Rapid and Robust Identification of Sepsis Using SeptiCyte RAPID in a Heterogeneous Patient Population

Robert Balk¹, Annette M Esper², Greg S Martin², Russell R Miller 3rd³, Bert K Lopansri^{4

5}, John P Burke^{4

5}, Mitchell Levy⁶, Richard E Rothman⁷, Franco R D'Alessio⁸, Venkataramana K Sidhaye⁷, Neil R Aggarwal⁹, Jared A Greenberg¹, Mark Yoder¹, Gourang Patel¹, Emily Gilbert¹⁰, Jorge P Parada¹⁰, Majid Afshar¹¹, Jordan A Kempker², Tom van der Poll¹², Marcus J Schultz^{13

14}, Brendon P Scicluna^{15

16}, Peter M C Klein Klouwenberg¹⁷, Janice Liebler^{18

19}, Emily Blodget^{18

19}, Santhi Kumar^{18

19}, Xue W Mei²⁰, Krupa Navalkar²¹, Thomas D Yager²¹, Dayle Sampson²¹, James T Kirk²¹, Silvia Cermelli²¹, Roy F Davis²¹, Richard B Brandon²¹

Affiliations

¹ Rush Medical College and Rush University Medical Center, Chicago, IL 60612, USA.
² Grady Memorial Hospital and Emory University School of Medicine, Atlanta, GA 30322, USA.
³ FirstHealth of the Carolinas, Pinehurst, NC 28374, USA.
⁴ Intermountain Medical Center, Murray, UT 84107, USA.
⁵ School of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
⁶ Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
⁷ School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
⁸ Pulmonary and Critical Care & Sleep Medicine, Department of Medicine, University of Miami, Miami, FL 33136, USA.
⁹ Anschutz Medical Campus, University of Colorado, Denver, CO 80045, USA.
¹⁰ Loyola University Medical Center, Maywood, IL 60153, USA.
¹¹ School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.
¹² Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
¹³ Division of Cardiothoracic and Vascular Anesthesia and Intensive Care Medicine, Department of Anesthesia, General Intensive Care, and Pain Management, Medical University of Vienna, 1090 Vienna, Austria.
¹⁴ Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK.
¹⁵ Centre for Molecular Medicine and Biobanking, University of Malta, Msida MSD 2080, Malta.
¹⁶ Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei Hospital, University of Malta, Msida MSD 2080, Malta.
¹⁷ Fundashon Mariadal, Kralendijk, Bonaire, Netherlands Antilles.
¹⁸ Keck Hospital of University of Southern California (USC), Los Angeles, CA 90033, USA.
¹⁹ Los Angeles General Medical Center, Los Angeles, CA 90033, USA.
²⁰ Princeton Pharmatech, Princeton, NJ 08540, USA.
²¹ Immunexpress Inc., Seattle, WA 98109, USA.

PMID: 39457994
PMCID: PMC11509035
DOI: 10.3390/jcm13206044

Rapid and Robust Identification of Sepsis Using SeptiCyte RAPID in a Heterogeneous Patient Population

Robert Balk et al. J Clin Med. 2024.

. 2024 Oct 10;13(20):6044.

doi: 10.3390/jcm13206044.

Authors

Affiliations

¹ Rush Medical College and Rush University Medical Center, Chicago, IL 60612, USA.
² Grady Memorial Hospital and Emory University School of Medicine, Atlanta, GA 30322, USA.
³ FirstHealth of the Carolinas, Pinehurst, NC 28374, USA.
⁴ Intermountain Medical Center, Murray, UT 84107, USA.
⁵ School of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
⁶ Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
⁷ School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
⁸ Pulmonary and Critical Care & Sleep Medicine, Department of Medicine, University of Miami, Miami, FL 33136, USA.
⁹ Anschutz Medical Campus, University of Colorado, Denver, CO 80045, USA.
¹⁰ Loyola University Medical Center, Maywood, IL 60153, USA.
¹¹ School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.
¹² Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
¹³ Division of Cardiothoracic and Vascular Anesthesia and Intensive Care Medicine, Department of Anesthesia, General Intensive Care, and Pain Management, Medical University of Vienna, 1090 Vienna, Austria.
¹⁴ Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK.
¹⁵ Centre for Molecular Medicine and Biobanking, University of Malta, Msida MSD 2080, Malta.
¹⁶ Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei Hospital, University of Malta, Msida MSD 2080, Malta.
¹⁷ Fundashon Mariadal, Kralendijk, Bonaire, Netherlands Antilles.
¹⁸ Keck Hospital of University of Southern California (USC), Los Angeles, CA 90033, USA.
¹⁹ Los Angeles General Medical Center, Los Angeles, CA 90033, USA.
²⁰ Princeton Pharmatech, Princeton, NJ 08540, USA.
²¹ Immunexpress Inc., Seattle, WA 98109, USA.

