An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression
Eddie Cano-Gamez, Katie L Burnham, Cyndi Goh, Alice Allcock, Zunaira H Malick, Lauren Overend, Andrew Kwok, David A Smith, Hessel Peters-Sengers, David Antcliffe, GAinS Investigators, Stuart McKechnie, Brendon P Scicluna, Tom van der Poll, Anthony C Gordon, Charles J Hinds, Emma E Davenport, Julian C Knight, Nigel Webster, Helen Galley, Jane Taylor, Sally Hall, Jenni Addison, Sian Roughton, Heather Tennant, Achyut Guleri, Natalia Waddington, Dilshan Arawwawala, John Durcan, Alasdair Short, Karen Swan, Sarah Williams, Susan Smolen, Christine Mitchell-Inwang, Tony Gordon, Emily Errington, Maie Templeton, Pyda Venatesh, Geraldine Ward, Marie McCauley, Simon Baudouin, Charley Higham, Jasmeet Soar, Sally Grier, Elaine Hall, Stephen Brett, David Kitson, Robert Wilson, Laura Mountford, Juan Moreno, Peter Hall, Jackie Hewlett, Stuart McKechnie, Christopher Garrard, Julian Millo, Duncan Young, Paula Hutton, Penny Parsons, Alex Smiths, Roser Faras-Arraya, Jasmeet Soar, Parizade Raymode, Jonathan Thompson, Sarah Bowrey, Sandra Kazembe, Natalie Rich, Prem Andreou, Dawn Hales, Emma Roberts, Simon Fletcher, Melissa Rosbergen, Georgina Glister, Jeronimo Moreno Cuesta, Julian Bion, Joanne Millar, Elsa Jane Perry, Heather Willis, Natalie Mitchell, Sebastian Ruel, Ronald Carrera, Jude Wilde, Annette Nilson, Sarah Lees, Atul Kapila, Nicola Jacques, Jane Atkinson, Abby Brown, Heather Prowse, Anton Krige, Martin Bland, Lynne Bullock, Donna Harrison, Gary Mills, John Humphreys, Kelsey Armitage, Shond Laha, Jacqueline Baldwin, Angela Walsh, Nicola Doherty, Stephen Drage, Laura Ortiz-Ruiz de Gordoa, Sarah Lowes, Charley Higham, Helen Walsh, Verity Calder, Catherine Swan, Heather Payne, David Higgins, Sarah Andrews, Sarah Mappleback, Charles Hind, Chris Garrard, D Watson, Eleanor McLees, Alice Purdy, Martin Stotz, Adaeze Ochelli-Okpue, Stephen Bonner, Iain Whitehead, Keith Hugil, Victoria Goodridge, Louisa Cawthor, Martin Kuper, Sheik Pahary, Geoffrey Bellingan, Richard Marshall, Hugh Montgomery, Jung Hyun Ryu, Georgia Bercades, Susan Boluda, Andrew Bentley, Katie Mccalman, Fiona Jefferies, Julian Knight, Emma Davenport, Katie Burnham, Narelle Maugeri, Jayachandran Radhakrishnan, Yuxin Mi, Alice Allcock, Cyndi Goh, Eddie Cano-Gamez, Katie L Burnham, Cyndi Goh, Alice Allcock, Zunaira H Malick, Lauren Overend, Andrew Kwok, David A Smith, Hessel Peters-Sengers, David Antcliffe, GAinS Investigators, Stuart McKechnie, Brendon P Scicluna, Tom van der Poll, Anthony C Gordon, Charles J Hinds, Emma E Davenport, Julian C Knight, Nigel Webster, Helen Galley, Jane Taylor, Sally Hall, Jenni Addison, Sian Roughton, Heather Tennant, Achyut Guleri, Natalia Waddington, Dilshan Arawwawala, John Durcan, Alasdair Short, Karen Swan, Sarah Williams, Susan Smolen, Christine Mitchell-Inwang, Tony Gordon, Emily Errington, Maie Templeton, Pyda Venatesh, Geraldine Ward, Marie McCauley, Simon Baudouin, Charley Higham, Jasmeet Soar, Sally Grier, Elaine Hall, Stephen Brett, David Kitson, Robert Wilson, Laura Mountford, Juan Moreno, Peter Hall, Jackie Hewlett, Stuart McKechnie, Christopher Garrard, Julian Millo, Duncan Young, Paula Hutton, Penny Parsons, Alex Smiths, Roser Faras-Arraya, Jasmeet Soar, Parizade Raymode, Jonathan Thompson, Sarah Bowrey, Sandra Kazembe, Natalie Rich, Prem Andreou, Dawn Hales, Emma Roberts, Simon Fletcher, Melissa Rosbergen, Georgina Glister, Jeronimo Moreno Cuesta, Julian Bion, Joanne Millar, Elsa Jane Perry, Heather Willis, Natalie Mitchell, Sebastian Ruel, Ronald Carrera, Jude Wilde, Annette Nilson, Sarah Lees, Atul Kapila, Nicola Jacques, Jane Atkinson, Abby Brown, Heather Prowse, Anton Krige, Martin Bland, Lynne Bullock, Donna Harrison, Gary Mills, John