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Article(id=1241720034851083253, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241720034091914228, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.06.01, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1691510400000, receivedDateStr=2023-08-09, revisedDate=null, revisedDateStr=null, acceptedDate=1703088000000, acceptedDateStr=2023-12-21, onlineDate=1773978726350, onlineDateStr=2026-03-20, pubDate=1719244800000, pubDateStr=2024-06-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773978726350, onlineIssueDateStr=2026-03-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773978726350, creator=13701087609, updateTime=1773978726350, updator=13701087609, issue=Issue{id=1241720034091914228, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='6', pageStart='401', pageEnd='480', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773978726169, creator=13701087609, updateTime=1773979021315, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241721272128828343, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241720034091914228, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241721272128828344, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241720034091914228, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=401, endPage=405, ext={EN=ArticleExt(id=1241720035106935802, articleId=1241720034851083253, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Attention to latent tuberculosis infection in rheumatic children, columnId=1241720035039826937, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Special Topics on Children’s Medicine, runingTitle=null, highlight=null, articleAbstract=

Latent tuberculosis infection (LTBI) is a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifested active tuberculosis. Although LTBI is not contagious, about 5%-15% patients will develop active tuberculosis. Young age and immunosuppression are risk factors for the progression of LTBI to active tuberculosis. Due to the immature immune system, rheumatic disease and anti-rheumatic drugs, children with rheumatic disease are more susceptible to Mycobacterium tuberculosis, and LTBI is also prone to develop into active tuberculosis. China is still a country with a high burden of tuberculosis, more attentions should be paid to LTBI in rheumatic children. Screening for LTBI and preventive anti-tuberculosis treatment can reduce the occurrence of active tuberculosis and ensure the health of rheumatic children.

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结核潜伏感染（LTBI）是一种机体对结核分枝杆菌抗原刺激的持续免疫反应状态，未发现活动性结核的临床证据。尽管LTBI不具有传染性，但约5%~15%的患者会发展为活动性结核病，年龄小和免疫抑制状态是LTBI进展为活动性结核病的危险因素。风湿病儿童由于自身免疫系统发育不成熟、风湿病本身及接受抗风湿药治疗等因素，结核分枝杆菌易感性增加，LTBI也容易发展为活动性结核病。我国仍是结核病高负担国家，应重视风湿病儿童LTBI，积极发现LTBI并进行预防性抗结核治疗，以防止活动性结核病发生，保证风湿病儿童健康。

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张伟
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隋坤鹏，男，住院医师，硕士，主要从事儿童风湿免疫病的研究，E-mail：

张伟，男，主任医师，博士，主要从事儿童风湿免疫病的研究，E-mail：

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重视风湿病儿童结核潜伏感染
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隋坤鹏 , 张伟
中国新药与临床杂志 | 儿童用药专题 2024,43(6): 401-405
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中国新药与临床杂志 | 儿童用药专题 2024, 43(6): 401-405
重视风湿病儿童结核潜伏感染
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隋坤鹏 , 张伟
作者信息
  • 电子科技大学医学院附属妇女儿童医院/成都市妇女儿童中心医院 儿童风湿免疫科，四川 成都　611731

    • 隋坤鹏，男，住院医师，硕士，主要从事儿童风湿免疫病的研究，E-mail：

    张伟，男，主任医师，博士，主要从事儿童风湿免疫病的研究，E-mail：

通讯作者:

张伟
Attention to latent tuberculosis infection in rheumatic children
Kun-peng SUI , Wei ZHANG
Affiliations
  • Pediatric Immunology and Rheumatology Department, the Affiliated Women’s and Children’s Hospital, School of Medicine, UESTC/ Chengdu Women’s and Children’s Central Hospital, Chengdu SICHUAN 611731, China
出版时间: 2024-06-25 doi: 10.14109/j.cnki.xyylc.2024.06.01
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摘要
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结核潜伏感染（LTBI）是一种机体对结核分枝杆菌抗原刺激的持续免疫反应状态，未发现活动性结核的临床证据。尽管LTBI不具有传染性，但约5%~15%的患者会发展为活动性结核病，年龄小和免疫抑制状态是LTBI进展为活动性结核病的危险因素。风湿病儿童由于自身免疫系统发育不成熟、风湿病本身及接受抗风湿药治疗等因素，结核分枝杆菌易感性增加，LTBI也容易发展为活动性结核病。我国仍是结核病高负担国家，应重视风湿病儿童LTBI，积极发现LTBI并进行预防性抗结核治疗，以防止活动性结核病发生，保证风湿病儿童健康。

