Hixon Alison M, Clarke Penny, Tyler Kenneth L
Medical Scientist Training Program.
Neuroscience Program.
J Infect Dis. 2017 Dec 5;216(10):1245-1253. doi: 10.1093/infdis/jix468.
Enterovirus D68 (EV-D68)-associated acute flaccid myelitis (AFM) is a devastating neurological disease for which there are no treatments of proven efficacy. The unpredictable temporal and geographic distribution of cases and the rarity of the disease make it unlikely that data from randomized controlled trials will be available to guide therapeutic decisions. We evaluated the following 3 widely used empirical therapies for the ability to reduce the severity of paralysis in a mouse model of EV-D68 infection: (1) human intravenous immunoglobulin (hIVIG), (2) fluoxetine, and (3) dexamethasone.
Neonatal mice were injected intramuscularly with a human 2014 EV-D68 isolate that reliably induces paralysis in mice due to infection and loss of spinal cord motor neurons. Mice receiving treatments were evaluated for motor impairment, mortality, and spinal cord viral load.
hIVIG, which contained neutralizing antibodies to EV-D68, reduced paralysis in infected mice and decreased spinal cord viral loads. Fluoxetine had no effect on motor impairment or viral loads. Dexamethasone treatment worsened motor impairment, increased mortality, and increased viral loads.
Results in this model of EV-D68-associated AFM provide a rational basis for selecting empirical therapy in humans and establish this model as a useful system for evaluating other potential therapies.
肠道病毒D68(EV-D68)相关急性弛缓性脊髓炎(AFM)是一种严重的神经系统疾病,目前尚无经证实有效的治疗方法。病例的时间和地理分布不可预测,且该疾病罕见,因此不太可能获得来自随机对照试验的数据来指导治疗决策。我们评估了以下3种广泛使用的经验性疗法在EV-D68感染小鼠模型中减轻瘫痪严重程度的能力:(1)人静脉注射免疫球蛋白(hIVIG),(2)氟西汀,以及(3)地塞米松。
给新生小鼠肌肉注射一株2014年的人源EV-D68分离株,该分离株因感染和脊髓运动神经元丧失而能可靠地诱导小鼠瘫痪。对接受治疗的小鼠进行运动功能障碍、死亡率和脊髓病毒载量评估。
含有针对EV-D68的中和抗体的hIVIG减轻了感染小鼠的瘫痪程度,并降低了脊髓病毒载量。氟西汀对运动功能障碍或病毒载量没有影响。地塞米松治疗使运动功能障碍恶化,增加了死亡率,并增加了病毒载量。
该EV-D68相关AFM模型的结果为选择人类经验性治疗提供了合理依据,并将该模型确立为评估其他潜在疗法的有用系统。