ABSTRACT

Historically, all efforts against tuberculosis were focused on rapid diagnosis and effective treatment to break the chain of transmission of Mycobacterium tuberculosis. However, in the last few years, more and more evidence has been found on the dramatic consequences of the condition defined as post-tuberculosis lung disease (PTLD). Approximately one third of patients surviving pulmonary tuberculosis face considerable ongoing morbidities, including respiratory impairment, psychosocial challenges, and reduced health-related quality of life after treatment completion. Given the important global and local burden of tuberculosis, as well as the estimated burden of PTLD, the development of a consensus document by a Brazilian scientific society-Sociedade Brasileira de Pneumologia e Tisiologia (SBPT)-was considered urgent for the prevention and management of this condition in order to allocate resources to and within tuberculosis services appropriately and serve as a guide for health care professionals. A team of eleven pulmonologists and one methodologist was created by the SBPT to review the current evidence on PTLD and develop recommendations adapted to the Brazilian context. The expert panel selected the topics on the basis of current evidence and international guidelines. During the first phase, three panel members drafted the recommendations, which were divided into three sections: definition and prevalence of PTLD, assessment of PTLD, and management of PTLD. In the second phase, all panel members reviewed, discussed, and revised the recommendations until a consensus was reached. The document was formally approved by the SBPT in a special session organized during the 2023 SBPT Annual Conference.

Keywords: Tuberculosis; Post-infectious disorders; Disease management.

RESUMO

Historicamente, todos os esforços contra a tuberculose concentraram-se no diagnóstico rápido e no tratamento efetivo para quebrar a cadeia de transmissão do Mycobacterium tuberculosis. No entanto, nos últimos anos, têm sido encontradas mais e mais evidências sobre as dramáticas consequências da condição definida como doença pulmonar pós-tuberculose (DPPT). Aproximadamente um terço dos pacientes que sobrevivem à tuberculose pulmonar enfrenta morbidades consideráveis e persistentes, incluindo comprometimento respiratório, desafios psicossociais e redução da qualidade de vida relacionada à saúde após o término do tratamento. Diante da importante carga global e local da tuberculose, bem como da carga estimada da DPPT, considerou-se urgente o desenvolvimento de um documento de consenso por uma sociedade científica brasileira — a Sociedade Brasileira de Pneumologia e Tisiologia (SBPT) — para a prevenção e manejo dessa condição, a fim de alocar recursos de forma adequada para e nos serviços de tuberculose e servir de guia para os profissionais de saúde. Uma equipe de onze pneumologistas e um metodologista foi criada pela SBPT para revisar as evidências atuais sobre a DPPT e desenvolver recomendações adaptadas ao contexto brasileiro. O painel de especialistas selecionou os temas com base nas evidências atuais e diretrizes internacionais. Durante a primeira fase, três membros do painel redigiram as recomendações, que foram divididas em três seções: definição e prevalência de DPPT, avaliação da DPPT e manejo da DPPT. Na segunda fase, todos os membros do painel analisaram, discutiram e revisaram as recomendações até chegar a um consenso. O documento foi aprovado formalmente pela SBPT em sessão especial organizada durante o Congresso Anual da SBPT de 2023.

Palavras-chave: Tuberculose; Transtornos pós-infecções; Gerenciamento clínico.

 
INTRODUCTION
 
Tuberculosis, in addition to the physical and psychological problems that are associated with the disease, the disease-related stigma, and considerable financial costs, also entails a condition defined as post-tuberculosis lung disease (PTLD), which has so far been little studied, but which has recently received the spotlight.(1)
 
Historically, all efforts against tuberculosis were focused on rapid diagnosis and effective treatment, trying to break the chain of transmission of Mycobacterium tuberculosis. However, in the last few years, the impact of damaging long-term sequelae due to pulmonary tuberculosis has duly been valued for individual patients, their households, their communities, and health systems.(2)
 
Approximately one third of patients who survive pulmonary tuberculosis face, after treatment completion, a considerable and often underrecognized burden of ongoing morbidity, including respiratory impairment, psychosocial challenges, and reduced health-related quality of life.(3,4) Even mortality is higher in PTLD patients, with a risk of death up to six times higher than in the general population.(5,6)
 
