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 Gordon, Charles Hinds, Emma E. Davenport, Julian C. Knight, Nigel R. Webster, Helen F. Galley, Jane R. Taylor, Sally Hall, Jenni Addison, Siân 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 J. Brett, David H. Kitson, Robert B. Wilson, Laura Mountford, Juan C. Moreno, Peter S Hall, Jackie Hewlett, Stuart McKechnie, Christopher S. Garrard, Julian Millo, Duncan Young, Paula Hutton, Penny Parsons, Alex Smiths, Roser Faras-Arraya, Jasmeet Soar, Parizade Raymode, Jonathan P. Thompson, Sarah Bowrey, Sandra Kazembe, Natalie Rich, Prem Andreou, Dawn Hales, Emma A. Roberts, Simon P. Fletcher, Melissa Rosbergen, Georgina Glister, Jeronimo 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 C. 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
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.