PMID: 39457994
PMCID: PMC11509035
DOI: 10.3390/jcm13206044

Abstract

Background/Objective: SeptiCyte RAPID is a transcriptional host response assay that discriminates between sepsis and non-infectious systemic inflammation (SIRS) with a one-hour turnaround time. The overall performance of this test in a cohort of 419 patients has recently been described [Balk et al., J Clin Med 2024, 13, 1194]. In this study, we present the results from a detailed stratification analysis in which SeptiCyte RAPID performance was evaluated in the same cohort across patient groups and subgroups encompassing different demographics, comorbidities and disease, sources and types of pathogens, interventional treatments, and clinically defined phenotypes. The aims were to identify variables that might affect the ability of SeptiCyte RAPID to discriminate between sepsis and SIRS and to determine if any patient subgroups appeared to present a diagnostic challenge for the test. Methods: (1) Subgroup analysis, with subgroups defined by individual demographic or clinical variables, using conventional statistical comparison tests. (2) Principal component analysis and k-means clustering analysis to investigate phenotypic subgroups defined by unique combinations of demographic and clinical variables. Results: No significant differences in SeptiCyte RAPID performance were observed between most groups and subgroups. One notable exception involved an enhanced SeptiCyte RAPID performance for a phenotypic subgroup defined by a combination of clinical variables suggesting a septic shock response. Conclusions: We conclude that for this patient cohort, SeptiCyte RAPID performance was largely unaffected by key variables associated with heterogeneity in patients suspected of sepsis.

Keywords: SIRS; SeptiCyte; host immune response; phenotype; sepsis; sepsis likelihood; stratification.

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Conflict of interest statement

K.N., T.D.Y., D.S., J.T.K., S.C., R.F.D. and R.B.B. declare they are present or past employees or shareholders of Immunexpress, Inc. X.W.M. declares that she is a present employee of Princeton Pharmatech, Inc. R.R.M. III discloses that, over the time period of relevance to this work he was paid (as a consultant) an honorarium by Immunexpress for conducting a critical review of a Clinical Evaluation Report of SeptiCyte technology, submitted by Immunexpress to the Therapeutic Goods Administration (TGA) of Australia. N.R.A. declares that he has received grants from the NIH and Department of Defense for non-related work and that payments from these grants are made to his institution, the University of Colorado. N.R.A. also declares that he is a committee member of the Pfizer Paxlovid U.S. Medical Advisory Committee formed to broadly discuss COVID-19-related therapeutic priorities and populations of interest. B.K.L. declares that he is a consultant for Karius Inc., is a member of the Scientific Advisory Board for Seegene Inc., and has received honoraria for speaking for Qiagen Inc. No other competing interests are declared.

Figures

**Figure 1**
Box and whisker plots of SeptiCyte RAPID performance in patients with (A) hyperglycemia, (B) impaired immunity, (C) hypertension, (D) cardiovascular disease, (E) kidney disease, and (F) obesity. The dotted horizontal lines indicate the SeptiScore band boundaries as defined by Balk et al. [16].

**Figure 2**
SeptiCyte RAPID performance stratified by infection source. The “other” group included the following (N per group): cellulitis (3), Fournier’s gangrene (1), hip arthroplasty (1), osteomyelitis (1), toe infection (1), sacral wound (1), post-surgical sternal wound (1), bladder/prostate abscess/peritonitis from cecum microperforation (1), influenza (1), tracheitis (1), erysipelas (1), skin or soft tissue necrotizing fasciitis (1). The dotted horizontal lines indicate the SeptiScore band boundaries as defined by Balk et al. [16]. Significance: p <= 0.01 **, p <= 0.001 ***.

**Figure 3**
Box and whisker plot of SeptiCyte RAPID performance for patients treated vs. not treated with immunosuppressants. The dotted horizontal lines indicate the SeptiScore band boundaries as defined by Balk et al. [16].

**Figure 4**
Box and whisker plots of the influence of antibiotic treatment (Abx) initiation time on SeptiCyte RAPID performance. The day of blood draw is defined as day 0. (**left**) treatment initiated −1 day to 0 days relative to blood draw; (**middle**) antibiotic treatment initiated on the same day as blood draw. (**right**) antibiotic treatment initiated +1 day after blood draw. The dotted horizontal lines indicate the SeptiScore band boundaries as defined by Balk et al. [16].

**Figure 5**
PCA plot of the sepsis group (N = 176) with superimposed HC using 16 phenotypic variables. In the plot, the peripheral points in each subgroup were used to define the cluster boundaries for that subgroup. Sepsis subgroup 1 (black) N = 110. Sepsis subgroup 2 (red) N = 50. Sepsis subgroup 3 (green) N = 15. Sepsis subgroup 4 (blue) N = 1.

**Figure 6**
Performance for discriminating sepsis vs. SIRS in different phenotypic subgroups defined by individual driving variables in PCA/HC and other biomarkers used for sepsis adjudication. Red: SeptiScore. Black: driving variable. Additional details corresponding to this figure are presented in Supplement Table S5.

**Figure 7**
Sepsis subgroups 1 (red; N = 96) and 2 (blue; N = 80) identified by k-means clustering. The small, most seriously ill subgroup 3 from the PCA/HC analysis (black; N = 15) is contained entirely within k-means group 2. The large colored symbols indicate the centroids of the subgroups.

See this image and copyright information in PMC

References

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Rapid and Robust Identification of Sepsis Using SeptiCyte RAPID in a Heterogeneous Patient Population

Affiliations

Rapid and Robust Identification of Sepsis Using SeptiCyte RAPID in a Heterogeneous Patient Population

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources