DEFINING PRIMARY HHV-6 AND HHV7 INFECTIONS IN CHILDREN

人类疱疹病毒6型（Human Herpesvirus-6，HHV-6）和人类疱疹病毒7型（Human Herpesvirus-7，HHV-7）是新近发现的疱疹病毒。 它们无处不在，在生命的头两年感染大多数个体。 像其他疱疹病毒一样，感染似乎是慢性的，并被认为在一生中周期性地重新激活。 尽管这些都是常见的感染，但它们的自然史并没有很好的定义。 本申请提出了三项研究来回答关于HHV-6和HHV-7原发感染流行病学的基本问题。迄今为止，对原发性感染的了解来自对急诊科儿童的研究。 我们提出的第一项研究是一项针对200名新生儿的大型、前瞻性、基于人群的研究，以更好地定义疾病的全部范围，并探索更严重疾病的潜在风险因素。 来自症状日记的数据将与通过唾液中的病毒发作定义的原发性感染相关。血清转换的记录是目前诊断HHV-6感染的金标准，但根据定义，它对急性环境中儿童的临床管理没有帮助。 PCR可以更快地诊断。 然而，用于快速诊断的血液和唾液PCR检测的灵敏度和特异性尚未确定。 第二项研究将调查到急诊室就诊的发热儿童，以评估PCR检测对原发性HHV-6感染的快速诊断。 在这项研究中，两岁以下的婴儿因发烧到急诊室就诊，将通过PCR检测全血、血浆和唾液中的HHV-6。 这些PCR结果将与HHV-6的急性和恢复期血清学进行比较，以确定各种体液的PCR对HHV-6快速诊断的价值。 PCR检测在发热婴儿管理中的效用也将使用这些数据进行建模。先天性HHV-6和HHV-7感染的频率和临床意义尚不清楚。 第三项研究将评价健康新生儿和异常新生儿，包括早产、先天性缺陷和急性疾病，以评价这些病毒感染导致的胎儿和婴儿发病率。先天性感染将通过在脐带血中检测到的特异性IgM抗体或通过在出生后第一周内唾液或婴儿血液中存在病毒DNA来定义。将比较健康新生儿和异常新生儿的HHV-6和HHV-7先天性感染频率。 如果在异常婴儿中发现先天性感染的频率较高，则将对不同异常进行亚组分析，以生成假设。婴儿和幼儿通常会感染HHV-6和HHV-7。 这些研究将进一步明确儿童疾病谱，评估PCR在原发性感染快速诊断中的实用性，并探讨先天性感染的临床意义。 这些研究也将使我有机会发展所需的技能，进行临床研究，并达到我的长期目标;成为一个独立的研究者在学术机构。

Human Herpesvirus-6 (HHV-6) and Human Herpesvirus-7 (HHV-7) are newly identified Herpesviruses. They are ubiquitous, infecting most individuals in the first two years of life. Like other Herpesviruses, infection appears to be chronic and is thought to reactivate periodically throughout life. Despite the fact that these are common infections, their natural history is not well defined. This application proposes three studies to answer basic questions regarding the epidemiology of primary infection with HHV-6 and HHV-7. To date, what is known about primary infection comes from studies of children seen in emergency departments. The first study we propose is a large, prospective, population-based study of 200 newborns to better define the full range of illness and to explore potential risk factors for more severe illness. Data from symptom diaries will be correlated with primary infection as defined by onset of the viruses in saliva. Documentation of seroconversion is the current gold standard for diagnosis of HHV-6 infection, but by definition, it is not helpful in the clinical management of children in the acute setting. Diagnosis can be made more quickly with PCR. However, the sensitivity and specificity of PCR testing of blood and saliva for rapid diagnosis has not yet been determined. The second study will investigate febrile children who present to the emergency department to evaluate a PCR test for the rapid diagnosis of primary HHV-6 infection. For this study, infants under the age of two years presenting to the emergency department with fever will have whole blood, plasma, and saliva tested by PCR for HHV-6. These PCR results will be compared to acute and convalescent serology for HHV-6 to define the value of PCR of various bodily fluids for rapid diagnosis of HHV-6. The utility of PCR testing in the management of febrile infants will also be modeled using these data. The frequency and clinical significance of congenital infection with HHV-6 and HHV-7 is unknown. The third study will evaluate healthy newborns and newborns with abnormalities including prematurity, congenital defects, and acute illness to evaluate fetal and infant morbidity due to these viral infections. Congenital infection will be defined by specific IgM antibodies detected in the cord blood or by the presence of viral DNA in the saliva or the infants' blood within the first week of life. Healthy newborns and newborns with abnormalities will be compared with regards to the frequency of HHV-6 and HHV-7 congenital infection. If a higher frequency of congenital infection is found in the infants with abnormalities, a sub-group analysis of the different abnormalities will be performed for the purpose of hypothesis generation. Infants and young children commonly become infected with HHV-6 and HHV-7. The proposed studies will further define the spectrum of disease in children, evaluate the utility of PCR in the rapid diagnosis of primary infection, and explore the clinical significance of congenital infection. These studies will also give me the opportunity to develop the required skills to perform clinical research and to reach my long term goal; to become an independent investigator in an academic institution.