8. Research priorities

This chapter includes research gaps or priorities that were identified by the GDG members while considering the evidence related to each of the PICO questions. Addressing the identified research gaps has the potential to inform the development of future research questions that can improve TB prevention and care. This list of research priorities is not exhaustive; but it complements the existing research agenda outlined in Research priorities for paediatric tuberculosis (127) and other WHO guidelines.

TB screening (adapted from WHO consolidated guidelines on tuberculosis. Module 2: screening - systematic screening for tuberculosis disease (11))

  • Studies evaluating the use of molecular WHO recommended rapid diagnostics for screening children and adolescents.
  • More research and development on better screening tools and approaches for use in children and adolescents (screening approaches that target specific and distinct age ranges including infants younger than 12 months, children younger than 5 years, children up to the age of 10 years and those aged 10-19 years).
  • Data to determine the frequency with which screening should be conducted among the subpopulations of children at highest risk of TB.
  • Well-designed clinical trials to provide evidence on patient-important outcomes for TB screening in children.

Diagnostic approaches

The use of integrated treatment decision algorithms in children with presumptive pulmonary TB attending health care facilities

  • External validation of the newly developed integrated treatment decision algorithms, including for specific subpopulations and in various settings.
  • Implementation/operational research on the use and impact of the newly developed integrated treatment decision algorithms, including how to tailor them to local epidemiological settings (such as settings with differing burdens of TB, different health care settings, including settings with limited access to CXR).
  • Modelling studies to determine the potential impact of treatment decision algorithms on case detection and treatment initiation.
  • Qualitative studies on the feasibility and acceptability of the newly developed integrated treatment decision algorithms among relevant stakeholders in various settings.
  • Diagnostic test accuracy studies and effectiveness studies of algorithms for the diagnosis of EPTB.

The use of Xpert Ultra in gastric aspirate or stool samples to diagnose pulmonary TB in children (adapted from 2021 rapid diagnostics guidelines (16) and 2018 research priorities for paediatric tuberculosis (127))

  • Evaluation of the benefits and incremental yield of combining multiple specimen types. Limited data suggest that the combination of non-invasive specimens performs comparably with traditional gastric specimens or induced sputum specimens.
  • Additional operational and qualitative research to determine the best approach to less invasive specimen collection in children, including: implementation studies on a method of suction for nasopharyngeal aspiration that is appropriate for low-skill or low-resource environments; research on the use of stool as a diagnostic specimen as part of treatment decision algorithms; definition of laboratory protocols that successfully balance the ease of implementation and diagnostic performance; and the impact of stool testing on patient-important outcomes.
  • Identification, evaluation and validation of host and pathogen associated biomarkers in paediatric populations as potential novel tests for TB infection, TB disease, risk of disease progression and response to treatment among children, ideally requiring non-invasive samples and for use at the point of care.
  • Optimization of the current microbiological reference standard by improving and harmonizing specimen collection; supporting laboratory research to improve specimen processing to optimize diagnostic yield using current assays; and improving phenotypic and genotypic drug-susceptibility testing on paediatric clinical specimens, including on stool samples.
  • Qualitative research on equity, acceptability and feasibility aspects of diagnostic approaches, including specimen types and diagnostic tools.

A four-month treatment regimen for children and adolescents with non-severe drug-susceptible TB

  • Stronger evidence on the feasibility of making a diagnosis of non-severe drug-susceptible TB among children and adolescents in settings with no access to diagnostic tools, in particular to CXR.
  • Evaluation of societal costs, including direct and indirect costs to persons with TB, in the implementation of shorter treatment regimens for drug-susceptible TB (including, but not limited to transport costs and loss of family income).
  • Automated software for CXR reading, including differentiating severe from non-severe forms of intrathoracic TB disease among children.

MDR/RR-TB treatment regimens for children Bedaquiline

  • Treatment outcomes in children with MDR/RR-TB of all ages treated with shorter and longer all-oral, bedaquiline containing regimens.
  • Studies aimed at optimizing dosing of bedaquiline in children.
  • Specific cost-effectiveness analyses on the use of bedaquiline in children.
  • Studies exploring mechanisms of acquisition of resistance to bedaquiline and genetic markers to identify resistance (this evidence is likely to come from studies on adults with MDR/RR-TB but will have implications for children and adolescents).
  • Studies exploring the optimization of the duration of bedaquiline use in children related to PK and safety.
  • Studies exploring the concomitant use of bedaquiline and delamanid in children related to PK and safety.
  • Qualitative research on acceptability, equity and feasibility issues. Delamanid
  • Data on long-term safety and side-effects of delamanid, especially related to neuropsychiatric safety signals.
  • Studies aimed at optimizing dosing of delamanid in children (some studies are already ongoing, such as IMPAACT P2005, "A phase I/II open-label, single-arm study to evaluate the PK, safety, and tolerability of delamanid in combination with optimized multidrug background regimen for multidrug-resistant tuberculosis (MDR-TB) in HIV-infected and HIV-uninfected children with MDR-TB)".
  • Specific cost-effectiveness studies on the use of delamanid in children.
  • Studies exploring mechanisms of acquisition of resistance to delamanid and genetic markers to identify resistance.
  • Studies exploring the optimization of the duration of delamanid use in children related to PK and safety.

Treatment of presumed or bacteriologically confirmed drug-susceptible TB meningitis in children and adolescents

  • Comparative efficacy and safety data on the short intensive and standard treatment regimens.
  • Dosing for the shorter intensive regimen and for alternative regimens under research, including regimens that include higher doses of medicines than are currently recommended.
  • Considerations regarding equity including equitable access to medicines in the short intensive regimen.
  • Cost-effectiveness of shorter regimens versus the current standard of care.
  • Feasibility and acceptability of regimens for the treatment of TBM.
  • Research on the sequelae of TBM (including the type and severity of sequelae and the ability to prevent or manage them) as well as objective measures of quality of life/functionality post-treatment.
  • Co-administration of anti-inflammatory agents in the treatment of children and adolescents with TBM.
  • Optimal regimens to treat TBM among CALHIV Models of TB care for children and adolescents

Decentralization of TB services for children and adolescents with signs and symptoms of TB and for children and adolescents exposed to TB

  • Cost-effectiveness of decentralization/integration for case detection and provision of TPT.
  • Impact of decentralization of services on health equity.
  • Acceptability and feasibility of decentralized approaches to child and adolescent TB care for case detection and for TPT provision.

Family-centred, integrated services for children and adolescents with signs and symptoms of TB and for children and adolescents exposed to TB

  • Detailed description of currently operating family-centred and integrated services; associated costs and cost-effectiveness.
  • Implementation research on the components of these interventions; assessment of real-world implementation of these programmes.
  • Feasibility and acceptability of family-centred, integrated and/or decentralized approaches to child and adolescent TB care for case detection and TPT provision in different settings, from person with TB, caregiver and provider perspectives.
  • Costs and catastrophic costs.
  • Cost-effectiveness evaluations of family-centred, integrated and/or decentralized approaches, considering currently available resources (some models assume that these interventions are built upon existing structures that may not be available).
  • Outcomes of interest: initiation of TPT; number of additional children and adolescents diagnosed; delay, retention in care, treatment completion, clinical outcomes (such as treatment success); qualitative research related stigma, mental health outcome, school interruption, equity.
  • Evaluation of outcomes of interest using randomized/non-randomized designs and qualitative design.
  • Baseline needs assessment in the community, community perceptions regarding TB care and prevention for children and adolescents.
  • Research on the quality of TB diagnosis in children - addressing both under-diagnosis and over-diagnosis.

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