人类疱疹病毒4感染对宫颈癌影响的Meta分析和临床研究

Meta-analysis and clinical study on the association of Epstein-Barr virus infection with the risk of cervical cancer

关键词:  宫颈癌  宫颈上皮内肿瘤  人类疱疹病毒4  人乳头瘤病毒  Meta分析

Key words:  cervical carcinoma  cervical intraepithelial neoplasms  Epstein-Barr virus  human papilloma virus  Meta analysis

摘要:

目的 探讨人类疱疹病毒4(Epstein-Barr virus, EBV)感染对宫颈癌变风险的影响。方法 根据关键词从PubMed、Web of Science检索相关文献，提取信息，采用Stata和RevMan软件进行Meta分析。同时采集40例临床确诊病例的组织样本进行EB病毒编码的小RNA(Epstein-Barr encoded RNA, EBER)检测，采集30例确诊病例的血液样本进行衣壳抗原(VCA)-IgM等抗体检测，并统计不同病程患者的感染率。结果 共16篇文献纳入Meta分析，包含2 199个病例。正常人、低级别鳞状上皮内病变（low-grade squamous intraepithelial lesion, LSIL）、高级别鳞状上皮内病变(high-grade squamous intraepithelial lesion, HSIL)、宫颈癌（squamous carcinoma of the cervix, SCC）患者中单纯EBV感染率分别为20.4%（95%CI: 0.0580.402）、9.8%（95%CI: 0.0290.193）、5.5%（95%CI: 0.0060.133）、3.2%（95%CI: 0.0060.071）；EBV和HPV共感染率分别为2.3%（95%CI: 0.0010.060）、14.9%（95%CI: 0.0860.221）、33.4%（95%CI: 0.2320.443）、42.0%（95%CI: 0.2790.567）。LSIL、HSIL和SCC患者中合并感染的致病风险分别是HPV单纯感染的0.77倍（95%CI: 0.630.94，P<0.05）、1.25倍（95%CI: 0.851.85，P=0.25）和1.49倍（95%CI: 0.942.35，P=0.09）。细胞刷法和宫颈拭子法采集的样本EBV检出率分别为36.9%（95%CI: 0.2190.532）和23.8%（95%CI: 0.0820.442）。40个临床患者病变组织的EBER检测结果显示无阳性，临床LSIL、HSIL和SCC患者血清VCA-IgM抗体阳性率分别为50%（1/2）、25%（6/24）和0（0/4）。结论 EBV与HPV共感染会增加宫颈癌发生和发展的风险，但单纯EBV感染与疾病进展的相关性不明显；EBV可能并不直接攻击宫颈上皮细胞。研究结果提示在EBV检样采集时细胞刷法敏感性高于宫颈拭子。

Abstract:

Objective To investigate the association of Epstein-Barr virus 4(EBV) infection with the risk of cervical cancer. Methods Relevant articles were searched from PubMed and Web of Science, information was extracted, and Meta-analysis was performed using Stata and RevMan software. Meanwhile, tissue samples from 40 clinically confirmed cervical cancer patients were collected for Epstein-Barr encoded RNA(EBER) testing. In addition, blood samples from 30 confirmed cases were collected for antibodies testing, including capsid antigen(VCA)-IgM, and the infection rate of EBV was calculated. Results A total of 16 articles involving 2 199 cases were included for Meta-analysis. The EBV infection rates in normal individuals, patients with low-grade squamous intraepithelial lesions(LSIL), high-grade squamous intraepithelial lesions(HSIL), and squamous cervical cancer(SCC) were 20.4%(95%CI: 0.058-0.402), 9.8%(95%CI: 0.029-0.193), 5.5%(95%CI: 0.006-0.133) and 3.2%(95%CI: 0.006-0.071), respectively; the co-infection rates of EBV and HPV were 2.3%(95%CI: 0.001-0.060), 14.9%(95%CI: 0.086-0.221), 33.4%(95%CI: 0.232-0.443) and 42.0%(95%CI: 0.279-0.567), respectively. The risk ratios of co-infection rate of EBV and HPV in patients with LSIL, HSIL, and SCC were 0.77 times(95%CI: 0.63-0.94, P<0.05), 1.25 times(95%CI: 0.85-1.85, P=0.25), and 1.49 times(95%CI: 0.94-2.35, P=0.09) higher than that of HPV infection alone, respectively. The detection rates of EBV in samples collected by cell brush method and cervical swab method were 36.9%(95%CI: 0.219-0.532) and 23.8%(95%CI: 0.082-0.442), respectively. No positive was detected in 40 clinical cases by EBER. The positive rates of serum VCA-IgM in LSIL, HSIL, and SCC patients were 50%(1/2), 25%(6/24), and 0(0/4), respectively. Conclusion Co-infection of EBV and HPV increases the risk of cervical cancer occurrence and development, however, no significant correlation between EBV infection alone and disease progression was observed. The study indicates that EBV may not directly attack cervical epithelial cells in the pathogenic pathway. Results also suggest that the sensitivity of the cell brush method was higher than that of cervical swabs when collecting EBV test samples.