Identification of two novel subtypes of hepatitis C virus genotype 8 and a potential new genotype successfully treated with direct acting antivirals.

BACKGROUND: Hepatitis C virus (HCV) has a high genetic diversity and is classified into 8 genotypes and over 90 subtypes with some endemic to specific world regions. This could compromise direct-acting antiviral (DAA) efficacy and global HCV elimination. METHODS: We characterised HCV subtypes 'rare' to the UK (non-1a/1b/2b/3a/4d) by whole genome sequencing via a national surveillance programme. Genetic analyses to determine the genotype of samples with unresolved genotypes were undertaken by comparison with ICTV HCV reference sequences. RESULTS: Two HCV variants were characterised as being closely related to the recently identified genotype 8 (GT8), with >85% pairwise genetic distance similarity to GT8 sequences and within the typical inter-subtype genetic distance range. The individuals infected by the variants were UK residents originally from Pakistan and India. In contrast, a third variant was only confidently identified to be more similar to GT6 compared to other genotypes across 6% of the genome and was isolated from a UK resident originally from Guyana. All three were cured with pangenotypic DAAs (Sofosbuvir + Velpatasvir or Glecaprevir + Pibrentasvir) despite the presence of resistance polymorphisms in NS3 (80 K/168E), NS5A (28 V/30S/62L/92S/93S) and NS5B (159F). CONCLUSIONS: This study expands our knowledge of HCV diversity by identifying two new GT8 subtypes and potentially a new genotype.

COVID-19 cluster surveillance using exposure data collected from routine contact tracing: The genomic validation of a novel informatics-based approach to outbreak detection in England.

Contact tracing was used globally to prevent onwards transmission of COVID-19. Tracing contacts alone is unlikely to be sufficient in controlling community transmission, due to the pre-symptomatic, overdispersed and airborne nature of COVID-19 transmission. We describe and demonstrate the validity of a national enhanced contact tracing programme for COVID-19 cluster surveillance in England. Data on cases occurring between October 2020 and September 2021 were extracted from the national contact tracing system. Exposure clusters were identified algorithmically by matching ≥2 cases attending the same event, identified by matching postcode and event category within a 7-day rolling window. Genetic validity was defined as exposure clusters with ≥2 cases from different households with identical viral sequences. Exposure clusters were fuzzy matched to the national incident management system (HPZone) by postcode and setting description. Multivariable logistic regression modelling was used to determine cluster characteristics associated with genetic validity. Over a quarter of a million (269,470) exposure clusters were identified. Of the eligible clusters, 25% (3,306/13,008) were genetically valid. 81% (2684/3306) of these were not recorded on HPZone and were identified on average of one day earlier than incidents recorded on HPZone. Multivariable analysis demonstrated that exposure clusters occurring in workplaces (aOR = 5·10, 95% CI 4·23-6·17) and education (aOR = 3·72, 95% CI 3·08-4·49) settings were those most strongly associated with genetic validity. Cluster surveillance using enhanced contact tracing in England was a timely, comprehensive and systematic approach to the detection of transmission events occurring in community settings. Cluster surveillance can provide intelligence to stakeholders to support the assessment and management of clusters of COVID-19 at a local, regional, and national level. Future systems should include predictive modelling and network analysis to support risk assessment of exposure clusters to improve the effectiveness of enhanced contract tracing for outbreak detection.

Risk of transmission of SARS-CoV-2 on international flights, a retrospective cohort study using national surveillance data in England.

