Interpretation of clinical standards for drug-susceptible tuberculosis in children and adolescents

doi:10.19982/j.issn.1000-6621.20240202

Abstract

Abstract:

To standardize and guide the diagnosis, treatment, and management of drug-sensitive tuberculosis (DS-TB) in children and adolescents, the International Journal of Tuberculosis and Lung Diseases published the Clinical Standards for Drug-Sensitive Tuberculosis in Children and Adolescents on February 27, 2023. These standards were developed by 52 global experts in pediatric tuberculosis diagnosis and treatment, basic research, public health, microbiology, epidemiology, and social sciences through a Delphi-method consensus. They recommended eight standards for optimal diagnosis, treatment, and management of DS-TB in children and adolescents. This article interprets these standards with the aim of promoting standardized management of DS-TB among healthcare professionals involved in tuberculosis diagnosis and treatment, ultimately contributing to the goal of ending tuberculosis.

Key words: Child, Adolescent, Tuberculosis, Reference standards

CLC Number:

Li Qinjing, Jiao Weiwei, Wang Zeming, Shen Adong. Interpretation of clinical standards for drug-susceptible tuberculosis in children and adolescents[J]. Chinese Journal of Antituberculosis, 2024, 46(8): 877-885. doi: 10.19982/j.issn.1000-6621.20240202

Figures/Tables 4

结核病类型/特征	症状和体征	特别说明
所有类型结核病	体质量减轻或发育停滞;发热;食欲不振;幼儿表现为活动减少,年长儿童或青少年表现为乏力;盗汗	使用生长曲线对发现体质量减轻或发育停滞很重要。很多症状逐渐出现且不易察觉,建议看护者对患儿与家庭中其他儿童或与自身1年前的表现进行比较
肺结核	慢性咳嗽超过14d,在年幼儿童或免疫缺陷儿童中可为急性发病;持续喘息或喘鸣;下呼吸道感染体征;咯血,主要发生在青少年空洞性肺结核患者中	喘息可以是单音性、单侧,不随支气管扩张而改善。下呼吸道感染体征包括:叩诊浊音;听诊时可闻及支气管呼吸音,爆裂音,单侧呼吸音弱。体征常与临床表现和影像学表现不一致
胸腔积液	胸痛,大量胸腔积液可引起急性呼吸短促;呼吸音减弱,叩诊浊音	大量胸腔积液主要发生在年长儿童和青少年
心包积液	急性呼吸窘迫;肝脏增大;心浊音界超过心尖搏动区;心音低钝	除非病情严重,否则临床诊断困难
周围淋巴结结核	可能没有全身症状或体征;通常是颈部多见、不对称、质硬、无痛的淋巴结肿大;淋巴结可能会粘连,有波动感或破溃形成窦道(瘰疬性皮肤结核)	95%的淋巴结结核发生在颈部,<1%为全身性淋巴结病。婴儿出现与卡介苗疤痕同侧的单侧腋窝淋巴结病变通常提示卡介苗并发症
结核性脑膜炎(中枢神经系统结核病的亚型)	不伴腹泻的呕吐;嗜睡;头疼;行为改变,包括活动减少;疾病早期若未及时诊治,晚期可出现乏力、瘫痪或抽搐,以及其他局灶性体征;脑膜刺激征(如颈抵抗)	脑膜炎早期通常表现为1~2周的非特异性症状,如发热和嗜睡。少数患者不发热。需警惕以同样表现反复就诊的患者。结核病的接触史是早期诊断的重要补充信息
结核瘤(中枢神经系统结核病的亚型)	头疼;不伴腹泻的呕吐;行为异常;乏力、瘫痪或抽搐;共济失调	伴或不伴有结核性脑膜炎。也可能是结核性脑膜炎治疗期间免疫重建炎症综合征的一种表现
粟粒性结核病	呼吸急促;肝脾肿大;肺部爆裂音(不常见)	体征可能不明显,通常依靠影像学诊断,典型的表现可能在病程后期出现。多与结核性脑膜炎同时存在
骨关节结核	慢性背痛(脊柱结核)或关节痛;背部肿块;关节疼痛、肿胀、发红;腹股沟区、下背部和臀部的冷脓肿,可能是脊柱结核导致的腰肌脓肿蔓延所致	通常有外伤史。骨关节结核最常发生在脊柱(50%)。受影响的关节主要是单侧承重关节
腹腔结核	急性或慢性腹痛;腹胀通常不伴压痛;腹部肿块	腹膜结核是最常见的亚型。影像学表现随受累器官不同而不同
耳/乳突结核	慢性化脓性中耳炎;耳后肿胀常伴淋巴结肿大

