Current status of maternal colonization with group B Streptococcus and new advances in prevention and treatment
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摘要:
B族链球菌(group B Streptococcus,GBS)是导致新生儿感染的主要病原体之一。在世界范围内,GBS在孕妇体内广泛定植,可定植在孕妇的消化道和泌尿生殖道,并在一定条件下由定植状态转变为感染状态,对孕产妇和新生儿的健康造成巨大影响。本研究介绍了GBS的生物学特征和流行病学特点,并对孕妇妊娠期GBS筛查、分娩时应用抗生素预防,以及GBS疫苗研制的现状进行了阐述,提出孕期GBS疫苗接种或将成为降低新生儿GBS病的有效手段,且结合规范、有效的筛查及产时抗生素预防,有望大幅减少孕产妇和新生儿的GBS感染。
Abstract:Group B Streptococcus (GBS) is the leading cause of newborn infection. GBS colonizes pregnant women worldwide and GBS can colonize in their maternal genitourinary and urogenital tracts. GBS can transit from an asymptomatic commensal member of the mucosal biome to a pathogenic bacterium under certain conditions, causing a high burden of neonatal and infant disease globally. Although antepartum screening for GBS and intrapartum antibiotic prophylaxis reduced the incidence of perinatal GBS disease, there are still many problems in practice, such as long testing time, delayed antibiotics use, and antibiotic resistance. This review introduces GBS colonization, biological characteristics, epidemiology, antepartum screening, intrapartum antibiotic prophylaxis, and the current status of vaccine development. Implementing vaccination for pregnant women may be a promising strategy to prevent neonatal and infant GBS disease. In combination with standardized and effective screening and intrapartum antibiotic prophylaxis, vaccination is expected to significantly reduce the morbidity of maternal and neonatal GBS disease.
