Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 191, Issue 3, Pages 309-315Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201410-1864OC
Keywords
sepsis; gene expression; subclassification; adaptive immunity; glucocorticoids
Categories
Funding
- National Institutes of Health [RO1GM064619, RO1GM099773, R01GM108025]
- Institutional Clinical and Translational Science Award NIH/NCRR [8 UL1 TR000077]
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Rationale: Using microarray data, we previously identified gene expression-based subclasses of septic shock with important phenotypic differences. The subclass-defining genes correspond to adaptive immunity and glucocorticoid receptor signaling. Identifying the subclasses in real time has theranostic implications, given the potential for immune-enhancing therapies and controversies surrounding adjunctive corticosteroids for septic shock. Objectives: To develop and validate a real-time subclassification method for septic shock. Methods: Gene expression data for the 100 subclass-defining genes were generated using a multiplex messenger RNA quantification platform (Nano String nCounter) and visualized using gene expression mosaics. Study subjects (n = 168) were allocated to the subclasses using computer-assisted image analysis and microarray-based reference mosaics. A gene expression score was calculated to reduce the gene expression patterns to a single metric. The method was tested prospectively in a separate cohort (n = 132). Measurements and Main Results: The Nano String-based data reproduced two septic shock subclasses. As previously, one subclass had decreased expression of the subclass-defining genes. The gene expression score identified this subclass with an area under the curve of 0.98 (95% confidence interval [CI95] = 0.96-0.99). Prospective testing of the subclassification method corroborated these findings. Allocation to this subclass was independently associated with mortality (odds ratio = 2.7; CI95 = 1.2-6.0; P = 0.016), and adjunctive corticosteroids prescribed at physician discretion were independently associated with mortality in this subclass (odds ratio =4.1; CI95 = 1.4-12.0; P=0.011). Conclusions: We developed and tested a gene expression-based classification method for pediatric septic shock that meets the time constraints of the critical care environment, and can potentially inform therapeutic decisions.
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