Tuberculosis Diagnostics: Towards More Precise Testing in Children

结核病诊断：对儿童进行更精确的检测

• 批准号: 7470622
• 负责人: JOSEPH Alphonso BELLANTI
• 金额: $ 7.61万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470622
• 关键词: 5 year old; AIDS/HIV problem; Acid Fast Bacillae Staining Method; Adolescent; Adult; Age; Age-Years; Agreement; Antigens; Australia; Bacillus (bacterium); Binding; Biological Assay; Blood Tests; Calmette-Guerin Bacillus; Cells; Cellular Immunity; Child; Childhood; Clinical; Communicable Diseases; Communities; Contracts; Developed Countries; Developing Countries; Diagnosis; Diagnostic; Diagnostic Procedure; Disadvantaged; Disease; Dose; Effectiveness of Interventions; False Positive Reactions; Gender; Genus Mycobacterium; Goals; Gold; Health Personnel; Homelessness; Hypersensitivity skin testing; Immigrant; Immune; In Vitro; Incidence; Individual; Infant; Infection; Interferon Type II; Jail; Laboratories; Lobe; Lymphocyte; Malaria; Measurement; Measures; Mediating; Methodology; Methods; Mycobacterium tuberculosis; Negative Skin Test; Older Population; Paper; Patients; Peptides; Persons; Pilot Projects; Population; Predisposition; Prevalence; Production; Proteins; Range; Rate; Reading; Reporting; Research; Resources; Severity of illness; Shelter facility; Sputum; Standards of Weights and Measures; Symptoms; Techniques; Testing; Tuberculin; Tuberculosis; United States Food and Drug Administration; Variant; Whole Blood; World Health Organization; age group; base; cell mediated immune response; clinical Diagnosis; cross reactivity; cytokine; disorder prevention; early childhood; improved; in vitro Assay; named group; response; tool

DESCRIPTION (provided by applicant): This is a revised R03 application to develop an improved in vitro assay of cell mediated immunity to measure cytokine production for the diagnosis of tuberculosis in children. The century-old tuberculin skin test remains the standard way of diagnosis of latent tuberculosis (TB) infection, and is often used as an ancillary test in the diagnosis of clinical TB. The skin test requires two separate encounters with a health-care provider, and there is a sizable proportion of persons, particularly in disadvantaged, immigrant populations, who find it difficult to return to have their skin tests read. In addition, the test requires careful application of the test dose, and careful reading to be reliable, and is often done poorly. Clearly, better tests are needed. A whole blood test based upon release of interferon-gamma from sensitized lymphocytes stimulated with PPD antigen (the QuantiFERON-TB test, from Cellestis Ltd. South Melbourne, Australia) had been previously approved by the FDA. Recently a newer version (the QuantiFERON-TB Gold test) has also been approved, but neither test for the pediatric population. The use of the recently available, highly specific pools of ESAT-6 and CFP-10 peptides (included in the QuantiFERON-TB Gold test) which are absent from all BCG strains and from most non-tuberculosis mycobacteria (with the exception of M. kansasii, M. szulgai, M. marinum, M. leprae, M. bovis and M. africanum) should aid diagnosis of tuberculosis and eliminate the problem of cross- reactivity in individuals infected with most non-tuberculous mycobacteria or previously immunized with BCG. In the present studies we shall be using the QuantiFERON-TB Gold Test which contains as individual components the newly available pools of overlapping peptides of ESAT-6 and CFP-10. We shall also employ cocktails of the two plus TB7.7 (p4), as well as RD1- selected peptides of ESAT-6 and CFP-10 provided by Dr. D. Goletti. A set of pilot studies based upon the use of this improved test will be performed in a clinically well pediatric, mostly immigrant population to evaluate its correlation with conventional tuberculin skin testing (TST), and, on a short-term basis, to determine its ability to predict clinical TB. A particular emphasis will be placed on the younger infant-child (1 to 5 year-old) population where both the severity of disease and the need is great. Moreover, since in patients with suspected clinical TB, there may be "false-negative" skin tests due to suppressor cytokines and other mechanisms related to maturational immaturity that may obscure true cell-mediated immunity to MTB, studies will be also included to determine optimal dose- response relationships (particularly important in children) which may permit overcoming this "false- negativity" in the laboratory. Thus, these studies will explore techniques for differentiating false negative and false positive reactions, and hopefully permit more reliable In vitro testing for the determination of true cell- mediated immunity to MTB and possible differentiating latent from active TB disease.

描述（由申请人提供）：这是修订的R03应用，以改善细胞介导的免疫的体外测定，以测量细胞因子的产生，以诊断儿童结核病。世纪历史的结核蛋白皮肤测试仍然是潜在结核病（TB）感染的标准诊断方式，并且经常被用作诊断临床结核病的辅助测试。皮肤测试需要与医疗保健提供者进行两次单独的相遇，并且有相当一部分的人，特别是在处境不利的移民人群中，他们发现很难返回以进行皮肤测试。此外，该测试需要仔细应用测试剂量，并且仔细阅读以可靠，并且通常做得不好。显然，需要更好的测试。 FDA先前已批准了基于PPD抗原刺激的敏化淋巴细胞（Quantiferon-TB检测，澳大利亚澳大利亚墨尔本）刺激的致敏性淋巴细胞的整体血液检查。最近，较新的版本（Quantiferon-TB黄金测试）也已批准，但两者都不对小儿种群进行测试。在所有BCG菌株以及大多数非链球菌的分生不清中都不存在ESAT-6和CFP-10肽的最近可用的，高度特定的ESAT-6和CFP-10肽（包括在Quantiferon-TB黄金测试中）（包括在Quantiferon-TB测试中）消除了感染大多数无结核分枝杆菌或以前用BCG免疫的个体中交叉反应性的问题。在目前的研究中，我们将使用Quantiferon-TB黄金测试，该测试包含单个组件，即ESAT-6和CFP-10的重叠肽的新可用池。我们还将使用D. Goletti博士提供的两种加上TB7.7（P4）的鸡尾酒以及RD1-选定的ESAT-6和CFP-10肽。一组基于这种改进测试的试验研究将在临床上良好的小儿（主要是移民人群）中进行，以评估其与常规结核蛋白皮肤测试（TST）的相关性，并在短期内确定其预测临床TB的能力。特别的重点将放在年轻的婴儿儿童（1至5岁）的人群上，疾病的严重程度和需求都很大。此外，由于在怀疑临床结核病的患者中，由于抑制细胞因子和与成熟的不成熟相关的其他机制，可能会进行“假阴性”皮肤测试，这些机制可能掩盖了对MTB的真实细胞介导的免疫力，还将包括对MTB进行的实际研究，以确定最佳剂量反应关系（在儿童中尤其重要），这可以允许克服该虚假性。因此，这些研究将探讨区分假阴性和假阳性反应的技术，并希望在确定对MTB的真实细胞介导的免疫力上，并可能在体外测试中获得更可靠的测试，并可能将潜在与活性TB疾病区分开。

项目成果

Rapid diagnosis of Mycobacterium tuberculosis infection in children using interferon-gamma release assays (IGRAs).

使用干扰素-γ释放测定（IGRA）快速诊断儿童结核分枝杆菌感染。

• DOI: 10.2500/aap.2012.33.3574
• 发表时间: 2012
• 期刊: Allergy and asthma proceedings
• 影响因子: 2.8
• 作者: Riazi,Shahla;Zeligs,Barbara;Yeager,Henry;Peters,StephenM;Benavides,GermanA;DiMita,Onorina;Bellanti,JosephA
• 通讯作者: Bellanti,JosephA