本文選題：結核病 + 肺結核��； 參考：《中國疾病預防控制中心》2014年博士論文

【摘要】：我國結核病和腸道寄生蟲病依然是危害人民健康、影響社會經濟發(fā)展的重要公共衛(wèi)生問題。目前,我國已經開展了一些關于結核病和腸道寄生蟲病疫情在局部區(qū)域的空間分布特征的研究。但在全國尺度下的肺結核患病率和腸道寄生蟲感染率的空間分布特征及其影響因素的研究非常缺乏,同時對兩類疾病雙重流行區(qū)域空間分布的研究仍是空白。雙重流行是指在同一區(qū)域內結核病和腸道寄生蟲病疫情均較為嚴重且兩類病原體極有可能在人體內發(fā)生雙重感染并在該區(qū)域造成傳播,因此雙重流行區(qū)域是發(fā)生雙重感染的高危區(qū)域。而雙重感染對人體造成的傷害可能會超過單類病原體的傷害或兩類病原體的單獨傷害之和。但對于結核菌和腸道寄生蟲雙重感染的流行病學調查以及雙重感染時機體免疫狀態(tài)變化情況的研究卻也相當匱乏。因此,我們從上述幾個方面對我國肺結核和腸道寄生蟲病雙重流行進行了研究,為制定兩類疾病的國家預防控制規(guī)劃提供技術支持。 首先,我們在全國尺度下分析了影響肺結核疫情的生態(tài)學因素以及這些因素的空間差異性。我們從國家結核病防治規(guī)劃(2001-2010年)終期評估報告、2002-2011年中國衛(wèi)生統(tǒng)計年鑒、2002-2011年中國統(tǒng)計年鑒以及各省級政府門戶網站上收集2001-2010年的有關數據,利用因子分析法從這些數據中提取潛在變量(肺結核疫情和生態(tài)學因素),然后利用偏最小二乘通徑模型建立肺結核疫情和生態(tài)學因素的結構方程模型。根據結構方程模型生成的參數,我們用地理加權回歸模型分析了每個生態(tài)學因素的空間差異性。我們提取出了“結核病疫情”以及“結核病防治投入水平”、“結核病防治服務水平”、“衛(wèi)生投入水平”、“居民健康水平”、“社會經濟水平”、“空氣質量”、“氣候因素”和“地理因素”共8個生態(tài)學因素。分析結果顯示,“結核病防治投入水平”、衛(wèi)生投入水平“、社會經濟水平”、空氣質量“、氣候因素”和“地理因素”對“結核病疫情”有明確的可解釋的影響,而在這些生態(tài)學因素中,在不考慮“結核病防治投入水平”和“衛(wèi)生投入水平”(其對結核病疫情有直接且顯著的影響)的前提下,“社會經濟水平”和“地理因素”對“結核病疫情”有相對較強的影響。此外,研究顯示,每個生態(tài)學因素在不同區(qū)域對“結核病疫情”的影響強度也不同,呈現顯著的空間差異性。這些結果提示我們,在制定全國結核病預防控制規(guī)劃時,不僅要綜合考慮多種因素的影響,而且要采取因地制宜的策略和措施。 在此研究結果的基礎上,我們在全國尺度下預測了2010年肺結核患病率的空間分布特征,這有助于合理分配國家結核病預防控制規(guī)劃的有限資源。我們利用2010年全國第五次結核病流行病學抽樣調查的調查點患病率數據,進行普通克里格插值以生成連續(xù)性表面的肺結核患病率地圖。為了生成較為準確的預測地圖,我們評估了普通克里格插值以及以社會經濟因素和地理因素作為協(xié)變量的協(xié)同克里格插值在不同條件下(去趨勢類型、半方差函數模型和各向異性)的預測準確性。根據評估結果,我們選取了以社會經濟因素和地理因素作為協(xié)變量的全局性協(xié)同克里格插值作為最優(yōu)的插值方法,并生成了肺結核患病率的預測地圖。預測地圖顯示,我國肺結核患病率在京津滬和東南沿海地區(qū)較低,在西部和西南地區(qū)較高,在中部地區(qū)呈現高低交錯分布的狀態(tài)。通過評估最優(yōu)插值方法,再次證實了社會經濟因素和地理因素對我國結核病疫情的影響。 第二,我們在全國尺度下探尋了肺結核和腸道寄生蟲病雙重流行的空間分布特征。我們利用2010年全國第五次結核病流行病學抽樣調查的調查點患病率數據以及2004年完成的第二次全國人體重要寄生蟲病現狀調查的調查點感染率數據,并在提供數據資源的網站上收集2001-2010年社會經濟、氣候、地理和環(huán)境因素的數據集,通過擬合貝葉斯地統(tǒng)計logistic回歸模型來分別分析肺結核和腸道蠕蟲感染與社會經濟、氣候、地理和環(huán)境因素之間的關系。