Application of lipoarabinomannan antigen in tuberculosis diagnostics: current evidence

Abstract

Tests based on the detection of mycobacterial lipoarabinomannan (LAM) antigen in urine have emerged as potential point-of-care tests for tuberculosis (TB). We aimed to assimilate the current evidence regarding the diagnostic performance of LAM assays and to ascertain their clinical indication in settings with high and low prevalence of HIV-TB co-infection. Owing to suboptimal sensitivity, the urinary LAM assays are unsuitable as general screening tests for TB. However, unlike traditional diagnostic methods, they demonstrate improved sensitivity in HIV-TB co-infection which further increases with low CD4 counts. Accordingly, these assays are indicated as rule-in tests for TB in patients with advanced HIV-induced immunosuppression, and facilitate the early initiation of antituberculous treatment in them. They also offer incremental sensitivity and specificity when used as adjunct tests to smear microscopy and chest radiography in HIV-TB co-infection. They obviate the biohazards associated with sputum samples and provide an alternative diagnostic tool in sputum-scarce patients. Notwithstanding these advantages, the specificity of these assays is variable, which is mostly attributable to misclassification bias and cross-reactivity with non-tuberculous mycobacteria or other commensal flora. Furthermore, the inability to detect low titres of antigen in HIV-uninfected patients makes these assays unsuitable for use in settings with a low HIV prevalence. Future research targeted towards inclusion of specific monoclonal antibodies and more sensitive immunoassay platforms might help to improve the diagnostic performance of these assays and extend their applicability to the general population of patients with TB.

A Novel Sensitive Immunoassay Targeting the 5-Methylthio- d -Xylofuranose–Lipoarabinomannan Epitope Meets the WHO's Performance Target for Tuberculosis Diagnosis

“…Lipoarabinomannan (LAM), a mycobacterial cell wall lipopolysaccharide and virulence factor, has been the most studied TB biomarker due to several attractive features: it is bacterially derived, is abundant in the cell wall of Mycobacterium tuberculosis , is heat and protease stable, and has structural epitopes that are unique to M. tuberculosis . There is extensive evidence that LAM is found in the urine of many TB patients ( 5 , 6 ), and other studies indicate that it may also be found in sputum ( 7 , 8 ) and blood ( 9 , 10 ). While several enzyme-linked immunosorbent assay (ELISA) and rapid (lateral flow) tests have been developed, the only LAM test currently on the market for the clinical diagnosis of TB is the Alere Determine TB LAM test (Alere LF-LAM) from Abbott Diagnostics, a lateral flow test for detecting LAM in urine.…”

Detection of the tuberculosis biomarker mannose-capped lipoarabinomannan in human serum: Impact of sample pretreatment with perchloric acid

“…Past studies on the clinical accuracy of ManLAM for TB diagnosis have reported high clinical specificities ( i.e., the reliability of a test to correctly identify a healthy patient as healthy), but widely varied and often low clinical sensitivities ( i.e., the reliability of a test to correctly identify a sick patient as sick) [37,38]. Along these lines, we recently found that the detectability of ManLAM in human serum significantly improved (∼250×) when analyzing the sample after acidification with perchloric acid (PCA) with an immunoassay as shown in Fig.…”

The cyanobacterial lectin, microvirin-N, enhances the specificity and sensitivity of lipoarabinomannan-based TB diagnostic tests

“…12 While poor specificity may reflect the shortcomings of individual assays, it is also possible that false-positive results are due to cross-reactivity with LAM molecules expressed by non-tuberculous mycobacteria (NTM), or related bacteria of the Actinomycetales order. 7,13,14 The LAM antigen has three structural domains: (1) a mannosyl-phosphatidyl-myo-inositol linker, (2) a polysaccharide backbone composed of a D-mannan core and D-arabinan branches, and (3) a capping motif on the terminal ends of the D-arabinan branches. 15 The linker and backbone are conserved in all LAM variants, while the capping motif differs depending on the species of mycobacterium.…”