Diagnostic Innovations for Pediatric Tuberculosis in Bolivia

玻利维亚儿童结核病的诊断创新

• 批准号: 10731855
• 负责人: ROBERT H GILMAN
• 金额: $ 75.1万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-07 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731855
• 关键词: Address; Adult; Age; Antibiotic Therapy; Area; Automobile Driving; Bacteria; Biological Assay; Biological Markers; Blood specimen; Bolivia; Cells; Chest; Child; Childhood; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Computational algorithm; Computer Assisted; Consensus; Control Groups; Country; Cryopreservation; DNA; Detection; Development; Devices; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Enrollment; Genes; Goals; Guidelines; HIV; Health Professional; High Prevalence; Household; Image; Laboratories; Lung; Lung diseases; Measures; Mediating; Methods; Molecular; Mycobacterium tuberculosis; Nature; Organ; Pediatric Hospitals; Peru; Pilot Projects; Polymerase Chain Reaction; Population; Predictive Value; Process; Proteomics; Pulmonary Pathology; Radiology Specialty; Rapid diagnostics; Reaction; Research; Resource-limited setting; Respiratory Disease; Risk; Serum; Specificity; Specimen; Sputum; Subgroup; System; Techniques; Testing; Thoracic Radiography; Time; Tuberculosis; Ultrasonography; United States National Institutes of Health; Universities; Validation; automated algorithm; cell free DNA; cofactor; cohort; cost; cost effective; detection method; diagnostic criteria; diagnostic platform; diagnostic strategy; diagnostic tool; genomic tools; high risk; imaging biomarker; improved; innovation; low and middle-income countries; machine learning algorithm; novel; novel diagnostics; pathology imaging; peripheral blood; point of care; portability; prisma; quantitative imaging; response; response biomarker; study population; tool; treatment response; tuberculosis treatment; ultrasound

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.

在低收入和中等收入国家，儿童结核病（TB）继续构成诊断挑战