Paediatric acute hepatitis of unknown aetiology: a national investigation and adenoviraemia case-control study in the UK.

BACKGROUND: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes. METHODS: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups. FINDINGS: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 37·4 [95% CI 15·5-90·3]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (ß 0·06 [95% CI 0·02-0·11]). No association was identified for SARS-CoV-2 antibody seropositivity. INTERPRETATION: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation. FUNDING: None.

A cross-sectional national investigation of COVID-19 outbreaks in nurseries during rapid spread of the Alpha (B.1.1.7) variant of SARS-CoV-2 in England.

BACKGROUND: In England, the emergence the more transmissible SARS-CoV-2 variant Alpha (B.1.1.7) led to a third national lockdown from December 2020, including restricted attendance at schools. Nurseries, however, remained fully open. COVID-19 outbreaks (≥ 2 laboratory-confirmed cases within 14 days) in nurseries were investigated to assess the risk of SARS-CoV-2 infection and cumulative incidence in staff and children over a three-month period when community SARS-CoV-2 infections rates were high and the Alpha variant was spreading rapidly across England. METHODS: This was a cross-sectional national investigation of COVID-19 outbreaks in nurseries across England. Nurseries reporting a COVID-19 outbreak to PHE between November 2020 and January 2021 were requested to complete a questionnaire about their outbreak. RESULTS: Three hundred and twenty-four nurseries, comprising 1% (324/32,852) of nurseries in England, reported a COVID-19 outbreak. Of the 315 (97%) nurseries contacted, 173 (55%) reported 1,657 SARS-CoV-2 cases, including 510 (31%) children and 1,147 (69%) staff. A child was the index case in 45 outbreaks (26%) and staff in 125 (72%) outbreaks. Overall, children had an incidence rate of 3.50% (95%CI, 3.21-3.81%) and was similar irrespective of whether the index case was a child (3.55%; 95%CI, 3.01-4.19%) or staff (3.44%; 95%CI, 3.10-3.82%). Among staff, cumulative incidence was lower if the index case was a child (26.28%; 95%CI, 23.54-29.21%%) compared to a staff member (32.98%; 95%CI, 31.19-34.82%), with the highest cumulative incidence when the index case was also a staff member (37.52%; 95%CI, 35.39-39.70%). Compared to November 2020, outbreak sizes and cumulative incidence was higher in January 2021, when the Alpha variant predominated. Nationally, SARS-CoV-2 infection rates in < 5 year-olds remained low and followed trends in older age-groups, increasing during December 2020 and declining thereafter. CONCLUSIONS: In this cross-sectional study of COVID-19 outbreaks in nurseries, one in three staff were affected compared to one in thirty children. There was some evidence of increased transmissibility and higher cumulative incidence associated with the Alpha variant, highlighting the importance of maintaining a low level of community infections.

Hepatitis of unknown aetiology in children - epidemiological overview of cases reported in Europe, 1 January to 16 June 2022.

Following the report of an excess in paediatric cases of severe acute hepatitis of unknown aetiology by the United Kingdom (UK) on 5 April 2022, 427 cases were reported from 20 countries in the World Health Organization European Region to the European Surveillance System TESSy from 1 January 2022 to 16 June 2022. Here, we analysed demographic, epidemiological, clinical and microbiological data available in TESSy. Of the reported cases, 77.3% were 5 years or younger and 53.5% had a positive test for adenovirus, 10.4% had a positive RT-PCR for SARS-CoV-2 and 10.3% were coinfected with both pathogens. Cases with adenovirus infections were significantly more likely to be admitted to intensive care or high-dependency units (OR = 2.11; 95% CI: 1.18-3.74) and transplanted (OR = 3.36; 95% CI: 1.19-9.55) than cases with a negative test result for adenovirus, but this was no longer observed when looking at this association separately between the UK and other countries. Aetiological studies are needed to ascertain if adenovirus plays a role in this possible emergence of hepatitis cases in children and, if confirmed, the mechanisms that could be involved.

Transmission dynamics of COVID-19 in household and community settings in the United Kingdom, January to March 2020.

