HHV-6 and CNS disease following stem cell transplant

描述（由申请人提供）：有令人信服的数据将人疱疹病毒6 （HHV-6）再激活与造血干细胞移植（HSCT）后严重的中枢神经系统（CNS）功能障碍（包括脑炎和癫痫发作）联系起来。尽管有适当的治疗，HHV-6中枢神经系统功能障碍仍与高死亡率和发病率相关。虽然抗病毒治疗可以消除病毒血症和脑脊液中可检测到的病毒水平，但所选择的药物，更昔洛韦和福司美，毒性很高，而且这种治疗的临床效果不确定。先发制人或预防性的方法可能会导致更好的临床结果，但在这些方法可以测试之前，HSCT后HHV-6中枢神经系统功能障碍的频谱、发生率和结果及其危险因素需要明确。我们从HSCT后谵妄的前瞻性试点研究中获得的初步数据表明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，大多数幸存者可能存在持久的神经系统后遗症。因此，我们假设HSCT后HHV-6再激活与比目前认识到的更广泛的中枢神经系统功能障碍相关，并导致持续的、严重的认知异常。

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.