Postpandemic Sentinel Surveillance of Respiratory Diseases in the Context of the World Health Organization Mosaic Framework: Protocol for a Development and Evaluation Study Involving the English Primary Care Network 2023-2024.

BACKGROUND: Prepandemic sentinel surveillance focused on improved management of winter pressures, with influenza-like illness (ILI) being the key clinical indicator. The World Health Organization (WHO) global standards for influenza surveillance include monitoring acute respiratory infection (ARI) and ILI. The WHO's mosaic framework recommends that the surveillance strategies of countries include the virological monitoring of respiratory viruses with pandemic potential such as influenza. The Oxford-Royal College of General Practitioner Research and Surveillance Centre (RSC) in collaboration with the UK Health Security Agency (UKHSA) has provided sentinel surveillance since 1967, including virology since 1993. OBJECTIVE: We aim to describe the RSC's plans for sentinel surveillance in the 2023-2024 season and evaluate these plans against the WHO mosaic framework. METHODS: Our approach, which includes patient and public involvement, contributes to surveillance objectives across all 3 domains of the mosaic framework. We will generate an ARI phenotype to enable reporting of this indicator in addition to ILI. These data will support UKHSA's sentinel surveillance, including vaccine effectiveness and burden of disease studies. The panel of virology tests analyzed in UKHSA's reference laboratory will remain unchanged, with additional plans for point-of-care testing, pneumococcus testing, and asymptomatic screening. Our sampling framework for serological surveillance will provide greater representativeness and more samples from younger people. We will create a biomedical resource that enables linkage between clinical data held in the RSC and virology data, including sequencing data, held by the UKHSA. We describe the governance framework for the RSC. RESULTS: We are co-designing our communication about data sharing and sampling, contextualized by the mosaic framework, with national and general practice patient and public involvement groups. We present our ARI digital phenotype and the key data RSC network members are requested to include in computerized medical records. We will share data with the UKHSA to report vaccine effectiveness for COVID-19 and influenza, assess the disease burden of respiratory syncytial virus, and perform syndromic surveillance. Virological surveillance will include COVID-19, influenza, respiratory syncytial virus, and other common respiratory viruses. We plan to pilot point-of-care testing for group A streptococcus, urine tests for pneumococcus, and asymptomatic testing. We will integrate test requests and results with the laboratory-computerized medical record system. A biomedical resource will enable research linking clinical data to virology data. The legal basis for the RSC's pseudonymized data extract is The Health Service (Control of Patient Information) Regulations 2002, and all nonsurveillance uses require research ethics approval. CONCLUSIONS: The RSC extended its surveillance activities to meet more but not all of the mosaic framework's objectives. We have introduced an ARI indicator. We seek to expand our surveillance scope and could do more around transmissibility and the benefits and risks of nonvaccine therapies.

Influenza vaccination during the 2021/22 season: A data-linkage test-negative case-control study of effectiveness against influenza requiring emergency care in England and serological analysis of primary care patients.

