked in 6MWT, after an eight-week PRP within a public hospital. In addition, a prospective nonrandomized open trial15 conducted over a 9-week period evidenced a statistically significant improvement of 42m in 6-min walking distance. In a study with COPD patients,24 the mean improvement in 6MWD was of 66 meters, similar to our study, that included more than 70% of patients with COPD in addition to PTLD. We also found that almost 70% of patients had an increase in 6MWD greater than 25m, which is considered the minimal important difference for COPD patients.24 However, patients with PTLD and without COPD also demonstrated improvement in distance walked on the 6MWT in our study.

To the best of our knowledge, this study was the first to document significant improvements of DLCO in PTLD patients who underwent PR whilst the control group significantly deteriorated their pulmonary gas exchange during the same period. The fact that only FEV1, FVC and DLCO, and not TLC or RV significantly improved after three months of PR underscore the possibility of PR to improve ventilation, hence pulmonary gas exchange. Such improvement might also account for improved exercise capacity and the 6MWT.

We conducted PR on an outpatient-basis, as feasible in Brazil, and considered 3 months as the most suitable time for the comparisons as the majority of patients needed 3 months to complete the post-PR evaluation (81 of 85–95.3%). Only four patients completed the rehabilitation program in 5 weeks. There was no difference between these patients and those who took 3 months to complete the program. A potential minor bias exists, related to the differences in time patients needed to complete the process (PR and evaluation), we cannot measure nor correct for. Furthermore, a limitation exists given the non-possibility of randomizing patients toward Group 1 or 2. In fact, after publication of the SBPT guidelines, it is considered non-ethical, when the feasibility exists, not to propose PR to PTLD patients. The control group was created the year before the SBPT guidelines’ approval, when creating evidence that non-rehabilitated patients deteriorated their functional status.

Probably, the best evaluation method would have been to use sham-rehabilitation, which is challenging and was not done, as the non-rehabilitated patients would be under supervision like those who were in PRP. Non-rehabilitated patients were yet followed-up on a monthly basis, therefore the possible bias would eventually be minimized. Also, we did not include pre- and post-rehabilitation quality of life assessment and this is an additional limitation of this study. Nevertheless, this is a multicentre study and, as far as we know, the largest evaluating patients with PTLD who underwent PR, and compared them with a cohort of non-rehabilitated patients. Furthermore, this is the first time PTLD patients with and without COPD were compared, with a sub-analysis conducted per COPD severity (severe and very severe vs. mild and moderate). The completeness of the functional evaluation is also a strength of the study. The involvement of three reference centers in Brazil, which applied the recommendations of the above-mentioned SBPT guidelines shows that evaluation of patients at the end of anti-TB treatment and outpatient rehabilitation of those suffering of PTLD is feasible in Brazil and, probably, in many other countries with sufficient resources. This experience offers new hopes for the thousands of patients suffering of PTLD around the globe.7,8 In addition, future studies should explore the potential for PRP to reduce DALY among PTLD patients.

In conclusion, we demonstrated the significant benefits from PR in patients with PTLD, with improvements in lung function and in exercise capacity in all PTLD patients (including those without COPD), although patients with severe and very severe COPD benefited most. Accessible and quality healthcare services should be available not only during TB treatment. National TB programs should ensure the availability of PR for PTLD patients.

DRS, GBM and RC had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

DRS and GBM wrote the first draft of the manuscript. DRS, GBM, FCQM, TSG, MD, RC, DV, LDA defined the study design. ATDX specifically evaluated the lung function tests data and their implications for post-TB lung disease patients. All authors contributed to the interpretation of results and critically reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

None of the material has been partially or totally produced with the help of any artificial intelligence software or tool.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The authors declare not to have any conflicts of interest that may be considered to influence directly or indirectly the content of the manuscript.