Abstract
儿童艰难梭菌感染(Clostridium difficile infection, CDI)是医院获得性胃肠道感染的主要原因。目前对儿童CDI的治疗主要是抗菌药物,然而部分儿童在抗生素治疗后出现复发,甚至首次复发的儿童使用抗生素治疗后仍有再复发可能,此时对治疗方案的选择需要慎重,粪菌移植治疗被证明可用于复发性CDI且安全性较高。该文就国内外儿童CDI发病机制、危险因素、诊断及治疗的最新研究进展作一综述,并对粪菌移植治疗作重点概述。
Keywords: 艰难梭菌感染, 治疗, 粪菌移植, 儿童
Abstract
Clostridium difficile infection (CDI) is a major cause of hospital-acquired gastrointestinal infections in children. Current treatment for pediatric CDI primarily involves antibiotics; however, some children experience recurrence after antibiotic treatment, and those with initial recurrence remain at risk for further recurrences following subsequent antibiotic therapy. In such cases, careful consideration of treatment options is necessary. Fecal microbiota transplantation has been shown to be effective for recurrent CDI and has a high safety profile. This article reviews the latest research on the pathogenesis, risk factors, diagnosis, and treatment of pediatric CDI domestically and internationally, with a particular focus on fecal microbiota transplantation therapy.
Keywords: Clostridium difficile infection, Treatment, Fecal microbiota transplantation, Child
自2000年以来,儿童艰难梭菌感染(Clostridium difficile infection, CDI)的发病率有所上升[1]。大多数CDI患儿有轻至中度腹泻,通过抗生素治疗可得到持续的临床治愈,然而部分患儿停药后可能会出现复发。复发性艰难梭菌感染(recurrent Clostridium difficile infection, rCDI)是指感染治愈后8周内再次发生相同或不同艰难梭菌(Clostridium difficile, CD)菌株的感染。虽然严重CDI在儿童中少见,但成人与儿童rCDI的发生率相似,为10%~30%[2-6]。近年来,多位学者已经证明粪菌移植(fecal microbiota transplantation, FMT)是治疗儿童和成人严重CDI及rCDI的有效微生物疗法,并且80%~100%的患儿经FMT后症状得到缓解[2,7-14]。与抗生素治疗相比,FMT能更有效、快速地治疗rCDI[15]。本文就儿童CDI的发病机制、危险因素、诊断及治疗作一综述,并重点概述FMT治疗的最新进展。
1. CDI发病机制
CDI主要是由于滥用抗生素后,导致肠道菌群严重失调,从而使CD在肠道大量繁殖[2,4]。例如,广谱抗生素的滥用可以抑制CD生长,但同时也会抑制正常肠道菌群的生长,从而引起肠道菌群紊乱并降低CD定植抗性,导致CDI复发[16]。CDI后,产生的毒素A/B会诱导固有层上皮细胞和免疫细胞释放炎性趋化因子和细胞因子,进而激活固有淋巴细胞启动宿主免疫[17]。有研究证明CDI患者肠道菌群中,对于抗生素敏感的肠道菌群(厚壁菌门、拟杆菌门等)减少,耐药菌群(放线菌门、变形菌门等)增多,拟杆菌门减少会导致CD过度繁殖,厚壁菌门减少会降低丁酸盐产生,破坏肠上皮细胞完整性[18]。在儿童中,瘤胃球菌和肺炎克雷伯菌与CD定植有关,而双歧杆菌与未定植有关,并且CDI患儿中双歧杆菌水平较低[19]。
2. 儿童感染CDI的危险因素
儿童CDI的危险因素与成人相似,包括近期使用抗生素(如氟喹诺酮类、克林霉素、第三代头孢菌素、质子泵抑制剂等)、住院治疗、潜在的复杂慢性疾病[如恶性肿瘤、实体器官移植和炎症性肠病(inflammatory bowel disease, IBD)]、近期手术、进行气管造口或胃造口[1-2,4,20-22]。并且,患IBD、囊性纤维化或恶性肿瘤的儿童,CD无症状定植的风险较高[23-25]。有研究发现,类固醇、免疫调节剂或生物制剂不太可能增加CDI风险,而5-氨基水杨酸会增加CDI风险(OR=1.95,95%CI:1.26~3.00)[26-27]。
3. 儿童CDI的诊断
目前用于CDI诊断的方法旨在检测粪便中产毒CD菌株或毒素。表1对主要检测方法特征作一简略概括。患IBD或恶性肿瘤的年轻CDI患者(尤其是小于12个月的婴儿),CD无症状定植的风险较高[1,28]。因此对于儿童,区分CDI和无症状定植至关重要。美国传染病协会和美国医疗保健流行病学协会指南建议,当有临床症状时,可以仅进行检测毒素A/B基因的核酸扩增试验(nucleic acid amplification test, NAAT),或者通过两步测试策略提高毒素测定灵敏度,即先进行NAAT或谷氨酸脱氢酶(glutamate dehydrogenase, GDH)检测,然后再进行毒素酶免疫分析(enzyme immunoassay, EIA)[29]。然而Parnell等[30]研究认为使用NAAT和EIA这两步测试不能区分有症状CDI和无症状定植,可以采用三步测试策略,即在两步测试策略基础上,对阴性标本再进行细胞毒性试验、CD的产毒素培养或NAAT等检测。
表1.
CDI常用诊断方法[1]
检测方法 | 优点 | 缺点 |
---|---|---|
NAAT | 灵敏度高、实施容易、成本较低、误报率低 | 不能确定体内是否正在产生毒素;可能导致过度诊断,需要与毒素测试结合 |
GDH | 灵敏度高 | 特异性低,不能区分产毒与非产毒艰难梭菌菌株 |
EIA | 价廉、易于实施 | 灵敏度低于NAAT,不建议作为单独检测方法 |
注:[NAAT]核酸扩增试验;[GDH]谷氨酸脱氢酶;[EIA]酶免疫分析。
4. 儿童CDI的治疗
4.1. 药物治疗
儿童和成人CDI的病理和临床表现不尽相同,儿童肠道微生物组处于动态变化中[31-32]。因此,将成人的临床用药方案直接运用到儿童存在争议。对于rCDI的治疗,停止使用任何有复发风险的抗生素是关键的第一步。对于需要持续抗生素治疗的患者,建议在尽可能短的时间内选择窄谱抗生素,以降低CDI复发风险。表2根据现有指南[29]概述了儿童CDI治疗方案。一项针对非严重CDI患儿的研究发现,与甲硝唑相比,接受万古霉素治疗的患儿症状缓解更早[33]。在美国和欧洲,甲硝唑治疗儿童CDI的临床治愈率显著低于万古霉素(95%CI:0.19~0.93,P=0.03),然而在亚洲,这两种抗生素的临床治愈率和复发率均无显著差异[34]。并且有研究表明,因其他疾病原因需要接受全身性抗生素治疗的同时,预防性口服万古霉素可降低CDI患儿的复发[35]。一项比较非达霉素和万古霉素对CDI患儿疗效的随机对照试验发现,经非达霉素治疗可获得较低复发率(11.8% vs 29.0%),并且非达霉素于2020年获得美国食品药品监督管理局批准用于治疗儿童CDI[36]。总的来说,万古霉素和非达霉素都应被视为儿童CDI和rCDI的首选治疗方案。
表2.
儿童CDI药物治疗方案[29]
CDI疾病程度 | 治疗方案 | 最大剂量 |
---|---|---|
初发,不严重 |
(1)口服甲硝唑10 d,7.5 mg/kg,tid或qid; (2)口服万古霉素10 d,10 mg/kg,qid |
(1)甲硝唑500 mg,tid或qid; (2)万古霉素125 mg,qid |
严重/暴发性 |
(1)口服万古霉素a 10 d,10 mg/kg,qid或tid,加或不加静脉注射甲硝唑 10 d,10 mg/kg,tid; (2)FMT; (3)结肠切除术b |
万古霉素500 mg,tid或qid |
首次复发,不严重 |
(1)口服甲硝唑10 d,7.5 mg/kg,tid或qid; (2)口服万古霉素10 d,10 mg/kg,qid; (3)口服非达霉素10 d,16 mg/kg,bid |
(1)甲硝唑500 mg,tid或qid; (2)万古霉素125 mg,qid; (3)非达霉素200 mg |
≥2次复发 |
(1)万古霉素渐进式脉冲方案c; (2)口服万古霉素10 d,10 mg/kg,qid,再口服利福昔明d 20 d,400 mg,tid; (3)FMTe |
(1)万古霉素125 mg,qid; (2)万古霉素500 mg,qid; 利福昔明400 mg,tid |
注:[FMT]粪菌移植;[CDI]艰难梭菌感染;[bid]每日2次;[tid]每日3次;[qid]每日4次。a不能耐受口服或有肠梗阻/巨结肠时可直肠用万古霉素;b患有中毒性巨结肠、结肠穿孔或感染性休克的儿童可考虑,转袢回肠造口伴结肠灌洗后顺行万古霉素冲洗是一种可改善预后的替代方法;c口服万古霉素10 mg/kg,qid,持续10~14 d,再换为10 mg/kg,bid,持续1周,再换为10 mg/kg,每日1次,持续1周,最后再换为10 mg/kg,2~3 d/次,持续2~8周;d利福昔明没有儿童剂量,在美国尚未被批准用于12岁以下儿童;e考虑用于多次CDI复发或抗生素治疗失败患儿。
