Transmission of SARS-CoV-2 Associated with Cruise Ship Travel: A Systematic Review.

Background: Maritime and river travel may be associated with respiratory viral spread via infected passengers and/or crew and potentially through other transmission routes. The transmission models of SARS-CoV-2 associated with cruise ship travel are based on transmission dynamics of other respiratory viruses. We aimed to provide a summary and evaluation of relevant data on SARS-CoV-2 transmission aboard cruise ships, report policy implications, and highlight research gaps. Methods: We searched four electronic databases (up to 26 May 2022) and included studies on SARS-CoV-2 transmission aboard cruise ships. The quality of the studies was assessed based on five criteria, and relevant findings were reported. Results: We included 23 papers on onboard SARS-CoV-2 transmission (with 15 reports on different aspects of the outbreak on Diamond Princess and nine reports on other international cruises), 2 environmental studies, and 1 systematic review. Three articles presented data on both international cruises and the Diamond Princess. The quality of evidence from most studies was low to very low. Index case definitions were heterogeneous. The proportion of traced contacts ranged from 0.19 to 100%. Studies that followed up >80% of passengers and crew reported attack rates (AR) up to 59%. The presence of a distinct dose−response relationship was demonstrated by findings of increased ARs in multi-person cabins. Two studies performed viral cultures with eight positive results. Genomic sequencing and phylogenetic analyses were performed in individuals from three cruises. Two environmental studies reported PCR-positive samples (cycle threshold range 26.21−39.00). In one study, no infectious virus was isolated from any of the 76 environmental samples. Conclusion: Our review suggests that crowding and multiple persons per cabin were associated with an increased risk of transmission on cruise ships. Variations in design, methodology, and case ascertainment limit comparisons across studies and quantification of transmission risk. Standardized guidelines for conducting and reporting studies on cruise ships of acute respiratory infection transmission should be developed.

A Hierarchical Framework for Assessing Transmission Causality of Respiratory Viruses.

Systematic reviews of 591 primary studies of the modes of transmission for SARS-CoV-2 show significant methodological shortcomings and heterogeneity in the design, conduct, testing, and reporting of SARS-CoV-2 transmission. While this is partly understandable at the outset of a pandemic, evidence rules of proof for assessing the transmission of this virus are needed for present and future pandemics of viral respiratory pathogens. We review the history of causality assessment related to microbial etiologies with a focus on respiratory viruses and suggest a hierarchy of evidence to integrate clinical, epidemiologic, molecular, and laboratory perspectives on transmission. The hierarchy, if applied to future studies, should narrow the uncertainty over the twin concepts of causality and transmission of human respiratory viruses. We attempt to address the translational gap between the current research evidence and the assessment of causality in the transmission of respiratory viruses with a focus on SARS-CoV-2. Experimentation, consistency, and independent replication of research alongside our proposed framework provide a chain of evidence that can reduce the uncertainty over the transmission of respiratory viruses and increase the level of confidence in specific modes of transmission, informing the measures that should be undertaken to prevent transmission.

Transmission of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) from pre and asymptomatic infected individuals: a systematic review.

BACKGROUND: The role of SARS-Cov-2-infected persons who develop symptoms after testing (presymptomatics) or not at all (asymptomatics) in the pandemic spread is unknown. OBJECTIVES: To determine infectiousness and probable contribution of asymptomatic persons (at the time of testing) to pandemic SARS-CoV-2 spread. DATA SOURCES: LitCovid, medRxiv, Google Scholar, and WHO Covid-19 databases (to 31 March 2021) and references in included studies. STUDY ELIGIBILITY CRITERIA: Studies with a proven or hypothesized transmission chain based either on serial PCR cycle threshold readings and/or viral culture and/or gene sequencing, with adequate follow-up. PARTICIPANTS: People exposed to SARS-CoV-2 within 2-14 days to index asymptomatic (at time of observation) infected individuals. INTERVENTIONS: Reliability of symptom and signs was assessed within contemporary knowledge; transmission likelihood was assessed using adapted causality criteria. METHODS: Systematic review. We contacted all included studies' corresponding authors requesting further details. RESULTS: We included 18 studies from a diverse setting with substantial methodological variation (this field lacks standardized methodology). At initial testing, prevalence of asymptomatic cases was 12.5-100%. Of these, 6-100% were later determined to be presymptomatic, this proportion varying according to setting, methods of case ascertainment and population. Nursing/care home facilities reported high rates of presymptomatic: 50-100% (n = 3 studies). Fourteen studies were classified as high risk of, and four studies as at moderate risk of symptom ascertainment bias. High-risk studies may be less likely to distinguish between presymptomatic and asymptomatic cases. Six asymptomatic studies and four presymptomatic studies reported culturing infectious virus; data were too sparse to determine infectiousness duration. Three studies provided evidence of possible and three of probable/likely asymptomatic transmission; five studies provided possible and two probable/likely presymptomatic SARS-CoV-2 transmission. CONCLUSION: High-quality studies provide probable evidence of SARS-CoV-2 transmission from presymptomatic and asymptomatic individuals, with highly variable estimated transmission rates.

