Over the last decades National TB Control Programmes concentrated their efforts on diagnosis and treatment of cases of sputum smear positive TB. The main target was to curb TB transmission by early diagnosis and successful treatment of infectious cases.1 This approach proved to be effective in reducing TB transmission and decreasing the burden of disease in many countries.

Nevertheless, concentrating efforts on the urgent need to reduce transmission of disease had some consequences on the health of survivors. Programmes are following-up patients till the end of treatment (when patients are declared cured and/or successfully treated/dead/lost to follow-up). Monitoring/evaluation of health outcomes after the end of treatment is not done. Even if recognised by clinicians as PTLD, TB sequelae after the end of treatment have been studied only recently.2–7 In fact, after TB treatment completion, a significant proportion of people (formally cured or not) present residual cough, weakness, dyspnoea, difficulties in climbing stairs or managing every-day or work activities. PTLD affects patients’ quality of life (QoL) while increasing the risk of death.2–7

Experts convening at the First International Symposium on Post-TB disease defined PTLD as: ‘Evidence of chronic respiratory abnormality, with or without symptoms attributable at least in part to previous (pulmonary) tuberculosis’.8

There is increasing evidence that up to 50% of TB patients (>70% among multidrug-resistant patients) report health problems consistent with PTLD after completion of treatment.9–18 Thus, PTLD is likely to cause a considerable burden of disease globally, suggesting opportunities for prevention, management and rehabilitation. It has been estimated that 138–171 million TB survivors were alive in 2020, of whom nearly one fifth had been treated in the previous 5 years.19 PTLD was estimated to account for approximately half of lifetime disability-adjusted life years (DALYs) caused by incident TB.17,20,21 However, PTLD is currently not considered as a health consequence in global disease burden estimates.

During the last two years the epidemic of the severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) infection caused COVID-19 in a significant proportion of those infected. The disease can cause pneumonia with variable degrees of severity, up to acute respiratory distress syndrome (ARDS) and death. It is well known that when ARDS occurs, whatever aetiology causes it, patients will later suffer from impaired lung function, reduced exercise capacity and quality of life for up to 5 years after the event.22 Given the recent appearance of the disease in different waves, the consistency of its long-term consequences is not yet completely understood. Unfortunately, albeit slowly, its impact continues to grow.

The post-COVID-19 phase is often difficult to define. Early studies aimed at defining and investigating symptoms and health consequences included hospitalised patients with short follow-up periods after discharge,23–25 while only recent studies included community patients, never hospitalized for COVID-19.26–29

In 2021, the WHO defined post-COVID-19 sequelae as the presence of symptoms in a patient with a history of probable or confirmed SARS-CoV-2 infection, usually at least 3 months from the onset of COVID-19, with symptoms lasting more than 2 months and not explained by an alternative diagnosis.30 Common symptoms used to diagnose this condition include fatigue, shortness of breath, cognitive dysfunction and other symptoms that generally have an impact on everyday functioning.31 A recent systematic review and meta-analysis reported that 80% of patients surviving COVID-19 had one or more symptoms compatible with post-COVID-19 sequelae, such as fatigue (58%), and dyspnoea (24%).32

Sequelae can be mild, moderate or severe. Mild sequalae include persistent but reversible symptoms with no need for treatment. Moderate sequelae, although generally treatable and reversible, require active intervention in terms of diagnosis and treatment. Finally, severe sequelae, although rare, present with chronic organ failure, such as cardiovascular events including myocarditis, renal failure or pulmonary fibrosis.33,34

Post-COVID sequelae may affect several organs or body systems, but in this scoping review the focus will be on the lungs.

Pulmonary fibrosis is a known sequela of severe lung damage secondary to many aetiologies including respiratory infections.35,36 Although the precise pathophysiological mechanisms underlying this complication remain unknown, the immune activation and alveolar epithelial injuries might lead to an aberrant reparative response with accumulation of fibroblasts and excessive deposition of collagen.35 Of note, persistent radiological signs of pulmonary fibrosis can be observed after 3 months since acute phase of disease in previously hospitalized patients.37,38

PTLD includes structural and functional lung sequelae, with varying severity, such as fibrosis, pleural thickening, cavitation, bronchiectasis, lung function deficits (obstruction, restriction and mixed patterns), pulmonary hypertension, and colonization and infection with Aspergillus fumigatus, non-tuberculous mycobacteria and other bacteria.7,11,12,39,40 PTLD patients have a two-fold higher risk of spirometry abnormalities in comparison to the general population,10 and approximately 10% of them have lost more than half of lung function.41 As a consequence, persistent respiratory symptoms are common, and include residual cough, dyspnoea, wheeze, and reduced exercise capacity.42

