Urine and sputum tuberculosis tests: defining the trade-offs in endemic HIV and tuberculosis settings

Clinicians need improved tests to diagnose tuberculosis, especially in people living with HIV. Sputum-based molecular tests (eg, the Xpert MTB/RIF and Xpert Ultra assays, Cepheid, Sunnyvale, CA, USA) perform well in adults with presumptive tuberculosis who are HIV-positive (ie, sensitivity ≥75% and specificity ≥93%),1Zifodya JS Kreniske JS Schiller I et al.Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis.Cochrane Database Syst Rev. 2021; 2CD009593PubMed Google Scholar but many patients are unable to produce a quality sputum sample. An alternative biomarker is lipoarabinomannan, a glycolipid from the cell wall of replicating Mycobacterium tuberculosis that enters the bloodstream, is filtered by the kidney, and concentrates in urine.2Bulterys MA Wagner B Redard-Jacot M et al.Point-of-care urine LAM tests for tuberculosis diagnosis: a status update.J Clin Med. 2019; 9: 111Crossref PubMed Scopus (60) Google Scholar Adults who are HIV-positive with newly diagnosed tuberculosis have higher urinary lipoarabinomannan concentrations than those without HIV.3Amin AG De P Spencer JS et al.Detection of lipoarabinomannan in urine and serum of HIV-positive and HIV-negative TB suspects using an improved capture-enzyme linked immuno absorbent assay and gas chromatography/mass spectrometry.Tuberculosis (Edinb). 2018; 111: 178-187Crossref PubMed Scopus (34) Google Scholar Two randomised controlled trials showed that a first-generation point-of-care assay (Alere Determine TB LAM [AlereLAM], Abbott, Chicago, IL, USA) reduced mortality among adults admitted to hospital and living with HIV;4Peter JG Zijenah LS Chanda D et al.Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial.Lancet. 2016; 387: 1187-1197Summary Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 5Gupta-Wright A Corbett EL van Oosterhout JJ et al.Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial.Lancet. 2018; 392: 292-301Summary Full Text Full Text PDF PubMed Scopus (125) Google Scholar participants with the highest risk of tuberculosis disease (ie, CD4 count <100 cells per μL, severe anaemia, or clinical features of tuberculosis) had the greatest mortality benefit from urine lipoarabinomannan testing.5Gupta-Wright A Corbett EL van Oosterhout JJ et al.Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial.Lancet. 2018; 392: 292-301Summary Full Text Full Text PDF PubMed Scopus (125) Google Scholar WHO recommends urine AlereLAM testing for adults who are HIV-positive and have signs and symptoms of tuberculosis, are immune suppressed or have advanced HIV disease, or are seriously ill.6WHOLateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis of active tuberculosis in people living with HIV, 2019 update.https://www.who.int/publications/i/item/9789241550604Date: Oct 28, 2019Date accessed: May 3, 2023Google Scholar In these groups, the AlereLAM test is reasonably specific, but has poor sensitivity and cannot be used to rule out tuberculosis disease. The narrow diagnostic indications and suboptimal performance characteristics contributed to its infrequent adoption within national tuberculosis treatment programmes.7Singhroy DN MacLean E Kohli M et al.Adoption and uptake of the lateral flow urine LAM test in countries with high tuberculosis and HIV/AIDS burden: current landscape and barriers.Gates Open Res. 2020; 4: 24Crossref PubMed Google Scholar However, in practical terms, collecting a small urine volume is generally easier and safer than obtaining a sputum specimen. Since AlereLAM can be used in patient care settings and provides results within 25 min, there might be benefits to using an imperfect, low-cost, urine-based test, particularly in patients who are unable to produce a sputum specimen. In The Lancet Global Health, Tobias Broger and colleagues conducted a systematic review and meta-analysis on 20 datasets of adults who were HIV-positive and being evaluated for tuberculosis.8Broger T Koeppel L Huerga H et al.Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant data.Lancet Glob Health. 2023; 11: e903-e916Summary Full Text Full Text PDF Scopus (1) Google Scholar To establish how urine lipoarabinomannan point-of-care testing compared with sputum Xpert laboratory testing, individual participant data were analysed from 10 202 participants. The median age of participants was 36 years (IQR 30–44), median CD4 count was 187 cells per μL (66–365), and proportion of participants with tuberculosis symptoms was 8525 (84%) of 10 202. Urine was collected from 9957 (98%) of 10 202 participants and sputum was collected from 8360 (82%) participants; however, only 2531 (69%) of 3662 inpatients provided sputum. The comparative usefulness of AlereLAM and Xpert was estimated by dividing the number of participants who were urine lipoarabinomannan-positive or sputum Xpert-positive (on the first diagnostic samples collected within 2 days of enrolment) by the number with microbiologically confirmed tuberculosis on Xpert or culture from any on-study sample from any body site—a proportion termed the diagnostic yield. 1615 participants (16%) contributed data to diagnostic yield analyses. Among inpatients who were enrolled irrespective of symptoms, the 2-day diagnostic yield was 51% (95% prediction interval [95% PrI] 15–82) for AlereLAM and 47% (4–100) for Xpert. The yield was similar for inpatients who had tuberculosis symptoms. AlereLAM diagnostic yield reached 65% (95% PrI 40–85) among inpatients with a CD4 count of less than 100 cells per μL whose symptoms were not assessed; the Xpert yield in this subgroup was 49% (4–100). By contrast, Xpert performed better than AlereLAM in outpatients whose symptoms were not assessed, with an overall yield of 70% (95% PrI 26–92) compared with the AlereLAM yield of 24% (3–74). These results provide further evidence that urine AlereLAM testing can be beneficial in some settings, but several limitations exist. First, diagnostic yield prediction intervals were wide, which can be attributed to study heterogeneity. Second, the clinical studies were not designed to calculate diagnostic yield, and combined secondary data from heterogeneous studies should be interpreted with caution. Third, most participants were not tested with the more sensitive Xpert Ultra assay, and participants with clinically diagnosed tuberculosis were excluded, both of which might have increased the number in the denominator and reduced the diagnostic yield. Fourth, participants were evaluated in research-enabled settings, which might limit generalisability to settings without this capability. Broger and colleagues8Broger T Koeppel L Huerga H et al.Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant data.Lancet Glob Health. 2023; 11: e903-e916Summary Full Text Full Text PDF Scopus (1) Google Scholar suggest expanding urine lipoarabinomannan testing to all inpatients who are HIV-positive, an approach that has been implemented in South Africa.9National Department of Health, South AfricaGuidance on the use of the lateral flow urine lipoarabinomannan assay for the diagnosis of active tuberculosis in people living with HIV. Policy update: February 2021.https://www.knowledgehub.org.za/system/files/elibdownloads/2021-11/TB%20LAM%20Guidelines%20-%2008%20Feb%202021%20%282%29.pdfDate: Nov 19, 2021Date accessed: May 3, 2023Google Scholar This change in recommendation might simplify and improve the implementation of lipoarabinomannan testing in other regions and help to detect more tuberculosis cases. By reinforcing the role of urine lipoarabinomannan testing, Broger and colleagues8Broger T Koeppel L Huerga H et al.Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant data.Lancet Glob Health. 2023; 11: e903-e916Summary Full Text Full Text PDF Scopus (1) Google Scholar provide additional impetus to develop and evaluate improved second-generation assays to further expedite early tuberculosis diagnosis. We declare no competing interests. Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant dataAlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples. Full-Text PDF Open Access