Searching for Strep A in the clinical environment during a human challenge trial: a sub-study protocol
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Introduction Streptococcus pyogenes (also known as Group A Streptococcus, Strep A) is an obligate human pathogen with significant global morbidity and mortality. Transmission is believed to occur primarily between individuals via respiratory droplets, however knowledge about other potential sources of transmission via aerosols or the environment is limited. Such knowledge is required to design optimal interventions to control transmission, particularly in endemic settings. We aimed to detail experimental methodology to assess the transmission potential of Strep A in a clinical environment. Materials and methods We will examine potential sources of transmission in up to 20 participants recruited to the Controlled human infection for penicillin against Streptococcus pyogenes (CHIPS) Trial. Three approaches to understanding transmission will be used: the use of selective agar settle plates to capture possible droplet or airborne spread of Strep A; measurement of the possible distance of Strep A droplet spread during conversation; and environmental swabbing of personal and common high-touch items to detect the presence of Strep A on hard and soft surfaces. All methods are designed to allow for an assessment of transmission potential by symptomatic, asymptomatic, and non-cases. Ethical approval has been obtained through Bellberry Human Research Ethics Committee (Approval 2021-03-295). Trial Registration number: ACTRN12621000751875. Discussion Any results elicited from these experiments will be of benefit to the scientific literature in improving our knowledge of opportunities to prevent Strep A transmission as a direct component of the primordial prevention of rheumatic fever. Findings will be reported at local, national, and international conferences and in peer-reviewed journals.
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Thank you for sufficiently addressing all reviewer comments. We welcome your revised submission for publication in Access Microbiology.
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Comments to Author
The authors outline a sub-study of the CHIPS study (ACTRN12621000751875). Briefly, the CHIPS study involves randomizing patients to six treatments (including placebo) of PCN prior to direct oropharyngeal challenge with Group A Strep (GAS). Notably, this research study will be conducted in a purpose built research facility resembling a hospital ward. 24h and 48h post challenge, the sub-study will examine the droplet/aerosolization of GAS by having subjects speak for 1 minute and collect agar plates at 30cm, 90cm and 180cm, also by agar plates 2m above the floor, and swabs of five high touch surfaces. 1. Methodological rigour, reproducibility and availability of underlying data The CHIPS study is an important randomized trial that is novel and likely to advance knowledge of GAS. The CHIPS study has …
Comments to Author
The authors outline a sub-study of the CHIPS study (ACTRN12621000751875). Briefly, the CHIPS study involves randomizing patients to six treatments (including placebo) of PCN prior to direct oropharyngeal challenge with Group A Strep (GAS). Notably, this research study will be conducted in a purpose built research facility resembling a hospital ward. 24h and 48h post challenge, the sub-study will examine the droplet/aerosolization of GAS by having subjects speak for 1 minute and collect agar plates at 30cm, 90cm and 180cm, also by agar plates 2m above the floor, and swabs of five high touch surfaces. 1. Methodological rigour, reproducibility and availability of underlying data The CHIPS study is an important randomized trial that is novel and likely to advance knowledge of GAS. The CHIPS study has many strong strengths (and likely very expensive), including randomizing subjects, direct challenge, and purpose built facility with monitoring for 6 days. The sub-study methods discussed in this manuscript also add additional data, including examining GAS in large droplet, small droplet, aerosol, and surfaces. Additional references for the distances (30cm, 90cm, 180cm), and durations of collection are welcomed. This reviewer also suggests that the discussions section expand on limitations of the study. One of the key components of the sub-study is examining aerosols as a mechanism of transmission; more discussion should be focused on this aspect, including alternative methods for detecting aerosolized bacteria (eg SKC BioSampler - see [1]). Also, aerosolized particles can persist in the environment (ie hospital room) and is affected by engineering factors, such as airflow (eg laminar) and the air exchange rate; these important factors are not discussed. Also, the authors need to carefully minimize the risk of cross contamination of subjects, both within room (eg if subjects sequentially use the same room) and between rooms (if multiple rooms are simultaneously used); this is not sufficiently discussed or addressed in the methods or discussion. [1] Li J, Leavey A, Wang Y, O'Neil C, Wallace MA, Burnham CD, Boon AC, Babcock H, Biswas P. Comparing the performance of 3 bioaerosol samplers for influenza virus. J Aerosol Sci. 2018 Jan;115:133-145. doi: 10.1016/j.jaerosci.2017.08.007. Epub 2017 Aug 24. PMID: 32287370; PMCID: PMC7125700. 2. Presentation of results - N/A; this is a methods paper. 3. How the style and organization of the paper communicates and represents key findings - Line 83 & 84: consider revising "sore throat" to "acute pharyngitis" 4. Literature analysis or discussion - Additional references regarding the methods selected is welcomed. 5. Any other relevant comments
Please rate the manuscript for methodological rigour
Satisfactory
Please rate the quality of the presentation and structure of the manuscript
Very good
To what extent are the conclusions supported by the data?
Not at all
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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The reviewers have highlighted minor concerns with the work presented. Please ensure that you address their comments.
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Comments to Author
1. Methodological rigour, reproducibility and availability of underlying data As this a is a pre-trial project publication, there is no availability of the underlying data. The overall experimental design is well detailed, though there are minor points for improvement. Minor Points -There was no mention of eliminating participants if they are positive for GAS prior to bacterial challenge. This appears to be an important consideration for potential participant exclusion. -Lines 188-190- is there a time limit for the duration the swabs can be kept at in the onsite fridge prior to transport to the lab for culture? Might consider have a time cutoff for this (i.e. within 12 hours) such that variation in swab storage times does not contribute as a major variable. -Line 201- is there a rationale for why …
Comments to Author
1. Methodological rigour, reproducibility and availability of underlying data As this a is a pre-trial project publication, there is no availability of the underlying data. The overall experimental design is well detailed, though there are minor points for improvement. Minor Points -There was no mention of eliminating participants if they are positive for GAS prior to bacterial challenge. This appears to be an important consideration for potential participant exclusion. -Lines 188-190- is there a time limit for the duration the swabs can be kept at in the onsite fridge prior to transport to the lab for culture? Might consider have a time cutoff for this (i.e. within 12 hours) such that variation in swab storage times does not contribute as a major variable. -Line 201- is there a rationale for why GAS can not be quantitated? I would think colony counts would at least be possible or qRT-PCR from the swabs? Or is there a technical barrier that does not make this feasible? -Line 209 - typically for a pre-trial project publication the statistical analysis being utilized is more detailed than what is presented here. Are there additional statistical analysis that the authors plan to incorporate into the study? 2. Presentation of results Not applicable (no results). Figures are concise and easy to interpret. 3. How the style and organization of the paper communicates and represents key findings Overall manuscript was concise and well written. Minor- typo on line 66. 4. Literature analysis or discussion Good discussion of previous work. Lines 218- it would be worth expanding this statement to include the key conclusions from the original transmission studies. 5. Any other relevant comments None noted.
Please rate the manuscript for methodological rigour
Good
Please rate the quality of the presentation and structure of the manuscript
Very good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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