Biomarker Signatures of TB Infection in Young Children With and Without HIV

感染和未感染艾滋病毒的幼儿结核感染的生物标志物特征

• 批准号: 10641224
• 负责人: Francesca Basile
• 金额: $ 112.77万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-28 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641224
• 关键词: 5 year old; Adult; Antibodies; Antigens; Bacteriology; Biological Assay; Biological Markers; Case Fatality Rates; Cells; Child; Clinical; Cohort Studies; Diagnosis; Diagnostic; Evaluation; Exposure to; Goals; HIV; Image; Intervention; Laboratories; Locales; Machine Learning; Mycobacterium tuberculosis; Performance; Population; Preventive therapy; Proteomics; Public Health; Reference Standards; Research Personnel; Risk; Sputum; Stomach; Symptoms; T-Cell Activation; Thoracic Radiography; Tuberculosis; Uganda; Vulnerable Populations; age group; aspirate; biomarker signature; computer aided detection; exosome; high risk; improved; isoniazid; multiple omics; novel diagnostics; novel strategies; point of care; progression risk; risk stratification; screening; tuberculosis drugs; tuberculosis treatment; ultrasound

Per year, globally an estimated one million children develop tuberculosis (TB) and more than 15 million children are estimated to be exposed to Mycobacterium tuberculosis (Mtb). The case fatality rate is high in children < 5 years of age. Current approaches to diagnosis and management of young children that are close contacts to a TB case are inadequate. Those that are symptomatic may undergo sputum-based diagnostics that are not well tolerated (eg gastric aspirates), require access to a reference laboratory, and are not sensitive because TB may be paucibacillary or extrapulmonary. For that reason empirical multidrug anti-TB treatment predominates in many locales. Management of the asymptomatics is sub-optimal as well. Given the poor performance of IGRAs and TST in this age group, most are treated with isoniazid preventive therapy (IPT). In adults, asymptomatic (subclinical TB) is at least as common as active TB and will not be detected by current symptom-based screening. We do not know how often this is the case in exposed children, however, IPT, would be inadequate in them. Further, about 19% of children in this age group with latent TB infection (LTBI) will progress to active TB, usually within the next 3-6 in the absence of IPT (and IPT is only 63% effective). The need therefore is to discover a biomarker or biomarkers that identify those children < 5 years of age with subclinical TB (likely to progress despite IPT); and those without subclinical TB that are likely to progress. These biomarkers would allow appropriate targeting of IPT and ATT to those likely to benefit. This consortium of investigators have on-going diagnostic and cohort studies of child (< 5 years of age) close contacts of TB cases in Uganda that include a rigorous bacteriologic reference standard applied to asymptomatic as well as symptomatics and evaluation of novel diagnostics and discovery of non-sputum- based approaches. We propose now to evaluate in children < 5years old that are close contacts of a TB case a diverse and complementary panel of bacterial, host-based and imaging non-sputum biomarkers that have shown promise as predictors of progression in adults. Further, we will discover relevant biomarkers in this population through an unbiased multi-omics approach using proteomics, single-cell omics, T-cell activation markers, antigen-specific antibody profiling, Mtb exosomal assays, computer-aided detection (CAD) for chest X-ray interpretation and point-of-care ultrasound (POCUS). Our goal is to characterize a biomarker or group of biomarkers that meet a minimal target performance profile to identify children with subclinical TB and/or at high risk of progression. We will apply advanced machine learning and integrative multiomics to identify combinations of these biomarker signatures alongside TB risk variables to improve precision of predicting progression. These results will provide novel approaches to risk-stratify children <5 years of age for targeting the administration of preventive therapy and ATT.

每年，全球估计有 100 万儿童罹患结核病 (TB)，超过 1500 万儿童患有结核病 (TB) 据估计，儿童会接触结核分枝杆菌 (Mtb)。病死率较高 5 岁以下的儿童。目前对幼儿的诊断和管理方法是接近的 与结核病病例的接触不足。有症状的人可能会接受基于痰的诊断 耐受性不好（例如胃抽吸物），需要进入参考实验室，并且不属于 敏感，因为结核病可能是少杆菌性的或肺外的。因此，经验性多药抗结核治疗 在许多地方，治疗占主导地位。对无症状患者的管理也不是最理想的。给定 该年龄段的 IGRA 和 TST 表现较差，大多数采用异烟肼预防性治疗 （IPT）。在成人中，无症状（亚临床结核病）至少与活动性结核病一样常见，并且不会被发现 通过当前基于症状的筛查。我们不知道暴露儿童中这种情况发生的频率， 然而，IPT 在这些方面还不够。此外，该年龄组中约 19% 的儿童患有潜伏性结核病 在没有 IPT 的情况下，感染 (LTBI) 通常会在接下来的 3-6 年内进展为活动性结核病（IPT 仅是 有效率 63%）。因此，需要发现一种或多种生物标记来识别那些 < 5 岁的儿童 患有亚临床结核病的年龄（尽管进行了 IPT，仍有可能进展）；以及那些没有亚临床结核病的人 可能会取得进展。这些生物标志物将允许 IPT 和 ATT 适当针对那些可能 益处。该研究人员联盟正在进行儿童（< 5 年）的诊断和队列研究 乌干达结核病病例的密切接触者，其中包括应用严格的细菌学参考标准 对无症状和有症状的新型诊断方法进行评估以及发现非痰 基于的方法。我们现在建议对 5 岁以下与结核病密切接触的儿童进行评估 案例一组多样化且互补的细菌、基于宿主和成像的非痰生物标志物 已显示出作为成人疾病进展预测因子的前景。此外，我们将发现相关的生物标志物 通过使用蛋白质组学、单细胞组学、T 细胞的公正多组学方法来研究这一群体 激活标记、抗原特异性抗体分析、Mtb 外泌体测定、计算机辅助检测 (CAD) 用于胸部 X 射线判读和护理点超声 (POCUS)。我们的目标是表征 满足最低目标表现特征的生物标志物或生物标志物组，以识别患有以下疾病的儿童 亚临床结核病和/或处于高进展风险。我们将应用先进的机器学习和集成 多组学来识别这些生物标志物特征与结核病风险变量的组合，以改善 预测进展的准确性。这些结果将为 <5 岁儿童的风险分层提供新方法 进行预防性治疗和 ATT 的年龄。