Browsing by Subject "Lipopolysaccharides"

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    Open Access
    Comparative performance characteristics of the urine lipoarabinomannan strip test and sputum smear microscopy in hospitalized HIV-infected patients with suspected tuberculosis in Harare, Zimbabwe
    (2015) Zijenah, Lynn Sodai; Kadzirange, Gerard; Bandason, Tsitsi; Chipiti, Maria Mary; Gwambiwa, Bevel; Makoga, Forget; Chungu, Pauline; Kaguru, Philip; Sabur, Natasha F
    BackgroundIn Zimbabwe, sputum smear microscopy (SSM) is the routinely used TB diagnostic tool in hospitalised HIV-infected patients. However, SSM has poor sensitivity in HIV-infected patients. We compared performance of urine lipoarabinomannan strip test (LAM) and SSM among hospitalized HIV-infected patients with suspected TB.MethodsHospitalized HIV-infected patients with suspected TB were randomized to LAM plus SSM or SSM alone groups as part of a larger multi-country parent study. Here we present a comparison of LAM versus SSM performance from the Zimbabwe study site. LAM analyses (grade 2 cut-off) were conducted using (i) a microbiological reference standard (MRS; culture positivity for M.tb and designated definite TB) and (ii) a composite reference standard (CRS; definite TB plus probable TB i.e. patients with clinical TB excluded from the culture negative group). CRS constituted the primary analysis.Results82/457 (18%) of the patients randomized to the LAM group were M.tuberculosis culture positive. Using CRS, sensitivity (%, 95 % CI) of LAM was significantly higher than SSM [49.2 (42.1-56.4) versus 29.4(23.2-36.3); p < 0.001]. Specificity and PPV were 98.1%, and 95.8%, respectively. By contrast, using MRS, LAM sensitivity was similar to SSM and specificity was significantly lower, however, the combined sensitivity of LAM and SSM was significantly higher than that of SSM alone, p = 0.009. Using CRS, LAM sensitivity (%, CI) was CD4 count dependent [60.6(50.7-69.8) at ≤50 cells/μL; 40.0(22.7-59.4) at 51-100 cells/μL, and 32.8(21.0-46.3) at >100 cells/μL. The combined sensitivity of LAM and SSM was higher than SSM alone being highest at CD4 counts <50 cells/μL [67.6(57.9-76.3); p = <0.001]. Specificity of LAM or SSM alone, or of combined LAM and SSM was >97% in all the 3 CD4 strata.ConclusionAmong hospitalized HIV-infected patients with suspected TB, the sensitivity of LAM is significantly higher than that of SSM, especially at low CD4 counts. LAM and SSM are complimentary tests for diagnosis of TB in HIV-infected patients. We recommend a combination of LAM and SSM for TB diagnosis in HIV-infected patients with low CD4 counts in HIV/TB co-endemic countries, where alternative methods are unavailable.
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    Detection of lipoarabinomannan (LAM) in urine is an independent predictor of mortality risk in patients receiving treatment for HIV-associated tuberculosis in sub-Saharan Africa: a systematic review and meta-analysis
    (2016) Gupta-Wright, Ankur; Peters, Jurgens A; Flach, Clare; Lawn, Stephen D
    BackgroundSimple immune capture assays that detect mycobacterial lipoarabinomannan (LAM) antigen in urine are promising new tools for the diagnosis of HIV-associated tuberculosis (HIV-TB). In addition, however, recent prospective cohort studies of patients with HIV-TB have demonstrated associations between LAM in the urine and increased mortality risk during TB treatment, indicating an additional utility of urinary LAM as a prognostic marker. We conducted a systematic review and meta-analysis to summarise the evidence concerning the strength of this relationship in adults with HIV-TB in sub-Saharan Africa, thereby quantifying the assay’s prognostic value.MethodsWe searched MEDLINE and Embase databases using comprehensive search terms for ‘HIV’, ‘TB’, ‘LAM’ and ‘sub-Saharan Africa’. Identified studies were reviewed and selected according to predefined criteria.ResultsWe identified 10 studies eligible for inclusion in this systematic review, reporting on a total of 1172 HIV-TB cases. Of these, 512 patients (44%) tested positive for urinary LAM. After a variable duration of follow-up of between 2 and 6months, overall case fatality rates among HIV-TB cases varied between 7% and 53%. Pooled summary estimates generated by random-effects meta-analysis showed a two-fold increased risk of mortality for urinary LAM-positive HIV-TB cases compared to urinary LAM-negative HIV-TB cases (relative risk 2.3, 95% confidence interval 1.6–3.1). Some heterogeneity was explained by study setting and patient population in sub-group analyses. Five studies also reported multivariable analyses of risk factors for mortality, and pooled summary estimates demonstrated over two-fold increased mortality risk (odds ratio 2.5, 95% confidence interval 1.4–4.5) among urinary LAM-positive HIV-TB cases, even after adjustment for other risk factors for mortality, including CD4 cell count.ConclusionsWe have demonstrated that detectable LAM in urine is associated with increased risk of mortality during TB treatment, and that this relationship remains after adjusting for other risk factors for mortality. This may simply be due to a positive test for urinary LAM serving as a marker of higher mycobacterial load and greater disease dissemination and severity. Alternatively, LAM antigen may directly compromise host immune responses through its known immunomodulatory effects. Detectable LAM in the urine is an independent risk factor for mortality among patients receiving treatment for HIV-TB. Further research is warranted to elucidate the underlying mechanisms and to determine whether this vulnerable patient population may benefit from adjunctive interventions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0603-9) contains supplementary material, which is available to authorized users.
