Validation of treatment decision algorithms for childhood tuberculosis at low levels of healthcare in high burden countries - effectiveness, implementation, and integration into policy and practices (Decide TB)

Evaluating algorithms for childhood TB treatment in high-burden countries to improve diagnosis at primary healthcare levels, informing effective implementation and policy integration, aligned with the End TB Strategy for global TB eradication by 2035

Mozambique, Zambia

Axis: Global Health inequities

Coordinating investigators:

– Olivier Marcy (UBx)
– Chishala Chabala (UNZA)

Teams:

– GHiGS, University of Bordeaux, France
– PACCI, Abidjan, Côte d’Ivoire
– University of Zambia (UNZA), Pediatric TB and HIV research center, Lusaka, Zambia
– National TB Program, Lusaka, Zambia
– National TB Program, Maputo, Mozambique
– University of Sheffield, School of Health and Related Research (ScHARR), UK
– Eduardo Mondlane University, Mozambique
– Imperial College of London, Centre for Environmental Policy, UK
– Centro de Investigação e Treino em Saúde da Polana Caniço (CISPOC), Instituto nacional de Saúde (INS), Maputo, Mozambique
– University of Stellenbosch, Department of Paediatrics and Child Health, South Africa

Funder: European Union (HORIZON-JU-GH-EDCTP3-2022-01)

Status: accepted

Impact:

4 doctoral fellowships are associated to the project :
– Name of doctoral fellow : Morton Khunga
– Title: Proposing Improved Use of Cost-Effectiveness Evidence in Priority Setting within the Context of Tuberculosis, in Zambia and Mozambique

– Name of doctoral fellow: Alan Kachuka
– Title: Integration of Treatment Decision Algorithms (TDA) for childhood TB diagnosis within Zambia National TB program: Implementation & Evaluation

– Name of doctoral fellow: Natacha Lebrun
– Title: Multidisciplinary evaluation of the implementation of TDAs in resource-limited countries

– Name of doctoral fellow: Cleia Etono
– Title: Optimizing Treatment Decision Algorithms Implementation Through Integrated Digital Health Systems: A Human-Centered Approach to Implementing CDSS and EMR in Pediatric TB Management

Background and justification

The End TB Strategy adopted by the World Health Assembly in 2014 aims to end the global tuberculosis (TB) epidemic by 2035 and to reduce TB deaths by 95%. The operationalisation of this strategy calls for innovative approaches and health technologies for TB prevention and care in the most vulnerable and most affected populations. Furthermore, bringing together researchers, end-users, decision-makers and program implementers is crucial to shorten time between the generation of scientific evidence and widespread adoption of policies and improved practices for childhood TB, that can contribute to reaching the Sustainable Development Goals (SDGs).

Each year an estimated 1.2 million children and young adolescents (<15 years) develop TB [2], of which more than 50% are aged below 5 years [3]. Modelling suggests that nearly 250,000 children die from TB yearly, and that over 95% of those dying of TB are undiagnosed. Globally, only 44% of children with TB are notified to the World Health Organization (WHO) by National TB Programs (NTPs), mainly because they are not diagnosed and consequently not treated. In children below 5 years this figure is as low as 35%. Low case detection is largely due to the paucibacillary nature of the disease and challenges in respiratory sample collection contributing to the low microbiological yield in children. Once diagnosed and treated, outcomes for children with TB are generally excellent with <1% mortality, but the case fatality rate for untreated TB can reach 44% in children below 5 years [6]. Children with inadequate immunity [e.g. children living with HIV (CLHIV), or those with severe acute malnutrition (SAM)] or severe pneumonia are at higher risk of underdiagnosis and of dying from TB.

WHO has identified that improvement in TB diagnostics is the highest research priority in the field of child TB. Currently, in the absence of highly sensitive TB diagnostic tool for children, most children are started on treatment only on the basis of high clinical suspicion. Treatment decision algorithms (TDAs), that assign scores to clinical and radiographic features or microbiological tests and recommend TB treatment initiation above a pre-defined total score, can enable rapid and uniform treatment decision-making. In March 2022, WHO issued an interim and conditional overall recommendation to use TDAs to diagnose pulmonary TB in children below 10 years. Furthermore, in the accompanying operational handbook [12], WHO suggested two specific TDAs for use in settings with and without access to chest X-ray (CXR), with a single diagnostic approach in both the general paediatric population and high-risk groups (age <2, CLHIV, and SAM). WHO has stated that external validation of these algorithms is an urgent priority in view of the conditional recommendation[1].

Decentralizing childhood TB services is essential to increase access to TB diagnosis. Use of TDAs at lower levels of care by overburdened Health Care Workers (HCWs) with limited child TB experience will require strengthening clinical skills and treatment decision-making capacity. Data on the diagnostic accuracy of TDAs, their feasibility, acceptability by end-users, effectiveness, and cost-effectiveness are crucial to update the current WHO policy and operational handbook, national policies, and clinical curricula. A comprehensive TB TDA-based approach could integrate other specific TDAs developed for CLHIV and those with SAM if they outperform the WHO-suggested TDAs and would also provide the opportunity to integrate a disease severity assessment step to assess eligibility for a shorter (4-month) treatment for non-severe TB cases in children as recommended by the WHO. Importantly, tools for integrated TDAs should be tailored to the needs and existing clinical practices of HCWs at primary health centre (PHC) and district hospital (DH) level, to which innovative digital tools (such as clinical decision support systems – CDSS) could contribute, in order to enhance adoption, delivery, and quality of decentralized TB services.

Objective

General : to generate scientific evidence for the implementation of a comprehensive Treatment Decision Algorithm (TDA)-based approach for screening, diagnosis and management of tuberculosis (TB) in children in high TB-burden and resource-limited countries, and to facilitate integration of this evidence within practices and policies.

Main methods

The concept of Decide-TB (figure 1 below) is to build on research results from several studies led by members of our consortium or to which we contributed: i) the WHO-commissioned Individual Patient Data (IPD) meta-analysis (2011-2012) on TDAs, ii) the Unitaid-funded TB-Speed diagnostic studies (2017-2022), iii) the UK Joint Global Health Trials-funded SHINE treatment trial (2016-2018), and iv) the EDCTP-funded RaPaed-TB and Umoya (2017- 2024) diagnostic studies. These results will be used for the design of a comprehensive TDA-based approach integrating TB screening, diagnosis, and treatment decision-making, and disease severity assessment for shorter treatment eligibility, for use at lower level of healthcare, and to be tested by NTPs in a programmatic pilot. We will develop a CDSS and strengthen district information systems (DHIS2) to collect individual data, which will contribute to monitoring and evaluation, clinical mentoring, and supervision by NTPs and to research in this proposal. The TDA-based approach will be tested in a hybrid effectiveness-implementation study based on a pragmatic stepped wedge cluster-randomized trial. In parallel, the diagnostic accuracy of different TDAs will be assessed through IPD meta-analysis of children with presumptive TB evaluated in recent prospective cohort studies. The pragmatic trial, the implementation research, and the IPD meta-analysis will contribute to thorough external validation of the WHO-suggested TDAs. Furthermore, engagement of key stakeholders and decision-makers throughout the project, following previously tested and effective strategies, will facilitate translation of the overall integrated TDA approach into clinical and implementation practices as well as policy at national and international levels.