Abstract
The performance of urine Xpert MTB/RIF Ultra (Xpert Ultra) for pulmonary TB diagnosis is unknown. HIV-positive and HIV-negative adults were enrolled at two health facilities in Kampala, Uganda. We compared the accuracy of urine Xpert Ultra and Determine TB-LAM in reference to sputum-based testing (positive Xpert MTB/RIF or culture), and assessed incremental yield. Urine Xpert Ultra had low sensitivity (17.2%, 95% CI 12.3–23.2) but high specificity (98.1%, 95% CI 94.4–99.6). Sensitivity reached 50.0% (95% CI 28.2–71.8) among HIV-positive patients with CD4 <100 cells/μL. Compared to Determine TB-LAM, urine Xpert Ultra was 9.4% (95% CI 3.8–14.9, p=0.01) more sensitive, and 17.2% (95% CI 4.5–29.8, p=0.01) more sensitive among HIV-positive patients. However, the incremental sensitivity of urine Xpert Ultra relative to sputum Xpert MTB/RIF was only 1% (95% CI −0.9 to 2.8). Urine Xpert Ultra could be an alternative for patients with advanced HIV infection unable to produce sputum.
Keywords: tuberculosis, diagnostics, urine, Xpert Ultra, lipoarabinomannan
1. Introduction
Semi-automated nucleic acid amplification testing (NAAT) with Xpert MTB/RIF (Cepheid, Sunnyvale, USA) has greatly improved the ability to diagnose pulmonary tuberculosis (TB) in low-resource settings (World Health Organization, 2013). Xpert MTB/RIF Ultra (“Xpert Ultra”) is a next-generation cartridge designed to lower the limit of detection and improve sensitivity (Chakravorty et al., 2017). A multi-center study found that, compared to Xpert MTB/RIF sputum testing with Xpert Ultra was 17% (63% vs. 46%) more sensitive in smear-negative patients and 13% (90% vs. 77%) more sensitive in HIV-positive patients (Dorman et al., 2018). Consequently, the World Health Organization (WHO) has recommended that Xpert Ultra should be used in all settings where Xpert MTB/RIF was in place (World Health Organization, 2017).
In addition to potential utility for diagnosing renal TB (Atherton et al., 2018), urine testing with Xpert Ultra may provide an opportunity to further increase diagnostic yield and/or an alternative means of pulmonary TB diagnosis when patients are unable to expectorate sputum. In pulmonary TB, studies among HIV-positive adults have found that urine testing with the older generation Xpert MTB/RIF cartridge had limited additional yield when combined with sputum-based testing, but was a useful alternative when sputum was unavailable (Lawn et al., 2015, Lawn et al., 2012, Peter et al., 2012). In comparison to Determine TB-LAM, a single study from South Africa found that urine Xpert MTB/RIF had the same sensitivity (both 48%), but higher specificity (98% vs. 85%) (Peter et al., 2012). However, it remains unknown whether the increased analytical sensitivity of Xpert Ultra can improve the clinical utility of urine-based testing for pulmonary TB.
We conducted the first study of urine Xpert Ultra testing among adults with presumed pulmonary TB. Our objectives were to compare the diagnostic accuracy of urine Xpert Ultra and Determine TB-LAM, and calculate the additional yield of one or both urine tests relative to sputum Xpert MTB/RIF alone.
2. Materials and Methods
2.1. Study design and population
In this cross-sectional study, from April to December 2018, we enrolled consecutive hospitalized and outpatient adults (>18 years) HIV-positive and HIV-negative who were undergoing sputum-based pulmonary TB evaluation at Kiruddu hospital and Kisenyi Health Center IV in Kampala, Uganda. At the time of the study, routine sputum-based TB testing at both sites was performed using the Xpert MTB/RIF assay. We included all patients with positive sputum Xpert MTB/RIF results and a random sample of patients with negative Xpert MTB/RIF results (1:1 sampling) tested on the same day. We excluded patients if 1) Xpert MTB/RIF test results were indeterminate; 2) they were already on anti-TB treatment or had taken agents with anti-TB activity such as amino quinolones in the prior 12 months; 3) they reported a prior episode of TB; or 4) they refused or were unable to provide informed consent. The Makerere University School of Medicine Research and Ethics Committee, the Uganda National Council for Science and Technology and the University of California San Francisco Committee on Human Research reviewed and approved the study. This study was performed according to the Standards for Reporting of Diagnostic Accuracy Studies (STARD) guidelines (Cohen et al., 2016).
2.2. Participant recruitment
To identify eligible patients, we screened the Xpert MTB/RIF testing log at each study site daily to identify all patients who submitted sputum for TB testing. Using the log, study staff first approached all patients with positive test results and then a random 1:1 sample of patients with negative test results. Patients were approached on the wards (if hospitalized) or when they returned to collect test results (if outpatient) to confirm eligibility and obtain informed consent.
2.3. Study procedures
Upon enrollment, we obtained a detailed demographic and medical history using a standardized form and collected blood for HIV testing and CD4 count (if HIV-positive), spot sputum samples and spontaneously voided urine from all patients. Sputum samples were used to perform Xpert MTB/RIF testing × 1 in all patients, and mycobacterial culture on solid and liquid media × 2 in patients with negative Xpert MTB/RIF results (i.e., culture was not performed to confirm positive Xpert MTB/RIF results). Trained laboratory technologists in the Kiruddu Hospital Microbiology Laboratory and the Makerere University College of Health Sciences Mycobacteriology Laboratory conducted all TB testing following standard protocols for Xpert Ultra (Chakravorty et al., 2017), Determine TB-LAM (Lawn, 2012), and mycobacterial culture (Stop TB Partnership Global Laboratory Initiative, 2014). Standard dipstick urinalysis was performed on all urine samples, and then tested using Xpert Ultra and Determine TB-LAM. Urine for Xpert Ultra testing was centrifuged (Thermo Scientific Heraeus Megafuge 8R Compact, Waltham, Massachusetts, USA) using swing-out rotor at 3000 rpm (2173 × g) ambient temperature for 15 minutes prior to adding sample reagent to deposit at a ratio of 1:1. For culture, sputum samples were digested and decontaminated using the sodium hydroxide/N-acetyl-L-cysteine method with a final concentration of 1.5%, neutralized with sterile phosphate-buffered solution, centrifuged, and re-suspended in phosphate-buffered solution. One Mycobacterial Growth Indicator Tube (MGIT) and one Lowenstein-Jensen (LJ) slant were inoculated with the decontaminated samples. Prior to inoculation a cocktail of antibiotics containing PANTA (polymyxin, amphotericin B, nalidixic acid, trimethoprim, azlocillin) mixed with OADC (oleic acid, bovine serum albumin, dextrose, and catalase) were added to MGIT tubes. MGIT tubes were incubated in a BACTEC MGIT 960 instrument (BD; Franklin Lakes, USA) for up to 42 days and LJ slants were incubated at 37° C for up to 8 weeks. Blood agar plates were prepared for to check for contamination of positive MGIT tubes or LJ slants, and a stained Ziehl Neelsen (ZN) smear was examined to check for the presence of AFB. Speciation was then performed to confirm the presence of M. tuberculosis complex using SD Bioline strips (SD MPT64TB Ag kit, South Korea).
2.4. Definitions of reference standard and index tests
We used results of sputum Xpert MTB/RIF and mycobacterial culture as the reference standard. We considered patients to have TB if they had either positive Xpert MTB/RIF based on routine testing, or positive culture if sputum Xpert MTB/RIF testing was negative. We considered patients not to have TB if both Xpert MTB/RIF and culture results were negative, excluding those with <2 negative culture results due to contamination. The index tests included urine Xpert Ultra and urine Determine TB-LAM. We followed WHO recommendations for categorizing urine Xpert Ultra (trace results considered positive only among HIV-infected patients) and Determine TB-LAM (positive if Grade 2 or higher) results (World Health Organization, 2015, 2017). Staff performing the index testing were blinded to the reference testing and vice versa. We considered an index test to be false-positive when the test result was positive but sputum Xpert MTB/RIF and culture results were negative.