更新的美国传染病协会、美国医疗保健流行病学协会、欧洲临床微生物学和传染病学会、澳大利亚传染病协会指南均推荐人源单克隆抗体贝洛托单抗(bezlotoxumab)用于6个月内出现第2次CDI复发的成人患者[11-12,37]。然而在儿童中,贝洛托单抗正处于3期临床研究中。
4.2. FMT治疗
4.2.1. FMT治疗CDI的机制
尽管目前FMT治疗CDI的机制尚不完全清楚,但有学者已经证明:(1)FMT可增强细菌多样性,表现为拟杆菌门等有益菌门丰度增加,变形杆菌门等致病菌门丰度减少,增加的有益菌群与CD竞争肠内营养以抑制其毒素合成[2,10]。(2)FMT可促进初级胆汁酸向次级胆汁酸转化,初级胆汁酸具有促进CD繁殖的作用,而次级胆汁酸则起到抑制作用[38-39]。(3)FMT还可分解肠道内碳水化合物为短链脂肪酸,短链脂肪酸能抑制炎症反应,从而抑制CD增殖[10,40]。
4.2.2. FMT治疗儿童rCDI的临床疗效
rCDI患儿在接受抗生素治疗时症状通常会消失,但部分患儿在停药后2~8周内会复发,并且使用甲硝唑、万古霉素等抗生素治疗rCDI可能会加剧肠道菌群失调,从而导致疾病反复[4-5,15]。因此,FMT在rCDI治疗中起着至关重要的作用。
FMT对免疫抑制的rCDI患儿(如患恶性肿瘤、接受器官移植或生物治疗)仍然有效[7,41-42]。一项多中心队列研究发现,患有IBD的CDI儿童首次FMT成功的可能性并不比非IBD儿童低(76% vs 81%,P=0.17)[9]。Tariq等[21]分析141例患有IBD的rCDI儿童,106例患儿在首次FMT后得到缓解,综合治愈率为78%(95%CI:58%~93%)。另有研究表明,在42例免疫功能低下的rCDI患儿中,第1次FMT成功率为79%,1次或多次FMT总成功率为86%,随访期间未出现死亡或多重耐药感染[43]。
2019年美国食品药品监督管理局针对FMT治疗CDI患儿的安全问题,建议应增强对FMT风险的认识[44]。为了指导儿童FMT的临床正确使用,儿童rCDI的专家共识及成人指南建议,当患儿经历初次CDI发作且至少2次复发、对标准治疗1周无反应的中度CDI或对标准治疗48 h无反应的重度CDI时,应考虑FMT[29]。
4.2.3. FMT治疗儿童rCDI疗效的影响因素
FMT治疗rCDI的成功率受多种因素影响。然而在大多数研究报道中,对于FMT前是否进行抗生素预处理及预处理时间、FMT剂量、FMT频次及途径、粪便标本的选择等未形成统一意见。
虽然FMT前的抗生素预处理时间尚未确定,但有研究建议在FMT前至少72 h进行适当的抗生素处理(如万古霉素、甲硝唑、非达霉素),FMT前24~48 h停用抗生素[5,45]。
FMT的途径多种多样。多项研究表明,通过下消化道进行FMT是治疗CDI的最有效途径[5,7,10,46]。结肠镜及结肠灌肠是广泛使用的输送方法。近年来兴起的粪菌胶囊逐渐成为儿科FMT的有效输送方式。在一项前瞻性研究中,82%的患者在口服第1个疗程的粪菌胶囊后实现治愈,91%的患者在第2个疗程后实现治愈[47]。对于能够接受并耐受口服胶囊途径且在治疗时无需进行结肠镜评估的患者,可考虑口服胶囊FMT。然而口服胶囊有卡在食管中并被误吸的风险,并且口服胶囊有效时间相对较短。每种FMT途径各有优缺点,临床医生应根据目的和技术能力选择适当的FMT途径。
