Jeremy Cohen1,2,3,4, Antje Blumenthal5, Gabriel Cuellar-Partida5, David M Evans5,6, Simon Finfer7,8,9,10, Qiang Li7, Johanna Ljungberg5, John Myburgh7,8,11, Elizabeth Peach5, Joseph Powell12,13, Dorrilyn Rajbhandari7, Andrew Rhodes14, Anne Senabouth12, Balasubramanian Venkatesh7,15,8,16. 1. The George Institute for Global Health, Sydney, Australia. cohenjeremy@me.com. 2. Royal Brisbane and Women's Hospital, University of Queensland, Brisbane, Australia. cohenjeremy@me.com. 3. The Wesley Hospital, Brisbane, Australia. cohenjeremy@me.com. 4. The University of Queensland, St Lucia, Australia. cohenjeremy@me.com. 5. University of Queensland Diamantina Institute, University of Queensland, St Lucia, Australia. 6. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK. 7. The George Institute for Global Health, Sydney, Australia. 8. University of New South Wales, Sydney, Australia. 9. Northern Clinical School, University of Sydney, Sydney, Australia. 10. Royal North Shore Hospital, Sydney, Australia. 11. St. George Hospital, University of New South Wales, Sydney, Australia. 12. Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute, Sydney, Australia. 13. UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, Australia. 14. St George's Hospital, London, UK. 15. The Wesley Hospital, Brisbane, Australia. 16. The Princess Alexandra Hospital, University of Queensland, Brisbane, Australia.
Abstract
PURPOSE: To determine if adrenocortical gene expression is associated with clinical outcomes or response to corticosteroid treatment in septic shock. METHODS: A pre-specified nested cohort study of a randomised controlled trial of hydrocortisone compared to placebo in septic shock. Blood was collected for RNAseq analysis prior to treatment with hydrocortisone or placebo. The expression of adrenocortical candidate genes related to pituitary releasing hormones, mineralocorticoid and glucocorticoid receptors, intracellular glucocorticoid metabolism and transport proteins was measured. RESULTS:From May 2014 to April 2017, 671 patients were enrolled in the nested cohort study, from which 494 samples were available for analysis. We found no evidence of an association between candidate gene expression levels and either 90-day mortality, 28-day mortality or time to shock reversal. We observed evidence of a significant interaction between expression and treatment group for time to shock reversal in two genes; GLCCI1 (HR 3.81, 95%CI 0.57-25.47 vs. HR 0.64, 95%CI 0.13-3.07 for hydrocortisone and placebo respectively, p for interaction 0.008) and BHSD1 (HR 0.55, 95%CI 0.28-1.09 vs. HR 1.32 95%CI 0.67-2.60, p for interaction 0.01). CONCLUSIONS: In patients with septic shock, there is no association between adrenocortical candidate gene expression and mortality. Patients with higher expression of GLCCI1 who received hydrocortisone achieved shock resolution faster than those receiving placebo; conversely, patients who had higher expression of BHSD1 who received hydrocortisone achieved shock resolution slower than those who received placebo. Variation in gene expression may be a mechanism for heterogeneity of treatment response to corticosteroids in septic shock.
RCT Entities:
PURPOSE: To determine if adrenocortical gene expression is associated with clinical outcomes or response to corticosteroid treatment in septic shock. METHODS: A pre-specified nested cohort study of a randomised controlled trial of hydrocortisone compared to placebo in septic shock. Blood was collected for RNAseq analysis prior to treatment with hydrocortisone or placebo. The expression of adrenocortical candidate genes related to pituitary releasing hormones, mineralocorticoid and glucocorticoid receptors, intracellular glucocorticoid metabolism and transport proteins was measured. RESULTS: From May 2014 to April 2017, 671 patients were enrolled in the nested cohort study, from which 494 samples were available for analysis. We found no evidence of an association between candidate gene expression levels and either 90-day mortality, 28-day mortality or time to shock reversal. We observed evidence of a significant interaction between expression and treatment group for time to shock reversal in two genes; GLCCI1 (HR 3.81, 95%CI 0.57-25.47 vs. HR 0.64, 95%CI 0.13-3.07 for hydrocortisone and placebo respectively, p for interaction 0.008) and BHSD1 (HR 0.55, 95%CI 0.28-1.09 vs. HR 1.32 95%CI 0.67-2.60, p for interaction 0.01). CONCLUSIONS: In patients with septic shock, there is no association between adrenocortical candidate gene expression and mortality. Patients with higher expression of GLCCI1 who received hydrocortisone achieved shock resolution faster than those receiving placebo; conversely, patients who had higher expression of BHSD1 who received hydrocortisone achieved shock resolution slower than those who received placebo. Variation in gene expression may be a mechanism for heterogeneity of treatment response to corticosteroids in septic shock.
Authors: Martin S Winkler; Marcin F Osuchowski; Didier Payen; Antoni Torres; Steffen Dickel; Tomasz Skirecki Journal: Crit Care Date: 2022-10-08 Impact factor: 19.334