风湿性疾病  /  儿童  /  分枝杆菌感染  /  结核

Latent tuberculosis infection (LTBI) is a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifested active tuberculosis. Although LTBI is not contagious, about 5%-15% patients will develop active tuberculosis. Young age and immunosuppression are risk factors for the progression of LTBI to active tuberculosis. Due to the immature immune system, rheumatic disease and anti-rheumatic drugs, children with rheumatic disease are more susceptible to Mycobacterium tuberculosis, and LTBI is also prone to develop into active tuberculosis. China is still a country with a high burden of tuberculosis, more attentions should be paid to LTBI in rheumatic children. Screening for LTBI and preventive anti-tuberculosis treatment can reduce the occurrence of active tuberculosis and ensure the health of rheumatic children.

rheumatic diseases  /  children  /  mycobacterium infections  /  tuberculosis
隋坤鹏, 张伟. 重视风湿病儿童结核潜伏感染. 中国新药与临床杂志, 2024 , 43 (6) : 401 -405 . DOI: 10.14109/j.cnki.xyylc.2024.06.01
Kun-peng SUI, Wei ZHANG. Attention to latent tuberculosis infection in rheumatic children[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (6) : 401 -405 . DOI: 10.14109/j.cnki.xyylc.2024.06.01
正文
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据世界卫生组织（WHO）2022年全球结核病报告[1]，2021年全球范围约有1 060万结核病新发病例，其中14岁以下儿童约120万例，占11.3%；约160万人死于结核病，其中儿童约22万，占13.8%；我国新发病例数78万，位列全球第三位，仍是结核病高负担国家。结核潜伏感染（latent tuberculosis infection，LTBI）是一种机体对结核分枝杆菌（Mycobacterium tuberculosis，MTB）抗原刺激的持续免疫应答状态，通过影像学及症状体征检查，未发现活动性结核的临床证据[2]。尽管LTBI不具有传染性，但约5%~15%的LTBI会发展为活动性结核病，因此预防LTBI发展为结核病是一项实现个人和公共卫生目标的重要措施[2]。风湿病患者由于存在自身免疫功能紊乱、使用免疫抑制剂等原因，发生LTBI风险增加，尤其年龄小于5岁的风湿病患儿的LTBI更容易进展为重症结核病[2]，在结核病高发地区，结核病是造成风湿病患者死亡的重要原因之一[3]。目前，国内外已有成人风湿病合并LTBI诊治的专家共识，但关于儿童风湿病合并LTBI的研究较少，结合我国结核病高负担的背景，应重视儿童风湿病合并LTBI，积极发现LTBI并进行预防性抗结核治疗，防止LTBI再激活，有效控制结核病，保证风湿病儿童健康。
风湿病儿童MTB易感性与LTBI再激活
