Catherine Moore

Comparisons of SARS‐CoV‐2 variants' severity in terms of outcomes such as hospitalisation are commonly reported. By contrast, despite the vital importance of understanding evolution of the SARS‐CoV‐2 symptom profile for public health surveillance, few comparative studies have investigated differences in variants' symptomatology. The aim of this comprehensive analysis was to investigate whether successive variants were indeed associated with distinct symptom patterns in a large Welsh sample covering a broad time period and multiple variant waves. Symptom and variant typing data were derived from contact tracing data and sequencing of positive SARS‐CoV‐2 PCR tests collected in Wales, respectively. Descriptive epidemiology and binary logistic regression modelling were then used to investigate differences in the symptom profile of N = 226 002 cases infected with Wild‐Type, Alpha, Delta, or Omicron variants of SARS‐CoV‐2. The median number of symptoms and the proportion of cases reporting as symptomatic were lower for those infected with Omicron (BA.4) and Omicron (BA.5) compared to those infected with Wild‐Type (B.1.612), Alpha (B.1.1.7), Delta (B.1.617.2 and descendent lineages, excluding AY.4.2), Delta (AY.4.2), Omicron (BA.1) and Omicron (BA.2). Indeed, the odds of being symptomatic when infected with the Omicron (BA.4) or Omicron (BA.5) variant were 83% and 84% lower, compared to those infected with Wild‐Type. Anosmia in particular, was reported in non‐Omicron variants at approximately three‐to‐five times the proportion of cases (range 20.23%–26.41%) compared to Omicron variants (range 4.18%–7.65%). Indeed, the odds of having anosmia when infected with an Omicron variant were 85%–91% lower than when infected with Wild‐Type, versus 32%–43% lower for non‐Omicron variants, relative to Wild‐Type. We suggest, given these changes in symptomatology and the vast reduction in testing and sequencing, symptom surveillance should continue, to approximate burden of infection and facilitate rapid updating of clinical case definitions following any further evolution in the symptom profile. While disentangling the contribution of genomic, immunological and sampling changes to our findings remains challenging, symptom surveillance could also potentially aid emerging variant detection when used in combination with other surveillance approaches.

Background/Objectives: Rapid and accurate pathogen identification is essential for the proper management of patients with infectious gastroenteritis, as well as for a better control of disease outbreaks. This observational, non-interventional, single-site study evaluated the diagnostic accuracy of LiquidArray^® Gastrointestinal VER 1.0, a multiplex PCR syndromic panel capable of detecting up to 26 clinically relevant enteropathogens. Methods: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and likelihood ratio (LR) were evaluated using stool samples from 1512 patients with suspected gastroenteritis and were compared to seven competitor assays. Results: LiquidArray^® Gastrointestinal VER 1.0 showed a very low invalid rate (0.5% at initial testing, down to 0% after repeat) and high sensitivity (>90% for most detected targets) and specificity (>99% for all detected targets). Accordingly, the PPV and NPV were high (>90% for most targets and >99% for all targets, respectively). The analytical performance of LiquidArray^® Gastrointestinal VER 1.0 was also excellent as to co-amplification capability, cross-reactivity and assay precision. Conclusions: This study demonstrates the excellent clinical performance of LiquidArray^® Gastrointestinal VER 1.0 and its suitability for implementation in clinical routine for the rapid and accurate diagnosis of infectious gastroenteritis.

The optimum treatment for persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not known. Our case series, across 5 hospitals in 3 countries, describes 11 cases where persistent SARS-CoV-2 infection was successfully treated with prolonged courses (median, 10 days [range, 10–18 days]) of nirmatrelvir/ritonavir (Paxlovid). Most cases (9/11) had hematological malignancy and 10 (10/11) had received CD20-depleting therapy. The median duration of infection was 103 days (interquartile range, 85–138 days). The majority (10/11) were hospitalized, and 7 (7/11) had severe/critical disease. All survived and 9 of 11 demonstrated viral clearance, almost half (4/9) of whom received nirmatrelvir/ritonavir as monotherapy. This case series suggests that prolonged nirmatrelvir/ritonavir has a role in treating persistent infection.

