PET CT Identifies Reactivation Risk in Cynomolgus Macaques with Latent M. tuberculosis.
PET CT Identifies Reactivation Risk in Cynomolgus Macaques with Latent M. tuberculosis.
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DOI：
10.1371/journal.ppat.1005739
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发表时间：
2016-07
期刊：
影响因子：
6.7
通讯作者：
Flynn JL
中科院分区：
文献类型：
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作者：
Lin PL;Maiello P;Gideon HP;Coleman MT;Cadena AM;Rodgers MA;Gregg R;O'Malley M;Tomko J;Fillmore D;Frye LJ;Rutledge T;DiFazio RM;Janssen C;Klein E;Andersen PL;Fortune SM;Flynn JL
从潜伏感染到活动性肺结核，结核分枝杆菌感染在人类中广泛存在。在潜伏性结核病患者中，现已认识到也存在一系列感染，这很可能导致结核病复发的不同风险。本研究采用18F-脱氧葡萄糖正电子发射断层扫描和计算机断层扫描(PET CT)对潜伏感染结核分枝杆菌的食蟹猴进行功能成像，以确定肿瘤坏死因子(TNF)中和后再激活的特征，并确定肿瘤坏死因子中和前的哪些影像特征区分再激活风险。对26只潜伏感染的猕猴(n=26)和25只潜伏感染的对照组(n=25)在肿瘤坏死因子中和治疗前和治疗过程中进行了PET CT检查。在接受肿瘤坏死因子中和抗体的潜伏感染的动物中，有50%的动物发生了再激活，其定义是在邻近或远处包括肺外部位发展至少一个新的肉芽肿。在肿瘤坏死因子中和之前，正电子发射计算机断层扫描测量的肺部炎症增加和肺外受累预测再激活的敏感性和特异性为92%。为了确定与再激活风险相关的生物学特征，我们使用这些PET CT参数来识别潜伏感染的具有高再激活风险的动物。与低危猕猴相比，高危动物具有更高的累积肺部细菌负荷和更高的最大皮损细菌负荷，肺肉芽肿中产生IL-2、IL-10和IL-17的T细胞更多。总体而言，这些数据支持再次激活的风险与肺部炎症和潜在结核分枝杆菌感染的猕猴较高的细菌负荷有关。结核分枝杆菌无症状感染，通常被称为潜伏性结核病，影响着20多亿人。活动性结核病潜伏感染的重新激活只发生在少数感染者中，但可能导致致命的疾病和传播。在这里，我们使用非人类灵长类动物模型显示，使用PET/CT成像可以识别与较高的再激活风险相关的某些特征。这些因素包括整体肺部炎症、肺部个别肉芽肿的细菌负荷较高，以及肺部以外的感染部位。使用这些参数可以发现关于潜伏性结核病再激活风险的外周生物标记物。这些生物标记物可以确定哪些人将从治疗潜伏性结核病中受益最大，以防止复发。
Mycobacterium tuberculosis infection presents across a spectrum in humans, from latent infection to active tuberculosis. Among those with latent tuberculosis, it is now recognized that there is also a spectrum of infection and this likely contributes to the variable risk of reactivation tuberculosis. Here, functional imaging with 18F-fluorodeoxygluose positron emission tomography and computed tomography (PET CT) of cynomolgus macaques with latent M. tuberculosis infection was used to characterize the features of reactivation after tumor necrosis factor (TNF) neutralization and determine which imaging characteristics before TNF neutralization distinguish reactivation risk. PET CT was performed on latently infected macaques (n = 26) before and during the course of TNF neutralization and a separate set of latently infected controls (n = 25). Reactivation occurred in 50% of the latently infected animals receiving TNF neutralizing antibody defined as development of at least one new granuloma in adjacent or distant locations including extrapulmonary sites. Increased lung inflammation measured by PET and the presence of extrapulmonary involvement before TNF neutralization predicted reactivation with 92% sensitivity and specificity. To define the biologic features associated with risk of reactivation, we used these PET CT parameters to identify latently infected animals at high risk for reactivation. High risk animals had higher cumulative lung bacterial burden and higher maximum lesional bacterial burdens, and more T cells producing IL-2, IL-10 and IL-17 in lung granulomas as compared to low risk macaques. In total, these data support that risk of reactivation is associated with lung inflammation and higher bacterial burden in macaques with latent Mtb infection. Asymptomatic infection with Mycobacterium tuberculosis, often called latent tuberculosis, affects more than 2 billion people. Reactivation of latent infection to active TB occurs in only a minority of those infected, yet can lead to deadly disease and transmission. Here we show, using a non-human primate model, that imaging using PET/CT can identify certain features that are associated with a higher risk of reactivation. These factors include overall lung inflammation, individual granulomas in the lung with higher bacterial burden, and a site of infection outside the lungs. Using these parameters may allow discovery of peripheral biomarkers regarding risk of reactivation from latent TB. Such biomarkers could identify those people who would benefit most from treatment of latent TB to prevent reactivation.