Validation of a Proteomic Signature and Assessment of Viremia in Children With Fever Without Source

Which Virus Leads to Viremia in Children With Fever Without Source and do New Biomarkers Correlate With Viral and Bacterial Infections?

The study is an observational blinded Validation study in pediatric patients below 3 years old with a diagnosis of Fever Without Source (FWS). In this study the investigators aim to validate the performance of a proteomic signature aiding the physicians to discriminate between viral and bacterial infections in febrile children. The study will also assess the prevalence of Human Enteroviruses (HEV), Human Parechoviruses (HPeV), Adenovirus (AdV) and Human Herpesvirus type 6 (HHV-6) viremia, as well as Kingella Kingae bacteremia in the study cohort.

Study Overview

• Status: Completed
• Conditions: Infectious Disease; Fever; Viremia

• Study Type: Observational
• Enrollment (Actual): 206

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland
    • Geneva University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Pediatric patients below three years old which were presented with a diagnosis of fever without source to the emergency room in the Children's Hospital, Geneva University Hospitals

Description

Inclusion Criteria:

• Clinical diagnosis of FWS (fever of less than 7 days with no cause determined by the history or the physical exam)
• Age < 3 years old
• Informed consent (IC) given by parent or legal guardian

Exclusion Criteria:

• Unavailable blood
• Comorbidities predisposing to infections such as cancer, primary or secondary immunodeficiency, and iatrogenic immunosuppression

Inclusion Criteria for healthy controls:

• Age < 3 years old
• Informed consent (IC) given by parent or legal guardian
• No suspicion of infectious or inflammatory disease at presentation and during the two weeks before.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Fever Without Source; Clinical diagnosis of FWS (fever of less than 7 days with no cause determined by the history and the physical exam).
Healthy control; Children visiting the hospital due to a non-infectious, non inflammatory etiology

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic accuracy compared to expert panel for bacterial versus viral.	Sensitivity, specificity, NPV and PPV were measured for ImmunoXpert and Labscore. The proteomic signature is a combination of different markers including: tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (pg/mL), interferon γ-induced protein-10 (IP-10) (pg/mL) and C-reactive protein (CRP) (mg/L). The proteomic signature is expressed as a score (no units. ranges 0-100). The Labscore is a combination of procalcitonin (ng/mL), C-reactive protein (CRP) (mg/L) and urinary dipstix (positive if presence of leucocyturia or nitrites). The Lab-score is expressed as a score (no units. ranges 0-9)	0-7 days after initiation of symptoms

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic accuracy compared to microbiology gold standard for ruling out invasive bacterial infection.	Case by case comparison between microbiology gold standard and ImmunoXpert and Labscore. The proteomic signature is a combination of different markers including: tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (pg/mL), interferon γ-induced protein-10 (IP-10) (pg/mL) and C-reactive protein (CRP) (mg/L). The proteomic signature is expressed as a score (no units, ranges 0-100). The Labscore is a combination of procalcitonin (ng/mL), C-reactive protein (CRP) (mg/L) and urinary dipstix (positive if presence of leucocyturia or nitrites). The Lab-score is expressed as a score (no units, ranges 0-9).	0-7 days after initiation of symptoms
Comparison of biomarker levels in patients with different etiologies as classified by the expert panel or healthy.	An expert panel classified a patient as experiencing a bacterial versus viral infection. In addition healthy patients were requited. The following biomarkers were examined across the healthy versus bacterial versus viral patients: The proteomic signature is a combination of different markers including: tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (pg/mL), interferon γ-induced protein-10 (IP-10) (pg/mL) and C-reactive protein (CRP) (mg/L). The proteomic signature is expressed as a score (no units, ranges 0-100).; The Labscore is a combination of procalcitonin (ng/mL), C-reactive protein (CRP) (mg/L) and urinary dipstix (positive if presence of leucocyturia or nitrites). The Lab-score is expressed as a score (no units, ranges 0-9).; Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (pg/mL).; interferon γ-induced protein-10 (IP-10) (pg/mL).; C-reactive protein (CRP) (mg/L).	0-7 days after initiation of symptoms in cases with infection.
Prevalence of viruses in children with fever without source.	Prevalence of Human Enteroviruses, Human Parechoviruses, Adenovirus and Human Herpesvirus type 6 viremia and viremia from other microorganism identified by Next-Generation Sequencing (NGS) (no units) or other techniques, as well as K. kingae bacteremia in children under three years old presenting with fever without source.	0-7 days after the initiation of symptoms

Collaborators and Investigators

• Sponsor: MeMed Diagnostics Ltd.
• Collaborators: University Hospital, Geneva

Publications and helpful links

General Publications

• Colvin JM, Muenzer JT, Jaffe DM, Smason A, Deych E, Shannon WD, Arens MQ, Buller RS, Lee WM, Weinstock EJ, Weinstock GM, Storch GA. Detection of viruses in young children with fever without an apparent source. Pediatrics. 2012 Dec;130(6):e1455-62. doi: 10.1542/peds.2012-1391. Epub 2012 Nov 5.
• Oved K, Cohen A, Boico O, Navon R, Friedman T, Etshtein L, Kriger O, Bamberger E, Fonar Y, Yacobov R, Wolchinsky R, Denkberg G, Dotan Y, Hochberg A, Reiter Y, Grupper M, Srugo I, Feigin P, Gorfine M, Chistyakov I, Dagan R, Klein A, Potasman I, Eden E. 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.
• Ambrosioni J, Bridevaux PO, Wagner G, Mamin A, Kaiser L. Epidemiology of viral respiratory infections in a tertiary care centre in the era of molecular diagnosis, Geneva, Switzerland, 2011-2012. Clin Microbiol Infect. 2014 Sep;20(9):O578-84. doi: 10.1111/1469-0691.12525. Epub 2014 Jan 24.
• L'Huillier AG, Mardegan C, Cordey S, Luterbacher F, Papis S, Hugon F, Kaiser L, Gervaix A, Posfay-Barbe K, Galetto-Lacour A. Enterovirus, parechovirus, adenovirus and herpes virus type 6 viraemia in fever without source. Arch Dis Child. 2020 Feb;105(2):180-186. doi: 10.1136/archdischild-2019-317382. Epub 2019 Aug 28.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): June 1, 2018
• Study Completion (Actual): August 1, 2018

Study Registration Dates

• First Submitted: July 17, 2017
• First Submitted That Met QC Criteria: July 18, 2017
• First Posted (Actual): July 21, 2017

Study Record Updates

• Last Update Posted (Estimate): January 6, 2023
• Last Update Submitted That Met QC Criteria: January 3, 2023
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Sepsis; Body Temperature Changes; Infections; Communicable Diseases; Fever; Viremia
• Other Study ID Numbers: MM-15082-Vir

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No