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Meta-Analysis
. 2016 May 10;2016(5):CD011420.
doi: 10.1002/14651858.CD011420.pub2.

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults

Maunank Shah  1 , Colleen Hanrahan, Zhuo Yu Wang, Nandini Dendukuri, Stephen D Lawn, Claudia M Denkinger, Karen R Steingart
Affiliations
Meta-Analysis

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults

Maunank Shah et al. Cochrane Database Syst Rev. .

Abstract

Background: Rapid detection of tuberculosis (TB) among people living with human immunodeficiency virus (HIV) is a global health priority. HIV-associated TB may have different clinical presentations and is challenging to diagnose. Conventional sputum tests have reduced sensitivity in HIV-positive individuals, who have higher rates of extrapulmonary TB compared with HIV-negative individuals. The lateral flow urine lipoarabinomannan assay (LF-LAM) is a new, commercially available point-of-care test that detects lipoarabinomannan (LAM), a lipopolysaccharide present in mycobacterial cell walls, in people with active TB disease.

Objectives: To assess the accuracy of LF-LAM for the diagnosis of active TB disease in HIV-positive adults who have signs and symptoms suggestive of TB (TB diagnosis).To assess the accuracy of LF-LAM as a screening test for active TB disease in HIV-positive adults irrespective of signs and symptoms suggestive of TB (TB screening).

Search methods: We searched the following databases without language restriction on 5 February 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE (PubMed,1966); EMBASE (OVID, from 1980); Science Citation Index Expanded (SCI-EXPANDED, from 1900), Conference Proceedings Citation Index-Science (CPCI-S, from 1900), and BIOSIS Previews (from 1926) (all three using the Web of Science platform; MEDION; LILACS (BIREME, from 1982); SCOPUS (from 1995); the metaRegister of Controlled Trials (mRCT); the search portal of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); and ProQuest Dissertations & Theses A&l (from 1861).

Selection criteria: Eligible study types included randomized controlled trials, cross-sectional studies, and cohort studies that determined LF-LAM accuracy for TB against a microbiological reference standard (culture or nucleic acid amplification test from any body site). A higher quality reference standard was one in which two or more specimen types were evaluated for TB, and a lower quality reference standard was one in which only one specimen type was evaluated for TB. Participants were HIV-positive people aged 15 years and older.

Data collection and analysis: Two review authors independently extracted data from each included study using a standardized form. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We evaluated the test at two different cut-offs: (grade 1 or 2, based on the reference card scale of five intensity bands). Most analyses used grade 2, the manufacturer's currently recommended cut-off for positivity. We carried out meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and estimated the models using a Bayesian approach. We determined accuracy of LF-LAM combined with sputum microscopy or Xpert® MTB/RIF. In addition, we explored the influence of CD4 count on the accuracy estimates. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results: We included 12 studies: six studies evaluated LF-LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were cross-sectional or cohort studies. Studies for TB diagnosis were largely conducted among inpatients (median CD4 range 71 to 210 cells per µL) and studies for TB screening were largely conducted among outpatients (median CD4 range 127 to 437 cells per µL). All studies were conducted in low- or middle-income countries. Only two studies for TB diagnosis (33%) and one study for TB screening (17%) used a higher quality reference standard.LF-LAM for TB diagnosis (grade 2 cut-off): meta-analyses showed median pooled sensitivity and specificity (95% credible interval (CrI)) of 45% (29% to 63%) and 92% (80% to 97%), (five studies, 2313 participants, 35% with TB, low quality evidence). The pooled sensitivity of a combination of LF-LAM and sputum microscopy (either test positive) was 59% (47% to 70%), which represented a 19% (4% to 36%) increase over sputum microscopy alone, while the pooled specificity was 92% (73% to 97%), which represented a 6% (1% to 24%) decrease from sputum microscopy alone (four studies, 1876 participants, 38% with TB). The pooled sensitivity of a combination of LF-LAM and sputum Xpert® MTB/RIF (either test positive) was 75% (61% to 87%) and represented a 13% (1% to 37%) increase over Xpert® MTB/RIF alone. The pooled specificity was 93% (81% to 97%) and represented a 4% (1% to 16%) decrease from Xpert® MTB/RIF alone (three studies, 909 participants, 36% with TB). Pooled sensitivity and specificity of LF-LAM were 56% (41% to 70%) and 90% (81% to 95%) in participants with a CD4 count of less than or equal to 100 cells per µL (five studies, 859 participants, 47% with TB) versus 26% (16% to 46%) and 92% (78% to 97%) in participants with a CD4 count greater than 100 cells per µL (five studies, 1410 participants, 30% with TB).LF-LAM for TB screening (grade 2 cut-off): for individual studies, sensitivity estimates (95% CrI) were 44% (30% to 58%), 28% (16% to 42%), and 0% (0% to 71%) and corresponding specificity estimates were 95% (92% to 97%), 94% (90% to 97%), and 95% (92% to 97%) (three studies, 1055 participants, 11% with TB, very low quality evidence). There were limited data for additional analyses.The main limitations of the review were the use of a lower quality reference standard in most included studies, and the small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution.

