key: cord-0966210-mmupyh63 authors: Jefferson, T.; Pluddemann, A.; Spencer, E.; Brassey, J.; Rosca, C.; ONAKPOYA, I.; Heneghan, C.; Evans, D.; Conly, J. title: The evidence on transmission dynamics of COVID-19 from pre and asymptomatic cases: protocol for a systematic review date: 2021-05-08 journal: nan DOI: 10.1101/2021.05.06.21256615 sha: 7797662927b4ea1afc9abe12544f49b2c4f47812 doc_id: 966210 cord_uid: mmupyh63 Background The role of cases of SARS-CoV-2 who remain without symptoms throughout the active phase of the disease (asymptomatics) and those who have not developed symptoms yet when surveyed (pre-symptomatics) is at present unclear, despite the important role that they may play in infecting third parties. There is also a lack of clarity on the role of pauci-symptomatic persons with COVID-19 and the degree to which they may be associated with transmission compared to fully symptomatic persons. Methods We will search LitCovid, medRxiv, Google Scholar and the WHO Covid-19 database using Covid-19, SARS-CoV-2, transmission, and appropriate synonyms as search terms. We will also search the reference lists of included studies are searched for additional relevant studies. We will include studies of people exposed to SARS CoV-2 within 2-14 days (incubation time) of close contact or suspected community or institutional exposure to index asymptomatic infected individuals, as defined in each study with secondary case(s) infected. We will only include studies which provide microbiological proof of transmission outcome (culturable virus and /or genic sequencing). The inclusion of higher-quality evidence should overcome the methodological shortcomings of lower quality studies. We will assess quality of the chain of transmission evidence, microbiological proof and adequacy of follow up and symptom monitoring. Expected results We intend to present the evidence in three distinct packages: study description, methodological quality assessment and data extracted. We intend summarising the evidence and drawing conclusions COVID-19 is a new disease, distinct from other diseases caused by coronaviruses, such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The SARS-CoV-2 virus is more contagious and has spread more widely leading us into the current pandemic in which we find ourselves. The overarching aim of the WHO's Global Strategic Preparedness and Response Plan for COVID-19 is to prevent transmission of SARS-CoV-2 and prevent associated illness and death. However, transmission of the SARS-CoV-2 virus and the disease it causes is not completely understood, and public health measures for restricting transmission are based on limited data with relatively few high-quality systematic reviews on the transmission of the SARS-CoV-2 virus available. The role of cases who remain without symptoms throughout the active phase 1 2 (asymptomatics) and those who have not developed symptoms yet when surveyed (pre-symptomatics) is at present unclear, partly because of poor methodologies 3 employed in the studies. In addition there is a lack of clarity on the role of pauci-symptomatic persons with COVID-19 and the degree to which they may be associated with transmission compared to fully symptomatic persons. There is a need to conduct regularly updated systematic reviews with the latest knowledge to inform public health recommendations using the most up-to-date reliable and highest quality information. We have carried out reviews of airborne, orofecal, close contact and fomite transmission [4] [5] [6] [7] . Objectives: To provide a rapid summary and evaluation of relevant data on the transmission of SARS-CoV-2 from pre and asymptomatic individuals, report important policy implications, and highlight research gaps of highest priority. The following electronic databases will be searched: LitCovid, medRxiv, Google Scholar and the WHO Provides a broad search for scholarly literature across many disciplines and sources: articles, theses, books, abstracts and court opinions, from academic publishers, professional societies, online repositories, universities and other web sites. We will also search the bibliographies of retrieved systematic reviews 8 . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 8, 2021. ; https://doi.org/10.1101/2021.05.06.21256615 doi: medRxiv preprint Population: people exposed to SARS CoV-2 within 2-14 days (incubation time) of close contact or suspected community or institutional exposure to index asymptomatic infected individuals, as defined in the study. Reference: secondary case infected Target: level 3 / level 4 evidence with confirmed transmission outcome 9 . Level 3/4 evidence with confirmed transmission pertains to higher-quality evidence that overcomes the methodological shortcomings of lower quality studies. More certainty is provided by cell culture and observation of the effects of inoculation of respiratory and other relevant clinical specimens (level 3 evidence), and immunohistochemistry directed at specific