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    Diagnosing tuberculosis in hospitalized HIV-infected individuals who cannot produce sputum: is urine lipoarabinomannan testing the answer?
    (2017) Sabur, Natasha F; Esmail, Aliasgar; Brar, Mantaj S; Dheda, Keertan
    Abstract Background Up to one third of HIV-infected individuals with suspected TB are sputum-scarce. The Alere Determine™ TB LAM Ag lateral flow strip test can be used to diagnose TB in HIV-infected patients with advanced immunosuppression. However, how urine LAM testing should be incorporated into testing algorithms and in the context of specific patient sub-groups remains unclear. Methods This study represents a post hoc sub-group analysis of data from a randomized multi-center parent study. The study population consisted of hospitalized HIV-infected patients with suspected TB who were unable to produce sputum and who underwent urine LAM testing. The diagnostic utility of urine LAM for TB in this group was compared to the performance of urine LAM in patients who did produce a sputum sample in the parent study. Results There were a total of 187 and 2341 patients in the sputum-scarce and sputum-producing cohorts, respectively. 80 of the sputum-scarce patients underwent testing with urine LAM. In comparison to those who did produce sputum, sputum-scarce patients had a younger age, a lower Karnofsky performance score, and a lower weight and BMI at admission. A greater proportion of sputum-scarce patients were urine LAM positive, compared to those who were able to produce sputum (31% vs. 21%, p = 0.04). A higher proportion of sputum-scarce patients died within 8 weeks of admission (32% vs. 24%, p = 0.013). We inferred that 19% of HIV-infected sputum-scarce patients suspected of TB were diagnosed with tuberculosis by urine LAM testing, with an estimated positive predictive value of 63% (95% CI 43–82%). Conclusions Urine LAM testing can effectively identify tuberculosis in HIV-infected patients who are at a higher risk of mortality yet are unable to generate a sputum sample for diagnostic testing. Our findings support the use of urine LAM testing in sputum-scarce hospitalized HIV-infected patients, and its incorporation into diagnostic algorithms for this patient population.
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    Diagnostic accuracy, incremental yield and prognostic value of Determine TB-LAM for routine diagnostic testing for tuberculosis in HIV-infected patients requiring acute hospital admission in South Africa: a prospective cohort
    (2017) Lawn, Stephen D; Kerkhoff, Andrew D; Burton, Rosie; Schutz, Charlotte; Boulle, Andrew; Vogt, Monica; Gupta-Wright, Ankur; Nicol, Mark P; Meintjes, Graeme
    Abstract Background We previously reported that one-third of HIV-positive adults requiring medical admission to a South African district hospital had laboratory-confirmed tuberculosis (TB) and that almost two-thirds of cases could be rapidly diagnosed using Xpert MTB/RIF-testing of concentrated urine samples obtained on the first day of admission. Implementation of urine-based, routine, point-of-care TB screening is an attractive intervention that might be facilitated by use of a simple, low-cost diagnostic tool, such as the Determine TB-LAM lateral-flow rapid test for HIV-associated TB. Methods Sputum, urine and blood samples were systematically obtained from unselected HIV-positive adults within 24 hours of admission to a South African township hospital. Additional clinical samples were obtained during hospitalization as clinically indicated. TB was defined by the detection of Mycobacterium tuberculosis in any sample using Xpert MTB/RIF or liquid culture. The diagnostic yield, accuracy and prognostic value of urine-lipoarabinomannan (LAM) testing were determined, but urine-LAM results did not inform treatment decisions. Results Consecutive HIV-positive adult acute medical admissions not already receiving TB treatment (n = 427) were enrolled regardless of clinical presentation or symptoms. TB was diagnosed in 139 patients (TB prevalence 32.6%; median CD4 count 80 cells/μL). In the first 24 hours of admission, sputum (spot and/or induced) samples were obtained from 37.0% of patients and urine samples from 99.5% of patients (P < 0.001). The diagnostic yields from these specimens were 19.4% (n = 27/139) for sputum-microscopy, 26.6% (n = 37/139) for sputum-Xpert, 38.1% (n = 53/139) for urine-LAM and 52.5% (n = 73/139) for sputum-Xpert/urine-LAM combined (P < 0.01). Corresponding yields among patients with CD4 counts <100 cells/μL were 18.9%, 24.3%, 55.4% and 63.5%, respectively (P < 0.01). The diagnostic yield of urine-LAM was unrelated to respiratory symptoms, and LAM assay specificity (using a grade-2 cut-off) was 98.9% (274/277; 95% confidence interval [CI] 96.9–99.8). Among TB cases, positive urine-LAM status was strongly associated with mortality at 90 days (adjusted hazard ratio 4.20; 95% CI 1.50–11.75). Conclusions Routine testing for TB in newly admitted HIV-positive adults using Determine TB-LAM to test urine provides major incremental diagnostic yield with very high specificity when used in combination with sputum testing and has important utility among those without respiratory TB symptoms and/or unable to produce sputum. The assay also rapidly identifies individuals with a poor prognosis.
