Educational aims
The reader will come to appreciate:
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Understand that the literature available on post-tuberculosis lung disease (PTLD) in children and adolescents lacks a consistent terminology or definition.
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Evaluate the various methods and tools used to measure PTLD in the current literature and identify the inconsistencies in the measurement techniques employed.
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Understand that the literature on post-TB research in children and adolescents has several gaps that need to be addressed.
Abstract
Tuberculosis (TB) survivors, especially children and adolescents, can develop chronic respiratory problems called post-tuberculosis lung disease (PTLD). We conducted a scoping review to identify the current knowledge gaps on PTLD definitions, measuring tools, and research specific to this age group. We searched MEDLINE, EMBASE, Global Health, CINAHL, and Web of Science for studies published between January 1, 2000, and March 1, 2024, and identified 16 studies.
Our review found that no consistent definition of PTLD was used in the studies, and the measurement tools used varied widely. Moreover, there was a lack of research on children under five years old, who are disproportionately affected by TB. Also, symptom screening tools designed for adults were frequently used in these studies, raising concerns about their accuracy in detecting PTLD in children and adolescents.
Several critical research gaps require attention to improve our understanding and treatment of PTLD. Firstly, the use of inconsistent definitions of PTLD across studies makes it challenging to compare research findings and gain a clear understanding of the condition. Therefore, we need to include an objective measurement of respiratory health, such as a comprehensive post-TB lung function assessment for children and adolescents. It is also crucial to determine the optimal timing and frequency of post-TB assessments for effective PTLD detection. Furthermore, we need more knowledge of the modifiable risk factors for PTLD. The scarcity of prospective studies makes it difficult to establish causality and track the long-term course of the disease in children and adolescents. Finally, current approaches to PTLD management often fail to consider patient-reported outcomes and strategies for social support. Addressing these research gaps in future studies can improve our understanding and management of paediatric PTLD, leading to better long-term health outcomes for this vulnerable population.
Introduction
The burden of chronic lung diseases attributable to tuberculosis (TB) is growing worldwide . It is estimated that between 1 % and 49 % of paediatric pulmonary tuberculosis (pTB) survivors experience sequelae characterised by persistent respiratory symptoms, radiographic abnormalities, or impaired lung function . While the diagnosis of TB in children remains a challenge, over 80 % of newly diagnosed children started on treatment each year will achieve a microbiological cure, thus adding to this growing pool of TB survivors .
Emerging evidence suggests that similar to adults, these childhood and adolescent pTB survivors are also susceptible to the long-term consequences of pTB . This residual respiratory impairment, known as post-tuberculosis lung disease (PTLD), can manifest beyond six months after treatment completion and have a significant impact on overall health and well-being . It is now evident that the impact of pTB extends beyond the initial infection and treatment period .
However, our understanding of PTLD in children and adolescents remains incomplete. Paediatric pTB differs significantly from adults . Children and adolescents have developing lungs that are susceptible to insults . Moreover, PTLD is particularly concerning in this younger population as they have a longer lifespan ahead of them. Furthermore, drug-resistant pTB often requires longer treatment and is associated with prolonged illness and an increased risk of lung damage . Consequently, children who contract TB face the potential to carry the detrimental effects of the disease for an extended period. Therefore, it is crucial to understand, correctly define, and mitigate the long-term consequences of pTB in children and adolescents, especially given the improving survival rates .
Several co-morbidities affect lung function and may potentially influence the development and progression of PTLD. HIV infection in children and adolescents has been linked to pulmonary complications and a higher prevalence of lung function impairment. Consequently, TB/HIV co-infected children and adolescents may be susceptible to more severe respiratory sequelae . Similarly, as post-COVID-19 disorders account for substantial lung health consequences, it is reasonable to assume that a TB and COVID-19 co-infection may be associated with worse outcomes .
Host factors such as genetics, nutritional status, and hereditary conditions like cystic fibrosis, as well as environmental exposure to pollutants and crowded living conditions, may play a critical role in exacerbating lung damage and altering the overall course of TB-associated respiratory morbidity . Therefore, it is essential to consider and address these in studies measuring PTLD in children.
