基因检测：快速鉴别细菌感染还是病毒感染

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发表在《JAMA》上的这项研究，发现了这两个称为IFI44L和FAM89A的基因只有当发生细菌感染时才转换至“开放”状态。这方面的知识使得医生可以区分细菌和病毒感染，并确定严重感染的早期病例，后者可能是致命性的。

虽然病毒感染比细菌感染更常见，但细菌感染往往更为严重。

脑膜炎、败血症、肺炎的发生都是细菌感染的结果。正确区分这些潜在的致命性感染和病毒可以让医疗机构提供更快速、更准确的治疗。

此外，正确区分一个人是发生了病毒感染还是细菌感染，还可以防止将抗生素处方用于病毒感染。抗生素只对细菌有效，而对病毒引起的感染，如感冒、流感、咽喉痛、支气管炎和许多鼻窦和耳部感染均无效。

处方对病毒感染无效的抗生素无法治愈包病毒感染，也无法预防生病，可能还会带来不必要的和有害的副作用，且可能有助于产生抗生素耐药性，一旦出现抗生素耐药性，细菌就可以抵抗抗生素的作用并继续对身体健康造成伤害。

抗生素是最常用的处方药。然而，高达50%的抗生素使用是不需要的，所用剂量是不正确的，且在错误的时间使用。

在美国，每年都有超过200万人发生对抗生素耐药的的细菌感染，至少有23,000人直接死于此类感染。

许多孩子被误诊为病毒感染

目前，当一个孩子因为发烧去看医生或看急诊时，没有什么快速方法可以确定孩子到底患的是细菌性抑或是病毒性疾病。

诊断依赖于血液或脊髓液样本，样本被送到实验室，并需要等待超过48小时才能看到样品中是否有细菌生长。

来自帝国理工学院医学系的Michael Levin教授负责这项研究，他解释说：“发烧是孩子们被带到医院看病的最常见原因之一。然而，每年都有许多孩子从急诊科或是医生的手术台上被送走，因为医疗团队认为他们是病毒性感染，而事实上，他们正在遭受着危及生命的细菌感染——而这往往太迟被诊断。”

“相反，许多其他孩子被送往医院并接受抗生素治疗，因为医疗团队无法立即排除细菌感染的可能性——但事实上，他们正遭受的是病毒感染，”他补充说。

在儿科感染性疾病科工作的Levin继续说道，虽然研究还处于早期阶段，但研究结果已经表明，细菌感染可以通过使用一种应对感染转换为“开放”或“关闭”的基因与其他发烧的原因（包括病毒感染）区别开来。

“目前面临的挑战是如何将我们的研究结果转化为一个可用于医院急诊科或全科医生手术的诊断性检测，确定哪些孩子需要使用抗生素，”Levin补充说。

两种基因预测细菌感染的准确度高达95-100 %

科学家们对240名分别来自英国、西班牙、荷兰和美国的因为发烧而到医院就诊的儿童进行了研究，这些儿童的平均年龄为19个月。

在使用传统方法确定孩子是否有细菌或病毒感染之后，研究人员分析了他们白细胞中已处于开放状态的基因。

通过使用RNA微阵列法——仅用一小滴血就可以同时检测48,000个基因的变化的，研究小组发现了两种基因在细菌感染过程中转换至开放状态。进一步调查表明，这两种基因预测细菌感染的准确度高达95-100 %。

该研究的共同作者，来自帝国理工学院儿科感染性疾病的高级讲师Jethro Herberg博士说：“我们正在面临着耐抗生素细菌日益增长的威胁。很大一部分抗生素的使用是由于我们无法可靠将少数细菌感染的儿童与大部分病毒感染的儿童区分开来，这部分儿童是不需要抗生素的。”

“害怕漏诊致命性的感染如脑膜炎和败血症，使得医生经常处方抗生素并进行腰椎穿刺等诊断性操作以求结果安全。基于我们已经确定的两种基因的快速检测技术可以彻底改变儿科的做法，使得我们只给那些的确存在细菌感染的儿童使用抗生素。”Jethro Herberg博士如是说。

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Preliminary Communication | August 23/30, 2016
INNOVATIONS IN HEALTH CARE DELIVERY
Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children
Jethro A. Herberg, PhD1; Myrsini Kaforou, PhD1; Victoria J. Wright, PhD1; Hannah Shailes, BSc1; Hariklia Eleftherohorinou, PhD1; Clive J. Hoggart, PhD1; Miriam Cebey-López, MSc2,3; Michael J. Carter, MRCPCH1; Victoria A. Janes, MD1; Stuart Gormley, MRes1; Chisato Shimizu, MD4,5; Adriana H. Tremoulet, MD4,5; Anouk M. Barendregt, BSc6; Antonio Salas, PhD2,3,7; John Kanegaye, MD4,5; Andrew J. Pollard, PhD8,9; Saul N. Faust, PhD10,11; Sanjay Patel, FRCPCH11; Taco Kuijpers, PhD6,12; Federico Martinón-Torres, PhD2,3; Jane C. Burns, MD4,5; Lachlan J. M. Coin, PhD13; Michael Levin, FRCPCH1 ; for the IRIS Consortium
[+] Author Affiliations
JAMA. 2016;316(8):835-845. doi:10.1001/jama.2016.11236.

http://jama.jamanetwork.com/article.aspx?articleid=2545687

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Importance  Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others.

Objective  To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children.

Design, Setting, and Participants  Febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets.

Exposures  A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis.

Main Outcomes and Measures  Definite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group.

Results  The discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller (2-transcript) signature (FAM89A and IFI44L) was identified by removing highly correlated transcripts. When this 2-transcript signature was implemented as a disease risk score in the validation group (130 children, with 23 definite bacterial, 28 definite viral, and 79 indeterminate infections; median age, 17 months; 57% male), all 23 patients with microbiologically confirmed definite bacterial infection were classified as bacterial (sensitivity, 100% [95% CI, 100%-100%]) and 27 of 28 patients with definite viral infection were classified as viral (specificity, 96.4% [95% CI, 89.3%-100%]). When applied to additional validation datasets from patients with meningococcal and inflammatory diseases, bacterial infection was identified with a sensitivity of 91.7% (95% CI, 79.2%-100%) and 90.0% (95% CI, 70.0%-100%), respectively, and with specificity of 96.0% (95% CI, 88.0%-100%) and 95.8% (95% CI, 89.6%-100%). Of the children in the indeterminate groups, 46.3% (63/136) were classified as having bacterial infection, although 94.9% (129/136) received antibiotic treatment.

Conclusions and Relevance  This study provides preliminary data regarding test accuracy of a 2-transcript host RNA signature discriminating bacterial from viral infection in febrile children. Further studies are needed in diverse groups of patients to assess accuracy and clinical utility of this test in different clinical settings.