我国结核病和肠道寄生虫病双重流行的研究

发布时间：2018-06-17 02:42

  本文选题：结核病 + 肺结核　； 参考：《中国疾病预防控制中心》2014年博士论文

【摘要】：我国结核病和肠道寄生虫病依然是危害人民健康、影响社会经济发展的重要公共卫生问题。目前,我国已经开展了一些关于结核病和肠道寄生虫病疫情在局部区域的空间分布特征的研究。但在全国尺度下的肺结核患病率和肠道寄生虫感染率的空间分布特征及其影响因素的研究非常缺乏,同时对两类疾病双重流行区域空间分布的研究仍是空白。双重流行是指在同一区域内结核病和肠道寄生虫病疫情均较为严重且两类病原体极有可能在人体内发生双重感染并在该区域造成传播,因此双重流行区域是发生双重感染的高危区域。而双重感染对人体造成的伤害可能会超过单类病原体的伤害或两类病原体的单独伤害之和。但对于结核菌和肠道寄生虫双重感染的流行病学调查以及双重感染时机体免疫状态变化情况的研究却也相当匮乏。因此,我们从上述几个方面对我国肺结核和肠道寄生虫病双重流行进行了研究,为制定两类疾病的国家预防控制规划提供技术支持。 首先,我们在全国尺度下分析了影响肺结核疫情的生态学因素以及这些因素的空间差异性。我们从国家结核病防治规划(2001-2010年)终期评估报告、2002-2011年中国卫生统计年鉴、2002-2011年中国统计年鉴以及各省级政府门户网站上收集2001-2010年的有关数据,利用因子分析法从这些数据中提取潜在变量(肺结核疫情和生态学因素),然后利用偏最小二乘通径模型建立肺结核疫情和生态学因素的结构方程模型。根据结构方程模型生成的参数,我们用地理加权回归模型分析了每个生态学因素的空间差异性。我们提取出了“结核病疫情”以及“结核病防治投入水平”、“结核病防治服务水平”、“卫生投入水平”、“居民健康水平”、“社会经济水平”、“空气质量”、“气候因素”和“地理因素”共8个生态学因素。分析结果显示,“结核病防治投入水平”、卫生投入水平“、社会经济水平”、空气质量“、气候因素”和“地理因素”对“结核病疫情”有明确的可解释的影响,而在这些生态学因素中,在不考虑“结核病防治投入水平”和“卫生投入水平”(其对结核病疫情有直接且显著的影响)的前提下,“社会经济水平”和“地理因素”对“结核病疫情”有相对较强的影响。此外,研究显示,每个生态学因素在不同区域对“结核病疫情”的影响强度也不同,呈现显著的空间差异性。这些结果提示我们,在制定全国结核病预防控制规划时,不仅要综合考虑多种因素的影响,而且要采取因地制宜的策略和措施。 在此研究结果的基础上,我们在全国尺度下预测了2010年肺结核患病率的空间分布特征,这有助于合理分配国家结核病预防控制规划的有限资源。我们利用2010年全国第五次结核病流行病学抽样调查的调查点患病率数据,进行普通克里格插值以生成连续性表面的肺结核患病率地图。为了生成较为准确的预测地图,我们评估了普通克里格插值以及以社会经济因素和地理因素作为协变量的协同克里格插值在不同条件下(去趋势类型、半方差函数模型和各向异性)的预测准确性。根据评估结果,我们选取了以社会经济因素和地理因素作为协变量的全局性协同克里格插值作为最优的插值方法,并生成了肺结核患病率的预测地图。预测地图显示,我国肺结核患病率在京津沪和东南沿海地区较低,在西部和西南地区较高,在中部地区呈现高低交错分布的状态。通过评估最优插值方法,再次证实了社会经济因素和地理因素对我国结核病疫情的影响。 第二,我们在全国尺度下探寻了肺结核和肠道寄生虫病双重流行的空间分布特征。我们利用2010年全国第五次结核病流行病学抽样调查的调查点患病率数据以及2004年完成的第二次全国人体重要寄生虫病现状调查的调查点感染率数据,并在提供数据资源的网站上收集2001-2010年社会经济、气候、地理和环境因素的数据集,通过拟合贝叶斯地统计logistic回归模型来分别分析肺结核和肠道蠕虫感染与社会经济、气候、地理和环境因素之间的关系。根据拟合的模型,利用贝叶斯克里格插值模型分别生成连续性表面的肺结核患病率地图和肠道蠕虫感染率地图。在此基础上,我们通过贝叶斯共有组分模型对两类疾病的预测地图进行联合分析,生成了两类疾病双重流行(共有组分)的相对危险地图。贝叶斯共有组分模型是在假设潜在共有危险因素的前提下评估两类疾病共有方差和专有方差占各自相对危险在空间上的总方差的比例,从而分析两类疾病相对危险的共有组分和专有组分。结果显示,人均GDP较高地区的肺结核患病率水平较低,而农村地区、干旱和高寒气候区域和海拔较高地区是肺结核患病率的高水平地区；人均GDP较高地区和距离水源较远地区的肠道蠕虫感染率水平较低,而暖湿气候区域和归一化植被指数较高地区是肠道蠕虫感染率的高水平地区。