Multivariate protein landscape of host response in hospitalised patients with suspected infection in the emergency department

Pratik Sinha (), Alexandra B. Spicer, Sivasubramanium Bhavani, Carlos López-Espina, Gregory L. Watson, Akhil Bhargava, Lee Schmalz, Shah Khan, Matthew D. Sims, Ashok V. Palagiri, Alon Dagan, Karthik V. Iyer, Matthew J. Crisp, Carmen DeMarco, Alexandra Halalau, Nicholas Maddens, Niko Kurtzman, Deesha Sarma, Falgun Gosai, Anwaruddin Syed, Saleem Azad, Aimee Espinosa, Francisco Davila, Hugo Davila, Neil Shadbeh Evans, Scott Smith, Bobby Reddy, Philip A. Verhoef and Matthew M. Churpek
Additional contact information
Pratik Sinha: Washington University School of Medicine
Alexandra B. Spicer: University of Wisconsin-Madison
Sivasubramanium Bhavani: Emory University
Carlos López-Espina: Prenosis Inc
Gregory L. Watson: Prenosis Inc
Akhil Bhargava: Prenosis Inc
Lee Schmalz: Prenosis Inc
Shah Khan: Prenosis Inc
Matthew D. Sims: Corewell Health William Beaumont University Hospital
Ashok V. Palagiri: Mercy Hospital
Alon Dagan: Beth Israel Deaconess Medical Center
Karthik V. Iyer: Mercy Hospital Jefferson
Matthew J. Crisp: OSF Saint Francis Medical Center
Carmen DeMarco: Corewell Health William Beaumont University Hospital
Alexandra Halalau: Corewell Health William Beaumont University Hospital
Nicholas Maddens: Corewell Health William Beaumont University Hospital
Niko Kurtzman: Emory University
Deesha Sarma: Beth Israel Deaconess Medical Center
Falgun Gosai: OSF Saint Francis Medical Center
Anwaruddin Syed: OSF Saint Francis Medical Center
Saleem Azad: Mercy Hospital Jefferson
Aimee Espinosa: Corewell Health William Beaumont University Hospital
Francisco Davila: Corewell Health William Beaumont University Hospital
Hugo Davila: Corewell Health William Beaumont University Hospital
Neil Shadbeh Evans: UC Davis Medical Center
Scott Smith: Corewell Health William Beaumont University Hospital
Bobby Reddy: Prenosis Inc
Philip A. Verhoef: Hawaii Permanente Medical Group
Matthew M. Churpek: University of Wisconsin-Madison

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62848-x

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