• Hector R Wong, Natalie Z Cvijanovich, Nick Anas, Geoffrey L Allen, Neal J Thomas, Michael T Bigham, Scott L Weiss, Julie Fitzgerald, Paul A Checchia, Keith Meyer, Thomas P Shanley, Michael Quasney, Mark Hall, Rainer Gedeit, Robert J Freishtat, Jeffrey Nowak, Raj S Shekhar, Shira Gertz, Emily Dawson, Kelli Howard, Kelli Harmon, Eileen Beckman, Erin Frank, and Christopher J Lindsell.
• 1 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, Ohio.
• Am. J. Respir. Crit. Care Med. 2015 Feb 1; 191 (3): 309-15.

RationaleUsing 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.ObjectivesTo develop and validate a real-time subclassification method for septic shock.MethodsGene expression data for the 100 subclass-defining genes were generated using a multiplex messenger RNA quantification platform (NanoString 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 ResultsThe NanoString-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).ConclusionsWe 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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