Prevalence of extrapulmonary tuberculosis in Indonesia: protocol for systematic review and meta-analysis ======================================================================================================== * Ika Nindya Kadariswantiningsih * Roy Novri Ramadhan * Derren David Christian Homenta Rampengan ## Abstract **Background** Extrapulmonary tuberculosis (EPTB) is a significant public health issue in Indonesia, a country with a high tuberculosis burden. EPTB accounts for 15%–20% of global TB cases, with the proportion rising in populations co-infected with HIV. In Indonesia, estimates of EPTB prevalence vary significantly due to inconsistencies in diagnostic criteria, population demographics and methodologies. These variations highlight the need for a systematic review to synthesise existing evidence and provide a comprehensive understanding of EPTB’s epidemiology in Indonesia. This study aims to consolidate findings from various studies to identify prevalence trends, inform public health strategies and address knowledge gaps in diagnosing and managing EPTB. **Methods** This systematic review will follow Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines and has been registered with PROSPERO (Registration Number: CRD42024601175). A comprehensive search will be conducted in databases including PubMed, Google Scholar, ScienceDirect, Scopus and Southeast Asian Index Medicus to identify studies published between 2005 and 2024. Inclusion criteria include observational studies reporting EPTB prevalence in Indonesia based on clinical, microbiological or radiological diagnoses. Two independent reviewers will conduct study selection, data extraction and quality assessments using the Newcastle-Ottawa Scale. Data will be analysed using a random-effects model to estimate pooled prevalence, and subgroup analyses will explore variability by region, age and clinical setting. The study selection process will be documented using a Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram, and potential publication bias will be evaluated with funnel plots and the trim-and-fill method. **Ethics and dissemination** As this review involves secondary analysis of published data, no ethical approval is required. Findings will be disseminated through peer-reviewed journal publications and conference presentations. * Prevalence * Systematic Review * Epidemiology * Tuberculosis ### STRENGTHS AND LIMITATIONS OF THIS STUDY * The study integrates data from various sources, including observational studies and grey literature, ensuring inclusivity and a comprehensive understanding of extrapulmonary tuberculosis prevalence in Indonesia. * The adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines and registration with PROSPERO demonstrates methodological rigour and transparency, enhancing the reliability of the study’s outcomes. * Challenges in accessing uniform diagnostic criteria across studies may introduce variability and limit the consistency of the pooled data analysis. ## Introduction Extrapulmonary tuberculosis (EPTB) poses a significant public health challenge, especially in developing countries like Indonesia, where tuberculosis (TB) remains a major health burden. Globally, EPTB accounts for approximately 15%–20% of all TB cases, with this proportion rising to as much as 50% among HIV co-infected populations.1 2 The prevalence of EPTB in Indonesia has been reported with significant variability across different studies, leading to conflicting conclusions regarding its actual burden. Some studies indicate that EPTB constitutes approximately 15% to 20% of all TB cases in the country, while others report figures around 11%.1 3 This discrepancy can be attributed to several factors, including variations in diagnostic criteria, the populations studied and the methodologies employed in these investigations. Moreover, the sensitivity of diagnostic tests, such as the QuantiFERON-TB Gold assay, has shown inconsistent results, with reported sensitivities varying from 38.5% to 81.5% depending on the specific site of EPTB.4 Additionally, challenges in accessing healthcare facilities, particularly in rural areas, may lead to under-reporting of EPTB cases, further complicating the understanding of its true prevalence.5 In Indonesia, factors like overcrowding, poor sanitation and malnutrition—common in many regions—contribute to the epidemiological patterns of EPTB.3 6 Diagnosing EPTB presents additional challenges due to its paucibacillary nature and the difficulty in obtaining samples from affected extrapulmonary sites.7 8 These barriers are compounded by limited awareness and diagnostic experience among healthcare providers, leading to frequent misdiagnosis or underdiagnoses.8 9 Consequently, these conflicting data highlight the urgent need for