In a cross-sectional study with 145 adults who completed TB treatment, 38% of participants had airflow obstruction, 58% low forced vital capacity (FVC), and the most frequent respiratory symptoms were wheeze (42%), dyspnoea (25%), and cough (19%).39 Functional impairment is even more prevalent in drug-resistant TB cases.43 In a prospective study with 405 patients in Malawi, 44% had bronchiectasis, and after 1 year, approximately 30% had respiratory symptoms and one in five had a decline of 100mL in forced expiratory volume in one second (FEV1).44 In accordance with these findings, in a Brazilian cohort of PTLD patients followed-up for a mean time of 8.3±4.9 years, a decline in FEV1, FVC, total lung capacity (TLC), Diffusing Capacity for carbon monoxide (DLCO), and six-minute walking test (6MWT) was demonstrated.45 The most important predictors of PTLD are generally a delay in diagnosis, multiple TB treatments, and drug-resistant TB.11

Every patient completing TB treatment should be clinically evaluated to identify PTLD, ideally as soon as possible at the end of treatment.1 Essential examinations/investigations recommended to identify post-TB sequelae include: clinical assessment (history, examination), chest imaging, in particular, chest X-ray and CT, where available and affordable, to detect fibrosis, cavities, pleural thickening, bronchiectasis, pulmonary hypertension, secondary bacterial and fungal infections; arterial blood gas analysis and/or pulse oximetry, pulmonary function testing (PFT), including 6MWT, spirometry, plethysmography and DLCO to detect obstructive, restrictive and mixed patterns; and cardiopulmonary exercise testing to assess the integrative responses of the cardiovascular, respiratory and musculoskeletal systems to incremental exercise in patients with PTLD and subjective evaluation (symptoms score and QoL questionnaire). In situations where all the examinations listed above cannot be performed, the following examinations/investigations should be prioritized: clinical history, symptom assessment and clinical examination; chest X-ray; spirometry; pulse oximetry; 6MWT; symptoms score and QoL questionnaire.1,7–10,39,43,46–49

COVID-19 can damage many organs, especially lung, heart, and brain. Patients surviving COVID-19 often experience persisting respiratory symptoms; abnormalities in PFT and chest CT images may persist for months after hospital admission.50–53 Pulmonary dysfunction may occur even in patients with mild disease presentation.54,55 Nevertheless, there is particular interest in long-term pulmonary sequelae in critical patients, i.e. those requiring intensive care unit (ICU) admission; among them a high prevalence of functional impairment and pulmonary structural abnormalities have been reported.31,50,56,57

The most commonly observed abnormalities are diffusion impairment, followed by restrictive ventilatory defects.50 Lung function alterations have been reported at the time of discharge, and at 3, 6 and 12 months.52,58–63 In a cohort of 110 patients in China,58 reductions in FEV1 were described in 13.6% of patients, FVC in 9.1%, TLC in 25%, and DLCO in 47.2% at the time of discharge. Persistent DLCO and TLC impairments were associated with the most severe SARS-CoV-2 cases.58,60 At 3 months of follow-up, DLCO deficits were present in 25% of individuals in a retrospective multicentre cohort study.59 Hellemons et al.64 showed impaired FVC and DLCO in 25% and 63% of patients, respectively, at 6 weeks. These percentages have improved at 6 months to 11% and 46% for FVC and DLCO, respectively. In another study61 that followed patients for 12 months after discharge, the authors noted a median DLCO of 77% of predicted at 3 months, 76% of predicted at 6 months, and 88% of predicted at 12 months. DLCO reductions (24–34%), restrictive defects (7–13%), and development of pulmonary fibrosis (19–26%) have been reported in several studies.52,61–63

The most important predictors of post-COVID-19 sequelae are older age, female sex, pre-existing comorbidities, and initial severity of the acute illness.65 In addition, the risk of long-term symptoms is associated with elevated body mass index and more than five symptoms in their first week of disease. Fatigue (OR 2.83, CI 2.09–3.83) and dyspnoea (OR 2.36, CI 1.91–2.91) in the first week of the acute phase were associated with persistent symptoms 28 days after recovery.66 Predictors of COVID-19-related pulmonary fibrosis include age, history of smoking or alcoholism, extent of lung injury, and length of mechanical ventilation.56,67,68

