Oro-faecal transmission of SARS-CoV-2: A systematic review of studies employing viral culture from gastrointestinal and other potential sources (preprint)

Background. The extent to which the oro-faecal route contributes to the transmission of SARS-CoV-2 is not established. Methods: We systematically reviewed the evidence on the presence of infectious SARS-CoV-2 in faeces and other gastrointestinal sources by examining studies that used viral culture to investigate the presence of replication-competent virus in these samples. We conducted searches in the WHO Covid-19 Database, LitCovid, medRxiv, and Google Scholar for SARS-CoV-2 using keywords and associated synonyms, with a search date up to 28th of November 2023. Results: We included 13 studies involving 328 COVID-19 subjects - providing 314 faecal or rectal swab SARS-CoV2 positive samples tested also with viral culture. The methods used for viral culture across the studies were heterogeneous. Three studies (2 cohorts and 1 case-series) reported observing replication-competent SARS-CoV-2 confirmed by quantitative RT-PCR (qPCR) and whole genome sequencing, and qPCR including appropriate cycle threshold changes. Overall, six (1.9%) of 314 faecal samples subjected to cell culture showed replication-competent virus. One study found replication competent samples from one immunocompromised patient. No studies were identified demonstrating direct evidence of oro-faecal transmission to humans. Conclusions: Our review found a relatively low frequency of replication-competent SARS-CoV-2 in faecal and other gastrointestinal sources. Although it is biologically plausible, more research is needed, using standardized cell culture methods, control groups, adequate follow-up and robust epidemiologic methods, including whether secondary infections occurred, to determine the role of the oro-faecal route in the transmission of SARS-CoV-2.

Coinfection with Strongyloides and SARS-CoV-2: protocol for a systematic review (preprint)

Rationale for the review: COVID-19 treatment can worsen parasitic disease in patients with coinfection. Consequently, there is a need to investigate the infection with SARS CoV 2 and Strongyloides. We aim to systematically review clinical and laboratory features of COVID 19 and Strongyloides coinfection, to investigate possible interventions and outcomes in this pathology. Also, we aim to identify difficulties in managing the parasitic disease manifestations in this context and to emphasize research gaps requiring further attention. Methods: We will search two electronic databases (LitCOVID, and WHO COVID 19) and will include studies on SARS CoV 2 and Strongyloides coinfection. We will adapt the WHO UMC system for standardized case causality assessment to evaluate if using corticosteroids or other immunosuppressive drugs in COVID 19 patients determined acute strongyloidiasis manifestations. Expected results: We will present the evidence in three distinct packages: study description, methodological quality assessment and data extracted. We will summarize the evidence and will draw conclusions as to the quality of the evidence.

Viral Cultures for Assessing Fomites Transmission of SARS-CoV-2: a Systematic Review Protocol (preprint)

This is a protocol for a systematic review to assess fomite transmission in SARS-CoV-2. Our research questions are as follows: 1. Are fomite samples infectious? 2 If so, what proportion are infectious, and what is the distance and duration of infectiousness in the air? 3. What is the relationship between fomites, infectiousness and PCR cycle threshold (Ct)? 4. Is there evidence of a chain of transmission that establishes an actual instance of fomite transmission of SARS-CoV-2? We will include studies of any design (and in any setting) that investigate fomite transmission (defined as any inanimate object that, when contaminated with or exposed to infectious agents, can transfer the agent to a new host). We will only include studies that performed viral culture which assessed cytopathic effect and verification techniques to ensure the cultured virus is SARS-CoV-2. We will assess the risk of bias using a checklist modified from the QUADAS-2 criteria.

