A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial

doi:10.1016/j.ccrj.2025.100109

. 2025 Jun 6;27(2):100109.

doi: 10.1016/j.ccrj.2025.100109. eCollection 2025 Jun.

A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial

Balasubramanian Venkatesh^{1

2

3

4}, Diego Ariel Rey⁵, David M Evans⁴, Lijing Yao⁵, Simon Finfer^{1

3

6

7}, Rinaldo Bellomo^{8

9}, Tiago Chedraoui Silva⁵, Jeremy Cohen^{1

4

10

11}, Yu Qiu⁵, Wellington Dos Reis Lucena⁵, Naomi Hammond^{1

3

6}, John Myburgh^{1

3

12}, Qiang Li^{1

3}, Lucas Petri Damiani¹³, Anthony Devaux^{1

3}, Rodrigo Octavio Deliberato^{14

15}

Affiliations

¹ The George Institute for Global Health, Sydney, Australia.
² Gold Coast University Hospital, Queensland, Australia.
³ University of New South Wales, Australia.
⁴ University of Queensland, Australia.
⁵ Research Department, Endpoint Health Inc, Palo Alto, CA, USA.
⁶ Royal North Shore Hospital, Sydney, Australia.
⁷ School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
⁸ Austin Hospital, Melbourne, Australia.
⁹ Australia and New Zealand Research Centre, Melbourne, Australia.
¹⁰ The Wesley Hospital, Brisbane, Australia.
¹¹ Royal Brisbane Hospital, Brisbane, Australia.
¹² St. George Hospital, Sydney, Australia.
¹³ HCor Research Institute, São Paulo, Brazil.
¹⁴ The Translational Health Intelligence and Knowledge (THINK) Lab, Department of Biostatistics, Health Informatics and Data Science, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁵ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

PMID: 40529301
PMCID: PMC12173105
DOI: 10.1016/j.ccrj.2025.100109

A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial

Balasubramanian Venkatesh et al. Crit Care Resusc. 2025.

. 2025 Jun 6;27(2):100109.

doi: 10.1016/j.ccrj.2025.100109. eCollection 2025 Jun.

Authors

Affiliations

¹ The George Institute for Global Health, Sydney, Australia.
² Gold Coast University Hospital, Queensland, Australia.
³ University of New South Wales, Australia.
⁴ University of Queensland, Australia.
⁵ Research Department, Endpoint Health Inc, Palo Alto, CA, USA.
⁶ Royal North Shore Hospital, Sydney, Australia.
⁷ School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
⁸ Austin Hospital, Melbourne, Australia.
⁹ Australia and New Zealand Research Centre, Melbourne, Australia.
¹⁰ The Wesley Hospital, Brisbane, Australia.
¹¹ Royal Brisbane Hospital, Brisbane, Australia.
¹² St. George Hospital, Sydney, Australia.
¹³ HCor Research Institute, São Paulo, Brazil.
¹⁴ The Translational Health Intelligence and Knowledge (THINK) Lab, Department of Biostatistics, Health Informatics and Data Science, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁵ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

PMID: 40529301
PMCID: PMC12173105
DOI: 10.1016/j.ccrj.2025.100109

Abstract

Background: Small observational studies suggest the effect of corticosteroids in patients with vasodilatory shock vary depending on endotypes determined by gene expression. We sought to replicate these findings in a larger cohort from a randomised clinical trial.

Methods: In a cross-sectional substudy of the Adjunctive Glucocorticoid Therapy In Septic Shock (ADRENAL) trial, patients were classified as one of two immune endotypes using predefined gene expression signatures: immune adaptive-prevalent (IA-P) or immune innate-prevalent (IN-P). We compared the outcomes of the two endotypes using a Bayesian analysis. The primary outcome was Day-28 mortality.

Findings: Of 540 patients, 267 (49.4%) were classified as IA-P and 273 (50.6%) as IN-P. In a Bayesian analysis using noninformative priors, there was no difference in the effect of hydrocortisone on 28-day mortality (odds ratio [OR] 1.43, 95% credible intervals [CrI] 0.72-2.87) and OR 1.39, 95% CrI 0.74-2.61, between the IA-P and IN-P groups, respectively. In the subgroup of patients with more severe shock (n = 215/540, 40%), the corresponding figures for IA-P and IN-P were 1.21, 95% CrI (0.31-4.74) and OR 0.72 (95% CrI 0.30-1.67), respectively. In the subgroup of patients with pulmonary sepsis (232/540, 43%), IA-P patients treated with hydrocortisone had increased mortality (OR 5.55, 95% CrI 1.81-21.2).