Despite the recent increase in PTLD-related publications, epidemiological data of the global burden and morbidity associated with PTLD are still limited because of lack of priority by national tuberculosis programs and the relative complexity of the diagnostic approach, which includes, among others, clinical, radiological, and lung function assessment.(7,8)
 
It is evident that PTLD sequelae contribute to excess mortality and morbidity,(9) causing radiological and functional disabilities, favoring other complications (e.g., other infections, hemoptysis, etc.), impairing quality of life, and, therefore, boosting hospitalization and costs to health care systems. Early assessment and management of PTLD-related morbidity guided by solid recommendations by a scientific society are of paramount importance to ensure appropriate allocation of resources to and within tuberculosis services in order to provide quality-assured PTLD prevention, diagnosis, and treatment.(3)
 
The present Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association) recommendations apply to patients with PTLD in the Brazilian context. A panel of 11 pulmonologists and one methodologist, including two international experts, were invited by the SBPT to review the current knowledge on the topic and develop Brazilian-specific recommendations. An expert panel selected the topics based on current evidence and international guidelines available as of July of 2023. During the first phase, three panel members drafted the recommendations, which were divided into three sections: PTLD description and prevalence; PTLD assessment; and PTLD management. In the second phase, all panel members reviewed, discussed, and revised the recommendations until a consensus was reached. The document was formally approved by the SBPT in a special session organized during the 2023 SBPT Annual Conference, held in the city of Curitiba, Brazil.
 
DEFINITION
 
PTLD was defined during the First International Symposium on Post-Tuberculosis disease, held in Stellenbosch, South Africa, as the “evidence of chronic respiratory abnormality, with or without symptoms, attributable at least in part to previous (pulmonary) tuberculosis.”(1) PTLD includes a wide variety of functional and structural lung sequelae, ranging from mild to severe disorders. Cavitation, bronchiectasis, pleural thickening, fibrosis, and pulmonary hypertension are some examples of tuberculosis sequelae. In addition, patients may suffer colonization and infection with Aspergillus fumigatus, nontuberculous mycobacteria, and other bacteria.(1,10-16) Lung function deficits described in patients with PTLD include obstruction, restriction, or a mixed pattern, and approximately 10% of those lose more than half of their lung function.(17) In fact, as compared to the general population, patients with PTLD are twice more likely to have spirometric abnormalities.(18) As a consequence of lung sequelae, persistent respiratory symptoms are frequent, such as dyspnea, cough, wheezing, and reduced exercise capacity.(19)
 
EPIDEMIOLOGY
 
Despite the recent increase in the number of PTLD-related publications, the real epidemiological burden of PTLD is not well known.(12) It is estimated that up to 50% of tuberculosis survivors live with some kind of sequelae.(20) Also, the mortality rate in this group of patients can be up to 3-to 6-fold higher when compared with that in the general population.(5,6,21)
 
According to previous studies, the prevalence of PTLD can vary from 18% to 87%.(22) This wide range can be attributed to the different scenarios analyzed and to the diverse parameters used to diagnose PTLD. In a recent comparison of three different cohort studies involving PTLD patients in Brazil, Italy, and Mexico, pulmonary function tests showed different results, the majority of which showed obstructive, mixed, and normal patterns, respectively.(23)
 
Another study used radiological patterns to evaluate the prevalence of PTLD, and the results varied according to the type of examination (chest CT or X-ray) and the residual abnormality found (cavitation, bronchiectasis, fibrosis, nodules, emphysema, or consolidation).(24)
 
The possible different ways to characterize and define PTLD hinder the generalization of several studies, and few data can correlate structural damage identified in chest radiological imaging, functional impairment, respiratory symptoms, and quality of life. In 2022, a meta-analysis conducted by Maleche-Obimbo et al.(25) identified pooled prevalence of abnormal lung function, persistent respiratory symptoms, and radiological abnormalities of 46.7%, 41.0%, and 64.6%, respectively. The magnitude of any type of PTLD varied according to HIV status, geographic settings, smoking habits, and urban/rural settings.
 
