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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。自从对新生儿单纯疱疹病毒（HSV）（1型和2型）感染引入抗病毒治疗以来，发病率和死亡率已得到显著改善。在局限于皮肤、眼睛和粘膜（SEM）的疾病、播散性疾病和中枢神经系统（CNS）疾病中观察到改善。虽然SEM疾病的死亡率基本上是不存在的，但这种形式的HSV感染可导致神经系统疾病。几乎40%未经治疗的SEM感染婴儿发生神经功能损害，即使临床上没有明显的中枢神经系统受累。这可能是新生儿期中枢神经系统潜伏感染的结果，在生命后期未检测到临床再激活。静脉内抗病毒治疗可以降低SEM疾病后的神经系统发病率，因此超过90%的此类婴儿在一岁时正常发育。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。即使给予抗病毒治疗，抗病毒治疗后皮肤复发的频率与SEM疾病婴儿神经功能缺损的发展之间也存在直接相关性。具体来说，在生命的第一年，如果有三次或三次以上的复发，正常发展的可能性只有64%，而不是没有损伤，复发较少。尽管进行了严格的临床随访和频繁的正常脑脊液（CSF）检查结果，但这意味着在皮肤以外的部位可能存在病毒再活化。尽管CSF检查结果正常并及时治疗，但局限于SEM的疾病患者仍发生神经系统后遗症，这说明了当前治疗的不足。为了进一步改善SEM疾病婴儿的神经功能结局，进行了一项初步研究，在静脉注射阿昔洛韦10天后，以300 mg/m2/剂量口服阿昔洛韦，每日两次或每日三次。婴儿继续口服阿昔洛韦6个月，并在12个月大时进行神经学评估。研究了18名婴儿。16名接受阿昔洛韦每日三次治疗的患者中有13名（81%）没有皮肤复发（54%为未经治疗的历史对照）。16例患者中有2例（12%）出现1次或2次复发，1例失访。18例患者中有13例在1岁时可供评估，所有患者均发育正常。本研究的目的是确定患有限于SEM的疾病的婴儿的结果，这些婴儿用标准疗法（每8小时20 mg/kg/剂量的阿昔洛韦14天）静脉内治疗，然后随机接受安慰剂或口服阿昔洛韦（300 mg/m2/剂量，每天三次）6个月。假设无环鸟苷抑制治疗将显著减少复发的数量，并将导致更好的神经功能结局。主要终点是12个月龄时的神经系统评估。次要终点为皮肤复发次数和复发期间的CSF参数。每次复发时，将停用“研究药物”（阿昔洛韦或安慰剂），并根据CSF结果给予“开放标签”阿昔洛韦口服或静脉给药，这是目前的标准治疗。安全监测和停止规则与开放标签阿昔洛韦的提供是该协议的一部分。入组者将被随访至5岁。计划进行两次中期分析，并考虑适当的统计学因素。

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.