BACKGROUND: It is not yet fully understood to what extent in-flight transmission contributed to the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This study aimed to determine the occurrence and extent of SARS-CoV-2 transmission in-flight and assess factors associated with transmission risk to inform future control strategies. METHODS: Retrospective cohort study using data obtained from contact tracing of international flights arriving in England between 02/08/2021-15/10/2021. Transmission risk was estimated by calculating the secondary attack rate (SAR). Univariable and multivariable analyses of the SAR by specific risk factors was undertaken, including: number of in-flight index cases; number of symptomatic index cases; contact vaccination status; flight duration; proximity to the index case(s); contact age. RESULTS: 11,307 index cases linked to 667,849 contacts with 5,289 secondary cases reported. In-flight SAR was 0.79% (95% CI: 0.77-0.81). Increasing numbers of symptomatic cases (when > 4 index cases compared to one index case aOR 1.85; 95% CI: 1.40-2.44) and seating proximity to an index case (seated within compared to outside of two rows OR 1.82; 95% CI: 1.50-2.22) were associated with increased risk of secondary cases. Full vaccination history was protective (aOR 0.52; 95% CI: 0.47-0.57). CONCLUSIONS: This study confirms that in-flight transmission of SARS-CoV-2 occurred. There are factors associated with increased risk of infection. Contact tracing identified exposed persons who subsequently developed infection. A targeted approach to contact tracing passengers with the highest exposure risk could be an effective use of limited public health resources.

The Utility of Ambulance Dispatch Call Syndromic Surveillance for Detecting and Assessing the Health Impact of Extreme Weather Events in England.

Extreme weather events present significant global threats to health. The National Ambulance Syndromic Surveillance System collects data on 18 syndromes through chief presenting complaint (CPC) codes. We aimed to determine the utility of ambulance data to monitor extreme temperature events for action. Daily total calls were observed between 01/01/2018−30/04/2019. Median daily 'Heat/Cold' CPC calls during "known extreme temperature" (identified a priori), "extreme temperature"; (within 5th or 95th temperature percentiles for central England) and meteorological alert periods were compared to all other days using Wilcoxon signed-rank test. During the study period, 12,585,084 calls were recorded. In 2018, median daily "Heat/Cold" calls were higher during periods of known extreme temperature: heatwave (16/day, 736 total) and extreme cold weather events (28/day, 339 total) compared to all other days in 2018 (6/day, 1672 total). Median daily "Heat/Cold" calls during extreme temperature periods (16/day) were significantly higher than non-extreme temperature periods (5/day, p < 0.001). Ambulance data can be used to identify adverse impacts during periods of extreme temperature. Ambulance data are a low resource, rapid and flexible option providing real-time data on a range of indicators. We recommend ambulance data are used for the surveillance of presentations to healthcare related to extreme temperature events.

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission.

Understanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.

Time-resolved fluorescence immunoassay for urine retinol-binding protein is more sensitive than polyclonal and monoclonal assays.

BACKGROUND: Retinol-binding protein4 (RBP) assays using polyclonal antibodies (pRBP) have major problems of non-linearity of dilution and a very small useable dynamic range. Our objective was to develop a specific assay with a wider dynamic range to detect tubular proteinuria. METHODS: mRBP (monoclonal capture and second antibody with colorimetric detection) and fluoroimmunoassays for RBP (fRBP) (polyclonal capture and monoclonal second antibody with fluorescence detection) were developed and compared with pRBP. Four hundred and eighty-eight patient samples were collected; 290 samples were analysed by mRBP and 198 samples with fRBP and compared with pRBP. RESULTS: mRBP assay has the advantages of better linearity on dilution and wider analytical range over pRBP. It is limited by poor signal in the patients with albuminuria and glomerular proteinuria and inferior discrimination between patient groups. fRBP had an intra-assay and inter-assay CV of <6% and <8%, respectively, and analytical range was 2.3-599 µg/L. fRBP was linear on dilution within the analytical range. Correlation (r) was 0.8722 (95% CI 0.7621 to 0.9333, P< 0.0001); Mann-Whitney test revealed no significant difference (U = 18,877, n = 198, P = 0.5244) asserting that the medians of the two samples were identical. Bland-Altman test between pRBP and fRBP showed a mean negative bias of 16.43 (CI -994 to 1027) µg/mmol. CONCLUSIONS: The combination assay with fluorescence detection (fRBP) proved more discriminatory than a purely monoclonal system especially in patients with significant proteinuria and has advantages of better linearity on dilution and wider analytical range than the existing pRBP assay and compared extremely well with pRBP.