Viral cultures, PCR Cycle threshold values and viral load estimation for COVID-19 infectious potential assessment in transplant patients: systematic review - Protocol Version 29 December 2021 (preprint)

This is the protocol for a systematic review focussing on people receiving solid organ or hematopoietic stem cell transplants. Our research questions are as follows: What is the relationship between serial PCR Ct value or other measures of viral burden, and the likelihood and duration of the presence of infectious virus from viral culture, among transplant recipients with SARS-CoV-2 infection? What is the influence of age, sex, underlying pathologies, degree of immunosuppression, vaccination status, COVID-19 symptoms and COVID-19 disease course on viral burden and the likelihood of presence of infectious SARS-CoV-2? We will include single studies reporting serial Cts from sequential rt-PCR testing or other measures of viral burden such as RNA gene copies of respiratory samples (from nasopharyngeal specimens) along with viral culture data on the same samples, from patients about to receive a transplant or who are post transplant with SARS-CoV-2 infection.

Transmission of SARS-CoV-2 associated with cruise ship travel: protocol for a systematic review (Version 1) (preprint)

Background: Maritime and river travel, including cruise ships, have been implicated with spreading viruses through infected passengers and crew. Given the novelty of the SARS-CoV-2 infection, early cruise ship travel transmission models of spread are based on what is known of the dynamics of other respiratory viral infections. Our objective is to provide a rapid summary and evaluation of relevant data on SARS-CoV-2 transmission aboard cruise ships, report policy implications, and highlight research gaps requiring attention. Methods: We will search LitCovid, medRxiv, Google Scholar, and the WHO Covid-19 database using COVID-19, SARS-CoV-2, transmission, and cruise ship appropriate synonyms. We will also search the reference lists of included studies for additional relevant studies. We will include studies reporting onboard SARS-CoV-2 transmission from passengers and/or crew to passengers and/or crew. We will consider any potential transmission mode. We will assess study quality based on five criteria and report important findings. The outcome will consist of the onboard cruise ships transmission of SARS-CoV-2. We will provide a narrative summary of the data and report the outcomes, including quantitative estimates where feasible and relevant. Where possible, compatible datasets may be pooled for meta-analysis. Expected results: We will present the evidence in three distinct packages: study description, methodological quality assessment and data extracted. We will summarize the evidence and will draw conclusions as to the quality of the evidence.

Transmission of SARS-CoV-2 from pre and asymptomatic infected individuals. A systematic review (preprint)

Background The transmission role of SARS-Cov-2 infected persons who develop symptoms post testing (pre symptomatics) or not at all throughout the course of positivity (asymptomatics) is unknown. We carried out a systematic review of available evidence to determine whether they were infectious or not and if so for how long and their probable contribution to the pandemic spread of SARS-CoV-2. Methods We searched LitCovid, medRxiv, Google Scholar and the WHO Covid-19 databases and reference lists of included studies. Search terms were COVID-19, SARS-CoV-2, transmission, asymptomatic, presymptomatic and appropriate synonyms. Searches were carried out to 31 March 2021. We included studies on people exposed to SARS CoV-2 within 2-14 days (incubation time) of close contact or suspected community or institutional exposure to index asymptomatic (at the time of observation) infected individuals, as defined in the study. We included studies with a proven or hypothesised chain of transmission with secondary case infected based on fulfilling a confirmed or probable case definition and confirmation of infectiousness and transmission outcome based either on serial PCR cycle threshold readings or viral culture or gene sequencing or any combination thereof and adequate follow up. We assessed the reliability of symptom and sign survey compatible with contemporary knowledge and extracted documentation of the likelihood of transmission, presence of replicating virus and/or documentation of phylodynamics (genetic sequence lineage) and/or adequate follow-up and reporting of symptoms and signs. We wrote to all included studies corresponding authors to request further details and assessed likelihood of transmission using adapted causality criteria. Results We included 18 studies from a variety of settings. Because of the current lack of standardized methodology and clear reporting criteria there was substantial methodological variation in transmission studies. Asymptomatic prevalence at the time of initial testing varied from 12.5% to 100% and of these 6% to 100% were pre-symptomatic cases, depending on the setting and the methods of case ascertainment and the population. Nursing/care home facilities reported high rates of presymptomatic: 50% - 100% (n=3 studies). Fifteen studies were classified as high risk and three studies at moderate risk of symptom ascertainment bias. In practice, this assessment means that high-risk studies may be less likely to distinguish between pre-symptomatic and asymptomatic cases. Six of the asymptomatic studies and four presymptomatic studies reported growing infectious virus although the data was too sparse to determine duration of infectiousness. Three studies were judged as providing possible and three of probable/likely evidence of asymptomatic transmission of SARs-CoV-2. Five studies provided evidence of possible and two of probable/likely presymptomatic transmission of SARs-CoV-2. Author response rate was 100%. Conclusions Reliable studies included here provide probable evidence of transmission of SARS-CoV-2 from presymptomatic and asymptomatic individuals. Single point in time estimates and binary PCR testing alone cannot provide reliable information on symptom status and information on infectivity. The number of studies and asymptomatic and presymptomatic cases eligible for inclusion was low, with more data and international standardisation of methods needed to further reduce uncertainty.

