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Point-of-care detection of lipoarabinomannan (LAM) in urine for diagnosis of HIV-associated tuberculosis: a state of the art review.

ABSTRACT: Detection of Mycobacterium tuberculosis antigens in urine is attractive as a potential means of diagnosing tuberculosis (TB) regardless of the anatomical site of disease. The most promising candidate antigen is the cell wall lipopolysaccharide antigen lipoarabinomannan (LAM), which has been used to develop commercially available enzyme-linked immunosorbent assays. Although highly variable diagnostic accuracy has been observed in different clinical populations, it is now clear that this assay has useful sensitivity for diagnosis of HIV-associated TB in patients with advanced immunodeficiency and low CD4 cell counts. Thus, this assay is particularly useful when selectively used among patients enrolling in antiretroviral treatment services or in HIV-infected patients requiring admission to hospital medical wards. These are the very patients who have the highest mortality risk and who stand to gain the most from rapid diagnosis, permitting immediate initiation of TB treatment. A recently developed low-cost, lateral-flow (urine 'dip-stick') format of the assay provides a result within 30 minutes and is potentially a major step forward as it can be used at the point-of-care, making the possibility of immediate diagnosis and treatment a reality. This paper discusses the likely utility of this point-of-care assay and how it might best be used in combination with other diagnostic assays for TB. The many further research studies that are needed on this assay are described. Consideration is particularly given to potential reasons for the variable specificity observed in existing field evaluations of LAM ELISAs. Whether this might be related to the assay itself or to the challenges associated with study design is discussed.

SUBMITTER: Lawn SD

PROVIDER: S-EPMC3423001 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Point-of-care detection of lipoarabinomannan (LAM) in urine for diagnosis of HIV-associated tuberculosis: a state of the art review.

Lawn Stephen D SD

BMC infectious diseases 20120426

Detection of Mycobacterium tuberculosis antigens in urine is attractive as a potential means of diagnosing tuberculosis (TB) regardless of the anatomical site of disease. The most promising candidate antigen is the cell wall lipopolysaccharide antigen lipoarabinomannan (LAM), which has been used to develop commercially available enzyme-linked immunosorbent assays. Although highly variable diagnostic accuracy has been observed in different clinical populations, it is now clear that this assay has ...[more]

PMID: 22536883

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Project description:The Fujifilm SILVAMP TB LAM (FujiLAM) assay offers improved sensitivity compared to Determine TB LAM Ag (AlereLAM) for detecting tuberculosis (TB) among people with HIV. Here, we examined the diagnostic value of FujiLAM testing on early morning urine versus spot urine and the added value of a two-sample strategy. We assessed the diagnostic accuracy of FujiLAM on cryopreserved urine samples collected and stored as part of a prospective cohort of adults with HIV presenting for antiretroviral treatment in Ghana. We compared FujiLAM sensitivity and specificity in spontaneously voided urine samples collected at inclusion (spot urine) versus in the first voided early morning urine (morning urine) and for a one (spot urine) versus two samples (spot and morning urine) strategy. Diagnostic accuracy was determined against both microbiological (using sputum culture and Xpert MTB/RIF testing of sputum and urine to confirm TB) and composite reference standards (including microbiologically confirmed and probable TB cases). Paired urine samples of spot and morning urine were available for 389 patients. Patients had a median CD4 cell count of 176 cells/μL (interquartile range [IQR], 52 to 361). Forty-three (11.0%) had confirmed TB, and 19 (4.9%) had probable TB. Overall agreement for spot versus morning urine test results was 94.6% (kappa, 0.81). Compared to a microbiological reference standard, the FujiLAM sensitivity (95% confidence interval [CI]) was 67.4% (51.5 to 80.9) for spot and 69.8% (53.9 to 82.8) for morning urine, an absolute difference (95% CI) of 2.4% (-10.2 to 14.8). Specificity was 90.2% (86.5 to 93.1) versus 89.0% (85.2 to 92.1) for spot and morning urine, respectively, a difference of 1.2% (-3.7 to 1.4). A two-sample strategy increased FujiLAM sensitivity from 67.4% (51.5 to 80.9) to 74.4% (58.8 to 86.5), a difference of 7.0% (-3.0 to 16.9), while specificity decreased from 90.2% (86.5 to 93.1) to 87.3% (83.3 to 90.6), a difference of -2.9% (-4.9 to -0.8). This study indicates that FujiLAM testing performs equivalently on spot and early morning urine samples. Sensitivity could be increased with a two-sample strategy but at the risk of lower specificity. These data can inform future guidelines and clinical practice. IMPORTANCE This study indicates that FujiLAM testing performs equivalently on spot and early morning urine samples for detecting tuberculosis among people with HIV. Sensitivity could be increased with a two-sample strategy but at the risk of lower specificity. These data can inform future guidelines and clinical practice around FujiLAM.