预测地图显示,我国西部地区是肺结核患病率的中高水平区域,但却是肠道蠕虫感染率的低水平区域；中部以北地区和东南沿海地区是肺结核患病率的中低水平区域,也是肠道蠕虫感染率的低水平区域；西南地区是肺结核患病率的中高水平区域,也是肠道蠕虫感染率的高水平区域。根据贝叶斯共有组分模型的分析结果,我们发现西南地区是我国肺结核和肠道寄生虫感染的双重流行区域,并推测社会经济因素如人均GDP可能是潜在共有危险因素。因此,我们应该把两类疾病的双重流行区域作为疾病防治的优先区域,制定以改善当地社会经济水平为主要措施的双重感染预防控制策略。 第三,在完成全国尺度下的研究后,我们开展了人体结核菌和肠道寄生虫双重感染的流行病学调查。我们在河南省的一个农业县开展了横断面调查,对该县正在接受抗结核治疗的肺结核患者以及按照邻近区域(同社区或同村)、年龄相仿(±5岁)和同性别匹配的健康对照人群进行了问卷调查,问卷调查内容包括社会人口学情况、健康状况、卫生习惯以及农田劳动情况,并采集了他们的粪样和血样分别进行了粪检、血常规和HIV检测。我们用Pearson x2检验进行肠道寄生虫感染的单因素分析(OR值和95%CI),用多因素logistic回归模型对潜在的混杂因素进行调整(AOR值和95%CI)。而且,我们利用Mantel-Haenszelχ2检验分析了抗结核治疗时间长度对肠道寄生虫感染率的影响。我们总共纳入369名肺结核患者和366名健康对照,他们均为HIV阴性。肺结核患者的肠道寄生虫总感染率为14.9%,其中肠道原虫感染率为7.9%,肠道蠕虫感染率为7.6%,其感染谱从低到高分别为人毛滴虫(0.3%)、华支睾吸虫(0.3%)、蛔虫(0.5%)、阿米巴(1.4%)、鞭虫(2.2%)、钩虫(4.6%)和人芽囊原虫(6.2%)。经过对潜在的混杂因素进行调整,我们没有发现肺结核患者和健康对照的肠道寄生虫总感染率有显著性差异,也未发现有影响因素能够导致两组人群总感染率出现差异。但女性(AOR=2.05,95%CI=1.01-4.17)、BMI≤19(AOR=3.02,95%CI=1.47-6.20)和贫血(AOR=2.43,95%CI=1.17-5.03)是肺结核患者感染肠道寄生虫的危险因素；而在农田平均劳动时间2个月(AOR=4.50,95%CI=2.03-10.00)是健康对照人群感染肠道寄生虫的危险因素。此外,我们未发现抗结核治疗时间长度与肠道寄生虫感染率之间存在剂量反应关系。因此,在本研究中我们尚未获得证据证明肺结核患者对肠道寄生虫易感,但发现在肺结核患者中女性和健康状况不良者更容易感染肠道寄生虫。 我们将肺结核患者分为四组：仅感染肠道原虫者、仅感染肠道蠕虫者、同时感染肠道原虫和蠕虫者以及未感染任何肠道寄生虫者,进一步分析了仅感染肠道原虫和仅感染肠道蠕虫的影响因素以及抗结核治疗时间长度对这两种感染状态的影响。我们发现有7.3%的肺结核患者仅感染了肠道原虫,其感染谱从高到低分别为人芽囊原虫(6.0%)、阿米巴(1.1%)和人毛滴虫(0.3%)；有7.0%的肺结核患者仅感染了肠道蠕虫,其感染谱从高到低分别为钩虫(4.3%)、鞭虫(1.9%)、蛔虫(0.5%)和华支睾吸虫(0.3%)；仅有0.5%的肺结核患者同时感染了肠道原虫和蠕虫。BMI≤18(AOR=3.30,95%CI=1.44-7.54)和饲养家禽或家畜(如,鸡、鸭、猪)(AOR=3.96,95%CI=1.32-11.89)是肺结核患者仅感染肠道原虫的危险因素；BMI≤18(AOR=3.32,95%CI=1.39-7.91)、贫血(AOR=3.40,95%CI=1.44-8.02)和曾在农田赤脚劳动(AOR=4.54,95%CI=1.88-10.92)是肺结核患者仅感染肠道蠕虫的危险因素。我们也未发现抗结核治疗时间长度与肠道原虫和蠕虫感染率之间存在剂量反应关系。总的来说,采取改善营养状况、避免非保护性接触原虫宿主、开展良好卫生习惯方面的健康教育(如外出要穿鞋)等措施有助于在肺结核患者中预防肠道原虫和蠕虫的感染。 第四,在流行病学调查的基础上,我们对结核菌和肠道寄生虫感染时宿主机体免疫反应的变化情况进行了研究。有研究显示,体液免疫和细胞免疫在结核菌感染时对宿主机体发挥着保护性作用,但也有研究显示,钩虫感染可降低宿主对钩虫和其他同时存在的病原体的免疫反应。