SARS-CoV-2 and the role of vertical transmission from infected pregnant women to their fetuses: systematic review. (preprint)

BackgroundVertical transmission of SARS-CoV-2 has been reported but does not appear to be common. This study aims to systematically review the evidence for vertical transmission of SARS-CoV-2. MethodsThis review is part of an Open Evidence Review on the transmission dynamics of SARS-CoV-2 and the role of intrauterine mother to fetus transmission. Literature searches were performed in the WHO Covid-19 Database, LitCovid, medRxiv, and Google Scholar for SARS-CoV-2 using keywords and associated synonyms, search date up to 20 December 2020, no language restrictions. ResultsWe included 106 studies assessing vertical transmission of SARS-CoV-2 from pregnant women to their neonates: these studies comprised 40 reviews (21 fulfilled systematic review methodology, including risk of bias assessment of included studies) and 66 primary studies including 32 case reports (of up to two cases) and 34 prospective and retrospective cohort studies, prospective and retrospective case series, observational studies (including asymptomatic screening), database studies and a quality improvement project. Almost all were conducted in a hospital setting. The 32 case reports were considered to be at high risk of bias, due to the study design; across the 34 remaining primary studies, risk of bias was low to moderate. Sixteen case reports examined vertical transmission, which was not related to maternal symptomatology. For the cohort and case series studies, the percentage of positive neonates ranged from 0% to 22% across the studies. Twenty studies reported no positive vertical transmission. Three studies that reported the highest positivity rates of 11%, 15% and 22% had specifically selected neonates with a positive test (within up to 35 days) within the study population and were therefore more selective populations. Across the cohort and case series studies there were 65/2391 (2.7%) neonates born to mothers with a diagnosis of COVID-19 tested positive for SARS-CoV-2 within 24 hours of birth. No evidence correlated maternal symptomatology to vertical transmission. Mode of delivery did not correlate with rates of vertical transmission. Of 25 studies, 7 identified SARS-CoV-2 in placental tissue; some of these did not demonstrate vertical transmission to the neonate. No study reported the results of viral culture to detect SARS-CoV-2. ConclusionsThe results of these studies indicate that vertical transmission is possible, but is not frequent, and factors that influence when vertical transmission occurs are unknown. Further studies using standardised methods to establish viral infection are needed to establish vertical transmission rates and to assess clinical and other conditions affecting transmission.

Transmission of SARS-CoV-2 associated with aircraft travel: a systematic review (Version 1) (preprint)

