Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV

BackgroundApproaches to screening for active tuberculosis (TB) among people living with HIV are inadequate, leading to missed diagnoses and poor implementation of preventive therapy.MethodsConsecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between June 2011 and July 2013 with a cough ≥ 2 weeks were enrolled. Patients underwent extensive evaluation for pulmonary TB. Concentrations of 43 cytokines/chemokines were measured at the same time point as C-reactive protein (CRP) in banked plasma samples using commercially-available multiplex kits. Advanced classification algorithms were used to rank cytokines/chemokines for their ability to identify TB, and to model the specificity of the top-ranked cytokines/chemokines individually and in combination with sensitivity constrained to ≥ 90% as recommended for TB screening.ResultsThe median plasma level of 5 biomarkers (IL-6, INF-γ, MIG, CRP, IL-18) was significantly different between patients with and without TB. With sensitivity constrained to 90%, all had low specificity with IL-6 showing the highest specificity (44%; 95% CI 37.4–49.5). Biomarker panels were found to be more valuable than any biomarker alone. A panel combining IFN-γ and IL-6 had the highest specificity (50%; 95% CI 46.7–53.3). Sensitivity remained high (>85%) for all panels among sputum smear-negative TB patients.ConclusionsDirect measurement of unstimulated plasma cytokines/chemokines in peripheral blood is a promising approach to TB screening. Cytokine/chemokine panels retained high sensitivity for smear-negative TB and achieved improved specificity compared to individual cytokines/chemokines. These markers should be further evaluated in outpatient settings where most TB screening occurs and where other illnesses associated with systematic inflammation are less common.

**背景**：针对人类免疫缺陷病毒（HIV，Human Immunodeficiency Virus）感染者的活动性肺结核（TB，Tuberculosis）筛查方案仍存在诸多不足，可导致诊断漏诊，同时不利于预防性治疗的规范推行。
**方法**：本研究纳入2011年6月至2013年7月期间，在乌干达坎帕拉市穆拉戈医院（Mulago Hospital）住院的连续就诊的HIV感染成年患者，所有受试者均存在持续≥2周的咳嗽症状。研究人员对患者开展了全面的肺结核相关评估；同时采用商品化多重检测试剂盒，对与C反应蛋白（CRP，C-reactive protein）同期采集的留存血浆样本中的43种细胞因子/趋化因子浓度进行检测。随后采用先进的分类算法，对各类细胞因子/趋化因子识别肺结核的效能进行排序，并针对肺结核筛查推荐的灵敏度约束≥90%的条件，对单种及联合使用的高排名细胞因子/趋化因子的特异性进行建模分析。
**结果**：合并肺结核与未合并肺结核的患者之间，5种生物标志物[白细胞介素-6（IL-6，Interleukin-6）、干扰素-γ（INF-γ，Interferon-γ）、γ干扰素诱导单核细胞因子（MIG）、C反应蛋白（CRP）、白细胞介素-18（IL-18，Interleukin-18）]的血浆中位数水平存在显著差异。当灵敏度约束为90%时，所有单种生物标志物的特异性均较低，其中IL-6的特异性最高（44%；95%置信区间37.4~49.5）。研究发现，生物标志物联合检测的整体效能优于任意单种生物标志物；其中联合使用干扰素-γ（IFN-γ）与IL-6的检测组合特异性最高（50%；95%置信区间46.7~53.3）。在痰涂片阴性的肺结核患者中，所有联合检测组合的灵敏度仍保持在85%以上。
**结论**：对外周血未刺激血浆中的细胞因子/趋化因子进行直接检测，是一种颇具前景的肺结核筛查手段。与单种细胞因子/趋化因子相比，细胞因子/趋化因子联合检测组合对痰涂片阴性肺结核仍可保持较高的灵敏度，且特异性得到显著提升。上述标志物需在多数肺结核筛查开展的门诊环境中开展进一步评估——这类环境中与系统性炎症相关的其他疾病相对少见。