This review looked at adults and adolescents with HIV who have signs and symptoms of tuberculosis (TB) disease. Diagnosis can be done using respiratory samples (fluids or mucus collected by coughing or using tubes to remove fluid from the throat, lungs, or stomach) or urine. We wanted to know whether using two rapid tests together - an automated test on a respiratory sample (LC-aNAAT) and a urine strip test (LF-LAM) - is better than using LC-aNAAT alone. Using these two tests together is called parallel testing.
Key messages
- Parallel testing finds more cases of TB than using just the LC-aNAAT alone.
- However, parallel testing may also lead to more false TB diagnoses in people who do not actually have TB, and this undesirable effect is likely more pronounced in settings where TB is less common.
- In places where TB is common, the benefit of parallel testing (i.e. detecting more people who actually have TB) may outweigh the harms (i.e. misdiagnoses, unnecessary treatment, and delayed diagnosis of other illnesses).
Why is it important to improve the diagnosis of TB amongst people with HIV?
People with HIV are at a higher risk of developing TB than those without HIV. TB in patients with HIV often presents with non-specific symptoms, and detecting the bacteria (Mycobacterium tuberculosis) with standard sputum (spit) tests can be difficult. This is partly due to challenges in coughing up a sputum sample, which may contain very few bacteria, and because TB may occur in parts of the body other than the lungs. As a result of delayed or missed diagnoses, TB is the leading cause of hospital admission and death amongst people living with HIV worldwide.
What is parallel testing?
Parallel testing refers to using more than one test at the same time. If any one of the tests returns a positive test result, we consider the parallel testing to have a positive test result. We studied parallel testing using LC-aNAAT on respiratory samples in combination with LF-LAM on urine.
What did we want to find out?
- How accurate is parallel testing for all forms of TB in adults and adolescents (aged 10 years and older) with HIV who have signs or symptoms of TB?
- How accurate is parallel testing for identifying TB compared to using respiratory LC-aNAAT alone?
What did we do?
We searched for studies that had investigated the accuracy of both respiratory LC-aNAAT and urine LF-LAM for TB in adults and adolescents living with HIV, and we combined the results of these studies.
What did we find?
The review included 27 studies that involved 12,651 participants, of whom 2368 (19%) had confirmed TB.
The included participants were from 19 low- and middle-income countries where HIV and TB are common. Many studies were from countries in sub-Saharan Africa. One study was conducted with adolescents, but the other studies were of adults.
Accuracy of parallel testing
The results of these studies indicate that in a group of 1000 people, of whom 200 (20%) actually have TB, then:
- parallel testing would correctly identify 155 as having TB, but would miss 45; for the remaining 800 people who do not have TB, parallel testing would correctly identify 715 as not having TB, but would misdiagnose 85 as having TB.
Parallel testing compared to respiratory LC-aNAAT alone
The results of these studies indicate that if a parallel test strategy was used instead of a respiratory LC-aNAAT test alone, in a group of 1000 people, of whom 200 (20%) actually have TB, then:
- parallel testing would accurately diagnose 13 more patients who actually have TB who would have been missed by LC-aNAAT on respiratory samples used alone (i.e. 13 fewer 'false negatives' with parallel testing). On the other hand, using parallel testing would misdiagnose 54 more people who do not have TB (54 more 'false positives' with parallel testing), compared to LC-aNAAT alone.
What are the limitations of the evidence?
The evidence for parallel testing in adolescents is limited. Although we included a large number of adults from different settings, only a small number of adolescents were part of this review.
Some studies in this review excluded patients who could not produce a sputum or urine sample. This may have resulted in an underestimation or overestimation of the accuracy of parallel testing.
Because it is difficult to detect TB in patients with HIV, the method for verifying whether a person truly has TB or not (what we call the 'reference standard') may not be perfect. This means that we might have underestimated or overestimated the accuracy of parallel testing. Some studies using a different reference standard (called a 'composite reference standard') showed different results, though these results were very uncertain.
How up to date is this evidence?
The evidence is based on searches conducted up to 3 November 2023.
