Ravi F Sood1, Nicole S Gibran, Brett D Arnoldo, Richard L Gamelli, David N Herndon, Ronald G Tompkins. 1. From the Department of Surgery (R.F.S., N.S.G.), UW Medicine Regional Burn Center, Harborview Medical Center, Seattle, Washington; Department of Surgery (B.D.A.), University of Texas Southwestern Medical School, Dallas; and Department of Surgery (D.N.H.), University of Texas Medical Branch and Shriners Hospitals for Children, Galveston, Texas; Department of Surgery (R.L.G.), Loyola University Stritch School of Medicine, Chicago, Illinois; and Department of Surgery (R.G.T.), Massachusetts General Hospital, Shriners Hospital for Children, and Harvard Medical School, Boston, Massachusetts.
Abstract
BACKGROUND: In the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors. METHODS: We performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20% or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05. RESULTS: After adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95% confidence interval [CI], 2.93-6.99), burn size greater than 40% TBS (RR, 4.24; 95% CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95% CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40% TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines. CONCLUSION: Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the "genomic storm" induced by a 20% or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40% TBS. LEVEL OF EVIDENCE: Epidemiologic study, level III.
BACKGROUND: In the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors. METHODS: We performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20% or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05. RESULTS: After adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95% confidence interval [CI], 2.93-6.99), burn size greater than 40% TBS (RR, 4.24; 95% CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95% CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40% TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines. CONCLUSION: Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the "genomic storm" induced by a 20% or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40% TBS. LEVEL OF EVIDENCE: Epidemiologic study, level III.
Authors: Barbara A Latenser; Sidney F Miller; Palmer Q Bessey; Susan M Browning; Daniel M Caruso; Manuel Gomez; James C Jeng; John A Krichbaum; Christopher W Lentz; Jeffrey R Saffle; Michael J Schurr; David G Greenhalgh; Richard J Kagan Journal: J Burn Care Res Date: 2007 Sep-Oct Impact factor: 1.845
Authors: Christopher S Davis; Scott E Janus; Michael J Mosier; Stewart R Carter; Jeffrey T Gibbs; Luis Ramirez; Richard L Gamelli; Elizabeth J Kovacs Journal: Ann Surg Date: 2013-06 Impact factor: 12.969
Authors: J Montojo; K Zuberi; H Rodriguez; F Kazi; G Wright; S L Donaldson; Q Morris; G D Bader Journal: Bioinformatics Date: 2010-10-05 Impact factor: 6.937
Authors: Junhee Seok; H Shaw Warren; Alex G Cuenca; Michael N Mindrinos; Henry V Baker; Weihong Xu; Daniel R Richards; Grace P McDonald-Smith; Hong Gao; Laura Hennessy; Celeste C Finnerty; Cecilia M López; Shari Honari; Ernest E Moore; Joseph P Minei; Joseph Cuschieri; Paul E Bankey; Jeffrey L Johnson; Jason Sperry; Avery B Nathens; Timothy R Billiar; Michael A West; Marc G Jeschke; Matthew B Klein; Richard L Gamelli; Nicole S Gibran; Bernard H Brownstein; Carol Miller-Graziano; Steve E Calvano; Philip H Mason; J Perren Cobb; Laurence G Rahme; Stephen F Lowry; Ronald V Maier; Lyle L Moldawer; David N Herndon; Ronald W Davis; Wenzhong Xiao; Ronald G Tompkins Journal: Proc Natl Acad Sci U S A Date: 2013-02-11 Impact factor: 11.205
Authors: A García-Avello; J A Lorente; J Cesar-Perez; L J García-Frade; R Alvarado; J M Arévalo; J L Navarro; A Esteban Journal: Thromb Res Date: 1998-01-15 Impact factor: 3.944
Authors: Ravi F Sood; Anne M Hocking; Lara A Muffley; Maricar Ga; Shari Honari; Alexander P Reiner; Ali Rowhani-Rahbar; Nicole S Gibran Journal: J Invest Dermatol Date: 2015-06-01 Impact factor: 8.551
Authors: Kiran Dyamenahalli; Gaurav Garg; Jeffrey W Shupp; Paulius V Kuprys; Mashkoor A Choudhry; Elizabeth J Kovacs Journal: J Burn Care Res Date: 2019-08-14 Impact factor: 1.845
Authors: Marc G Jeschke; Margriet E van Baar; Mashkoor A Choudhry; Kevin K Chung; Nicole S Gibran; Sarvesh Logsetty Journal: Nat Rev Dis Primers Date: 2020-02-13 Impact factor: 52.329
Authors: Stephanie C Dreckmann; Saeid Amini-Nik; Ronald G Tompkins; Miliana Vojvodic; Marc G Jeschke Journal: PLoS One Date: 2019-12-13 Impact factor: 3.240