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

仅限于皮肤、眼睛和口腔的新生儿单纯疱疹病毒感染

• 批准号: 7378813
• 负责人: Timothy G Townsend
• 金额: $ 0.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378813
• 关键词: NEONATAL; HERPES; SIMPLEX; VIRUS; INFECTION

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。自从针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着改善。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) 疾病已得到改善。虽然 SEM 疾病基本上不存在死亡率，但这种形式的 HSV 感染可能导致神经系统发病。即使没有临床上明显的中枢神经系统受累，近 40% 未经治疗的 SEM 感染婴儿也会出现神经系统损伤。这很可能是新生儿时期中枢神经系统隐匿感染，并在以后的生活中未被发现的临床再激活的结果。通过静脉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发育正常。这种损伤在一岁时出现，并不轻微，包括痉挛、小头畸形和脉络膜视网膜炎。即使进行抗病毒治疗，在患有 SEM 疾病的婴儿中，抗病毒治疗后皮肤复发的频率与神经系统损伤的发生之间也存在直接相关性。具体而言，在生命的第一年，如果出现 3 次或以上复发，则正常发育的可能性仅为 64%，而如果复发次数较少，则没有损害。尽管进行了严格的临床随访和正常脑脊液（CSF）检查的频繁发现，但这仍然意味着病毒在皮肤以外的部位重新激活的可能性。尽管脑脊液检查结果正常并且及时治疗，但患有局限于 SEM 的疾病的患者仍出现神经系统后遗症，这说明了当前治疗的不足。为了进一步改善患有 SEM 疾病的婴儿的神经系统结果，进行了一项初步研究，在静脉注射阿昔洛韦 10 天后，每天两次或每天三次口服阿昔洛韦 300 mg/m2/剂量。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。对十八名婴儿进行了研究。每天接受阿昔洛韦治疗 3 次的 16 人中，有 13 人 (81%) 未出现皮肤复发（未经治疗的历史对照组为 54%）。 16 例中有 2 例 (12%) 出现一两次复发，其中 1 例失访。 18 名患者中有 13 名在一岁时即可接受评估，并且全部发育正常。本研究的目的是确定患有局限于 SEM 的疾病的婴儿的结局，这些婴儿接受标准疗法静脉注射（阿昔洛韦 20 mg/kg/剂，每 8 小时 14 天），然后随机接受安慰剂或口服阿昔洛韦（300 mg/m2/剂，每天 3 次），持续 6 个月。假设阿昔洛韦抑制治疗将显着减少复发次数，并带来更好的神经学结果。主要终点是 12 个月大时的神经系统评估。次要终点是皮肤复发的次数和这些复发期间的脑脊液参数。每次复发时，将停止“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，这是目前的标准护理。提供开放标签阿昔洛韦的安全监测和停止规则是该方案的一部分。参与者将被跟踪至 5 岁。计划进行两项具有适当统计考虑的中期分析。