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Medical Sciences
Published on Aug 03, 2024DOI

Reviews of "Persistent Mycobacterium Tuberculosis Bioaerosol Release in a Tuberculosis-Endemic Setting"

Reviewers: N Mistry & K Sriraman & A Shaikh (The Foundation for Medical Research) | 📒📒📒 ◻️◻️ • C Roy (Tulane University) | 📒📒📒◻️◻️

by Nerges Mistry, Kalpana Sriraman, Ambreen Shaikh, and Chad Roy
Published onAug 03, 2024
Reviews of "Persistent Mycobacterium Tuberculosis Bioaerosol Release in a Tuberculosis-Endemic Setting"
key-enterThis Pub is a Review of
Persistent Mycobacterium tuberculosis bioaerosol release in a tuberculosis-endemic setting
Persistent Mycobacterium tuberculosis bioaerosol release in a tuberculosis-endemic setting
by Ryan Dinkele, Sophia Gessner, Benjamin Patterson, Andrea McKerry, Zeenat Hoosen, Andiswa Vazi, Ronnett Seldon, Anastasia Koch, Digby F. Warner, and Robin Wood
  • Published on Apr 03, 2024
  • www.medrxiv.org
Description

Abstract Pioneering studies linking symptomatic disease and cough-mediated release of Mycobacterium tuberculosis (Mtb) established the infectious origin of tuberculosis (TB), simultaneously informing the pervasive notion that pathology is a prerequisite for Mtb transmission. Our prior work has challenged this assumption: by sampling TB clinic attendees, we detected equivalent release of Mtb-containing bioaerosols by confirmed TB patients and individuals not receiving a TB diagnosis, and we demonstrated a time-dependent reduction in Mtb bioaerosol positivity during six-months’ follow-up, irrespective of anti-TB chemotherapy. Now, by extending bioaerosol sampling to a randomly selected community cohort, we show that Mtb release is common in a TB-endemic setting: of 89 participants, 79.8% (71/89) produced Mtb bioaerosols independently of QuantiFERON-TB Gold status, a standard test for Mtb infection; moreover, during two-months’ longitudinal sampling, only 2% (1/50) were serially Mtb bioaerosol negative. These results necessitate a reframing of the prevailing paradigm of Mtb transmission and infection, and may explain the current inability to elucidate Mtb transmission networks in TB-endemic regions.Summary Elucidating chains of Mycobacterium tuberculosis transmission is limited by a dependence on linking sputum-positive tuberculosis cases. Here, we report persistent M. tuberculosis bioaerosol release in the majority of a randomly selected community cohort. The contribution to tuberculosis transmission is unknown.

To read the original manuscript, click the link above.

Summary of Reviews: The study measures bioaerosol release from community members of a high TB area and found that upwards of 80% of the study participants continue to breathe out Mycobacterium tuberculosis (Mtb) months after no longer considered pathologic. Despite the interesting findings, the reviewers found several significant limitations, including but not limited to potentially overestimated aerosol sampling, questionable specificity of staining technique, and lack of follow up GeneXpert testing. In addition, they agree that the study challenges existing knowledge of TB transmission but needs to address the limitations before its findings can be considered robust and accepted.

Reviewer 1 (Nerges M… & Kalpana S… & Ambreen S…) | 📒📒📒 ◻️◻️

Reviewer 2 (Chad R…) | 📒📒📒 ◻️◻️

RR:C19 Strength of Evidence Scale Key

📕 ◻️◻️◻️◻️ = Misleading

📙📙 ◻️◻️◻️ = Not Informative

📒📒📒 ◻️◻️ = Potentially Informative

📗📗📗📗◻️ = Reliable

📘📘📘📘📘 = Strong

To read the reviews, click the links below. 