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MTB侵入机体后，肺内巨噬细胞首先与MTB接触并通过吞噬-溶酶体融合、募集溶酶体酶、产生活性氧以及自噬和凋亡等机制，发挥抗MTB作用，并上调多种细胞因子如肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1和粒细胞巨噬细胞集落刺激因子（GM-CSF）等诱导其他免疫细胞向MTB感染部位迁移，帮助控制感染[4]。吞噬MTB的树突状细胞迁移到外周淋巴结，启动适应性免疫应答，刺激T淋巴细胞分化并迁移到MTB感染部位，参与形成肉芽肿，并产生γ-干扰素（IFN-γ）、TNF-α、IL-2细胞因子发挥清除病原作用[5]。B淋巴细胞作为抗原提呈细胞参与MTB特异性T淋巴细胞分化，产生MTB特异性抗体，分泌细胞因子调节效应细胞功能，限制结核感染播散[6]。宿主可通过固有免疫和获得性免疫应答清除MTB感染，MTB也可通过多种免疫逃逸机制避免被免疫系统清除[7]，LTBI被认为是MTB和宿主免疫系统之间的动态平衡[2]。由于风湿病发病机制涉及T、B淋巴细胞异常反应及活化，自身免疫耐受受损，导致机体处于免疫紊乱状态，增加了MTB易感性。其可能机制包括自身T淋巴细胞稳态失衡引起T细胞耗竭，不能产生足够对抗外界抗原的T细胞[8]；T细胞功能紊乱，原始CD4+ T细胞分化成具有促炎和组织侵袭的效应细胞，而不是分化为参与感染免疫的记忆T细胞，削弱了抗MTB的作用[9]；补体受体表达降低，使得补体介导的微生物清除受到影响，导致感染风险增加[10]。各种免疫紊乱打破了MTB和宿主免疫系统之间的动态平衡，导致LTBI再激活发展为活动性结核病，也容易增加MTB的易感性。目前风湿病患者LTBI的发生情况尚无准确的流行病学数据，已有的研究结果显示，结核病高负担国家中的风湿病患者LTBI发病率高于普通人群[11]。
风湿病治疗药物主要为各种免疫抑制剂，包括糖皮质激素和改善病情抗风湿药（disease modifying antirheumatic drugs, DMARDs）等，这些药物的使用使患者处于一种暂时的免疫抑制状态，是导致MTB易感及LTBI再激活风险增加的主要原因。
糖皮质激素使MTB感染风险增加的结论比较明确，研究显示糖皮质激素剂量>7.5 mg·d-1是患结核病的独立危险因素[12]，长期、每日糖皮质激素超过15 mg的风湿病患者的LTBI再激活风险明显增高[13]。而使用传统DMARDs治疗的类风湿关节炎患者的活动性结核病发病风险是普通人群的3.17倍，其中甲氨蝶呤、来氟米特、环孢素的风险相对更高[14]。
生物制剂DMARDs的出现极大改善风湿病儿童预后，但也导致风湿病儿童MTB感染风险增加，尤其是TNF抑制剂[15]。TNF-α抑制剂可以抑制由TNF-α介导的T淋巴细胞和巨噬细胞向MTB感染部位募集，阻碍肉芽肿形成，并下调巨噬细胞、自然杀伤细胞和CD8+ T细胞功能活性，因此，使用TNF抑制剂治疗的患者极易导致LTBI进展为活动性结核病[4]。且使用TNF-α单克隆抗体发展为活动性结核病的风险较TNF-α受体抗体融合蛋白类高[16,17]。
使用IL-6受体单克隆抗体治疗风湿病，在多个Ⅲ期临床试验及真实世界研究中未发现结核感染，显示出良好的安全性[18-21]，但以上研究是在结核低负担国家完成的。在结核病高负担的印度，使用IL-6受体单克隆抗体的174例风湿病患者有13例发生LTBI，但无进展为活动性结核病的病例[22]。IL-1在控制MTB感染中发挥重要作用，IL-1α/IL-1β的表达缺陷会导致胞内MTB大量增殖[23]，实际临床研究中，IL-1抑制剂并没有增加MTB感染风险[24,25]。在我国结核病高负担的背景下，风湿病儿童使用IL-6、IL-1抑制剂的结核感染问题仍需持谨慎态度。
无论是在结核病高负担或是低负担国家，选择性T淋巴细胞共刺激调节剂阿巴西普在风湿病成人和儿童的研究均未发现MTB感染风险的增加[26,27]。但目前研究认为，巨噬细胞控制MTB感染的作用，需要经T淋巴细胞激活并到达肺部才能有效发挥[4]。阿巴西普是一种可溶性融合蛋白，通过与抗原提呈细胞表面的CD80和CD86结合，阻断后者与T淋巴细胞表面CD28的相互作用，抑制T细胞活化，减弱下游免疫及炎症反应[27]。阿巴西普的药品说明书强调在开始阿巴西普治疗前应筛查有无LTBI，也提示该药抑制了T细胞激活，有增加MTB感染或LTBI再激活的可能。