BackgroundAir travel may be associated with the spread of viruses via infected passengers and potentially through in-flight transmission. Given the novelty of the SARS-CoV-2 virus, transmission associated with air travel is based on what is known about the dynamics of transmission of other respiratory virus infections, especially those due to other coronaviruses and influenza. Our objective was to provide a rapid summary and evaluation of relevant data on the transmission of SARS-CoV-2 aboard aircraft, report important policy implications, and highlight research gaps requiring urgent attention. MethodsThis review is part of an Open Evidence Review on Transmission Dynamics of SARS-CoV-2. We searched LitCovid, medRxiv, Google Scholar, and the WHO Covid-19 database from 1 February 2020 to 27 January 2021 and included studies on the transmission of SARS-CoV-2 aboard aircraft. We assessed study quality based on five criteria and reported important findings. ResultsWe included 18 studies on in-flight transmission of SARS-CoV-2, representing 130 unique flights and two studies on wastewater from aircraft. The overall quality of reporting was low. Two wastewater studies reported PCR-positive SARS-CoV-2 samples, but with relatively high Cycle threshold values ranging from 36 to 40. The definition of an index case was very heterogeneous across the studies. The proportion of contacts traced ranged from 0.68% to 100%. In total, the authors successfully traced 2800/19729 passengers, 140/180 crew members, and 8/8 medical staff. Altogether, 273 index cases were reported, with 64 secondary cases. No secondary cases were reported in three studies, each investigating one flight. The secondary attack rate among the studies that followed up >80% of the passengers and crew (including data on 10 flights) varied between 0% and 8.2%. The included studies reported on the possibility of SARS-CoV-2 transmission from asymptomatic, pre-symptomatic, and symptomatic individuals. Viral cultures were performed in two studies, with 10 positive results reported. Genomic sequencing and phylogenetic analysis were performed in individuals from four flights, with the completeness of genomic similarity ranging from 81-100%. ConclusionCurrent evidence suggests that SARS-CoV-2 can be transmitted during aircraft travel, but the published data do not permit any conclusive assessment of the likelihood and extent. Furthermore, the quality of evidence from most published studies is low. The variation in study design and methodology restricts the comparison of findings across studies. Standardized guidelines for conducting and reporting future studies of transmission on aircrafts should be developed.

Seroconversion following SARS-CoV-2 Infection or Vaccination in Pediatric IBD Patients (preprint)

Objective: Inflammatory bowel disease (IBD) patients are commonly treated with immunomodulatory medications, and the effect of these medications on seroconversion to SARS-CoV-2 infection and vaccination are scant, particularly in pediatrics. We sought to determine serologic responses to SARS-CoV-2 infection and vaccination in pediatric IBD patients. Design: We conducted a single-center, retrospective study of all pediatric ([≤]21 years old) IBD patients in whom a SARS-CoV-2 IgG Antibody Assay was performed between April 2020 and May 2021 at our tertiary care center. This assay measures IgG antibody to the full-length SARS-CoV-2 spike protein and was routinely collected at infusion and outpatient clinic visits. The primary outcome was SARS-CoV-2 seroconversion, and the secondary outcome was titer level, with high titer defined as [≥]960 titer or >40 AU/mL. Clinical characteristics, including demographics, IBD location, behavior, activity, and therapy, SARS-CoV-2 exposures, COVID-19 testing and symptoms, SARS-CoV-2 infection status (WHO COVID-19: Case Definitions, 2020) and COVID-19 vaccination status and type, were gathered, and univariate analyses examined associations between clinical characteristics and outcome measures. Results: There were 340 pediatric patients with SARS-CoV-2 Antibody Testing; 15% for confirmed or probable COVID-19, 2% for suspected COVID-19, 16% for asymptomatic exposure to a close contact with SARS-CoV-2 infection, 61% without any prior symptoms or exposures, and 6% for history of COVID-19 vaccination. Patients with confirmed or probable COVID-19 infection had a 90% rate of seroconversion, with 76% of these patients on biologic therapy. Patients post-infection without seroconversion had a significantly longer interval between infection and antibody assay (P=0.03). Within those with asymptomatic SARS-CoV-2 exposure, 43% had seroconversion, and there were no identified clinical characteristics associated with positive titer. All pediatric patients who received vaccination seroconverted, and all who received mRNA vaccinations, including one after a single dose, achieved high titer levels; 100% of those who received vaccination were on biologic or small molecule therapy, including one on combination therapy with ustekinumab and tofacitinib. Conclusion: Pediatric IBD patients have strong serologic antibody responses to SARS-CoV-2 infection and COVID-19 vaccination despite high rates of immunomodulatory therapy.