Diagnosis of Tuberculosis in Swiss Children (CITRUS)

Evaluation and Validation of Novel Immunodiagnostic Tests for Childhood Tuberculosis Infection and Disease in Switzerland. The CITRUS (ChIldhood TubeRcUlosis in Switzerland) Study.

1. The primary objective is to improve the sensitivity of novel immunodiagnostic tests for detection of TB disease in children.
2. The secondary objective is to determine biomarkers that discriminate children with TB infection and disease.

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis; Mycobacterium Tuberculosis
• Intervention / Treatment: Diagnostic test: Secreted cytokine assay; Diagnostic test: Intracellular cytokine assay

Detailed Description

1. This will be done by measuring a variety of parameters in the blood samples and compare them with the current diagnostic gold standard for TB or for culture/NAAT non-confirmed TB cases a consensus case definition is used.

   Currently available immunodiagnostic tests (IGRA/TST) will be compared to novel immunodiagnostic tests which will include:

   • several novel, additional M. tuberculosis-specific Antigens
   • cytokines that are highly expressed

2. Since there is no diagnostic gold standard for TB infection we will rely on a clinical composite reference standard for diagnosing TB infection. Biomarkers will be determined by:

   • including M. tuberculosis-specific antigens that are specifically expressed in either TB infection or disease,
   • measuring phenotypes and cytokine production of M. tuberculosis-specific cells.

• Study Type: Observational
• Enrollment (Anticipated): 190

Contacts and Locations

• Study Contact: Name: Nora Fritschi, Dr med; Phone Number: +41617042947; Email: nora.fritschi@ukbb.ch
• Study Contact Backup: Name: Nicole Ritz, PD Dr med PhD; Phone Number: +41617042947; Email: nicole.ritz@unibas.ch

Study Locations

• Switzerland
  • Aarau, Switzerland, 5001
    • Recruiting
    • Kantonspital Aarau
    • Contact: Sara Bernhard-Stirnemann, Dr med; Phone Number: +41628384192; Email: sara.bernhard@ksa.ch
  • Basel, Switzerland, 4031
    • Recruiting
    • Nora Fritschi
    • Contact: Nora Fritschi, Dr med; Phone Number: +41617042947; Email: nora.fritschi@ukbb.ch
    • Principal Investigator: Nicole Ritz, PD Dr med
    • Sub-Investigator: Hanna Schmid, Dr med
    • Sub-Investigator: Anja Jochmann, Dr med
    • Sub-Investigator: Daniel Trachsel, PD Dr med
  • Bellinzona, Switzerland, 6500
    • Recruiting
    • Ospedale Regionale Di Bellinzona
    • Contact: Lisa Kottanattu, Dr med; Phone Number: +41918118538; Email: lisa.kottanattu@eoc.ch
  • Bern, Switzerland, 3010
    • Recruiting
    • Inselspital Bern
    • Contact: Andrea Duppenthaler, Dr. med.; Phone Number: +41316329414; Email: andrea.duppenthaler@insel.ch
  • Genève, Switzerland, 1205
    • Recruiting
    • Hôpital des enfants - HUG
    • Contact: Anne Mornand, Dr. med.; Phone Number: +41223724579; Email: anne.mornand@hcuge.ch
    • Sub-Investigator: Marie Rohr, Dr. med.
  • Luzern, Switzerland, 6016
    • Recruiting
    • Kinserspital Luzern
    • Contact: Michael Buettcher, Dr med; Phone Number: +41412056657; Email: michael.buettcher@luks.ch
  • St. Gallen, Switzerland, 9006
    • Recruiting
    • Kinderspital St Gallen
    • Contact: Jürg Barben, Prof Dr med; Phone Number: +41712437111; Email: juerg.barben@kispisg.ch
    • Sub-Investigator: Christian Kahlert, Dr med
  • Zürich, Switzerland, 8032
    • Recruiting
    • Kinderklinik Zürich
    • Contact: Christoph Berger, Prof Dr med; Phone Number: +41442667840; Email: christoph.berger@kispi.uzh.ch
    • Sub-Investigator: Christa Relly, Dr med

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

It will be a national multicentre study in Switzerland. Children will be recruited within SwissPedNet, the Swiss Research Network of Clinical Paediatric Hubs, which includes five University Children's Hospitals (Basel, Bern, Geneva, Lausanne and Zürich) and four cantonal A-clinics (Aarau, Bellinzona, Luzern and St. Gallen). Currently approximately 20-30 children with TB disease are notified in Switzerland each year. For TB infection in children there are no data available in Switzerland. However, data from the "Lungenliga Schweiz" show that in 2014, at least 232 children were examined for a TB contact investigation (correspondence with Jean-Pierre Zellweger and Jean-Marie Egger, Lungenliga Schweiz 13.08.2015). Of these 13 % (i.e. around 30 children) are categorized as TB infection per year.

