Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial.
Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial.
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DOI：
10.1016/j.ebiom.2017.10.018
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发表时间：
2017-11
期刊：
影响因子：
11.1
通讯作者：
Nahid P
中科院分区：
文献类型：
--
作者：
Sigal GB;Segal MR;Mathew A;Jarlsberg L;Wang M;Barbero S;Small N;Haynesworth K;Davis JL;Weiner M;Whitworth WC;Jacobs J;Schorey J;Lewinsohn DM;Nahid P
结核病需要更有效的治疗方案，然而，由于缺乏疾病严重程度和治疗效果的可靠生物标志物，药物开发受到阻碍。我们对参加结核病临床试验的参与者进行了宿主生物标志物的定向筛选，以满足这一需求。作为国际2期试验的一部分，对319例方案正确、培养证实的肺结核患者的血清样本进行了70种感染、炎症和代谢标志物的筛选。生物标志物测定是专门为这项研究开发的，并使用一种新型的多重电化学发光测定法进行定量。我们使用Bonferroni校正的线性回归模型评估了生物标志物与基线特征以及详细微生物学数据的相关性。在众多分析中，SAA 1、PCT、IL-1β、IL-6、CRP、PTX-3和MMP-8等7种蛋白质显示与基线疾病严重程度、涂片分级和空洞标记物的复发性强相关性;受结核病治疗的强烈调节;并且在8周培养转化的患者中具有更大的应答。随着治疗的进行，除了骨钙素、MCP-1和MCP-4显著增加外，所有蛋白质均降低。先前报道的几种假定的结核病相关生物标志物（HOMX 1，新蝶呤和cathelicidin）与治疗反应无显著相关性。总之，在一项临床试验中，在地理分布多样且人数众多的结核病患者中，先前报道的几种推定生物标志物与治疗反应无显著相关性，然而，7种蛋白质与基线放射学和疾病严重程度的微生物学指标以及早期治疗反应反复存在强相关性，值得进一步研究。SAA 1、PCT、IL-1β、IL-6、CRP、PTX-3和MMP-8等7种蛋白质与基线结核病严重程度、涂片分级和空洞形成标志物之间存在反复的强相关性。这些蛋白质受结核病治疗的强烈调节，并且在8周培养转化的患者中反应更大。在我们的临床试验队列中，先前报道的几种假定的结核病相关生物标志物（HOMX 1、新蝶呤和抗菌肽）与治疗反应无显著相关性。世卫组织国际结核病研究路线图已将确定结核病治疗效果的改进生物标志物视为一个关键研究领域，因为它将加速新药和治疗方案的开发，并可能改善患者监测方法。我们在一项严格进行的2期临床试验中发现，在众多分析中，7种蛋白质复发与基线疾病严重程度和治疗效果密切相关。这些标记物被鉴定的一致性为它们的进一步研究以及基于血液的治疗监测测定开发的未来追求提供了动力。
More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8 weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study. Seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, show recurring strong associations with markers of baseline tuberculosis disease severity, smear grade and cavitation These same proteins were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8 weeks. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response in our clinical trial cohort. The identification of improved biomarkers of tuberculosis treatment effect has been recognized as a key research area by the WHO International Roadmap for Tuberculosis Research because it would accelerate the development of new drugs and regimens, and potentially improve approaches to patient monitoring. Our findings within a rigorously conducted phase 2 clinical trial are that across numerous analyses, seven proteins recur with strong associations with both baseline disease severity and treatment effect. The consistency with which these markers are identified provides impetus for their further study as well as the future pursuit of blood-based treatment monitoring assay development.
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影响因子：
5.8
作者：
Pauwels NS;Bracke KR;Maes T;Van Pottelberge GR;Garlanda C;Mantovani A;Joos GF;Brusselle GG
通讯作者：
Brusselle GG
DOI：
10.1164/rccm.201105-0827ws
发表时间：
2011-10-15
影响因子：
24.7
作者：
Nahid, Payam;Saukkonen, Jussi;Burman, William
通讯作者：
Burman, William
DOI：
10.1016/0925-4439(92)90068-x
发表时间：
1992-12-10
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
BABA, S;TAKAHASHI, T;SHIRASAWA, H
通讯作者：
SHIRASAWA, H
DOI：
10.1016/j.tube.2014.01.006
发表时间：
2014-05
期刊：
Tuberculosis (Edinburgh, Scotland)
影响因子：
--
作者：
Nahid P;Bliven-Sizemore E;Jarlsberg LG;De Groote MA;Johnson JL;Muzanyi G;Engle M;Weiner M;Janjic N;Sterling DG;Ochsner UA
通讯作者：
Ochsner UA
影响因子：
4.3
作者：
Sakamoto, Noriho;Ishimatsu, Yuji;Kohno, Shigeru
通讯作者：
Kohno, Shigeru