Tuberculosis, Tuberculosis, Miliary, Tuberculosis, Pulmonary
Conditions
Keywords
Tests, Diagnostic, Mycobacterium tuberculosis, Mycobacterium tuberculosis antigens, TB, Tuberculosis, Tuberculosis, Pulmonary, Tuberculosis, Miliary, Lipoarabinomannan
Brief summary
The purpose of this study is to evaluate the accuracy, diagnostic yield, operational performance, and time to diagnosis of a novel lateral-flow urine LAM test in detecting tuberculosis in HIV-infected adults. A secondary study objective is to evaluate the accuracy and diagnostic yield of the Cepheid Xpert MTB/Rif test in detecting tuberculosis in the blood of HIV-infected adults.
Detailed description
Background: Tuberculosis (TB) incidence and mortality have increased dramatically as a result of the HIV epidemic. In parts of sub-Saharan Africa, TB is the leading cause of death among HIV-infected patients and approximately 50% of TB patients are HIV co-infected. Early treatment of TB is hindered by the lack of rapid, accurate diagnostic modalities that can be applied in resource-constrained settings. Mycobacterial culture is the laboratory standard for diagnosis of active TB, but it is costly, requires access to specialized laboratories, and takes weeks to provide results. Sputum smear microscopy detects less than half of HIV-infected TB cases in many settings. The Global Plan to Stop TB has prioritized the development of simple, accurate, inexpensive tests for TB case detection in HIV-positive individuals. LAM: As a strategy for rapid TB diagnosis, the detection of Mycobacterium tuberculosis antigens has been explored over several decades. Lipoarabinomannan (LAM), a glycolipid component of the outer cell wall of mycobacteria, is an attractive diagnostic target for several reasons: it is heat-stable; cleared by the kidney; detectable in urine; and as a bacterial product, has the theoretical potential to discriminate active TB from latent TB infection independent of human immune responses. A urine test could facilitate TB diagnosis in patients in whom sputum is uninformative or not obtainable, and lacks the infection-control risks associated with sputum production or blood collection. Urine LAM detection may be amenable to simple, rapid, inexpensive point-of-care platforms. This is a prospective study to evaluate the accuracy, diagnostic yield, operational performance, and time to diagnosis of a novel lateral-flow urine LAM test in detecting tuberculosis in HIV-infected adults. HIV-positive adults suspected to have TB will be enrolled after providing informed consent. Urine will be obtained for testing using the novel lateral flow urine LAM assay and an existing ELISA-based urine LAM assay. Conventional microbiological tests for TB and chest x-rays will also be performed. These tests will be performed on all participants enrolled (target sample size = 500). A secondary study objective is to determine the accuracy and diagnostic yield of the Cepheid Xpert MTB/Rif test in detecting tuberculosis in the blood of HIV-infected adults (the same set of participants on whom the LAM testing is done; approximate sample size = 500).
Interventions
lateral-flow (point-of-care) urine test to detect the lipoarabinomannan (LAM) component of the M. tuberculosis antigen in the urine of TB suspects, in vitro. Manufacturer: Alere
ELISA-based urine test to detect the lipoarabinomannan component of the M. tuberculosis antigen in the urine of TB suspects, in vitro. Manufacturer: Alere.
DEVICECepheid Xpert MTB/Rif assay
Sponsors
University of Cape Town
Tuberculosis Clinical Diagnostics Research Consortium
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(Individuals must meet all of the following inclusion criteria in order to be eligible to participate): * Informed consent * Suspected active tuberculosis * Willingness and ability to comply with study procedures * Any one or more of the following: * Current cough * Fever at any time within the preceding 4 weeks * Night sweats at any time within the preceding 4 weeks * Weight loss within the preceding 4 weeks * HIV-positive based on any one or more of the following: * written results of a positive HIV antibody test, and/or * written results of a positive HIV viral load, and/or * documentation in the medical record of positive HIV status by a treating clinician.