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    Early morning urine collection to improve urinary lateral flow LAM assay sensitivity in hospitalised patients with HIV-TB co-infection
    (2017) Gina, Phindile; Randall, Philippa J; Muchinga, Tapuwa E; Pooran, Anil; Meldau, Richard; Peter, Jonny G; Sabur, Natasha F
    BACKGROUND: Urine LAM testing has been approved by the WHO for use in hospitalised patients with advanced immunosuppression. However, sensitivity remains suboptimal. We therefore examined the incremental diagnostic sensitivity of early morning urine (EMU) versus random urine sampling using the Determine® lateral flow lipoarabinomannan assay (LF-LAM) in HIV-TB co-infected patients. METHODS: Consenting HIV-infected inpatients, screened as part of a larger prospective randomized controlled trial, that were treated for TB, and could donate matched random and EMU samples were included. Thus paired sample were collected from the same patient, LF-LAM was graded using the pre-January 2014, with grade 1 and 2 manufacturer-designated cut-points (the latter designated grade 1 after January 2014). Single sputum Xpert-MTB/RIF and/or TB culture positivity served as the reference standard (definite TB). Those treated for TB but not meeting this standard were designated probable TB. RESULTS: 123 HIV-infected patients commenced anti-TB treatment and provided matched random and EMU samples. 33% (41/123) and 67% (82/123) had definite and probable TB, respectively. Amongst those with definite TB LF-LAM sensitivity (95%CI), using the grade 2 cut-point, increased from 12% (5-24; 5/43) to 39% (26-54; 16/41) with random versus EMU, respectively (p = 0.005). Similarly, amongst probable TB, LF-LAM sensitivity increased from 10% (5-17; 8/83) to 24% (16-34; 20/82) (p = 0.001). LF-LAM specificity was not determined. CONCLUSION: This proof of concept study indicates that EMU could improve the sensitivity of LF-LAM in hospitalised TB-HIV co-infected patients. These data have implications for clinical practice.
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    Lipoarabinomannan in urine during tuberculosis treatment: association with host and pathogen factors and mycobacteriuria
    (BioMed Central Ltd, 2012) Wood, Robin; Racow, Kimberly; Bekker, Linda-Gail; Middelkoop, Keren; Vogt, Monica; Kreiswirth, Barry; Lawn, Stephen
    BACKGROUND:Detection of lipoarabinomannan (LAM), a Mycobacterium tuberculosis (Mtb) cell wall antigen, is a potentially attractive diagnostic. However, the LAM-ELISA assay has demonstrated variable sensitivity in diagnosing TB in diverse clinical populations. We therefore explored pathogen and host factors potentially impacting LAM detection. METHODS: LAM-ELISA assay testing, sputum smear and culture status, HIV status, CD4 cell count, proteinuria and TB outcomes were prospectively determined in adults diagnosed with TB and commencing TB treatment at a South African township TB clinic. Sputum TB isolates were characterised by IS61110-based restriction fragment length polymorphism (RFLP) and urines were tested for mycobacteriuria by Xpert(R) MTB/RIF assay. RESULTS: 32/199 (16.1%) of patients tested LAM-ELISA positive. Median optical density and proportion testing LAM positive remained unchanged during 2 weeks of treatment and then declined over 24 weeks. LAM was associated with positive sputum smear and culture status, HIV infection and low CD4 cell counts but not proteinuria, RFLP strain or TB treatment outcome. The sensitivity of LAM for TB in HIV-infected patients with CD4 counts of [greater than or equal to] 200, 100-199, 50-99, and < 50 cells/mul, was 15.2%, 32%, 42.9%, and 69.2% respectively. Mycobacteriuria was found in 15/32 (46.9%) of LAM positive patients and in none of the LAM negative controls. CONCLUSIONS: Urinary LAM was related to host immune factors, was unrelated to Mtb strain and declined steadily after an initial 2 weeks of TB treatment. The strong association of urine LAM with mycobacteriuria is a new finding, indicating frequent TB involvement of the renal tract in advanced HIV infection.