Transmission of SARS-CoV-2 associated with aircraft travel: a systematic review.

RATIONALE FOR THE REVIEW: Air travel may be associated with viruses spread via infected passengers and potentially through in-flight transmission. Given the novelty of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, transmission associated with air travel is based on transmission dynamics of other respiratory viruses. Our objective was to provide a rapid summary and evaluation of relevant data on SARS-CoV-2 transmission aboard aircraft, report policy implications and to highlight research gaps requiring urgent attention. METHODS: We searched four electronic databases (1 February 2020-27 January 2021) and included studies on SARS-CoV-2 transmission aboard aircraft. We assessed study quality based on five criteria and reported important findings. KEY FINDINGS: We included 18 studies on in-flight SARS-CoV-2 transmission (130 unique flights) and 2 studies on wastewater from aircraft. The quality of evidence from most published studies was low. Two wastewater studies reported PCR-positive samples with high cycle threshold values (33-39). Index case definition was heterogeneous across studies. The proportion of contacts traced ranged from 0.68 to 100%. Authors traced 2800/19 729 passengers, 140/180 crew members and 8/8 medical staff. Altogether, 273 index cases were reported, with 64 secondary cases. Three studies, each investigating one flight, reported no secondary cases. Secondary attack rate among studies following up >80% of passengers and crew (including data on 10 flights) varied between 0 and 8.2%. The studies reported on the possibility of SARS-CoV-2 transmission from asymptomatic, pre-symptomatic and symptomatic individuals. Two studies performed viral cultures with 10 positive results. Genomic sequencing and phylogenetic analysis were performed in individuals from four flights. CONCLUSION: Current evidence suggests SARS-CoV-2 can be transmitted during aircraft travel, but published data do not permit any conclusive assessment of likelihood and extent. The variation in design and methodology restricts the comparison of findings across studies. Standardized guidelines for conducting and reporting future studies of transmission on aircraft should be developed.

SARS-CoV-2 and the role of fomite transmission: a systematic review.

Background: SARS-CoV-2 RNA has been detected in fomites which suggests the virus could be transmitted via inanimate objects. However, there is uncertainty about the mechanistic pathway for such transmissions. Our objective was to identify, appraise and summarise the evidence from primary studies and systematic reviews assessing the role of fomites in transmission.  Methods: This review is part of an Open Evidence Review on Transmission Dynamics of SARS-CoV-2. We conduct ongoing searches using WHO Covid-19 Database, LitCovid, medRxiv, and Google Scholar; assess study quality based on five criteria and report important findings on an ongoing basis. Results: We found 64 studies: 63 primary studies and one systematic review (n=35). The settings for primary studies were predominantly in hospitals (69.8%) including general wards, ICU and SARS-CoV-2 isolation wards. There were variations in the study designs including timing of sample collection, hygiene procedures, ventilation settings and cycle threshold. The overall quality of reporting was low to moderate. The frequency of positive SARS-CoV-2 tests across 51 studies (using RT-PCR) ranged from 0.5% to 75%. Cycle threshold values ranged from 20.8 to 44.1. Viral concentrations were reported in 17 studies; however, discrepancies in the methods for estimation prevented comparison. Eleven studies (17.5%) attempted viral culture, but none found a cytopathic effect. Results of the systematic review showed that healthcare settings were most frequently tested (25/35, 71.4%), but laboratories reported the highest frequency of contaminated surfaces (20.5%, 17/83).  Conclusions: The majority of studies report identification of SARS-CoV-2 RNA on inanimate surfaces; however, there is a lack of evidence demonstrating the recovery of viable virus. Lack of positive viral cultures suggests that the risk of transmission of SARS-CoV-2 through fomites is low. Heterogeneity in study designs and methodology prevents comparisons of findings across studies. Standardized guidelines for conducting and reporting research on fomite transmission is warranted.

SARS-CoV-2 and the role of orofecal transmission: a systematic review.

