Biomarker Profiles for Carbon Monoxide Poisoning

描述（由申请人提供）：一氧化碳（CO）是全世界中毒造成伤害和死亡的主要因素。非特异性症状可能会延迟CO中毒的诊断，从而妨碍早期治疗和污染源的识别。幸存者面临着心脏和神经功能的潜在损害。神经系统后遗症是最常见的发病形式，功能障碍可能急性发生或延迟发生。虽然少数严重中毒患者会出现急性异常，但23 - 46%的患者会在中毒后约5周内出现迟发性神经系统变化。临床综述表明，迫切需要严重CO中毒的客观生物标志物，以选择可能受益于积极治疗的患者。碳氧血红蛋白（COHb）的形成是一氧化碳暴露的公认效应;然而，COHb值与临床结局的相关性很差。即使一氧化碳中毒看起来相对较轻，仍然可能发生迟发性神经系统后遗症。一些研究小组正在进行详细的研究，以评估与CO中毒相关的个体生物标志物的表达，作为诊断工具。然而，用于测量细胞因子、趋化因子或其他生物标志物的血浆或血清水平的标准方法是使用酶联免疫吸附测定一次测量一种。对每种推定的生物标志物进行一次一次的评估会花费大量的时间、成本和样本量。显然，没有一个单一的分子标记，或一小群标记，将能够准确地分类个人在最高风险。因此，系统鉴定蛋白质谱、预测临床事件风险、评价治疗反应和确定潜在机制的能力受到严重限制。Rules-Based Medicine开发了多分析物图谱（MAP），使用基于微珠的多重免疫测定法平行筛选大量生物标志物。该技术使用非常小的样品体积（10 - 20 μ L）以fg/mL至mg/mL的动态范围提供蛋白质表达模式的定量评价。该I期项目的目标是确定一系列分层生物标志物，用于快速评估疑似CO中毒的患者。RBM与宾夕法尼亚大学合作，建议对从疑似CO中毒的急诊科患者与正常年龄和性别匹配的对照组中获得的血浆样本中的蛋白质谱进行表征。将研究暴露于CO后蛋白质表达的水平和模式。预计从拟议的研究中获得的生理洞察力可用于更好地定义与CO中毒相关的病理机制。识别新的生物标志物模式的个人与CO中毒，以及个人在发展神经系统后遗症的高风险，将具有重要的临床实用性。更广泛地说，中毒严重程度的客观测定可用作定义患者人群的方法，以更好地评估治疗效果。一氧化碳（CO）是全世界因中毒造成伤害和死亡的主要因素。不幸的是，目前使用碳氧血红蛋白（COHb）值的诊断与临床结果相关性很差。鉴定CO中毒个体以及神经功能障碍和发病率高风险个体的新型生物标志物模式，将通过客观选择可能受益于积极治疗的患者，帮助确定治疗有效性，定义潜在机制，改善病情管理，并将为开发和评估新治疗提供框架。

DESCRIPTION (provided by applicant): Carbon monoxide (CO) is the leading agent of injury and death by poisoning worldwide. Diagnosis of CO poisoning can be delayed by non-specific symptoms, thus preventing early treatment and identification of the contamination source. Survivors are faced with potential impairments to cardiac and neurological function. Neurological sequelae are the most frequent form of morbidity, and dysfunction may occur acutely or arise in a delayed fashion. While acute abnormalities develop in a minority of severely poisoned patients, delayed neurological changes develop in 23-46 % of patients up to ~5 weeks after poisoning. Clinical reviews have expressed the urgent need for objective biomarkers of serious CO poisoning to select patients who may benefit from aggressive treatment. The formation of carboxy-hemoglobin (COHb) is a recognized effect of CO exposure; however, COHb values correlate poorly with clinical outcomes. Even when CO poisoning appears to be relatively mild, delayed neurological sequelae can still occur. A number of research groups are performing detailed studies to evaluate the expression of individual biomarkers associated with CO poisoning for use as a diagnostic tool. However, the standard method for measuring plasma or serum levels of cytokines, chemokines or other biomarkers is to measure them one at a time using Enzyme-Linked Immunosorbent Assay. One-at-a- time assessment of each putative biomarker incurs considerable time, cost and sample volume. Clearly, no single molecular marker, or small group of markers, will be able to accurately classify individuals at highest risk. The ability to systematically identify protein profiles, predict risk of clinical events, evaluate therapeutic response, and define underlying mechanisms is thereby limited severely. Rules-Based Medicine has developed Multi-Analyte Profiles (MAPs) to screen large numbers of biomarkers in parallel, using bead-based multiplex immunoassays. This technology provides a quantitative evaluation of protein expression patterns using very small sample volumes (10-20 <L) with a dynamic range of fg/mL to mg/mL. The goal of this Phase I program is to identify a hierarchical series of biomarkers for the rapid assessment of patients suspected of CO poisoning. RBM, in collaboration with the University of Pennsylvania, proposes to characterize the protein profiles in plasma samples obtained from emergency department patients with suspected CO poisoning vs. normal age- and gender-matched controls. The level and pattern of protein expression after exposure to CO will be studied. It is expected that the physiological insight obtained from the proposed study may be used to better define the pathological mechanisms associated with CO poisoning. The identification of novel biomarker patterns of individuals with CO poisoning, as well as, individuals at high risk for developing neurological sequelae, would have important clinical utility. More broadly, objective determination of severity of poisoning could be used as a method of defining patient populations to better assess treatment efficacy. PUBLIC HEALTH RELEVANCE: Carbon monoxide (CO) is the leading agent of injury and death by poisoning worldwide. Unfortunately, current diagnosis using carboxy-hemoglobin (COHb) values correlate poorly with clinical outcomes. The identification of novel biomarker patterns of individuals with CO poisoning, as well as, individuals at high risk for developing neurological dysfunction and morbidity, will allow for improved management of the condition by selecting objectively patients who may benefit from aggressive treatment, aiding the determination of treatment effectiveness, defining underlying mechanisms, and will provide a framework for developing and evaluating new treatments.