Diagnostic Accuracy of CAD4TB and C-reactive Protein Assay as Triage Tests for Pulmonary Tuberculosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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HIV, Pulmonary Tuberculosis, Tuberculosis Diagnosis, Covid-19

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any study-related procedure Adults (≥18 years) Any of the cardinal symptoms of TB (cough, weight loss, night sweats, fever) of any duration Exclusion Criteria: Pregnancy (based on oral information from participant) 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 Critically sick patients who need immediate medical care Current anti-TB treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Adult presumptive TB cases<br>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<br>* 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.<br>Diagnostic Test: CAD4COVID+WBC and COVID-19 RDT for SARS-CoV-2 infection<br>* 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)<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Presumptive adult TB, C Reactive Protein assay, CAD4TB, Point of Care Test, TB Triage Test, Diagnostic Accuracy, CAD4COVID, COVID-19 RDT, Advanced HIV Disease (AHD) care package, HIV testing, Community-based triage testing for TB