因此,为了评估结核菌和钩虫双重感染时宿主机体B、T淋巴细胞免疫反应的变化情况,我们从前期流行病学调查的研究对象中选择了17个感染钩虫的肺结核患者、26个未感染任何肠道寄生虫的肺结核患者、15个感染钩虫的健康对照和24个未感染任何肠道寄生虫的健康对照,利用多色流式细胞术对所选研究对象外周血中CD3、CD4、 CD8、CD10、CD19、CD20、CD21、CD25、CD27、CD38、FoxP3和PD-1的表达进行了检测。对于感染钩虫的肺结核患者,其B淋巴细胞亚群(CD19+)中的幼稚B细胞(CD10-CD27-CD21+CD20+)、浆细胞(CD10-CD27+CD21-CD20-)和组织样记忆B细胞(CD10-CD27-CD21-CD20+)的比例较其他组高,静息记忆B细胞(CD10-CD27+CD21+CD20+)的比例较其他组低,而活化的记忆B细胞(CD10-CD27+CD21-CD20+)的比例在各组之间无差异；其T淋巴细胞亚群(CD3+)中的调节性T细胞(CD4+CD25+Foxp3+)、耗竭性CD4+T细胞(CD4+PD-1+)和耗竭性CD8+T细胞(CD8+PD-1+)的比例较其他组高,活化的CD4+T细胞(CD4+CD38+)和活化的CD8+T细胞(CD8+CD38+)的比例较其他组低。结果表明,在结核菌和钩虫双重感染时宿主机体的体液免疫反应和细胞免疫反应均可能受到更多抑制,从而导致肺结核患者的不良治疗结局以及增大其在人群中传播的机会,提示在结核病和肠道寄生虫病双重流行区域预防和控制双重感染的重要性。 综上所述,虽然我们在我国中部农村地区开展了结核菌和肠道寄生虫双重感染的流行病学调查,但却发现西南地区结核病和肠道寄生虫病双重流行的风险要高于中部地区,因此我们建议在我国西南地区开展结核菌和肠道寄生虫双重感染的流行病学调查,全面了解当地疫情,并采取有针对性的干预措施控制双重感染的发生和发展。我们认为在双重流行的高风险地区要采取大力发展当地经济、改善人群营养状况、强化大众健康教育以及培养大众良好卫生习惯的综合防控双重感染的措施,同时要对肺结核患者进行肠道寄生虫感染的筛查,尤其是女性患者和久治不愈的患者,还要制定抗结核和驱虫的联合用药方案对双重感染患者进行规范治疗。
[Abstract]:Tuberculosis and intestinal parasitology in China are still an important public health problem endangering the health of the people and affecting social and economic development. At present, some studies have been carried out on the spatial distribution characteristics of tuberculosis and intestinal parasitic diseases in local areas. However, the prevalence of tuberculosis and intestinal parasites at the national scale are also studied. The study of the spatial distribution characteristics of the infection rate and its influencing factors is very short. At the same time, the study of the spatial distribution of the double epidemic regions of the two types of diseases is still blank. Regions cause transmission, so double epidemic areas are high risk areas for double infection. And double infection may cause more harm than single pathogens or two types of pathogens alone. Therefore, we have studied the dual epidemic of tuberculosis and intestinal parasitology in China from these aspects, and provide technical support for the national prevention and control planning for the formulation of two kinds of diseases.
