Biomarker Profiles for Carbon Monoxide Poisoning

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 contamin ation 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 dev elop 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 patient s 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 neuro logical 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 o r 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 mec hanisms 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 ltL) 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 patter n 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 corr elate 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 cond ition 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.