Humphreys, Kelsey Armitage, Shond Laha, Jacqueline Baldwin, Angela Walsh, Nicola Doherty, Stephen Drage, Laura Ortiz-Ruiz de Gordoa, Sarah Lowes, Charley Higham, Helen Walsh, Verity Calder, Catherine Swan, Heather Payne, David Higgins, Sarah Andrews, Sarah Mappleback, Charles Hind, Chris Garrard, D Watson, Eleanor McLees, Alice Purdy, Martin Stotz, Adaeze Ochelli-Okpue, Stephen Bonner, Iain Whitehead, Keith Hugil, Victoria Goodridge, Louisa Cawthor, Martin Kuper, Sheik Pahary, Geoffrey Bellingan, Richard Marshall, Hugh Montgomery, Jung Hyun Ryu, Georgia Bercades, Susan Boluda, Andrew Bentley, Katie Mccalman, Fiona Jefferies, Julian Knight, Emma Davenport, Katie Burnham, Narelle Maugeri, Jayachandran Radhakrishnan, Yuxin Mi, Alice Allcock, Cyndi Goh
Abstract
Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.
Conflict of interest statement
Competing interests
ACG has received consulting fees as part of a Data Monitoring Committee from 30 Respiratory paid to his institution. All remaining authors declare that they have no competing interests.
Figures
References
- GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–1222.
- van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017;17:407–420.
- Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, Fleischmann-Struzek C, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395:200–211.
- Sandhu C, Qureshi A, Emili A. Panomics for Precision Medicine. Trends Mol Med. 2018;24:85–101.
- Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, Rautanen A, Gordon AC, Garrard C, Hill AVS, Hinds CJ, et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med. 2016;4:259–271.
- Burnham KL, Davenport EE, Radhakrishnan J, Humburg P, Gordon AC, Hutton P, Svoren-Jabalera E, Garrard C, Hill AVS, Hinds CJ, Knight JC. Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia. Am J Respir Crit Care Med. 2017;196:328–339.
- Scicluna BP, van Vught LA, Zwinderman AH, Wiewel MA, Davenport EE, Burnham KL, NÜrnberg P, Schultz MJ, Horn J, Cremer OL, Bonten MJ, et al. MARS consortium, Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med. 2017;5:816–826.
- Sweeney TE, Perumal TM, Henao R, Nichols M, Howrylak JA, Choi AM, Bermejo-Martin JF, Almansa R, Tamayo E, Davenport EE, Burnham KL, et al. A community approach to mortality prediction in sepsis via gene expression analysis. Nat Commun. 2018;9:694.
- Baghela A, Pena OM, Lee AH, Baquir B, Falsafi R, An A, Farmer SW, Hurlburt A, Mondragon-Cardona A, Rivera JD, Baker A, et al. Predicting sepsis severity at first clinical presentation: The role of endotypes and mechanistic signatures. EBioMedicine. 2022:103776.
- Seymour CW, Kennedy JN, Wang S, Chang CCH, Elliott CF, Xu Z, Berry S, Clermont G, Cooper G, Gomez H, Huang DT, et al. Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis. JAMA. 2019;321:2003–2017.
- Wong HR, Cvijanovich N, Allen GL, Lin R, Anas N, Meyer K, Freishtat RJ, Monaco M, Odoms K, Sakthivel B, Shanley TP. Genomics of Pediatric SIRS/Septic Shock Investigators, Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum. Crit Care Med. 2009;37:1558–1566.
- Banerjee S, Mohammed A, Wong HR, Palaniyar N, Kamaleswaran R. Machine Learning Identifies Complicated Sepsis Course and Subsequent Mortality Based on 20 Genes in Peripheral Blood Immune Cells at 24 H Post-ICU Admission. Front Immunol. 2021;12:592303.
- Wong HR, Caldwell JT, Cvijanovich NZ, Weiss SL, Fitzgerald JC, Bigham MT, Jain PN, Schwarz A, Lutfi R, Nowak J, Allen GL, et al. Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model. Sci Transl Med. 2019;11
- Antcliffe DB, Burnham KL, Al-Beidh F, Santhakumaran S, Brett SJ, Hinds CJ, Ashby D, Knight JC, Gordon AC. Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial. Am J Respir Crit Care Med. 2019;199:980–986.