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B族链球菌(group B Streptococcus,GBS)又称无乳链球菌,是一种兼性厌氧的革兰阳性球菌,可间断性、一过性或持续性定植于消化道和生殖道。孕妇GBS定植是指孕妇于孕期在阴道、直肠或肛周取样培养GBS呈阳性。侵袭性GBS病是指在正常情况下无菌部位取样(如血液及脑脊液)培养呈GBS阳性,并伴随相关临床症状[1]。在一定条件下GBS可由定植状态转为条件致病菌,导致孕妇出现无症状性菌尿、膀胱炎、肾盂肾炎、菌血症、羊膜腔感染、肺炎、早产、产后子宫内膜炎、产后脓毒血症,以及胎儿宫内死亡[2]。对于孕妇GBS定植,若不加以干预,50%的患者会垂直传播至胎儿或新生儿,是导致新生儿早发型GBS病(GBS early-onset disease,GBS-EOD)的重要原因[2]。GBS的孕晚期筛查和产时抗生素的应用主要是为了切断产时的垂直传播,降低围产期新生儿感染GBS的可能性。目前,仍缺乏有效手段减少孕期GBS定植,多为定植转为感染状态、出现症状后才采取治疗措施。本文将回顾性分析孕妇妊娠期GBS定植及防治现状,以探寻更好的防治策略,降低GBS对孕母及新生儿的危害。
1. GBS的生物学特征和流行病学特点
GBS在全球范围内广泛分布,不同国家和地区的孕妇GBS定植率有所不同。2017年的一项系统评价纳入了来自85个国家的390篇研究,共涉及299 924例孕妇,研究显示全球孕产妇GBS定植率为18%(95% CI:17% ~ 19%),不同区域定植率存在差异,变化范围为11% ~ 35%,其中南亚地区和东亚地区定植率较低,分别为12.5%(95% CI:10.0% ~ 15.0%)和11.0%(95% CI:10.0% ~ 12.0%)[3]。一项纳入我国2001 — 2020年52篇文章,涉及195 303例妊娠期女性的meta分析显示,我国孕妇GBS的总定植率为8.1%(95% CI:7.2% ~ 8.9%)[4]。
B族链球菌作为一种革兰阳性球菌,具有富含唾液酸的荚膜多糖(capsular polysaccharide,CPS)。CPS是一种主要的毒力因子,通过抑制补体调节和通过与唾液酸结合免疫球蛋白型凝集素相互作用调节宿主免疫应答来保护GBS免受吞噬[5]。新生儿的原始免疫细胞可能将GBS的唾液酸识别为人类细胞的唾液酸,并允许细菌在体内存活,导致感染[6]。CPS除了在与宿主细胞表面的抗原表位结合侵入细胞发挥了巨大作用外,还是GBS血清学分类的依据。目前,GBS可识别的类型多达10种血清型。这些血清型的分布和优势株受变异影响,并且可以随时间改变。妊娠期间可能发生不同血清型类型的定植[7]。血清型Ⅰ ~ Ⅴ型占全球已确定的定植GBS分离株的98%[3]。血清型Ⅲ型与侵袭性疾病相关,GBS定植率占25%(95% CI:23% ~ 28%),但该流行株在一些南美和亚洲国家较少见。血清型Ⅵ ~ Ⅸ型则在亚洲更为常见[3]。
GBS作为一种阴道定植菌,阴道环境从酸性生态位到中性生态位的转变开启了GBS毒力相关基因,有利于GBS从共生细菌病原体向侵入性细菌病原体的转变。当女性合并阴道炎时会增加GBS的定植风险。2020年,Mohamed等[8]发现细菌性阴道病孕妇的阴道微生态失调伴随着链球菌患病率的增加。2014 — 2015年,在伦敦一个种族多元化地区,当地非洲裔孕妇的GBS定植率占39.5%,英国白人占27.4%,南亚人占23.3%[9],这种差异可能与不同种族人群阴道微生物群的不同有关[10],非洲裔女性的乳酸菌定植率则较低。此外,糖尿病、癌症、肾脏疾病、肥胖、高龄和免疫功能低下是妇女患侵袭性GBS病的高危因素[11]。
GBS在一定条件下可导致孕产妇及新生儿患侵袭性GBS病。孕妇GBS定植,若不加以干预,50%的患者会垂直传播给胎儿或新生儿,约98%的定植新生儿预后良好,而1% ~ 3%的定植新生儿患有GBS-EOD[2],可造成新生儿败血症和新生儿脑膜炎等[12]。GBS-EOD发生在新生儿出生至产后6 d内(≤ 6 d)。新生儿晚发型GBS病(GBS late-onset disease,GBS-LOD)发生在产后7 d至产后3月内。GBS在孕产妇中一般以定植状态存在,对孕产妇造成严重侵袭性疾病的几率较低。目前,尚缺乏孕产妇侵袭性GBS病发病率的具体数据。但在新生儿中,GBS感染是新生儿死亡的重要原因之一,目前临床上对于GBS的防治重点在于阻断孕妇与胎儿/新生儿间的垂直传播。全球新生儿GBS患病率分析显示,非洲新生儿GBS的感染率最高,约占活产新生儿的1.12‰,亚洲新生儿GBS的感染率最低,约占活产新生儿的0.3‰[13]。一项对2000 — 2017年报告的流行病学研究的荟萃分析显示,全球侵袭性新生儿GBS疾病的总体发病率占活产新生儿的0.49‰,与之相关的死亡率达8.4%[14]。母体GBS定植状态被认为是新生儿败血症的预测因素,并已纳入新生儿败血症的预测模型[15-16]。