针对B淋巴细胞的生物制剂由于不抑制参与抗MTB的T淋巴细胞，导致MTB感染及再激活风险较小，随机对照研究显示，无论成人还是儿童系统性红斑狼疮患者，贝利尤单抗治疗没有增加MTB感染或LTBI再激活风险[28,29]。真实世界研究证实，利妥昔单抗导致MTB感染风险较低，即使存在LTBI的情况，也没有报告发生LTBI再激活[30,31]。
化学靶向DMARDs主要为JAK/STAT信号通路抑制剂，主要包括托法替布、巴瑞替尼、芦可替尼，其中托法替布最为常用。系统性评价研究发现，成人JAK/STAT信号通路抑制剂与MTB感染有关，尤其是在经济状况较差、结核病流行的国家和地区[32]。关于儿童的安全性研究较少，托法替布治疗幼年特发性关节炎的Ⅲ期临床研究中无MTB感染发生[33]。
目前风湿病儿童使用抗风湿药，尤其是生物制剂DMARDs及化学靶向DMARDs的安全性数据还不充分，尤其缺乏在结核病高负担国家的研究数据，考虑我国结核病高负担的背景，在风湿病儿童治疗前及治疗中应重视LTBI的筛查。
风湿病儿童LTBI的诊断
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各种抗风湿药的使用增加了风湿病儿童MTB感染及LTBI再激活风险，建议抗风湿治疗前应行LTBI筛查，在治疗过程中至少每年筛查1次[11,34]。LTBI者无临床表现与影像学异常，且诊断缺乏金标准，主要通过结核菌素皮肤试验（TST）或IFN-γ释放试验（IGRA）检测对MTB抗原刺激的细胞介导免疫反应，间接评估是否感染[2]。
TST是检测MTB感染的经典方法，采用结核菌素纯蛋白衍生物（PPD）皮下注射，观察皮肤硬结大小来判断结果，其操作简单，价格低廉，符合成本-效益原则，至今仍作为LTBI诊断的重要方法。由于TST所用PPD与卡介苗（BCG）疫苗及非结核分枝杆菌（NTM）存在交叉抗原，结果容易受BCG和NTM的影响，出现较高的假阳性率[2,35]，因此特异性稍差。
IGRA则是通过监测MTB抗原刺激后，致敏的T淋巴细胞释放IFN-γ的水平来确定是否存在MTB感染[2]。由于实验用抗原是BCG菌株和大多数NTM的基因组不能编码产生的抗原蛋白，如早期分泌抗原-6（ESAT-6）和培养滤液蛋白-10（CFP-10），其结果不受BCG疫苗接种或大多数NTM感染的影响，特异性较高，但费用较贵[2]。目前IGRA常用两种方法检测，一种是通过酶联免疫吸附法（ELISA）检测MTB感染后全血中INF-γ的水平；另一种是T细胞酶联免疫斑点法（ELISPOT），该方法是使用MTB特异性抗原进行刺激，对外周血中释放IFN-γ的T淋巴细胞数量进行测定[2]。一项荟萃分析评价上述检测方法在儿童结核感染中的诊断效能，发现上述方法对活动性结核病的敏感性相似（ELISA为70%，ELISPOT为62%，TST为71%），ELISA检测特异性为100%，ELISPOT为90%，TST为56%[35]。由于LTBI诊断缺乏金标准，风湿病患者使用免疫抑制剂可能使TST或IGRA出现假阴性，在有条件的情况下联合TST和IGRA进行筛查，可以提高检测敏感性[11,36]。
LTBI判断标准[37]：（1）未接种BCG疫苗或无NTM影响时，PPD试验硬结平均直径≥5 mm，判定为存在MTB感染；（2）已接种BCG疫苗或有NTM影响时，PPD试验硬结平均直径≥10 mm，判定为存在MTB感染；（3）与活动性肺结核患者有密切接触的5岁以下儿童或HIV感染或使用免疫抑制剂治疗大于1个月，PPD皮试硬结平均直径≥5 mm，判定为存在MTB感染；（4）TST阳性即表明受到MTB感染；（5）IGRA检测阳性说明存在MTB感染。在判断LTBI时应注意，由于以上检测方法受患者免疫状态和年龄等方面影响，提示结果阴性时不能盲目排除MTB感染，应结合患儿病情综合判断。
风湿病儿童LTBI的预防性抗结核治疗和管理
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风湿病儿童若发现LTBI应尽早进行预防性抗结核治疗，研究显示风湿病合并LTBI患儿经预防性抗结核治疗多预后良好，很少发生活动性结核病甚至播散性结核。西班牙的一项研究[38]提示，风湿病儿童开始抗TNF-α治疗前对LTBI预防性抗结核治疗，随访中位时间为6.4年，12例LTBI患者仅有1例发生活动性结核病，但该例患者在LTBI预防性抗结核治疗后曾与结核病患者接触，且两者菌株分型完全同源，提示很可能为新发MTB感染而非LTBI再激活。另一项研究也显示，无论结核病低负担国家（西班牙），还是高负担国家（巴西），在风湿病合并LTBI患儿中积极预防性抗结核治疗的益处，40例（31例LTBI、9例有结核病患者接触史）儿童接受预防性治疗，只有3例发生了活动性结核病[39]。