2.5. Statistical Approach
We summarized demographic and clinical data using appropriate descriptive statistics and calculated the sensitivity and specificity of each index test (urine Xpert Ultra and urine Determine TB-LAM) along with the 95% confidence interval (CI) using our reference standard definition of TB. In our primary analysis, we compared differences in sensitivity and specificity between index tests using McNemar’s test for paired proportions, and by HIV status and CD4 cell count category using chi-squared or Fisher’s Exact tests. We also calculated the incremental sensitivity of urine Xpert Ultra and Determine TB-LAM testing alone and in combination relative to Xpert MTB/RIF overall and among HIV-positive participants. Individuals with missing results were excluded. We used STATA 15 (StataCorp, College Station, TX, USA) for all analyses.
3. Results
3.1. Sample characteristics
During the nine-month study period, 2,347 individuals were referred for TB testing at the two sites (Figure 1). Of these, 397 were Xpert MTB/RIF positive and 188 were enrolled. We selected a random 1:1 sample of 188 Xpert MTB/RIF negative individuals and 169 were enrolled, of which 15 participants were subsequently culture-positive. Thus, 357 participants (203 with and 154 without TB) were included in the final analysis.
Figure 1.
Flowchart of Participants
Most participants (N=297, 83%) were outpatients, the median age was 32 years (IQR 25–39), and 249 (70%) were male (Table 1). The median Karnofsky score was 80 (IQR 70–90), but over a third were undernourished with a BMI <18.5 (N=144, 40%). Proteinuria of grade 2+ (100 mg/dL) or more was present in 54 (15%) participants. Among the 116 (32%) participants who were HIV positive, 34 (29%) had a CD4 cell count <100 cells/μL.
Table 1.
Sample Characteristics (N=357)
Characteristica | N (%) |
---|---|
Age in years, median (IQR) | 32 (25–39) |
Male Sex | 249 (70) |
Cough ≥ 30 days | 252 (71) |
Heart rate > 120 bpm | 55 (15) |
Fever ≥ 39°C | 17 (5) |
BMI < 18.5 | 144 (40) |
Karnofksy Score median (IQR) (n=283) | 80 (70–90) |
Hospitalized | 60 (17) |
Smoking in last 30 days | 55 (15) |
Proteinuria 2+ or greaterb | 54 (15) |
HIV-positive | 116 (32) |
CD4 cell count <100 cells/μL (n=116) | 34 (29) |
BMI: Body Mass Index; bpm: beats per minute; IQR: Interquartile Range; TB: Tuberculosis
N=357 unless indicated
Defined as semi-quantitative protein level > 100 mg/dL
3.2. Diagnostic accuracy
As shown in Table 2, the sensitivity of urine testing was poor with both Xpert Ultra (17.2%, 95% CI 12.3–23.2) and Determine TB-LAM (7.9%, 95% CI 4.6–12.5). Urine Xpert Ultra was 9.4% (95% CI 3.8–14.9, p<0.001) more sensitive than Determine TB-LAM. Both tests had high (>98%) specificity.
Table 2.
