NEONATAL HERPES SIMPLEX VIRUS INFECTION LIMITED TO THE SKIN, EYE, AND MOUTH

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。自从对新生儿单纯疱疹病毒(HSV)(1型和2型)感染采用抗病毒治疗以来，发病率和死亡率已有显著改善。在仅限于皮肤、眼睛和粘膜(SEM)的疾病、播散性疾病和中枢神经系统(CNS)疾病方面已见改善。虽然山姆病的死亡率基本上是不存在的，但这种形式的单纯疱疹病毒感染可能导致神经系统疾病。即使在临床上没有明显的中枢神经系统受累的情况下，近40%未经治疗的新城疫感染婴儿也会出现神经损害。这很可能是新生儿期潜伏的中枢神经系统感染的结果，在以后的生活中没有检测到临床上的重新激活。静脉注射抗病毒治疗可以减少脑膜瘤后神经系统的发病率，因此90%以上的这类婴儿在出生一年时发育正常。一岁时出现的损害并不轻微，包括痉挛、小头畸形和脉络膜视网膜炎。即使在给予抗病毒治疗的情况下，在患有SEM病的婴儿中，抗病毒治疗后皮肤复发的频率与神经损害的发展也有直接的相关性。具体地说，在生命的第一年，如果有三次或三次以上的复发，正常发育的可能性只有%，而不是没有损害，复发较少。尽管进行了严格的临床随访和频繁的脑脊液(CSF)检查，但这意味着病毒有可能在皮肤以外的部位重新激活。尽管脑脊液检查结果正常并及时治疗，但扫描电子显微镜下局限性疾病患者的神经后遗症的发生说明了目前治疗的不足。为进一步改善系统性红斑狼疮患儿的神经系统预后，在静脉注射阿昔洛韦10天后口服阿昔洛韦300 mg/m2/剂量，每日2次或每日3次。婴儿继续服用阿昔洛韦6个月，并在12个月大时接受神经学预后评估。对18名婴儿进行了研究。在每天接受三次阿昔洛韦治疗的16名患者中，有13名(81%)没有皮肤复发(54%的未经治疗的历史对照组)。16例中有2例(12%)1~2次复发，1例失访。18名患者中有13名在一岁时可以进行评估，所有人都发育正常。本研究的目的是观察标准疗法(阿昔洛韦20 mg/kg/剂量，每8小时静脉注射14天)，然后随机给予安慰剂或口服阿昔洛韦(300 mg/m2/剂量，每天3次)治疗6个月的患儿的预后。假设阿昔洛韦抑制治疗将显著减少复发次数，并将导致更好的神经学结果。主要终点是12个月龄时的神经学评估。次要终点是皮肤复发的次数和复发期间的脑脊液参数。每次复发，将停用“研究药物”(阿昔洛韦或安慰剂)，并根据脑脊液检查结果给予“开放标签”阿昔洛韦口服或静脉注射，这是目前的标准治疗。提供开放标签阿昔洛韦的安全监测和停药规则是协议的一部分。参赛者将被跟踪到5岁。计划进行两项带有适当统计考虑的中期分析。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Since the introduction of antiviral therapy for neonatal Herpes simplex virus (HSV) (type 1 and type 2) infection, dramatic improvements in morbidity and mortality have been realized. Improvements have been seen in disease limited to the skin, eye, and mucous membranes (SEM), disseminated disease, and central nervous system (CNS) disease. While mortality from SEM disease is essentially non-existent, neurologic morbidity can result from this form of HSV infection. Neurologic impairment occurs in almost 40% of untreated SEM infected infants even without clinically apparent central nervous system involvement. This is likely the consequence of insidious infection of the central nervous system during the neonatal period with undetected clinical reactivation later in life. Neurologic morbidity following SEM disease can be decreased with intravenous antiviral therapy, such that over 90% of such infants develops normally at one year of life. The impairment, which appears by one year of age, is not subtle, consisting of spasticity, microcephaly, and chorioretinitis. Even with the administration of antiviral therapy there is a direct correlation between the frequency of cutaneous recurrences following antiviral therapy and development of neurologic impairment among infants with SEM disease. Specifically, during the first year of life, the likelihood of developing normally is only 64% if there are three or more recurrences as opposed to no impairment with fewer recurrences. This, despite rigorous follow-up both clinically and frequent findings of normal cerebrospinal fluid (CSF) examinations), would imply the possibility of viral reactivation at sites other than the skin. The occurrence of neurologic sequelae in patients with disease localized to the SEM despite normal CSF findings and prompt treatment illustrates the inadequacies of current therapies. To try to further improve the neurologic outcome of infants with SEM disease, a pilot study of oral acyclovir at 300 mg/m2/dose given either twice daily or three times daily following 10 days of intravenous acyclovir was done. Infants remained on oral acyclovir for 6 months and were neurologically evaluated for outcome at 12 months of age. Eighteen infants were studied. Thirteen (81%) of the 16 who received acyclovir three times a day had no cutaneous recurrences (54% of untreated historical controls). Two (12%) of the 16 had one or two recurrences and one was lost to follow-up. Thirteen of the 18 patients were available for evaluation at one year of age and all were developing normally. The purpose of this study is to determine the outcome of infants with disease limited to the SEM who are treated intravenously with standard therapy (14 days of acyclovir at 20 mg/kg/dose every 8 hours) and then randomized to placebo or oral acyclovir (300 mg/m2/dose three times per day) for 6 months. The hypothesis is that acyclovir suppressive therapy will reduce significantly the number of recurrences and will result in better neurological outcomes. Primary endpoint is the neurologic assessment at 12 months of age. Secondary endpoints will be the number of cutaneous recurrences and CSF parameters during those recurrences. With each recurrence "study drug" (acyclovir or placebo) will be stopped and "open label" acyclovir oral or intravenous, depending on CSF findings, will be given which is standard of care at the present time. Safety monitoring and stopping rules with the offering of open label acyclovir are part of the protocol. Enrollees will be followed to age 5 years. Two interim analyses with appropriate statistical considerations are planned.