First, we analyzed the ecological factors affecting the tuberculosis epidemic and the spatial differences of these factors at the national scale, and we collected 2001- from the national tuberculosis control program (2001-2010 years), the 2002-2011 year Chinese Health Statistics Yearbook, the 2002-2011 year Chinese unification Yearbook and the provincial government portal. The related data in 2010 are used to extract potential variables (tuberculosis and ecological factors) from these data by factor analysis, and then use the partial least squares path model to establish the structural equation model of the epidemic and ecological factors of tuberculosis. We have extracted the "tuberculosis epidemic" and "tuberculosis prevention and control input level", "tuberculosis control service level", "health input level", "health level of residents", "socioeconomic level", "air quality", "climate factors" and "geographical factors" altogether 8 ecology. The results show that "tuberculosis control input level", health input level, socioeconomic level, air quality, climate factors and geographical factors have a clear and interpretable effect on "tuberculosis epidemic", and in these ecological factors, "tuberculosis control input level" and "Wei" are not considered. The "socioeconomic level" and "geographical factors" have a relatively strong impact on the "tuberculosis epidemic" on the premise of a direct and significant impact on the epidemic. Furthermore, the study shows that the impact of each ecological factor on the "tuberculosis epidemic" varies in different regions, showing significant vacant levels. These results suggest that we should not only consider the impact of a variety of factors, but also take measures and measures adapted to local conditions in the formulation of the national tuberculosis prevention and control plan.
