Multivariate protein landscape of host response in hospitalised patients with suspected infection in the emergency department
Suspected infection requiring hospitalisation has highly heterogenous presentation. Yet, variances in host response and its implications are largely unknown. In this multicentre cohort of 3802 individual patients presenting to the Emergency Department (ED) with suspected infection requiring hospitalisation, we apply uniform manifold approximation and projections and K-means clustering to 29 plasma proteins to identify biologically discrete host response clusters. In this work, we first describe two large clusters, called "Dysregulated" and "Undifferentiated", with abnormal protein concentrations and adverse outcomes in the former. Through further clustering, we identify 4 sub-clusters in the Dysregulated cluster, each with discrete biological signatures, clinical correlates, and outcomes. Clusters 3 and 4 are characterised by renal impairment and viral infections respectively. Clusters 5 and 6 are associated with bacterial culture positivity, with the former consistent with an immunosuppressed signature and worse outcomes, and the latter with gram-negative bacteria, higher IL-6 and IL-8, and better outcomes despite higher vasopressor use. These clusters are a biologically driven approach to characterising acute suspected infection and may lead to more targeted therapeutics.
Authors
- Shah Salman Khan
- Matthew Sims (ORCID: https://orcid.org/0000-0002-4427-6653)
- Anwaruddin Syed (ORCID: https://orcid.org/0000-0001-9134-7840)
- Scott Smith
- Ashok Palagiri
- Nicholas Maddens
- Karthik Iyer
- Philip A. Verhoef (ORCID: https://orcid.org/0000-0002-1502-5468)
- Carmen DeMarco
- Neil R. Evans (ORCID: https://orcid.org/0000-0001-5602-2370)
- Pratik Sinha (ORCID: https://orcid.org/0000-0003-3751-9079)
- Aimee Espinosa
- Matthew J. Crisp
- Falgun Gosai (ORCID: https://orcid.org/0000-0002-5588-9463)
- Carlos G. Lopez-Espina
- Alexandra Halalau (ORCID: https://orcid.org/0000-0002-1805-992X)
- Alon Dagan (ORCID: https://orcid.org/0000-0002-3404-9983)
- Lee Schmalz
- Alexandra B. Spicer (ORCID: https://orcid.org/0000-0001-9195-2143)
- Akhil Bhargava (ORCID: https://orcid.org/0009-0006-9314-0863)
- Sivasubramanium V. Bhavani (ORCID: https://orcid.org/0000-0002-9640-6720)
- Gregory L. Watson (ORCID: https://orcid.org/0000-0001-7597-7359)
- Francisco Davila (ORCID: https://orcid.org/0000-0002-2539-3379)
- Matthew M. Churpek (ORCID: https://orcid.org/0000-0002-4030-5250)
- Nicholas Kurtzman (ORCID: https://orcid.org/0000-0003-2251-2405)
- Deesha Sarma (ORCID: https://orcid.org/0000-0003-1970-9290)
- Hugo Dávila
- Bobby Reddy
- Saleem Azad
Institutions
- University of Hawaiʻi at Mānoa (US)
- Beth Israel Deaconess Medical Center (US)
- University of Wisconsin–Madison (US)
- Emory University (US)
- Oakland University (US)
- Washington University in St. Louis (US)
- OSF Saint Francis Medical Center (US)
- Beaumont Hospital, Royal Oak (US)
- Mercy Hospital (US)
- Jefferson Hospital (US)
- Precision Research (United States) (US)
- University of California Davis Medical Center (US)
- Hawaii Permanente Medical Group (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1038/s41467-025-62848-x
- Citations
- 2
- Primary Topic
- Sepsis Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 2.71
Funders
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences