Diagnostic Accuracy of CAD4TB and C-reactive Protein Assay as Triage Tests for Pulmonary Tuberculosis (TB TRIAGE+)

Prospective, Multicentre Evaluation of the Accuracy of CAD4TB and C-reactive Protein Assay as Triage Tests for the Diagnosis of Pulmonary Tuberculosis in Presumptive Adult TB Patients (TB TRIAGE+ Accuracy)

In the TB TRIAGE+ ACCURACY study, the accuracy of the following products will be determined:

• CAD4TB (Delft Imaging System, NL), a digital chest x-ray analysis software
• Afinion CRP assay (Alere Afinion, USA), which detects a cytokine induced acute phase protein

CAD4TB and the C-reactive protein assay are two tests with great potential of becoming a triage test for the diagnosis of tuberculosis (TB). These potential triage tests for TB are intended to serve as rule-out tests with a high sensitivity and negative predictive value.

Before impact and cost-effectiveness of new TB triage tests for intensified active case finding can be determined, the diagnostic test accuracy needs to be assessed in comparison to confirmatory reference tests. This accuracy study will define cut-off values for CAD4TB as well as for the Afinion CRP assay to be used in a future cluster-randomised trial on impact and cost-effectiveness of TB triage strategies for intensified active case finding in Lesotho and KwaZulu-Natal, South Africa.

A sub-study (detailed in a separate study protocol), hereafter called AHD-FEASIBILITY, explores the feasibility of implementing a series of point-of-care tests, including the new VISITECT CD4 Advanced Disease Test (Omega Diagnostics, UK) as part of the WHO-recommended advanced HIV Disease care package in the context of community-based HIV/TB campaigns.

Due to the coinciding pandemics and the overlapping symptoms of TB and COVID-19, it is critical to test for SARS-Cov-2 infections in the study population. In addition, this study will contribute to the evaluation of a novel SARS-Cov-2 antigen rapid diagnostic test (from the diagnostic pipeline of FIND) and CAD4COVID, a digital chest x-ray analysis software (Delft Imaging System, NL) in combination with differential white blood cell count.

Study Overview

• Status: Completed
• Conditions: Covid-19; HIV; Pulmonary Tuberculosis; Tuberculosis Diagnosis
• Intervention / Treatment: Diagnostic test: Accuracy of CAD4TB and Afinion CRP assay for pulmonary TB; Diagnostic test: CAD4COVID+WBC and COVID-19 RDT for SARS-CoV-2 infection

Detailed Description

This is a prospective, partially blinded, two-centre cross-sectional study in which the diagnostic test accuracy of CAD4TB and an Afinion CRP assay test for TB will be assessed at facility level by evaluating a sample of 1400 adults (age ≥18years) with one or more TB symptoms (WHO recommended four-symptom screening; cough, weight loss, night sweats, fever) of any duration.

Presumptive TB patients will be recruited (i) at the outpatient departments of the Butha-Buthe District Hospital (Butha-Buthe, Lesotho) and the Caluza Clinic (Pietermaritzburg, KwaZulu-Natal, South Africa) and (ii) during community-based health campaigns by SolidarMed in Lesotho and HSRC in South Africa. Participants will be enrolled after giving written informed consent.

Study procedures comprise the following (detailed in the schedule of events): collection of contact, anthropometric, demographic and clinical data, HIV testing and counselling per national guidelines, collection of capillary blood for HIV testing, Afinion CRP assay, differential white blood cell count, VISITECT CD4 Advanced Disease Test (if HIV-positive), CrAg Lateral Flow Assay (if HIV positive and CD4 count <200 cells/μl as per VISITECT CD4 Advanced Disease Test, and no history of cryptococcal meningitis treatment); collection of urine (if HIV positive) for Alere Determine TB LAM Ag test; chest radiography for CAD4TB and CAD4COVID analysis and remote expert reading; nasopharyngeal swabs for SARS-Cov-2 real-time PCR and SARS-Cov-2 antigen test, collection of two spot sputa samples (S1,S2) for Xpert MTB/RIF, Xpert MTB/RIF Ultra (S1) and for mycobacterial culture [MGIT] (S2). At week 12 (±2weeks), we will contact each participant by phone and collect data on their vital status, and any TB treatment since enrolment. For individuals on TB treatment, further information, e.g. on reasons for empirical treatment, will be collected at the health facility the participant started TB treatment.