comprehensive epidemiological studies to accurately assess the burden of EPTB in Indonesia and inform effective public health strategies. In light of these challenges and the increasing incidence of EPTB, this systematic review aims to synthesise existing data on the prevalence of EPTB in Indonesia. By consolidating findings from various studies, this review seeks to provide a comprehensive understanding of the current state of EPTB, identify gaps in the literature and inform future diagnostic and treatment strategies. Understanding the prevalence and unique characteristics of EPTB is essential for developing targeted interventions and policies to address this complex public health issue in Indonesia. ## Methods and analysis ### Protocol and registration This systematic review is designed to evaluate the prevalence of EPTB in Indonesia, covering studies conducted from 2005 to 2024. The methodology follows the principles outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P).10 The PRISMA-P checklist is provided as a supplementary material. Additionally, the protocol for this review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO), under the registration number CRD42024601175. ### Patient and public involvement No patients were involved in the study’s design. We will disseminate study summaries to relevant clinicians and patient groups. ### Data source and search strategy A comprehensive search will be conducted to identify all relevant studies on EPTB in Indonesia, covering the period from 2005 to 2024. Articles in both English and Indonesian will be retrieved from databases including PubMed, Google Scholar, ScienceDirect, Scopus and Southeast Asian Index Medicus. To ensure inclusivity, a manual search using Google and the references cited in identified articles will also be performed to capture any additional relevant studies. The search strategy will be structured using the Condition, Context, Population framework to define research questions and search terms clearly.11 Key search terms will include (“extrapulmonary tuberculosis”), (EPTB), (“prevalence”) and (“Indonesia”). These terms will be combined with Boolean operators ‘OR’ and ‘AND’ to refine the search and optimise the retrieval of relevant articles. The Population, Intervention, Comparison, and Outcome (PICO) table is available as online supplemental table 1. Details of the search strategy are presented in table 1 and online supplemental table 2, while the flowchart for this systematic review is illustrated in figure 1. ### Supplementary data [[bmjopen-2024-098140supp001.pdf]](pending:yes) ![Figure 1](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/5/e098140/F1.medium.gif) [Figure 1](http://bmjopen.bmj.com/content/15/5/e098140/F1) Figure 1 Planned Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart of the study. View this table: [Table 1](http://bmjopen.bmj.com/content/15/5/e098140/T1) Table 1 Search strategy based on Condition, Context, Population (CoCoPop) framework ### Eligibility criteria This review will include studies focusing on individuals of any age group (neonates, children, adults), any gender and any ethnicity diagnosed with EPTB in Indonesia. The diagnosis of EPTB is based on EPTB cases based on clinical, microbiological or radiological diagnoses. We will include the paper with all variants of EPTB such as tuberculous lymphadenitis, tuberculous meningitis, pleural TB, gastrointestinal TB, osteoarticular TB and genitourinary TB. Only studies conducted in Indonesia will be considered to ensure data are representative of the local epidemiology and disease burden. Eligible studies include observational designs such as cohort, cross-sectional and case-control studies, as well as clinical trials that report on the prevalence, clinical outcomes or any other measure related to the burden of EPTB. Both published works and grey literature, including theses, dissertations and conference proceedings in either English or Indonesian, will be included. Studies must specifically report outcomes related to EPTB, such as prevalence rates, clinical manifestations, diagnostic challenges, treatment outcomes, morbidity or mortality. The study must be published in the last 20 years to reflect current trends and prevalence rates. Conversely, studies conducted outside Indonesia or that fail to provide data relevant to the Indonesian context will be excluded. Reviews (eg, narrative reviews, systematic reviews and meta-analyses), editorials and opinion pieces will not be considered. Non-human studies, including those focusing on veterinary medicine, agriculture (eg, livestock and aquaculture), environmental samples (eg, soil and water) or laboratory-based studies will also be excluded unless they directly address implications of EPTB for human health. Studies