上海地区结核病患者接触者感染率和结核易感性研究

  本文关键词：上海地区结核病患者接触者感染率和结核易感性研究，由笔耕文化传播整理发布。

        目的：通过现场流行病学调查,初步掌握上海市结核病患者密切接触者结核潜隐感染现状及其影响因素,为降低上海地区结核新发感染率以及发病率提供依据。通过病例对照研究,探讨细胞因子相关基因Y-干扰素(interferon-y, IFN-y)基因+874位点、白介素-10(interleukin-10, IL-10)-1082G/A位点及肿瘤坏死因子-α(TNF-a)-308位点单核苷酸多态性(single nucleotide polymorphisms, SNP)与上海地区人群结核菌感染及肺结核发病易感性的关系；揭示结核菌感染和肺结核发病环境危险因素；初步分析环境与基因以及基因和基因交互作用对上海地区人群结核菌感染、肺结核发病的影响。方法：1.横断面研究：2010年2月至2010年12月期间,于上海市7个区共挑选982名结核病患者密切接触者进行问卷调查并采集血样进行TSPOT.TB实验检测结核感染状态,获得结核密切接触者潜隐结核感染率；结合人口学、临床特征、接触结核患者既往治疗史、人口流动等因素,采用单因素χ2检验和logistic回归分析初步探讨潜隐结核感染的环境危险因素。2.双病例对照研究：肺结核发病易感性研究研究对象为肺结核病人和结核潜隐感染者,结核菌感染易感性研究研究对象为结核潜隐感染者和非结核感染者。2011年5月-2011年12月期间,于上海市闵行区疾病预防控制中心收集肺结核病人109例,于上海市结核病患者密切接触者感染率调查的密切接触者中选取确诊的结核潜隐感染的密接183人和非结核感染的密接314人作为本研究的对象。问卷调查获得研究对象社会人口学及环境因素资料,采集血样并提取DNA,对IFN-y基因+874位点、IL-10基因-1082位点、TNF-a基因-308位点进行基因扩增,数据的录入与分析分别采用EpiData3.0和SPSS16.0(Chicago, Illinois, USA)统计软件,应用单因素χ2检验和多因素logistic回归分析环境因素、基因多态及其交互作用与结核菌感染、肺结核发病之间的关系。结果：1.横断面研究：研究期间,共对982名结核病患者密切接触者进行问卷调查和血样采集,有13人因为基本信息缺失或TSPOT.TB实验失败而被排除,共计969名接触者被纳入作为本研究的对象。288人(29.7%)被检测为结核感染阳性,其中1人经影像学诊断为结核病,其余287人被诊断为潜隐结核感染。不同区县接触者的结核潜隐感染率存在明显不同,最低为长宁区(19.9%),最高为浦东区(45.0%)；结核潜隐感染在男性和女性人群中分布无明显差异(27.8%vs31.0%,p=0.29)；结核潜隐感染风险随年龄有增加趋势,在30岁以上人群中这一趋势尤其明显。logistic多因素分析结果显示接触涂阳结核病人发生结核潜隐感染的风险是接触涂阴病人的2.24倍(33.9%vs19.4%；OR,2.24；95%CI：1.59-3.16)；家庭接触发生结核潜隐感染的风险是其他场所接触的1.52倍(32.3%vs21.3%；OR,1.52；95%CI：1.06-2.18)；与接触场所面积<60m2相比,接触场所面积为60-120m2(OR,0.69；95%CI：0.51-0.94)和>120m2(OR,49；95%CI：0.30-0.80)对结核潜隐感染有保护作用；同样接触时间(OR,1.003；95%CI：1.001-1.005)与接触者发生结核潜隐感染的风险相关。2.病例对照研究：肺结核发病易感性研究共计纳入肺结核病人109人,平均年龄44.5±17.2岁,男性67.9%；结核潜隐感染者183人,平均年龄50.5±18.1岁,男性38.8%。结核菌感染易感性研究纳入结核潜隐感染者(同肺结核发病易感性研究)；以及非结核感染者314人,平均年龄49.4±18.4岁,男性38.8%。采用非条件logistic回归模型对结核菌感染易感性相关因素进行多因素分析,结果显示,接触涂阳结核病人发生潜隐感染的风险是接触涂阴病人的2.33倍(aOR,2.33；95％CI:1.27-4.27)；接触有咳嗽症状的结核病人发生潜隐感染的风险是接触无咳嗽症状病人的1.84倍(aOR,1.84；95％CI:1.11-3.06)；未发现接触时间、接触场所面积、接触场所通风条件,BMI、流动人口、受教育程度,以及IFN-γ+874T/A、IL-10-1082G/A、TNF-α-308G/A位点型基因多态性与结核潜隐感染相关。采用非条件logistic回归模型对肺结核发病易感性研究相关因素进行多因素分析,结果显示,男性肺结核发病风险为女性的3.92倍(aOR,3.92;95%CI:2.02-5.50);与BMI指数≥18.5的个体相比,BMI指数<18.5的个体肺结核病发病风险显著增高(aOR,5.09;95%CI:1.83-14.18);与本地常住人口相比,流动人口结核病发病风险显著增加,为前者的53.61倍(aOR,53.61;95%CI:87.06-999.99)；与IFN-γ+874位点野生型TT相比,纯合突变型AA比值比aOR为4.88(95%CI：1.61-14.86),将突变型TA和AA合并后aOR为2.58(95%CI：1.11-6.00),纯合突变型AA及突变型(TA或AA)为肺结核发病危险因素；与IL-10-1082位点野生型GG相比,杂合型GA和纯合突变型AA的aOR分别为0.19(95%CI：0.06-0.62)和0.20(95%CI：0.06-0.66),突变型GA和AA均为肺结核发病保护性因素；与TNF-α-308位点野生型GG相比,杂合型GA的aOR为5.47(95%CI：2.33-12.86),将突变型GA和AA合并后aOR为4.36(95%CI：1.99-9.57),杂合型GA和突变型(GA和AA)为肺结核发病危险因素；未发现受教育程度及年龄与肺结核发病风险相关。与IFN-y+874位点TT野生型和TNF-α-308位点GG野生型相比,同时携带IFN-y+874位点突变型(AA或AT)与TNF-α-308位点GG野生型结核潜隐感染发生风险显著降低(OR,0.55；95%CI：0.35-0.86)；未见IFN-γ+874T/A和IL-10-1082G/A,以及IL-10-1082G/A和TNF-α-308G/A基因多态间存在有统计学意义的联系。与携带IL-10-1082位点突变型(GA或AA)和接触痰涂片阴性肺结核病人相比,携带IL-10-1082位点突变型(GA或AA)同时接触痰涂片阳性肺结核病人结核潜隐感染发生率显著增加(OR,2.18；95%CI：1.22-3.90)；未见IFN-γ+874T/A基因多态与接触肺结核病人痰涂片,以及TNF-α-308G/A基因多态与接触肺结核病人痰涂片间存在有统计学意义的联系。