HIV合并结核感染与HIV合并HPV感染的流行病学与临床研究

发布时间：2018-04-25 17:25

本文选题：人免疫缺陷病毒 + 结核　；参考：《北京协和医学院》2011年硕士论文

【摘要】：背景 HIV合并活动性结核感染是HIV感染者死亡的重要原因之一。我国HIV感染人群中结核病的发病率高,造成了严重的疾病负担。提高潜伏结核和活动性结核的诊断准确性,对控制HIV患者中结核病的治疗和控制至关重要。结核分枝杆菌IFN-γ酶联免疫斑点技术(Enzyme-Linked ImmunoSpot Assay, ELISPOT),在体外利用结核特异性抗原肽刺激外周血单个核细胞,通过酶联显色,计数释放IFN-γ的细胞数,是目前最敏感的检测抗原特异性T细胞的方法之一。其在HIV感染人群及非HIV感染人群中诊断活动性结核的准确性已得到了证实,对结核暴露的相关性也优于TST,提示其诊断LTBI的准确性优于TST。但结核分枝杆菌IFN-γ ELISPOT是否可以有效的监测活动性结核或潜伏结核的治疗效果,是否可以预测活动性结核的发生,目前尚无一致的结论。本实验旨在对活动性结核和潜伏性结核患者进行治疗与随访,探讨结核分枝杆菌IFN-γ ELISPOT对于结核治疗监测和预测活动性结核的应用价值。目的探讨结核分枝杆菌IFN-γ ELISPOT在HIV感染人群中对结核治疗监测和预测活动性结核的应用价值。方法对2009年1月至2010年8月初次于深圳市东湖医院艾滋病门诊就诊的病人进行症状学筛查、结核特异性IFN-γ ELISPOT检测(T-SPOT.TB)、TST、CD4细胞计数及胸部X线或CT检查。对可疑活动性结核的患者进一步行痰涂片(至少连续三次)、痰培养,必要时行肺组织穿刺活检、抗酸染色及组织结核杆菌培养。可疑肺外结核的患者进一步行病变部位组织活检及抗酸染色,以诊断或排除活动性结核。从而评价T-SPOT.TB诊断活动性结核的准确性,以及外周血CD4+T细胞对T-SPOT.TB的影响。将排除活动性结核的T-SPOT.TB阳性的HIV感染者定义为潜伏性结核感染者,随机分为两组分别予INH6个月和INH+RFP3个月预防性抗结核治疗,同时在治疗前、疗程结束和疗程结束后3-6个月进行T-SPOT.TB监测,观察T-SPOT.TB结果在不同治疗方案下的变化。活动性结核感染者,也同样给予正规抗结核治疗,分别在0、3、6、9、12月随访T-SPOT.TB,观察T-SPOT.TB结果随着治疗的变化,评价其用于治疗监测的价值。结果共筛查HIV感染者317例,其中2人因年龄小于18周岁,10人因T-SPOT.TB检验结果不可判断被排除。余下的305人中,32人病原学或临床诊断为活动性结核,273人经症状学筛查和胸部X线片排除活动性结核。活动性结核患者的CD4+T细胞计数低于排除活动性结核患者(median:96vs.222; Mann-Whitney U test, P0.01)。诊断为活动性结核的32人中,24例T-SPOT.TB阳性,余273例排除活动性结核HIV感染者中,54例为T-SPOT.TB阳性。T-SPOT.TB诊断HIV/ATB的灵敏度和特异度分别为75.0%(95%CI：56.6%-88.6%)和80.2%(95%CI：75.0%-84.8%)。在病原学诊断的HIV/ATB患者中,T-SPOT.TB的阳性率升高为90.0%(95%CI：78.3%-98.8%)。比较T-SPOT和TST两种检测方法,T-SPOT.TB检测HIV/ATB的阳性率较高(McNema test,χ2=8.45, P0.05),且不受外周血CD4+T细胞计数水平的影响。在HIV/nonATB患者中,T-SPOT.TB与TST的阳性率分别为19.8%(54/273,95%CI：15.2%-25.0%)和16.1%(41/255,95%CI：11.8%-21.2%),无统计学显著性差异(McNemar test, χ2=2.2, P=0.14),但两者一致性差(kappa=0.2790)。T-SPOT.TB与TST在HIV/nonATB患者中的阳性率均随着CD4+T细胞水平的降低而下降(χ2test for trend, p0.05).基线诊断为HIV/LTBI的54例患者中,22例完成了预防性抗结核治疗和至少1次的随访。2例病人分别在预防性抗结核治疗的第136和191天诊断为活动性结核,余20例病人平均随访373.1+176.4天均未出现活动性结核的表现。