Connections
1 of 2
A Supplement to this Pub
Review 1: "Persistent Mycobacterium Tuberculosis Bioaerosol Release in a Tuberculosis-Endemic Setting"
Review 1: "Persistent Mycobacterium Tuberculosis Bioaerosol Release in a Tuberculosis-Endemic Setting"
by Nerges Mistry, Kalpana Sriraman, and Ambreen Shaikh
  • Published on Aug 03, 2024
  • rrid.mitpress.mit.edu
Description

Reviewers agree that the study challenges existing knowledge of TB transmission but needs to address the limitations before its findings can be considered robust and accepted.

A Supplement to this Pub
Review 2: "Persistent Mycobacterium Tuberculosis Bioaerosol Release in a Tuberculosis-Endemic Setting"
Review 2: "Persistent Mycobacterium Tuberculosis Bioaerosol Release in a Tuberculosis-Endemic Setting"
by Chad Roy
  • Published on Aug 03, 2024
  • rrid.mitpress.mit.edu
Description

Reviewers agree that the study challenges existing knowledge of TB transmission but needs to address the limitations before its findings can be considered robust and accepted.

License
Creative Commons Attribution 4.0 International License (CC-BY 4.0)
Comments
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Ryan Dinkele:

We thank the reviewers for their considered appraisals of our preprint. Below, we have attempted to respond to the salient concerns and critiques and have tried to clarify key misconceptions. At the outset, however, we should point out that many of the issues raised have been addressed in a revised version of this manuscript which was recently accepted for publication in iScience (doi:10.1016/j.isci.2024.110731).

In this work, we sought to elucidate the prevalence of Mycobacterium tuberculosis (Mtb) bioaerosol release in a tuberculosis (TB)-endemic community by applying a previously published bioaerosol capture methodology (doi:10.1073/pnas.2314813121). The approach centers on the use of a custom-designed Respiratory Aerosol Sampling Chamber (RASC) located in a purpose-built bioaerosol sampling facility – the Aerobiology Research Centre (ARC) – that adjoins the study community in Masiphumelele, Cape Town, South Africa. This is important: the RASC is not located in a TB clinic but is deliberately situated in a facility (ARC) in which no other Mtb work is conducted. This is done to ensure limited potential for contamination.

As an additional control measure, an “empty RASC” sample is collected between every participant to enable rapid detection of potential carry-over/contamination events; this control sample is de-identified and processed together with participant samples in the same batch. In the work described in this manuscript, none of the “empty RASC” samples returned an Mtb-bioaerosol positive reading; therefore, it seems highly unlikely that contamination during sample collection or processing contributed to any of the reported results.

In establishing this methodology, we developed a stringent set of morphological criteria to ensure that only DMN-trehalose-positive bacilli falling within the specified length and width ranges would be considered putative Mtb (doi:10.1371/journal.ppat.1009262). While this approach inevitably eliminates bacilli that might exist in previously unobserved morphologies (i.e., increases the chance of false negative assignments), it reduces the possibility of false positives. In previous work, further evidence of the presence of Mtb was obtained via whole-genome sequencing of organisms cultured in vitro in liquid growth media following bioaerosol capture. Notably, Mtb sequence was detected in three separate bioaerosol samples, two of which originated from individuals diagnosed as not having TB (doi:10.1073/pnas.2314813121). Importantly, the WGS data confirmed that Mtb bacilli were present in the samples, that the bacilli were not lab contaminants, and that no NTMs (nor other bacteria that might assimilate the DMN-trehalose probe) were present. Therefore, while possible that some false positives occur, we suggest that this is unlikely to explain all our observations. Instead, the results indicate that the prevalence of Mtb bioaerosol release in this community is far more common than previously suspected.

Finally, we acknowledge that the contribution of asymptomatic Mtb transmission to prevalent TB remains unknown. That said, our finding that aerosolization of Mtb is common in TB-endemic settings, occurs independently of symptoms, and is not detectable by standard diagnostics appears consistent with recent results suggesting the de-linking of infectiousness from symptomatic disease (doi:10.1016/s1473-3099(24)00011-2). At the very least, these and related observations emphasize the need to re-evaluate prevailing dogma about Mtb transmission and disease risk.

Rapid Reviews Infectious Diseases
Rapid Reviews Infectious Diseases
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