IFN-y+874与IL-10-1082,IFN-y+874与TNF-α-308,IL-10-1082与TNF-α-308交互效应比值比OR分别为1.95(95%CI:0.45-8.44, p=0.374),2.05(95%CI:0.73-5.78,p=0.173),3.08(95%CI:0.52-18.23,ρ=0.216), IFN-γ+874、IL-10-1082及TNF-α-308位点基因多态与BMI的交互效应比值比OR分别为3.08(95%CI：0.82-11.61,p=0.097),2.71(95%CI:0.28-26.76,p=0.393),1.21(95%CI：0.33-4.38,p=0.775),未见三位点基因多态与BMI,以及IFN-y+874、IL-10-1082及TNF-α-308位点基因多态间存在有统计学意义的相乘交互效应。结论：上海地区结核病患者密切接触者中的结核感染率较高,家庭接触是导致接触者发生结核潜隐感染的主要场所,接触时间的增加会增加结核潜隐感染的风险,同时接触场所面积、通风情况与结核感染风险相关。男性、营养不良、外来流动人口可能与肺结核发病风险增高相关；IFN-γ基因、IL-10基因和TNF-α基因可能是肺结核发病易感基因；接触肺结核病人痰涂片阳性、接触肺结核病人咳嗽为结核菌感染的环境危险因素。本研究提示对痰涂片阳性和有咳嗽症状的肺结核病人应及时治疗,并在结核病患者密切接触者中及时筛查结核潜隐感染者；对潜隐结核感染中的特定高危人群及时监测或给予预防性治疗以进一步降低结核新发感染率和发病率。

    ObjectiveTo investigate the prevalence of latent TB infection (LTBI) and its related factors among the intimate contactors of active pulmonary tuberculosis patients through the field epidemiology survey, aim to provide the basis for decreasing the incidence of LTBI and TB. To explore the possible environmental risk factors of LTBI and pulmonary tuberculosis; relationship between the+874T/A single nucleotide polymorphisms (SNP) in interferon-r (IFN-γ) gene, the-1082G/A SNP in interleukin-10(IL-10), the-308G/A SNP in tumor necrosis factor-α gene of population and susceptibility to LTBI and pulmonary tuberculosis, and further to explore the interaction with environmental factors to LTBI and pulmonary tuberculosis.Methods1. Cross sectional study:From the February of2010to the December of2010,982persons closely contacted with pulmonary tuberculosis patients were enrolled from seven districts of Shanghai. Questionnaire interview was applied to investigate the socio-demographic and clinical information related to LTBI. The T-SPOT.TB method was used to detect LTBI in the studied subjects. Prevalence of LTBI were acquired, χ2test and unconditional logistic regression were occupied to identify the risk factors associated with LTBI among the contacts.2. Case control study:Between1st May2011and15th December2011,109pulmonary tuberculosis cases meeting to standard coming from MinHang Center for Disease Control and Prevention were collected, LTBI and non tuberculsos infection were enrolled from the survey of the prevalence of LTBI in the intimate contactors with active pulmonary tuberculosis patients in Shanghai,183LTBI and314non tuberculsos infection were enrolled in this study. Face to face interviews were carried out to collect their socio-demographic and clinical information, and blood samples were collected after informed consent. The+874IFN-γT/A,-1082IL-10G/A,-308 TNF-α G/A SNP were detected in subjects by polymerase chain reaction (PCR) and DN A sequencing. EpiData3.0software and SPSS16.0statistical software were use to input and analyze data,χ2test and unconditional logistic regression were occupied to measure the relationship between environmental factors, genetic polymorphisms, and the possible gene-environment and gene-gene interaction in the risk of LTBI and pulmonary tuberculosis by calculating odds ratio(OR) and95%confidence interval(95%CI).Results1. Cross sectional study:Totally,982intimate contactors of active pulmonary tuberculosis patients were collect questionnaires and blood samples, among them13persons were excluded for basic information missing or T-SPOT.TB test failure, finally969contacts were enrolled in this study. T-SPOT.TB test identified288(29.7%) contacts with the positive result, among them one person were further diagnosed with TB; meanwhile without clinical sign and symptom relevant to TB under the further medical examination, the rest287contacts were defined with LTBI. The prevalence of LTBI was different between districts, lowest in ChangNing district (19.9%) and highest in PuDong district (45.0%). No difference in prevalence was seen in male and female. The risk of LTBI was increased along with the increase of age, the tendency was especially apparent in the age greater than30years old population. In multivariate logistic analysis, compared with contact with sputum negative TB patients, contact with sputum positivity TB patients significantly increased the risk of LTBI (33.9%vs19.4%;OR,2.24;95%CI:1.59-3.16); compared with other contact place, contact within the family is also a risk factors of LTBI (32.3%vs21.3%;OR,1.52;95%CI:1.06-2.18); compared with contact place area<60m2, contact place area was between60and120m2(OR,0.69;95%CI:0.51-0.94)和>120m2(OR,0.49;95%CI:0.30-0.80) were protective factors for TB infection; the time of contact is also associated with LTBI (OR,1.003;95%CI:1.001-1.005).2. Case control study:Totally,109pulmonary tb patients(men67.9%) were enrolled in this study with the average age of44.5±17.2,183LTBI(men38.6%, age in mean of50.5±18.1years old) and314non tb infection(men38.6%, age in mean of49.4±18.4years old)were encruited.The result from unconditional logistic regression suggested that contact with sputum positivity TB patients could increase the risk of LTBI with aOR of2.33(95%CI:1.27-4.27); contact with TB patients who has a cough sympton could increase the risk of LTBI with aOR of1.84(95%CI:1.11-3.06). We didn’t found the relationship between the time of contact, the area and the ventilation of the contact place, gender, age, nutrition, floating population, education,+874IFN-y T/A,-1082IL-10G/A,-308TNF-a G/A SNP with the risk of LTBI.The result from unconditional logistic regression suggested that male is a risk factors of LTBI with a aOR of3.34(95%CI:2.02-5.50); malnutrition (BMK18.5) could increase the risk of pulmonary TB with aOR of2.29(95%CI:1.25-4.20); floating population could increase the risk of pulmonary TB with aOR of53.61(95%CI:87.06-999.99); compared with+874IFN-y TT genotype, subjects with AA and TA/AA genotype has aORs of4.88(95%CI:1.61-14.86),2.58(95%CI:1.11-6.00), respectively; compared with-1082IL-10GG genotype, subjects with GA, AA genotype has aORs of0.19(95%CI:0.06-0.62),0.20(95%CI:0.06-0.66), respectively; compared