BackgroundHouseholds appear to be the highest risk setting for COVID-19 transmission. Large household transmission studies in the early stages of the pandemic in Asia reported secondary attack rates ranging from 5 to 30%.AimWe aimed to investigate the transmission dynamics of COVID-19 in household and community settings in the UK.MethodsA prospective case-ascertained study design based on the World Health Organization FFX protocol was undertaken in the UK following the detection of the first case in late January 2020. Household contacts of cases were followed using enhanced surveillance forms to establish whether they developed symptoms of COVID-19, became confirmed cases and their outcomes. We estimated household secondary attack rates (SAR), serial intervals and individual and household basic reproduction numbers. The incubation period was estimated using known point source exposures that resulted in secondary cases.ResultsWe included 233 households with two or more people with 472 contacts. The overall household SAR was 37% (95% CI: 31-43%) with a mean serial interval of 4.67 days, an R0 of 1.85 and a household reproduction number of 2.33. SAR were lower in larger households and highest when the primary case was younger than 18 years. We estimated a mean incubation period of around 4.5 days.ConclusionsRates of COVID-19 household transmission were high in the UK for ages above and under 18 years, emphasising the need for preventative measures in this setting. This study highlights the importance of the FFX protocol in providing early insights on transmission dynamics.

The impact of social and physical distancing measures on COVID-19 activity in England: findings from a multi-tiered surveillance system.

BackgroundA multi-tiered surveillance system based on influenza surveillance was adopted in the United Kingdom in the early stages of the coronavirus disease (COVID-19) epidemic to monitor different stages of the disease. Mandatory social and physical distancing measures (SPDM) were introduced on 23 March 2020 to attempt to limit transmission.AimTo describe the impact of SPDM on COVID-19 activity as detected through the different surveillance systems.MethodsData from national population surveys, web-based indicators, syndromic surveillance, sentinel swabbing, respiratory outbreaks, secondary care admissions and mortality indicators from the start of the epidemic to week 18 2020 were used to identify the timing of peaks in surveillance indicators relative to the introduction of SPDM. This timing was compared with median time from symptom onset to different stages of illness and levels of care or interactions with healthcare services.ResultsThe impact of SPDM was detected within 1 week through population surveys, web search indicators and sentinel swabbing reported by onset date. There were detectable impacts on syndromic surveillance indicators for difficulty breathing, influenza-like illness and COVID-19 coding at 2, 7 and 12 days respectively, hospitalisations and critical care admissions (both 12 days), laboratory positivity (14 days), deaths (17 days) and nursing home outbreaks (4 weeks).ConclusionThe impact of SPDM on COVID-19 activity was detectable within 1 week through community surveillance indicators, highlighting their importance in early detection of changes in activity. Community swabbing surveillance may be increasingly important as a specific indicator, should circulation of seasonal respiratory viruses increase.

Epidemiological and clinical characteristics of early COVID-19 cases, United Kingdom of Great Britain and Northern Ireland.

OBJECTIVE: To describe the clinical presentation, course of disease and health-care seeking behaviour of the first few hundred cases of coronavirus disease 2019 (COVID-19) in the United Kingdom of Great Britain and Northern Ireland. METHODS: We implemented the World Health Organization's First Few X cases and contacts investigation protocol for COVID-19. Trained public health professionals collected information on 381 virologically confirmed COVID-19 cases from 31 January 2020 to 9 April 2020. We actively followed up cases to identify exposure to infection, symptoms and outcomes. We also collected limited data on 752 symptomatic people testing negative for COVID-19, as a control group for analyses of the sensitivity, specificity and predictive value of symptoms. FINDINGS: Approximately half of the COVID-19 cases were imported (196 cases; 51.4%), of whom the majority had recent travel to Italy (140 cases; 71.4%). Of the 94 (24.7%) secondary cases, almost all reported close contact with a confirmed case (93 cases; 98.9%), many through household contact (37 cases; 39.8%). By age, a lower proportion of children had COVID-19. Most cases presented with cough, fever and fatigue. The sensitivity and specificity of symptoms varied by age, with nonlinear relationships with age. Although the proportion of COVID-19 cases with fever increased with age, for those with other respiratory infections the occurrence of fever decreased with age. The occurrence of shortness of breath also increased with age in a greater proportion of COVID-19 cases. CONCLUSION: The study has provided useful evidence for generating case definitions and has informed modelling studies of the likely burden of COVID-19.