疗程结束和疗程结束后3-6个月,患者对ESAT-6(median:23vs.7; Wilcoxon signed rank, P=0.002)和CFP-10的应答水平(median:24.5vs.5; Wilcoxon signed rank,P0.005)均较治疗前降低,但疗程结束后有仅31.6%的患者T-SPOT.TB转阴,不同治疗方案见无统计学显著性差异。队列中的34例活动性结核,有27人接受了正规的抗结核治疗,并完成了至少一次的随访。基线ESAT-6或CFP-10ELISPOT阳性的患者,对ESAT-6(β=-0.1580, P=0.0001)或CFP-10的反应水平(β=-0.1472,P=0.0012)均随着治疗而逐渐下降。但仅有25%的患者在最后一次随访时,T-SPOT.TB已转阴。结论在HIV感染人群中,T-SPOT.TB作为一种诊断活动性结核的辅助手段,其灵敏度和特异度均优于TST,且不受CD4+T细胞计数水平的影响。在广泛接种BCG的国家,其诊断潜伏性结核的准确度不受BCG的影响,优于TST。不论是潜伏性结核或活动性结核,ESAT-6和CFP-10的应答水平均随治疗下降,为T-SPOT.TB用于ATB或LTBI的治疗监测提供了理论依据,但仅有一小部分人群在随访结束时T-SPOT.TB转阴,提示我们应延长随访时间和扩大试验人群,明确T-SPOT.TB持续阳性的原因。背景人乳头状瘤病毒感染是目前已知的与恶性肿瘤发生最为密切的病毒之一,目前已知与HPV感染有密切相关性的恶性肿瘤有宫颈癌、阴道癌、阴户癌、阴茎癌及肛门癌,甚至在部分头颈部肿瘤,尤其是扁桃体癌中同样可以检测到HPV的存在。HPV与HIV均可通过性行为传播,在HIV感染的MSM人群中HPV合并感染率高,且HPV相关的癌前病变在HIV感染的MSM人群中更为常见。本实验旨在研究HIV感染MSM中肛周及口腔HPV感染情况及具体基因型,评估该人群肛门上皮内瘤变、肛门癌及口腔部位肿瘤的潜在风险。目的调查HIV感染MSM肛周及口腔HPV感染情况及具体基因型,评估HPV感染的危险因素,及该人群肛门上皮内瘤变、肛门癌及口腔部位肿瘤的潜在风险。方法对2011年2月至2011年4月,深圳市第三人民医院艾滋病门诊HIV感染的MSM进行肛周及皮肤视诊、醋酸白实验及CD4+T细胞计数,部分病人进行肛周及口腔咽侧壁HPV-DNA检测。观察该人群典型尖锐湿疣的发病率、HPV感染情况,并对年龄、吸烟、男性性伴侣总数、近半年男性性伴侣数、近半年性行为频率、安全套使用频率、包皮环切、药物滥用史、性伴侣尖锐湿疣史以及目前CD4+T细胞计数、最低CD4+T细胞计数、HAART状态等生殖器HPV感染危险因素,以及口生殖器性行为、口交套等口腔HPV感染危险因素进行评估。结果共筛查HIV感染MSM138人,其中20人(14.5%)肛周有典型的尖锐湿疣,38人(27.5%)有可疑皮损,80人(58.0%)肛周无明显皮肤改变。共62人进行口腔及肛周的HPV-DNA检查,13人有典型皮损,28人有可疑皮损,21人无明显肛周皮肤改变,无人有口腔尖锐湿疣表现。肛周HPV-DNA检测在三组人群中阳性率分别为100.0%(13/13)、75.0%(21/28)、71.5%(15/21)；仅2例为口腔HPV-DNA阳性,其口腔及肛周均无明显皮肤改变。HPV-6、11、16、18四型在三组人群中感染率均较高。其它较常见的基因型有HPV45、52、58、53、66等。高危型阳性率在三组人群中分别为69.2%(9/13)、67.9%(19/28)、57.14%(12/21)。HPV感染者中,63.3%为2种及以上基因型感染,仅36.7%为单基因型或未知基因型感染。对年龄、吸烟、男性性伴侣总数、近半年男性性伴侣数、近半年性行为频率、安全套使用频率、包皮环切、药物滥用史、性伴侣尖锐湿疣史以及目前CD4+T细胞计数、最低CD4+T细胞计数、HAART状态等因素,对肛周HPV感染或肛周尖锐湿疣的影响均无统计学显著性。结论中国广东省深圳市HIV感染的MSM人群中,有典型症状尖锐湿疣感染率为14.5%,有症状患者中HPV-DNA阳性率为100%,而在无典型症状患者中HPV-DNA阳性率在75%左右。除HPV-6、11、16、18外,HPV45、52、58、53、66等基因型也较为常见。混合感染率高。口腔尖锐湿疣发病率和口腔HPV感染率低。高危型HPV感染率高,提示需要对该人群进行定期的肛门癌筛查,以及时诊断和治疗。