推荐方案	适用年龄	适用疾病类型及注意事项
4个月方案[2H-R-Z(E)/2H-R]	3个月~<16岁,且≥3kg	1.胸部X线检查符合非重症肺结核:(1)淋巴结肿大未造成气道压迫/阻塞;(2)病变仅局限单个肺叶且无空洞,无粟粒型表现 2.单纯性结核性胸腔积液 3.单纯性外周淋巴结结核
6个月方案[2H-R-Z(E)/4H-R]	所有年龄	1.不符合非重症肺结核或肺外结核的标准 2.其他肺外结核:除结核性脑膜炎和骨关节结核外的其他肺外结核 3.年龄<3个月或体质量<3kg的婴儿结核病患者
4个月方案(2H-Rpt-Mfx-Z/2H-Rpt-Mfx)	≥12岁,且≥40kg	各种类型肺结核
12个月方案(2R-H-Z-E/10R-H)	所有年龄	1.世界卫生组织建议用于治疗结核性脑膜炎,但应考虑以下注意事项:(1)没有明确的数据显示该方案比其他方案更有效;(2)最新研究数据表明,高剂量的R(20~30mg/kg)能改善神经系统结局;(3)最新的药代动力学研究数据也表明,使用高剂量的R、H、Z能改善神经系统结局;(4)有专家建议使用中枢神经系统渗透性更强的药物Lfx(20mg/kg,1次/d)代替E 2.骨关节结核
结核性脑膜炎的6个月强化方案(6R-H-Z-Eth)	所有年龄	结核性脑膜炎:(1)采用较高剂量的R和H;(2)合并HIV感染的儿童和青少年应延长至9个月
糖皮质激素(强的松或地塞米松)	所有年龄	推荐治疗剂量和时间:强的松2mg·kg^-1·d^-1,最大量60mg/d(或地塞米松0.3mg·kg^-1·d^-1,最大量9mg/d),可连续用药4周,随后2~4周逐渐减量,然后停药适应证:(1)结核性脑膜炎治疗的最初6~8周(强烈推荐);(2)中枢神经系统结核发生免疫重建炎症综合征(强烈推荐);(3)其他类型的结核病发生免疫重建炎症综合征(可考虑);(4)支气管结核或胸内淋巴结炎伴有气道压迫(应考虑);(5)结核性心包炎(部分专家推荐)
维生素B6	所有年龄	对于以下情况,建议在H治疗的同时,给予维生素B6,1~2mg·kg^-1·d^-1,最大剂量25mg/d,以降低儿童和青少年神经病变的风险:(1)合并HIV感染的儿童;(2)营养不良的儿童;(3)所有婴儿;(4)所有青少年,尤其是孕妇;(5)接受高剂量H(15~20mg·kg^-1·d^-1)治疗的儿童和青少年

治疗方案	用法用量	预期治疗剂量数	80%的预期治疗剂量数	可接受的完成结核病预防性治疗的时间	特别说明	治疗中断的管理
6H(或9H)	6个月或9个月H,1次/d,10~15mg·kg^-1·d^-1,最大剂量300mg/d	6H:182次;9H:270次	6H:146次;9H:216次	6H:239d;9H:360d	1.该方案是经典的标准方案,但完成度和安全性低于短程方案 2.适用于合并HIV感染且接受抗逆转录病毒治疗的儿童,在青少年中更推荐短程方案^a 3.在美国使用9H而不是6H	1.中断时间<2周,继续完成剩余剂量 2.中断时间≥2周,(1)若已完成≥80%的预期剂量,则继续完成剩余剂量;(2)若已完成<80%的预期剂量,但整个方案可以在可接受的时间内完成,则继续完成剩余剂量;(3)若已完成<80%的预期剂量,但整个方案不可能在可接受的时间内完成,则重新开始结核病预防性治疗
3H-R	3个月R和H,1次/d,R:10~20mg·kg^-1·d^-1,最大剂量600mg/d,H:10~15mg·kg^-1·d^-1,最大剂量300mg/d	84次	68次	120d	适用于<5岁HIV阴性的结核病接触儿童,使用分散剂型的固定剂量复合剂H-R(75mg/50mg)	同6H(或9H)方案
4R	4个月R,1次/d,10~20mg·kg^-1·d^-1,最大剂量600mg/d	120次	96次	160d	1.若有合适的单一R制剂,适用于HIV阴性的儿童及青少年 2.不推荐幼儿使用液体剂型(生物利用率低),但可以打开胶囊,与食物或水混合服用	同6H(或9H)方案
3H-Rpt	3个月H和Rpt,1次/周(12次)^b	12次	-	16周	1.推荐用于HIV感染且抗逆转录病毒治疗方案中包含富马酸替诺福韦二吡酯、依法韦仑、度鲁特韦或雷特格韦的青少年 2.不推荐用于<2岁的儿童 3.目前的药物剂型不适用于幼儿^c	1.漏服1剂:(1)若在2d内补充漏服剂量,则继续原计划治疗;(2)若未在2d内补服,立即补服,并将每周服药时间改为补服的当天,直到方案完成(避免2次服药间隔时间≤4d) 2.若不能在16周内完成治疗计划,则重新开始治疗
1H-Rpt	1个月Rpt和H,1次/d,Rpt:600mg/d,H:300mg/d	28次	23次	6周或8周	1.目前不推荐用于<13岁的儿童或青少年 2.可用于HIV感染且抗逆转录病毒治疗方案中包含富马酸替诺福韦二吡酯、依法韦仑、度鲁特韦或雷特格韦的≥13岁的青少年	1.当中断时间<7d时,(1)若已完成≥80%的预期剂量,则继续完成剩余治疗;(2)若已完成<80%的预期剂量,则在6周内完成剩余治疗 2.若累计中断时间≥7d,但不连续中断,则在8周内完成剩余治疗 3.若连续中断时间≥7d,则重新开始治疗

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药物	剂量范围(最大量)	结核性脑膜炎治疗方案(6H-R-Z-Eth) 的剂量范围(最大量)	2H-Rpt-Mfx-Z/2H-Rpt-Mfx 方案的剂量^b
H	7~15mg/kg(300mg)	15~20mg/kg(400mg)	300mg
R	10~20mg/kg(600mg)	22.5~30mg/kg(600mg)
Z	30~40mg/kg(2000mg)	35~45mg/kg(2000mg)	1500~1600mg; ≥65kg 2000mg
E	15~25mg/kg(1600mg)
Eth		17.5~22.5mg/kg(750mg)
Rpt			1200mg
Mfx			400mg