BACKGROUND: Modes of transmission of SARS-CoV-2 are of key public health importance. SARS-CoV-2 has been detected in the feces of some COVID-19 patients, suggesting the possibility that the virus could, in addition to droplet and fomite transmission, be transmitted via the orofecal route. METHODS: This review is part of an Open Evidence Review on Transmission Dynamics of COVID-19. We conduct ongoing searches using WHO COVID-19 Database, LitCovid, medRxiv, and Google Scholar; assess study quality based on five criteria and report important findings. Where necessary, authors are contacted for further details on the content of their articles. RESULTS: We include searches up until 20 December 2020. We included 110 relevant studies: 76 primary observational studies or reports, and 35 reviews (one cohort study also included a review) examining the potential role of orofecal transmission of SARS-CoV-2. Of the observational studies, 37 were done in China. A total of 48 studies (n=9,081 patients) reported single cases, case series or cohort data on individuals with COVID-19 diagnosis or their contacts and 46 (96%) detected binary RT-PCR with 535 out of 1358 samples positive for SARS-CoV-2 (average 39.4%). The results suggest a long duration of fecal shedding, often recorded after respiratory samples tested negative, and symptoms of gastrointestinal disease were reported in several studies. Twenty-nine studies reported finding SARS-CoV-2 RNA in wastewater, river water or toilet areas. Six studies attempted viral culture from COVID-19 patients' fecal samples: culture was successful in 3 of 6 studies, and one study demonstrated invasion of the virus into intestinal epithelial cells. CONCLUSIONS: Varied observational and mechanistic evidence suggests SARS-CoV-2 can infect and be shed from the gastrointestinal tract, including some data demonstrating viral culture in fecal samples. To fully assess these risks, quantitative data on infectious virus in these settings and infectious dose are needed.

SARS-CoV-2 and the role of close contact in transmission: a systematic review.

Background: SARS-CoV-2 transmission has been reported to be associated with close contact with infected individuals. However, the mechanistic pathway for transmission in close contact settings is unclear. Our objective was to identify, appraise and summarise the evidence from studies assessing the role of close contact in SARS-CoV-2 transmission.  Methods: This review is part of an Open Evidence Review on Transmission Dynamics of SARS-CoV-2. We conduct ongoing searches using WHO Covid-19 Database, LitCovid, medRxiv, PubMed and Google Scholar; assess study quality based on the QUADAS-2 criteria and report important findings on an ongoing basis. Results: We included 278 studies: 258 primary studies and 20 systematic reviews. The settings for primary studies were predominantly in home/quarantine facilities (39.5%) and acute care hospitals (12%). The overall reporting quality of the studies was low-to-moderate. There was significant heterogeneity in design and methodology. The frequency of attack rates (PCR testing) varied between 2.1-75%; attack rates were highest in prison and wedding venues, and in households. The frequency of secondary attack rates was 0.3-100% with rates highest in home/quarantine settings. Three studies showed no transmission if the index case was a recurrent infection. Viral culture was performed in four studies of which three found replication-competent virus; culture results were negative where index cases had recurrent infections. Eighteen studies performed genomic sequencing with phylogenetic analysis - the completeness of genomic similarity ranged from 77-100%. Findings from systematic reviews showed that children were significantly less likely to transmit SARS-CoV-2 and household contact was associated with a significantly increased risk of infection. Conclusions: The evidence from published studies demonstrates that SARS-CoV-2 can be transmitted in close contact settings. The risk of transmission is greater in household contacts. There was a wide variation in methodology. Standardized guidelines for reporting transmission in close contact settings should be developed.

Developing a fully automated evidence synthesis tool for identifying, assessing and collating the evidence.

Evidence synthesis is a key element of evidence-based medicine. However, it is currently hampered by being labour intensive meaning that many trials are not incorporated into robust evidence syntheses and that many are out of date. To overcome this, a variety of techniques are being explored, including using automation technology. Here, we describe a fully automated evidence synthesis system for intervention studies, one that identifies all the relevant evidence, assesses the evidence for reliability and collates it to estimate the relative effectiveness of an intervention. Techniques used include machine learning, natural language processing and rule-based systems. Results are visualised using modern visualisation techniques. We believe this to be the first, publicly available, automated evidence synthesis system: an evidence mapping tool that synthesises evidence on the fly.

Viral Cultures for Coronavirus Disease 2019 Infectivity Assessment: A Systematic Review.

