Yoshikawa Hideo
Kouhoku Total Health Office of Adachi Public Center, Adachi City of Tokyo, 2-30-40, Nishiarai Honcho, Adachi-ku, Tokyo 123-0845, Japan.
Kekkaku. 2012 Sep;87(9):557-64.
Recently, several reports have described a waning response of Mycobacterium tuberculosis (TB)-specific interferon-gamma (IFN-gamma) release assays (IGRAs) performed years after the initial TB infection. Since a considerable part of elderly people in Japan was infected with TB in their youth, it was hypothesized that if the general population was screened with IGRAs, the mean IFN-gamma value of positive subjects (POSITIVES) would be reduced as the age of the subjects increased. Conversely, in subjects who were recently exposed to TB (CONTACTS), it was assumed that the POSITIVES would include subjects with new TB infections who show a high IFN-gamma value and those with old TB infections who show a low IFN-gamma value. Since the presence of subjects with old infections among the POSITIVES cannot be avoided during examinations, it is hypothesized that the mean IFN-gamma value of the POSITIVES decreases as the age of the CONTACTS increases.
To test this hypothesis for CONTACTS, data acquired during the contact examinations at Adachi Public Health Center in Tokyo, Japan were analyzed. Since it is thought that the grade of exposure of the TB index case (INDEX CASE) influences the IFN-gamma value, its relationship with the INDEX CASE and the infectivity of the INDEX CASE were also investigated. In the CONTACTS, as only a few healthcare workers are < 20 years old or > 70 years old, the subjects were chosen from individuals aged in the range of 20-69 years who had been in contact with a TB patient within the past 3 months. The IFN-gamma value of the 188 POSITIVES in the 1145 CONTACTS who underwent a contact examination using the IGRA QuantiFERON-TB Gold In-Tube (QFT-G-IT) assay was investigated. The POSITIVES were divided according to their age class, and their IFN-gamma values were compared. In addition, after dividing all POSITIVES into groups to assess their relationship with the INDEX CASE (i.e., household, relative, healthcare worker, and others), the IFN-gamma values of the 20-49- and 50-69-year-old classes were compared in each group.
There was no significant difference in the IFN-gamma values between the age classes, (Kruskal-Wallis test, P = 0.598). When the IFN-gamma values of the POSITIVES in the 20-49- and 50-69-year-old classes were compared for each relationship group, the mean IFN-gamma value of the POSITIVES increased in proportion to the rise in age only in the healthcare worker group. This occurred even though the mean IFN-gamma value of the POSITIVES decreased in many groups as their age increased. A significant difference was confirmed in the IFN-gamma values between the age classes in the healthcare worker group (Wilcoxon rank-sum test, P < 0.001). No significant difference was observed in the infectivity of the INDEX CASE between the age classes in the healthcare worker group.
Initially, it seemed that the high infectivity of the INDEX CASE affected the IFN-gamma values of the POSITIVES in the oldest age class; in other words, the factor expected to decrease actually increased. However, comparison of the IFN-gamma value by age class in each relationship group revealed that, in the healthcare worker group only, the IFN-gamma value of POSITIVES increased in proportion to the rise in age regardless of infectivity of the INDEX CASE. Since it has been hypothesized that healthcare workers have an increased chance of contact with TB patients than other relationships, this outcome suggests the existence of a booster effect on people who are repeatedly exposed to TB, as assessed using IGRAs, as one of the several possibilities. If this booster effect seen with IGRAs is proven, predicting the development of symptoms and presuming the infection time by using IFN-gamma values will be difficult. To validate the present results, animal experiments that can be adjusted for various biases and confounding factors are necessary.
最近，有几份报告描述了在初次感染结核分枝杆菌（TB）数年之后进行的结核特异性干扰素-γ（IFN-γ）释放试验（IGRAs）反应减弱的情况。由于日本相当一部分老年人在年轻时感染过TB，因此有人推测，如果对普通人群进行IGRAs筛查，随着受试者年龄的增加，阳性受试者（POSITIVES）的平均IFN-γ值将会降低。相反，在近期接触过TB的受试者（CONTACTS）中，假定阳性受试者包括IFN-γ值高的新发TB感染受试者和IFN-γ值低的陈旧TB感染受试者。由于在检查过程中无法避免阳性受试者中存在陈旧感染的受试者，因此推测随着接触者（CONTACTS）年龄的增加，阳性受试者的平均IFN-γ值会降低。
为验证接触者（CONTACTS）的这一假设，对日本东京足立区公共卫生中心在接触者检查期间获取的数据进行了分析。由于认为TB索引病例（INDEX CASE）的接触程度会影响IFN-γ值，因此还研究了其与索引病例的关系以及索引病例的传染性。在接触者（CONTACTS）中，由于只有少数医护人员年龄小于20岁或大于70岁，因此从过去3个月内接触过TB患者的20至69岁个体中选取受试者。对1145名接受了使用IGRA QuantiFERON-TB Gold In-Tube（QFT-G-IT）检测的接触者检查的接触者中的188名阳性受试者（POSITIVES）的IFN-γ值进行了研究。将阳性受试者（POSITIVES）按年龄组划分，并比较其IFN-γ值。此外，在将所有阳性受试者（POSITIVES）分为几组以评估其与索引病例（即家庭、亲属、医护人员和其他）的关系之后，比较了每组中20至49岁和50至69岁年龄组的IFN-γ值。
各年龄组之间的IFN-γ值无显著差异（Kruskal-Wallis检验，P = 0.598）。当比较每个关系组中20至49岁和50至69岁年龄组的阳性受试者（POSITIVES）的IFN-γ值时，仅在医护人员组中，阳性受试者的平均IFN-γ值随年龄增长而升高。尽管在许多组中阳性受试者的平均IFN-γ值随着年龄的增加而降低，但仍出现了这种情况。医护人员组各年龄组之间的IFN-γ值证实存在显著差异（Wilcoxon秩和检验，P < 0.001）。医护人员组各年龄组之间的索引病例（INDEX CASE）传染性未观察到显著差异。
最初，似乎索引病例（INDEX CASE）的高传染性影响了最年长者组中阳性受试者（POSITIVES）的IFN-γ值；换句话说，预期会降低的因素实际上增加了。然而，对每个关系组中按年龄组比较的IFN-γ值显示，仅在医护人员组中，无论索引病例（INDEX CASE）的传染性如何，阳性受试者（POSITIVES）的IFN-γ值均随年龄增长而升高。由于有人推测医护人员比其他关系人群接触TB患者的机会更多，因此这一结果表明，作为几种可能性之一，使用IGRAs评估时，反复接触TB的人群存在增强效应。如果IGRAs所见的这种增强效应得到证实，那么通过IFN-γ值预测症状的发展和推测感染时间将变得困难。为验证目前的结果，需要进行能够针对各种偏差和混杂因素进行调整的动物实验。