全球每年有> 50万的新生儿死于早产,占5岁以下儿童死亡总数的44%[17]。大多数早产是由微生物感染引起的,其中10%是由GBS引起的[18-19]。在队列研究和横断面研究中,怀孕期间有GBS定植的妇女与没有GBS定植的妇女相比,早产的风险比为1.21。在病例对照研究中,与非定植组早产发生率比较,GBS定植组孕妇早产发生率较高,OR值为1.85。在患有GBS菌尿的妇女中观察到发生早产的风险比更高,OR值为1.98[20]。有关研究显示,产时抗生素预防(intrapartum antibiotic prophylaxis,IAP)可使GBS定植妇女所生婴儿的GBS-EOD风险降低86% ~ 89%[21],是目前预防新生儿GBS病的重要手段。
除早产外,GBS感染也是死产的重要原因之一。根据美国感染病协会在统计全球发病率及结合模型中的计算,每年至少有409 000例孕产妇/胎儿/婴儿病例和147 000例死产和婴儿死亡[22],GBS是孕产妇和新生儿不良结局的主要因素。
2. 妊娠期孕妇GBS筛查
孕妇GBS定植多无自觉症状,目前临床上关于GBS的防治工作重点在于预防新生儿定植和感染,而非预防孕妇GBS定植,而产时抗生素的预防是阻断垂直传播的主要手段。产时抗生素的使用主要基于GBS筛查结果或临床存在GBS感染的高危险因素。美国疾病控制与预防中心建议孕妇在妊娠晚期普遍采用核酸检测的方法或培养的方法来筛查GBS定植,以降低新生儿GBS的感染风险[21]。有多中心研究及系统综述提示,与基于风险的预防方案相比,基于普遍筛查的预防方案与GBS-EOD疾病的发病率较低相关,且没有明显地使妇女过度地暴露于抗生素[23-24]。目前,我国主要采用普遍筛查模式,即基于GBS筛查结果,对于筛查阳性者在阴道分娩时预防性应用抗生素以减少新生儿感染。
2021年版《预防围产期B链球菌病(中国)专家共识》建议在妊娠35 ~ 37周时对孕妇进行普通筛查取样,在不用窥阴器的情况下,同一拭子取阴道下1/3和直肠内样本[25],取样后需24 h内尽快送检,可采用培养及核酸扩增实验(nucleic acid amplification testing,NAAT)的方式来检测鉴定GBS,而国内一般采用富集培养的方法来筛查GBS。如用NAAT法来筛查GBS,据称有100%的敏感度和97.5%的特异度[26],1 ~ 2 h就能得到检测结果,且在分娩开始时成为可行的筛查方案[27]。该方式可以有效筛查存在感染风险的孕妇,并且减少非GBS携带者因无并发症发热(通常继发于硬膜外麻醉[28]而不是绒毛膜炎)而接受分娩时抗生素预防的妇女人数。但NAAT法的缺点是比棉签培养法昂贵得多,且无法做药敏。因此, NAAT法可用于未行产前GBS筛查孕妇的产程中即时检测,而不能代替常规GBS产前筛查。
除了推荐的孕晚期阴道及肛门采样,2020年美国妇产科医师协会发布的预防新生儿GBS-EOD的指南中[2]还指出妊娠期任何时间检测到的任何浓度的GBS菌尿都代表母体阴道-直肠GBS的大量定植,这表明需要在妊娠36+0 ~ 37+6周进行IAP,而不需要进行GBS筛查阴道-直肠培养。妊娠期间任何时间发现菌尿浓度 ≥ 105 CFU/mL时,都应在产前及时给予母体抗生素治疗,并在分娩时给予IAP[2]。如果浓度 < 105 CFU/mL,产前则不需要母体抗生素治疗,但在分娩时需要IAP。当无症状菌尿GBS菌落计数 < 105 CFU/mL时,并没有证据表明产前母体应用抗生素可以改善孕母和新生儿的结局[2]。妊娠期GBS尿培养取样比阴道及肛门取样更方便,是对妊娠35 ~ 37周阴道及肛门采样培养的有益补充,可减少筛查假阴性的发生。
3. GBS防治
3.1 分娩时应用抗生素预防的现状
对于有GBS定植的孕妇,产时应用抗生素可显著减少新生儿GBS-EOD[29-31]。产时静脉抗生素应用优于产前静脉抗生素应用,优于产时口服或肌内注射抗生素[32],且应用时首选青霉素类抗生素。
