Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: Update of a living systematic review and meta-analysis.

BACKGROUND: Debate about the level of asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection continues. The amount of evidence is increasing and study designs have changed over time. We updated a living systematic review to address 3 questions: (1) Among people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? (2) What is the infectiousness of asymptomatic and presymptomatic, compared with symptomatic, SARS-CoV-2 infection? (3) What proportion of SARS-CoV-2 transmission in a population is accounted for by people who are asymptomatic or presymptomatic? METHODS AND FINDINGS: The protocol was first published on 1 April 2020 and last updated on 18 June 2021. We searched PubMed, Embase, bioRxiv, and medRxiv, aggregated in a database of SARS-CoV-2 literature, most recently on 6 July 2021. Studies of people with PCR-diagnosed SARS-CoV-2, which documented symptom status at the beginning and end of follow-up, or mathematical modelling studies were included. Studies restricted to people already diagnosed, of single individuals or families, or without sufficient follow-up were excluded. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with a bespoke checklist and modelling studies with a published checklist. All data syntheses were done using random effects models. Review question (1): We included 130 studies. Heterogeneity was high so we did not estimate a mean proportion of asymptomatic infections overall (interquartile range (IQR) 14% to 50%, prediction interval 2% to 90%), or in 84 studies based on screening of defined populations (IQR 20% to 65%, prediction interval 4% to 94%). In 46 studies based on contact or outbreak investigations, the summary proportion asymptomatic was 19% (95% confidence interval (CI) 15% to 25%, prediction interval 2% to 70%). (2) The secondary attack rate in contacts of people with asymptomatic infection compared with symptomatic infection was 0.32 (95% CI 0.16 to 0.64, prediction interval 0.11 to 0.95, 8 studies). (3) In 13 modelling studies fit to data, the proportion of all SARS-CoV-2 transmission from presymptomatic individuals was higher than from asymptomatic individuals. Limitations of the evidence include high heterogeneity and high risks of selection and information bias in studies that were not designed to measure persistently asymptomatic infection, and limited information about variants of concern or in people who have been vaccinated. CONCLUSIONS: Based on studies published up to July 2021, most SARS-CoV-2 infections were not persistently asymptomatic, and asymptomatic infections were less infectious than symptomatic infections. Summary estimates from meta-analysis may be misleading when variability between studies is extreme and prediction intervals should be presented. Future studies should determine the asymptomatic proportion of SARS-CoV-2 infections caused by variants of concern and in people with immunity following vaccination or previous infection. Without prospective longitudinal studies with methods that minimise selection and measurement biases, further updates with the study types included in this living systematic review are unlikely to be able to provide a reliable summary estimate of the proportion of asymptomatic infections caused by SARS-CoV-2. REVIEW PROTOCOL: Open Science Framework (https://osf.io/9ewys/).

Recommendations for SARS-CoV-2/COVID-19 testing: a scoping review of current guidance.

BACKGROUND: Testing used in screening, diagnosis and follow-up of COVID-19 has been a subject of debate. Several organisations have developed formal advice about testing for COVID-19 to assist in the control of the disease. We collated, delineated and appraised current worldwide recommendations about the role and applications of tests to control SARS-CoV-2/COVID-19. METHODS: We searched for documents providing recommendations for COVID-19 testing in PubMed, EMBASE, LILACS, the Coronavirus Open Access Project living evidence database and relevant websites such as TRIP database, ECRI Guidelines Trust, the GIN database, from inception to 21 September 2020. Two reviewers applied the eligibility criteria to potentially relevant citations without language or geographical restrictions. We extracted data in duplicate, including assessment of methodological quality using the Appraisal of Guidelines for Research and Evaluation-II tool. RESULTS: We included 47 relevant documents and 327 recommendations about testing. Regarding the quality of the documents, we found that the domains with the lowest scores were 'Editorial independence' (Median=4%) and 'Applicability' (Median=6%). Only six documents obtained at least 50% score for the 'Rigour of development' domain. An important number of recommendations focused on the diagnosis of suspected cases (48%) and deisolation measures (11%). The most frequently recommended test was the reverse transcription-PCR (RT-PCR) assay (87 recommendations) and the chest CT (38 recommendations). There were 22 areas of agreement among guidance developers, including the use of RT-PCR for SARS-Cov-2 confirmation, the limited role of bronchoscopy, the use chest CT and chest X-rays for grading severity and the co-assessment for other respiratory pathogens. CONCLUSION: This first scoping review of recommendations for COVID-19 testing showed many limitations in the methodological quality of included guidance documents that could affect the confidence of clinicians in their implementation. Future guidance documents should incorporate a minimum set of key methodological characteristics to enhance their applicability for decision making.