Project description:BackgroundTuberculosis (TB) is a serious co-morbidity among children with severe acute malnutrition (SAM) and TB diagnosis remains particularly challenging in the very young. We explored whether, in a low HIV-prevalence setting, the detection of mycobacterial lipoarabinomannan (LAM) antigen in urine may assist TB diagnosis in SAM children, a pediatric population currently not included in LAM-testing recommendations. To that end, we assessed LAM test-positivity among SAM children with and without signs or symptoms of TB.MethodsA cross-sectional assessment (February 2016-August 2017) included children <5 years with SAM from an Intensive-Therapeutic-Feeding-Centre in Madaoua, Niger. Group 1: children with signs or symptoms suggestive of TB. Group 2: children without any sign or symptom of TB. Urine-specimens were subjected to DetermineTM TB-LAM lateral-flow-test (using a 4-grade intensity scale for positives). LAM-results were used for study purposes and not for patient management. Programmatic TB-diagnosis was primarily based on patients' clinical symptoms and TB contact history with no systematic access to X-ray or microbiological reference testing.Results102 (Group 1) and 100 children (Group 2) were included (median age 18 months, 59.4% male, 1.0% HIV-positive). In Group 1, 22 (21.6%) children were started on TB-treatment (probable TB) and none of the children in Group 2. LAM-positivity was 52.0% (53/102) and 37.0% (37/100) in Group 1 and 2, respectively. Low-intensity (Grade 1) LAM test-positivity was similarly high in both Groups (37.3% and 36.0%, respectively), while Grade 2 or 3-positives were mainly detected in Group 1 (Group 1: 14.7%, Group 2: 1.0%, p<0.001). When considering only Grades >1 as positive, LAM-testing detected 22.7% (95%CI: 7.8, 45.4) among probable TB cases, while 99% (95%CI: 94.6, 99.9) of unlikely TB cases (Group 2) tested negative.ConclusionThese findings suggest the potential utility of LAM urine testing in HIV-negative children with SAM. Determine LAM-positivity with Grades >1 may identify HIV-negative SAM children that are eligible for rapid TB-treatment initiation, though low-intensity (Grade 1) LAM-positive results may not be helpful in this way. Further studies in this specific pediatric population are warranted, including evaluations of new generation LAM tests.

Project description:BACKGROUNDInadequate tuberculosis (TB) diagnostics are a major hurdle in the reduction of disease burden, and accurate point-of-care tests (POCTs) are urgently needed. We assessed the diagnostic accuracy of Fujifilm SILVAMP TB lipoarabinomannan (FujiLAM) POCT for TB diagnosis in HIV-negative outpatients and compared it with Alere Determine TB LAM Ag (AlereLAM) POCT and a laboratory-based ultrasensitive electrochemiluminescence LAM research assay (EclLAM).METHODSIn this multicenter diagnostic test accuracy study, we recruited HIV-negative adults with symptoms suggestive of pulmonary TB presenting to outpatient health care centers in Peru and South Africa. Urine samples were tested using FujiLAM, AlereLAM, and EclLAM, and the diagnostic accuracy was assessed against a microbiological reference standard (MRS) and a composite reference standard.RESULTSThree hundred seventy-two HIV-negative participants were included and the prevalence of microbiologically confirmed TB was 30%. Compared with the MRS, the sensitivities of AlereLAM, FujiLAM, and EclLAM were 10.8% (95% confidence interval [CI] 6.3%-18.0%), 53.2% (95% CI 43.9%-62.1%), and 66.7% (95% CI 57.5%-74.7%), respectively. The specificities of AlereLAM, FujiLAM, and EclLAM were 92.3% (95% CI 88.5%-95.0%), 98.9% (95% CI 96.7%-99.6%), and 98.1% (95% CI 95.6%-99.2%), respectively. Positive likelihood ratios of AlereLAM, FujiLAM, and EclLAM were 1.4, 46.2, and 34.8, respectively, and positive predictive values were 37.5%, 95.2%, and 93.7%, respectively.CONCLUSIONCompared with AlereLAM, FujiLAM detected 5 times more patients with TB in HIV-negative participants, had a high positive predictive value, and has the potential to improve rapid diagnosis of TB at the point-of-care. EclLAM demonstrated that additional sensitivity gains are possible, which highlights LAM's potential as a biomarker. Additional research is required to assess FujiLAM's performance in prospective cohorts, its cost-effectiveness, and its impact in real-world clinical settings.FUNDINGGlobal Health Innovative Technology Fund, the UK Department for International Development, the Dutch Ministry of Foreign Affairs, the Bill and Melinda Gates Foundation, the Australian Department of Foreign Affairs and Trade, the German Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, and the NIH and National Institute of Allergy and Infectious Diseases.