风湿病合并LTBI接受预防性抗结核治疗的时机尚无儿童数据，参考成人诊疗建议[11]：当病情危重需要立即使用生物制剂治疗时，临床医生应充分评估患者LTBI激活风险，在预防性抗结核治疗的基础上同时使用生物制剂；若病情可暂缓糖皮质激素、传统DMARDs、生物制剂DMARDs（非TNF抑制剂）治疗时，应在预防性抗结核治疗1个月后启动抗风湿治疗；尽可能在预防性抗结核治疗完成后再启动TNF抑制剂治疗。
根据我国相关共识，风湿病儿童LTBI预防性抗结核治疗方案以单用异烟肼（isoniazid, INH）6个月或9个月（6 INH或9 INH）、联合使用INH和利福平（rifampicin, RFP）3~4个月（3~4 INH+RFP）为常用治疗方案；单用RFP 3~4个月（3~4 RFP）为备选治疗方案[40]。中国防痨协会发布的《T/CHATA 015-2021儿童结核分枝杆菌潜伏感染检测和预防性治疗》标准在上述方案基础上，增加了INH和利福喷丁（rifapentine）联合使用3个月，每周2次，作为5岁以上LTBI的预防性抗结核治疗方案[36]。
风湿病患儿预防性抗结核治疗前，首先应排除活动性结核病，同时排除没有预防性抗结核治疗的禁忌，充分告知并签署知情同意书，加强宣教，提高儿童治疗依从性，做好登记管理，定期随访观察，监测药物不良反应，并密切观察临床疗效，一旦发展为活动性结核病，须立即停止预防性抗结核治疗，采用规范的抗结核治疗。
小结
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风湿病儿童由于年龄小、疾病本身及抗风湿药的使用，增加了MTB感染及LTBI发展为活动性结核病的风险。应重视对风湿病儿童LTBI的临床研究，规范开展LTBI筛查，及时预防性抗结核治疗，减少活动性结核病的发生，保证风湿病患儿健康。
基金
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  • 四川省卫生健康委员会重点研究项目(20ZD019)
  • 成都市技术创新研发项目(2022-YF05-01236-SN)
  • 四川省妇幼保健协会科研课题(2020ZD06)
  • 湖北陈孝平科技发展基金会2021年度免疫性疾病研究槐杞黄专项基金(CXPJJH121002-202149)
  • 成都市妇女儿童中心医院2021年院内科研课题(2022JC06)
文献
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2024年第43卷第6期
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doi: 10.14109/j.cnki.xyylc.2024.06.01
  • 接收时间：2023-08-09
  • 首发时间：2026-03-20
  • 出版时间：2024-06-25
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  • 收稿日期：2023-08-09
  • 录用日期：2023-12-21
基金
四川省卫生健康委员会重点研究项目(20ZD019)
成都市技术创新研发项目(2022-YF05-01236-SN)
四川省妇幼保健协会科研课题(2020ZD06)
湖北陈孝平科技发展基金会2021年度免疫性疾病研究槐杞黄专项基金(CXPJJH121002-202149)
成都市妇女儿童中心医院2021年院内科研课题(2022JC06)
作者信息
    电子科技大学医学院附属妇女儿童医院/成都市妇女儿童中心医院 儿童风湿免疫科，四川 成都　611731

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张伟
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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