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Review 1: "Tongue Swab Testing on Two Automated Tuberculosis Diagnostic Platforms, Cepheid Xpert® MTB/RIF Ultra and Molbio Truenat® MTB Ultima"

The reviewers found the methods rigorous, and with conclusions and interpretations supported by their results. Reviewers did comment that additional detail in describing their methods, such as by following established guidelines, would offer additional clarity.

Published onNov 14, 2023
Review 1: "Tongue Swab Testing on Two Automated Tuberculosis Diagnostic Platforms, Cepheid Xpert® MTB/RIF Ultra and Molbio Truenat® MTB Ultima"
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key-enterThis Pub is a Review of
Tongue swab testing on two automated tuberculosis diagnostic platforms, Cepheid Xpert® MTB/RIF Ultra and Molbio Truenat® MTB Ultima
Tongue swab testing on two automated tuberculosis diagnostic platforms, Cepheid Xpert® MTB/RIF Ultra and Molbio Truenat® MTB Ultima
Description

ABSTRACT Tongue dorsum swabbing is a potential alternative to sputum collection for tuberculosis (TB) testing. Previous studies showed that Cepheid Xpert® MTB/RIF Ultra (Xpert Ultra) can detect Mycobacterium tuberculosis (MTB) DNA in tongue swabs stored in buffer, with 72% sensitivity and 100% specificity relative to a sputum microbiological reference standard (sputum MRS). The present study evaluated a more convenient sample collection protocol (dry swab storage), combined with streamlined sample processing protocols, for side-by-side analysis using two commercial TB diagnostic tests: Xpert Ultra and Molbio Truenat® MTB Ultima (MTB Ultima). Copan FLOQSwabs were self-collected, or collected by study workers, from 321 participants in Western Cape, South Africa. All participants had symptoms suggestive of TB, and 245 of them had sputum MRS-confirmed TB (by sputum culture and/or Xpert Ultra). One tongue swab per participant was tested on Xpert Ultra and another tongue swab was tested with MTB Ultima. Xpert Ultra was 75.4% sensitive and 100% specific, and MTB Ultima was 71.6% sensitive and 96.9% specific, relative to sputum MRS. When sample lysates that were false-negative by MTB Ultima were frozen, thawed, and re-tested, MTB Ultima sensitivity rose to 79.1%. Both tests were more sensitive with swabs from participants with higher sputum Xpert semi-quantitative results. The protocol for Xpert Ultra enabled fast and easy testing of dry-stored swabs with no loss of accuracy relative to previous methods. MTB Ultima testing of dry-stored swabs exhibited comparable performance to Xpert Ultra. These results further support tongue swabs as easy-to-collect samples for high-throughput TB testing.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: 

The authors of this manuscript present evidence to support use of dry tongue swabs as diagnostic specimen for the detection of tuberculosis. In this study sensitivity/ specificity for testing using tongue swabs was 75.4%/100% for Cepheid Xpert® MTB/RIF Ultra and 71.6%/96.9% for Molbio Truenat® MTB Ultima. The study also streamlined a protocol which reduced sample processing time to 15mins for Xpert Ultra with a low (1%) error rate. 

This is a very well conducted study evaluating tongue swabs as alternatives to sputum for tuberculosis testing. Cepheid Xpert® MTB/RIF Ultra and Molbio Truenat® MTB Ultima were evaluated as tools to detect MTB in tongue swabs. 
As emphasis on easy to collect samples and in particular role of dry tongue swabs for diagnosis of TB increases, the findings of this study reporting sensitivities of over 75% (for Xpert Ultra), and 72% (79% on re-testing) for MTB Ultima become critical in moving forward with this approach.

A few clarifications are requested below:

  • Methods section: Line 91 states that sampling was split into “3 cases”. Case 1 is described as swabs collected prior to eating/drinking or performing oral hygiene. What then were cases 2 and 3? Do the authors mean cohorts?

  • Both cohort 1 and cohort 2 samples were from MRS confirmed TB patients and were collected prior to eating/drinking or performing oral hygiene. As such the difference between cohort 1 and 2 requires clarity. Currently it appears to be linked only to the number of swabs collected; Cohort 1 (6 swabs collected on day 1) versus Cohort 2 (5 swabs on day 1, and 2 swabs “self-collected” under supervision on day 2).

  • The day 2 sample swabs were “self-collected” by participants at their homes. Clarity is required as to whether these were “self-collected swabs” under study worker supervision.

  • Line 124 states that the post collection swabs were stored at -80 °C. Presumably -80oC storage was linked to sample shipment and will not be required as part of routine testing. For purposes of routine use and field applicability, that clarification would be useful to make.

  • Results section: Line 215 referring to Table 2, states that for MTB Ultima analysis of 225 swab samples from participants with confirmed TB identified; 161 swabs were true-positive relative to sputum MRS, and that 60 were false-negative… Should this be 64 (161/225) false negatives?

  • Repeat testing of “false negatives” was limited to MTB Ultima. Could the authors add why the 31 Xpert Ultra false negatives were not re-tested as well. 

To date diagnosis of pulmonary tuberculosis has relied on sputum as a diagnostic specimen. However, sputum may be difficult to produce, especially in children. This study using tongue swabs (that are fast and easy to collect) combined with commercially available rapid diagnostic tests shows great promise not only towards increasing access to TB testing, but also towards reducing occupational risks to healthcare workers.

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Comments
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Jerry Cangelosi:

Dear Dr. Hasan,

Thank you for these thoughtful comments. Many of them were echoed by reviewers of our peer-reviewed version, which is currently in revision.

Jerry Cangelosi