On the basis of this study, we predict the spatial distribution characteristics of the prevalence of tuberculosis in 2010 at the national scale, which helps to allocate the limited resources of the national tuberculosis prevention and control program. We use the data of the prevalence rate of the fifth tuberculosis epidemiological survey in 2010 to carry out the general Kerrey Lattice interpolation to generate a map of the prevalence of tuberculosis on a continuous surface. In order to generate a more accurate prediction map, we evaluated the prediction of common Craig interpolation and cooperative Craig interpolation with socioeconomic factors and geographical factors as covariate in different conditions (detrending type, semi variance function model and anisotropy). According to the results, we selected the global cooperative Craig interpolation using socioeconomic factors and geographical factors as the covariate as the best interpolation method, and generated a prediction map of the prevalence of tuberculosis. The prediction map shows that the prevalence rate of tuberculosis in China is lower in the Beijing, Tianjin, Shanghai and southeast coastal areas, in the West and in the West. The southwest region is high in the middle region and presents a state of high and low staggered distribution. By evaluating the optimal interpolation method, the influence of socioeconomic factors and geographical factors on the epidemic situation of tuberculosis in China is confirmed again.
Second, we explored the spatial distribution characteristics of the dual epidemic of tuberculosis and intestinal parasitosis at the national scale. We used the data of the prevalence of the survey points in the 2010 National fifth tuberculosis epidemiological survey and the survey point of the infection rate of the survey of the status of the second national human weight parasitism survey completed in 2004. The data collection of social economic, climatic, geographical and environmental factors for 2001-2010 years is collected on the web site which provides data resources. The relationship between tuberculosis and intestinal worms infection and socioeconomic, climatic, geographical and environmental factors is analyzed by fitting Bayesian statistical logistic regression model. On the basis of the Bayesian common component model, we jointly analyze the prediction maps of the two types of diseases and generate the relative risk map of the dual epidemic (common components) of the two types of diseases. The component model is to assess the proportion of the total variance and exclusive variance of two types of diseases, which account for the relative risk in the space, on the premise of the potential common risk factors, and then analyze the common components and the proprietary components of the relative risk of the two types of diseases. The results show that the prevalence of pulmonary tuberculosis in higher areas with higher GDP per capita is lower than that in the higher areas. In rural areas, arid and alpine climates and high altitude regions are high levels of the prevalence of tuberculosis; the rate of intestinal helminth infection is low in higher areas with per capita GDP and in areas far away from the water source, while the warm and wet regions and the higher normalized vegetation index areas are high levels of the infection rate of intestinal worms. The picture shows that the western region of China is the middle and high level area of the prevalence of tuberculosis, but it is a low level area of the infection rate of the intestinal worms; the north region and the southeast coastal area are the middle and low level area of the prevalence of tuberculosis, and the low level of the infection rate of the intestinal worms; the southwest is the middle and high water of the prevalence of tuberculosis. The flat area is also a high level area for the infection rate of intestinal worms. According to the analysis of the Bayesian common component model, we found that the southwest region is a dual epidemic area of tuberculosis and intestinal parasitic infection in China, and that the socioeconomic factors, such as per capita GDP, may be potential common risk factors. Therefore, we should put two types of diseases. The dual epidemic area of disease is a priority area for disease prevention and control, and a dual infection prevention and control strategy is established to improve local social and economic level.
