Research progress of interferon-gamma-dependent immune response in tuberculous pleuritis
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摘要: 结核性胸膜炎(TP)是肺外结核的常见表现形式, 通常由结核分枝杆菌(MTB)感染胸膜所致，胸膜腔中会积累大量的免疫活性细胞并伴随细胞因子的释放，其中最为关键的是γ干扰素(IFN-γ)。IFN-γ既是宿主保护性免疫细胞分泌的重要因子，也是抗MTB免疫反应中特有的促炎性细胞因子环境标志物。本文对IFN-γ依赖性免疫应答在TP发病机制、诊断及治疗监测中的研究进展进行综述，以期为TP的诊治提供新的思路。Abstract: Tuberculous pleuritis (TP) is a common manifestation of extrapulmonary tuberculosis, which is usually caused by Mycobacterium tuberculosis(MTB) infection of the pleura. A large number of immunocompetent cells are accumulated in the pleural cavity, accompanied by the release of cytokines, among which interferon-gamma (IFN-γ) is the most important. IFN-γ is not only an important factor secreted by the host protective immune cells, but also a specific environmental marker of pro-inflammatory cytokines in anti-MTB immune response. This article reviewed the research progress of IFN-γ-dependent immune response in the pathogenesis, diagnosis and therapeutic monitoring of TP in order to provide new ideas for the diagnosis and treatment of TP.
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新生儿胎粪吸入综合征(MAS)是新生儿常见并发症，由胎儿宫内窘迫、胎粪吸入呼吸道、肺泡机械性阻塞等因素导致，具有较高病死率[1-2]。据统计[3], MAS患病率为1.2%~2.3%, 病死率占7.5%~15.0%, 存活者多伴中枢神经系统后遗症、颅内出血等并发症，预后欠佳。目前，临床治疗MAS尚无统一标准性方案，以呼吸机、高浓度氧疗、高频通气等方式为主，对MAS治疗有一定效果，但呼吸机因操作复杂、并发症多等，且呼吸机使用难以逆转肺表面活性物质(PS)失活现象，影响患儿恢复效果[4-5]。PS是肺泡Ⅱ型上皮细胞分泌脂蛋白，具降低肺泡表面张力、改善肺氧合能力作用。因此有研究[6]提出，对MAS患儿采取PS治疗，以纠正广泛性肺泡萎缩、PS失活表现。本研究对本院2018年1月—2019年3月收治的200例MAS患儿采取PS联合呼吸机治疗，现将结果报告如下。
1. 资料与方法
1.1 一般资料
