Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV

Why is improving the diagnosis of tuberculosis important?

Tuberculosis causes more deaths in people living with HIV than any other disease. The lateral flow urine lipoarabinomannan assay (LF-LAM, Alere Determine™ TB LAM Ag assay) is a World Health Organization-recommended rapid test to assist in detection of active tuberculosis in HIV-positive people with severe HIV disease. Rapid and early tuberculosis diagnosis may allow for prompt treatment and alleviate severe illness and death. An incorrect tuberculosis diagnosis may result in anxiety and unnecessary treatment.

What is the aim of this review?

To find out how accurate LF-LAM is for diagnosing tuberculosis in HIV-positive people with tuberculosis symptoms (symptomatic participants) and those not assessed for tuberculosis symptoms (unselected participants). This is an update of the 2016 Cochrane Review.

What was studied in this review?

LF-LAM is a commercially available point-of-care test that detects lipoarabinomannan (LAM), a component of the bacterial cell walls, present in some people with active tuberculosis. The test is simple and shows results in 25 minutes. LF-LAM results were measured against culture or molecular tests (benchmark).

What are the main results of this review?

Fifteen studies: eight studies evaluated LF-LAM for tuberculosis among symptomatic participants and seven studies among unselected participants. All studies were conducted in low- or middle-income countries.

Tuberculosis diagnosis among symptomatic participants: LF-LAM registered positive in 42% (sensitivity) of people who actually had tuberculosis and did not register positive in 91% of people who were actually negative (specificity).

Tuberculosis diagnosis among unselected participants: LF-LAM sensitivity was 35% and specificity 95%.

How confident are we in the review’s results?

Several studies excluded participants who could not produce sputum and most studies relied on a lower quality benchmark. Few studies and participants were included in some analyses and only one study was conducted outside of sub-Saharan Africa. Results should be interpreted with caution.

What do the results mean?

Among symptomatic participants, in theory, for a population of 1000 people where 300 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 189 to be LF-LAM positive: of these, 63 (33%) would not have tuberculosis (false-positives); and 811 to be LF-LAM negative: of these, 174 (21%) would have tuberculosis (false-negatives).

Among unselected participants, in theory, for a population of 1000 people where 100 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 80 to be LF-LAM positive: of these, 45 (56%) would not have tuberculosis (false-positives); and 920 to be LF-LAM negative: of these, 65 (7%) would have tuberculosis (false-negatives).

Who do the review’s results apply to?

HIV-positive people with tuberculosis symptoms and those not assessed for tuberculosis symptoms.

What are the implications of this review?

LF-LAM has sensitivity around 40% to detect tuberculosis. As the test does not require sputum collection, LF-LAM may be the only way to diagnose tuberculosis when sputum cannot be produced.

How up-to-date is this review?

To 11 May 2018.

Authors' conclusions: 

We found that LF-LAM has a sensitivity of 42% to diagnose tuberculosis in HIV-positive individuals with tuberculosis symptoms and 35% in HIV-positive individuals not assessed for tuberculosis symptoms, consistent with findings reported previously. Regardless of how people are enrolled, sensitivity is higher in inpatients and those with lower CD4 cell, but a concomitant lower specificity. As a simple point-of-care test that does not depend upon sputum evaluation, LF-LAM may assist with the diagnosis of tuberculosis, particularly when a sputum specimen cannot be produced.

Read the full abstract...
Background: 

The lateral flow urine lipoarabinomannan (LF-LAM) assay Alere Determine™ TB LAM Ag is recommended by the World Health Organization (WHO) to help detect active tuberculosis in HIV-positive people with severe HIV disease. This review update asks the question, "does new evidence justify the use of LF-LAM in a broader group of people?”, and is part of the WHO process for updating guidance on the use of LF-LAM.

Objectives: 

To assess the accuracy of LF-LAM for the diagnosis of active tuberculosis among HIV-positive adults with signs and symptoms of tuberculosis (symptomatic participants) and among HIV-positive adults irrespective of signs and symptoms of tuberculosis (unselected participants not assessed for tuberculosis signs and symptoms).

The proposed role for LF-LAM is as an add on to clinical judgement and with other tests to assist in diagnosing tuberculosis.

Search strategy: 

We searched the Cochrane Infectious Diseases Group Specialized Register; MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, without language restriction to 11 May 2018.

Selection criteria: 

Randomized trials, cross-sectional, and observational cohort studies that evaluated LF-LAM for active tuberculosis (pulmonary and extrapulmonary) in HIV-positive adults. We included studies that used the manufacturer's recommended threshold for test positivity, either the updated reference card with four bands (grade 1 of 4) or the corresponding prior reference card grade with five bands (grade 2 of 5). The reference standard was culture or nucleic acid amplification test from any body site (microbiological). We considered a higher quality reference standard to be one in which two or more specimen types were evaluated for tuberculosis diagnosis and a lower quality reference standard to be one in which only one specimen type was evaluated.

Data collection and analysis: 

Two review authors independently extracted data using a standardized form and REDCap electronic data capture tools. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool and performed meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and a Bayesian approach. We analyzed studies enrolling strictly symptomatic participants separately from those enrolling unselected participants. We investigated pre-defined sources of heterogeneity including the influence of CD4 count and clinical setting on the accuracy estimates. We assessed the certainty of the evidence using the GRADE approach.

Main results: 

We included 15 unique studies (nine new studies and six studies from the original review that met the inclusion criteria): eight studies among symptomatic adults and seven studies among unselected adults. All studies were conducted in low- or middle-income countries. Risk of bias was high in the patient selection and reference standard domains, mainly because studies excluded participants unable to produce sputum and used a lower quality reference standard.

Participants with tuberculosis symptoms

LF-LAM pooled sensitivity (95% credible interval (CrI) ) was 42% (31% to 55%) (moderate-certainty evidence) and pooled specificity was 91% (85% to 95%) (very low-certainty evidence), (8 studies, 3449 participants, 37% with tuberculosis).

For a population of 1000 people where 300 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 189 to be LF-LAM positive: of these, 63 (33%) would not have tuberculosis (false-positives); and 811 to be LF-LAM negative: of these, 174 (21%) would have tuberculosis (false-negatives).

By clinical setting, pooled sensitivity was 52% (40% to 64%) among inpatients versus 29% (17% to 47%) among outpatients; and pooled specificity was 87% (78% to 93%) among inpatients versus 96% (91% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count.

Unselected participants not assessed for signs and symptoms of tuberculosis

LF-LAM pooled sensitivity was 35% (22% to 50%), (moderate-certainty evidence) and pooled specificity was 95% (89% to 96%), (low-certainty evidence), (7 studies, 3365 participants, 13% with tuberculosis).

For a population of 1000 people where 100 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 80 to be LF-LAM positive: of these, 45 (56%) would not have tuberculosis (false-positives); and 920 to be LF-LAM negative: of these, 65 (7%) would have tuberculosis (false-negatives).

By clinical setting, pooled sensitivity was 62% (41% to 83%) among inpatients versus 31% (18% to 47%) among outpatients; pooled specificity was 84% (48% to 96%) among inpatients versus 95% (87% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count.

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