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Whole blood transcriptomics identifies subclasses of pediatric septic shock

2023; BioMed Central; Volume: 27; Issue: 1 Linguagem: Inglês

10.1186/s13054-023-04689-y

1466-609X

Jamie O. Yang, Matt S. Zinter, Matteo Pellegrini, M Wong, Kinisha Gala, Daniela Markovic, Brian B. Nadel, Kerui Peng, Nguyen Do, Serghei Mangul, Vinay Nadkarni, Aaron Karlsberg, Dhrithi Deshpande, Manish J. Butte, Lisa A. Asaro, Michael S. D. Agus, Anil Sapru, Michael S. D. Agus, Vijay Srinivasan, Ranjit S. Chima, Neal J. Neal, Christopher J. L. Newth, Amanda Hassinger, Kris Bysani, E. Vincent S. Faustino, Faustino Hirshberg, Kupper A. Wintergerst, Simon Li, Adam J. Schwarz, Lauren R. Sorce, Lauren Marsillio, Natalie Z. Cvijanovich, Heidi R. Flori, Flori Pham, Mary K. Dahmer, Myke Federman, Kayley Wong, Sitaram S. Vangala, Matteo Pellegrini, Brunilda Balliu, Kinisha Gala, Sholeen Nett, Marcy Singleton, Neethi Pinto, Grace Chong, Shirley Viteri, Anil Sapru, Patrick S. McQuillen, Matt S. Zinter, Kerry Coughlin-Wells, Kyle Hughes, Jaclyn French, Meghan Fitzgerald, Martha Sisko, Kelli Howard, Rhonda M. Jones, Debbie Spear, Peter J. Eldridge, Jeni Kwok, Haiping Qiao, Tracey Monjure, Joana Tala, Sarah A. Kandil, Tyler D. Quinn, Jennifer Lilley, Kristen Lee, Cathy Flores, Ofelia Vargas-Shiraishi, Avani Shukla, Becky Brumfield, Cheryl Stone, Chaandini Jayachandran, Theresa Kirkpatrick, Tanaya Deshmukh, Manvita Mareboina, Nguyen Do, Neda Ashtari, Anna Ratiu, Dean Jarvis, Mary McNally, Karlyn Martini, Chiara Rodgers, Ramany John, Teresa Mulholland, Gwen Pellicciotti, Shrey Goel, Mustafa F. Alkhouli, Anne McKenzie, Denise Villarreal-Chico,

Immune Response and Inflammation

Abstract Background Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles. Methods The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses. Results Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires. Conclusions Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.