BACKGROUND: We aimed to review the evidence from studies relating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) culture with the results of reverse-transcription polymerase chain reaction (RT-PCR) and other variables that may influence the interpretation of the test, such as time from symptom onset. METHODS: We searched LitCovid, medRxiv, Google Scholar, and the World Health Organization coronavirus disease 2019 (COVID-19) database for COVID-19 up to 10 September 2020. We included studies attempting to culture or observe SARS-CoV-2 in specimens with RT-PCR positivity. Studies were dual-extracted and the data summarized narratively by specimen type. Where necessary, we contacted corresponding authors of included papers for additional information. We assessed quality using a modified Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS 2) risk-of-bias tool. RESULTS: We included 29 studies reporting attempts at culturing, or observing tissue infection by, SARS-CoV-2 in sputum, nasopharyngeal or oropharyngeal, urine, stool, blood, and environmental specimens. The quality of the studies was moderate with lack of standardized reporting. The data suggest a relationship between the time from onset of symptom to the timing of the specimen test, cycle threshold (Ct), and symptom severity. Twelve studies reported that Ct values were significantly lower and log copies higher in specimens producing live virus culture. Two studies reported that the odds of live virus culture were reduced by approximately 33% for every 1-unit increase in Ct. Six of 8 studies reported detectable RNA for >14 days, but infectious potential declined after day 8 even among cases with ongoing high viral loads. Four studies reported viral culture from stool specimens. CONCLUSIONS: Complete live viruses are necessary for transmission, not the fragments identified by PCR. Prospective routine testing of reference and culture specimens and their relationship to symptoms, signs, and patient co-factors should be used to define the reliability of PCR for assessing infectious potential. Those with high Ct are unlikely to have infectious potential.

The TRIP database showed most acute respiratory infections questions were already addressed by Cochrane reviews.

OBJECTIVES: Cochrane systematic reviews require more methodological support from Cochrane Review Groups (CRGs) than is customarily received by authors from journals; CRGs must therefore prioritize reviews to conserve resources. The TRIP database provided a data set of questions to guide prioritization for the acute respiratory infections (ARIs) CRG. STUDY DESIGN AND SETTING: We extracted the ARI searches from the TRIP database (2010 to 2017) that contained at least one disease and one clinical management term, (defined as a "search"), and tabulated these by frequency. RESULTS: There were 314,346 ARI searches from which we inferred 45,497 clinical questions, covering 365 topics. Two-thirds (30,541) of these addressed 20 clinical questions, of which treatment were the most frequent, followed by diagnosis, mortality, and prognosis. The five most frequent clinical questions were "Influenza + Vaccination" 4,989 (12.1%), "acute otitis media + antibiotics" 3,578 (8.7%), "common cold + vitamin C" 3,528 (8.6%), "meningitis + corticosteroids" 1,910 (4.6%), and "pneumonia + general treatment" 1,765 (4.3%). The 20 most frequent clinical questions were addressed by Cochrane reviews or protocols. CONCLUSION: ARI questions are common and repeated often. Most may have been addressed by Cochrane reviews. The remainder form the basis of a priority list to assign resources for future Cochrane topics.

Rapid reviews may produce different results to systematic reviews: a meta-epidemiological study.

OBJECTIVE: To simulate possible changes in systematic review results if rapid review methods were used. STUDY DESIGN AND SETTING: We recalculated meta-analyses for binary primary outcomes in Cochrane systematic reviews, simulating rapid review methods. We simulated searching only PubMed, excluding older articles (5, 7, 10, 15, and 20 years before the search date), excluding smaller trials (<50, <100, and <200 participants), and using the largest trial only. We examined percentage changes in pooled odds ratios (ORs) (classed as no important change [<5%], small [<20%], moderate [<30%], or large [≥30%]), statistical significance, and biases observed using rapid methods. RESULTS: Two thousand five hundred and twelve systematic reviews (16,088 studies) were included. Rapid methods resulted in the loss of all data in 3.7-44.7% of meta-analyses. Searching only PubMed had the smallest risk of changed ORs (19% [477/2,512] were small changes or greater; 10% [260/2,512] were moderate or greater). Changes in ORs varied substantially with each rapid review method; 8.4-21.3% were small, 1.9-8.8% were moderate, and 4.7-34.1% were large. Changes in statistical significance occurred in 6.5-38.6% of meta-analyses. Changes from significant to nonsignificant were most common (2.1-13.7% meta-analyses). We found no evidence of bias with any rapid review method. CONCLUSION: Searching PubMed only might be considered where a ∼10% risk of the primary outcome OR changing by >20% could be tolerated. This could be the case in scoping reviews, resource limitation, or where syntheses are needed urgently. Other situations, such as clinical guidelines and regulatory decisions, favor more comprehensive systematic review methods.