Sensitivity and Specificity of Urine Xpert Ultra and Determine TB LAM with 95% CI
Sensitivity | Specificity | ||
---|---|---|---|
Determine TB-LAM | Determine TB-LAM | ||
Total Cohort (N=203 with TB, N=154 No TB) | 7.9 (4.6, 12.5) | 98.7 (95.4, 99.8) | |
HIV-negative (N=139 with TB, N=102 No TB) | 4.3 (1.6, 9.2) | 99.0 (94.7, 100) | |
HIV-positive (N=64 with TB, N=52 No TB) | 15.6b (7.6, 26.9) | 98.1 (89.7, 100) | |
CD4 < 100 (N=22 with TB, N=12 No TB) | 31.8c (13.9, 54.9) | 91.7 (61.5, 99.8) | |
CD4 ≥ 100 (N=42 with TB, N=40 No TB) | 7.1 (1.5, 19.5) | 100 (91.2, 100) |
p<0.05 compared with Determine TB-LAM
p<0.05 compared with HIV-negative
p<0.05 compared with CD4 ≥ 100
As expected, the sensitivity of urine testing varied by HIV status and degree of HIV-related immune suppression (Table 2). Sensitivity was considerably higher in HIV-positive vs. HIV-negative participants for both urine Xpert Ultra (32.8% vs. 10.1%, p<0.001) and Determine TB-LAM (15.6% vs. 4.3%, p=0.01). Urine Xpert Ultra continued to have higher sensitivity than Determine TB-LAM among HIV-positive patients (difference 17.2%, 95% CI 4.5 to 29.8, p = 0.01), without a difference in specificity.
When stratified by CD4 category, the sensitivity of urine Xpert Ultra was significantly higher among HIV-positive participants with CD4 count <100 cells/μL (50.0%, 95% CI 28.2–71.8) than CD4 count ≥100 cells/μL (23.8%, 95% CI 12.1–39.5), a difference of 26.2% (95% CI 1.6–50.7, p=0.03). The same pattern was observed for Determine TB-LAM (31.8% in CD4 count <100 cells/μL vs. 7.1% if CD4 count ≥100 cells/μL, difference 24.7%, 95% CI 3.7–45.6, p = 0.01). While urine Xpert Ultra was 18.2% more sensitive than Determine TB-LAM among individuals with CD4 count <100 cells/μL, the difference was not statistically significant (95% CI −2.5 to 38.8, p = 0.12).
3.3. Incremental yield of urine testing
Performing urine Xpert Ultra yielded two additional cases over sputum Xpert MTB/RIF (both HIV-positive, CD4 cell count 93 and 108 cells/μL, incremental sensitivity 1.0%, 95% CI −0.9 to 2.8), while performing Determine TB-LAM also yielded two additional TB cases (both HIV-positive with CD4 cell count 93 and 104 cells/μL, incremental sensitivity 1.0%, 95% CI −0.9 to 2.8) (Table 3). Adding both urine tests to sputum Xpert MTB/RIF testing yielded three additional cases (all HIV-positive as above, incremental sensitivity 1.5%, 95% CI −0.7 to 3.6). Results were similar when the analysis was limited to HIV-positive participants.
Table 3.
Incremental sensitivity of urine testing relative to sputum Xpert MTB/RIF
Incremental Yield | |||
---|---|---|---|
Strategy | # Additional Cases Detected | % Increase in Sensitivity (95% CI) | p-value for difference |
All Participants with TB (N=203) | |||
Sputum Xpert MTB/RIF | REF | REF | - |
Sputum Xpert MTB/RIF + | |||
Urine Xpert Ultra | 2 | 1.0% (−0. 9 to 2.8) | 0. 5 |
Determine TB-LAM | 2 | 1.0% (−0.9 to 2.8) | 0.5 |
Urine Xpert Ultra + Determine TB-LAM | 3 | 1.5% (−0.7 to 3.6) | 0.25 |
HIV-positive with TB (N= 64) | |||
Sputum Xpert MTB/RIF | REF | REF | - |
Sputum Xpert MTB/RIF + | |||
Urine Xpert Ultra | 2 | 3.1% (−2. 8 to 9.0) | 0. 5 |
Determine TB-LAM | 2 | 3.1% (−2.8 to 9.0) | 0.5 |
Urine Xpert Ultra + Determine TB-LAM | 3 | 4.7% (−2.1 to 11.4) | 0.25 |
3.4. Characteristics of potential false positive cases
False positive cases were defined as a result positive by urine Xpert Ultra or Determine TB-LAM but negative by Xpert MTB/RIF and culture. There were five patients with potential false positive urine Xpert Ultra or Determine TB-LAM results, with characteristics presented in Table 4. None had both urine tests positive; three of the five were urine Xpert Ultra positive but Determine TB-LAM negative, while two were Determine TB-LAM positive but urine Xpert Ultra negative. All participants had low-grade positive results (Very Low for Xpert Ultra and Grade 2 for Determine TB-LAM), and two were HIV-positive (one urine Ultra positive and the other Determine TB-LAM positive). If all false positive cases were considered to be true TB cases (Supplemental Table 1), performing both urine tests was associated with a small increase in incremental sensitivity relative to sputum Xpert MTB/RIF (5 more cases detected, incremental sensitivity 3.8%, 95% CI 0.8 to 6.9, p = 0.01).