Authors' conclusions: We found that LF-LAM has low sensitivity to detect TB in adults living with HIV whether the test is used for diagnosis or screening. For TB diagnosis, the combination of LF-LAM with sputum microscopy suggests an increase in sensitivity for TB compared to either test alone, but with a decrease in specificity. In HIV-positive individuals with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB.

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Conflict of interest statement

Development of the systematic review was in part made possible with financial support from the United States Agency for International Development (USAID) administered by the World Health Organization (WHO) Global TB Programme,Switzerland. KRS, MS, CH, and ZYW received funding to carry out the review from USAID. KRS served as Co‐ordinator of the Evidence Synthesis and Policy Subgroup of Stop TB Partnership’s New Diagnostics Working Group through 2015. SDL has received Wellcome Trust grant funds to conduct primary research evaluating diagnostic tests using this product. SDL published primary research that was included in the review and provided intellectual input to the review, but did not participate directly in the application of the inclusion criteria, 'Risk of bias' assessment, or data extraction. CMD is employed by FIND, a Swiss non‐profit organization. FIND provided funding for an initial assessment of data available for the review. KRS, MS, and ZYW received funding from FIND for an initial assessment. We presented the findings from the initial assessment at the Union World Conference on Lung Health, Barcelona, October 2014. MS is supported through an National Institute of Health (NIH) K23 grant (K23AI089259). ND has no declarations of interest to declare. The review authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the review apart from those disclosed.