During the second International Post-Tuberculosis Symposium, a definition for paediatric PTLD was proposed as ‘evidence of chronic respiratory impairment in an individual previously treated for pulmonary tuberculosis in whom active tuberculosis is excluded, and in whom no other cause of chronic lung disease is the predominant cause.’ Although this definition aimed to standardise the literature, its practical implementation remains unclear. There are still several unanswered questions about paediatric PTLD, such as what to measure , when to measure , and which tools to use for the measurement . Therefore, we conducted a scoping review to evaluate the current state of evidence regarding the definition and measurement of paediatric PTLD in the literature. Additionally, we sought to report the research gaps identified in the few published studies.
Methods
Scoping review questions
In this scoping review, we sought to answer the following questions: 1) What are the different terms and definitions used in the literature to describe paediatric PTLD? 2) What tools are used to measure paediatric PTLD in the literature? 3) What are the research gaps in the literature regarding paediatric PTLD?
Search strategy
We conducted a literature search across five databases, which included MEDLINE, EMBASE, Global Health, CINAHL, and Web of Science. To ensure a comprehensive search, we followed a three-step strategy recommended by the Joanna Briggs Institute . First, we conducted a preliminary search of MEDLINE and Web of Science on January 18, 2024, using the key search concepts “Paediatric,” “Post-TB,” and “Sequel.” After analysing the text words in the title and abstract of the retrieved papers, as well as the indexing terms, we refined the initial search strategy by including additional key concepts. Our librarian provided input to develop and refine the search strategy, which is available in Supplementary Material Table 1 .
In the second step, we conducted a full search on March 27, 2024, across all five included databases using the refined search strategy from the first step. We adapted the search strategy to fit the search terminologies for each database. In the third step, we searched the reference list of the included papers from the database search for additional sources not previously retrieved.
Inclusion criteria
We included studies that fulfilled the following criteria: 1) studies that included children and adolescents aged ≤19 years, including mixed population studies. This was because we anticipated a lack of publications specifically focused on paediatric populations; 2) Sequelae measured after pTB treatment completion; and 3) observational studies and clinical trials. Considering the limited number of studies in the field, we did not exclude any studies based on the language of publication. However, we only considered studies published from January 1, 2000 to March 1, 2024. We extended the search to March 1, 2024, to include up-to-date evidence on paediatric post-TB sequelae. We excluded systematic reviews, study protocols, journal commentaries, and conference papers.
Study selection
We imported the retrieved articles into Endnote 21 (Clarivate Analytics) for the de-duplication of records. Subsequently, we exported the records to Rayyan, a web-based application for screening review articles . Two reviewers (EN and SAO) independently screened the titles and abstracts for relevance using the eligibility criteria. We exported the records that met the eligibility criteria to Endnote for full-text retrieval, screening, and extraction. One reviewer (EN) screened the full text of the records to ensure their suitability for full data extraction, while the other reviewer (SAO) verified all decisions. Final decisions regarding the eligibility of articles were made through consensus. A third member of the review team (VFE) was consulted to resolve disagreements when the two initial reviewers failed to reach a consensus. All decisions were based on consensus.
Data extraction and collation
We used a data extraction template to extract relevant information from the articles included in the study. The template was adapted from the JBI data extraction tool specifically designed for scoping reviews. Before initiating data extraction, two members of the review team piloted the template on five randomly selected articles and refined it based on feedback. One reviewer (EN) extracted data from the articles, while another reviewer (SAO) cross-checked the full-text articles to ensure the extracted variables were correct.
Patient and public involvement
Patients and the public were not involved in the design, conduct, reporting or dissemination of this research.
