Background

Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood.

Methods

In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).

Findings

In total, study groups from 46 cohort studies in 34 countries—29 (63%) prospective studies and 17 (37%) retrospective—agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4–37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30–0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05–0·15]) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit.

Interpretation

The risk of developing tuberculosis among exposed infants and young children is very high. Most cases occurred within weeks of contact investigation initiation and might not be preventable through prophylaxis. This suggests that alternative strategies for prevention are needed, such as earlier initiation of preventive therapy through rapid diagnosis of adult cases or community-wide screening approaches.

Funding

National Institutes of Health.

中文翻译：

---

儿童近距离接触后患结核病的风险：系统评价和个体参与者荟萃分析。

背景

全球每年有数千万儿童接触结核分枝杆菌；然而，目前还没有对暴露儿童患结核病的风险进行估计。接触者调查和预防性治疗的有效性仍然知之甚少。

方法

在这项系统回顾和荟萃分析中，我们调查了密切接触结核病病例的儿童中结核病的发展情况，并跟踪了发病情况。我们将搜索范围限制为 1998 年 1 月 1 日至 2018 年 4 月 6 日期间在 MEDLINE、Web of Science、BIOSIS 和 Embase 电子数据库中发表的队列研究。所有符合条件的研究的作者都要求提供个体参与者数据和预先指定的变量列表。其中包括暴露儿童的特征、指示病例和环境特征。为了有资格纳入最终分析，数据集需要包括： (1) 19 岁以下的个人；(2) 结核病随访至少6个月；(3) 与结核病患者有家庭接触或密切接触的个人；（四）儿童的年龄、性别信息；(5) 随访开始和结束日期。评估结核病但没有随访日期或时间的研究被排除在外。我们的分析有两个主要目的：（1）通过随访时间段、人口统计（年龄、地区）和临床特征（HIV、结核感染状况、既往结核病）估计患结核病的风险；(2) 评估预防性治疗和卡介苗疫苗接种对患结核病风险的有效性。我们使用混合效应逻辑模型估计了结核病流行的几率，并使用混合效应泊松回归模型估计了结核病发病率的调整后风险比（HR）。通过倾向评分匹配评估结核病预防治疗的有效性。该研究方案已在 PROSPERO 注册（CRD42018087022）。

发现

总的来说，来自 34 个国家 46 项队列研究的研究小组（29 项 (63%) 前瞻性研究和 17 项 (37%) 回顾性研究）同意分享他们的数据并纳入最终分析。对 137 647 名结核病暴露儿童进行了基线评估，并对 130 512 名儿童进行了 429 538 人年的随访，在此期间诊断出 1299 例流行结核病病例和 999 例结核病发病病例。未接受预防性治疗且结核感染结果呈阳性的儿童的 2 年累积结核病发病率显着高于结核感染结果阴性的儿童，且该发病率在 5 岁以下儿童中最高（19·0% [95] % CI 8·4–37·4]）。所有暴露儿童中预防性治疗的有效性为 63%（调整后 HR 0·37 [95% CI 0·30–0·47]），91%（调整后 HR 0·09 [0·05–0·15]） ）在结核感染结果呈阳性的人群中。在所有患结核病的 5 岁以下儿童中，83% 在基线就诊后 90 天内被诊断出来。

解释

接触该病毒的婴儿和幼儿患结核病的风险非常高。大多数病例发生在接触调查开始后几周内，并且可能无法通过预防来预防。这表明需要采取替代预防策略，例如通过成人病例的快速诊断或社区范围的筛查方法来尽早开始预防性治疗。

资金

美国国立卫生研究院。