exclusively focused on pulmonary TB without mention or data on extrapulmonary manifestations will be excluded. Additionally, studies that do not specifically focus on EPTB or its outcomes, as well as case reports and case series, will be omitted due to the risk of bias and the limited generalisability of data derived from single or small numbers of cases. ### Data management and study selection The management of articles will be facilitated using Cadima to streamline the process of organising search results, removing duplicates, screening titles and abstracts, reviewing full texts, extracting data and performing quality assessments. This method ensures an efficient workflow for handling the extensive data typically involved in systematic reviews. A centralised master database will document all relevant information for each study, providing a transparent audit trail from initial identification to final inclusion. Cloud-based platforms will support collaborative efforts in screening and data extraction. Throughout the process, all evaluations will be conducted by at least two independent reviewers to ensure objectivity and minimise bias. The study selection process will involve multiple stages. First, titles and abstracts will be screened by two independent reviewers based on the inclusion criteria. Any discrepancies will be resolved through discussion or, if necessary, consultation with a third reviewer. Subsequently, full-text articles will undergo a detailed review, with reasons for exclusions meticulously recorded. The quality of randomised controlled trials (RCTs) will be assessed using the Risk of Bias 2 (RoB 2) tool, while observational studies will be evaluated using the Newcastle-Ottawa Quality Assessment Scale. Any disagreements in the quality assessment process will be resolved by consensus or by involving a third reviewer, ensuring a rigorous and unbiased selection process. Final inclusion decisions will be made following a thorough review of full texts and quality assessments. The rationale for including or excluding each study will be clearly documented. The entire selection process will be visualised using a PRISMA flow diagram in the final review. This structured and transparent methodology ensures the systematic review’s integrity and ensures that its conclusions are based on high-quality, relevant evidence. ### Data extraction The study selection process will involve a rigorous screening and evaluation of identified studies based on predefined criteria. Titles and abstracts of all retrieved studies will be screened independently by two reviewers to assess their relevance according to the inclusion and exclusion criteria. Studies identified as potentially relevant will proceed to a full-text review. Any disagreements between the reviewers during either stage will be resolved through discussion, and if consensus cannot be reached, a third reviewer will be consulted. The inclusion criteria will focus on the study population, definition of EPTB, study design and geographical focus on Indonesia. The entire selection process will be documented using a PRISMA flow diagram, which will also include reasons for exclusion at the full-text screening stage. Data extraction will be conducted using a structured and standardised approach to ensure consistency and reliability. The extracted data will include details about the study (author, year of publication, study design and location), population characteristics (age, gender, HIV status and comorbidities) and specific features of EPTB (diagnostic methods and affected anatomical sites). The outcomes of interest will include the overall prevalence of EPTB as well as stratified data based on factors such as age group, region and anatomical site. A standardised data extraction form will be developed and piloted to guide the process. Two independent reviewers will extract the relevant data from each included study and record it in a predesigned database. Any discrepancies between the reviewers will be resolved through discussion, with unresolved issues referred to a third reviewer. This approach ensures a systematic and unbiased collection of data, providing a robust foundation for analysis and interpretation. ### Quality assessment The methodological quality of all included studies will be assessed independently by two reviewers, with the choice of assessment tool determined by study design. For observational studies, including cross-sectional, cohort and case-control studies, we will use a modified version of the Newcastle-Ottawa Scale. This tool evaluates methodological quality across three major domains: selection of study participants, comparability between groups and the ascertainment of outcomes of interest. Points (or ‘stars’) are awarded for each domain, with a