Table 4.
Characteristics of patients with urine Xpert Ultra and Determine TB-LAM false-positive resultsa
Description | |||||
---|---|---|---|---|---|
Age (Yrs) | 33 | 21 | 32 | 42 | 30 |
Sex | Male | Male | Female | Male | Male |
Patient type | Outpatient | Outpatient | Outpatient | Outpatient | Outpatient |
HIV status | Negative | Positive | Negative | Negative | Positive |
CD4 count (cells/μL) | - | 430 | - | - | 33 |
Prior ART use | - | Y | - | - | N |
Karnofsky score | 90 | - | 90 | 90 | 80 |
TB Contact | N | N | N | N | N |
Symptoms last 30d | |||||
Hemoptysis | Y | Y | N | Y | N |
Fever | Y | Y | Y | N | Y |
Night sweats | Y | Y | Y | Y | N |
Weight loss >5kg | Y | Y | N | Y | Y |
Cough | Y | Y | Y | Y | Y |
Urine Xpert Ultra | Positive (VL) | Positive (VL) | Negative | Positive (VL) | Negative |
Determine TB-LAM | Negative (Grade 0) | Negative (Grade 0) | Positive (Grade 2) | Negative (Grade 0) | Positive (Grade 2) |
ART: antiretroviral therapy;; HIV: human immunodeficiency virus; LAM: lipoaribomannan; TB: tuberculosis; Y: Yes; N: No; VL: Very Low
False positive defined as positive index test but negative sputum Xpert MTB/RIF and liquid/solid culture results
4. Discussion
Urine testing has the potential to increase diagnostic yield and to provide an alternative means of confirming pulmonary TB in sputum-scarce patients. We conducted the first assessment of urine Xpert Ultra testing for the diagnosis of pulmonary TB. We found that urine Xpert Ultra was more sensitive than Determine TB-LAM, but like Determine TB-LAM, testing was most beneficial among HIV-positive patients with low CD4 counts. Overall, urine testing (Xpert Ultra and/or Determine TB-LAM) provided little additional yield relative to sputum Xpert MTB/RIF testing, including among HIV-positive patients.
While urine Xpert MTB/RIF has shown utility in extrapulmonary TB (Atherton et al., 2019, Atherton et al., 2018, Penz et al., 2015), polymerase chain reaction (PCR) testing of urine for pulmonary TB has shown modest results. A meta-analysis of eight studies on the use of urine NAATs for pulmonary TB found an overall sensitivity of 55% and specificity of 94% (Marangu et al., 2015). Our data on urine Xpert Ultra testing is largely consistent with prior studies evaluating urine Xpert MTB/RIF testing for pulmonary TB, including for HIV-positive patients. In two studies of HIV-positive adults in South Africa, sensitivity of urine Xpert MTB/RIF testing was 19% and 48% overall and increased to 44% and 61%, respectively, among patients in the lowest CD4 cell count stratum (Lawn et al., 2012, Peter et al., 2015). Similarly, we found that sensitivity of urine Xpert Ultra testing was 32.8% overall among HIV-positive participants, increasing to 50% among those with CD4 count <100 cells/μL. Given individuals with advanced HIV infection are at high risk of TB-related mortality (Tornheim and Dooley, 2017), urine Xpert Ultra provides an alternative means of testing when sputum is unavailable.