大多数情况下,只需1次FMT即可治愈CDI(定义为FMT后2~3个月内症状消退且无复发),但有些患者可能需要多次FMT或继续使用抗生素治疗[21,46]。一项针对300多例儿童及年轻CDI患者的多中心回顾性研究显示,第1次和第2次FMT成功率分别为81%和87%[7]。
粪便标本的选择也至关重要。有研究发现,对于CDI患儿,接受新鲜粪便标本FMT较接受冷冻粪便标本FMT成功率更高[7]。然而既往成人随机对照试验并未证明使用新鲜或冷冻粪便样本的区别会对CDI患儿的治愈率造成显著差异[45]。由于儿童微生物群的发育与成人不同,因此在使用健康成人供体粪便进行FMT时,要考虑儿童肠道微生物群恢复的特异性。Wu等[16]在儿科FMT队列研究中发现,成人供体粪便可以有效地移植到2~18岁的儿童中,并且在rCDI患儿FMT中占主导地位。
还有一些与FMT成功率有关的其他因素。通过结肠镜进行FMT、不使用饲管以及接受FMT前CDI发作次数较少者,FMT成功率更高[7]。回顾性研究发现,在患有IBD的CDI儿童中,使用新鲜的供体粪便、FMT前没有活动性腹泻以及CDI诊断和FMT操作之间的间隔时间较短,FMT成功率更高[9,27]。
4.2.4. FMT治疗儿童rCDI的安全性
在儿童rCDI中,FMT是一种效果显著且相对安全的治疗方法[3,5,7,10]。在Marcella等[48]的荟萃分析中,常见不良事件是出现胃肠道症状(如呕吐、腹痛等)。即使在免疫功能低下的患儿中,FMT通常也不会发生严重不良事件(serious adverse event, SAE)[49]。一项包括372例CDI患儿的队列研究发现,17例患儿在FMT后出现SAE,其中只有2例SAE(吸入性肺炎和住院治疗脱水)与FMT有关,但均未死亡[7]。
4.3. 益生菌治疗
益生菌可能通过抵消抗生素对肠道微生物群的破坏作用,从而有效预防使用抗生素的儿童发生CDI。虽然有研究认为将益生菌用于临床试验之外的CDI一级预防欠妥[29]。然而Cochrane对39项临床试验的审查发现,与对照组相比,益生菌组患CDI的风险降低了60%(95%CI:30%~52%)[50]。同时,美国胃肠病学协会在2020年建议使用抗生素治疗的成人和儿童服用益生菌来预防CDI(低质量证据的有条件建议)[51]。
4.4. 生物治疗
鉴于FMT缺乏标准化和长期安全性不明确等问题,生物治疗或许是未来治疗rCDI的有效方式。例如,SER-109是来自健康捐赠者的纯化细菌孢子悬浮液,是第一个被批准用于预防rCDI的口服微生物疗法[52]。还有一些生物治疗药物,例如RBX2660、VE303、CP101等目前仍处于临床试验阶段[20]。尽管这些生物治疗药物非常有前途,但由于缺乏儿童临床试验,儿科患者在短期内无法从中获益[8]。
5. 总结与展望
儿童肠道微生物组特点与成人不尽相同,因此在CDI诊断和治疗上有所差异,临床医生应根据现有儿科临床指南及经验选择合适的治疗方案。目前对于儿童CDI的治疗主要是抗生素,然而抗生素的滥用可能会导致CDI复发。近年来,FMT已得到广泛应用,对于CDI患儿来说是有效且安全的,rCDI患儿可尽早考虑FMT。虽然FMT对成人和儿童CDI疗效显著,但儿科FMT的临床实践还有待完善和补充。未来需要进行更多更大规模的研究来阐明FMT在儿科患者中的安全性和有效性。
基金资助
四川省自然科学基金青年项目(2023NSFSC1614);川北医学院2022年度四川省基层卫生事业发展研究中心资助项目(SWFZ22-C-87)。
利益冲突声明
所有作者声明无利益冲突。
作者贡献
甘宇负责文献检索及撰写;吴志鸿和李前龙负责文章检索;卢朝霞负责论文修改及审校;陈琳琳负责论文选题及修改。
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