Essential examinations/investigations recommended to identify post-COVID-19 sequelae include: clinical history (persistent fatigue or respiratory symptoms; presence of comorbidities), evaluation of QoL (Euroqol five dimensions [EQ-5D]; Short-Form 36; St George's Respiratory Questionnaire), evaluation of functional status (Post-COVID-19 Functional Status [PCSF]; Functional Impairment Checklist [FIC]; Functional Independence Measure [FIM]; Barthel's Index), exercise capacity (Cardiopulmonary exercise test and/or 6MWT and/or One minute Sit to Stand Test and/or Maximal voluntary contraction and/or One Maximum Repetition and/or Short Physical Performance Battery), pulmonary function tests (spirometry with plethysmography, if available, and DLCO, blood gas analysis and/or pulse oximetry, and radiological evaluation (chest X-ray and CT, where available and affordable).

In situations where all the examinations listed above cannot be performed, the following examinations/investigations should be prioritized: clinical history; evaluation of QoL; evaluation of functional status; 6MWT; spirometry; pulse oximetry, and chest X-ray.

Clinical Standards on PTLD recommended that former TB patients with clinical and radiological signs and symptoms consistent with post-TB sequelae should be evaluated for PR.1 Patients with functional impairments such as reduced pulmonary function (airflow obstruction or restriction or mixed abnormalities, and/or impaired diffusing capacity for carbon monoxide), abnormal blood gas (PaO2<80mmHg and/or PaCO2>45mmHg and/or nocturnal and exercise-induced desaturation), and reduced exercise capacity should also benefit from PR. In addition, PR can be indicated in the presence of comorbidities, like chronic obstructive pulmonary disease, asthma, bronchiectasis, pulmonary fibrosis, and pulmonary hypertension. PR is also beneficial for patients with at least one hospitalization or two exacerbations in the last 12 months, and impairment in QoL.1

Clinical Standards on post-COVID-19 sequelae recommend that every patient with previous history of COVID-19, lung function impairment (airflow obstruction or restriction or mixed and/or impaired DLCO), reduced exercise tolerance and related impairment in QoL and other relevant signs or symptoms (fatigue or exhaustion or asthenia or weakness; respiratory symptoms [dyspnoea, cough, chest pain]; PaO2<80mmHg and/or PaCO2>45mmHg and/or exercise-induced desaturation) should be evaluated for PR.

Debeaumont et al. evaluated COVID-19 patients, 6 months after their discharge from the hospital, and showed that persistent dyspnoea was associated with reduced physical fitness.69 Those patients should benefit from PR. In addition, patients who had severe acute illness, and those with abnormal chest X-ray or CT or reduced DLCO will probably need early and effective respiratory rehabilitation.70

Post-ICU patients with COVID-19 should be a target population for rehabilitation.55 Patients with severe lung impairment during COVID-19 acute illness are prone to pulmonary function tests and 6MWT alterations, and are a subgroup of patients that could also benefit from PR.71

Pulmonary rehabilitation programmes cannot be planned without considering local organisation of health services. They should also be organised according to feasibility, effectiveness and cost-effectiveness criteria.

Knowledge on PR is mostly derived from experiences in chronic respiratory diseases, especially chronic obstructive pulmonary disease (COPD). In this setting, PR showed to be relatively more cost-effective than pharmacotherapy.72 There are obviously notable differences between these conditions, PTLD and/or post-COVID.

Any programme, to qualify as PR, should have some minimum and unavoidable requirements. These include comprehensive baseline and post-PR outcome measurements, a structured and supervised exercise training programme, an education/behavioural programme intended to foster long-term health-enhancing behaviour, and provision of recommendations for home-based exercise and self or supervised physical activity programmes.1,73

Some evidence on effectiveness of PR programmes targeting PTLD patients exists only in selected settings with adequate resources, logistics, and expert healthcare providers.74–77 Recently, a few positive experiences of PR programmes targeting post-COVID patients have been reported.31,78–85 Depending on the residual individual deficits in post-COVID patients, PR should be offered with the objective to improve respiratory, physical and psychological impairments.31,78,86–88

PR programmes should be adapted to the context and resources available to make them as accessible as possible for those benefiting from it (including children and adolescents) in different settings.9,89–95 The core components of a PR programme are summarised in Table 1.96–105

The Global Tuberculosis Network (GTN) is monitoring PR pilot testing activities and it will share the results when available.

