DataSheet_2_Harnessing Big Data to Optimize an Algorithm for Rapid Diagnosis of Pulmonary Tuberculosis in a Real-World Setting.docx

BackgroundThe prompt diagnosis of pulmonary tuberculosis (PTB) remains a challenge in clinical practice. The present study aimed to optimize an algorithm for rapid diagnosis of PTB in a real-world setting.
Methods28,171 adult inpatients suspected of having PTB in China were retrospectively analyzed. Bronchoalveolar lavage fluid (BALF) and/or sputum were used for acid-fast bacilli (AFB) smear, Xpert MTB/RIF (Xpert), and culture. A positive mycobacterial culture was used as the reference standard. Peripheral blood mononuclear cells (PBMC) were used for T-SPOT.TB. We analyzed specimen types’ effect on these assays’ performance, determined the number of smears for diagnosing PTB, and evaluated the ability of these assays performed alone, or in combination, to diagnose PTB and nontuberculous mycobacteria (NTM) infections.
ResultsSputum and BALF showed moderate to substantial consistency when they were used for AFB smear or Xpert, with a higher positive detection rate by BALF. 3-4 smears had a higher sensitivity than 1-2 smears. Moreover, simultaneous combination of AFB and Xpert correctly identified 44/51 of AFB+/Xpert+ and 6/7 of AFB+/Xpert- cases as PTB and NTM, respectively. Lastly, when combined with AFB/Xpert sequentially, T-SPOT showed limited roles in patients that were either AFB+ or Xpert+. However, T-SPOTMDC (manufacturer-defined cut-off) showed a high negative predicative value (99.1%) and suboptimal sensitivity (74.4%), and TBAg/PHA (ratio of Mycobacterium tuberculosis-specific antigens to phytohaemagglutinin spot-forming cells, which is a modified method calculating T-SPOT.TB assay results) ≥0.3 demonstrated a high specificity (95.7%) and a relatively low sensitivity (16.3%) in AFB-/Xpert- patients.
ConclusionsConcurrently performing AFB smear (at least 3 smears) and Xpert on sputum and/or BALF could aid in rapid diagnosis of PTB and NTM infections in a real-world high-burden setting. If available, BALF is preferred for both AFB smear and Xpert. Expanding this algorithm, PBMC T-SPOTMDC and TBAg/PHA ratios have a supplementary role for PTB diagnosis in AFB-/Xpert- patients (moderately ruling out PTB and ruling in PTB, respectively). Our findings may also inform policy makers’ decisions regarding prevention and control of TB in a high burden setting.

背景 肺结核（pulmonary tuberculosis, PTB）的快速诊断仍是临床实践中的一大难题。本研究旨在优化真实世界场景下的肺结核快速诊断算法。
方法 本研究回顾性分析了中国28171例疑似肺结核的成年住院患者。采集支气管肺泡灌洗液（bronchoalveolar lavage fluid, BALF）和/或痰液进行抗酸杆菌（acid-fast bacilli, AFB）涂片、Xpert MTB/RIF（简称Xpert）检测及分枝杆菌培养。以分枝杆菌培养阳性作为参考标准。采集外周血单个核细胞（peripheral blood mononuclear cells, PBMC）进行T-SPOT.TB检测。本研究分析了标本类型对各项检测方法性能的影响，明确了用于肺结核诊断的涂片次数阈值，并评估了单项及联合检测对肺结核与非结核分枝杆菌（nontuberculous mycobacteria, NTM）感染的诊断能力。
结果 痰液与支气管肺泡灌洗液用于抗酸杆菌涂片或Xpert检测时，一致性中等至极佳，且支气管肺泡灌洗液的阳性检出率更高。3~4次涂片的敏感性优于1~2次涂片。联合抗酸杆菌涂片与Xpert检测可分别正确识别44/51例AFB+/Xpert+病例与6/7例AFB+/Xpert-病例为肺结核与非结核分枝杆菌感染。进一步分析显示，序贯联合抗酸杆菌涂片/Xpert检测时，T-SPOT.TB对AFB+或Xpert+患者的诊断价值有限。不过，T-SPOT.TB制造商定义临界值（T-SPOTMDC）的阴性预测值高达99.1%，敏感性为74.4%（欠佳）；而在AFB-/Xpert-患者中，结核抗原/植物血凝素（TBAg/PHA）≥0.3（即结核分枝杆菌特异性抗原与植物血凝素斑点形成细胞比值，为T-SPOT.TB检测结果的改良计算方式）的特异性达95.7%，但敏感性仅为16.3%。
结论 在真实世界高负担地区，同时对痰液和/或支气管肺泡灌洗液进行抗酸杆菌涂片（至少3次）与Xpert检测，有助于快速诊断肺结核与非结核分枝杆菌感染。若条件允许，抗酸杆菌涂片与Xpert检测优先选用支气管肺泡灌洗液标本。将本算法拓展后，外周血单个核细胞的T-SPOTMDC及TBAg/PHA比值对AFB-/Xpert-患者的肺结核诊断具有辅助价值（分别可中度排除肺结核与确诊肺结核）。本研究结果可为高负担地区结核病防控的政策制定提供参考依据。