Interpretation: Gene expression data from patients with septic shock reveal distinct immune endotypes. There was no evidence of a heterogeneity of treatment effect of hydrocortisone on mortality in the 2 endotypes or in the subgroup with severe shock. Patients with the IA-P endotype and pulmonary sepsis appear to be harmed by corticosteroids.

Keywords: Corticosteroids; Endotypes; RNA-Seq; Septic shock; Transcriptomics.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Balasubramanian Venkatesh reports financial support was provided by The George Institute for Global Health. Balasubramanian Venkatesh reports a relationship with The George Institute for Global Health that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Fig. 1**
**Fold-change in gene expression between IA-P and IN-P endotypes**. TLRs: toll-like receptors; DAMPs: damage-associated molecular patterns; MMPs: matrix metalloproteinases; IL-1: interleukin-1; TNF: tumor necrosis factor alpha; MHC-II: major histocompatibility complex II; TCR: T cell receptors; IL-7: interleukin-7. IA-P, immune adaptive-prevalent; IN-P, immune innate-prevalent.

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References

1. Singer M., Deutschman C.S., Seymour C.W., Shankar-Hari M., Annane D., Bauer M., et al. The Third International consensus definitions for sepsis and septic shock (sepsis-3) JAMA. 2016;315(8):801–810. - PMC - PubMed
1. Reinhart K., Daniels R., Kissoon N., Machado F.R., Schachter R.D., Finfer S. Recognizing sepsis as a Global Health Priority - A WHO Resolution. N Engl J Med. 2017;377(5):414–417. - PubMed
1. Venkatesh B., Finfer S., Cohen J., Rajbhandari D., Arabi Y., Bellomo R., et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797–808. - PubMed
1. Annane D., Renault A., Brun-Buisson C., Megarbane B., Quenot J.P., Siami S., et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378(9):809–818. - PubMed
1. Venkatesh B., Cohen J. Corticosteroids in septic shock secondary to community acquired pneumonia: clarity mixed with uncertainty. Lancet Respir Med. 2024 May;12(5):338–339. doi: 10.1016/S2213-2600(23)00470-8. Epub 2024 Feb 1. PMID: 38310916. - DOI - PubMed

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[1] Singer M., Deutschman C.S., Seymour C.W., Shankar-Hari M., Annane D., Bauer M., et al. The Third International consensus definitions for sepsis and septic shock (sepsis-3) JAMA. 2016;315(8):801–810. - PMC - PubMed

[2] Singer M., Deutschman C.S., Seymour C.W., Shankar-Hari M., Annane D., Bauer M., et al. The Third International consensus definitions for sepsis and septic shock (sepsis-3) JAMA. 2016;315(8):801–810. - PMC - PubMed

[3] Reinhart K., Daniels R., Kissoon N., Machado F.R., Schachter R.D., Finfer S. Recognizing sepsis as a Global Health Priority - A WHO Resolution. N Engl J Med. 2017;377(5):414–417. - PubMed

[4] Reinhart K., Daniels R., Kissoon N., Machado F.R., Schachter R.D., Finfer S. Recognizing sepsis as a Global Health Priority - A WHO Resolution. N Engl J Med. 2017;377(5):414–417. - PubMed

[5] Venkatesh B., Finfer S., Cohen J., Rajbhandari D., Arabi Y., Bellomo R., et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797–808. - PubMed

[6] Venkatesh B., Finfer S., Cohen J., Rajbhandari D., Arabi Y., Bellomo R., et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797–808. - PubMed

[7] Annane D., Renault A., Brun-Buisson C., Megarbane B., Quenot J.P., Siami S., et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378(9):809–818. - PubMed

[8] Annane D., Renault A., Brun-Buisson C., Megarbane B., Quenot J.P., Siami S., et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378(9):809–818. - PubMed

[9] Venkatesh B., Cohen J. Corticosteroids in septic shock secondary to community acquired pneumonia: clarity mixed with uncertainty. Lancet Respir Med. 2024 May;12(5):338–339. doi: 10.1016/S2213-2600(23)00470-8. Epub 2024 Feb 1. PMID: 38310916. - DOI - PubMed

[10] Venkatesh B., Cohen J. Corticosteroids in septic shock secondary to community acquired pneumonia: clarity mixed with uncertainty. Lancet Respir Med. 2024 May;12(5):338–339. doi: 10.1016/S2213-2600(23)00470-8. Epub 2024 Feb 1. PMID: 38310916. - DOI - PubMed

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A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial

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A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial

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Abstract

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