根據擬合的模型,利用貝葉斯克里格插值模型分別生成連續(xù)性表面的肺結核患病率地圖和腸道蠕蟲感染率地圖。在此基礎上,我們通過貝葉斯共有組分模型對兩類疾病的預測地圖進行聯(lián)合分析,生成了兩類疾病雙重流行(共有組分)的相對危險地圖。貝葉斯共有組分模型是在假設潛在共有危險因素的前提下評估兩類疾病共有方差和專有方差占各自相對危險在空間上的總方差的比例,從而分析兩類疾病相對危險的共有組分和專有組分。結果顯示,人均GDP較高地區(qū)的肺結核患病率水平較低,而農村地區(qū)、干旱和高寒氣候區(qū)域和海拔較高地區(qū)是肺結核患病率的高水平地區(qū)；人均GDP較高地區(qū)和距離水源較遠地區(qū)的腸道蠕蟲感染率水平較低,而暖濕氣候區(qū)域和歸一化植被指數較高地區(qū)是腸道蠕蟲感染率的高水平地區(qū)。預測地圖顯示,我國西部地區(qū)是肺結核患病率的中高水平區(qū)域,但卻是腸道蠕蟲感染率的低水平區(qū)域；中部以北地區(qū)和東南沿海地區(qū)是肺結核患病率的中低水平區(qū)域,也是腸道蠕蟲感染率的低水平區(qū)域；西南地區(qū)是肺結核患病率的中高水平區(qū)域,也是腸道蠕蟲感染率的高水平區(qū)域。根據貝葉斯共有組分模型的分析結果,我們發(fā)現西南地區(qū)是我國肺結核和腸道寄生蟲感染的雙重流行區(qū)域,并推測社會經濟因素如人均GDP可能是潛在共有危險因素。因此,我們應該把兩類疾病的雙重流行區(qū)域作為疾病防治的優(yōu)先區(qū)域,制定以改善當地社會經濟水平為主要措施的雙重感染預防控制策略。 第三,在完成全國尺度下的研究后,我們開展了人體結核菌和腸道寄生蟲雙重感染的流行病學調查。我們在河南省的一個農業(yè)縣開展了橫斷面調查,對該縣正在接受抗結核治療的肺結核患者以及按照鄰近區(qū)域(同社區(qū)或同村)、年齡相仿(±5歲)和同性別匹配的健康對照人群進行了問卷調查,問卷調查內容包括社會人口學情況、健康狀況、衛(wèi)生習慣以及農田勞動情況,并采集了他們的糞樣和血樣分別進行了糞檢、血常規(guī)和HIV檢測。我們用Pearson x2檢驗進行腸道寄生蟲感染的單因素分析(OR值和95%CI),用多因素logistic回歸模型對潛在的混雜因素進行調整(AOR值和95%CI)。而且,我們利用Mantel-Haenszelχ2檢驗分析了抗結核治療時間長度對腸道寄生蟲感染率的影響。我們總共納入369名肺結核患者和366名健康對照,他們均為HIV陰性。肺結核患者的腸道寄生蟲總感染率為14.9%,其中腸道原蟲感染率為7.9%,腸道蠕蟲感染率為7.6%,其感染譜從低到高分別為人毛滴蟲(0.3%)、華支睪吸蟲(0.3%)、蛔蟲(0.5%)、阿米巴(1.4%)、鞭蟲(2.2%)、鉤蟲(4.6%)和人芽囊原蟲(6.2%)。經過對潛在的混雜因素進行調整,我們沒有發(fā)現肺結核患者和健康對照的腸道寄生蟲總感染率有顯著性差異,也未發(fā)現有影響因素能夠導致兩組人群總感染率出現差異。但女性(AOR=2.05,95%CI=1.01-4.17)、BMI≤19(AOR=3.02,95%CI=1.47-6.20)和貧血(AOR=2.43,95%CI=1.17-5.03)是肺結核患者感染腸道寄生蟲的危險因素；而在農田平均勞動時間2個月(AOR=4.50,95%CI=2.03-10.00)是健康對照人群感染腸道寄生蟲的危險因素。此外,我們未發(fā)現抗結核治療時間長度與腸道寄生蟲感染率之間存在劑量反應關系。因此,在本研究中我們尚未獲得證據證明肺結核患者對腸道寄生蟲易感,但發(fā)現在肺結核患者中女性和健康狀況不良者更容易感染腸道寄生蟲。 我們將肺結核患者分為四組：僅感染腸道原蟲者、僅感染腸道蠕蟲者、同時感染腸道原蟲和蠕蟲者以及未感染任何腸道寄生蟲者,進一步分析了僅感染腸道原蟲和僅感染腸道蠕蟲的影響因素以及抗結核治療時間長度對這兩種感染狀態(tài)的影響。