Analysis
We used descriptive statistics to summarise the extracted data and presented the results as tables and charts. We evaluated each study to see if it aligned with the current definition of paediatric PTLD. To assess the “ evidence of chronic respiratory impairment” , we rated each study using the ten parameters proposed in the PTLD measurement toolbox to determine how it would perform compared to the current definition . Each parameter received a score of one if the authors reported measuring it. The minimum score was zero if no parameter was measured, and a maximum of ten if all parameters were measured. We presented the measuring tools for pulmonary sequelae based on the classification of toolboxes for post-TB assessment proposed in the clinical standards for PTLD : 1) Clinical assessment; 2) radiological assessment; 3) lung function assessment; and 4) other tools that may have been used for functional evaluation to assess the health and well-being following TB treatment completion.
We followed a thematic analytic approach to identify the research gaps in each included study . This approach involved three stages: 1) coding of the findings from each study while examining for meaning and content; 2) reorganising the codes into categories; and 3) examining and comparing the categories for similarities and differences to allow clear identification of themes arising from the data.
Role of the funding source
The funder of the research had no role in the design, selection, data collection, data analysis, data interpretation, or writing of the report of this scoping review.
Results
The initial search yielded 887 articles, as shown in Fig. 1 . After removing duplicates, 666 articles were retrieved and reviewed for inclusion. After full-text screening, 16 articles were included in the analysis.
Characteristics of the included studies
Table 1 gives a detailed summary of the studies included in the review. The studies were conducted in 13 countries across four continents, with publication dates ranging from 2005 to 2024. Most studies (n = 9) were conducted in sub-Saharan Africa, with ten studies coming from high-burden TB countries. The primary language of publication was English for all the studies. The review included four retrospective , seven cross-sectional , and five prospective studies .
| Study | Year of publication | Country | Study design | Age of participants (years) | Proportion of participants that are children & adolescents (n/N) | Proportion of participants that are HIV + | Type of TB in participants | Timing of post-TB assessment |
|---|---|---|---|---|---|---|---|---|
| Binegdie et al . | 2015 | Ethiopia | Retrospective | ≥12 | 18*/134 | ? | ? | ? |
| Gandhi et al . | 2015 | India | Prospective | ≥14 | 59*/146 | ? | ? | ? |
| Snène et al . | 2016 | Tunisia | Retrospective | ≤18 | 46/46 | 18% | ? | ? |
| Mbatchou et al . | 2016 | Cameroun | Cross-sectional | ≥15 | ?/269 | ? | ? | Within 3 years post-treatment |
| Byrne et al . | 2017 | Peru | Retrospective | 10 to 70 | 20 # /177 | ? | DSTB+DRTB | Within 12 months and 36 months post-treatment for DSTB & DRTB respectively |
| Attia et al . | 2018 | Kenya | Cross-sectional | ≥10 | 52 ^ /427 | 100% | ? | ? |
| van Kampen et al . | 2018 | Uganda | Cross-sectional | ≥15 | 109*/798 | ? | ? | ? |
| Katoto et al . | 2018 | DRC | Cross-sectional | ≥15 | 121 @ /441 | ? | ? | ? |
| Singla et al . | 2018 | India | Cross-sectional | ≥1 | 1 ∼ /46 | 0% | DRTB | ? |
| Soriano-Arandes et al . | 2019 | Catalonia | Cross-sectional | <2 | 134/134 | 0% | DSTB | Within 2 years post-treatment |
| Meghji et al . | 2020 | Malawi | Prospective | ≥15 | 17 ^ /405 | 60% | DSTB | At 6-months and 12-months post-treatment |
| Dias et al . | 2022 | Brazil | Retrospective | ≥14 | ?/54 | 11% | ? | ? |
| Ravindranath et al . | 2022 | India | Prospective | ≤65 | 26*/130 | ? | DSTB | ? |
| Nkereuwem et al . | 2023 | The Gambia | Cross-sectional | 5 to 18 | 68/68 | 13% | DSTB | Beyond 6-months post-treatment |
| Martinez et al . | 2023 | South Africa | Prospective | ≤5 | 96/96 | <1% | DSTB+DRTB | At 6 months, 12 months, then annually for the first 5 years of life |
| van der Zalm et al . | 2024 | South Africa | Prospective | 10 to 19 | 50/50 | 6% | DSTB+DRTB | At treatment completion and 12 months later |
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