Project description:BackgroundTuberculosis (TB) is a global burden, and this is likely to remain the case due to a lack of adequate and accurate point-of-care diagnostic tests. Obtaining good-quality sputum from the bottom of the respiratory tract of children is challenging. Lipoarabinomannan (LAM) is a specific component of the mycobacterial cell envelope that is excreted in the urine of people with active TB. This study aimed to assess the performance of different types of urine-based LAM antigen tests for the diagnosis of TB in children.MethodsRelevant databases were searched for studies that used urine-based LAM tests to diagnose TB in children. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Tool. Pooled sensitivity and specificity were calculated using the random-effect model in STATA Version 16.0. Moreover, subgroup analysis was undertaken to hinder the heterogeneity of the studies.ResultsEleven articles were included in the final systematic review and meta-analysis. The pooled sensitivity and specificity of the Mycobacterium tuberculosis enzyme-linked immunosorbent assay (MTB-LAM-ELISA), Alere Determine TB LAM Ag (Alere LAM) test and the Fujifilm SILVAMP TB LAM (Fuji LAM) test in children aged <15 years with TB were 16.0% [95% confidence interval (CI) 10.25-42.25] and 95.61% (95% CI 93.74-97.74); 45.90% (95% CI 40.40-51.40) and 80.42% (95% CI 69.39-91.46); and 52.32% (95% CI 35.03-69.62) and 89.37% (95% CI 82.88-95.86), respectively. Subgroup analysis revealed that the pooled sensitivity and specificity of MTB-LAM-ELISA, Alere LAM test and Fuji LAM test were 33.5% (95% CI 34.86-100) and 95.83% (95% CI 91.50-100); 46.59% (95% CI 32.98-60.19) and 76.45% (95% CI 57.07-95.82); and 57.89% (95% CI 48.44-67.35%) and 87.66% (95% CI 75.29-100), respectively, in human immunodeficiency virus (HIV)-positive children; and 3.35% (95% CI 1.61-8.31) and 96.0% (95% CI 93.88-98.11); 32.33% (95% CI 7.63-57.03) and 79.07% (95% CI 62.62-95.51); and 50.95% (95% CI 27.45-74.45) and 89.47% (95% CI 84.72-94.22), respectively, in HIV-negative children.ConclusionThe Fuji LAM and Alere LAM tests may be useful for the diagnosis of TB in children in conjunction with other more sensitive and specific tests, although a prospective study in relevant clinical settings is needed to evaluate this. There is a need for more evidence-based data on the use of these rapid diagnostic tools to diagnose TB in children independent of HIV status.

Project description:BACKGROUND:Simple 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. METHODS:We 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. RESULTS:We 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 6 months, 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. CONCLUSIONS:We 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.

Dataset Information

Point-of-care detection of lipoarabinomannan (LAM) in urine for diagnosis of HIV-associated tuberculosis: a state of the art review.

Publications

Point-of-care detection of lipoarabinomannan (LAM) in urine for diagnosis of HIV-associated tuberculosis: a state of the art review.

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