Assessment Of Patients With Lyme Infection

莱姆病感染患者的评估

• 批准号: 6986002
• 负责人: ADRIANA R MARQUES
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6986002
• 关键词: Borrelia; Lyme disease; audiometry; bacteria infection mechanism; biomarker; children; chronic disease /disorder; communicable disease diagnosis; diagnosis design /evaluation; disease /disorder etiology; emerging infectious disease; host organism interaction; human subject; human therapy evaluation; magnetic resonance imaging; medical complication; microorganism disease chemotherapy; microorganism immunology; molecular pathology; neuropsychological tests; patient oriented research; polymerase chain reaction; sign /symptom

Lyme disease is a multisystem illness caused by infection with the spirochete Borrelia burgdorferi and it is the leading vector-borne disease in the United States. Lyme disease is also common in Europe (mainly middle Europe and Scandinavia) and also occurs in Russia, China and Japan. In humans, B. burgdorferi infection causes infection primarily in the skin, nervous system, heart and joints. Lyme disease can usually be treated successfully with antibiotic therapy, with the best results seen in patients with early disease. Unfortunately, some patients may not have a complete response to therapy. We currently have two clinical protocols studying patients with Lyme disease. Both protocols are natural history studies and serve as the basis for multiple lines of investigation. One protocols addresses patients with post treatment Lyme disease syndrome. The other protocol allow for the study of patients with classical Lyme disease. Our work has addressed 3 areas in Lyme disease: laboratory diagnosis, clinical manifestations and immunological responses to B. burgdorferi. Regarding laboratory diagnostics, we have focused in developing better tests for both diagnosis and for persistence of infection. We collaborate with Dr. Mario Philipp and his group at Tulane University Medical Center, in the development of the C6 peptide ELISA. This test is simple to perform and is highly sensitive and specific. An important advantage of this test is that it can be used to diagnose Lyme disease in patients who have received the Lyme disease vaccine, and it can be used in Europe, where Lyme disease may be caused by B. garinii and B. afzelli. We also collaborated with the CDC to evaluate the C6 antibody response, as well as the antibody response to other recombinant antigens and synthetic peptides, in comparison with the 2-tier testing. When used alone, the C6 ELISA had similar sensitivity to 2-tier test. Moreover, when used in combination with the detection of IgM antibodies to a ten-amino acid peptide found at the C-terminus of most OspC proteins (pepC10), the combination had significantly higher sensitivity for diagnosing exposure to B. burgdorferi in patients with acute Lyme disease. Besides the use of the C6 antibody response for diagnosis of Lyme disease, we are currently evaluating this response as a possible marker for clearance of infection. Our results showed that the amount of antibody against C6 declines after successful antibiotic therapy of Lyme disease. These results suggest that a change in the anti-C6 antibody titer may serve as an indicator of therapy outcome for patients with acute and disseminated Lyme disease. Patients with post treatment Lyme disease syndrome participating in a double-blind placebo controlled trial of antibiotic therapy had very low levels of C6 antibody and there was no correlation between a decline of C6 antibody titer and clinical outcome. Further studies with more patients are needed to clarify how the test may be used in the clinical setting. Regarding immunological responses, in collaboration with Dr. Roland Martin (Neuroimmunology Branch, NINDS), we are studying the specificity repertoires and function of Borrelia burgdorferi-specific T cell clones using a novel methodology to decrypt the antigen specificity of T cell clones. In follow up to this study, we developed a highly specific and sensitive technique to track single T cell clones through the detection and quantification of T cell receptor (TCR) alpha or beta chain complementarity-determining region 3 transcripts by real-time RT-PCR. We examined the frequency of the candidate pathogenic T cell clones in the peripheral blood and cerebrospinal fluid (CSF) during the course of neurological disease. Using this approach, we detected variations of clonal frequencies that appeared to be related to clinical course, significant enrichment in the CSF, or both. We are also very interested in investigating the innate immune response to B. burgdorferi infection. We have examined the transcription profile of human peripheral blood mononuclear cells in response to B.burgdorferi lysate using oligonucleotide microarrays, as a basis for establishing new hypotheses regarding the molecular pathogenesis of Lyme disease. Regarding clinical manifestations, we have evaluated the audiological system in our patient cohort. These evaluations included studies with puretone sensitivity measurements, speech reception threshold, speech recognition, tolerance for speech and other studies of speech functions at high intensity presentation levels. It also included biomechanical studies of middle ear integrity and otoacoustic emissions to identify (or rule out) cochlear damage, and assessment of the auditory brainstem response to identify or rule out damage to the ascending auditory brainstem pathways. Our most significant finding was a reduced loudness tolerance in the presence of either normal or minimally impaired hearing.

