Diagnostic accuracy of 3 urine lipoarabinomannan tuberculosis assays in HIV-negative outpatients

Abstract

BACKGROUND Inadequate tuberculosis (TB) diagnostics are a major hurdle in the reduction of disease burden, and accurate point-of-care tests (POCTs) are urgently needed. We assessed the diagnostic accuracy of Fujifilm SILVAMP TB lipoarabinomannan (FujiLAM) POCT for TB diagnosis in HIV-negative outpatients and compared it with Alere Determine TB LAM Ag (AlereLAM) POCT and a laboratory-based ultrasensitive electrochemiluminescence LAM research assay (EclLAM). METHODS In this multicenter diagnostic test accuracy study, we recruited HIV-negative adults with symptoms suggestive of pulmonary TB presenting to outpatient health care centers in Peru and South Africa. Urine samples were tested using FujiLAM, AlereLAM, and EclLAM, and the diagnostic accuracy was assessed against a microbiological reference standard (MRS) and a composite reference standard. RESULTS Three hundred seventy-two HIV-negative participants were included and the prevalence of microbiologically confirmed TB was 30%. Compared with the MRS, the sensitivities of AlereLAM, FujiLAM, and EclLAM were 10.8% (95% confidence interval [CI] 6.3%–18.0%), 53.2% (95% CI 43.9%–62.1%), and 66.7% (95% CI 57.5%–74.7%), respectively. The specificities of AlereLAM, FujiLAM, and EclLAM were 92.3% (95% CI 88.5%–95.0%), 98.9% (95% CI 96.7%–99.6%), and 98.1% (95% CI 95.6%–99.2%), respectively. Positive likelihood ratios of AlereLAM, FujiLAM, and EclLAM were 1.4, 46.2, and 34.8, respectively, and positive predictive values were 37.5%, 95.2%, and 93.7%, respectively. CONCLUSION Compared with AlereLAM, FujiLAM detected 5 times more patients with TB in HIV-negative participants, had a high positive predictive value, and has the potential to improve rapid diagnosis of TB at the point-of-care. EclLAM demonstrated that additional sensitivity gains are possible, which highlights LAM’s potential as a biomarker. Additional research is required to assess FujiLAM’s performance in prospective cohorts, its cost-effectiveness, and its impact in real-world clinical settings. FUNDING Global Health Innovative Technology Fund, the UK Department for International Development, the Dutch Ministry of Foreign Affairs, the Bill and Melinda Gates Foundation, the Australian Department of Foreign Affairs and Trade, the German Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, and the NIH and National Institute of Allergy and Infectious Diseases.

The potential impact of urine-LAM diagnostics on tuberculosis incidence and mortality: A modelling analysis

“…While much of the existing literature on LF-LAM addresses its diagnostic performance and implementation in defined clinical settings [ 9 , 10 , 12 , 14 ], our work complements this evidence basis by addressing the population level in countries with a high HIV and TB burden. To our knowledge, this is the first modelling study to examine the potential incidence and mortality impact that LF-LAM tests may offer.…”

“…For the performance of the former, we drew from a systematic review of LF-LAM [ 12 ]. For the latter, we took SILVAMP-LAM as an illustrative example, drawing from a recent study that estimated the performance of this test in HIV-negative patients [ 14 ]. This same study highlighted the potential of future LAM tests to have improved performance compared to SILVAMP-LAM: Our parameters for future LAM tests could therefore be interpreted as a lower bound for their performance [ 9 ] ( Table 4 ).…”

“…The technology continues to improve: A newly developed lateral flow test, Fujifilm SILVAMP TB LAM (‘SILVAMP-LAM’), has shown improved sensitivity for TB compared to LF-LAM, with comparable specificity [ 9 ]. Further, a recent study in programmatic conditions demonstrated the potential for SILVAMP-LAM to identify TB amongst HIV-negative patients, showing a sensitivity of approximately 50% in this population [ 14 ]. In the same study, the additional positivity from a laboratory-based LAM assay demonstrated the potential sensitivity gains for future LAM tests.…”

Diagnosing pulmonary tuberculosis using sequence-specific purification of urine cell-free DNA

“…Ongoing efforts aim to improve urine LAM detection sensitivity. The Fujifilm SILVAMP TB LAM test improves sensitivity relative to Alere LAM in both HIV-positive (70% vs. 42%) and HIV-negative (53% vs. 11%) individuals (38,39). As antigen-based tests, however, LAM assays may not be able to achieve the sensitivity afforded by nucleic acid amplification tests.…”

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

“…In this issue of the JCI, Broger and Nicol et al investigated a recently developed and more accurate urine LAM test (FujiLAM) for its sensitivity and specificity in active pulmonary TB. Importantly, the researchers restricted their analysis to ambulatory patients without HIV suspected of having TB in South Africa and Peru (16). In their population of 372 individuals with suspected pulmonary TB, the FujiLAM test demonstrated 53% sensitivity and 99% specificity when using sputum mycobacterial culture as the gold standard.…”