Risk of symptomatic COVID-19 due to aircraft transmission: a retrospective cohort study of contact-traced flights during England's containment phase.

BACKGROUND: Knowledge gaps remain regarding SARS-CoV-2 transmission on flights. We conducted a retrospective cohort study to estimate risk of acquiring symptomatic SARS-CoV-2 on aircraft, to inform contact tracing and infection control efforts. METHODS: We identified co-passengers of infectious passengers on 18 England-bound flights from European cities up to 12/03/2020, using manifests received for contact tracing. Infectious passengers were laboratory-confirmed cases with symptom onset from 7 days before to 2 days after the flight. Possible aircraft-acquired cases were laboratory-confirmed with onset 3-14 days post-flight with no known non-flight exposure. Manifests was merged with the national case management dataset (identifying cases, onset dates, contact tracing status) and the national COVID-19 linelist. Contact tracing notes were reviewed to identify non-flight exposures. We calculated attack rates (ARs) among all co-passengers and within subgroups, including by distance from infectious cases and number of infectious cases on-board. RESULTS: There were 55 infectious passengers and 2313 co-passengers, including 2221 flight-only contacts. Five possible aircraft-acquired cases were identified; ARs of 0.2% (95%CI 0.1-0.5) among all flight-only contacts and 3.8% (95%CI 1.3-10.6) among contact-traced flight-only contacts sat within a two-seat radius. The AR among 92 co-travellers with known non-flight exposure to infectious cases was 13.0% (95%CI 7.6%-21.4%). There were insufficient numbers to assess differences between subgroups. CONCLUSION: We conclude that risk of symptomatic COVID-19 due to transmission on short to medium-haul flights is low, and recommend prioritising contact-tracing of close contacts and co-travellers where resources are limited. Further research on risk on aircraft is encouraged.

Risk of herpes zoster after exposure to varicella to explore the exogenous boosting hypothesis: self controlled case series study using UK electronic healthcare data.

OBJECTIVE: To assess the magnitude and duration of any hypothesised protective effect of household exposure to a child with varicella on the relative incidence of herpes zoster in adults. DESIGN: Self controlled case series. SETTING: UK general practices contributing to Clinical Practice Research Datalink. PARTICIPANTS: 9604 adults (≥18 years) with a diagnosis of herpes zoster (in primary care or hospital records) between 1997 and 2018, who during their observation period lived with a child (<18 years) with a diagnosis of varicella. MAIN OUTCOME MEASURES: Relative incidence of herpes zoster in the 20 years after exposure to a child with varicella in the household compared with baseline time (all other time, excluding the 60 days before exposure). RESULTS: 6584 of the 9604 adults with herpes zoster (68.6%) were women. Median age of exposure to a child with varicella was 38.3 years (interquartile range 32.3-48.8 years) and median observation period was 14.7 (11.1-17.7) years. 4116 adults developed zoster in the baseline period, 433 in the 60 days before exposure and 5055 in the risk period. After adjustment for age, calendar time, and season, strong evidence suggested that in the two years after household exposure to a child with varicella, adults were 33% less likely to develop zoster (incidence ratio 0.67, 95% confidence interval 0.62 to 0.73) compared with baseline time. In the 10-20 years after exposure, adults were 27% less likely to develop herpes zoster (0.73, 0.62 to 0.87) compared with baseline time. A stronger boosting effect was observed among men than among women after exposure to varicella. CONCLUSIONS: The relative incidence of zoster was lower in the periods after exposure to a household contact with varicella, with modest but long lasting protective effects observed. This study suggests that exogenous boosting provides some protection from the risk of herpes zoster, but not complete immunity, as assumed by previous cost effectiveness estimates of varicella immunisation.

