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Of the 1.3 million children less than 15 years old estimated to have tuberculosis (TB) worldwide, about half are not reported to public health programs.1,2 India has the largest estimated number of childhood TB cases, representing 28% of the global burden, and 13% of all TB cases in India.3,4 However, children represented only 5% of the reported TB cases in 2022 in India,1 highlighting the large current diagnostic gap. This further contributes to delays in treatment, as we have achieved only 71% of the United Nations high level meeting target for TB treatment in children.1 There are several important initiatives to increase TB notifications,5 including in India that has a large private sector,6 and ongoing efforts to improve provider education and integration of TB screening and care with routine child services.7,8
Despite these programs, an ongoing major challenge is the lack of adequate TB diagnostics for children.2 Sputum-based testing to find the TB bacteria is the standard of care for diagnosing TB, but children are often unable to expectorate sputum on their own and frequently require collection with induced sputum or gastric/nasopharyngeal aspiration which may not be available or feasible in lower level facilities.9 At the same time, children have a low amount of bacteria in their sputum (paucibacillary), and so the currently available molecular testing is unable to identify a large proportion of TB cases (poor sensitivity). Although there has been greater funding in research and development for paediatric TB, it is far below the goal target.10 As outlined by the World Health Organization (WHO), a simple, non-invasive, non-sputum-based test that can be implemented at the point-of-care is urgently needed to support TB diagnosis for children and guide the rapid initiation of treatment.11
To achieve this goal, we need to reassess and invest in each step of the diagnostic development pipeline to ensure they are serving the unique needs of children, including (1) Discovery; (2) Design; (3) Evaluation; and (4) Implementation.
Discovery
There are key differences in how TB presents in children compared to adults.12 Children are more likely to develop TB symptoms after exposure (primary disease), while adults are more likely to reactivate TB disease after previously controlling the infection. Children are also more likely than adults to have disease manifestations outside of the lung, including the lymph nodes and brain. These differences reflect that children have a developing immune system,13 which alters how they respond to TB as they get older.14 Consequently, it is not surprising that biomarkers and biosignatures that have been discovered and used for adults frequently do not translate well for children. For example, C-reactive protein (CRP) and the three-gene Sweeney biosignature are less accurate for TB triage in children than when used for adults.15,16 On the pathogen marker side, the cell wall marker lipoarabinomannan (LAM) can be detected in urine, but it has low sensitivity in children given their paucibacillary disease.17 There are a number of biomarkers in plasma, urine and breath that have been found to distinguish TB disease in children,18-21 but these need greater validation in larger, diverse, cohorts. We also need a better understanding of the fundamental pathogenesis and host response of TB in children to guide key pathways and candidate biomarkers.22
The same concept also applies to novel artificial intelligence (AI) models and digital biomarkers. There are a number of groups developing algorithms for TB screening to automatically read chest x-rays (Computer-aided detection or CAD),23 and analyze cough sounds,24,25 but these predominantly use adult data. These algorithms will need to be fine-tuned or developed specifically with paediatric data to more accurately reflect both their normal physiology and their unique presentation of TB disease.
Design
Diagnostics for TB are often design-locked before they are assessed in children. However, there are several key features that should be considered when designing a new TB test to optimize feasibility and accuracy for children.11,26 Sample collection should be simple and non-invasive, with minimal volume requirements clearly indicated. Assays designed for sputum-based testing should also support detection in other respiratory samples collected in children, including gastric aspirates, nasopharyngeal aspirates, oral swabs, and stool. In addition, as children can have more extrapulmonary manifestations, the application of these assays for other sample types including lymph node aspirate and cerebrospinal fluid would be valuable. For diagnostics that detect the TB bacteria or its components, tests should be designed to be sensitive enough with a lower limit of detection to identify individuals with paucibacillary disease, as seen in children. For digital diagnostics, data collection approaches may need to be adapted for children; for example, requesting solicited cough sounds may not be feasible for young children. To develop new tools that best serve this group, it is important to incorporate feedback from children, adolescent and their caregivers throughout the design process.26,27
Evaluation
New TB diagnostics are frequently evaluated in children after they have shown promise, or even approved, in adults. Several reasons have been cited, including greater availability of samples, clearer reference standards, and study costs.26 These benefits may be particularly applicable for a pathogen-based test that seeks to detect the TB bacteria regardless of the individual. Also, from an ethical perspective, it is important to consider potential harm in children without some preliminary data to show utility, and it may be prudent to save precious paediatric samples for the most promising tests.
However, there are limitations to this approach. First, the threshold to move forward from early to late-stage evaluation studies may be different for adults and children. If an assay does not perform as well as current tests in adults, it may still perform better than or complement current tests for children. It also may have other design advantages that may be more favorable for children; for example, oral swab-based testing for TB may have lower accuracy than sputum-based testing, but have higher yield in children because of greater feasibility to collect and test a sample.28 In addition, adolescents frequently have adult-like disease, but they are often excluded in adult studies. While the results of pathogen-based assays in adults may inform utility in children, this is not necessarily true of host-based or digital tests as children have different immune responses and TB disease presentation as described above.
To better guide the approach to including children and adolescents in TB diagnostic development and evaluation, we recently published a consensus statement that included stakeholders from academia, industry, advocacy, non-profits, and government.26 We recommended that adolescents be included in adult studies, and that host-based assays should be evaluated in children in parallel to adults and adolescents. For pathogen-based testing, parallel assessment should occur if the collection or performance of the test causes minimal harm to children. Diagnostic development and evaluation are frequently iterative, and the goal of this framework is to support early discussion between developers, researchers, and users on how and when children can be included as early as possible in the process.
Implementation
If the above steps are followed, there should be sufficient evidence to guide the assessment for approval and implementation of a new TB diagnostic for children at the same time or soon after approval in adults and adolescents. It is possible a test will not perform well and not be approved in children, which would prevent unnecessary burden, cost and potential harm on the child and family. It could also guide next steps for improvement and future paediatric use. If endorsed for children, operational research and implementation studies are further needed to guide the most feasible, acceptable and effective approach.26,27 For example, we will need to determine how to integrate new diagnostics into current TB treatment decision algorithms (TDAs) for children that were conditionally recommended by the WHO.29 In addition, there are a number of efforts to decentralize TB care for children in lower-level facilities,7,8,30 and it will be important to assess how to best include novel tests in routine child care assessment. Throughout, there again should be ongoing input from children, adolescents, caregivers, providers and other users and stakeholders to ensure the care workflow is meeting their needs and supporting greater detection and reporting of paediatric TB cases.27
In a Nutshell
TB is a curable disease, and children who are diagnosed early and rapidly started on treatment have favorable outcomes. If we want TB diagnostics to work for all, we need to recognize the variation in TB disease throughout the life course and how this may impact the performance and needs of new TB tests. By having a clear intention to invest and develop TB diagnostics that can be used in children, this creates an opportunity to engage with users and key stakeholders throughout the discovery, design, evaluation and implementation process and reduce the delays in innovation and access to improved childhood TB care.
Dr. Devan Jaganath, MD, MPH, is an Pediatric Infectious Diseases specialist and Assistant Professor of Pediatrics at the University of California, San Francisco. His clinical and research focus is on paediatric TB, in particular how to develop and evaluate novel TB diagnostics for children. He leverages clinical research and data science approaches to oversee biomarker and digital marker discovery initiatives, while forming global partnerships to conduct multi-country prospective studies to assess new TB tools for children.
India Health Fund is registered as Confluence for Health Action and Transformation Foundation (CHATF), a Section 8
charitable company incorporated in India, supported by the Tata Trusts.