Extracting the Population, Intervention, Comparison and Sentiment from Randomized Controlled Trials.

In this paper, an identification approach for the Population (e.g. patients with headache), the Intervention (e.g. aspirin) and the Comparison (e.g. vitamin C) in Randomized Controlled Trials (RCTs) is proposed. Contrary to previous approaches, the identification is done on a word level, rather than on a sentence level. Additionally, we classify the sentiment of RCTs to determine whether an Intervention is more effective than its Comparison. Two new corpora were created to evaluate both approaches. In the experiments, an average F1 score of 0.85 for the PIC identification and 0.72 for the sentiment classification was achieved.

Catalogue of bias: observer bias.

This article is part of a series featured from the Catalogue of Bias introduced in this volume of BMJ Evidence-Based Medicine that describes biases and outlines their potential impact in research studies. Observer bias is systematic discrepancy from the truth during the process of observing and recording information for a study. Many healthcare observations are at risk of this bias. Evidence shows that treatment effect estimates can be exaggerated by a third to two-thirds in the presence of observer bias in outcome assessment. Preventing observer bias involves proper masking in intervention studies including the use of matched placebo interventions where appropriate and training of observers to make assessment consistent and reduce biases resulting from conscious or unconscious prejudices. Where observers are involved in a research study, it is probably not possible for the study to be entirely free of observer biases.

Can we rely on the best trial? A comparison of individual trials and systematic reviews.

BACKGROUND: The ideal evidence to answer a question about the effectiveness of treatment is a systematic review. However, for many clinical questions a systematic review will not be available, or may not be up to date. One option could be to use the evidence from an individual trial to answer the question? METHODS: We assessed how often (a) the estimated effect and (b) the p-value in the most precise single trial in a meta-analysis agreed with the whole meta-analysis. For a random sample of 200 completed Cochrane Reviews (January, 2005) we identified a primary outcome and extracted: the number of trials, the statistical weight of the most precise trial, the estimate and confidence interval for both the highest weighted trial and the meta-analysis overall. We calculated the p-value for the most precise trial and meta-analysis. RESULTS: Of 200 reviews, only 132 provided a meta-analysis of 2 or more trials, with a further 35 effect estimates based on single trials. The average number of trials was 7.3, with the most precise trial contributing, on average, 51% of the statistical weight to the summary estimate from the whole meta-analysis. The estimates of effect from the most precise trial and the overall meta-analyses were highly correlated (rank correlation of 0.90).There was an 81% agreement in statistical conclusions. Results from the most precise trial were statistically significant in 60 of the 167 evaluable reviews, with 55 of the corresponding systematic reviews also being statistically significant. The five discrepant results were not strikingly different with respect to their estimates of effect, but showed considerable statistical heterogeneity between trials in these meta-analyses. However, among the 101 cases in which the most precise trial was not statistically significant, the corresponding meta-analyses yielded 31 statistically significant results. CONCLUSIONS: Single most precise trials provided similar estimates of effects to those of the meta-analyses to which they contributed, and statistically significant results are generally in agreement. However, "negative" results were less reliable, as may be expected from single underpowered trials. For systematic reviewers we suggest that: (1) key trial(s) in a review deserve greater attention (2) systematic reviewers should check agreement of the most precise trial and the meta analysis. For clinicians using trials we suggest that when a meta-analysis is not available, a focus on the most precise trial is reasonable provided it is adequately powered.

Using the Turning Research Into Practice (TRIP) database: how do clinicians really search?

OBJECTIVES: Clinicians and patients are increasingly accessing information through Internet searches. This study aimed to examine clinicians' current search behavior when using the Turning Research Into Practice (TRIP) database to examine search engine use and the ways it might be improved. METHODS: A Web log analysis was undertaken of the TRIP database-a meta-search engine covering 150 health resources including MEDLINE, The Cochrane Library, and a variety of guidelines. The connectors for terms used in searches were studied, and observations were made of 9 users' search behavior when working with the TRIP database. RESULTS: Of 620,735 searches, most used a single term, and 12% (n = 75,947) used a Boolean operator: 11% (n = 69,006) used "AND" and 0.8% (n = 4,941) used "OR." Of the elements of a well-structured clinical question (population, intervention, comparator, and outcome), the population was most commonly used, while fewer searches included the intervention. Comparator and outcome were rarely used. Participants in the observational study were interested in learning how to formulate better searches. CONCLUSIONS: Web log analysis showed most searches used a single term and no Boolean operators. Observational study revealed users were interested in conducting efficient searches but did not always know how. Therefore, either better training or better search interfaces are required to assist users and enable more effective searching.