A novel host-proteome signature for distinguishing between acute bacterial and viral infections

PLoS One. 2015 Mar 18;10(3):e0120012. doi: 10.1371/journal.pone.0120012. eCollection 2015.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Bacterial Infections / diagnosis*
  • Bacterial Infections / metabolism*
  • Biomarkers / metabolism
  • Child
  • Child, Preschool
  • Cohort Studies
  • Diagnosis, Differential
  • Female
  • Humans
  • Male
  • Middle Aged
  • Proteomics*
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Virus Diseases / diagnosis*
  • Virus Diseases / metabolism*
  • Young Adult

Substances

  • Biomarkers

Grant support

This study was funded by MeMed. KO, AC, OB, RN, TF, LE, EB and EE are employed by MeMed. YF and OK were previously employed by MeMed. MeMed provided support in the form of salaries for authors KO, AC, OB, RN, TF, LE, EB, EE, YF and OK, and was responsible for protein measurements and multiparametric signature development. Clinical investigators and MeMed affiliated authors collaborated on the study design, data collection and analysis, decision to publish, and preparation of the manuscript as articulated in the ‘author contributions’ section. Galit Denkberg is employed by Applied Immune Technologies. GD contributed to this work in her free time without any compensation from MeMed or Applied Immune Technologies. Applied Immune Technologies did not have a role in the study, design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.