Urine testing with Determine TB-LAM for pulmonary TB is currently recommended as an adjunct to sputum testing in HIV-positive individuals with advanced disease or serious illness (World Health Organization, 2015). A meta-analysis found Determine TB-LAM combined with sputum Xpert MTB/RIF increased sensitivity by 13% among HIV-positive adults to 75% (Shah et al., 2014). A prospective cohort in Kenya found that Determine TB-LAM increased sensitivity of sputum or urine Xpert MTB/RIF by 11.6% to 85.3% (Huerga et al., 2017). Urine Xpert MTB/RIF as an adjunct to sputum Xpert MTB/RIF is less studied but has shown a smaller incremental yield (Lawn et al., 2012). In contrast, we did not find that urine testing with either Determine TB-LAM or urine Xpert Ultra significantly increased diagnostic yield relative to Xpert MTB/RIF testing alone. Even when including both urine tests and considering false-positive results to be true-positive, only five additional cases were identified. Further studies are needed among HIV-positive individuals with significant immunosuppression and/or serious illness to better characterize any potential benefit of urine Xpert Ultra testing as an adjunct to sputum Xpert MTB/RIF in this population.
When sputum testing is not possible, we found that urine Xpert Ultra had higher accuracy than Determine TB-LAM for pulmonary TB diagnosis. Urine Xpert Ultra was 9.4% more sensitive than Determine TB-LAM overall, without significant difference in specificity, and continued to have higher sensitivity than Determine TB-LAM among HIV-positive patients (difference 17.2%). At CD4 count <100 cells/μL, urine Xpert Ultra was 18.2% more sensitive than Determine TB-LAM, but the sample size was small and the difference was not statistically significant. In contrast to our findings, past studies have found that urine Xpert MTB/RIF had lower or similar sensitivity to Determine TB-LAM in HIV-positive adults (Huerga et al., 2017, Lawn et al., 2012, Peter et al., 2012). While the sensitivity of Determine TB-LAM among HIV-infected participants in our study is lower than that reported in a meta-analysis (Shah et al., 2016), they noted moderate to high heterogeneity and our estimate was consistent with a previous study from Uganda of 26% sensitivity (Yoon et al., 2019). While we found urine Xpert Ultra to have higher sensitivity than Determine TB-LAM, factors such as cost, time, and availability may make Determine TB-LAM easier to implement and requires further evaluation (Lawn, 2012, Shah et al., 2013).
We present a well-characterized cohort of both HIV-positive and HIV-negative adults referred by clinicians for sputum-based TB testing. However, there are several limitations. We did not confirm positive sputum Xpert MTB/RIF results with culture. However, Xpert MTB/RIF is known to have high specificity (98%) (Horne et al., 2019), and we minimized the likelihood of false-positive Xpert MTB/RIF results by excluding patients treated previously for TB. We also did not directly compare urine Xpert MTB/RIF with urine Xpert Ultra, primarily because Xpert Ultra is expected to replace Xpert MTB/RIF. Because 1:1 sampling was performed to recruit Xpert-negative patients, we could not calculate positive or negative predictive value. Selection bias is also a concern as the inability to find patients was a common reason for exclusion. However, any such bias is unlikely to have a differential effect on urine Xpert Ultra vs. Determine TB-LAM and thus impact our primary finding.
Given the ease in obtaining urine, greater efforts are needed to lower the level of detection for current assays and identify novel urine-based diagnostics for pulmonary TB. A study in Peru utilized hydrogel nanocages to concentrate urine LAM and increase the sensitivity to >95% in HIV-negative adults (Paris et al., 2017). There has been growing interest in detection of trans-renal or cell-free DNA in urine for non-genitourinary TB (Fernandez-Carballo et al., 2018, Green et al., 2009). Biomarker discovery in urine also has the potential to identify novel assays for TB diagnosis (Wang et al., 2018). Meanwhile, we should take advantage of current diagnostics. Our findings support urine Xpert Ultra testing in HIV-positive individuals, in particular those with advanced disease and when sputum is unavailable.