莱姆病是由伯氏疏螺旋体感染引起的多系统疾病，是美国主要的媒介传播疾病。莱姆病在欧洲也很常见（主要是中欧和斯堪的纳维亚半岛），也发生在俄罗斯，中国和日本。在人类中，B。伯氏感染主要在皮肤，神经系统，心脏和关节引起感染。莱姆病通常可以用抗生素治疗成功，在早期疾病患者中效果最好。不幸的是，有些患者可能对治疗没有完全反应。我们目前有两个研究莱姆病患者的临床方案。这两种方案都是自然史研究，并作为多线调查的基础。一个方案针对治疗后莱姆病综合征的患者。另一种方案允许对典型莱姆病患者进行研究。我们的工作涉及莱姆病的3个方面：实验室诊断、临床表现和对B的免疫反应。burgdorferi。 在实验室诊断方面，我们一直致力于开发更好的检测方法，用于诊断和检测感染的持续性。我们与杜兰大学医学中心的Mario Philipp博士及其团队合作开发C6肽ELISA。该测试操作简单，灵敏度和特异性高。该检测的一个重要优点是，它可以用于诊断接种过莱姆病疫苗的患者的莱姆病，而且它可以在欧洲使用，那里的莱姆病可能是由B引起的。garinii和B. afzelli。我们还与CDC合作，评价C6抗体应答，以及对其他重组抗原和合成肽的抗体应答，并与2级检测进行比较。单独使用时，C6 ELISA的敏感性与两层试验相似。此外，当与针对在大多数OspC蛋白的C末端发现的10个氨基酸肽（pepC 10）的IgM抗体的检测组合使用时，该组合对于诊断暴露于B具有显著更高的灵敏度。急性莱姆病患者的伯氏症。除了使用C6抗体反应诊断莱姆病外，我们目前正在评估这种反应作为清除感染的可能标志物。我们的研究结果表明，莱姆病的抗生素治疗成功后，抗C6抗体的量下降。这些结果表明，抗C6抗体滴度的变化可以作为急性和播散性莱姆病患者治疗结果的指标。参与抗生素治疗的双盲安慰剂对照试验的治疗后莱姆病综合征患者的C6抗体水平非常低，并且C6抗体滴度下降与临床结局之间没有相关性。需要对更多患者进行进一步研究，以澄清如何在临床环境中使用该测试。 关于免疫应答，与罗兰马丁博士（神经免疫学分支，NINDS）合作，我们正在研究伯氏疏螺旋体特异性T细胞克隆的特异性库和功能，使用一种新的方法来解密T细胞克隆的抗原特异性。在本研究的后续工作中，我们开发了一种高度特异性和灵敏度的技术，通过实时RT-PCR检测和定量T细胞受体（TCR）α或β链互补决定区3转录本来跟踪单个T细胞克隆。我们研究了在神经系统疾病过程中外周血和脑脊液（CSF）中候选致病性T细胞克隆的频率。使用这种方法，我们检测到的克隆频率的变化，似乎与临床过程，在CSF中的显着富集，或两者兼而有之。我们对研究对B的先天免疫反应也非常感兴趣。伯氏感染我们已经研究了人类外周血单个核细胞的转录谱响应于B.伯氏菌裂解物使用寡核苷酸芯片，作为建立新的假说的基础上莱姆病的分子发病机制。 关于临床表现，我们评估了患者队列的听力系统。这些评价包括对纯音敏感性测量、言语接收阈值、言语识别、言语耐受性的研究以及在高强度呈现水平下对言语功能的其他研究。它还包括中耳完整性和耳声发射的生物力学研究，以识别（或排除）耳蜗损伤，并评估听觉脑干反应，以识别或排除听觉脑干上行通路的损伤。我们最重要的发现是在听力正常或轻微受损的情况下，响度耐受性降低。