Validation of SeptiCyte RAPID to discriminate sepsis from non-infectious systemic inflammation

Background SeptiCyte RAPID is a molecular test for distinguishing sepsis from non-infectious systemic inflammation. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospective (banked) and prospectively collected patient samples. Methods The cartridge-based SeptiCyte RAPID assay accepts a PAXgene blood RNA sample and provides sample-to-answer processing in about 1 hour. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (banked) and prospective samples from adult patients in ICU either having systemic inflammatory response syndrome (SIRS), or suspected of sepsis under either the Sepsis-2 or Sepsis-3 definition were tested, and results were compared to a gold standard of clinical evaluation by a blinded, three-physician external panel. A multivariable analysis was performed, in which SeptiScore was combined with other clinical variables. Results With adjudication under the Sepsis-2 definition, SeptiCyte RAPID performance for the complete cohort (356 retrospective + 63 prospective patients) had Area Under the ROC Curve (AUC) ranging from 0.82-0.85, negative predictive value 0.91 (sensitivity 0.94) for SeptiScores between 0.1 and 5.0 (Band 1, lowest risk of sepsis), and positive predictive value 0.81 (specificity 0.90) for SeptiScores between 7.4 and 15 (Band 4, highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. Comparable results were obtained when the data were reanalyzed under the Sepsis-3 definition. Conclusions This study validates SeptiCyte RAPID for differentiating patients with sepsis vs. SIRS, on the first day of ICU admission. Trial Registration : [NCT01905033][1] (MARS), [NCT02127502][2] (VENUS), [NCT05469048][3] (NEPTUNE, retrospectively registered) at clinicaltrials.gov. Sources of Support: This study was supported by Immunexpress Inc. Best Descriptor: CRITICAL CARE, 4.12 Sepsis/Multiple Organ Failure ### Competing Interest Statement The following coauthors are employees and/or shareholders of Immunexpress: Krupa Navalkar, Thomas D. Yager, Dayle Sampson, James T. Kirk, Silvia Cermelli, Roy F. Davis, Richard B. Brandon ### Funding Statement This study was funded by Immunexpress, Inc. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for this work has been granted by the following ethics committees/IRBs: Amsterdam Medical Center (10-056C), Intermountain Medical Center/Latter Day Saints Hospital (1024931); Johns Hopkins Hospital (IRB00087839); Rush University Medical Center (15111104-IRB01 & 19101603-IRB01); Loyola University Medical Center (208291); Northwell Healthcare (16-02-42-03); Grady Memorial Hospital (000-87806 & 00-115400), Emory University (IRB00115400), University of Southern California Medical Center (HS-19-0884-CR001). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data produced in the present study are available upon reasonable request to the authors. * ### Abbreviations %A : Percent Agreement ANOVA : Analysis of Variance AUC : Area Under (Receiver Operator Characteristic) Curve CAD : Coronary artery disease CKD : Chronic kidney disease CPAP : Continuous positive airway pressure Cq : Quantification Cycle (for PCR) CRP : C-Reactive Protein ED : Emergency Department ICU : Intensive Care Unit IQR : Interquartile Range Ku : Unweighted inter-observer kappa Kw : Linearly weighted inter-observer kappa LR : Likelihood Ratio PCR : Polymerase Chain Reaction PCT : Procalcitonin PLA2G7 : Phospholipase A2, Group VII PLAC8 : Placenta associated 8 ROC : Receiver Operator Characteristic (curve) RPD : Retrospective Physician Diagnosis RT-qPCR : Reverse Transcription - Quantitative Polymerase Chain Reaction SIRS : Systemic Inflammatory Response Syndrome SSC : Surviving Sepsis Campaign Tukey HSD : Tukey Honestly Significant Difference WBC : White Blood Cell [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01905033&atom=%2Fmedrxiv%2Fearly%2F2023%2F03%2F17%2F2022.07.20.22277648.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02127502&atom=%2Fmedrxiv%2Fearly%2F2023%2F03%2F17%2F2022.07.20.22277648.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05469048&atom=%2Fmedrxiv%2Fearly%2F2023%2F03%2F17%2F2022.07.20.22277648.atom