with-308TNF-a GG genotype, subjects with GA and GA/AA has aORs of5.47(95%CI:2.33-12.86),4.36(95%CI:1.99-9.57), respectively. We didn’t found the relationship of age, education with the risk of pulmonary TB.Compared with wild genotypes of+874IFN-γ and-308TNF-α, subjects with+874IFN-γ variant genotype (TA or AA) and-308TNF-a GG genotype had a significant lower risk of LTBI (OR,0.55;95%CI:0.35-0.86), we didn’t found any relationship between+874IFN-y and-1082IL-10,-1082IL-10and-308TNF-a to LTBI. Compared with subjects with-1082IL-10variant genotype (GA or AA) and contact with sputum negative TB patients, subjects with-1082IL-10variant genotype (GA or AA) and contact with sputum positivity TB patients had a significant higher risk LTBI. we didn’t found any relationship between+874IFN-y and the sputum result of TB patients,-308TNF-a and the sputum result of TB patients to LTBI.The ORs for interaction of+874IFN-y and-1082IL-10,+874IFN-y and-308TNF-a,-1082IL-10and-308TNF-a were1.95(95%CI:0.45-8.44, p=0.374),2.05(95%CI:0.73-5.78,p=0.173),3.08(95%CI:0.52-18.23,p=0.216), respectively. The ORs for interaction of+874IFN-y,-1082IL-10,-308TNF-a SNP, and BMI were3.08(95%CI:0.82-11.61, p=0.097),2.71(95%CI:0.28-26.76,p=0.393),1.21(95%CI:0.33-4.38, p=0.775), respectively. We did not found a positive multiple interaction between IFN-y+874, IL-10-1082, TNF-α-308SNP and the BMI to pulmonary TB; and the interaction between IFN-y+874and IL-10-1082, IFN-y+874and TNF-α-308, IL-10-1082and TNF-α-308SNP to pulmonary TB.ConclusionThe prevalence of LTBI among the intimate contactors with active pulmonary tuberculosis patients was high in ShangHai. Household was the main place of contact, the contact duration, area and ventilation condition of the contact place are associated with the LTBI. Male, malnutrition, floating population+874IFN-y AA,308TNF-a AA SNP are risk factors of pulmonary TB but not of LTBI,-1082IL-10AA is protective factor of pulmonary TB but not of LTBI. Contact with patients who has a cough symptom or positive sputum are risk factors of LTBI. Suggest that timely treatment for TB patients, especially sputum positive TB patients or patients who has a cough symptom, should be of top priorities for TB control in contact in Shanghai, and house-hold contact follow up is important for TB intervention, especially those with a poor ventilation condition or small area of the contact place. In order to decreasing the pulmonary TB incidence, closely attention should be payed to carry malnutrition or floating population among LTBI, preventive treatment should be given if is possible.

上海地区结核病患者接触者感染率和结核易感性研究

常用缩略语3-4目录4-5中文摘要5-9Abstract9-12前言13-19第一部分 上海地区结核病患者接触者结核感染状况及其危险因素研究19-32    对象和方法20-24    结果24-29    讨论29-31    小结31-32第二部分 上海地区结核菌感染和肺结核发病易感性研究32-57    对象和方法33-37    结果37-52    讨论52-56    小结56-57总结57-60参考文献60-70致谢70-71附录一 综述71-80    参考文献76-80附录二 硕士研究生期间发表的论文80-81

  本文关键词：上海地区结核病患者接触者感染率和结核易感性研究，，由笔耕文化传播整理发布。