A Blueprint to Address Research Gaps in the Development of Biomarkers for Pediatric Tuberculosis
CID
A Blueprint to Address Research Gaps in the Development of Biomarkers for Pediatric Tuberculosis
Mark Patrick Nicol () 0
Devasena Gnanashanmugam 0
Renee Browning 0
Eleanor S. Click 0
Luis E. Cuevas 0
Anne Detjen 0
Steve M. Graham 0
Michael Levin 0
Mamodikoe Makhene 0
Payam Nahid 0
Carlos M. Perez-Velez 0
Klaus Reither 0
Rinn Song 0
Hans M. L. Spiegel 0
Carol Worrell 0
Heather J. Zar 0
Gerhard Walzl 0
0 Anzio Road, Observatory , Cape Town, 7925 South Africa
Childhood tuberculosis contributes significantly to the global tuberculosis disease burden but remains challenging to diagnose due to inadequate methods of pathogen detection in paucibacillary pediatric samples and lack of a child-specific host biomarker to identify disease. Accurately diagnosing tuberculosis in children is required to improve case detection, surveillance, healthcare delivery, and effective advocacy. In May 2014, the National Institutes of Health convened a workshop including researchers in the field to delineate priorities to address this research gap. This blueprint describes the consensus from the workshop, identifies critical research steps to advance this field, and aims to catalyze efforts toward harmonization and collaboration in this area.
-
tuberculosis; children; diagnosis; biomarker; blueprint.
Childhood tuberculosis is estimated to account for 6%
of the tuberculosis caseload globally, and for 4%–21%
of the caseload in the 22 high-incidence countries
that account for 80% of global tuberculosis cases [1].
Mathematical modeling suggests that only 35% of
tuberculosis cases in children are detected [2]. Improving the
accuracy of tuberculosis diagnosis in children is required
to improve case detection and outcomes, surveillance,
efficiency of healthcare delivery, future research, and
effective advocacy.
However, attaining an accurate diagnosis in children
in tuberculosis-endemic settings remains challenging.
There is overlap of the clinical presentation of
tuberculosis with other common childhood diseases such as
pneumonia, human immunodeficiency virus (HIV)–
associated lung disease, and severe malnutrition [3].
Clinical and chest radiographic features are often
nonspecific and subject to variable interpretation [4].
Structured diagnostic scoring systems based on clinical and
radiological findings and tuberculin skin testing show high
variability in case yield, with poor agreement between
scoring systems [5]. Microbiological confirmation is
possible in children of all ages, but is rarely attempted due to
perceived difficulties in obtaining respiratory specimens
and because both culture [6] and automated real-time nucleic
acid amplification tests are only positive in a proportion of
children who have been clinically diagnosed with tuberculosis [7–
9]. Current diagnostics that measure immunological responses
following infection with Mycobacterium tuberculosis have
uncertain sensitivity and are unable to distinguish active
tuberculosis from latent tuberculosis [10]. The clinical distinction
between latent and active tuberculosis is unlikely to be
dichotomous, especially following recent infection—a common
scenario in children.
In 2014, the National Institutes of Health (NIH) of the United
States convened a group of panelists to develop a blueprint for the
process of discovery and implementation of new diagnostic
biomarkers for pediatric tuberculosis. In the 19th century, a
“blueprint” was a reproduction of a technical drawing through a
contact print process on light-sensitive sheets that allowed the
rapid and accurate reproduction of documents but was unable
to reproduce color or shades of gray. This article shares several
similarities with the original blueprint method, inasmuch as it
builds on existing efforts for pediatric diagnostic biomarker
discovery, qualification, validation, and implementation, but does
not dictate the exact approach in view of the rapidly changing
technological, regulatory, and health implementation realities.
The blueprint presented here outlines the issues facing the field
of pediatric tuberculosis biomarker development and is aligned
with the Stop TB Partnership and the World Health
Organization (WHO) International Roadmap for Tuberculosis Research
[11]. The blueprint covers the following critical steps:
The target audience for this article includes researchers,
healthcare providers, funding agencies, and regulatory bodies,
in an effort to coordinate and streamline the challenging
process of pediatric tuberculosis diagnostic biomarker discovery,
validation, qualification, and implementation.
CONSENSUS STATEMENT PREPARATION
Wide consultation was sought in the development of this
blueprint with input from international experts from relevant clinical,
basic science, public health and regulatory fields, and other
stakeholders. Among the panelists specifically included were pediatric
tuberculosis clinicians, tuberculosis researchers, HIV research
network representatives, ethicists, representatives f (...truncated)