At Issue

Where should TB research focus?

At the U.N. General Assembly high-level meeting in September 2018, heads of state committed to ending the tuberculosis epidemic by 2030. An agreement was signed at the meeting that promised $2 billion a year for TB research. Infectious Diseases in Children asked two experts — Mario C. Raviglione, FRCP (UK), FERS, Hon RSP (RF), professor of global health at the University of Milan and the Global Studies Institute of the University of Geneva, and former director of WHO’s Global Tuberculosis Program, and Lisa V. Adams, MD, associate dean of global health at the Geisel School of Medicine at Dartmouth — what research should be a priority in an effort to end the global epidemic of TB in children.

Raviglione: With 1 million children affected every year and a quarter of them dying from it, pediatric TB is a major global health issue that requires a serious rethinking of the commitment to fight it and the investments to control it. Often ignored by national TB programs and experts alike who are under the false impression that pediatricians will take good care, this neglected form of TB is finally reaching necessary attention. The first Roadmap for Childhood TB that WHO published in 2013 together with key partners like UNICEF, CDC and USAID, recognized 10 steps toward better care, control and prevention of TB in children. Among those, it emphasized the urgent need for research to improve the available limited interventions. This need was reiterated in the following years in various official reports, resolutions and declarations, including the new WHO’s End TB Strategy for 2016 to 2030, the 2017 Moscow Declaration to end TB, and the final political declaration at the U.N. General Assembly high-level meeting on TB in September 2018.

Mario C. Raviglione

Therefore, after a ton of good words and stated intentions, the issue is now one of making things happen in concrete terms. This begins with research funders and investors. One has yet to see that childhood TB is a stated priority among major donors, although in 2017, the global spending on pediatric TB nearly doubled, reaching $56.4 million from $29 million in 2016. However, this sum remains a small 7% of the total investments in TB research of about $772 million in 2017. Indeed, the unique aspects of pediatric TB require fully dedicated research efforts if solutions are to be identified. In turn, this requires donors with the vision of focusing investments on proposals to address immunopathogenesis, epidemiology and development and implementation of better tools.

Prioritized research agendas have been compiled for some years. First, there is wide recognition that we do not fully understand the immune response and pathogenesis of TB in children and adolescents. This basic science issue requires focused research, as does the epidemiology of pediatric TB, starting with an improved understanding of its true burden through dedicated surveys. Second, a prevention revolution will occur when novel biomarkers are identified, allowing one to predict the progression from latency to disease. Similarly, biomarkers of active disease allowing point-of-care detection will be another crucial step, considering the tremendous challenge of making a diagnosis in children. Third, novel regimens for TB disease, drug-resistant TB and latent infection that are safe, shorter and adaptable to the presence of comorbidities such as HIV would dramatically change the current pattern of care if studied specifically for children in consideration of their biological and pharmacokinetic differences, rather than adapted from adult trials. Of great importance would be the identification of a prophylactic regimen for young contacts of patients with multidrug-resistant TB. Fourth, and the ultimate solution to TB, focused research on pre-exposure and post-exposure vaccines is a key priority where investments need to increase greatly. Furthermore, operational and programmatic research have roles to define the best delivery of any existing and new prevention and care interventions, including community engagement and integration with general pediatric services. Given its enormous potential, assessing how contact investigation can best be undertaken would be a great benefit to burdened communities. Finally, studying social aspects of the disease, its socioeconomic impact, the challenge of access to services by adolescents and the alleviation of stigma will better serve this vulnerable population.

In the end, it is a matter of political commitment and financial investment. The excellent wording of resolutions will be useless unless it is followed by action. It should inspire activism and put healthy pressure on those who pledged support and speak on behalf of those who are suffering voicelessly.

Disclosure: Raviglione reports no relevant financial disclosures.

Adams: Officials at the U.N. high-level meeting on TB last year adopted a declaration to end TB by 2030 — a bold commitment that holds great promise for the WHO-estimated 10 million individuals who develop TB each year, 1 million of whom are children. Until recently, pediatric TB was a neglected area of TB care and prevention, but effective advocacy is now helping to address critical gaps in child TB detection, treatment and prevention. Success in each of these areas will require robust partnerships between governments and donors and significant investments in research to identify new child-appropriate diagnostics, medications and a vaccine — and the best methods for operationalizing each of these crucial tools.

Recent TB research advances have led to innovations that best serve adults, with minimal trickle-down benefits to children. With WHO reporting more than 60% of childhood TB cases missed each year, approaches to reach and maintain more children throughout the care cascade must be coupled with efforts to develop a nonsputum-based point-of-care diagnostic test. Implementing studies to identify and evaluate novel host biomarkers to diagnose TB infection, disease and risk for disease progression in children is one promising approach.

Lisa V. Adams

Research is needed to develop shorter regimens for both drug-sensitive and drug-resistant TB, with child-friendly formulations for all medications comprising current treatment regimens. A vaccine that can provide greater protection than bacillus Calmette-Guérin vaccine and can be used in all age groups is also a priority. Lastly, a critical (and often overlooked) research priority is to determine optimal models of integrated, family-centered care delivery to ensure that new technologies and practices reach all pediatric populations, including the most vulnerable.

These research efforts will require an increase in the historically small fraction of research funding dedicated to childhood TB — estimated by the Treatment Action Group as only 3% of total TB research funding in 2016. Only through such investments can we expect to reach the current ambitious target of eliminating TB in the next decade.

Disclosure: Adams reports no relevant financial disclosures.

Editor’s note: To read our May cover story, click here.