SARS-CoV-2 infections in children following the full re-opening of schools and the impact of national lockdown: Prospective, national observational cohort surveillance, July-December 2020, England.

INTRODUCTION: The reopening of schools during the COVID-19 pandemic has raised concern for the safety of staff and students, their families and the wider community. We monitored SARS-CoV-2 infection rates in school-aged children and compared them with adult infection rates before and after schools reopened in England. METHODS: Public Health England receives daily electronic reports of all SARS-CoV-2 tests nationally. SARS-CoV-2 infection rates by school year from July to December 2020 were analysed, including the effect of a national month-long lockdown whilst keeping schools open in November 2020 RESULTS: SARS-CoV-2 infections rates were low during early summer but started increasing in mid-August, initially in young adults followed by secondary and then primary school-aged children prior to schools reopening in September 2020. Cases in school-aged children lagged behind and followed adult trends after schools reopened, with a strong age gradient in weekly infection rates. There was a strong (P<0.001) correlation in regional infection rates between adults and secondary (R2=0.96-0.98), primary (R2=0.93-0.94) and preschool-aged (R2=0.62-0.85) children. The November lockdown was associated with declines in adult infection rates, followed a week later, by declines in student cases. From 23 November 2020, cases in adults and children increased rapidly following the emergence of a more transmissible novel variant of concern (VOC-202,012/01; B.1.1.7). CONCLUSIONS: In school-aged children, SARS-CoV-2 infections followed the same trajectory as adult cases and only declined after national lockdown was implemented whilst keeping schools open. Maintaining low community infection rates is critical for keeping schools open during the pandemic.

All-cause excess mortality observed by age group and regions in the first wave of the COVID-19 pandemic in England.

England has experienced one of the highest excess in all-cause mortality in Europe during the current COVID-19 pandemic. As COVID-19 emerged, the excess in all-cause mortality rapidly increased, starting in March 2020. The excess observed during the pandemic was higher than excesses noted in the past 5 years. It concerned all regions and all age groups, except the 0-14 year olds, but was more pronounced in the London region and in those aged ≥ 85 years.

Dairy Products and Dairy-Processing Environments as a Reservoir of Antibiotic Resistance and Quorum-Quenching Determinants as Revealed through Functional Metagenomics.

Here, the role of the dairy-processing chain as a reservoir of antimicrobial resistance (AR) determinants and a source of novel biocontrol quorum-sensing inhibitors is assessed through a functional metagenomics approach. A metagenomic library comprising ∼22,000 recombinant clones was built from DNA isolated from raw milk, raw milk cheeses, and cheese-processing environment swab samples. The high-throughput sequencing of 9,216 recombinant clones showed that lactic acid bacteria (LAB) dominated the microbial communities of raw milk cheese, while Gram-negative microorganisms of animal or soil origin dominated the microbiota of raw milk and cheese-processing environments. Although functional screening of the metagenomic library did not recover potential quorum-sensing inhibitors, in silico analysis using an in-house database built specifically for this study identified homologues to several genes encoding proteins with predicted quorum-quenching activity, among which, the QsdH hydrolase was the most abundant. In silico screening of the library identified LAB, and especially Lactococcus lactis, as a relevant reservoir of AR determinants in cheese. Functional screening of the library allowed the isolation of 13 recombinant clones showing an increased resistance toward ampicillin, which in all cases was accompanied by a reduced susceptibility to a wide range of ß-lactam antibiotics. This study shows that the dairy-processing environment is a rich reservoir of AR determinants, which vary by sample source, and suggests that combining next-generation sequencing with functional metagenomics can be of use in overcoming the limitations of both approaches.IMPORTANCE The study shows the potential of functional metagenomics analyses to uncover the diversity of functions in microbial communities prevailing in dairy products and their processing environments, evidencing that lactic acid bacteria (LAB) dominate the cheese microbiota, whereas Gram-negative microorganisms of animal or soil origin dominate the microbiota of milk and cheese-processing environments. The functional and in silico screening of the library allowed the identification of LAB, and especially Lactococcus lactis, as a relevant reservoir of antimicrobial resistance (AR) determinants in cheese. Quorum-quenching (QQ) determinants were not recovered through the execution of wet-lab function-based screenings but were detected through in silico sequencing-based analyses.

