Payam Nahid1, Erin Bliven-Sizemore2, Leah G Jarlsberg3, Mary A De Groote4, John L Johnson5, Grace Muzanyi6, Melissa Engle7, Marc Weiner7, Nebojsa Janjic8, David G Sterling8, Urs A Ochsner9. 1. Pulmonary and Critical Care Medicine, University of California, San Francisco at San Francisco General Hospital, 1001 Potrero Ave, 5K1, San Francisco, CA 94110, USA. Electronic address: pnahid@ucsf.edu. 2. Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd., NE, MS E10, Atlanta, GA 30333, USA. 3. Pulmonary and Critical Care Medicine, University of California, San Francisco at San Francisco General Hospital, 1001 Potrero Ave, 5K1, San Francisco, CA 94110, USA. 4. Department of Microbiology, Immunology and Pathology, Colorado State University, Campus Box 1682, Fort Collins, CO 80523, USA; SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA. 5. Tuberculosis Research Unit, Division of Infectious Diseases, Case Western Reserve University, Cleveland, OH, USA; Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda. 6. Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda. 7. Department of Medicine, Division of Infectious Diseases, University of Texas Health Science Center, San Antonio, TX, USA. 8. SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA. 9. SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA. Electronic address: uochsner@somalogic.com.
Abstract
BACKGROUND: New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing. METHODS: In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial. RESULTS: We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC = 0.96, sensitivity = 0.95 and specificity = 0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1). CONCLUSIONS: Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study.
RCT Entities:
BACKGROUND: New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing. METHODS: In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial. RESULTS: We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC = 0.96, sensitivity = 0.95 and specificity = 0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1). CONCLUSIONS: Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study.
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