A novel cause of chronic viral meningoencephalitis: Cache Valley virus.

Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients. We present the case of a 34‐year‐old man with X‐linked agammaglobulinemia from Australia suffering from 3 years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen. Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue. Cache Valley virus, a mosquito‐borne orthobunyavirus, has only been identified in 3 immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self‐limiting meningitis to a rapidly fatal meningoencephalitis with multiorgan failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Our research subject traveled to North and South Carolina and Michigan in the weeks prior to the onset of his illness. This report demonstrates that metagenomic next generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes. Ann Neurol 2017;82:105–114

免疫缺陷患者尤其易受神经侵袭性感染，这些感染可能难以诊断。宏基因组新一代测序能够识别不常见或新型微生物，因此非常适合用于研究免疫缺陷患者慢性脑膜脑炎的病因。 我们介绍一名来自澳大利亚的34岁男性X连锁无丙种球蛋白血症患者的病例，该患者患脑膜脑炎3年，尽管进行了广泛的常规检测，包括脑活检，但病因诊断不明。对其脑脊液和脑活检组织进行了宏基因组新一代测序以确定病原体。 通过宏基因组新一代测序鉴定出与多个峡谷热病毒基因匹配的序列。逆转录聚合酶链反应和免疫组织化学随后证实脑活检组织中存在峡谷热病毒。 峡谷热病毒是一种由蚊子传播的正布尼亚病毒，此前仅在3名有免疫能力的北美急性神经侵袭性疾病患者中被发现。报道的病情严重程度从自限性脑膜炎到伴有多器官衰竭的快速致命性脑膜脑炎不等。此前从未发现该病毒在人类中引起慢性全身性或神经性感染。峡谷热病毒此前也从未在澳大利亚大陆被检测到。我们的研究对象在发病前几周去过北卡罗来纳州、南卡罗来纳州和密歇根州。本报告表明，宏基因组新一代测序可实现无偏倚的病原体识别，在新出现的病毒传播到新地区时早期检测到它们，并发现新的疾病表型。《神经病学年鉴》2017年；82卷：105 - 114页