本文關(guān)鍵詞：上海地區(qū)結(jié)核病患者接觸者感染率和結(jié)核易感性研究，由筆耕文化傳播整理發(fā)布。

        目的：通過現(xiàn)場流行病學(xué)調(diào)查,初步掌握上海市結(jié)核病患者密切接觸者結(jié)核潛隱感染現(xiàn)狀及其影響因素,為降低上海地區(qū)結(jié)核新發(fā)感染率以及發(fā)病率提供依據(jù)。通過病例對照研究,探討細胞因子相關(guān)基因Y-干擾素(interferon-y, IFN-y)基因+874位點、白介素-10(interleukin-10, IL-10)-1082G/A位點及腫瘤壞死因子-α(TNF-a)-308位點單核苷酸多態(tài)性(single nucleotide polymorphisms, SNP)與上海地區(qū)人群結(jié)核菌感染及肺結(jié)核發(fā)病易感性的關(guān)系；揭示結(jié)核菌感染和肺結(jié)核發(fā)病環(huán)境危險因素；初步分析環(huán)境與基因以及基因和基因交互作用對上海地區(qū)人群結(jié)核菌感染、肺結(jié)核發(fā)病的影響。方法：1.橫斷面研究：2010年2月至2010年12月期間,于上海市7個區(qū)共挑選982名結(jié)核病患者密切接觸者進行問卷調(diào)查并采集血樣進行TSPOT.TB實驗檢測結(jié)核感染狀態(tài),獲得結(jié)核密切接觸者潛隱結(jié)核感染率；結(jié)合人口學(xué)、臨床特征、接觸結(jié)核患者既往治療史、人口流動等因素,采用單因素χ2檢驗和logistic回歸分析初步探討潛隱結(jié)核感染的環(huán)境危險因素。2.雙病例對照研究：肺結(jié)核發(fā)病易感性研究研究對象為肺結(jié)核病人和結(jié)核潛隱感染者,結(jié)核菌感染易感性研究研究對象為結(jié)核潛隱感染者和非結(jié)核感染者。2011年5月-2011年12月期間,于上海市閔行區(qū)疾病預(yù)防控制中心收集肺結(jié)核病人109例,于上海市結(jié)核病患者密切接觸者感染率調(diào)查的密切接觸者中選取確診的結(jié)核潛隱感染的密接183人和非結(jié)核感染的密接314人作為本研究的對象。問卷調(diào)查獲得研究對象社會人口學(xué)及環(huán)境因素資料,采集血樣并提取DNA,對IFN-y基因+874位點、IL-10基因-1082位點、TNF-a基因-308位點進行基因擴增,數(shù)據(jù)的錄入與分析分別采用EpiData3.0和SPSS16.0(Chicago, Illinois, USA)統(tǒng)計軟件,應(yīng)用單因素χ2檢驗和多因素logistic回歸分析環(huán)境因素、基因多態(tài)及其交互作用與結(jié)核菌感染、肺結(jié)核發(fā)病之間的關(guān)系。結(jié)果：1.橫斷面研究：研究期間,共對982名結(jié)核病患者密切接觸者進行問卷調(diào)查和血樣采集,有13人因為基本信息缺失或TSPOT.TB實驗失敗而被排除,共計969名接觸者被納入作為本研究的對象。288人(29.7%)被檢測為結(jié)核感染陽性,其中1人經(jīng)影像學(xué)診斷為結(jié)核病,其余287人被診斷為潛隱結(jié)核感染。不同區(qū)縣接觸者的結(jié)核潛隱感染率存在明顯不同,最低為長寧區(qū)(19.9%),最高為浦東區(qū)(45.0%)；結(jié)核潛隱感染在男性和女性人群中分布無明顯差異(27.8%vs31.0%,p=0.29)；結(jié)核潛隱感染風(fēng)險隨年齡有增加趨勢,在30歲以上人群中這一趨勢尤其明顯。logistic多因素分析結(jié)果顯示接觸涂陽結(jié)核病人發(fā)生結(jié)核潛隱感染的風(fēng)險是接觸涂陰病人的2.24倍(33.9%vs19.4%；OR,2.24；95%CI：1.59-3.16)；家庭接觸發(fā)生結(jié)核潛隱感染的風(fēng)險是其他場所接觸的1.52倍(32.3%vs21.3%；OR,1.52；95%CI：1.06-2.18)；與接觸場所面積<60m2相比,接觸場所面積為60-120m2(OR,0.69；95%CI：0.51-0.94)和>120m2(OR,49；95%CI：0.30-0.80)對結(jié)核潛隱感染有保護作用；同樣接觸時間(OR,1.003；95%CI：1.001-1.005)與接觸者發(fā)生結(jié)核潛隱感染的風(fēng)險相關(guān)。2.病例對照研究：肺結(jié)核發(fā)病易感性研究共計納入肺結(jié)核病人109人,平均年齡44.5±17.2歲,男性67.9%；結(jié)核潛隱感染者183人,平均年齡50.5±18.1歲,男性38.8%。結(jié)核菌感染易感性研究納入結(jié)核潛隱感染者(同肺結(jié)核發(fā)病易感性研究)；以及非結(jié)核感染者314人,平均年齡49.4±18.4歲,男性38.8%。采用非條件logistic回歸模型對結(jié)核菌感染易感性相關(guān)因素進行多因素分析,結(jié)果顯示,接觸涂陽結(jié)核病人發(fā)生潛隱感染的風(fēng)險是接觸涂陰病人的2.33倍(aOR,2.33；95％CI:1.27-4.27)；接觸有咳嗽癥狀的結(jié)核病人發(fā)生潛隱感染的風(fēng)險是接觸無咳嗽癥狀病人的1.84倍(aOR,1.84；95％CI:1.11-3.06)；未發(fā)現(xiàn)接觸時間、接觸場所面積、接觸場所通風(fēng)條件,BMI、流動人口、受教育程度,以及IFN-γ+874T/A、IL-10-1082G/A、TNF-α-308G/A位點型基因多態(tài)性與結(jié)核潛隱感染相關(guān)。