An international review team has prepared a Cochrane Library systematic review to assess the accuracy of a point-of-care urine test for diagnosing and screening tuberculosis (TB) in people living with human immunodeficiency virus (HIV), reports Health Canal.
TB is a leading cause of death in HIV-positive people. Conventional sputum tests for TB take time and are not always accurate in people with HIV. A point-of-care test that does not depend on sputum evaluation, if sufficiently accurate, could help HIV-positive people who suffer high morbidity and mortality, by earlier detection of TB that may be missed by conventional sputum testing.
This review looks at accuracy of the lateral flow urine lipoarabinomannan assay (LF-LAM), a commercially available test that detects lipoarabinomannan (LAM), a component of mycobacterial cell walls, which is present in some people with active TB. The test is simple to carry out, requires no special equipment and provides a result within 25 minutes.
The review author team from Johns Hopkins University, US; McGill University, Canada; London School of Hygiene and Tropical Medicine, UK; and FIND, Switzerland examined all data published up until 5 February 2015 and included 12 studies. Six of the studies evaluated LF-LAM for TB diagnosis, looking at people with HIV and TB symptoms, while the other six evaluated the test for TB screening looking at people with HIV regardless of the presence of TB symptoms.
Sensitivity indicates the percentage of patients who have a positive test and are correctly diagnosed with disease; specificity indicates the percentage of patients who are correctly identified as not having disease. In HIV-positive people with TB symptoms, LF-LAM shows an average sensitivity and specificity of 45% and 92%. Based on these results, in 1000 HIV-positive people where 30% (300 people) actually have TB, LF-FAM will identify 135 people with TB and miss the diagnosis in 165 with TB. For the 700 people who do not have TB, the test will correctly identify 644 people as not having TB, but will misclassify 56 as having TB.
However, the sensitivity of the test is higher in HIV-positive individuals with low CD4 cell counts who are at risk of life-threatening illnesses. In patients with a CD4 ≤ 100 cells per µL, LF-LAM sensitivity was 56% versus 26% in patients with a CD4 count > 100 cells per µL.
Dr Karen Steingart from LSTM is the senior author of the review. She said: “LF-LAM, whether used for diagnosis or screening, has low sensitivity to diagnose TB. However, and this is key, in HIV-positive individuals with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB.” Steingart added, “the review findings should be interpreted with caution due to small number of studies and participants involved at this point.” The draft of this systematic review informed the WHO policy recommendations on the use of LF-LAM for the diagnosis and screening of active TB in people living with HIV.
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.
Maunank Shah, Colleen Hanrahan, Zhuo Yu Wang, Nandini Dendukuri, Stephen D Lawn, Claudia M Denkinger, Karen R Steingart