[Abstract]:background
HIV combined active tuberculosis infection is one of the important causes of death of HIV infected people. The incidence of tuberculosis in HIV infected people in China is high, causing serious disease burden. It is important to improve the diagnostic accuracy of latent tuberculosis and active tuberculosis. It is very important to control the treatment and control of tuberculosis in HIV patients. IFN- gamma enzyme linked by Mycobacterium tuberculosis Enzyme-Linked ImmunoSpot Assay (ELISPOT), using TB specific antigen peptide to stimulate peripheral blood mononuclear cells in vitro, and count the number of IFN- gamma cells through enzyme linked color, is one of the most sensitive methods for detecting antigen specific T cells at present. It is disconnected in HIV infected people and non HIV infected people. The accuracy of dynamic tuberculosis has been confirmed, the correlation of tuberculosis exposure is also better than TST, suggesting that the accuracy of the diagnosis of LTBI is better than that of TST., but whether Mycobacterium tuberculosis IFN- gamma ELISPOT can effectively monitor the therapeutic effect of active tuberculosis or latent tuberculosis and whether it can predict the occurrence of active tuberculosis, there is no consistent conclusion at present. The purpose of this experiment is to treat and follow up the patients with active tuberculosis and latent tuberculosis, and to explore the application value of Mycobacterium tuberculosis IFN- gamma ELISPOT for the monitoring of tuberculosis treatment and prediction of active tuberculosis.
objective
Objective to investigate the application value of Mycobacterium tuberculosis IFN- gamma ELISPOT in monitoring and predicting active tuberculosis in patients with HIV infection.
