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.

小儿结核病（TB）继续在低收入和中等收入国家构成诊断挑战 由于paucibaCillarry疾病对儿童的影响有很好的影响，TB疾病发生率很高 培养和聚合酶 - 链反应测试由于成本，可用性限制和 年幼儿童的标本的敏感性不佳。我们来自杜兰（Johns）的专家团队 霍普金斯大学，佩鲁纳·卡耶塔诺·埃雷迪亚大学，阿斯科西亚·贝菲卡·普里斯玛（AsociaciónBenéficaPrisma） 所有这些挑战通过在秘鲁和玻利维亚进行了25年以上的合作。我们的目标是直接 通过评估MPI Tony Hu开发的新诊断方法来应对儿童中结核病的挑战 在杜兰大学使用CRISPR介导的结核病测定法（CRISPR-TB），以检测循环 结核分枝杆菌无细胞的DNA（MTB-CFDNA），用于分析试验中的冷冻血清 成人和患有假定结核病的儿童的研究，无症状的家庭接触和一群 艾滋病毒（CLHIV）的有症状儿童患结核病的风险很高。有症状的成人队列的结果 产生的汇总灵敏度为93％； 93％的特异性；正预测值为95％；和负面的预测 价值92％。在有限的CLHIV CRISPR-TBD结果中的初步研究中，所有已确认的结核 （13/13）和大多数未经证实的结核病儿童（80％; 52/65）。我们建议注册200个假定结核病 在2个研究人群中的每个人群中，病例和相等数量的井对照受试者（测试人群和 通过与“ Mario Ortiz Suarez博士”儿童医院相关的诊所确定的验证人群） 在玻利维亚的圣克鲁斯。我们将在“测试中”确定外周血中CfDNA浓度的分布 人口”由两个基于年龄的儿童组（2个月至6岁，7-14岁）组成 根据NIH共识案例定义，通过结核病可能分组的疾病（确认的结核病，未经证实 TB，不太可能的TB）以及通过潜在结核病感染（LTBI）分组的年龄匹配对照 CFDNA在接受抗生素疗法的结核病病例中串行测量。我们还将验证标准 为TB疾病或LTBI儿童的临床亚组建立的定量CFDNA范围 独立验证队列。另一个目标将确定定量cfDNA和 基于定量成像的结核病分数基于肺中的疾病证据，肺是结核病中的主要靶向器官 疾病，通过（1）胸部X光片，通过使用CAD4TB V7系统进行计算机辅助分析，并通过 （2）肺超声，用机器学习算法的辅助/低成本探针进行 自动解释。这些生物标志物将被测试为可能与 外周血中的CFDNA水平，以改善儿童TB疾病的检测。这项研究的结果 将是找到允许检测许多“未经证实”的结核病案件的途径的过程中的第一步 理想情况下，将小儿结核病的诊断范围用于迫切需要的低资源设置。