Diagnostic Innovations for Pediatric Tuberculosis in Bolivia - Trial NCT06113861

Timeline & Enrollment

Primary Outcome

Cell free DNA level

Summary

Pediatric tuberculosis (TB) continues to pose diagnostic challenges in low- and middle-income
 countries with high rates of TB disease, due to the well-described impact of paucibacillary
 disease in children, and current TB culture and polymerase-chain reaction tests are of
 limited usefulness due to cost, restricted availability, and poor sensitivity in specimens
 available from younger children. Our team of experts from Tulane, Johns Hopkins University,
 Universidad Peruana Cayetano Heredia, and Asociación Benéfica Prisma have confronted all of
 these challenges through more than 25 years of collaboration in Peru and Bolivia. Our goal is
 to directly address the challenges of TB in children by evaluating a new diagnostic approach
 developed by MPI Tony Hu at Tulane University using a CRISPR-mediated TB assay (CRISPR-TB)
 optimized to detect circulating Mycobacterium tuberculosis cell-free DNA (Mtb-cfDNA), and
 used to analyze cryopreserved serum in pilot studies from adults and children with
 presumptive TB, their asymptomatic household contacts, and a cohort of symptomatic children
 living with HIV (CLHIV) at high risk for TB. Results from symptomatic adult cohorts yielded a
 pooled sensitivity of 93%; specificity of 93%; positive predictive value of 95%; and negative
 predictive value of 92%. In limited pilot studies in CLHIV CRISPR-TBD results accurately
 identified all confirmed TB (13/13) and most children with unconfirmed TB (80%; 52/65). We
 propose to enroll 200 presumptive TB cases and an equal number of well control subjects in
 each of 2 study populations (test population and validation population) identified through
 clinics associated with the Dr. Mario Ortiz Suarez Children's Hospital in Santa Cruz,
 Bolivia. We will determine the distribution of cfDNA concentrations in peripheral blood in a
 test population composed of two age-based groups of children (2 months-6 years, 7-14 years)
 with respiratory disease grouped by likelihood of TB based on the NIH consensus case
 definitions (confirmed TB, unconfirmed TB, and unlikely TB) and in age-matched controls
 grouped by presence of latent TB infection (LTBI), with cfDNA measured serially in time among
 TB cases receiving antibiotic therapy. We will also validate standard ranges of quantitative
 cfDNA established for clinical subgroups of children with TB disease or LTBI in an
 independent validation cohort. An additional aim will determine the correlation between
 quantitative cfDNA and quantitative imaging-based TB scores based on evidence of disease in
 the lung, the primary target organ in TB disease, by (1) chest radiograph, measured by
 computer-aided analysis using the CAD4TB v7 system, and by (2) lung ultrasound, performed
 with a portable/low-cost probe assisted by machine learning algorithms for automatic
 interpretation. These biomarkers will be tested as potential cofactors that may be combined
 with cfDNA levels in peripheral blood, to improve the detection of TB disease in children.
 The results of this study will be the first step in a process to find a path to allow
 detection of the many unconfirmed TB cases and ideally make the diagnosis of pediatric TB
 in reach for low resource settings where it is so critically needed.

ICD-10 Classifications