Recombination, the process whereby a segment of genetic material from one genome is inserted into another, producing a new chimeric genome, is an important evolutionary mechanism frequently observed in coronaviruses. The risks posed by recombination include the shuffling of advantageous mutations that may increase transmissibility, severity or vaccine escape. We present a genomic and epidemiological description of a new recombinant lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), XR, first identified in Wales. The Pathogen Genomics Unit (Public Health Wales, UK) sequences positive SARS-CoV-2 PCR tests using the ARTIC SARS-CoV-2 sequencing protocol. Recombinants were detected using an in-house pipeline and the epidemiological data analysed in R. Nosocomial cases were defined as those with samples taken after >7 days in hospital. Between February and March 2022, we identified 78 samples with highly similar genomes, comprising a BA.1-like 5' end, a BA.2-like 3' end and a BA.2-like spike protein. This signature is consistent with recombination and was defined as XR by Pangolin (PANGO v1.8). A total of 50 % of cases had a sample collected whilst in hospital and the first three cases were immunocompromised patients. The patient median age was 58 years (range: 4–95 years) and most of the patients were fully vaccinated against SARS-CoV-2 (74 % third dose/booster). Three patients died within 28 days of their sample collection date, one of whom had COVID-19 listed amongst ICD10 (International Classification of Diseases 10) coded causes of death. Our integrated system enabled real-time monitoring of recombinant SARS-CoV-2 for early detection, in order to rapidly risk assess and respond. This work highlights the importance of setting-based surveillance of recombinant SARS-CoV-2, as well as the need to monitor immunocompromised populations through repeat testing and sequencing.

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK¹. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Summary: Since the first reports of hepatitis of unknown aetiology occurring in UK children, over 1000 cases have been reported worldwide, including 268 cases in the UK, with the majority younger than 6 years old. Using genomic, proteomic and immunohistochemical methods, we undertook extensive investigation of 28 cases and 136 control subjects. In five cases who underwent liver transplantation, we detected high levels of adeno-associated virus 2 (AAV2) in the explanted livers. AAV2 was also detected at high levels in blood from 10/11 non-transplanted cases. Low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), both of which enable AAV2 lytic replication, were also found in the five explanted livers and blood from 15/17 and 6/9 respectively, of the 23 non-transplant cases tested. In contrast, AAV2 was detected at low titre in 6/100 whole bloods from child controls from cohorts with presence or absence of hepatitis and/or adenovirus infection. Our data show an association of AAV2 at high titre in blood or liver tissue, with unexplained hepatitis in children infected in the recent HAdV-F41 outbreak. We were unable to find evidence by electron microscopy, immunohistochemistry or proteomics of HAdV or AAV2 viral particles or proteins in explanted livers, suggesting that hepatic pathology is not due to direct lytic infection by either virus. The potential that AAV2, although not previously associated with disease, may, together with HAdV-F41 and/or HHV-6, be causally implicated in the outbreak of unexplained hepatitis, requires further investigation.

Background: The Omicron (lineage B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was first reported in Wales, UK, on 3 December 2021. The aim of the study was to describe the first 1000 cases of the Omicron variant by demographic, vaccination status, travel and severe outcome status and compare this to contemporaneous cases of the Delta variant.Methods: Testing, typing and contact tracing data were collected by Public Health Wales and analysis undertaken by the Communicable Disease Surveillance Centre (CDSC). Risk ratios for demographic factors and symptoms were calculated comparing Omicron cases to Delta cases identified over the same time period.Results: By 14 December 2021, 1000 cases of the Omicron variant had been identified in Wales. Of the first 1000, just 3% of cases had a prior history of travel revealing rapid community transmission. A higher proportion of Omicron cases were identified in individuals aged 20–39, and most cases were double vaccinated (65.9%) or boosted (15.7%). Age‐adjusted analysis also revealed that Omicron cases were less likely to be hospitalised (0.4%) or report symptoms (60.8%). Specifically a significant reduction was observed in the proportion of Omicron cases reporting anosmia (8.9%).Conclusion: Key findings include a lower risk of anosmia and a reduced risk of hospitalisation in the first 1000 Omicron cases compared with co‐circulating Delta cases. We also identify that existing measures for travel restrictions to control importations of new variants identified outside the United Kingdom did not prevent the rapid ingress of Omicron within Wales.

Introduction Prisons are susceptible to outbreaks. Control measures focusing on isolation and cohorting negatively affect wellbeing. We present an outbreak of COVID-19 in a large male prison in Wales, UK, October 2020 to April 2021, and discuss control measures. Methods We gathered case-information, including demographics, staff-residence postcode, resident cell number, work areas/dates, test results, staff interview dates/notes and resident prison-transfer dates. Epidemiological curves were mapped by prison location. Control measures included isolation (exclusion from work or cell-isolation), cohorting (new admissions and work-area groups), asymptomatic testing (case-finding), removal of communal dining and movement restrictions. Facemask use and enhanced hygiene were already in place. Whole genome sequencing (WGS) and interviews determined genetic relationship between cases plausibility of transmission. Results Of 453 cases, 53% (n=242) were staff, most aged 25-34 years (11.5% females, 27.15% males) and symptomatic (64%). Crude attack-rate was higher in staff (29%, 95%CI: 26-64%) than in residents (12%, 95%CI: 9-15%). Conclusions Whole genome sequencing can help differentiate multiple introductions from person-to-person transmission in prisons. It should be introduced alongside asymptomatic testing as soon as possible to control prison outbreaks. Timely epidemiological investigation, including data visualisation, allowed dynamic risk assessment and proportionate control measures, minimising reduction in resident welfare.