Getting to the point in point-of-care diagnostics for tuberculosis

Ignatius, Elisa H.; Cohen, Keira A.; Bishai, William R.

doi:10.1172/jci142497

Cited by 5 publications

(4 citation statements)

References 23 publications

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“…To improve the diagnosis of TB in high burden countries there is an urgent need for an effective non-sputum-based rapid diagnostic test or a triage tool that has the necessary performance to rapidly identify diseased patients for confirmatory testing and treatment [6][7][8][9]. Lipoarabinomannan (LAM) is a lipoglycan that is a major structural component of the mycobacterial cell wall and also acts as an immunomodulator that may play a role in its pathogenesis [10,11].…”

Section: Introductionmentioning

confidence: 99%

Performance of novel antibodies for lipoarabinomannan to develop diagnostic tests for Mycobacterium tuberculosis

et al. 2022

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Lipoarabinomannan (LAM), a component of the Mycobacterium tuberculosis (MTB) cell wall, is detectable in the urine of MTB infected patients with active tuberculosis (TB). LAM-specific antibodies (Igs) have been developed by a variety of traditional and recombinant methods for potential use in a rapid diagnostic test (RDT). We evaluated the analytical performance of the TB LAM Igs to identify pairs that offer superior performance over existing urine LAM tests. We assessed 25 new and 4 existing Igs in a matrixed format using a multiplex electrochemiluminescence-based liquid immunoassay. A total of 841 paired Ig combinations were challenged with in vitro cultured LAM (cLAM) derived from MTB strains representing diverse phylogenetic lineages, alongside urinary LAM (uLAM) from the urine of adults with active pulmonary TB. Analytical sensitivity of down-selected Ig pairs was determined using MTB Aoyama-B cLAM, while diagnostic accuracy was determined using clinical samples. When testing cLAM, the reactivity of Ig pairs was similar across MTB lineages 1–4 but lineage 5:6 had significantly more reactivity among Ig pairs. Overall, 41 Ig pairs had a strong binding affinity to cLAM, as compared to the reference pair of S4-20/A194-01, and 28 Ig pairs therein exhibited a strong affinity for both cLAM and uLAM. Retrospective testing on clinical urine specimens demonstrated varying sensitivities (12–80%) and specificities (14–100%). The five top pairs had a similar analytical limit of detection to the reference pair but in four instances, the sensitivity and specificity with clinical uLAM samples was poor. Overall, epitopes presented by uLAM are different from cLAM, which may affect antibody performance when testing uLAM in patient samples. Several new Ig pairs had similar ranges of high sensitivity to cLAM but overall, there were no new candidate Ig pairs identified in this round of screening with increased performance with uLAM as compared to an existing optimal pair.

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Section: Introductionmentioning

confidence: 99%

Performance of novel antibodies for lipoarabinomannan to develop diagnostic tests for Mycobacterium tuberculosis

et al. 2022

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“…We examined the accuracy of the recently developed FujiLAM to diagnose paediatric TB across the available literature. While there are numerous studies evaluating FujiLAM for diagnosing TB in adults,5 8 12–15 there are only three paediatric publications 21 22 26. The estimated sensitivities ranged from 42% to 63%, whereas specificity was higher, ranging from 84% to 93%, when applying an MRS.…”

Section: Discussionmentioning

confidence: 99%

“…Compared with the increasing number of publications in adults,5 8 12–15 few studies have explored the performance of FujiLAM in children. In children, diagnostic yield, which represents both the diagnostic accuracy of a test and feasibility of obtaining a specimen,16 is improved by the availability of a specimen such as urine, compared with sputum.…”