Implementation of a rehabilitation programme implies a plan to evaluate its effectiveness. The main recommendation is generally to compare the core variables before and after rehabilitation.1

As previously discussed, on completion of TB treatment or at discharge from hospital post COVID, before starting a PR programme tailored to a patient's needs, a comprehensive assessment is necessary. Therefore, having a baseline assessment, i.e., before programme, the simplest way to evaluate the effectiveness of PR is to compare the core variables at baseline vs. at the end of the programme.74–76,89 The minimal evaluation set includes the patient's functional exercise capacity, dyspnoea and health status.8,9,17 If possible, a series of health outcomes including social, economic and psychological impact should be evaluated in clinical studies.8,17

The most popular tool to measure exercise capacity is the 6MWT.73–75,90 Nevertheless, the cardiopulmonary exercise test or the incremental shuttle walk test and the 5 repetition ‘sit to stand’ test are recommended, too.89,106 Regarding PTLD patients, PR has proven to significantly improve the distance covered during the 6MWT (by approximately 35–45m), an improvement comparable to that observed in subjects with COPD.107 QoL evaluation is extremely important, but it is usually measured by questionnaires, with inter-studies variability. Nevertheless, the questionnaires whose use actually show significant improvement were the St George's Respiratory Questionnaire, the Short Form Health Survey 36 and the Clinical COPD questionnaire.107–109 Similarly, the clinical evaluation based on symptoms (dyspnoea, chest pain, haemoptysis and cough) employed different scales. Unfortunately, no data are available on other strong outcomes such as mortality and morbidity.

Monitoring of patients undergoing PR is important during PR and at its end, this should occur with a formal evaluation. The impact of PR needs to be assessed also in the longer term since the early (end of programme) evaluation could miss clinical problems arising later and miss if the benefits achieved after PR are maintained and for how long. Any follow-up has to be arranged based on local feasibility and organisation of health services. In fact, for TB, individuals completing an episode of TB treatment, especially those with residual pulmonary sequelae (e.g. residual cavitations), and/or affected by other infections (e.g., aspergilloma and/or non-tubercular mycobacteria) remain at elevated risk of recurrent TB.110,111 Recurrence may occur due to endogenous reactivation or following exogenous reinfection.112,113

Patients with sequelae, but without apparent need (or with contra-indications) for PR have a lower priority. However, if feasible, their follow-up can also be considered. In consideration of the risk of recurrence PTLD patients have, infection control and prevention measures (and reassessment of the patient's potential contagiousness) are recommended during all steps of the process.

Every patient who participates in a PR programme should undergo counselling/health education. Patients should be counselled about their disease, available treatments, benefit of healthy lifestyle, and smoking avoidance. Booklets, videos, and telehealth can be used for patient education, and the patient's family should be encouraged to participate. Counselling/health education should include a follow-up plan to maintain the results achieved with PR1,114 (Table 2).

PR is one of the most cost-effective interventions in patients with COPD, resulting in substantial cost savings through the prevention of readmission.115–117 Although PR is associated with significant improvements in pulmonary function in post-TB patients,7 and could accelerate the recovery of lung disease in post-COVID-19 patients,118 there is a need for randomized-controlled trials to identify effective and cost-effective strategies to deliver PR in different settings and populations.1

In addition to cost-effectiveness, we have to consider the feasibility of PR programmes in low and high burden countries. In fact, the idea inspiring the recently published reference document1 was to generate universal standards, offering to countries/settings an ideal guide where to go, although not all countries or settings are immediately able to meet them.

COVID-19 has impacted healthcare systems globally, with many services reduced or temporarily cancelled.119 In this sense, several PR programmes had to be adapted to ensure their continuity. Due to social distancing, and movement restrictions preventing attendance to in- or outpatient PR programmes, traditional face-to-face rehabilitation needs to be adapted through the use of tele-rehabilitation.114,120–122 It has been shown that tele-rehabilitation is as effective as traditional PR, and could alleviate burden on health systems.123 However, PR programmes should have a plan to work with a limited rehabilitation team.114 In a Northern Italian rehabilitation hospital, organizational changes were required to overcome work overload during COVID-19 pandemic. Remodelled tasks, development of algorithms on patient management, and use of online communications systems helped to relieve the workload.124

There is obviously a strong need for extensive research on the epidemiology, assessment and management of both PTLD and post-COVID in adults and children to gain a better understanding on the two diseases and to guide the development of future standards and guidelines. Political commitment and appropriate funding mechanisms will be essential to enable research in these fields in the forthcoming years. Key research priorities are highlighted in Table 3.

Among others, the priority studies needed to respond the main research questions include cohort, case–control, cross-sectional, diagnostic accuracy and operational research studies, as well as randomized controlled trials.