viruses. Genome sequencing can assist in excluding co-infection and provides a high probability of the correct identification of the agent and can assess viral similarity between donor and recipient (level 4 evidence) 5 . If we do not identify any level 3/4 evidence, then the review will be expanded to include evidence that only provides quantitative PCR or antigen results (level 2 evidence) and if serial values have been obtained. Focussing on higher-quality evidence provides links in a chain that can reduce the uncertainties over transmission and increase confidence in establishing the degree to which asymptomatic and pre-symptomatic transmission are driving the spread of the pandemic 9 . We will include prospective or retrospective observational studies including case series and ecological designs or interventional including randomised trials and clinical reports, outbreak reports, case-control studies and experimental studies. Studies incorporating models to describe observed data are included. Studies reporting solely predictive modelling are excluded. There are no formal quality assessment and reporting criteria for transmission studies, a situation reminiscent of the early days of Evidence Based Medicine . Some authors have adapted observational checklists to assess quality 8 . However pre-existing tools and adaptations do not adequately account for the biases that might influence understanding of the chain of transmission and the need to obtain microbiological as well as clinical confirmation of transmission. This is even more important in the case of asymptomatic transmission. In addition, available gene sequencing technologies need to be harnessed appropriately to shed light on transmission and diminish the uncertainty on its likelihood by a certain means or in certain settings 9 . On the basis of our experience to date in reviewing transmission studies and establishing a hierarchical framework for assessing transmission causality, we will assess quality based on three items: 1) Was transmission documented; 2) Were viable replicating viruses and/or phylodynamics documented and 3) Was follow-up adequate. The rationale for our three points is explained here 5 . The following quality items will be assessed in duplicate as yes/no/unclear: 1a Was the chain of transmission adequately described and reported Demonstrable and replicable chain of transmission (Gwaltney's postulates 10 + 1 -replicability). • Viral growth at the proposed anatomic site of origin. The last item should be considered an ideal aim, as most transmission studies are one off and observational. However, the body of high-quality evidence should be compatible with the conclusions on mode of transmission. Outlying studies, those that reach different conclusions, should be assessed to ascertain reasons for diversity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 8, 2021. ; https://doi.org/10.1101/2021.05.06.21256615 doi: medRxiv preprint • A follow-up period is required to assess the presence or absence of symptoms. Inadequate follow-up may misclassify pre-symptomatic individuals 3 . -A discrete definition is required using a comprehensive list of symptoms and signs must be used and applied in each and every case with the use of ancillary data gathering for children, the elderly and those with cognitive impairment . -An assessment of other underlying reasons for the presence of symptoms and signs should be applied in all cases -A self-administered questionnaire would not be considered adequate unless corroborated by interview process in a certain percentage with adequate correlation A reassessment of symptoms and signs should be recorded by another interviewer in a proportion of the cases as a data quality check. Search yields will be screened in duplicate and included study data will be extracted into templates that include study characteristics and methodological quality of studies and a summary of the main findings. References will be included in alphabetical order as a web appendix that facilitates updating. We will follow PRISMA reporting guidelines as indicated for systematic or scoping reviews where applicable (PRISMA checklist) 13 . Data extraction will be performed by one author and independently checked by a second author. Where there is disagreement, a third author arbitrates. Outcomes of interest are listed in the inclusion criteria. We will summarise data narratively and report the outcomes as stated in the paper, including quantitative estimates where feasible and relevant. We will report the detection of a live culture of SARS-CoV-2 when reported (see also subgroups). Where possible, compatible datasets may be pooled for meta-analysis. We may write to authors for clarification of data, and also report research and policy implications. As important new data accumulates, we will produce a report as an individual rapid review and aim to make all our work available by depositing the review findings in an open access repository (e.g., the Oxford Research Archive). This work is at present unfunded. All authors contributed in equal part to the conceptualisation and development of the content. TJ and CH wrote the first draft. All authors contributed to the subsequent drafts and approved the final version. TJ was in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews (2015 to 2018). In 2014 to 2016, he was a member of three advisory boards for Boehringer Ingelheim. TJ was a member of an independent data monitoring committee for a . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 8, 2021. ; https://doi.org/10.1101/2021.05.06.21256615 doi: medRxiv preprint Sanofi Pasteur clinical trial on an influenza vaccine. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products for which he receives fees (current). TJ was a member of three advisory boards for Boehringer Ingelheim (2014 to 16). TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine (2015 to 2017). TJ is a relator in a False Claims Act lawsuit on behalf of the United States that involves sales of Tamiflu for pandemic stockpiling. If resolved in the United States favor, he would be entitled to a percentage of the recovery. CJH holds grant funding from the NIHR, the NIHR School of Primary Care Research, the NIHR BRC Oxford and the World Health Organization for a series of Living rapid review on the modes of transmission of SARs CoV 2 reference WHO registration No2020/1077093. He has received financial remuneration from an asbestos case and given legal advice on mesh and hormone pregnancy tests cases. He has received expenses and fees for his media work including occasional payments from BBC Radio 4 Inside Health and The Spectator. He receives expenses for teaching EBM and is also paid for his GP work in NHS out of hours (contract Oxford Health NHS Foundation Trust). He has also received income from the publication of a series of toolkit books and for appraising treatment recommendations in non NHS settings. He is Director of CEBM and is an NIHR Senior Investigator. DE holds grant funding from the Canadian Institutes for Health Research and Li Ka Shing Institute of Virology relating to the development of Covid 19 vaccines as well as the Canadian Natural Science and Engineering Research Council concerning Covid 19 aerosol transmission. He is a recipient of World Health Organization and Province of Alberta funding which supports the provision of BSL3 based SARS CoV 2 culture services to regional investigators. He also holds public and private sector contract funding relating to the development of poxvirus based Covid 19 vaccines, SARS CoV 2 inactivation technologies, and serum neutralization testing. JMC holds grants from the Canadian Institutes for Health Research on acute and primary care preparedness for COVID 19 in Alberta, Canada and was the primary local Investigator for a Staphylococcus aureus vaccine study funded by Pfizer for which all funding was provided only to the University of Calgary. He is a co investigator on a WHO funded study using integrated human factors and ethnography approaches to identify and scale innovative IPC guidance implementation supports in primary care with a focus on low resource settings and using drone aerial systems to deliver medical supplies and PPE to remote First Nations communities during the COVID 19 pandemic. He also received support from the Centers for Disease Control and Prevention (CDC) to attend an Infection Control Think Tank Meeting. He is a member of the WHO Infection Prevention and Control Research and Development Expert Group for COVID 19 and the WHO Health Emergencies Programme (WHE) Ad hoc COVID 19 IPC Guidance Development Group, both of which provide multidisciplinary advice to the WHO, for which no funding is received and from which no funding recommendations are made for any WHO contracts or grants. He is also a member of the Cochrane Acute Respiratory Infections Group. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 8, 2021. ; https://doi.org/10.1101/2021.05.06.21256615 doi: medRxiv preprint JB is a major shareholder in the Trip Database search engine (www.tripdatabase.com) as well as being an employee. In relation to this work Trip has worked with a large number of organisations over the years, none have any links with this work. The main current projects are with AXA and Collateral Global. IJO, EAS, and AP have no interests to disclose. No approval was necessary All data included in the review will be provided in the tables and text. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 8, 2021. ; https://doi.org/10.1101/2021.05.06.21256615 doi: medRxiv preprint Operational planning guidance to support country preparedness and response SARS-CoV-2, SARS-CoV-1 and MERS-CoV viral load dynamics, duration of viral shedding and infectiousness: a living systematic review and meta-analysis. medRxiv Towards an accurate and systematic characterisation of persistently asymptomatic infection with SARS-CoV-2. 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