Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children.
Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children.
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DOI：
10.1001/jama.2016.11236
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发表时间：
2016-08-23
期刊：
影响因子：
--
通讯作者：
IRIS Consortium
中科院分区：
文献类型：
--
作者：
Herberg JA;Kaforou M;Wright VJ;Shailes H;Eleftherohorinou H;Hoggart CJ;Cebey-López M;Carter MJ;Janes VA;Gormley S;Shimizu C;Tremoulet AH;Barendregt AM;Salas A;Kanegaye J;Pollard AJ;Faust SN;Patel S;Kuijpers T;Martinón-Torres F;Burns JC;Coin LJ;Levin M;IRIS Consortium
由于临床特征无法可靠地区分细菌和病毒感染，世界各地的许多儿童接受了不必要的抗生素治疗，而其他儿童却忽视了细菌感染。识别发热儿童中区分细菌和病毒感染的血液 RNA 表达特征。前瞻性招募了 2009 年至 2013 年间在英国、西班牙、荷兰和美国的参与医院就诊的发热儿童，包括发现组和验证组。经过微生物学调查后将各组分类为确定的细菌感染、确定的病毒感染或不确定的感染。在发现组中确定了区分特定细菌和病毒感染的 RNA 表达特征，并在验证组中评估了诊断性能。在对患有脑膜炎球菌病 (n=24) 和炎症性疾病 (n=48) 的儿童的单独研究中以及已发表的基因表达数据集上进行了额外的验证。根据临床和微生物学诊断评估了区分细菌感染和病毒感染的 2 转录本 RNA 表达特征。通过病原体培养或分子检测证实确定的细菌和病毒感染。在确定的细菌和病毒组以及不确定组中评估了 RNA 特征的性能。研究对象包括 240 名儿童（中位年龄 19 个月，62% 为男性），其中 52 名患有明确的细菌感染，其中 36 名（69%）需要重症监护； 92 名确诊病毒感染者，其中 32 名（35%）需要重症监护。 96名儿童患有不确定感染。 RNA 表达数据的生物信息分析确定了区分细菌和病毒感染的 38 个转录本特征。通过删除高度相关的转录本，鉴定出较小的（2 转录本）签名（FAM89A 和 IFI44L）。当在验证组（130 名儿童，包括 23 名细菌性儿童、28 名病毒性儿童、79 名不确定儿童；中位年龄 17 个月，57% 为男性）中将此 2 转录本签名实施为疾病风险评分时，在所有 23 名微生物学确诊的明确细菌患者中均发现了细菌感染，敏感性为 100%（95% 置信区间 [CI]，100 - 100），并且在 28 名儿童中的 1 名中发现了细菌感染。明确的 病毒患者，特异性为 96.4% (95% CI, 89.3 – 100)。当应用于脑膜炎球菌和炎症性疾病患者的其他验证数据集时，细菌感染的敏感性分别为 91.7% (79.2-100) 和 90.0% (70.0-100)，特异性为 96.0% (88.0-100) 和 95.8% (89.6-100)。不确定组中的少数儿童被归类为细菌感染（136 名中的 63 名，46.3%），尽管大多数儿童接受了抗生素治疗（136 名中的 129 名，94.9%）。这项研究提供了关于 2 转录本宿主 RNA 特征区分发热儿童细菌和病毒感染的测试准确性的初步数据。需要对不同的患者群体进行进一步的研究，以评估该测试在不同临床环境中的准确性和临床实用性。
As clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment whilst bacterial infection is missed in others. To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children. Febrile children presenting to participating hospitals in UK, Spain, Netherlands and USA between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation into definite bacterial, 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) inflammatory diseases (n=48), and on published gene expression datasets. A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis. 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 the indeterminate group. The discovery cohort of 240 children (median age 19 months, 62% males) 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. 96 children had indeterminate infection. Bioinformatic 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, including 23 bacterial, 28 viral, 79 indeterminate; median age 17 months, 57% males), bacterial infection was identified in all 23 microbiologically-confirmed definite bacterial patients, with a sensitivity of 100% (95% confidence interval [CI], 100 - 100), and in 1 of 28 definite viral patients, with specificity of 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% (79.2-100) and 90.0% (70.0-100) respectively, and with specificity of 96.0% (88.0-100) and 95.8% (89.6-100). A minority of children in the indeterminate group were classified as having bacterial infection (63 of 136, 46.3%), although most received antibiotic treatment (129 of 136, 94.9%). 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.
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影响因子：
3.7
作者：
Cebey-López M;Herberg J;Pardo-Seco J;Gómez-Carballa A;Martinón-Torres N;Salas A;Martinón-Sánchez JM;Gormley S;Sumner E;Fink C;Martinón-Torres F;GENDRES network
通讯作者：
GENDRES network
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
20.3
作者：
Ramilo, Octavio;Allman, Windy;Chaussabel, Damien
通讯作者：
Chaussabel, Damien
DOI：
10.1093/infdis/jiv047
发表时间：
2015-07-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Suarez NM;Bunsow E;Falsey AR;Walsh EE;Mejias A;Ramilo O
通讯作者：
Ramilo O
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y