Abstract

Early diagnosis and identification of causative pathogens using blood culture in patients suspected of Blood Stream Infection (BSI) and sepsis are critical for improving patient outcomes through early and more targeted treatment.

Methods Post-hoc retrospective analysis of indiviudal patient data from three prospective clinical studies, conducted in North America, Europe and Africa, to investigate the association between SeptiCyte RAPID test results (SeptiScores) and blood culture results.

Hypothesis that a significant correlation exists between elevated SeptiScores and positive blood culture results, and between low SeptiScores and negative blood culture results.

Results As the SeptiScore increases, the relative probabilty of a septic patient being BC(+) as opposed to BC(−) also increases. A non-linear positive correlation is observed. Below SeptiScores of 10, the ratio of probabilities of BC(+) sepsis / BC(−) sepsis is <1 while above SeptiScores of 10 this ratio is >1. Thus, septic patients with SeptiScores >10 have a higher probability of being BC(+) compared to BC(−).

Conclusions Elevated SeptiScores, obtained before blood culture results, are indicative of increased blood culture positivity. This may have clinical utility, particularly in resource limited settings, as an aid for improving the efficiency of blood culture practice, for instance by informing patient selection and interpretation of blood culture results.

Competing Interest Statement

M.vdF. has received consulting fees from Roche Diabetes and scientific funding from Immunexpress Inc. M.D. has received con-sulting fees from Roche Diabetes, payment or honoraria for lectures from CSL Behring, and scientific funding from Immunexpress Inc. 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. K.N., T.D.Y., R.B.B. declare that they are current employees and shareholders of Immunexpress, Inc. The remaining authors declare no com-peting interests.

Clinical Trial

DRKS00024891

Funding Statement

This research was funded in part by Immunexpress Inc. and by the DRIVe Solving Sepsis program of the Biomedical Advanced Research and Development Authority (BARDA) - a branch of the US HHS Office of the Assistant Secretary for Preparedness and Response. Funding was also provided in part by the Joint Program Executive Office for Chemical Biological Radiological and Nuclear Defense (JPEO-CBRND) Joint Project Lead for CBRND Enabling Biotechnologies (JPEO CBRND JPL EB) on behalf of the Department of Defense Chemical and Biological Defense Program. This effort was in collaboration with the Defense Health Agency (DHA) COVID funding initiative for The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. under award W911QY-20-9-0004. Funding was also provided in part by the Defense Health Agency Joint Program Committee-2/Military Infectious Diseases Research Program (JPC-2/MIDRP) under the HJF- (DoD-Navy) Cooperative Agreement N626451920001.

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:

All research reported in this study was conducted in accordance with the Declaration of Helsinki, and in accordance with relevant guidelines and regulations. Informed Consent was obtained from all subjects or their legal representatives. The SeptAsTERS component of this study was approved by the Ethics Committee of the Medical Faculty of Heidelberg University (S-118/2021) and was registered in the German Clinical Trials Register (DRKS00024891) prior to enrolment. The Uganda component of this study was approved under IRB NMRC.2016.0004-GHA and NMRC.2017.0001. The Ghanaian supplement to this study was conducted under protocol number NMRC.2016.0004-GHA (An Observational Study of Sepsis in Kumasi, Ghana) and approved by the Komfo Anokye Teaching Hospital IRB and the Naval Medical Research Center (NMRC) IRB prior to enrolment, in compliance with all applicable US Federal regulations governing the protection of human subjects. The 510k component of this study was conducted under the following approvals. Ethics approval for the MARS trial was given by the medical ethics committee of AMC, Amsterdam (approval # 10-056C, 16 June 2010). Ethics approvals for the VENUS trial were given by the relevant Institutional Review Boards as follows: Intermountain Medical Center/Latter Day Saints Hospital (approval # 1024931, 21 January 2014); Johns Hopkins Hospital (approval # IRB00087839, 28 January 2016); Rush University Medical Center (approval # 15111104-IRB01, 11 March 2016); Loyola University Medical Center (approval # 208291, 10 March 2016); Northwell Healthcare (approval #16-02-42-03, 1 April 2016). Ethics approvals for the NEPTUNE trial were given by the relevant Institutional Review Boards as follows: Emory University (approval # IRB00115400, 3 December 2019); Grady Memorial Hospital (approval # 00-115400, 14 January 2020); Rush University Medical Center (approval # 19101603-IRB01, 16 January 2020); University of Southern California Medical Center (approval # HS-19-0884-CR001, 10 February 2020).

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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Footnotes

krupa.nimmunexpress.com (K.N.); thomas.yimmunexpress.com (T.D.Y.); Richard.bimmunexpress.com (R.B.B.)

AWheelockaceso-sepsis.org (A.W.); DClarkaceso-sepsis.org (D.C.); Melissa.gregory2nih.gov (M.G.)

hkibuukamuwrp.org (H.K.); sokellomuwrp.org (S.O.); satukundamuwrp.org (S.A.)

awailagalaidi.co.ug (A.Wa.); PWaittidi.co.ug (P.W.); fkakoozaidi.co.ug (F.K.)

gdodurohotmail.com (G.O.)

nehkonti.adams.milhealth.mil (N.A.)

Maximilian.dietrichmed.uni-heidelberg.de (M.D.); Maik.Forstmed.uni-heidelberg.de (M.v.d.F.)

marcus.j.schultzgmail.com (M.J.S.)

neil.aggarwalcuanschutz.edu (N.A.)

Jared_Greenbergrush.edu (J.G.)

AbbreviationsANOVAAnalysis of varianceAUCarea under [ROC] curveBCblood culture(s)BSIbloodstream infectionCIConfidence intervalCqThreshold-crossing cycle (in qPCR)CRPC-reactive proteinEDEmergency departmentFfemaleFDAFood and Drug Administration (USA)FUBCfollow-up blood cultureICUIntensive care unitLMICLower and middle income countryLR+Positive likelihood ratioMmalemLMilliliterNDNot determinedPLA2G7Phospholipase A2 group VII (mRNA transcript)PLAC8Placenta-associated 8 (mRNA transcript)ROCreceiver operating characteristic (curve)RPDRetrospective physician diagnosisRT-qPCRreverse transcription – quantitative polymerase chain reactionSIRSsystemic inflammatory response syndromeSOFASequential organ failure assessment (score)WBCwhite blood cell