Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Johannesburg, South Africa.
Johns Hopkins University Center for TB Research, Baltimore, Maryland, United States of America.
PLoS Med. 2023 May 22;20(5):e1004237. doi: 10.1371/journal.pmed.1004237. eCollection 2023 May.
The World Health Organization (WHO) recommends systematic symptom screening for tuberculosis (TB). However, TB prevalence surveys suggest that this strategy does not identify millions of TB patients, globally. Undiagnosed or delayed diagnosis of TB contribute to TB transmission and exacerbate morbidity and mortality. We conducted a cluster-randomized trial of large urban and rural primary healthcare clinics in 3 provinces of South Africa to evaluate whether a novel intervention of targeted universal testing for TB (TUTT) in high-risk groups diagnosed more patients with TB per month compared to current standard of care (SoC) symptom-directed TB testing.
Sixty-two clinics were randomized; with initiation of the intervention clinics over 6 months from March 2019. The study was prematurely stopped in March 2020 due to clinics restricting access to patients, and then a week later due to the Coronavirus Disease 2019 (COVID-19) national lockdown; by then, we had accrued a similar number of TB diagnoses to that of the power estimates and permanently stopped the trial. In intervention clinics, attendees living with HIV, those self-reporting a recent close contact with TB, or a prior episode of TB were all offered a sputum test for TB, irrespective of whether they reported symptoms of TB. We analyzed data abstracted from the national public sector laboratory database using Poisson regression models and compared the mean number of TB patients diagnosed per clinic per month between the study arms. Intervention clinics diagnosed 6,777 patients with TB, 20.7 patients with TB per clinic month (95% CI 16.7, 24.8) versus 6,750, 18.8 patients with TB per clinic month (95% CI 15.3, 22.2) in control clinics during study months. A direct comparison, adjusting for province and clinic TB case volume strata, did not show a significant difference in the number of TB cases between the 2 arms, incidence rate ratio (IRR) 1.14 (95% CI 0.94, 1.38, p = 0.46). However, prespecified difference-in-differences analyses showed that while the rate of TB diagnoses in control clinics decreased over time, intervention clinics had a 17% relative increase in TB patients diagnosed per month compared to the prior year, interaction IRR 1.17 (95% CI 1.14, 1.19, p < 0.001). Trial limitations were the premature stop due to COVID-19 lockdowns and the absence of between-arm comparisons of initiation and outcomes of TB treatment in those diagnosed with TB.
Our trial suggests that the implementation of TUTT in these 3 groups at extreme risk of TB identified more TB patients than SoC and could assist in reducing undiagnosed TB patients in settings of high TB prevalence.
South African National Clinical Trials Registry DOH-27-092021-4901.
世界卫生组织（WHO）建议对结核病（TB）进行系统的症状筛查。然而，TB 流行率调查表明，这种策略并未在全球范围内发现数百万 TB 患者。TB 的未确诊或延迟诊断导致 TB 传播加剧，并导致发病率和死亡率上升。我们在南非 3 个省份的大型城市和农村初级保健诊所进行了一项集群随机试验，以评估针对高危人群的新型 TB 靶向普遍检测（TUTT）干预措施是否比当前的基于症状的 TB 检测的标准护理（SoC）每月诊断出更多的 TB 患者。
62 家诊所被随机分组；从 2019 年 3 月开始，干预诊所逐步启动。由于诊所限制了患者的就诊机会，该研究于 2020 年 3 月提前停止，一周后又因 2019 年冠状病毒病（COVID-19）全国封锁而停止；到那时，我们已经积累了与预期效果相似的 TB 诊断数量，并永久性地停止了试验。在干预诊所中，居住在 HIV 中的患者、自我报告最近与 TB 有密切接触的患者或以前有过 TB 发作的患者，均提供 TB 痰检，无论他们是否报告有 TB 症状。我们使用泊松回归模型分析了从国家公共部门实验室数据库中提取的数据，并比较了研究臂之间每月每个诊所诊断的 TB 患者数量的平均值。干预诊所诊断出 6777 例 TB 患者，每月每诊所 20.7 例 TB（95%CI16.7，24.8），而对照诊所每月诊断出 6750 例 TB 患者，每月每诊所 18.8 例 TB（95%CI15.3，22.2）。在研究月份，对省级和诊所 TB 病例量分层进行调整后，直接比较并未显示 2 个手臂之间的 TB 病例数量存在显著差异，发病率比（IRR）为 1.14（95%CI1.14，1.18，p=0.46）。然而，预设的差异分析表明，尽管对照诊所的 TB 诊断率随时间下降，但与前一年相比，干预诊所每月诊断的 TB 患者相对增加了 17%，交互 IRR 为 1.17（95%CI1.14，1.19，p<0.001）。试验的局限性在于 COVID-19 封锁导致的提前停止，以及在诊断出 TB 的患者中，缺乏关于 TB 治疗开始和结果的臂间比较。
我们的试验表明，在这 3 个极高风险的 TB 人群中实施 TUTT 比 SoC 发现了更多的 TB 患者，并可能有助于减少高 TB 流行地区的未确诊 TB 患者。
南非国家临床试验注册处 DOH-27-092021-4901。
