A multidisciplinary, collaborative effort involving investigators at 6 organizations is proposed to develop novel, in vitro diagnostic tests (IVD) for severe sepsis (SS) and community acquired pneumonia (CAP).
Specific Aim 1 : Early, accurate identification of sepsis patients who will develop organ dysfunction (SS) is critical for effective management and positive outcome. We propose to develop a rapid, point-of-care (POC) IVD for early diagnosis of SS. Our preliminary studies have identified candidate biomarkers of SS that we propose to validate in a prospective clinical study of sepsis at 3 tertiary care hospitals and emergency departments employing proteomic technologies (mass spectrometry and multiplexed immunoassays). Bivariable analyses will be performed to identify and validate biomarker differences between groups. Multivariable analyses will be performed on validated biomarkers to derive a biomarker panel for early diagnosis of SS. The biomarker panel will be compared with prognostic indices, such as metabolic endpoints and APACHE II score. The biomarker panel will be developed into an oligoplex IVD immunoassay performed on a single blood sample on the Biosite Triage platform, with a time-to-result of less than 30 minutes.
Specific Aim 2 : Complications of CAP are major determinants of morbidity and mortality. Early, accurate identification of patients with CAP who will have a complicated course or poor outcome (severe CAP) is critical for effective management and positive outcome. We propose to identify biomarkers for early diagnosis of severe CAP by separate analysis of CAP patients in the Aim 1 clinical study. Bi- and multivariable analyses will be performed to identify biomarker differences and derive a biomarker panel for early diagnosis of severe CAP. This panel will be compared with prognostic indices, such as PORT score.
Specific Aim 3 : Currently, initial antimicrobial treatment of sepsis and CAP is empiric. We propose to identify host biomarkers for early differentiation of common etiologic agents in sepsis and CAP, in order to allow more targeted initial therapy, thereby decreasing cost associated with ineffective therapy and lessening likelihood of antibiotic resistance. Bi- and multi-variable analyses will be performed on groups of patients from the Aim 1 study with confirmed sepsis and CAP pathogens (such as pneumococcus) in order to identify biomarkers and a biomarker panel for early differentiation of specific class agent in sepsis and CAP.
|Duplessis, Christopher; Gregory, Michael; Frey, Kenneth et al. (2018) Evaluating the discriminating capacity of cell death (apoptotic) biomarkers in sepsis. J Intensive Care 6:72|
|Han, Sangyeul; Lee, Seung-Jun; Kim, Kyung Eun et al. (2016) Amelioration of sepsis by TIE2 activation-induced vascular protection. Sci Transl Med 8:335ra55|
|Tsalik, Ephraim L; Henao, Ricardo; Nichols, Marshall et al. (2016) Host gene expression classifiers diagnose acute respiratory illness etiology. Sci Transl Med 8:322ra11|
|Tsalik, Ephraim L; Willig, Laurel K; Rice, Brandon J et al. (2015) Renal systems biology of patients with systemic inflammatory response syndrome. Kidney Int 88:804-14|
|Kamisoglu, Kubra; Haimovich, Beatrice; Calvano, Steve E et al. (2015) Human metabolic response to systemic inflammation: assessment of the concordance between experimental endotoxemia and clinical cases of sepsis/SIRS. Crit Care 19:71|
|Langley, Raymond J; Tipper, Jennifer L; Bruse, Shannon et al. (2014) Integrative ""omic"" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes. Am J Respir Crit Care Med 190:445-55|
|Tsalik, Ephraim L; Langley, Raymond J; Dinwiddie, Darrell L et al. (2014) An integrated transcriptome and expressed variant analysis of sepsis survival and death. Genome Med 6:111|
|Rogers, Angela J; McGeachie, Michael; Baron, Rebecca M et al. (2014) Metabolomic derangements are associated with mortality in critically ill adult patients. PLoS One 9:e87538|
|Xiao, Bin; Wang, Yu; Li, Wei et al. (2013) Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease. Blood 122:3365-75|
|Dinwiddie, Darrell L; Kingsmore, Stephen F; Caracciolo, Sonia et al. (2013) Combined DOCK8 and CLEC7A mutations causing immunodeficiency in 3 brothers with diarrhea, eczema, and infections. J Allergy Clin Immunol 131:594-7.e1-3|
Showing the most recent 10 out of 37 publications