maximum possible score of nine. Studies that receive between zero and three stars will be classified as low quality, those with four to five stars as moderate quality and those with six to nine stars as high quality. The quality category assigned will be used to inform sensitivity analyses, allowing us to explore the robustness of the pooled prevalence estimates and to assess the potential impact of study quality on the observed heterogeneity. This stratification will also guide narrative synthesis and subgroup analyses, particularly when evaluating differences across geographic regions or clinical settings. For RCTs, we will apply the Cochrane RoB 2 tool to evaluate the risk of bias across domains that reflect the trial’s internal validity. These domains include the randomisation process, deviations from intended interventions, missing outcome data, measurement of outcomes and selection of the reported results. Based on the RoB 2 algorithm, each RCT will be classified as having low risk of bias, some concerns, or high risk of bias. The resulting judgments will be considered when interpreting effect estimates and in conducting sensitivity analyses to explore the influence of methodological rigour on overall findings. Any discrepancies between reviewers during the quality assessment process will be resolved through discussion, and unresolved differences will be adjudicated by a third reviewer. ### Outcome variables The primary outcome of this systematic review is to determine the prevalence of EPTB in Indonesia. Prevalence, for the purposes of this review, is defined as the proportion of individuals diagnosed with EPTB relative to the total population at risk or studied within a specified timeframe. This measure will provide a comprehensive understanding of the burden of EPTB in the Indonesian context, contributing valuable insights for public health planning and intervention strategies. ### Data synthesis and statistical analysis A random-effects model will be applied to estimate the pooled prevalence of EPTB in Indonesia. To explore potential sources of variability among studies, subgroup and meta-regression analyses will be conducted. Heterogeneity will be assessed using Cochran’s Q test and the I² statistic, with a p value of <0.05 for I² considered indicative of significant heterogeneity. To account for this variability, the Der Simonian-Laird random-effects model will be used. The Meta-Essentials software, which integrates seamlessly with Microsoft Excel and offers flexibility and expandability, will be employed for the statistical analysis.12 The results will be presented in tables and visually summarised using forest plots. Funnel plot symmetry will be assessed to evaluate potential publication bias. If asymmetry is detected, the trim-and-fill method will be used to adjust for missing studies and provide corrected estimates of the pooled prevalence. ## Ethics and dissemination The findings of this systematic review will provide a comprehensive overview of the prevalence of EPTB in Indonesia, highlighting the burden of this condition within the country. Understanding the prevalence of EPTB is critical for identifying at-risk populations and informing targeted public health interventions. This review will also shed light on regional and demographic variations in EPTB prevalence, which could reflect differences in access to healthcare, diagnostic capacities and environmental or socioeconomic factors. Additionally, this review aims to address existing gaps in knowledge about EPTB in Indonesia. By synthesising data from various studies, it will contribute to a better understanding of the clinical and epidemiological characteristics of EPTB. This information is crucial for developing effective policies to improve the early detection and management of EPTB, particularly in resource-limited settings. Furthermore, the review will identify areas where future research is needed, such as the impact of comorbidities like HIV on EPTB prevalence and outcomes. The analysis of heterogeneity among studies will provide insights into the variability of findings across regions and subpopulations. This will help to contextualise the pooled prevalence estimates and understand the broader implications of the data. By incorporating robust statistical methods, the review will ensure the reliability and generalisability of its conclusions, ultimately contributing to improved public health strategies for addressing TB in Indonesia. As this systematic review involves the analysis of previously published studies, no ethical approval is required. The findings will be disseminated through peer-reviewed journal publications and conference presentations to ensure broad access to the data. This dissemination strategy aims to inform healthcare