Third, after completing a national scale study, we carried out an epidemiological survey of the dual infection of human tuberculosis and intestinal parasites. We conducted a cross-sectional survey in an agricultural county in Henan Province, which was the same age as tuberculosis patients in the county and in the neighbouring region (with the community or the same village). A questionnaire survey was conducted among healthy controls matched by 5 years of age. The questionnaire included social demography, health, health habits, and farmland work, and collected feces and blood samples from their feces, blood routine and HIV tests. We used Pearson x2 test to infect intestinal parasites. A single factor analysis (OR value and 95%CI) was used to adjust potential confounding factors (AOR and 95%CI) with multiple factor Logistic regression models. Furthermore, we used the Mantel-Haenszel chi 2 test to analyze the effect of the time length of anti tuberculosis treatment on the infection rate of intestinal parasites. We included 369 tuberculosis patients and 366 healthy controls. The total infection rate of intestinal parasites in the patients with pulmonary tuberculosis was 14.9%, of which the infection rate of intestinal protozoa was 7.9%, the infection rate of intestinal worms was 7.6%, and the infection spectrum from low to high was Mao Dichong (0.3%), Clonorchis sinensis (0.3%), Ascaris (0.5%), Amiba (1.4%), flagellum (2.2%), hookworm (4.6%) and human bud bursoma (6.2%). We did not find a significant difference in the total infection rate of the intestinal parasites in the pulmonary tuberculosis patients and the healthy controls, and there were no factors that could lead to the difference in the total infection rate between the two groups, but women (AOR=2.05,95%CI=1.01-4.17), BMI < 19 (AOR=3.02,95%CI=1.47-6.20) and anemia (AOR=2.43,95%CI= 1.17-5.03) is a risk factor for the infection of intestinal parasites in patients with pulmonary tuberculosis; and the average working time of 2 months (AOR=4.50,95%CI=2.03-10.00) is a risk factor for the infection of intestinal parasites in healthy controls. In addition, we have not found a dose response relationship between the length of anti tuberculosis treatment time and the rate of intestinal parasite infection. In this study, we have not yet obtained evidence that tuberculosis patients are susceptible to intestinal parasites, but it is found that in patients with tuberculosis, women and those with poor health are more likely to infect intestinal parasites.
We divided the pulmonary tuberculosis patients into four groups: infected with intestinal protozoa only, infected with intestinal helminth only, infected with intestinal protozoa and worms, and those who did not infect any intestinal parasites, further analyzed the factors affecting intestinal protozoa and only infection of intestinal worms, and the length of anti tuberculosis treatment time to these two infections. We found that 7.3% of tuberculosis patients were infected only with intestinal protozoa, whose infection spectrum was from high to low (6%), Amiba (1.1%) and human Mao Dichong (0.3%); 7% of tuberculosis patients were infected only with intestinal worms, and the infection spectrum from high to low were hookworm (4.3%), flagellum (1.9%), Ascaris (0.5%) and Chinese branch. Testosterone (0.3%); only 0.5% of tuberculosis patients infected with intestinal protozoa and worm.BMI less than 18 (AOR=3.30,95%CI=1.44-7.54) and poultry or domestic animals (such as chickens, ducks, pigs) (AOR=3.96,95%CI=1.32-11.89) were the risk factors for the infection of the intestinal protozoa only in the patients with pulmonary tuberculosis; BMI < 18 (AOR=3.32,95%CI=1.39-7.91), anemia (AOR=3.40,95%CI=). 1.44-8.02) and former cropland barefoot labor (AOR=4.54,95%CI=1.88-10.92) are the risk factors for the only infection of intestinal worms in patients with tuberculosis. We have not found a dose response relationship between the length of anti tuberculosis treatment and the rate of intestinal protozoa and worm infection. In general, it is necessary to improve nutritional status and avoid unprotected contact with protozoa. The main idea is to carry out health education in good health habits (such as shoes to go out) and other measures to prevent infection of intestinal protozoa and worms in patients with pulmonary tuberculosis.
Fourth, based on the epidemiological investigation, we studied the changes in the host immune response to the tuberculosis and intestinal parasites. Studies have shown that humoral and cellular immunity play a protective role in the host organism when the Mycobacterium tuberculosis infection is infected, but there are also studies showing that the hookworm infection can reduce the host's effect. The immune responses of the hookworm and other concurrently existing pathogens, so in order to assess the changes in the immune response of the host body B and T lymphocytes during the dual infection of tuberculosis and hookworm, we selected 17 lung nodules from the early epidemiological investigation and 26 lungs that were not infected with any intestinal parasite. TB patients, healthy controls of 15 hookworm infections and 24 healthy controls that were not infected with any intestinal parasite, were tested by polychromatic cytometry for the expression of CD3, CD4, CD8, CD10, CD19, CD20, CD21, CD25, CD27, CD38, FoxP3 and PD-1 in the peripheral blood of selected subjects.
【学位授予单位】：中国疾病预防控制中心
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R52;R53
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本文编号：2029274