选取本院2018年1月—2019年3月收治的200例MAS患儿，按数字随机表法分为2组。对照组100例，男53例，女47例; 胎龄38~41周，平均(39.50±0.41)周; 出生体质量2.07~4.01 kg, 平均(2.94±0.43) kg; 出生至发病时间2~10 h, 平均(5.41±0.42) h; 新生儿1 min Apgar评分(6.84±0.35)分。观察组100例，男55例，女45例; 胎龄38~42周，平均(39.51±0.42)周; 出生体质量2.05~4.02 kg, 平均(2.95±0.42) kg; 出生至发病时间3~10 h, 平均(5.45±0.40) h; 新生儿1 min Apgar评分(6.85±0.35)分。2组患儿基线资料比较无显著差异(P>0.05), 可进行比较。纳入标准: ①患儿羊水被胎粪污染、气管内吸出胎粪污染羊水，经临床表现、影像学技术等综合检查，与《实用儿科学》[7]中MAS诊断标准相符; ②符合《新生儿机械通气治疗学》[8]中呼吸机治疗标准; ③患儿家长或法定监护人知情研究，签署同意书; ④研究内容符合医学伦理委员会审批标准。排除标准: ①出生体质量 < 2.0 kg; ②出生至发病时间>12 h; ③出生10 min Apgar评分 < 3分; ④先天性畸形、血液系统疾病或先天性心脏病者; ⑤预计生存时间 < 3个月; ⑥中途退出研究者。
1.2 治疗方法
2组患儿入院常规治疗，常规保暖、祛痰、清理呼吸道分泌物、抗生素预防感染、营养能量供给、心功能支持、维持水电解质平衡。对照组患儿在常规治疗基础上接受呼吸机治疗，使用Stephanie型呼吸机(德国斯蒂芬公司生产)，设置压力控制、同步间歇指令通气模式，呼吸频率20~50次/min, 吸气时间0.4~0.5 s, 吸入气氧浓度(FiO2)0.5~0.8, 平均气道压(MAP)10~17 cmH2O, 呼吸峰压18~25 cmH2O, 呼吸末正压3~5 cmH2O, 同时依据经皮血氧饱和度(SaO2)调整呼吸机参数。观察组联合呼吸机与PS治疗，呼吸机治疗同对照组, PS治疗如下。取外源性PS(国药准字H20052128, 华润双鹤药业股份有限公司)一次性给药，剂量200 mg/kg, 先将药物复温，取仰卧位，吸尽呼吸道内分泌物，清洁消毒，气管内注入，取5 mL注射器抽取PS, 于气管导管内穿刺，药液匀速注入肺内，使用气囊加压给氧，于肺内充分弥散，维持SaO2≥90%, 给药6~8 h内不得吸痰。
1.3 观察指标
① 肺氧合功能: 氧合指数(OI); ②血气指标: 动脉血氧分压[p(O2)]、动脉血二氧化碳分压[p(CO2)]; ③呼吸机参数: MAP、FiO2及上机时间; ④统计2组患儿治疗并发症，包括呼吸机相关性肺炎、缺氧缺血性脑病、肺气漏等。
1.4 统计学方法
采用SPSS 23.0统计学软件包对研究数据进行处理。变量资料采用(x±s)表示，行t检验; 无序分类资料采用百分比表示，采取χ2检验; 以P < 0.05为差异有统计学意义。
2. 结果
2.1 2组治疗前后肺氧合功能比较
治疗前, 2组OI比较无显著差异(P>0.05); 2组治疗12、24 h OI较治疗前下降，观察组较对照组下降更显著，差异有统计学意义(P < 0.05), 见表 1。
表 1 2组治疗前后氧合指数比较(x±s)组别 治疗前 治疗12 h 治疗24 h 观察组(n=100) 22.10±1.96 14.28±1.41*# 11.05±1.29*# 对照组(n=100) 22.08±1.95 18.95±1.52* 15.96±1.31* 与治疗前比较, *P < 0.05; 与对照组比较, #P < 0.05。 2.2 2组血气分析指标比较
治疗前, 2组血气分析指标比较无显著差异(P>0.05); 治疗12、24 h后，血气分析指标较治疗前改善，且观察组较对照组改善更显著(P < 0.05), 见表 2。
表 2 2组血气分析指标比较(x±s)mmHg 组别 p(CO2) p(O2) 治疗前 治疗12 h 治疗24 h 治疗前 治疗12 h 治疗24 h 观察组(n=100) 60.05±2.96 47.04±3.15*# 38.96±3.05*# 45.21±7.15 64.27±6.96*# 78.41±7.01*# 对照组(n=100) 59.96±2.84 53.41±3.08* 49.24±3.08* 45.30±7.16 54.04±6.98* 62.75±7.00* p(O2): 动脉血氧分压; p(CO2): 动脉血二氧化碳分压。与治疗前比较, *P < 0.05; 与对照组比较, #P < 0.05 2.3 2组治疗前后呼吸机参数比较