We present England 2021/22 end-of-season adjusted vaccine effectiveness (aVE) against laboratory confirmed influenza related emergency care use in children aged 1-17 and in adults aged 50+, and serological findings in vaccinated vs unvaccinated adults by hemagglutination inhibition assay. Influenza vaccination has been routinely offered to all children aged 2-10 years and adults aged 65 years + in England. In 2021/22, the offer was extended to children to age 15 years, and adults aged 50-64 years. Influenza activity rose during the latter half of the 2021/22 season, while remaining comparatively low due to COVID-19 pandemic control measures. Influenza A(H3N2) strains predominated. A test negative design was used to estimate aVE by vaccine type. Cases and controls were identified within a sentinel laboratory surveillance system. Vaccine histories were obtained from the National Immunisation Management Service (NIMS), an influenza and COVID-19 vaccine registry. These were linked to emergency department presentations (excluding accidents) with respiratory swabbing ≤ 14 days before or ≤ 7 days after presentation. Amongst adults, 423 positive and 32,917 negative samples were eligible for inclusion, and 145 positive and 6,438 negative samples among children. Those admitted to hospital were further identified. In serology against the circulating A(H3N2) A/Bangladesh/4005/2020-like strain, 61 % of current season adult vaccinees had titres ≥ 1:40 compared to 17 % of those unvaccinated in 2020/21 or 2021/22 (p < 0.001). We found good protection from influenza vaccination against influenza requiring emergency care in children (72.7 % [95 % CI 52.7, 84.3 %]) and modest effectiveness in adults (26.1 % [95 % CI 4.5, 42.8 %]). Adult VE was higher for A(H1N1) (81 % [95 % CI 50, 93 %]) than A(H3N2) (33 % [95 % CI 6, 53 %]). Consistent protection was observable across preschool, primary and secondary school aged children. Imperfect test specificity combined with very low prevalence may have biased estimates towards null. With limited influenza circulation, the study could not determine differences by vaccine types.

COVID-19 vaccine effectiveness against hospitalisation and death of people in clinical risk groups during the Delta variant period: English primary care network cohort study.

BACKGROUND: COVID-19 vaccines have been shown to be highly effective against hospitalisation and death following COVID-19 infection. COVID-19 vaccine effectiveness estimates against severe endpoints among individuals with clinical conditions that place them at increased risk of critical disease are limited. METHODS: We used English primary care medical record data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre sentinel network (N > 18 million). Data were linked to the National Immunisation Management Service database, Second Generation Surveillance System for virology test data, Hospital Episode Statistics, and death registry data. We estimated adjusted vaccine effectiveness (aVE) against COVID-19 infection followed by hospitalisation and death among individuals in specific clinical risk groups using a cohort design during the delta-dominant period. We also report mortality statistics and results from our antibody surveillance in this population. FINDINGS: aVE against severe endpoints was high, 14-69d following a third dose aVE was 96.4% (95.1%-97.4%) and 97.9% (97.2%-98.4%) for clinically vulnerable people given a Vaxzevria and Comirnaty primary course respectively. Lower aVE was observed in the immunosuppressed group: 88.6% (79.1%-93.8%) and 91.9% (85.9%-95.4%) for Vaxzevria and Comirnaty respectively. Antibody levels were significantly lower among the immunosuppressed group than those not in this risk group across all vaccination types and doses. The standardised case fatality rate within 28 days of a positive test was 3.9/1000 in people not in risk groups, compared to 12.8/1000 in clinical risk groups. Waning aVE with time since 2nd dose was also demonstrated, for example, Comirnaty aVE against hospitalisation reduced from 96.0% (95.1-96.7%) 14-69days post-dose 2-82.9% (81.4-84.2%) 182days+ post-dose 2. INTERPRETATION: In all clinical risk groups high levels of vaccine effectiveness against severe endpoints were seen. Reduced vaccine effectiveness was noted among the immunosuppressed group.

The Impact of Point-of-Care Testing for Influenza on Antimicrobial Stewardship (PIAMS) in UK Primary Care: Protocol for a Mixed Methods Study.