研究发现,预防性使用抗生素2 h后阴道GBS计数明显减少,使用4 h后预防效果更佳[33-34]。临床上在确认临产后即可开始使用抗生素。虽然使用时机明确,但临床工作中临产的开始有时难以准确把控,并非所有孕妇临产时都有典型的规律宫缩,而且产程时间有时难以准确预计,存在用药过度或用药难以满足有效预防时限的问题。
GBS筛查阳性孕妇启用IAP方案时,若产程过快,则药物难以充分达到有效时间。除了自然临产,临床上还面临着催产临产;且对于有妊娠合并症的妇女,通常在自然临产前便开始产科指征的引产。有时催产素诱发的规律宫缩与实际临产的宫缩难以界定,若催产出现规律宫缩即应用抗生素预防感染,则面临着过度使用抗生素、增加细菌耐药的风险。此外,临床上也存在孕妇未规律产检、未行GBS筛查的情况,以及GBS筛查结果未出而孕妇胎膜早破或临产的情况。在非胎膜早破的情况下,排除GBS感染高危因素,目前没有证据表明GBS筛查结果未知的孕妇临产前预防性应用抗生素有获益。
此外,抗生素耐药也是产时预防性应用抗生素所面临的问题,青霉素虽然是首选用药,但临床上不可避免地会遇到青霉素过敏或皮试阳性的患者,需要选择其他药物。一项纳入20篇中国研究的系统性综述显示,GBS对四环素的耐药率为98.0%,克林霉素为73.3%,红霉素为64.4%,环丙沙星为25.0%,却尚未报道GBS对青霉素、阿莫西林、万古霉素和利奈唑胺的耐药情况[1]。有关报道显示,GBS的耐药性呈上升趋势,一项纳入国内52篇文献,涉及195 303例妊娠期女性的meta分析显示,我国东北地区GBS菌株对克林霉素耐药率最高,为74.3%(95% CI:69.4% ~ 79.3%),其次是西北地区和西南地区,分别为65.1%和61.5%(95% CI:62.4% ~ 67.8%,95% CI:59.2% ~ 63.7%),华北地区GBS耐药率最低,为33.6%(95% CI:30.7% ~ 36.4%)[4,35]。且有研究指出,与引起侵袭性疾病的菌株相比,定植菌株的耐药性明显更高[36]。
一项研究中26个国家和地区的研究所提供了病原菌感染数据,其中9个实验室收集了GBS感染数据,并将2020年的感染数据与2018、2019年数据相对比,发现新发传染病疫情后并未增加侵袭性GBS的感染风险[37]。一项来自巴西的研究指出,虽然在新发传染病疫情前后的GBS易感性没有发现显著差异,但在大流行期间观察到红霉素和四环素的耐药率呈上升趋势,这可能与大环内酯类药物在很多国家或地区作为治疗新发传染病的第二大处方药有关[38]。综合来看,世界范围内的GBS IAP方案面临着抗生素耐药增加的风险。
总的来说,目前IAP治疗存在以下3个问题:第一,若孕晚期GBS筛查结果未知,IAP的应用则存在不及时性;第二,对难以预见的早产和急产孕妇会出现应用不及时的情况;第三,抗生素的耐药情况日益突出。虽然分娩前及分娩时使用抗生素预防降低了早发型新生儿感染的发生率,但这些措施并不能预防妊娠早期可能发生的逆行性感染以及其导致的早产、死产和晚发型新生儿感染[13,39]。虽然普遍筛查后采用IAP给药在预防GBS-EOD方面非常有效,但有关研究显示,21世纪初GBS-EOD的发病率明显下降,之后趋于平稳[21],到达一定瓶颈,且IAP并不能很有效地预防GBS-LOD。另有研究指出,61%的GBS-EOD足月婴儿母亲GBS筛查结果为阴性,这表明在筛查试验后和分娩之间发生了GBS定植,或者筛查结果为假阴性[35]。母乳中也可培养得到GBS,并可通过母乳喂养传给婴儿,增加其患GBS-LOD及复发的风险。但目前尚不清楚这种感染是由于婴儿吸吮的乳汁受到污染,还是由于婴儿口腔到母乳的逆行感染所致。目前,与母乳相关的GBS-LOD的预防和管理尚未建立共识[40]。
虽然快速有效的筛查手段和规范的抗生素使用可以减少临床抗生素耐药情况的发生,但目前IAP策略在降低宫内GBS感染及GBS相关早产、死胎,预防新生儿GBS-LOD方面仍存在明显不足,后续GBS相关疫苗的研制及临床应用或许可以弥补现阶段的不足。
3.2 GBS疫苗研制