Clonal expansion of community-associated meticillin-resistant Staphylococcus aureus (MRSA) in people who inject drugs (PWID): prevalence, risk factors and molecular epidemiology, Bristol, United Kingdom, 2012 to 2017.

BACKGROUND: In 2015, Bristol (South West England) experienced a large increase in cases of meticillin-resistant Staphylococcus aureus (MRSA) infection in people who inject drugs (PWID). AIM: We aimed to characterise and estimate the prevalence of MRSA colonisation among PWID in Bristol and test evidence of a clonal outbreak. METHODS: PWID recruited through an unlinked-anonymous community survey during 2016 completed behavioural questionnaires and were screened for MRSA. Univariable logistic regression examined associations with MRSA colonisation. Whole-genome sequencing used lineage-matched MRSA isolates, comparing PWID (screening and retrospective bacteraemia samples from 2012-2017) with non-PWID (Bristol screening) in Bristol and national reference laboratory database samples. RESULTS: The MRSA colonisation prevalence was 8.7% (13/149) and was associated with frequently injecting in public places (odds ratio (OR): 5.5; 95% confidence interval (CI):1.34-22.70), recent healthcare contact (OR: 4.3; 95% CI: 1.34-13.80) and injecting in groups of three or more (OR: 15.8; 95% CI: 2.51-99.28). People reporting any one of: injecting in public places, injection site skin and soft tissue infection or hospital contact accounted for 12/13 MRSA positive cases (sensitivity 92.3%; specificity 51.5%). Phylogenetic analysis identified a dominant clade associated with infection and colonisation among PWID in Bristol belonging to ST5-SCCmecIVg. CONCLUSIONS: MRSA colonisation in Bristol PWID is substantially elevated compared with general population estimates and there is evidence of clonal expansion, community-based transmission and increased infection risk related to the colonising strain. Targeted interventions, including community screening and suppression therapy, education and basic infection control are needed to reduce MRSA infections in PWID.

Social network analysis and whole genome sequencing in a cohort study to investigate TB transmission in an educational setting.

BACKGROUND: TB outbreaks in educational institutions can result in significant transmission and pose a considerable threat to TB control. Investigation using traditional microbiological and epidemiological tools can lead to imprecise screening strategies due to difficulties characterising complex transmission networks. Application of whole genome sequencing (WGS) and social network analysis can provide additional information that may facilitate rapid directed public health action. We report the utility of these methods in combination with traditional approaches for the first time to investigate a TB outbreak in an educational setting. METHODS: Latent tuberculosis infection (LTBI) cases were screenees with a positive T-SPOT®.TB test. Active TB cases were defined through laboratory confirmation of M. tuberculosis on culture or through clinical or radiological findings consistent with infection. Epidemiological data were collected from institutional records and screenees. Samples were cultured and analysed using traditional M. tuberculosis typing and WGS. We undertook multivariable multinomial regression and social network analysis to identify exposures associated with case status and risk communities. RESULTS: We identified 189 LTBI cases (13.7% positivity rate) and nine active TB cases from 1377 persons screened. The LTBI positivity rate was 39.1% (99/253) among persons who shared a course with an infectious case (odds ratio 7.3, 95% confidence interval [CI] 5.2 to 10.3). The community structure analysis divided the students into five communities based on connectivity, as opposed to the 11 shared courses. Social network analysis identified that the community including the suspected index case was at significantly elevated risk of active disease (odds ratio 7.5, 95% CI 1.3 to 44.0) and contained eight persons who were lost to follow-up. Five sputum samples underwent WGS, four had zero single nucleotide polymorphism (SNP) differences and one had a single SNP difference. CONCLUSION: This study demonstrates the public health impact an undiagnosed case of active TB disease can have in an educational setting within a low incidence area. Social network analysis and whole genome sequencing provided greater insight to evolution of the transmission network and identification of communities of risk. These tools provide further information over traditional epidemiological and microbiological approaches to direct public health action in this setting.