In the diagnosis of tuberculosis disease in people with HIV who present with presumptive tuberculosis, parallel testing (LC-aNAAT on respiratory samples and LF-LAM on urine) improves sensitivity at the cost of reduced specificity compared to LC-aNAAT on respiratory samples alone. The gain in sensitivity should be weighed against the loss of specificity, taking into consideration the varying tuberculosis prevalence in different settings. For low-prevalence settings, using the tests in parallel may lead to a large increase in false-positive results. In settings with high tuberculosis prevalence, the benefit of identifying additional patients with tuberculosis at the point-of-care likely outweighs the relatively lower risk of overtreatment of those without tuberculosis.
Low-complexity automated nucleic acid amplification tests (LC-aNAATs) are molecular World Health Organization (WHO)-recommended rapid diagnostic tests (also known as mWRDs) widely used to diagnose tuberculosis disease. The lateral flow urine lipoarabinomannan assay (LF-LAM) is recommended by the WHO to assist in diagnosing tuberculosis disease amongst people with HIV. Previous systematic reviews have assessed the diagnostic accuracy of LC-aNAATs and LF-LAM used in isolation for the detection of tuberculosis, but in clinical practice the tests may be used in parallel (i.e. LC-aNAAT in combination with LF-LAM).
To compare the diagnostic accuracy of the parallel use of LC-aNAAT on respiratory samples and LF-LAM on urine versus LC-aNAATs on respiratory samples alone for detection of tuberculosis disease in adults and adolescents with HIV who present with presumptive tuberculosis.
We searched Cochrane CENTRAL, MEDLINE, Embase, Science Citation Index-Expanded, Biosis Previews, Conference Proceedings Citation Index – Science, Scopus, WHO Global Index Medicus, ProQuest Dissertations & Theses, ClinicalTrial.gov, and the WHO International Clinical Trials Registry up to 3 November 2023.
We included studies that allowed assessment of the diagnostic accuracy of parallel testing and LC-aNAAT on respiratory samples in the same study group. Participants were adults and adolescents (defined as 10 years of age and older) with HIV who presented with presumptive tuberculosis. The reference standards we used for the detection of tuberculosis disease were microbiological or composite.
As well as published studies, we included unpublished data if the data provided by study authors on request were the final data and could be used to compare diagnostic accuracy of parallel testing to one of the component tests.
Two review authors independently extracted data using a standardised form and assessed methodological quality using QUADAS-2 and QUADAS-C tools. We performed bivariate random-effects meta-analysis using a Bayesian approach to estimate sensitivity, specificity, and absolute differences between index tests. We performed subgroup analyses based on the presence of signs and symptoms, CD4 cell count, and clinical setting, as well as separate analyses for those with a positive screen for tuberculosis, advanced HIV, or serious illness.
In 27 studies involving 12,651 participants, of whom 2368 (19%) had tuberculosis based on a microbiological reference standard, the parallel use of respiratory LC-aNAAT and urine LF-LAM had a pooled sensitivity of 77.5% (95% credible interval (CrI) 73.4 to 81.3) and specificity of 89.4% (95% CrI 85.8 to 92.3). Compared to respiratory LC-aNAAT alone, parallel testing had 6.7 (95% CrI 3.8 to 10.7) percentage points higher sensitivity (low certainty) and −6.8 (95% CrI −9.5 to −4.7) percentage points difference in specificity (low-certainty evidence), using a microbiological reference standard.
In 23 studies, 11,109 participants, of whom 3723 (34%) had tuberculosis based on a composite reference standard, parallel testing had a pooled sensitivity of 67.6% (95% CrI 59.9 to 74.6) and a pooled specificity of 96.2% (95% CrI 92.8 to 98.1). Compared to respiratory LC-aNAAT alone, parallel testing had 16.0 (10.7 to 22.9) percentage points higher sensitivity (low-certainty evidence) and −3.5 (95% CrI −6.6 to −1.7) percentage points difference in specificity (very low certainty evidence), using a composite reference standard.
Internal sources: Liverpool School of Tropical Medicine, UK
External sources: Foreign, Commonwealth and Development Office (FCDO), UK. Project number 300342-104; WHO, TB Prevention, Diagnosis, Treatment, Care & Innovation (PCI), Global TB Programme
Protocol available via https://doi.org/10.1002/14651858.CD016070, version published 13 May 2024