Screening for congenital cytomegalovirus infection using newborn urine samples collected on filter paper: feasibility and outcomes from a multicentre study.
Screening for congenital cytomegalovirus infection using newborn urine samples collected on filter paper: feasibility and outcomes from a multicentre study.
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DOI：
10.1136/bmjopen-2011-000118
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发表时间：
2011-07-29
期刊：
影响因子：
2.9
通讯作者：
Japanese Congenital Cytomegalovirus Study Group
中科院分区：
文献类型：
--
作者：
Koyano S;Inoue N;Oka A;Moriuchi H;Asano K;Ito Y;Yamada H;Yoshikawa T;Suzutani T;Japanese Congenital Cytomegalovirus Study Group
由于先天性巨细胞病毒（CMV）感染不仅在出生时而且在以后作为神经系统后遗症引起显著的临床后果，因此建立筛查先天性感染新生儿的策略至关重要。先前的研究已经确定了基于使用干血斑（DBS）的筛查方法的灵敏度不足。评估作者最近开发的用于大规模筛查先天性CMV感染的方法的可行性，并确定先天性感染的危险因素。在日本六个地理上独立的地区的25个地点登记了21000多名新生儿。将尿液收集到放置在尿布中的过滤卡上，然后使用过滤盘直接作为模板通过定量PCR进行分析。新生儿的临床和体格检查结果摘自其医疗记录。对来自病例及其兄弟姐妹的CMV毒株进行遗传比较。从一些病例中获得的DBS中的病毒载量与尿液过滤器中的病毒载量进行了比较。先天性CMV感染的发生率为0.31%（95%CI 0.24%~ 0.39%），30%（20/66）的患儿出生时有典型的临床表现和/或脑影像学异常。虽然我们的筛查的阳性预测值为94%，但由于缺乏与金标准测定的任何比较，因此无法计算阴性预测值。几乎三分之二的病例有兄弟姐妹，这一频率明显高于未感染的新生儿。大多数病例（21/25）排出的CMV株与其同胞的CMV株相同。在12份可回收DBS标本中，有3份未检出CMV DNA。实施有效的大规模先天性CMV感染筛查计划是可行的。麻疹是先天性巨细胞病毒感染的主要危险因素，这强调了对母亲的教育以及疫苗开发的必要性。关键是要建立一个战略，筛选新生儿感染先天性巨细胞病毒（CMV），因为他们有发展神经后遗症的风险。然而，由于新生儿CMV筛查干血斑的基础上的灵敏度不足，一种替代方法，使用尿液标本的可行性需要进行评估。不仅需要人群流行病学研究，而且需要前瞻性分子研究来阐明先天性CMV感染的传播途径。将尿液样本收集到放置在尿布中的过滤卡上，使得大规模筛查先天性CMV感染可行且有效，而不会影响检测灵敏度。每300名新生儿中就有1名先天性感染CMV，在CMV血清阳性率为70%的社会中，30%的病例有症状，表明先天性CMV感染的频率与唐氏综合征是同一水平的医学问题。我们的直接分子证据表明，兄弟姐妹是先天性CMV感染的主要风险。这项多中心大规模筛选研究表明，我们的尿液过滤器为基础的方法是强大和可靠的。然而，由于缺乏与金标准测定的任何比较，无法确定假阴性结果的确切频率。对母亲的血清学研究需要与新生儿筛查相结合，以确认传播是否主要通过母亲原发感染发生。
As congenital cytomegalovirus (CMV) infection causes significant clinical consequences not only at birth but also later as neurological sequelae, it is critical to establish a strategy for screening congenitally infected newborns. Previous studies have identified an insufficient sensitivity in screening methods based on the use of dried blood spots (DBSs). To evaluate the feasibility of the authors' recently developed method for large-scale screening for congenital CMV infection and to identify risk factors for congenital infection. More than 21 000 newborns were enrolled at 25 sites in six geographically separate areas of Japan. Urine was collected onto filter cards placed in the diapers, which were then analysed by quantitative PCR using the filter disc directly as a template. Clinical and physical findings of the newborns were extracted from their medical records. CMV strains from the cases and their siblings were genetically compared. Viral loads in DBSs obtained from some of the cases were compared with those in the urine filters. Congenital CMV infection was identified in 0.31% (95% CI 0.24% to 0.39%) of the newborns, and 30% of the cases (20/66) had typical clinical manifestations and/or showed abnormalities in brain images at birth. Although the positive predictive value of our screening was 94%, the lack of any comparison with a gold standard assay prevented calculation of the negative predictive value. Almost two-thirds of the cases had siblings, a significantly higher frequency than for uninfected newborns. Most of the cases (21/25) excreted CMV strains identical to those of their siblings. CMV DNA was undetectable in three out of 12 retrievable DBS specimens. Implementation of an effective large-scale screening programme for congenital CMV infection is feasible. Siblings are the major risk factor for congenital CMV infection, which emphasises the need for education of mothers-to-be as well as vaccine development. It is critical to establish a strategy for screening newborns infected congenitally with cytomegalovirus (CMV), as they are at risk for the development of neurological sequelea. However, because of the insufficient sensitivity of newborn CMV screening based on dried blood spots, the feasibility of an alternative approach using urine specimens needs to be evaluated. Not only population-based epidemiological studies, but also prospective molecular studies, are necessary to clarify the transmission routes of congenital CMV infection. Collection of urine specimens onto filter cards placed in the diapers made large-scale screening for congenital CMV infection feasible and effective without compromising detection sensitivity. One out of every 300 newborns is congenitally infected with CMV, and 30% of the cases were symptomatic in the society where the CMVseroprevalence is 70%, indicating that the frequency of congenital CMV infections is a medical problem of the same level as Down's syndrome. Our direct molecular evidence indicates that siblings are the major risk for congenital CMV infection. This multicentre large-scale screening study demonstrates that our urine-filter-based method is robust and reliable. However, the lack of any comparison with a gold standard assay prevented the determination of the exact frequency of false-negative results. Serological studies on mothers need to be combined with newborn screening to confirm whether transmission predominantly occurs via maternal primary infection.
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