我們發(fā)現有7.3%的肺結核患者僅感染了腸道原蟲,其感染譜從高到低分別為人芽囊原蟲(6.0%)、阿米巴(1.1%)和人毛滴蟲(0.3%)；有7.0%的肺結核患者僅感染了腸道蠕蟲,其感染譜從高到低分別為鉤蟲(4.3%)、鞭蟲(1.9%)、蛔蟲(0.5%)和華支睪吸蟲(0.3%)；僅有0.5%的肺結核患者同時感染了腸道原蟲和蠕蟲。BMI≤18(AOR=3.30,95%CI=1.44-7.54)和飼養(yǎng)家禽或家畜(如,雞、鴨、豬)(AOR=3.96,95%CI=1.32-11.89)是肺結核患者僅感染腸道原蟲的危險因素；BMI≤18(AOR=3.32,95%CI=1.39-7.91)、貧血(AOR=3.40,95%CI=1.44-8.02)和曾在農田赤腳勞動(AOR=4.54,95%CI=1.88-10.92)是肺結核患者僅感染腸道蠕蟲的危險因素。我們也未發(fā)現抗結核治療時間長度與腸道原蟲和蠕蟲感染率之間存在劑量反應關系�？偟膩碚f,采取改善營養(yǎng)狀況、避免非保護性接觸原蟲宿主、開展良好衛(wèi)生習慣方面的健康教育(如外出要穿鞋)等措施有助于在肺結核患者中預防腸道原蟲和蠕蟲的感染。 第四,在流行病學調查的基礎上,我們對結核菌和腸道寄生蟲感染時宿主機體免疫反應的變化情況進行了研究。有研究顯示,體液免疫和細胞免疫在結核菌感染時對宿主機體發(fā)揮著保護性作用,但也有研究顯示,鉤蟲感染可降低宿主對鉤蟲和其他同時存在的病原體的免疫反應。因此,為了評估結核菌和鉤蟲雙重感染時宿主機體B、T淋巴細胞免疫反應的變化情況,我們從前期流行病學調查的研究對象中選擇了17個感染鉤蟲的肺結核患者、26個未感染任何腸道寄生蟲的肺結核患者、15個感染鉤蟲的健康對照和24個未感染任何腸道寄生蟲的健康對照,利用多色流式細胞術對所選研究對象外周血中CD3、CD4、 CD8、CD10、CD19、CD20、CD21、CD25、CD27、CD38、FoxP3和PD-1的表達進行了檢測。對于感染鉤蟲的肺結核患者,其B淋巴細胞亞群(CD19+)中的幼稚B細胞(CD10-CD27-CD21+CD20+)、漿細胞(CD10-CD27+CD21-CD20-)和組織樣記憶B細胞(CD10-CD27-CD21-CD20+)的比例較其他組高,靜息記憶B細胞(CD10-CD27+CD21+CD20+)的比例較其他組低,而活化的記憶B細胞(CD10-CD27+CD21-CD20+)的比例在各組之間無差異；其T淋巴細胞亞群(CD3+)中的調節(jié)性T細胞(CD4+CD25+Foxp3+)、耗竭性CD4+T細胞(CD4+PD-1+)和耗竭性CD8+T細胞(CD8+PD-1+)的比例較其他組高,活化的CD4+T細胞(CD4+CD38+)和活化的CD8+T細胞(CD8+CD38+)的比例較其他組低。結果表明,在結核菌和鉤蟲雙重感染時宿主機體的體液免疫反應和細胞免疫反應均可能受到更多抑制,從而導致肺結核患者的不良治療結局以及增大其在人群中傳播的機會,提示在結核病和腸道寄生蟲病雙重流行區(qū)域預防和控制雙重感染的重要性。 綜上所述,雖然我們在我國中部農村地區(qū)開展了結核菌和腸道寄生蟲雙重感染的流行病學調查,但卻發(fā)現西南地區(qū)結核病和腸道寄生蟲病雙重流行的風險要高于中部地區(qū),因此我們建議在我國西南地區(qū)開展結核菌和腸道寄生蟲雙重感染的流行病學調查,全面了解當地疫情,并采取有針對性的干預措施控制雙重感染的發(fā)生和發(fā)展。我們認為在雙重流行的高風險地區(qū)要采取大力發(fā)展當地經濟、改善人群營養(yǎng)狀況、強化大眾健康教育以及培養(yǎng)大眾良好衛(wèi)生習慣的綜合防控雙重感染的措施,同時要對肺結核患者進行腸道寄生蟲感染的篩查,尤其是女性患者和久治不愈的患者,還要制定抗結核和驅蟲的聯(lián)合用藥方案對雙重感染患者進行規(guī)范治療。
[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.
【學位授予單位】：中國疾病預防控制中心
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R52;R53
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本文編號：2029274