False-negative results of initial RT-PCR assays for COVID-19: A systematic review.

BACKGROUND: A false-negative case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is defined as a person with suspected infection and an initial negative result by reverse transcription-polymerase chain reaction (RT-PCR) test, with a positive result on a subsequent test. False-negative cases have important implications for isolation and risk of transmission of infected people and for the management of coronavirus disease 2019 (COVID-19). We aimed to review and critically appraise evidence about the rate of RT-PCR false-negatives at initial testing for COVID-19. METHODS: We searched MEDLINE, EMBASE, LILACS, as well as COVID-19 repositories, including the EPPI-Centre living systematic map of evidence about COVID-19 and the Coronavirus Open Access Project living evidence database. Two authors independently screened and selected studies according to the eligibility criteria and collected data from the included studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We calculated the proportion of false-negative test results using a multilevel mixed-effect logistic regression model. The certainty of the evidence about false-negative cases was rated using the GRADE approach for tests and strategies. All information in this article is current up to July 17, 2020. RESULTS: We included 34 studies enrolling 12,057 COVID-19 confirmed cases. All studies were affected by several risks of bias and applicability concerns. The pooled estimate of false-negative proportion was highly affected by unexplained heterogeneity (tau-squared = 1.39; 90% prediction interval from 0.02 to 0.54). The certainty of the evidence was judged as very low due to the risk of bias, indirectness, and inconsistency issues. CONCLUSIONS: There is substantial and largely unexplained heterogeneity in the proportion of false-negative RT-PCR results. The collected evidence has several limitations, including risk of bias issues, high heterogeneity, and concerns about its applicability. Nonetheless, our findings reinforce the need for repeated testing in patients with suspicion of SARS-Cov-2 infection given that up to 54% of COVID-19 patients may have an initial false-negative RT-PCR (very low certainty of evidence). SYSTEMATIC REVIEW REGISTRATION: Protocol available on the OSF website: https://tinyurl.com/vvbgqya.

Current methods for development of rapid reviews about diagnostic tests: an international survey.

BACKGROUND: Rapid reviews (RRs) have emerged as an efficient alternative to time-consuming systematic reviews-they can help meet the demand for accelerated evidence synthesis to inform decision-making in healthcare. The synthesis of diagnostic evidence has important methodological challenges. Here, we performed an international survey to identify the current practice of producing RRs for diagnostic tests. METHODS: We developed and administered an online survey inviting institutions that perform RRs of diagnostic tests from all over the world. RESULTS: All participants (N = 25) reported the implementation of one or more methods to define the scope of the RR; however, only one strategy (defining a structured question) was used by ≥90% of participants. All participants used at least one methodological shortcut including the use of a previous review as a starting point (92%) and the use of limits on the search (96%). Parallelization and automation of review tasks were not extensively used (48 and 20%, respectively). CONCLUSION: Our survey indicates a greater use of shortcuts and limits for conducting diagnostic test RRs versus the results of a recent scoping review analyzing published RRs. Several shortcuts are used without knowing how their implementation affects the results of the evidence synthesis in the setting of diagnostic test reviews. Thus, a structured evaluation of the challenges and implications of the adoption of these RR methods is warranted.