Description

Inclusion Criteria:

• all children / adolescents < 18 years of age undergoing evaluation for TB exposure, infection or disease.

Exclusion Criteria:

• children / adolescents with TB infection or disease who have already been started on anti-mycobacterial treatment, children who have been treated for TB previously.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
TB exposure	Diagnostic test: Secreted cytokine assay; Blood collected in a sodium-heparin tube will be used for the assay using novel TB-specific antigens. After incubation the supernatant will be harvested and cryopreserved at -80 °C for further testing of cytokines. Cytokines will be measured using a bead-based multiplex assay reader (MAGPIX, Luminex Crop., Austin, USA).; Diagnostic test: Intracellular cytokine assay; Blood will be stimulated with recombinant MTB-specific antigens, ESAT-6, CFP-10, positive control or left unstimulated. Following an initial duration of stimulation, Brefeldin-A will be added and the blood incubated for a further 5 hours. White cells will be fixed and cryopreserved at - 80°. Batched analysis within 6 months of cryopreservation will be done using multi-colour flow cytometry.
TB infection (latent TB)	Diagnostic test: Secreted cytokine assay; Blood collected in a sodium-heparin tube will be used for the assay using novel TB-specific antigens. After incubation the supernatant will be harvested and cryopreserved at -80 °C for further testing of cytokines. Cytokines will be measured using a bead-based multiplex assay reader (MAGPIX, Luminex Crop., Austin, USA).; Diagnostic test: Intracellular cytokine assay; Blood will be stimulated with recombinant MTB-specific antigens, ESAT-6, CFP-10, positive control or left unstimulated. Following an initial duration of stimulation, Brefeldin-A will be added and the blood incubated for a further 5 hours. White cells will be fixed and cryopreserved at - 80°. Batched analysis within 6 months of cryopreservation will be done using multi-colour flow cytometry.
TB disease (active TB)	Diagnostic test: Secreted cytokine assay; Blood collected in a sodium-heparin tube will be used for the assay using novel TB-specific antigens. After incubation the supernatant will be harvested and cryopreserved at -80 °C for further testing of cytokines. Cytokines will be measured using a bead-based multiplex assay reader (MAGPIX, Luminex Crop., Austin, USA).; Diagnostic test: Intracellular cytokine assay; Blood will be stimulated with recombinant MTB-specific antigens, ESAT-6, CFP-10, positive control or left unstimulated. Following an initial duration of stimulation, Brefeldin-A will be added and the blood incubated for a further 5 hours. White cells will be fixed and cryopreserved at - 80°. Batched analysis within 6 months of cryopreservation will be done using multi-colour flow cytometry.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of immunodiagnostic tests for TB in children.	Based on current evidence it is estimated that the sensitivity of the immunodiagnostic tests with regard to the identification of patients with TB infection or disease versus no TB is approximately 80 %. By applying a sample size approximation a minimum sample size of 126 patients with TB infection or disease (with a precision given by a 95 % confidence interval with a width of 20 %) will be needed to statistically show a significant result.	27 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Indicative markers identification for TB infection and disease distinction	A minimum sample size of 84 patients with TB infection is needed (with a precision given by a 95 % confidence interval with a width of 30 %). Among patients with TB infection or TB disease, a novel test is used to discriminate between these patient groups. It is estimated that the sensitivity of this test with regard to the identification of patients with TB infection (secondary outcome) is approximately 60 %.	27 months

Collaborators and Investigators

• Sponsor: University Children's Hospital Basel
• Collaborators: University Hospital, Geneva; University Hospital Inselspital, Berne; Kantonsspital Aarau; University of Lausanne Hospitals; University Children's Hospital, Zurich; Luzerner Kantonsspital; Cantonal Hospital of St. Gallen; Ospedale Regionale Bellinzona e Valli
• Investigators: Principal Investigator: Nicole Ritz, PD Dr med, UKBB

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2017
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: February 3, 2017
• First Submitted That Met QC Criteria: February 3, 2017
• First Posted (Estimate): February 7, 2017

Study Record Updates

• Last Update Posted (Actual): May 17, 2022
• Last Update Submitted That Met QC Criteria: May 16, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Biomarkers; Immunodiagnostics tests; TB exposure; Latent TB; TB disease
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: CITRUS

Plan for Individual participant data (IPD)

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