Method
Symptomatic screening, tuberculosis specific IFN- gamma ELISPOT detection (T-SPOT.TB), TST, CD4 cell count and chest X - ray or CT examination were performed on patients in the AIDS clinic of Shenzhen hospital from January 2009 to early August 2010. Sputum smears (at least three consecutive times) for suspected active tuberculosis patients, sputum culture, necessary Pulmonary tissue biopsy, acid stain and Mycobacterium tuberculosis culture. Patients with suspected extrapulmonary tuberculosis were further performed biopsy and anti acid staining to diagnose or eliminate active tuberculosis. The accuracy of T-SPOT.TB diagnosis of active tuberculosis and the effect of CD4+ T cells in peripheral blood on T-SPOT.TB were evaluated. The T-SPOT.TB positive HIV infection in the nucleus was defined as latent tuberculosis infection, which were randomly divided into two groups for INH6 months and INH+RFP3 months for preventive anti tuberculosis treatment. At the same time, T-SPOT.TB monitoring was carried out at the end of the course of treatment and 3-6 months after the end of the course of treatment. The changes of T-SPOT.TB fruit were observed under different treatments. Active tuberculosis was observed. The infected people were also given regular anti tuberculosis treatment and were followed up for T-SPOT.TB at 0,3,6,9,12 months, and the results of T-SPOT.TB were observed with the change of treatment and the value of their use for treatment monitoring.
Result
A total of 317 cases of HIV infection were screened, of which 2 were aged less than 18 years old and 10 were unable to judge the results of T-SPOT.TB test. Among the remaining 305, 32 were pathogenic or clinically diagnosed as active tuberculosis, 273 were screened by symptomatic screening and chest X ray were excluded from active tuberculosis. The CD4+T cell count of active tuberculosis patients was lower than the exclusion. Patients with active tuberculosis (median:96vs.222; Mann-Whitney U test, P0.01). Among 32 patients diagnosed as active tuberculosis, 24 were T-SPOT.TB positive, and the other 273 excluded active tuberculosis HIV infection, and 54 were T-SPOT.TB positive.T-SPOT.TB diagnostic HIV/ATB sensitivity and specificity were 75% (95%CI:56.6%-88.6%) and 80.2% (95%CI:75.0%-84.8) (95%CI:75.0%-84.8). In the HIV/ATB patients diagnosed by etiology, the positive rate of T-SPOT.TB increased by 90% (95%CI:78.3%-98.8%). Compared with two methods of T-SPOT and TST, the positive rate of HIV/ATB was higher by T-SPOT.TB (McNema test, Chi 2=8.45, P0.05), and was not affected by the level of peripheral blood CD4+T cell counts. The positive rates were 19.8% (54/273,95%CI:15.2%-25.0%) and 16.1% (41/255,95%CI:11.8%-21.2%), and there was no statistically significant difference (McNemar test, Chi 2=2.2, P=0.14), but the positive rates of both kappa=0.2790.T-SPOT.TB and TST in HIV/nonATB patients were decreased with the decrease of CD4+T cell level. 05. Of the 54 patients with a baseline diagnosis of HIV/LTBI, 22 patients completed preventive anti tuberculosis treatment and at least 1 times of follow-up,.2 patients were diagnosed as active tuberculosis on 136th and 191st days of preventive anti tuberculosis treatment. The remaining 20 cases were followed up for 373.1+176.4 days without active tuberculosis. After the end of the course of treatment and the end of the course of treatment. 3-6 months, the patients' response to ESAT-6 (median:23vs.7; Wilcoxon signed rank, P=0.002) and CFP-10 (median:24.5vs.5; Wilcoxon signed rank, P0.005) were lower than before the treatment, but only 31.6% of the patients turned negative after the course of treatment. There were no statistically significant differences in different treatment cases. 34 cases of active tuberculosis in the queue, 27 people received regular anti tuberculosis treatment and completed at least one follow-up. The level of response to ESAT-6 (beta =-0.1580, P=0.0001) or CFP-10 (beta =-0.1472, P=0.0012) in both baseline ESAT-6 or CFP-10ELISPOT positive patients (beta =-0.1472, P=0.0012) gradually declined with treatment. But only 25% of the patients were in the last follow-up, and T-SPOT.TB had turned negative.