Exclusion criteria
(Any subjects meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sensitivity of the lateral-flow urine LAM assay (LF-LAM) | One year | * Conventional TB tests (mycobacterial blood & sputum culture) will be the reference standard used to calculate sensitivity of the LF-LAM test * Sensitivity is defined as TP/(TP+FN), or the number of true positives over (the number of true positives + the number of false negatives) * true positive = a positive LF-LAM result in a patient also having ≥1 culture positive for M. tuberculosis * false negative = a negative LF-LAM result in a patient also having ≥1 culture positive for M. tuberculosis |
| Failure rate of the lateral-flow urine LAM assay | One year | Failure rate expressed as the proportion of lateral flow urine LAM tests that require repeating due to an unevaluable initial result |
| Inter-reader variability of the lateral-flow urine LAM assay | One year | Expressed as the percent agreement |
| Specificity of the lateral-flow urine LAM assay (LF-LAM) | One year | * Conventional TB tests (blood & sputum culture) will be the reference standard used to calculate specificity (Sp) of the LF-LAM * Sp=TN/(TN+FP), or #true negatives / (#true negatives + #false positives) * true negative = negative LF-LAM in Not TB patient * false positive = positive LF-LAM in Not TB patient * Not TB = meets all criteria below * no sputum/blood culture positive for MTB * no smear microscopy positive for acid-fast bacilli * no granulomas/caseous necrosis on histopathology * no clinical response to TB treatment * a plausible alternative diagnosis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Satisfaction of lateral-flow urine LAM test operators | One year | Based on questionnaire assessment |
| Sensitivity of the ELISA-based urine LAM test | One year | * Conventional TB tests (mycobacterial blood & sputum culture) will be the reference standard used to calculate sensitivity of the ELISA LAM test * Sensitivity is defined as TP/(TP+FN), or the number of true positives over (the number of true positives + the number of false negatives) * true positive = a positive ELISA LAM result in a patient also having ≥1 culture positive for M. tuberculosis * false negative = a negative ELISA LAM result in a patient also having ≥1 culture positive for M. tuberculosis |
| Sensitivity of the Xpert MTB/Rif test to detect MTB in blood | One year | Conventional mycobacterial blood culture will be the reference standard used to calculate sensitivity of Xpert MTB/Rif in blood * Sensitivity is defined as TP/(TP+FN), or the number of true positives over (the number of true positives + the number of false negatives) * true positive = a positive Xpert MTB/Rif result in a patient also having ≥1 mycobacterial blood culture positive for M. tuberculosis * false negative = a negative Xpert MTB/Rif result in a patient also having ≥1 mycobacterial blood culture positive for M. tuberculosis |
| Specificity (Sp) of the ELISA-based urine LAM test | One year | * Conventional TB tests (blood & sputum culture) will be the reference standard used to calculate Sp of ELISA LAM * Sp=TN/(TN+FP), or #true negatives / (#true negatives + #false positives) * true negative = negative ELISA LAM in Not TB patient * false positive = positive ELISA LAM in Not TB patient * Not TB = meets all criteria below * no sputum/blood culture positive for MTB * no smear microscopy positive for acid-fast bacilli * no granulomas/caseous necrosis on histopathology * no clinical response to TB treatment * a plausible alternative diagnosis |
| Diagnostic yield (expressed as number of TB cases detected) of various diagnostic strategies (see description) | One year | Diagnostic yield will be measured for strategies including a) lateral flow urine LAM testing plus sputum smear microscopy; b) ELISA urine LAM testing plus sputum smear microscopy; c) sputum smear microscopy plus sputum culture; d) sputum culture plus mycobacterial blood culture. |
| Time to diagnosis (expressed in days) of various diagnostic strategies (see description) | One year | Time to diagnosis will be measured for strategies including a) lateral flow urine LAM testing plus sputum smear microscopy; b) ELISA urine LAM testing plus sputum smear microscopy; c) sputum smear microscopy plus sputum culture; d) sputum culture plus mycobacterial blood culture. |
| Accuracy, efficiency, costs, and cost-effectiveness of various combinations of TB diagnostic tests | One year | TB diagnostic tests to be included in this analysis: sputum smear microscopy, sputum culture, mycobacterial blood culture, chest X-ray, lateral-flow urine LAM testing, ELISA urine LAM testing, and Xpert MTB/Rif. |
Countries
South Africa
Outcome results
None listed