• Study Type: Observational
• Enrollment (Actual): 1400

Contacts and Locations

Study Locations

• Lesotho
  • Butha-Buthe, Lesotho
    • Butha-Buthe District Hospital
• South Africa
  • KwaZulu-Natal
    • Pietermaritzburg, KwaZulu-Natal, South Africa
      • Caluza Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult presumptive TB cases (age ≥18years) with one or more TB symptoms (WHO recommended four-symptom screening; cough, weight loss, night sweats, fever) of any duration.

Presumptive TB patients will be recruited (i) at the outpatient departments of the Butha-Buthe District Hospital (Butha-Buthe, Lesotho) and the Caluza Clinic (Pietermaritzburg, KwaZulu-Natal, South Africa) and (ii) during community-based health campaigns by SolidarMed in Lesotho and HSRC in South Africa.

Description

Inclusion Criteria:

1. Willing and able to provide signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any study-related procedure
2. Adults (≥18 years)
3. Any of the cardinal symptoms of TB (cough, weight loss, night sweats, fever) of any duration

Exclusion Criteria:

1. Pregnancy (based on oral information from participant)
2. Any condition for which participation in the study, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments
3. Critically sick patients who need immediate medical care
4. Current anti-TB treatment

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Adult presumptive TB cases; Adult presumptive TB cases (age ≥18years) with one or more TB symptoms (WHO recommended four-symptom screening; cough, weight loss, night sweats, fever) of any duration.

Diagnostic test: Accuracy of CAD4TB and Afinion CRP assay for pulmonary TB; CAD4TB version 6 and 7: Software tool for detecting lung abnormalities in computer tomogram images (pulmonary abnormalities) and frontal chest radiograph images (tuberculosis abnormalities) ; availability is guaranteed by Delft Imaging System; EC 0344 Certificate (vs.6); CE mark pending (vs.7). Will be performed by a registered and qualified radiographer in accordance with national regulations. Afinion AS100 Analyzer and Afinion CRP: In vitro diagnostic to determine the amount of CRP in human whole blood, serum or plasma; CE-mark ; Will be performed by qualified, GCP-trained study personnel.; Diagnostic test: CAD4COVID+WBC and COVID-19 RDT for SARS-CoV-2 infection; CAD4COVID: Non-commercial product. Software tool for detecting pneumonia-related features to be expected in COVID-19 patients; availability is guaranteed by Delft Imaging System; CE certified. Will be performed by a registered and qualified radiographer/health professional in accordance with national regulations. Analysis in combination with differential white blood cell count. SD Biosensor, STANDARDTM Q COVID-19 Ag Test (rapid chromatographic immunoassay for the qualitative detection of specific antigens to SARS-CoV-2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine CAD4TB cut-off value	Receiver operating characteristic analysis (ROC) of CAD4TB against a composite microbiological reference standard (mycobacterial culture [MGIT] or Xpert MTB/RIF) to define an acceptable diagnostic cut-off value.	15 months after first patient visit
Determine Afinion CRP assay cut-off value	Receiver operating characteristic analysis (ROC) of Afinion CRP assay against a composite microbiological reference standard (mycobacterial culture [MGIT] or Xpert MTB/RIF) to define an acceptable diagnostic cut-off value.	15 months after first patient visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate CAD4TB ROC against reference standard	Receiver operating characteristic analysis (ROC) of CAD4TB against a single microbiological reference standard (mycobacterial culture [MGIT] alone, Xpert MTB/RIF alone, Xpert MTB/RIF Ultra alone), against a composite reference standard and against a radiological reference standard	15 months after first patient visit
Evaluate Afinion CRP assay ROC against reference standard	Receiver operating characteristic analysis (ROC) of Afinion CRP assay against a single microbiological reference standard (mycobacterial culture [MGIT] alone, Xpert MTB/RIF alone, Xpert MTB/RIF Ultra alone) and against a composite reference standard	15 months after first patient visit
Evaluate CAD4COVID and COVID-19 RDT ROC against reference standard	Receiver operating characteristic analysis (ROC) of CAD4COVID combined with differential white blood cell count and point estimates of sensitivity and specificity the novel SARS-Cov-2 antigen rapid diagnostic test, both against a single microbiological reference standard (SARS-Cov-2 real-time PCR)	15 months after first patient visit