2组治疗前MAP、FiO2比较无显著差异(P>0.05); 治疗12、24 h MAP、FiO2下降，观察组较对照组下降更显著，差异有统计学意义(P < 0.05), 观察组上机时间短于对照组，差异有统计学意义(P < 0.05), 见表 3。
表 3 2组治疗前后呼吸机参数比较(x±s)组别 MAP/cmH2O FiO2 上机时间/h 治疗前 治疗12 h 治疗24 h 治疗前 治疗12 h 治疗24 h 对照组(n=100) 17.28±1.64 16.96±1.10* 15.05±1.51* 0.55±0.11 0.50±0.11* 0.46±0.12* 85.46±24.08 观察组(n=100) 17.30±1.65 14.36±1.05*# 12.15±1.48*# 0.56±0.12 0.42±0.10*# 0.31±0.10*# 42.05±9.63# FiO2: 吸入气氧浓度; MAP: 平均气道压。与治疗前比较, *P < 0.05; 与对照组比较, #P < 0.05。 2.4 2组并发症及病死率比较
观察组呼吸机相关性肺炎、肺气漏发生率及病死率均低于对照组，差异有统计学意义(P < 0.05), 见表 4。
表 4 2组并发症及病死率比较[n(%)]组别 呼吸机相关性肺炎 肺气漏 缺氧缺血性脑病 死亡 观察组(n=100) 5(5.00)* 7(7.00)* 8(8.00) 2(2.00)* 对照组(n=100) 16(16.00) 21(21.00) 11(11.00) 13(13.00) 与对照组比较, *P < 0.05。 3. 讨论
MAS是因胎儿宫内吸入混有胎粪羊水，导致小气道机械性梗阻，在吸入12~24 h刺激小气道，引起肺部高炎症反应、肺间质水肿及气道完全或不完全梗阻。呼吸机是治疗MAS的常用手段，可有效纠正机体缺氧、酸中毒状态，增加肺泡面积、提高肺顺应性，减少肺内分流，改善呼吸道塌陷，减少呼吸阻力，促使肺通气功能改善[9]。但MAS患儿在呼吸机治疗期间，会损伤气道黏膜，促使细菌迁移及繁殖，增高呼吸机相关性肺炎、肺气漏等并发症发生率，因此联合其他方式成为当前临床研究重点。
MAS患儿多存在PS灭活现象，因胎粪中溶蛋白酶、磷脂、游离脂肪酸等物质使PS灭活，造成继发性PS缺乏，肺泡萎陷、肺急性损伤、肺顺应性下降等[10]。PS物质主要覆盖于肺泡内面，是维持肺通气功能的重要物质，具降低肺泡内压、减少肺泡渗出等作用[11]。王娴等[12]对MAS患儿重复使用PS, 结果患儿治疗后血氧分压升高, MAP、FiO2下降，较治疗前比较有显著差异(P < 0.05), 所有患儿存活，无死亡病例。黎敏等[13]对PS患儿采取机械通气联合PS治疗，联合组患儿机械通气时间、氧暴露时间、住院时间较机械通气组患儿缩短，存活率为95.24%, 高于机械通气治疗组的90.47%。樊晓艳等[14]对MAS患儿采取PS气管内注射，机械通气时间、氧暴露时间及住院时间缩短, OI指数下降。本研究中，观察组治疗后肺氧合功能、血气分析指标较对照组改善，治疗12、24 h MAP、FiO2低于对照组，上机时间短于对照组。结果发现，对MAS患儿采取呼吸机联合PS治疗，可提高肺顺应性，增强肺氧合功能，改善肺通气功能，且能缩短患儿上机时间，使患儿尽快接受治疗。
外源性PS给药能拮抗肺组织间隙内蛋白渗出，减轻肺炎症反应，并能减少胎粪中胆固醇、胆红素等有害物质，在最大程度上改善肺部功能，减轻肺部炎症程度[15-16]。对MAS患儿采取外源性PS给药，能够缓解因高氧暴露、正压通气造成的气道损伤、肺部损伤; 增强肺表面活性物质代谢能力，抑制蛋白渗入肺泡间隙，抑制该物质合成及分泌[17]; 降低核转录因子Kb表达，调控炎症反应[18]。本研究观察组呼吸机相关性肺炎、肺气漏发生率、病死率低于对照组。因此, PS联合呼吸机可降低肺损伤发生率，提高患儿存活率。综上所述, PS联合呼吸机治疗MAS能获得理想效果，可改善肺功能，降低并发症发生率，提升MAS存活率，临床价值高。
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