ASSESSMENT OF PTLD
 
Ideally, every patient completing tuberculosis treatment should be clinically evaluated to identify post-tuberculosis sequelae as soon as possible.(26) Essential examinations/investigations recommended to identify PTLD are described in Chart 1. It is likely that not all of those examinations/investigations can be performed in many settings. In that case, some examinations/investigations should be prioritized, especially in those patients with persistent symptoms. (1,4,10,12,22,26-32)
 

 
Clinical history and examination
 
The clinical patterns of PTLD include a wide spectrum of signs and symptoms, varying from asymptomatic to severe disability. Tuberculosis survivors usually present with a high prevalence of respiratory manifestations such as chronic cough and dyspnea.(33) The clinical examination must focus on respiratory rate, heart rate, and BMI on a routine basis.(1)
 
Patients with residual structural abnormalities can have infectious exacerbations and are even at a higher risk of having active tuberculosis again. (34) Bacterial, viral, fungal, and nontuberculous mycobacterial diseases, which might complicate due to subsequent hemoptysis, can be severe and potentially life-threatening.(7) Patients also experience high rates of hospitalization and respiratory-related mortality.(33)
 
It is noteworthy that factors other than tuberculosis sequelae can influence PTLD and its outcomes, such as environmental exposure to smoking, substance abuse, biomass smoke and occupational exposures. In addition, cardiopulmonary comorbidities and those caused by other diseases can also worsen PTLD outcomes.(1,7,22)
 
Chest imaging
 
Although chest imaging is an important tool for evaluating PTLD patients, it should not be used alone to define post-tuberculosis lung damage, as patients can be asymptomatic or have no functional impairment, and have abnormal imaging indicating post-tuberculosis cure.(35)
 
Both chest X-rays and chest CTs are useful in the evaluation of lung structural damage of tuberculosis survivors.(24) Although CT imaging showed to be more sensitive in the identification of a diverse range of residual pathologies,(24) CT availability, costs, and radiation impact must be taken into consideration to decide which option best fits each specific case and scenario.
 
The most common radiological patterns of PTLD reported in a systematic review were cavitation, bronchiectasis, and fibrosis. In addition, nodules, consolidation, emphysema, pleural thickening, and mosaic patterns can also be noticed.(35) Figure 1 shows some radiological patterns of PTLD.
 

 
Pulmonary function testing
 
In 2015, a study designated Burden of Obstructive Lung Disease(11) assessed the association of pulmonary function impairment with a history of tuberculosis in a large, international, population-based sample and found that previous tuberculosis was associated with both airflow obstruction and spirometric restriction, and it should be considered as a potentially important cause of obstructive disease and reduced lung function.
 
Until now, there has been no consensus on which disorder is the most prevalent in individuals with tuberculosis sequelae. A recent prospective cohort study conducted in Malawi showed that 34.4% of participants had abnormal spirometry by the end of antituberculosis treatment.(33) After 3 years, 27.9% still presented abnormal pulmonary function test results, mostly of obstructive nature (15.8%).(33)
 
The healing process that the lungs undergo during and after antituberculosis treatment is likely to cause structural damage, leading to loss of parenchymal tissue and restrictive pattern on spirometry. It is less clear what mechanisms cause airflow obstruction associated with tuberculosis. The two most widely accepted hypotheses are (i) the development of airway disease (bronchiectasis and bronchial stenosis), and (ii) immunological factors that can induce bronchial hyperresponsiveness.(11)
 
Therefore, whenever plethysmography or lung volume measurements are feasible, they should complement spirometry to confirm obstructive, restrictive, or even mixed patterns of pulmonary disease since the type of ventilatory defect can be heterogeneous and vary in different populations.(23)
 
Decreases in DLCO can occur even in patients with normal spirometry and could be a better tool for lung function evaluation in PTLD patients.(36) Furthermore, they can also correlate with cardiopulmonary exercise testing and predict oxygen consumption when that test is unavailable.(37)
 
As well as for the evaluation of other pulmonary and cardiac diseases, the six-minute walk test (6MWT) helps evaluate PTLD patients. This test is cheap, simple, and very useful for studying functional limitations in tuberculosis survivors and for designing appropriate rehabilitation programs for PTLD patients.(38)
 
Blood gas analysis
 
In patients with severe clinical, radiological, and/or functional disabilities, arterial blood gas analysis (whenever possible) or even oxygen saturation measurement using pulse oximetry can identify hypoxemic patients.
 