Collaborators and Investigators

• Sponsor: Klaus Reither
• Collaborators: Radboud University Medical Center; Charite University, Berlin, Germany; University Hospital, Basel, Switzerland; Foundation for Innovative New Diagnostics, Switzerland; Institute of Tropical Medicine, Belgium; European and Developing Countries Clinical Trials Partnership (EDCTP); Human Sciences Research Council; Ministry of Health, Lesotho; SolidarMed
• Investigators: Principal Investigator: Klaus Reither, MD, PhD, Swiss Tropical & Public Health Institute

Publications and helpful links

General Publications

• Gils T, Lynen L, Muhairwe J, Mashaete K, Lejone TI, Joseph P, Ngubane T, Keter AK, Reither K, van Heerden A. Feasibility of implementing the advanced HIV disease care package as part of community-based HIV/TB activities: a mixed-methods study protocol. BMJ Open. 2022 Feb 7;12(2):e057291. doi: 10.1136/bmjopen-2021-057291.
• Glaser N, Bosman S, Madonsela T, van Heerden A, Mashaete K, Katende B, Ayakaka I, Murphy K, Signorell A, Lynen L, Bremerich J, Reither K. Incidental radiological findings during clinical tuberculosis screening in Lesotho and South Africa: a case series. J Med Case Rep. 2023 Aug 25;17(1):365. doi: 10.1186/s13256-023-04097-4.
• Bosman S, Ayakaka I, Muhairwe J, Kamele M, van Heerden A, Madonsela T, Labhardt ND, Sommer G, Bremerich J, Zoller T, Murphy K, van Ginneken B, Keter AK, Jacobs BKM, Bresser M, Signorell A, Glass TR, Lynen L, Reither K. Evaluation of C-Reactive Protein and Computer-Aided Analysis of Chest X-rays as Tuberculosis Triage Tests at Health Facilities in Lesotho and South Africa. Clin Infect Dis. 2024 Nov 22;79(5):1293-1302. doi: 10.1093/cid/ciae378.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2021
• Primary Completion (Actual): April 5, 2022
• Study Completion (Actual): August 11, 2022

Study Registration Dates

• First Submitted: December 7, 2020
• First Submitted That Met QC Criteria: December 7, 2020
• First Posted (Actual): December 14, 2020

Study Record Updates

• Last Update Posted (Estimated): September 22, 2025
• Last Update Submitted That Met QC Criteria: September 16, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Diagnostic Accuracy; CAD4TB; HIV testing; Presumptive adult TB; C Reactive Protein assay; Point of Care Test; TB Triage Test; CAD4COVID; COVID-19 RDT; Advanced HIV Disease (AHD) care package; Community-based triage testing for TB
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Genetic Diseases, Inborn; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Biliary Tract Diseases; Liver Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Congenital Abnormalities; Cardiovascular Abnormalities; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Heart Defects, Congenital; Abnormalities, Multiple; Bile Duct Diseases; Actinomycetales Infections; Mycobacterium Infections; Cholestasis, Intrahepatic; Cholestasis; Tuberculosis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; COVID-19; Tuberculosis, Pulmonary; Alagille Syndrome
• Other Study ID Numbers: P1685-20A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All data will be stored securely in a way that allows future access for the research team. We will adhere to the FAIR Guiding Principles for data management and stewardship 20. After completion of the studies and after anonymization (e.g. replace subject identifier with a new random subject identifier), analysis datasets will be made publicly available in a timely manner on a non-commercial data platform according to the FAIR principles. The principles of data sharing will be explained in the informed consent form. All data will be owned by the Sponsor-Investigator and investigators of TB TRIAGE+, while a Data Access Committee will review all requests for data sharing.
• IPD Sharing Time Frame: 12 months after completion of the EDCTP-funded TB TRIAGE+ project
• IPD Sharing Access Criteria: The Executive Group of the TB TRIAGE+ project will establish a Data Access Committee (DAC). The DAC will review all requests for data sharing. After approval by the DAC, the final verified and anonymised datasets and support for analysis will be made available to all relevant stakeholders, both at local level (health facility, region and country) as well as international decision makers (e.g. WHO) and interested research groups in order to advance research in TB.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No