Figures

Figure 1
Figure 1
(A) Alere DetermineTM TB LAM Ag tests. To the sample pad (white pad marked by the arrow symbols) 60 µL of urine is applied and visualized bands are read 25 minutes later. (B) Reference card accompanying test strips to 'grade' the test result and determine positivity (33). Copyright © [2014] [Alere Inc]: reproduced with permission.
Figure 2
Figure 2
Study flow diagram.
Figure 3
Figure 3
LF‐LAM for TB diagnosis. 'Risk of bias' and applicability concerns summary: review authors' judgements about each domain for each included study.
Figure 4
Figure 4
LF‐LAM for TB screening. 'Risk of bias' and applicability concerns summary: review authors' judgements about each domain for each included study.
Figure 5
Figure 5
Forest plots of LF‐LAM (Grade 1 and 2) sensitivity and specificity for TB against a microbiological reference standard (TB diagnosis). TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative. Between brackets are the 95% confidence interval (CI) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).
Figure 6
Figure 6
Forest plots of LF‐LAM (grade 2) sensitivity and specificity for TB against a composite reference standard (TB diagnosis). TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative. Between brackets are the 95% confidence interval (CI) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).
Figure 7
Figure 7
Accuracy of smear microscopy (black circle) and smear microscopy in combination with LF‐LAM (Grade 2) (blue circle) plotted in receiver operating characteristic (ROC) space. The dashed lines are only for illustration to show how sensitivity and specificity changed with the addition of the LF‐LAM test.
Figure 8
Figure 8
Accuracy of Xpert® MTB/RIF (black circle) and Xpert® MTB/RIF in combination with LF‐LAM (grade 2) (blue circle) plotted in receiver operating characteristic (ROC) space. The dashed lines are only for illustration to show how sensitivity and specificity changed with the addition of the LF‐LAM test.
Figure 9
Figure 9
Forest plots of LF‐LAM (grade 2) sensitivity and specificity for TB against a microbiological reference standard, by CD4 strata (TB Diagnosis). TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative. Between brackets are the 95% confidence interval (CI) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).
Figure 10
Figure 10
Plots of (A) sensitivity and (B) specificity of LF‐LAM (grade 2) for TB diagnosis stratified by CD4 count. Plots were derived using a sample from the posterior distribution of the pooled sensitivity (A) and specificity (B). Circle represents the pooled estimates (median), with bars representing 95% credible intervals.
Figure 11
Figure 11
Forest plots of LF‐LAM (grade 2) sensitivity and specificity for TB against a microbiological reference standard, by health care setting (TB Diagnosis). TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative. Between brackets are the 95% confidence interval (CI) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).
Figure 12
Figure 12
Forest plots of LF‐LAM (grade 1 and 2) sensitivity and specificity for TB against a microbiological reference standard (TB Screening). TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative. Between brackets are the 95% confidence interval (CI) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).
Figure 13
Figure 13
Forest plots of LF‐LAM (grade 2) sensitivity and specificity for TB against a composite reference standard (TB Screening). TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative. Between brackets are the 95% confidence interval (CI) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).
Figure 14
Figure 14
Accuracy of smear microscopy (black circle) and smear microscopy in combination with LF‐LAM (grade 2) (blue circle) plotted in receiver operating characteristic (ROC) space. The dashed lines are only for illustration to show how sensitivity and specificity changed with the addition of the LF‐LAM test.
Figure 15
Figure 15
Forest plots of LF‐LAM (grade 2) sensitivity and specificity for TB (TB Screening). TP = True Positive; FP = stratified by CD4 count. False Positive; FN = False Negative; TN = True Negative. Between brackets are the 95% confidence interval (CI) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).
Test 1
Test 1
Diagnosis of TB against microbiological reference at Grade 1: all participants.
Test 2
Test 2
Diagnosis of TB against microbiological reference at Grade 2: all participants.
Test 3
Test 3
Diagnosis of TB against composite reference at Grade 1: all participants.
Test 4
Test 4
Diagnosis of TB against composite reference at Grade 2: all participants.
Test 5
Test 5
Diagnosis of TB against microbiological reference at Grade 1, CD4 > 200.
Test 6
Test 6
Diagnosis of TB against microbiological reference at Grade 1, CD4 < 200.
Test 7
Test 7
Diagnosis of TB against microbiological reference at Grade 1, CD4 > 100.
Test 8
Test 8
Diagnosis of TB against microbiological reference at Grade 1, CD4 < 100.
Test 9
Test 9
Diagnosis of TB against microbiological reference at Grade 1, CD4 > 50.
Test 10
Test 10
Diagnosis of TB against microbiological reference at Grade 1, CD4 < 50.
Test 11
Test 11
Diagnosis of TB against microbiological reference at Grade 2, CD4 > 200.
Test 12
Test 12
Diagnosis of TB against microbiological reference at Grade 2, CD4 < 200.
Test 13
Test 13
Diagnosis of TB against microbiological reference at Grade 1, CD4 > 100.
Test 14
Test 14
Diagnosis of TB against microbiological reference at Grade 1, CD4 < 100.
Test 15
Test 15
Diagnosis of TB against microbiological reference at Grade 1, CD4 > 50.
Test 16
Test 16
Diagnosis of TB against microbiological reference at Grade 1, CD4 < 50.
Test 17
Test 17
Diagnosis of TB against microbiological reference at Grade 1: inpatients.
Test 18
Test 18
Diagnosis of TB against microbiological reference at Grade 2: inpatients.
Test 19
Test 19
Diagnosis of TB against microbiological reference at Grade 1: outpatients.
Test 20
Test 20
Diagnosis of TB against microbiological reference at Grade 2: outpatients.
Test 21
Test 21
Diagnosis of TB with LAM at Grade 2 (among studies comparing with smear).
Test 22
Test 22
Diagnosis of TB with smear (among studies comparing with LAM).
Test 23
Test 23
Diagnosis of TB with combination of LAM at Grade 2 with smear.
Test 24
Test 24
Diagnosis of TB with LAM at Grade 2 (among studies comparing with Xpert®).
Test 25
Test 25
Diagnosis of TB with Xpert® (among studies comparing with LAM).
Test 26
Test 26
Diagnosis of TB with combination of LAM at Grade 2 with Xpert®.
Test 27
Test 27
Screening for TB against microbiological reference at Grade 1: all participants.
Test 28
Test 28
Screening for TB against microbiological reference at Grade 2: all participants.
Test 29
Test 29
Screening for TB against composite reference at Grade 1: all participants.
Test 30
Test 30
Screening for TB against composite reference at Grade 2: all participants.
Test 31
Test 31
Screening for TB against microbiological reference at Grade 1, CD4 > 200.
Test 32
Test 32
Screening for TB against microbiological reference at Grade 1, CD4 < 200.
Test 33
Test 33
Screening for TB against microbiological reference at Grade 1, CD4 > 100.
Test 34
Test 34
Screening for TB against microbiological reference at Grade 1, CD4 < 100.
Test 35
Test 35
Screening for TB against microbiological reference at Grade 1, CD4 > 50.
Test 36
Test 36
Screening for TB against microbiological reference at Grade 1, CD4 < 50.
Test 37
Test 37
Screening for TB against microbiological reference at Grade 2, CD4 > 100.
Test 38
Test 38
Screening for TB against microbiological reference at Grade 2, CD4 < 100.
Test 39
Test 39
Screening for TB against microbiological reference at Grade 1: outpatients.
Test 40
Test 40
Screening for TB with LAM at Grade 2 (among studies comparing with smear microscopy).
Test 41
Test 41
Screening for TB with smear microscopy (among studies comparing with LAM).
Test 42
Test 42
Screening for TB with the combination of LAM (Grade 2) and smear microscopy.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD011420

References

References to studies included in this review

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References to ongoing studies

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Additional references

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References to other published versions of this review

    1. Shah M, Hanrahan C, Wang ZY, Steingart KR, Lawn SD, Denkinger C, et al. Urine lateral flow lipoarabinomannan assay for diagnosing active tuberculosis in adults living with HIV. Cochrane Database of Systematic Reviews 2014, Issue 12. [DOI: 10.1002/14651858.CD011420] - DOI - PMC - PubMed

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