The indications for home oxygen therapy should be the same as those for patients with chronic airway diseases, that is, PaO2 < 55 mmHg, SpO2 < 88% on room air, PaO2 between 56 and 59 mmHg associated with cor pulmonale, and/or hematocrit > 55%.(39)
 
Cardiopulmonary exercise testing
 
Cardiopulmonary exercise testing provides a global assessment of integrative exercise responses involving cardiovascular, respiratory, muscular, and metabolic systems during exertion, being considered the gold standard for cardiorespiratory functional assessment.(40)
 
In 2022, Curry et al.(37) found that, although statistically significant, the correlations of any lung function patterns, if measured using spirometry, DLCO, or even plethysmography, with oxygen consumption measured on cardiopulmonary exercise testing, which is considered to be the gold standard for lung capacity measurement, were weak.(1) Despite its importance, cardiopulmonary exercise testing is not always available.
 
Symptom and quality of life scores
 
Specific severity scores are still unavailable for PTLD patients, but there is consensus on the urgency of a scoring system evaluating mortality, health-related quality of life, rate of lung function decline, exacerbations/hospitalizations, and tuberculosis recurrence.(1)
 
Different questionnaires of health-related quality of life are available and should be used in the follow-up of PTLD patients, such as the St George’s Respiratory Questionnaire and the Short-Form Health Survey (with 12 or 36 questions).(1,26)
 
Specific considerations for children
 
Evaluation at the end of treatment should follow the same recommendations proposed for adults, although there is a lack of data regarding children. Chest CT is not usually indicated due to radiation exposure, but it may be considered in cases with chronic symptoms and abnormal radiological findings in order to assess the extent of disease and/or exclude other diagnoses. Pulmonary function tests should be considered in all 4-to 6-year-old children with severe lung impairment. In children ≥ 4 years of age, exercise capacity can be assessed using the 6MWT. Quality of life questionnaires such as the EQ-5D-Y and the Toddler and Infant (TANDI) instrument can be used with local adaptations for younger children.(26)
 
MANAGEMENT OF PTLD
 
Currently, there are no evidence-based guidelines for PTLD management, but the increasing scientific literature on the topic has raised several issues that could help the follow-up of these patients.(2,26)
 
Inhaled and oral treatment
 
For those whose functional obstructive disease has been established, inhaled bronchodilators may be useful to reduce symptoms of dyspnea and prevent a decline in lung function.(7) Despite the absence of evidence to recommending routine bronchodilator use in PTLD, small studies have suggested that long-acting β2 agonists and long-acting muscarinic antagonists could improve lung function and dyspnea.(7,24)
 
Inhaled corticosteroids must be avoided since they can increase the frequency of exacerbations and the risk of mycobacterial diseases.(41,42) However, following the recommendations applied to noncystic bronchiectasis, in cases of PTLD associated with asthma, inhaled corticosteroid therapy may be justified.(24) Similarly, for chronic inflammation in patients with noncystic fibrosis bronchiectasis, the use of macrolides is recommended for a minimum period of 6-12 months in patients with bronchiectasis and at least two exacerbations per year.(39)
 
Infectious complications
 
Clinical approach to exacerbations of infectious and noninfectious etiology must be the same as those applied for noncystic fibrosis bronchiectasis.(39)
 
In addition to respiratory infections of bacterial and viral etiology, fungal complications are frequent in post-tuberculosis lung sequelae. Aspergillus sp. can present in different ways and severity levels—from only colonization in a fungus ball shaping (aspergilloma) to infiltration in the lung parenchyma and/or pleural tissue with destruction and new cavities (chronic pulmonary aspergillosis). (7,32) Diagnostic criteria for this last presentation include the presence of respiratory or constitutional symptoms for at least 3 months, suggestive radiological findings, and serological or microbiological evidence of Aspergillus sp. Treatment for aspergillomas in asymptomatic patients could be only “follow-up”; however, surgical management is necessary in cases with multiple episodes of hemoptysis. On the other hand, invasion and destruction of lung parenchyma will require antifungal management. (32) Prescription of long-term oral antifungal drugs, such as itraconazole at a dose of 400 mg/day or voriconazole at a dose of 400 mg/day, administered for at least 6 months is the recommended first-line therapy for chronic pulmonary aspergillosis and has been associated with improvement in quality of life, relief of symptoms, and delay in disease progression.(43)
 
