HHV-6 and CNS disease following stem cell transplant

描述(申请人提供)：有令人信服的数据将人类疱疹病毒6型(HHV-6)重新激活与严重的中枢神经系统(CNS)功能障碍联系起来，包括脑炎和造血干细胞移植(HSCT)后的癫痫发作。尽管进行了适当的治疗，但HHV-6中枢神经系统功能障碍与高死亡率和发病率有关。虽然抗病毒治疗可能会消除脑脊液中的病毒血症和可检测到的病毒水平，但首选药物更昔洛韦和复康的毒性很高，这种治疗的临床效果尚不确定。预防性或预防性方法可能会带来更好的临床结果，但在测试这些方法之前，需要确定HSCT后HHV-6中枢神经系统功能障碍的谱系、发生率和结果及其危险因素。我们的初步数据来自于一项关于HSCT后精神障碍的前瞻性先导性研究，初步数据表明HHV-6与中枢神经系统功能障碍之间存在关联。此外，我们中心对HHV-6脑炎患者的总结表明，大多数幸存者可能会有持久的神经后遗症。因此，我们假设HSCT后HHV-6的重新激活与比目前认识到的更大范围的中枢神经系统功能障碍有关，这导致持续的、严重的认知异常。 目的1.评价人类疱疹病毒6型(HHV-6)重新激活与中枢神经系统功能障碍的关系，明确HHV-6重新激活之前中枢神经系统功能障碍的发生率和谱系。 目的2.明确HHV-6相关性中枢神经系统功能障碍在HSCT后的长期结局。 我们提出了一项针对造血干细胞移植受者的大型前瞻性研究。患者的血浆将使用实时荧光探针聚合酶链式反应(PCR)进行每周两次HHV-6筛查。所有用于常规或紧急用途的脑脊液样本也将进行HHV-6检测。患者将使用已在HSCT接受者中成功使用的经过验证的神经精神病学工具，每周三次筛查中枢神经系统功能障碍。神经心理学测试将在研究期间的三个时间点进行，以确定与HHV-6中枢神经系统功能障碍相关的短期和长期认知后遗症。该项目的数据不仅将为HHV-6中枢神经系统功能障碍的当前诊断和预后提供信息，还将用于设计一项干预试验。

DESCRIPTION (provided by applicant): There are compelling data linking human herpesvirus 6 (HHV-6) reactivation and serious central nervous system (CNS) dysfunction including encephalitis and seizures following hematopoietic stem cell transplant (HSCT). Despite appropriate therapy, HHV-6 CNS dysfunction is associated with high mortality and morbidity. While antiviral therapy may abrogate viremia and detectable levels of virus in CSF, the toxicity of the drugs of choice, ganciclovir and foscamet, are high and the clinical effects of such therapy uncertain. Preemptive or prophylactic approaches may result in better clinical outcomes, but before such approaches can be tested, the spectrum, incidence, and outcomes of HHV-6 CNS dysfunction following HSCT as well as its risk factors need to be defined. Our preliminary data from a prospective pilot study of delirium after HSCT suggests an association between HHV-6 and CNS dysfunction. Also, a summary of patients with HHV-6 encephalitis from our center suggests that there may be lasting neurological sequelae in the majority of survivors. Thus, we hypothesize that HHV-6 reactivation after HSCT is associated with a larger spectrum of CNS dysfunction than currently recognized and that this leads to persistent, severe cognitive abnormalities. Aim 1. To evaluate the association between HHV-6 reactivation and CNS dysfunction and to define the spectrum and incidence of CNS dysfunction preceded by HHV-6 reactivation. Aim 2. To define the long-term outcomes of HHV-6 associated CNS dysfunction following HSCT. We propose a large prospective study of HSCT recipients. Patients' plasma will be screened twice weekly for HHV-6 using a real-time quantitative fluorescent-probe polymerase chain reaction (PCR) assay. All CSF specimens obtained for routine or urgent purposes will also be tested for HHV-6. Patients will be screened three times weekly for CNS dysfunction using validated neuropsychiatric instruments that have been used successfully in HSCT recipients. Neuropsychological testing will be performed at three time points during the study to define short- and long-term cognitive sequelae associated with HHV-6 CNS dysfunction. Data from this project will not only inform current diagnosis of and prognosis for HHV-6 CNS dysfunction, but will also be used to design an intervention trial.