Stool-Xpert® MTB/RIF Ultra for Tuberculosis Screening and Diagnosis in Children at Primary and Higher-level Healthcare Centers in Padang Municipality, Indonesia

Abstract

Background ABSTRACT In 2023, Indonesia notified 137,969 childhood TB cases or 16% of total 821,200 TB cases in Indonesia. The NTP found 79,566 children aged <5 years and 58,403 children aged 5-14 years with TB disease. It means there were 50 per 10,000 children aged <5 years and 21 per 10,000 children aged 5-14 years living with TB disease. However, these numbers indicate under-TB detection since there were 335,691 cases estimated to be unreported during 2022 in Indonesia. In Indonesia, childhood TB detection program is available in all levels of health services, starting from the community health center as primary level health service. However, childhood TB control and prevention of the National Tuberculosis Program (NTP) in Indonesia face poor performance of early screening and diagnostic equipment in community health center which leads to high morbidity and high mortality of TB among children. Partly, it is still underutilized for childhood TB program since children unable to expectorate sputum used as the main specimen for TB testing. Sputum induction and gastric aspiration can be done to obtain specimen from children; however, both are invasive which become stressful for children and parents, moreover it cannot be done in low-resources setting. Other available screening methods such as symptoms screening and TST, cannot differentiate TB infection and disease which leads to high number of false positive and risk of putting children under unnecessary treatment. Thus, suspected children need to be referred to higher-level healthcare, go through further clinical assessment, and do invasive method of sample collection procedure such as sputum induction and gastric aspiration. This referral system is time-consuming and costly, which leads to delayed TB diagnosis and increasing risk of developing active or severe TB in children. Therefore, in 2020, WHO started to recommends stool-Xpert testing as initial TB diagnostic among children with signs and symptoms of TB to fill the gap of childhood TB program. Furthermore, studies have shown the possibility of using stoolXpert in primary level of health service with non-invasive, simple, and cheap procedure to make it able to routinely run in lower-level laboratory with Xpert machine and none additional equipment. The study aimed to estimate the properties and feasibility of stool-Xpert MTB/RIF Ultra for childhood TB screening in primary healthcare and childhood TB diagnosis in higher-level healthcare centers. Methods The study was divided into community screening program with crosssectional study design and key informant interviews conducted eight health services in Padang Municipality, Indonesia, between September 2023 to April 2024. These health facilities consisted one provincial referral hospital, one regional hospital, and six primary healthcare. The stool-Xpert MTB/RIF Ultra screening was done among two groups of children aged <15 years: children in primary healthcare who investigated from index cases with bacteriologically confirmed pulmonary TB and had household contact with children at least 3 months before the start of current TB treatment, and children referred to hospital with different level of signs and symptoms of TB, several of them may have clear history of TB contact or even unknown. Data were recorded with paper-based case report form and coded into Excel at the end of each examination. The data recorded will be checked for completeness, accuracy, and consistency before participants leave the health services by rotating check of all research team involved in data collection. Descriptive analyses were used for participant characteristics. We used chi-square and Fisher’s exact test to analyzed information related to socio-demographic characteristics, risk of TB identification, investigation of index TB cases, result of clinical assessment, tuberculosis screening and diagnosis, and final diagnosis. Prevalence, sensitivity,specificity, PPV, and NPV with 95% CI will be applied as statistical measurements for performance of stool-Xpert exam. Concordance and discordance were showed to explained the agreement among stool-Xpert with other screening and diagnostic tests. All analysis were performed with R version 4.2.3 with ‘epicalc’, ‘dplyr’, ‘epiR’, and ‘epitools’ packages. The key informant interviews were done among health workers and primary caretakers from Puskesmas as primary healthcare and hospitals as higher-level healthcare. The recordings from the interviews were transcribe verbatim and translated into English. A quality check was done on all transcripts before the coding and analysis. Thematic analysis was conducted with ATLAST.ti 24. The codebook was developed and applied to a specimen of transcript; cross-checked codes; resolved discrepancies; and refined the codes. This process was repeated until the codebook adequately captured the interview content. The final codebook was applied to all transcripts. Trends and patterns were discussed by and some of the themes were refined. Following the process, all 40 interviews started to reveal similar information therefore saturation was reached. Results There were 125 children who were met the eligible criteria and their primary caretakers approached to collect stool specimen. All of primary caretakers from 125 child patients showed interest but 2 child patients from hospital passed away before stool collection procedure done due to critical illness, 31 child patients not adhere due to several reasons and 6 child patients lost to follow-up. Therefore, a total of 86 child patients including 42 children with TB household contact from Puskesmas and 44 children with presumptive TB from hospitals enrolled in the study. In total, 54 children (43.2% of 125) were diagnosed with TB, of whom, 8 (15%) had bacteriologically TB whether with sputum-AFB, sputum-Xpert, or culture with any specimen. A valid stool-Xpert test was obtained for 86/125 children with 15% (95% CI: 5.7-29.8) of sensitivity and 100% (95% CI: 92.2-100.0) specificity against to final diagnosis made by pediatrician with PPV and NPV were 100% (95% CI: 54.1100.0) and 57.5% (95% CI: 54.3-60.1). The sensitivity was increased to 18.2% (95%CI: 6.9-35.5) among children with presumptive TB and various severity of disease with PPV and NPV were 100% (95% CI: 54.1-100.0) and 51.8% (95% CI: 47.8-55.8). Stool-Xpert results showed low agreement with final TB diagnosis made by pediatrician while it showed high agreement with another laboratory exam such as sputum-Xpert and sputum-AFB. It also highly agreed with the result of culture with several specimen such as sputum, blood, and LCS. Unfortunately, stool-Xpert also showed low agreement with other TB screening method of signs and symptoms screening, TST, and CXR. In the other hand, most of the informants from key interviews agreed that stool-Xpert have chance to be implement. This chance came after the benefits of stool is out such as applicable for younger children or asymptomatic children who cannot produce sputum and no need referral process. Others still unsure about the referral specimen mechanism from Puskesmas to hospitals. Stool collection found to be more acceptable for primary caretakers since it was non-invasive than TST that commonly used for early screening. However, implementation of stool-Xpert is still debatable since there is no standardized guideline provided from the Ministry of Health, specimen cannot be assessed at Puskesmas to limited biocontainment equipment. It was also notified by the primary caretakers. Therefore, several recommendations come from primary caretakers and health workers if stool-Xpert will be implemented further in Puskesmas and hospital: need to be done alongside with other screening and diagnosis method, comprehensive training for all health workers related with TB , clear instructions or guideline, health promotion related with TB and stool-Xpert, availability of the tools or equipment, expansion on health workers number, and children aged under-5 years. Conclusion The performance of stool-Xpert MTB/RIF Ultra for TB screening was not comparable with other screening methods or standard care. However, the result of stool-Xpert specimen showed an agreement with sputum-Xpert for TB diagnosis. In general, the main barriers of further implementation of stool-Xpert in Padang Municipality is limited resources available in each healthcare. Nonetheless, primary caretakers and health workers who done stool collection and stool exam believe that stool specimen can be used as an alternative for respiratory specimen and was shown to be non-invasive test for children who cannot produce sputum.