providers, policymakers and researchers about the burden of EPTB in Indonesia, supporting evidence-based decision-making and guiding future research initiatives. ## Ethics statements ### Patient consent for publication Not applicable. ## Acknowledgments We thank Airlangga University and Sam Ratulangi University for providing the resources and access to conduct this study. ## Footnotes * Contributors INK, RNR and DDCHR played equal roles in conceptualising the study and developing the research protocol. INK will conduct the literature search, while DDCHR and RNR will extract data. INK provided input on the study design offered methodological guidance and critically reviewed the manuscript. Additionally, INK oversaw the entire research protocol. All authors participated in drafting and revising the manuscript and approved the final version for submission. INK served as the guarantor of the study. * Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. * Competing interests None declared. * Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. * Provenance and peer review Not commissioned; externally peer reviewed. * Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. [http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/) This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: [http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/). ## References 1. Nayak MM, Thakker HS, Gotmare R. Genexpert - is it an expert in diagnosis of extrapulmonary tuberculosis? Jebmh 2017;4:3079–82. [doi:10.18410/jebmh/2017/611](http://dx.doi.org/10.18410/jebmh/2017/611) 2. Delyuzar D, Sinulingga AB, Suryadi D. Association between fine-needle aspiration cytological features and CD4 level in human immunodeficiency virus-associated tuberculous lymphadenitis patients admitted to Haji Adam Malik hospital in 2017. Open Access Maced J Med Sci 2019;7:3475–7. [doi:10.3889/oamjms.2019.449](http://dx.doi.org/10.3889/oamjms.2019.449) 3. Lesmana A, Dewanti HR, Angin LBP, et al. Tuberculosis mimicking-musculoskeletal tumor of the hand: an uncommon case of extrapulmonary tuberculosis. Joints 2023;12:77–82. [doi:10.20473/joints.v12i2.2023.77-82](http://dx.doi.org/10.20473/joints.v12i2.2023.77-82) 4. Nguyen DT, Phan H, Trinh T, et al. Sensitivity and characteristics associated with positive QuantiFERON-TB Gold-Plus assay in children with confirmed tuberculosis. PLoS One 2019;14:e0213304. [doi:10.1371/journal.pone.0213304](http://dx.doi.org/10.1371/journal.pone.0213304) 5. Hassanain SA, Edwards JK, Venables E, et al. Conflict and tuberculosis in Sudan: a 10-year review of the National Tuberculosis Programme, 2004-2014. Confl Health 2018;12:18. [doi:10.1186/s13031-018-0154-0](http://dx.doi.org/10.1186/s13031-018-0154-0) 6. Ayu Widyanti NN, Putra WWS, Yaniswari NMD, et al. Colonic tuberculosis mimicking ascending colon neoplasm: a case report. EJMED 2022;4:28–30. [doi:10.24018/ejmed.2022.4.6.1613](http://dx.doi.org/10.24018/ejmed.2022.4.6.1613) 7. Samaila MOA, Oluwole OP. Extrapulmonary tuberculosis: fine needle aspiration cytology diagnosis. Niger J Clin Pract 2011;14:297–9. [doi:10.4103/1119-3077.86771](http://dx.doi.org/10.4103/1119-3077.86771) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=22037072&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe098140.atom) 8. Sandgren A, Hollo V, van der Werf MJ. Extrapulmonary tuberculosis in the European Union and European Economic Area, 2002 to 2011. Euro Surveill 2013;18:20431. [doi:10.2807/ese.18.12.20431-en](http://dx.doi.org/10.2807/ese.18.12.20431-en) 9. Fiske CT, Griffin MR, Erin H, et al. Black race, sex, and extrapulmonary tuberculosis risk: an observational study. BMC Infect Dis 2010;10:16. [doi:10.1186/1471-2334-10-16](http://dx.doi.org/10.1186/1471-2334-10-16) 10. Sarkis-Onofre R, Catalá-López F, Aromataris E, et al. How to properly use the PRISMA Statement. Syst Rev 2021;10:117:117. [doi:10.1186/s13643-021-01671-z](http://dx.doi.org/10.1186/s13643-021-01671-z) 11. Munn Z, Moola S, Lisy K, et al. Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data. Int J Evid Based Healthc 2015;13:147–53. [doi:10.1097/XEB.0000000000000054](http://dx.doi.org/10.1097/XEB.0000000000000054) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/XEB.0000000000000054&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=26317388&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe098140.atom) 12. Suurmond R, van Rhee H, Hak T. Introduction, comparison, and validation of Meta-Essentials: A free and simple tool for meta-analysis. Res Synth Methods 2017;8:537–53. [doi:10.1002/jrsm.1260](http://dx.doi.org/10.1002/jrsm.1260) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1002/jrsm.1260&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=28801932&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe098140.atom)