conclusion
The sensitivity and specificity of T-SPOT.TB, as a supplementary means for diagnosing active tuberculosis in HIV infected people, are superior to TST and are not affected by the level of CD4+T cells. The accuracy of the diagnosis of latent tuberculosis is not affected by BCG in the widely inoculated countries with BCG, which is superior to TST., whether it is latent tuberculosis or active tuberculosis, ESAT The response levels of both -6 and CFP-10 decreased with treatment, providing a theoretical basis for T-SPOT.TB for ATB or LTBI treatment monitoring, but only a small group of people turned negative at the end of follow-up at the end of the follow-up, suggesting that we should extend the follow-up time and expand the test population to make clear the reasons for the persistent positive of T-SPOT.TB.
background
Human papillomavirus (HPV) infection is one of the most closely related viruses known to occur at present. It is known that malignant tumors, which are closely related to HPV infection, are cervical, vaginal, vulva, penis and anal cancer, and even in some head and neck cancers, especially in tonsillar cancer, the presence of.HPV is also detected. And HIV can be transmitted through sexual behavior, with high incidence of HPV associated infection in HIV infected MSM population, and HPV related precancerous lesions are more common in HIV infected MSM population. The purpose of this study was to study the infection of perianal and HPV in HIV infected MSM and the specific genotypes, and to evaluate the intraepithelial neoplasia, anal and oral swollen in the human group. The potential risk of a tumor.
objective
To investigate the incidence of HPV infection in the perianal and oral MSM and the specific genotype of HIV, to assess the risk factors of HPV infection, and the potential risk of anus intraepithelial neoplasia, anal and oral tumor.
Method
From February 2011 to April 2011, the MSM of HIV infection in AIDS clinic of the third people's Hospital of Shenzhen city was treated with perianal and skin inspection, acetic acid white test and CD4+T cell count. Some patients were detected by HPV-DNA in perianal and oral pharyngeal wall. The incidence of typical condyloma acuminatum, HPV infection, age, smoking and male sex were observed. The total number of partners, the number of sexual partners in the near half of the year, the frequency of the condom use, the frequency of condom use, the circumcision, the history of drug abuse, the history of the condyloma acuminata, the current CD4+T cell count, the lowest CD4+T cell count, the risk factors for the HPV infection in the genitals, as well as the oral genital behavior, and the oral HPV infection, and the risk of HPV infection. Risk factors are evaluated.
Result
A total of MSM138 people were screened for HIV infection, of which 20 (14.5%) had typical condyloma acuminata, 38 (27.5%) had suspected skin lesions, 80 (58%) had no obvious skin changes in perianal. A total of 62 people performed HPV-DNA examination in oral and anal weeks, 13 had typical skin lesions, 28 had suspected skin lesions, 21 people had no obvious perianal skin changes, no one had oral condyloma appearance. The positive rate of perianal HPV-DNA detection in three groups was 100% (13/13), 75% (21/28), 71.5% (15/21); only 2 cases were oral HPV-DNA positive, and there were no obvious skin changes in the oral and anal weeks. The infection rate of.HPV-6,11,16,18 four was higher in the three groups. The other more common genotypes were HPV45,52,58,53,66, and the positive rate of high risk type. Among the three groups, 69.2% (9/13), 67.9% (19/28), 57.14% (12/21).HPV infection, 2 or more genotypes were infected, only 36.7% were monogenic or unknown genotypes. The history of substance abuse, the history of condyloma acuminatum, the current CD4+T cell count, the lowest CD4+T cell count, the HAART state and other factors, had no statistically significant effects on the perianal HPV infection or the perianal condyloma acuminata.
conclusion
Among the MSM population infected with HIV in Shenzhen, Guangdong, China, the infection rate of condyloma acuminata is 14.5%, and the positive rate of HPV-DNA in symptomatic patients is 100%, while the positive rate of HPV-DNA is about 75% in the patients with typical symptoms. Besides HPV-6,11,16,18, the HPV45,52,58,53,66 genotypes are also more common. The mixed infection rate is high. Morbidity and oral HPV infection rate are low. High risk HPV infection rate is high, suggesting the need for regular screening for anal cancer and timely diagnosis and treatment.

【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R512.91;R378.911

【共引文献】