Pulmonary rehabilitation
 
Former tuberculosis patients with clinical, functional, or radiological findings consistent with PTLD should be evaluated for pulmonary rehabilitation (PR). (26) Chart 2 shows the indications for PR in detail, including impaired pulmonary function and/or impaired DLCO(44); abnormal blood gas analysis results and/or nocturnal and exercise-induced desaturation(45); impaired exercise capacity(1,38,46,47); persistent respiratory symptoms(48-51); ineffective cough and/or difficulty to clear bronchial secretions(52,53); at least one hospitalization or two exacerbations in the last 12 months(1,28,54,55); presence of comorbid conditions, including COPD, asthma, bronchiectasis, pulmonary fibrosis, pulmonary hypertension, and/or need for surgery(11,18,56); and impaired quality of life.(57-59)
 

 
The PR program should be coordinated according to the local organization of health services, taking into consideration feasibility, effectiveness, and cost-effectiveness criteria.(26) The core components of a PR program are summarized in Chart 3.
 

 
Evaluation of effectiveness of PR should be carried out by comparing the core variables before and after PR,(26) as shown in Chart 4.
 

 
Vaccination
 
Similarly to other chronic respiratory disorders, PTLD may cause infectious complications, and some of these can be prevented with vaccinations. Influenza, pneumococcal, and COVID-19 vaccines should be recommended for PTLD patients.
 
Influenza vaccination must be repeated annually following local vaccination campaigns. For pneumococcal prevention, the Brazilian Immunization Association recommends either the 13-valent pneumococcal conjugate vaccine or the 15-valent pneumococcal conjugate vaccine, which has stronger immunogenic—use depends on availability—and, 6 months to 1 year later, the 23-valent pneumococcal polysaccharide vaccine, which can be boosted by a second dose administered 5 years later.(24)
 
There are some vaccines recommended for the general population (or specific age groups) of which PTLD patients are likely to benefit from, such as those against tetanus, diphtheria, pertussis, measles, and shingles. Measles vaccination is recommended if there is no evidence of immunity (e.g., being born before 1957, lack of documented proof of having received the measles-mumps-rubella vaccine, or laboratory evidence of immunity or disease) is lacking. Patients with PTLD > 50 years of age can also benefit from vaccination against shingles. The tetanus-diphtheria-pertussis vaccine is recommended for the general population and should be considered for not previously vaccinated PTLD patients; also, booster doses should be repeated every 10 years in adults.(60)
 
Education and counseling for PTLD patients
 
Every patient who participates in a PR program should undergo counseling and health education. Patients should be educated on the basic principles of the disease (epidemiology, clinical aspects, transmission, diagnosis, and treatment); common symptoms that they might experience after acute disease; how to monitor and manage their symptoms at home, and when they should visit a health care facility/call a doctor; and risks of reinfection and how they can manage this risk. In addition, patients should be counseled about the benefits of a healthy lifestyle (such as physical activity, adequate nutrition, and smoking cessation). Telehealth, videos, and booklets can be used for patient education. Family member of patients should also be encouraged to participate. Counseling/health education should include maintenance of the results obtained with PR through a follow-up plan.(26,61)
 
FINAL CONSIDERATIONS
 
As more and more evidence is available on the deleterious consequences of PTLD, the development of a consensus statement directed toward this condition has become a priority for the SBPT. Approximately one third of patients who survive pulmonary tuberculosis can face a considerable ongoing morbidity, and the present recommendations apply to them. In the present manuscript, prepared by 11 pulmonologists and one methodologist with extensive experience in this area, recommendations for prevention, diagnosis, and management have been made, and the latest international guidelines have been adapted to the Brazilian context.
 
ACKNOWLEDGMENTS
 
We would like to acknowledge the support from Lia D’Ambrosio (Public Health Consulting Group, Lugano, Switzerland) and Rosella Centis (Istituti Clinici Scientifici Maugeri, IRCCS, Tradate, Italy) for their useful comments on the manuscript.
 
AUTHOR CONTRIBUTIONS
 
DRS, APS, GBM, and FCQM: drafting of the manuscript. All authors reviewed and approved the final version of the manuscript.
 
CONFLICTS OF INTEREST
 
None declared.
 
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