Biofilms in Food Processing Environments: Challenges and Opportunities.

This review examines the impact of microbial communities colonizing food processing environments in the form of biofilms on food safety and food quality. The focus is both on biofilms formed by pathogenic and spoilage microorganisms and on those formed by harmless or beneficial microbes, which are of particular relevance in the processing of fermented foods. Information is presented on intraspecies variability in biofilm formation, interspecies relationships of cooperativism or competition within biofilms, the factors influencing biofilm ecology and architecture, and how these factors may influence removal. The effect on the biofilm formation ability of particular food components and different environmental conditions that commonly prevail during food processing is discussed. Available tools for the in situ monitoring and characterization of wild microbial biofilms in food processing facilities are explored. Finally, research on novel agents or strategies for the control of biofilm formation or removal is summarized.

New Weapons to Fight Old Enemies: Novel Strategies for the (Bio)control of Bacterial Biofilms in the Food Industry.

Biofilms are microbial communities characterized by their adhesion to solid surfaces and the production of a matrix of exopolymeric substances, consisting of polysaccharides, proteins, DNA and lipids, which surround the microorganisms lending structural integrity and a unique biochemical profile to the biofilm. Biofilm formation enhances the ability of the producer/s to persist in a given environment. Pathogenic and spoilage bacterial species capable of forming biofilms are a significant problem for the healthcare and food industries, as their biofilm-forming ability protects them from common cleaning processes and allows them to remain in the environment post-sanitation. In the food industry, persistent bacteria colonize the inside of mixing tanks, vats and tubing, compromising food safety and quality. Strategies to overcome bacterial persistence through inhibition of biofilm formation or removal of mature biofilms are therefore necessary. Current biofilm control strategies employed in the food industry (cleaning and disinfection, material selection and surface preconditioning, plasma treatment, ultrasonication, etc.), although effective to a certain point, fall short of biofilm control. Efforts have been explored, mainly with a view to their application in pharmaceutical and healthcare settings, which focus on targeting molecular determinants regulating biofilm formation. Their application to the food industry would greatly aid efforts to eradicate undesirable bacteria from food processing environments and, ultimately, from food products. These approaches, in contrast to bactericidal approaches, exert less selective pressure which in turn would reduce the likelihood of resistance development. A particularly interesting strategy targets quorum sensing systems, which regulate gene expression in response to fluctuations in cell-population density governing essential cellular processes including biofilm formation. This review article discusses the problems associated with bacterial biofilms in the food industry and summarizes the recent strategies explored to inhibit biofilm formation, with special focus on those targeting quorum sensing.

Biotechnological applications of functional metagenomics in the food and pharmaceutical industries.

Microorganisms are found throughout nature, thriving in a vast range of environmental conditions. The majority of them are unculturable or difficult to culture by traditional methods. Metagenomics enables the study of all microorganisms, regardless of whether they can be cultured or not, through the analysis of genomic data obtained directly from an environmental sample, providing knowledge of the species present, and allowing the extraction of information regarding the functionality of microbial communities in their natural habitat. Function-based screenings, following the cloning and expression of metagenomic DNA in a heterologous host, can be applied to the discovery of novel proteins of industrial interest encoded by the genes of previously inaccessible microorganisms. Functional metagenomics has considerable potential in the food and pharmaceutical industries, where it can, for instance, aid (i) the identification of enzymes with desirable technological properties, capable of catalyzing novel reactions or replacing existing chemically synthesized catalysts which may be difficult or expensive to produce, and able to work under a wide range of environmental conditions encountered in food and pharmaceutical processing cycles including extreme conditions of temperature, pH, osmolarity, etc; (ii) the discovery of novel bioactives including antimicrobials active against microorganisms of concern both in food and medical settings; (iii) the investigation of industrial and societal issues such as antibiotic resistance development. This review article summarizes the state-of-the-art functional metagenomic methods available and discusses the potential of functional metagenomic approaches to mine as yet unexplored environments to discover novel genes with biotechnological application in the food and pharmaceutical industries.