临床宏基因组测序在脑膜炎和脑炎诊断中的应用。
Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.
机构信息
From the Departments of Neurology (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), Biochemistry and Biophysics (H.A.S., K.C.Z., J.L.D.), Laboratory Medicine (S.A., G.Y., S.F., D.S., B.B., B.H., S.M., C.Y.C.), and Epidemiology and Biostatistics (J.N.), the Department of Medicine, Division of Infectious Diseases (C.L., C.Y.C.), the Department of Medicine, Division of Hospital Medicine (A.B.), and Weill Institute for Neurosciences (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), University of California, San Francisco (UCSF), UCSF-Abbott Viral Diagnostics and Discovery Center (S.A., G.Y., S.F., D.S., B.B., C.Y.C.), the Chan Zuckerberg Biohub (C.L., J.L.D.), and Zuckerberg San Francisco General Hospital (B.H.), San Francisco, the School of Public Health, University of California, Berkeley, Berkeley (B.D.F.), Children's Hospital Los Angeles (S.N.N., J.B., J.D.B.), the Department of Medicine, Division of Infectious Diseases (J.M., M.C., T.V., P.R.A., J.D.K.), and the Departments of Neurology (P.M.V.) and Pathology and Laboratory Medicine (S.C., R.M.H.), University of California, Los Angeles, Los Angeles, and the Departments of Pathology and Laboratory Medicine (C.D.G., F.M., N.A.O., C.R.P.) and Neurological Surgery (L.L.Z.) and the Department of Internal Medicine, Division of Infectious Diseases (S.H.C., C.R.P.), University of California, Davis, Davis - all in California; the Children's National Medical Center and George Washington University School of Medicine, Washington, DC (R.L.D.); St. Jude Children's Research Hospital, Memphis, TN (R.D., G.M., R.H.); and Children's Hospital Colorado, Aurora (K.M., S.R.D.).
出版信息
N Engl J Med. 2019 Jun 13;380(24):2327-2340. doi: 10.1056/NEJMoa1803396.
BACKGROUND
Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.
METHODS
In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review.
RESULTS
We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment.
CONCLUSIONS
Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).
背景
对脑脊液（CSF）进行宏基因组下一代测序（NGS）有可能在单次检测中鉴定出广泛的病原体。
方法
在一项为期 1 年的多中心前瞻性研究中，我们研究了 CSF 宏基因组 NGS 对住院患者感染性脑膜炎和脑炎的诊断价值。通过正交实验室检测对宏基因组 NGS 检测到的所有病原体阳性结果进行确认。通过电话会议和临床微生物测序委员会的调查收集医生反馈。通过回顾性病历审查评估临床效果。
结果
我们在 8 家医院招募了 204 名儿科和成人患者。患者病情严重：48.5%被收住重症监护病房，所有研究患者的 30 天死亡率为 11.3%。在 57 名患者中诊断了 58 例神经系统感染（27.9%）。在这 58 例感染中，宏基因组 NGS 鉴定出了 13 例（22%）在源医院的临床检测中未识别的感染。在其余的 45 例（78%）感染中，宏基因组 NGS 做出了 19 例合并诊断。在未通过宏基因组 NGS 识别的 26 例感染中，有 11 例仅通过血清学检测诊断，7 例通过 CSF 以外的组织样本诊断，8 例由于 CSF 中病原体滴度低而在宏基因组 NGS 上呈阴性。仅通过宏基因组 NGS 做出的 13 项诊断中的 8 项具有可能的临床效果，其中 7 项指导了治疗。
结论
常规微生物学检测通常不足以检测所有神经侵袭性病原体。在这项研究中，从脑膜炎或脑炎患者中获取的 CSF 进行宏基因组 NGS 提高了神经系统感染的诊断，并在某些情况下提供了可操作的信息。（由美国国立卫生研究院等资助；PDAID ClinicalTrials.gov 编号，NCT02910037。）
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