Supplementary Material
Table S1. Comparison of incremental sensitivity of urine testing relative to sputum Xpert MTB/RIF with and without false positive cases
Acknowledgements
We thank the patients and staff of Kiruddu Hospital and Kisenyi Health Center IV, the staff and management of Mycobacteriology laboratory at the Makerere University College of Health Sciences, and Christine Bachman and Dr. David Bell of the Global Good Fund, Intellectual Ventures Laboratory. We also acknowledge the Center for Emerging and Neglected Diseases (CEND) - University of California, Berkeley.
Funding
Funding was supported by the Bill and Melinda Gates Foundation Trust through Global Good Fund at Intellectual Ventures. AA is a PhD student at Makerere University (Kampala, Uganda) and supported by The Pulmonary Complications of AIDS Research Training (PART) Program (National Institutes of Health-Fogarty International Center D43TW009607). DJ is a Fellow in the Pediatric Scientist Development Program and is supported by K12 HD000850 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Footnotes
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Declarations of Interest: None
References
- Atherton RR, Cresswell FV, Ellis J, Kitaka SB, Boulware DR. Xpert MTB/RIF Ultra for tuberculosis testing in children: A mini-review and commentary. Frontiers in pediatrics 2019;7:34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Atherton RR, Cresswell FV, Ellis J, Skipper C, Tadeo KK, Mugumya G, et al. Detection of Mycobacterium tuberculosis in urine by Xpert MTB/RIF Ultra: A useful adjunctive diagnostic tool in HIV-associated tuberculosis. Int J Infect Dis 2018;75:92–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chakravorty S, Simmons AM, Rowneki M, Parmar H, Cao Y, Ryan J, et al. The New Xpert MTB/RIF Ultra: Improving Detection of Mycobacterium tuberculosis and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing. MBio 2017;8(4):e00812–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen JF, Korevaar DA, Altman DG, Bruns DE, Gatsonis CA, Hooft L, et al. STARD 2015 guidelines for reporting diagnostic accuracy studies: explanation and elaboration. BMJ Open 2016;6(11):e012799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dorman SE, Schumacher SG, Alland D, Nabeta P, Armstrong DT, King B, et al. Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study. Lancet Infect Dis 2018;18(1):76–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fernandez-Carballo BL, Broger T, Wyss R, Banaei N, Denkinger CM. Towards the development of a cfDNA-based in-vitro diagnostic test for infectious diseases: A review of evidence for tuberculosis. J Clin Microbiol 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Green C, Huggett JF, Talbot E, Mwaba P, Reither K, Zumla AI. Rapid diagnosis of tuberculosis through the detection of mycobacterial DNA in urine by nucleic acid amplification methods. Lancet Infect Dis 2009;9(8):505–11. [DOI] [PubMed] [Google Scholar]
- Horne DJ, Kohli M, Zifodya JS, Schiller I, Dendukuri N, Tollefson D, et al. Xpert MTB/RIF and Xpert MTB/RIF Ultra for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2019;6:Cd009593. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huerga H, Ferlazzo G, Bevilacqua P, Kirubi B, Ardizzoni E, Wanjala S, et al. Incremental yield of including Determine-TB LAM assay in diagnostic algorithms for hospitalized and ambulatory HIV-positive patients in Kenya. PLoS ONE 2017;12(1):e0170976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lawn SD. Point-of-care detection of lipoarabinomannan (LAM) in urine for diagnosis of HIV-associated tuberculosis: a state of the art review. BMC Infect Dis 2012;12:103-. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lawn SD, Kerkhoff AD, Burton R, Schutz C, van Wyk G, Vogt M, et al. Rapid microbiological screening for tuberculosis in HIV-positive patients on the first day of acute hospital admission by systematic testing of urine samples using Xpert MTB/RIF: a prospective cohort in South Africa. BMC Med 2015;13(1):192. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lawn SD, Kerkhoff AD, Vogt M, Wood R. High diagnostic yield of tuberculosis from screening urine samples from HIV-infected patients with advanced immunodeficiency using the Xpert MTB/RIF assay. J Acquir Immune Defic Syndr 2012;60(3):289–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marangu D, Devine B, John-Stewart G. Diagnostic accuracy of nucleic acid amplification tests in urine for pulmonary tuberculosis: a meta-analysis. Int J Tuberc Lung Dis 2015;19(11):1339–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paris L, Magni R, Zaidi F, Araujo R, Saini N, Harpole M, et al. Urine lipoarabinomannan glycan in HIV-negative patients with pulmonary tuberculosis correlates with disease severity. Sci Transl Med 2017;9(420). [DOI] [PMC free article] [PubMed] [Google Scholar]
- Penz E, Boffa J, Roberts DJ, Fisher D, Cooper R, Ronksley PE, et al. Diagnostic accuracy of the Xpert(R) MTB/RIF assay for extra-pulmonary tuberculosis: a meta-analysis. Int J Tuberc Lung Dis 2015;19(3):278–84, i-iii. [DOI] [PubMed] [Google Scholar]
- Peter J, Theron G, Chanda D, Clowes P, Rachow A, Lesosky M, et al. Test characteristics and potential impact of the urine LAM lateral flow assay in HIV-infected outpatients under investigation for TB and able to self-expectorate sputum for diagnostic testing. BMC Infect Dis 2015;15:262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peter JG, Theron G, Muchinga TE, Govender U, Dheda K. The diagnostic accuracy of urine-based Xpert MTB/RIF in HIV-infected hospitalized patients who are smear-negative or sputum scarce. PLoS ONE 2012;7(7):e39966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shah M, Dowdy D, Joloba M, Ssengooba W, Manabe YC, Ellner J, et al. Cost-effectiveness of novel algorithms for rapid diagnosis of tuberculosis in HIV-infected individuals in Uganda. AIDS 2013;27(18):2883–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shah M, Hanrahan C, Wang ZY, Dendukuri N, Lawn SD, Denkinger CM, et al. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults. Cochrane Database Syst Rev 2016(5):Cd011420. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shah M, Ssengooba W, Armstrong D, Nakiyingi L, Holshouser M, Ellner JJ, et al. Comparative performance of urinary lipoarabinomannan assays and Xpert MTB/RIF in HIV-infected individuals. AIDS 2014;28(9):1307–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stop TB Partnership Global Laboratory Initiative. Mycobacteriology Laboratory Manual. Available at: http://www.stoptb.org/wg/gli/assets/documents/gli_mycobacteriology_lab_manual_web.pdf. Last accessed 4 Aug 2019 2014.
- Tornheim JA, Dooley KE. Tuberculosis associated with HIV infection. Microbiol Spectr 2017;5(1). [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang J, Zhu X, Xiong X, Ge P, Liu H, Ren N, et al. Identification of potential urine proteins and microRNA biomarkers for the diagnosis of pulmonary tuberculosis patients. Emerg Microbes Infect 2018;7(1):63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- World Health Organization. Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Available at: https://www.who.int/tb/publications/xpert-mtb-rif-assay-diagnosis-policy-update/en/ Last accessed 4 Aug 2019 2013. [PubMed]
- World Health Organization. The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV: Policy guidance. Available at: http://www.who.int/tb/areas-of-work/laboratory/policy_statement_lam_web.pdf. Last accessed 4 Aug 2019 2015.
- World Health Organization. WHO meeting report of a technical expert consultation: Non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF. Available at: https://www.who.int/tb/publications/2017/XpertUltra/en/ Last accessed 4 Aug 2019 2017.
- Yoon C, Semitala FC, Asege L, Katende J, Mwebe S, Andama AO, et al. Yield and efficiency of novel intensified tuberculosis case-finding algorithms for people living with HIV. Am J Respir Crit Care Med 2019;199(5):643–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Supplementary Materials
Table S1. Comparison of incremental sensitivity of urine testing relative to sputum Xpert MTB/RIF with and without false positive cases