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Review 1: "Urine lipoarabinomannan concentrations among HIV-uninfected adults with pulmonary or extrapulmonary tuberculosis disease in Vietnam"

Reviewers agree that the preprint's authors clearly present their results and acknowledge their limitations. The study’s larger sample size and cohort design confirms previously published work, primarily consisting of smaller, case-control studies.

Published onSep 19, 2023
Review 1: "Urine lipoarabinomannan concentrations among HIV-uninfected adults with pulmonary or extrapulmonary tuberculosis disease in Vietnam"
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Urine lipoarabinomannan concentrations among HIV-uninfected adults with pulmonary or extrapulmonary tuberculosis disease in Vietnam
Urine lipoarabinomannan concentrations among HIV-uninfected adults with pulmonary or extrapulmonary tuberculosis disease in Vietnam

Abstract Lipoarabinomannan (LAM) is a Mycobacterial cell wall glycolipid excreted in urine, and a target biomarker of rapid diagnostic tests (RDTs) for tuberculosis (TB) disease. Urine LAM (uLAM) testing by RDT has been approved for people living with HIV, but there is limited data regarding uLAM levels in HIV-negative adults with TB disease. We conducted a clinical study of adults presenting with TB-related symptoms at the National Lung Hospital in Hanoi, Vietnam. The uLAM concentrations were measured using electrochemiluminescent immunoassays and compared to a microbiological reference standard (MRS) of sputum, GeneXpert Ultra and TB culture. Additional microbiological testing was conducted for possible extrapulmonary TB, when clinically indicated. Among 745 participants enrolled, 335 (44.9 %) participants recruited from the pulmonary TB wards (PR-PTBW) and 6 (11.3%) participants recruited from the EPTB wards (PR-EPTBW) had confirmed TB disease. The MRS positive cohort measured median uLAM concentration for S4-20/A194-01 (S/A) were 14.5 pg/mL and 51.5 pg/mL, respectively. The FIND28/A194-01 (F/A) antibody pair overall and TB-positive cohort measured mean uLAM was 44.4 pg/mL and 78.1 pg/mL, respectively. Overall, the S/A antibody pair had a sensitivity of 39% (95% Confidence Interval [CI] 0.33, 0.44) and specificity of 97% (95% CI 0.96, 0.99) against the MRS. The F/A antibody pair had a sensitivity of 41% (95% CI 0.35, 0.47) and specificity of 79% (95% CI 0.75, 0.84). The areas under the receiver operating curves were 0.748 for S/A and 0.629 for F/A. There was little difference between the S/A median uLAM concentration with pulmonary (55 pg/mL) and extrapulmonary (36 pg/mL) TB disease. With F/A the medians for pulmonary and extrapulmonary TB disease were 79% and 76.5% respectively. Among HIV-negative adults in Vietnam, concentrations of uLAM remained relatively low for people with TB disease, which may present challenges for developing a more sensitive rapid uLAM test.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



The current study aimed to assess urine Lipoarabinomannan (uLAM) testing by the rapid diagnostic test in HIV-uninfected adult TB disease patients. The concentration of uLAM in the urine specimens was measured using highly sensitive electrochemiluminescent (ECL) immunoassays. The method used in this study seems to be complex, but researchers have used this approach earlier, and the respective references were cited in this study. The authors separately evaluated two different monoclonal capture antibodies, FIND28 and S4-20, that were biotinylated for both capture antibodies. The authors used the same recombinant detector antibody, A194-01, which was labeled with the GOLD SULFO-TAG NHS- Ester. The uLAM concentration in each specimen was calculated for both antibody pairs. The authors used the LOD established from each plate to score the test results and so afford greater accuracy, as opposed to earlier approaches of applying universal cutoff values. The study results showed reduced sensitivity in both S/A and F/A compared to the previously published study (PMID:32692731). However, the present study has double the sample size compared to the previously published studies. The study limitations portions were nicely covered. The present study included extra-pulmonary TB cases, which is a good aspect; however, the sample size is not large. The authors concluded that this study's results didn’t meet the TPP criteria for an effective diagnostic test for TB disease and suggested developing a better uLAM assay to diagnose the majority of people with TB disease may require novel antibodies. Nevertheless, developing non-sputum based RDTs to diagnose people with TB disease needs to remain a global health priority.

Figure 2 information is not clear. What do the curves demonstrate? What do green and pink curves represent? And why did the authors use Log10 concentration in the x-axis instead of pg/ml?

Other areas to consider:

  • The manuscript partially confirms the previous work with a larger sample size than previous studies.

  • The manuscript cited current literature and discussed the limitations.

  • The work is clearly presented, well-structured, and nicely written. The results are presented here for the key audiences.

  • The authors adequately discussed ethical concerns.

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