- Haghverdi L, Lun ATL, Morgan MD, Marioni JC. Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors. Nat Biotechnol. 2018;36:421–427.
- Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS) A prospective study JAMA. 1995;273:117–123.
- Rhee C, Klompas M. Elucidating the Spectrum of Disease Severity Encompassed by Sepsis. JAMA Netw Open. 2022;5:e2147888.
- Pearl J. Interpretation and identification of causal mediation. Psychol Methods. 2014;19:459–481.
- Imai K, Keele L, Tingley D. A general approach to causal mediation analysis. Psychol Methods. 2010;15:309–334.
- COMBAT Consortium. A blood atlas of COVID-19 defines hallmarks of disease severity and specificity. Cell. 2022;185:916–938.
- Parnell GP, Tang BM, Nalos M, Armstrong NJ, Huang SJ, Booth DR, Mc AS. Identifying key regulatory genes in the whole blood of septic patients to monitor underlying immune dysfunctions. Shock. 2013;40:166–174.
- Gajic O, Ahmad SR, Wilson ME, Kaufman DA. Outcomes of critical illness: what is meaningful. Curr Opin Crit Care. 2018;24:394–400.
- Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, Moffatt MF, et al. Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza. Nat Immunol. 2018;19:625–635.
- Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche J-D, Coopersmith CM, Hotchkiss RS, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315:801–810.
- Aschenbrenner AC, Mouktaroudi M, Krämer B, Oestreich M, Antonakos N, Nuesch-Germano M, Gkizeli K, Bonaguro L, Reusch N, Baßler K, Saridaki M, Knoll R, et al. German COVID-19 Omics Initiative (DeCOI), Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients. Genome Med. 2021;13:7.
- Wong HR, Sweeney TE, Hart KW, Khatri P, Lindsell CJ. Pediatric Sepsis Endotypes Among Adults With Sepsis. Crit Care Med. 2017;45:e1289–e1291.
- Olwal CO, Nganyewo NN, Tapela K, Djomkam Zune AL, Owoicho O, Bediako Y, Duodu S. Parallels in Sepsis and COVID-19 Conditions: Implications for Managing Severe COVID-19. Front Immunol. 2021;12:602848.
- Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20:195–203.
- Clermont G, Bartels J, Kumar R, Constantine G, Vodovotz Y, Chow C. In silico design of clinical trials: a method coming of age. Crit Care Med. 2004;32:2061–2070.
- Cockrell RC, An G. Examining the controllability of sepsis using genetic algorithms on an agent-based model of systemic inflammation. PLoS Comput Biol. 2018;14:e1005876.
- Kwok AJ, Allcock A, Ferreira RC, Smee M, Cano-Gamez E, Burnham KL, Zurke YX, McKechnie S, Monaco C, Udalova I, Hinds CJ, et al. Identification of deleterious neutrophil states and altered granulopoiesis in sepsis. medRxiv. 2022
- Lelubre C, Vincent J-L. Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol. 2018;14:417–427.
- Inouye M, Silander K, Hamalainen E, Salomaa V, Harald K, Jousilahti P, Männistö S, Eriksson JG, Saarela J, Ripatti S, Perola M, et al. An Immune Response Network Associated with Blood Lipid Levels. PLoS Genet. 2010;6:e1001113.
- Mayerle J, den Hoed CM, Schurmann C, Stolk L, Homuth G, Peters MJ, Capelle LG, Zimmermann K, Rivadeneira F, Gruska S, Völzke H, et al. Identification of genetic loci associated with Helicobacter pylori serologic status. JAMA. 2013;309:1912–1920.
- Westra H-J, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE, Zhernakova A, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013;45:1238–1243.
- Aguirre-Gamboa R, de Klein N, di Tommaso J, Claringbould AM, van der Wijst G, de Vries D, Brugge H, Oelen R, Võsa U, Zorro MM, Chu X, et al. Deconvolution of bulk blood eQTL effects into immune cell subpopulations. BMC Bioinformatics. 2020;21:243.
- Netea MG, Joosten LAB, Li Y, Kumar V, Oosting M, Smeekens S, Jaeger M, Ter Horst R, Schirmer M, Vlamakis H, Notebaart R, et al. Understanding human immune function using the resources from the Human Functional Genomics Project. Nat Med. 2016;22:831–833.
- Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.
- Fang H, Knezevic B, Burnham KL, Knight JC. XGR software for enhanced interpretation of genomic summary data, illustrated by application to immunological traits. Genome Med. 2016;8:129.
Source: PubMed