title: A novel host-proteome signature for distinguishing between acute bacterial and viral infections.
abstract: Bacterial and viral infections are often clinically indistinguishable, leading to inappropriate patient management and antibiotic misuse. Bacterial-induced host proteins such as procalcitonin, C-reactive protein (CRP), and Interleukin-6, are routinely used to support diagnosis of infection. However, their performance is negatively affected by inter-patient variability, including time from symptom onset, clinical syndrome, and pathogens. Our aim was to identify novel viral-induced host proteins that can complement bacterial-induced proteins to increase diagnostic accuracy. Initially, we conducted a bioinformatic screen to identify putative circulating host immune response proteins. The resulting 600 candidates were then quantitatively screened for diagnostic potential using blood samples from 1002 prospectively recruited patients with suspected acute infectious disease and controls with no apparent infection. For each patient, three independent physicians assigned a diagnosis based on comprehensive clinical and laboratory investigation including PCR for 21 pathogens yielding 319 bacterial, 334 viral, 112 control and 98 indeterminate diagnoses; 139 patients were excluded based on predetermined criteria. The best performing host-protein was TNF-related apoptosis-inducing ligand (TRAIL) (area under the curve [AUC] of 0.89; 95% confidence interval [CI], 0.86 to 0.91), which was consistently up-regulated in viral infected patients. We further developed a multi-protein signature using logistic-regression on half of the patients and validated it on the remaining half. The signature with the highest precision included both viral- and bacterial-induced proteins: TRAIL, Interferon gamma-induced protein-10, and CRP (AUC of 0.94; 95% CI, 0.92 to 0.96). The signature was superior to any of the individual proteins (P<0.001), as well as routinely used clinical parameters and their combinations (P<0.001). It remained robust across different physiological systems, times from symptom onset, and pathogens (AUCs 0.87-1.0). The accurate differential diagnosis provided by this novel combination of viral- and bacterial-induced proteins has the potential to improve management of patients with acute infections and reduce antibiotic misuse.
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel.
authors.forename: Kfir
authors.initials: K
authors.lastname: Oved
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel.
authors.forename: Asi
authors.initials: A
authors.lastname: Cohen
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Boico
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel.
authors.forename: Roy
authors.initials: R
authors.lastname: Navon
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel; Rambam Medical Center, Haifa, Israel.
authors.forename: Tom
authors.initials: T
authors.lastname: Friedman
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel; Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Etshtein
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel.
authors.forename: Or
authors.initials: O
authors.lastname: Kriger
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel; Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Pediatrics, Bnai-Zion Medical Center, Haifa, Israel.
authors.forename: Ellen
authors.initials: E
authors.lastname: Bamberger
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel.
authors.forename: Yura
authors.initials: Y
authors.lastname: Fonar
authors.affiliation: Department of Pediatrics, Hillel Yaffe Medical Center, Hadera, Israel.
authors.forename: Renata
authors.initials: R
authors.lastname: Yacobov
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Wolchinsky
authors.affiliation: Applied Immune Technologies, Haifa, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Denkberg
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Internal Medicine, Bnai-Zion Medical Center, Haifa, Israel.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Dotan
authors.affiliation: Department of Pediatrics, Hillel Yaffe Medical Center, Hadera, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Hochberg
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Reiter
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Infectious Diseases Unit, Bnai-Zion Medical Center, Haifa, Israel.
authors.forename: Moti
authors.initials: M
authors.lastname: Grupper
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Pediatrics, Bnai-Zion Medical Center, Haifa, Israel.
authors.forename: Isaac
authors.initials: I
authors.lastname: Srugo
authors.affiliation: Faculty of Industrial Engineering and Management, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Paul
authors.initials: P
authors.lastname: Feigin
authors.affiliation: Faculty of Industrial Engineering and Management, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Malka
authors.initials: M
authors.lastname: Gorfine
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Pediatrics, Bnai-Zion Medical Center, Haifa, Israel.
authors.forename: Irina
authors.initials: I
authors.lastname: Chistyakov
authors.affiliation: Pediatric Infectious Disease Unit and Clinical Microbiology Laboratory, Soroka Medical Center, Beer-Sheva, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Dagan
authors.affiliation: Department of Pediatrics, Hillel Yaffe Medical Center, Hadera, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Klein
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Infectious Diseases Unit, Bnai-Zion Medical Center, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Potasman
authors.affiliation: MeMed Diagnostics, Tirat Carmel, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Eden
mesh_terms: D000293:Adolescent; D000328:Adult; D001424:Bacterial Infections / Q000175:diagnosis* / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D040901:Proteomics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014777:Virus Diseases / Q000175:diagnosis* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015415:Biomarkers