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) 继续给低收入和中等收入国家带来诊断挑战 由于少杆菌病对儿童的影响已得到充分描述，以及当前的结核病，结核病发病率很高 培养和聚合酶链反应测试由于成本、可用性有限以及 我们来自约翰斯杜兰大学的专家团队对年幼儿童的标本敏感性较差。 霍普金斯大学、Universidad Peruana Cayetano Heredia 和 Asociación Benéfica Prisma 面临着 通过在秘鲁和玻利维亚超过 25 年的合作，我们的目标是直接应对所有这些挑战。 通过评估 MPI Tony Hu 开发的新诊断方法来应对儿童结核病的挑战 杜兰大学使用 CRISPR 介导的结核病检测 (CRISPR-TB) 进行优化以检测循环 结核分枝杆菌无细胞 DNA (Mtb-cfDNA)，用于分析中试冷冻保存的血清 对疑似结核病成人和儿童、他们的无症状家庭接触者以及一组 有症状的艾滋病毒感染者 (CLHIV) 结核病高危儿童的结果来自有症状的成人队列。 汇总敏感性为 93%；阳性预测值为 95%； 在 CLHIV CRISPR-TBD 的有限试点研究中，准确率高达 92%。 (13/13) 和大多数患有未确诊结核病的儿童 (80%; 52/65) 我们建议登记 200 名疑似结核病患者。 2 个研究人群（测试人群和 验证人群）通过与“马里奥·奥尔蒂斯·苏亚雷斯博士”儿童医院相关的诊所确定 在玻利维亚圣克鲁斯，我们将通过“测试”确定外周血中 cfDNA 浓度的分布。 “人口”由两个年龄组（2 个月至 6 岁、7-14 岁）患有呼吸道疾病的儿童组成 根据 NIH 共识病例定义（确诊结核病、未确诊结核病）按结核病可能性对疾病进行分组 结核病和不太可能的结核病）和按潜伏性结核感染（LTBI）分组的年龄匹配对照组， 在接受抗生素治疗的结核病病例中及时连续测量 cfDNA 我们还将验证标准。 为结核病或 LTBI 儿童临床亚组建立定量 cfDNA 范围 独立验证队列的另一个目标是确定定量 cfDNA 和 基于成像的结核病评分，基于肺疾病的定量证据，肺是结核病的主要靶器官 疾病，通过 (1) 胸部 X 光片，使用 CAD4TB v7 系统通过计算机辅助分析进行测量，以及 (2) 肺部超声检查，使用便携式/低成本探头在机器学习算法的辅助下进行 这些生物标志物将作为可能与其他药物相结合的潜在辅助因子进行测试。 这项研究的结果是，通过检测外周血中的 cfDNA 水平，提高对儿童结核病的检测。 将是寻找检测许多“未经确诊”结核病例的途径的第一步 理想情况下，可以在资源匮乏、急需诊断的地区实现儿童结核病的诊断。