DEFINING PRIMARY HHV-6 AND HHV7 INFECTIONS IN CHILDREN

人类疱疹病毒6型(HHV-6)和人类疱疹病毒7型(HHV-7)是新发现的疱疹病毒。它们无处不在，在生命的头两年感染了大多数人。像其他疱疹病毒一样，感染似乎是慢性的，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，但它们的自然历史并没有得到很好的界定。本申请提出了三项研究，以回答与HHV-6和HHV-7初次感染的流行病学有关的基本问题。到目前为止，人们对原发感染的了解来自于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，以更好地定义各种疾病，并探索更严重疾病的潜在危险因素。症状日记中的数据将与唾液中病毒的发病定义的初次感染相关。记录血清转换是目前诊断HHV-6感染的金标准，但从定义上讲，它对急性环境下儿童的临床治疗没有帮助。用聚合酶链式反应可以更快地做出诊断。然而，血液和唾液的聚合酶链式反应检测用于快速诊断的敏感性和特异性尚未确定。第二项研究将调查到急诊科就诊的发热儿童，以评估一种快速诊断HHV-6原发感染的聚合酶链式反应检测方法。在这项研究中，两岁以下到急诊科就诊的发烧婴儿将接受全血、血浆和唾液的HHV-6聚合酶链式反应检测。这些聚合酶链式反应结果将与HHV-6的急性和恢复期血清学进行比较，以确定各种体液的聚合酶链式反应在快速诊断HHV-6方面的价值。还将使用这些数据模拟聚合酶链式反应检测在发热婴儿管理中的作用。先天性感染HHV-6和HHV-7的频率和临床意义尚不清楚。第三项研究将评估健康的新生儿和有异常的新生儿，包括早产、先天性缺陷和急性疾病，以评估这些病毒感染导致的胎儿和婴儿发病率。先天性感染的定义是在出生后第一周内在脐带血中检测到特定的IgM抗体，或在唾液或婴儿血液中检测到病毒DNA。健康新生儿和异常新生儿将就HHV-6和HHV-7先天性感染的频率进行比较。如果在有异常的婴儿中发现先天感染的频率较高，将对不同的异常进行分组分析，以产生假设。婴幼儿通常会感染HHV-6和HHV-7。这些研究将进一步确定儿童的疾病谱，评估聚合酶链式反应在原发感染快速诊断中的应用，并探讨先天性感染的临床意义。这些研究还将使我有机会发展进行临床研究所需的技能，并实现我的长期目标；成为一家学术机构的独立研究员。

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.