现已有研究表明,针对GBS的免疫球蛋白G抗体可以透过胎盘传给新生儿[41],GBS疫苗的研制可能是未来预防新生儿GBS感染的一个发展方向。世界卫生组织(World Health Organization,WHO)2016年专门就开发孕产妇免疫疫苗进行磋商后,宣布迫切需要一种GBS疫苗,以保护全球婴儿的健康和生命[42]。根据2015年全球疾病估计建立的模型预测,GBS疫苗的有效率为80%,孕产妇覆盖率为90%的GBS疫苗可以预防世界上107 000名婴儿死亡和死产[22]。另一项研究对比了1980 — 2010年不同血清型在欧洲、美洲、非洲、西太平洋地区和东地中海地区的分布情况,发现并没有太大变化[43];且孕产妇GBS病、孕母定植和新生儿GBS-EOD中GBS血清型分布相似[14],这些使得疫苗的研制更具可行性。
从卫生经济学的角度出发,普及GBS疫苗意义重大。美国一项以人口为基础的经济分析得出以下结论:有80%的孕妇接种疫苗,就可以减少在34周及以后出生的婴儿中80%的病例,相当于每年预防约4 100例新生儿病例的发生,净节省1.31亿美元[44]。南非的一项研究也得出类似结论,根据WHO的指导方针,孕妇接种GBS疫苗将具有很高的成本效益[45]。
一种有效的疫苗需要针对目前90%以上的侵袭性疾病分离株,需克服GBS荚膜类型的多样性或是针对蛋白质表达的多态性和患病率[46-47]。目前在研的疫苗主要分为2种:第一种是针对大多数致病血清型设计的多价CPS结合疫苗,另一种是蛋白质亚单位疫苗[48]。Bianchi-Jassir等[49]认为,CPS蛋白结合疫苗可以针对大多数致病血清型,因此,其有可能预防95%的产妇GBS侵袭性病例,99%的GBS相关性死产,以及99%的新生儿GBS。
Ⅰa、Ⅰb和Ⅲ血清型是世界范围内主要的GBS定植类型。目前基于Ⅰa、Ⅰb和Ⅲ血清型的三价GBS结合疫苗的安全性和免疫原性已在Ⅰ期和Ⅱ期试验中进行了评估,并对Ⅲ期试验进行了考虑[50-55]。此外,目前GBS六价疫苗在研(包含血清型Ⅰa、 Ⅰb、Ⅱ、Ⅲ、Ⅳ和V),若研制成功可使得约98%的GBS侵袭性感染患者受益[56]。
在蛋白疫苗亚单位疫苗研究领域,Fisher等[57]于2021年发表了一种GBS蛋白亚单位疫苗(a protein GBS vaccine based on the highly immunogenic N-terminal domains,GBS-NN )的一期临床试验。GBS-NN由2种普遍存在的GBSα样表面蛋白的n端结构域组成的融合蛋白衍生而来,即αC和Rib。编码αC和Rib的基因相对保守,存在于美国70%以上的GBS侵袭性分离株中[58]。研究者在报告中指出GBS-NN的疫苗在240名健康成年女性的队列研究中被证明是安全且具有免疫原性的[57]。
3.3 其他辅助防治措施
除了GBS疫苗及IAP策略外,也有其他一些治疗方案可降低GBS定植。比如:阴道炎会增加女性GBS定植的风险,可采取益生菌干预,通过酸化、免疫调节和黏附等机制对GBS产生拮抗作用。一项临床试验的荟萃分析结果显示,益生菌是一种中等有效的干预措施,可减少产前GBS定植[59]。在抗生素治疗期间也可使用益生菌以减少抗生素相关性腹泻,但每次益生菌的使用要间隔2 ~ 4 h[60]。有研究显示,大蒜对于治疗GBS感染也有帮助[61]。这些或许都可以成为临床上的辅助治疗方式。
综上所述,孕妇GBS筛查及分娩时应用抗生素预防促进了世界范围内新生儿死亡率的降低。在美国,国家产时抗生素预防策略的实施使得GBS-EOD的发生率降低了超过80%,从20世纪90年代的每千名活产新生儿1.8名GBS-EOD患者下降到2015年的每千名活产新生儿0.23名患者[62]。解决GBS围产期定植的全球负担已被列入WHO议程,该议程确定的目标包括[63]:第一,到2023年,完成GBS传播和风险因素的完整研究;第二,到2026年,除了为GBS定植和感染的诊断提供有效和可获得的方案外,至少获得1种许可用于怀孕期间免疫的疫苗;第三,到2030年,在至少80%的国家实施这些措施。随着GBS疫苗的不断研究与应用,孕期GBS疫苗接种或将成为预防孕产妇和新生儿侵袭性GBS病的有效手段,结合规范、有效的筛查及产时抗生素预防,有望大幅减少孕产妇和新生儿的GBS感染,且GBS疫苗的广泛接种也可使其他非妊娠高危人群获益。
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