采用非條件logistic回歸模型對肺結(jié)核發(fā)病易感性研究相關(guān)因素進行多因素分析,結(jié)果顯示,男性肺結(jié)核發(fā)病風(fēng)險為女性的3.92倍(aOR,3.92;95%CI:2.02-5.50);與BMI指數(shù)≥18.5的個體相比,BMI指數(shù)<18.5的個體肺結(jié)核病發(fā)病風(fēng)險顯著增高(aOR,5.09;95%CI:1.83-14.18);與本地常住人口相比,流動人口結(jié)核病發(fā)病風(fēng)險顯著增加,為前者的53.61倍(aOR,53.61;95%CI:87.06-999.99)；與IFN-γ+874位點野生型TT相比,純合突變型AA比值比aOR為4.88(95%CI：1.61-14.86),將突變型TA和AA合并后aOR為2.58(95%CI：1.11-6.00),純合突變型AA及突變型(TA或AA)為肺結(jié)核發(fā)病危險因素；與IL-10-1082位點野生型GG相比,雜合型GA和純合突變型AA的aOR分別為0.19(95%CI：0.06-0.62)和0.20(95%CI：0.06-0.66),突變型GA和AA均為肺結(jié)核發(fā)病保護性因素；與TNF-α-308位點野生型GG相比,雜合型GA的aOR為5.47(95%CI：2.33-12.86),將突變型GA和AA合并后aOR為4.36(95%CI：1.99-9.57),雜合型GA和突變型(GA和AA)為肺結(jié)核發(fā)病危險因素；未發(fā)現(xiàn)受教育程度及年齡與肺結(jié)核發(fā)病風(fēng)險相關(guān)。與IFN-y+874位點TT野生型和TNF-α-308位點GG野生型相比,同時攜帶IFN-y+874位點突變型(AA或AT)與TNF-α-308位點GG野生型結(jié)核潛隱感染發(fā)生風(fēng)險顯著降低(OR,0.55；95%CI：0.35-0.86)；未見IFN-γ+874T/A和IL-10-1082G/A,以及IL-10-1082G/A和TNF-α-308G/A基因多態(tài)間存在有統(tǒng)計學(xué)意義的聯(lián)系。與攜帶IL-10-1082位點突變型(GA或AA)和接觸痰涂片陰性肺結(jié)核病人相比,攜帶IL-10-1082位點突變型(GA或AA)同時接觸痰涂片陽性肺結(jié)核病人結(jié)核潛隱感染發(fā)生率顯著增加(OR,2.18；95%CI：1.22-3.90)；未見IFN-γ+874T/A基因多態(tài)與接觸肺結(jié)核病人痰涂片,以及TNF-α-308G/A基因多態(tài)與接觸肺結(jié)核病人痰涂片間存在有統(tǒng)計學(xué)意義的聯(lián)系。IFN-y+874與IL-10-1082,IFN-y+874與TNF-α-308,IL-10-1082與TNF-α-308交互效應(yīng)比值比OR分別為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位點基因多態(tài)與BMI的交互效應(yīng)比值比OR分別為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),未見三位點基因多態(tài)與BMI,以及IFN-y+874、IL-10-1082及TNF-α-308位點基因多態(tài)間存在有統(tǒng)計學(xué)意義的相乘交互效應(yīng)。結(jié)論：上海地區(qū)結(jié)核病患者密切接觸者中的結(jié)核感染率較高,家庭接觸是導(dǎo)致接觸者發(fā)生結(jié)核潛隱感染的主要場所,接觸時間的增加會增加結(jié)核潛隱感染的風(fēng)險,同時接觸場所面積、通風(fēng)情況與結(jié)核感染風(fēng)險相關(guān)。男性、營養(yǎng)不良、外來流動人口可能與肺結(jié)核發(fā)病風(fēng)險增高相關(guān)；IFN-γ基因、IL-10基因和TNF-α基因可能是肺結(jié)核發(fā)病易感基因；接觸肺結(jié)核病人痰涂片陽性、接觸肺結(jié)核病人咳嗽為結(jié)核菌感染的環(huán)境危險因素。本研究提示對痰涂片陽性和有咳嗽癥狀的肺結(jié)核病人應(yīng)及時治療,并在結(jié)核病患者密切接觸者中及時篩查結(jié)核潛隱感染者；對潛隱結(jié)核感染中的特定高危人群及時監(jiān)測或給予預(yù)防性治療以進一步降低結(jié)核新發(fā)感染率和發(fā)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.

上海地區(qū)結(jié)核病患者接觸者感染率和結(jié)核易感性研究

常用縮略語3-4目錄4-5中文摘要5-9Abstract9-12前言13-19第一部分 上海地區(qū)結(jié)核病患者接觸者結(jié)核感染狀況及其危險因素研究19-32    對象和方法20-24    結(jié)果24-29    討論29-31    小結(jié)31-32第二部分 上海地區(qū)結(jié)核菌感染和肺結(jié)核發(fā)病易感性研究32-57    對象和方法33-37    結(jié)果37-52    討論52-56    小結(jié)56-57總結(jié)57-60參考文獻60-70致謝70-71附錄一 綜述71-80    參考文獻76-80附錄二 碩士研究生期間發(fā)表的論文80-81

  本文關(guān)鍵詞：上海地區(qū)結(jié)核病患者接觸者感染率和結(jié)核易感性研究，，由筆耕文化傳播整理發(fā)布。