Section: Introductionmentioning

confidence: 99%

FujiLAM for the diagnosis of childhood tuberculosis: a systematic review

Olbrich

Khambati

Bijker

et al. 2022

bmjpo

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BackgroundChildhood tuberculosis (TB) remains underdiagnosed. The novel lateral flow FujiLAM assay detects lipoarabinomannan (LAM) in urine, but data on performance in children remain limited.MethodsWe conducted a systematic review assessing the diagnostic performance of FujiLAM for diagnosing paediatric TB. The last search was conducted in November 2021.ResultsWe included three studies with data from 698 children for FujiLAM. For FujiLAM, sensitivity using a microbiological reference standard were 60% (95% CI 15 to 95), 42% (95% CI 31 to 53) and 63% (95% CI 50 to 75), respectively. Specificity was 93% (95% CI 85 to 98), 92% (95% CI 85 to 96) and 84% (95% CI 80 to 88). Using a composite reference standard, sensitivity was 11% (95% CI 4 to 22), 27% (95% CI 20 to 34) and 33% (95% CI 26 to 40), and specificity was 92% (95% CI 73 to 99), 97% (95% CI 87 to 100) and 85% (95% CI 79 to 89). Subgroup analyses for sensitivity of FujiLAM in children living with HIV (CLHIV) compared with those who were negative for HIV infection were inconsistent across studies. Among CLHIV, sensitivity appeared higher in those with greater immunosuppression, although wide CIs limit the interpretation of observed differences. Meta-analysis was not performed due to considerable study heterogeneity.ConclusionThe high specificity of FujiLAM demonstrates its potential as a point-of-care (POC) rule-in test for diagnosing paediatric TB. As an instrument-free POC test that uses an easy-to-obtain specimen, FujiLAM could significantly improve TB diagnosis in children in low-resource settings, however the small number of studies available highlight that further data are needed. Key priorities to be addressed in forthcoming paediatric evaluations include prospective head-to-head comparisons with AlereLAM using fresh specimens, specific subgroup analysis in CLHIV and extrapulmonary disease and studies in different geographical locations.CRD42021270761.

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“…To improve the diagnosis of TB in high burden countries there is an urgent need for an effective non-sputum-based rapid diagnostic test or a triage tool that has the necessary performance to rapidly identify diseased patients for confirmatory testing and treatment (6)(7)(8)(9). Lipoarabinomannan (LAM) is a lipoglycan that is a major structural component of the mycobacterial cell wall and also acts as an immunomodulator that may play a role in its pathogenesis (10,11).…”

Section: Introductionmentioning

confidence: 99%

Performance of novel antibodies for lipoarabinomannan to develop diagnostic tests for Mycobacterium tuberculosis

Cantera

Lillis

Peck

et al. 2022

Preprint

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Lipoarabinomannan (LAM), a component of the Mycobacterium tuberculosis (MTB) cell wall, is detectable in the urine of MTB infected patients with active tuberculosis (TB). LAM-specific antibodies (Igs) have been developed by a variety of traditional and recombinant methods for potential use in a rapid diagnostic test (RDT). We evaluated the analytical performance of the TB LAM Igs to identify pairs that offer superior performance over existing urine LAM tests. We assessed 25 new and 4 existing Igs in a matrixed format using a multiplex electrochemiluminescence-based liquid immunoassay. A total of 841 paired Ig combinations were challenged with in vitro cultured LAM (cLAM) derived from MTB strains representing diverse phylogenetic lineages, alongside urinary LAM (uLAM) from the urine of adults with active pulmonary TB. Analytical sensitivity of down-selected Ig pairs was determined using MTB Aoyama-B cLAM, while diagnostic accuracy was determined using clinical samples. When testing cLAM, the reactivity of Ig pairs was similar across MTB lineages 1-4 but lineage 5:6 had significantly more reactivity among Ig pairs. Overall, 41 Ig pairs had a strong binding affinity to cLAM, as compared to the reference pair of S4-20/A194-01, and 28 Ig pairs therein exhibited a strong affinity for both cLAM and uLAM. Retrospective testing on clinical urine specimens demonstrated varying sensitivities (12-80%) and specificities (14-100%). The five top pairs had a similar analytical limit of detection to the reference pair but in four instances, the sensitivity and specificity with clinical uLAM samples was poor. Overall, epitopes presented by uLAM are different from cLAM, which may affect antibody performance when testing uLAM in patient samples. Several new Ig pairs had similar ranges of high sensitivity to cLAM but overall, there were no new candidate Ig pairs identified in this round of screening with increased performance with uLAM as compared to an existing optimal pair.

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Getting to the point in point-of-care diagnostics for tuberculosis

Abstract: EHI is supported by T32 GM066691-17. KAC reports research support funding from the Burroughs Wellcome Fund Career Award for Medical Scientists, the Cystic Fibrosis Foundation, and NIH grant K08 HL139994. WRB gratefully acknowledges the support of NIH grant AI 037856.

Cited by 5 publications

References 23 publications

Performance of novel antibodies for lipoarabinomannan to develop diagnostic tests for Mycobacterium tuberculosis

Performance of novel antibodies for lipoarabinomannan to develop diagnostic tests for Mycobacterium tuberculosis

FujiLAM for the diagnosis of childhood tuberculosis: a systematic review

Performance of novel antibodies for lipoarabinomannan to develop diagnostic tests for Mycobacterium tuberculosis

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