At the U.N. General Assembly high-level meeting in September 2018, heads of state committed to ending the tuberculosis epidemic by 2030. An agreement was signed at the meeting that promised $2 billion a year for TB research. Infectious Diseases in Children asked two experts — Mario C. Raviglione, FRCP (UK), FERS, Hon RSP (RF), professor of global health at the University of Milan and the Global Studies Institute of the University of Geneva, and former director of WHO’s Global Tuberculosis Program, and Lisa V. Adams, MD, associate dean of global health at the Geisel School of Medicine at Dartmouth — what research should be a priority in an effort to end the global epidemic of TB in children.

Raviglione: With 1 million children affected every year and a quarter of them dying from it, pediatric TB is a major global health issue that requires a serious rethinking of the commitment to fight it and the investments to control it. Often ignored by national TB programs and experts alike who are under the false impression that pediatricians will take good care, this neglected form of TB is finally reaching necessary attention. The first Roadmap for Childhood TB that WHO published in 2013 together with key partners like UNICEF, CDC and USAID, recognized 10 steps toward better care, control and prevention of TB in children. Among those, it emphasized the urgent need for research to improve the available limited interventions. This need was reiterated in the following years in various official reports, resolutions and declarations, including the new WHO’s End TB Strategy for 2016 to 2030, the 2017 Moscow Declaration to end TB, and the final political declaration at the U.N. General Assembly high-level meeting on TB in September 2018.

Mario C. Raviglione

Therefore, after a ton of good words and stated intentions, the issue is now one of making things happen in concrete terms. This begins with research funders and investors. One has yet to see that childhood TB is a stated priority among major donors, although in 2017, the global spending on pediatric TB nearly doubled, reaching $56.4 million from $29 million in 2016. However, this sum remains a small 7% of the total investments in TB research of about $772 million in 2017. Indeed, the unique aspects of pediatric TB require fully dedicated research efforts if solutions are to be identified. In turn, this requires donors with the vision of focusing investments on proposals to address immunopathogenesis, epidemiology and development and implementation of better tools.

Prioritized research agendas have been compiled for some years. First, there is wide recognition that we do not fully understand the immune response and pathogenesis of TB in children and adolescents. This basic science issue requires focused research, as does the epidemiology of pediatric TB, starting with an improved understanding of its true burden through dedicated surveys. Second, a prevention revolution will occur when novel biomarkers are identified, allowing one to predict the progression from latency to disease. Similarly, biomarkers of active disease allowing point-of-care detection will be another crucial step, considering the tremendous challenge of making a diagnosis in children. Third, novel regimens for TB disease, drug-resistant TB and latent infection that are safe, shorter and adaptable to the presence of comorbidities such as HIV would dramatically change the current pattern of care if studied specifically for children in consideration of their biological and pharmacokinetic differences, rather than adapted from adult trials. Of great importance would be the identification of a prophylactic regimen for young contacts of patients with multidrug-resistant TB. Fourth, and the ultimate solution to TB, focused research on pre-exposure and post-exposure vaccines is a key priority where investments need to increase greatly. Furthermore, operational and programmatic research have roles to define the best delivery of any existing and new prevention and care interventions, including community engagement and integration with general pediatric services. Given its enormous potential, assessing how contact investigation can best be undertaken would be a great benefit to burdened communities. Finally, studying social aspects of the disease, its socioeconomic impact, the challenge of access to services by adolescents and the alleviation of stigma will better serve this vulnerable population.

In the end, it is a matter of political commitment and financial investment. The excellent wording of resolutions will be useless unless it is followed by action. It should inspire activism and put healthy pressure on those who pledged support and speak on behalf of those who are suffering voicelessly.

Disclosure: Raviglione reports no relevant financial disclosures.

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Adams: Officials at the U.N. high-level meeting on TB last year adopted a declaration to end TB by 2030 — a bold commitment that holds great promise for the WHO-estimated 10 million individuals who develop TB each year, 1 million of whom are children. Until recently, pediatric TB was a neglected area of TB care and prevention, but effective advocacy is now helping to address critical gaps in child TB detection, treatment and prevention. Success in each of these areas will require robust partnerships between governments and donors and significant investments in research to identify new child-appropriate diagnostics, medications and a vaccine — and the best methods for operationalizing each of these crucial tools.

Recent TB research advances have led to innovations that best serve adults, with minimal trickle-down benefits to children. With WHO reporting more than 60% of childhood TB cases missed each year, approaches to reach and maintain more children throughout the care cascade must be coupled with efforts to develop a nonsputum-based point-of-care diagnostic test. Implementing studies to identify and evaluate novel host biomarkers to diagnose TB infection, disease and risk for disease progression in children is one promising approach.

Lisa V. Adams

Research is needed to develop shorter regimens for both drug-sensitive and drug-resistant TB, with child-friendly formulations for all medications comprising current treatment regimens. A vaccine that can provide greater protection than bacillus Calmette-Guérin vaccine and can be used in all age groups is also a priority. Lastly, a critical (and often overlooked) research priority is to determine optimal models of integrated, family-centered care delivery to ensure that new technologies and practices reach all pediatric populations, including the most vulnerable.

These research efforts will require an increase in the historically small fraction of research funding dedicated to childhood TB — estimated by the Treatment Action Group as only 3% of total TB research funding in 2016. Only through such investments can we expect to reach the current ambitious target of eliminating TB in the next decade.

Disclosure: Adams reports no relevant financial disclosures.

Editor’s note: To read our May cover story, click here.