BACKGROUND: Molecular point-of-care testing (POCT) used in primary care can inform whether a patient presenting with an acute respiratory infection has influenza. A confirmed clinical diagnosis, particularly early in the disease, could inform better antimicrobial stewardship. Social distancing and lockdowns during the COVID-19 pandemic have disturbed previous patterns of influenza infections in 2021. However, data from samples taken in the last quarter of 2022 suggest that influenza represents 36% of sentinel network positive virology, compared with 24% for respiratory syncytial virus. Problems with integration into the clinical workflow is a known barrier to incorporating technology into routine care. OBJECTIVE: This study aims to report the impact of POCT for influenza on antimicrobial prescribing in primary care. We will additionally describe severe outcomes of infection (hospitalization and mortality) and how POCT is integrated into primary care workflows. METHODS: The impact of POCT for influenza on antimicrobial stewardship (PIAMS) in UK primary care is an observational study being conducted between December 2022 and May 2023 and involving 10 practices that contribute data to the English sentinel network. Up to 1000 people who present to participating practices with respiratory symptoms will be swabbed and tested with a rapid molecular POCT analyzer in the practice. Antimicrobial prescribing and other study outcomes will be collected by linking information from the POCT analyzer with data from the patient's computerized medical record. We will collect data on how POCT is incorporated into practice using data flow diagrams, unified modeling language use case diagrams, and Business Process Modeling Notation. RESULTS: We will present the crude and adjusted odds of antimicrobial prescribing (all antibiotics and antivirals) given a POCT diagnosis of influenza, stratifying by whether individuals have a respiratory or other relevant diagnosis (eg, bronchiectasis). We will also present the rates of hospital referrals and deaths related to influenza infection in PIAMS study practices compared with a set of matched practices in the sentinel network and the rest of the network. We will describe any difference in implementation models in terms of staff involved and workflow. CONCLUSIONS: This study will generate data on the impact of POCT testing for influenza in primary care as well as help to inform about the feasibility of incorporating POCT into primary care workflows. It will inform the design of future larger studies about the effectiveness and cost-effectiveness of POCT to improve antimicrobial stewardship and any impact on severe outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46938.

Development of a modified Cambridge Multimorbidity Score for use with SNOMED CT: an observational English primary care sentinel network study.

BACKGROUND: People with multiple health conditions are more likely to have poorer health outcomes and greater care and service needs; a reliable measure of multimorbidity would inform management strategies and resource allocation. AIM: To develop and validate a modified version of the Cambridge Multimorbidity Score in an extended age range, using clinical terms that are routinely used in electronic health records across the world (Systematized Nomenclature of Medicine - Clinical Terms, SNOMED CT). DESIGN AND SETTING: Observational study using diagnosis and prescriptions data from an English primary care sentinel surveillance network between 2014 and 2019. METHOD: In this study new variables describing 37 health conditions were curated and the associations modelled between these and 1-year mortality risk using the Cox proportional hazard model in a development dataset (n = 300 000). Two simplified models were then developed - a 20-condition model as per the original Cambridge Multimorbidity Score and a variable reduction model using backward elimination with Akaike information criterion as the stopping criterion. The results were compared and validated for 1-year mortality in a synchronous validation dataset (n = 150 000), and for 1-year and 5-year mortality in an asynchronous validation dataset (n = 150 000). RESULTS: The final variable reduction model retained 21 conditions, and the conditions mostly overlapped with those in the 20-condition model. The model performed similarly to the 37- and 20-condition models, showing high discrimination and good calibration following recalibration. CONCLUSION: This modified version of the Cambridge Multimorbidity Score allows reliable estimation using clinical terms that can be applied internationally across multiple healthcare settings.

Representativeness, Vaccination Uptake, and COVID-19 Clinical Outcomes 2020-2021 in the UK Oxford-Royal College of General Practitioners Research and Surveillance Network: Cohort Profile Summary.

BACKGROUND: The Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) is one of Europe's oldest sentinel systems, working with the UK Health Security Agency (UKHSA) and its predecessor bodies for 55 years. Its surveillance report now runs twice weekly, supplemented by online observatories. In addition to conducting sentinel surveillance from a nationally representative group of practices, the RSC is now also providing data for syndromic surveillance. OBJECTIVE: The aim of this study was to describe the cohort profile at the start of the 2021-2022 surveillance season and recent changes to our surveillance practice. METHODS: The RSC's pseudonymized primary care data, linked to hospital and other data, are held in the Oxford-RCGP Clinical Informatics Digital Hub, a Trusted Research Environment. We describe the RSC's cohort profile as of September 2021, divided into a Primary Care Sentinel Cohort (PCSC)-collecting virological and serological specimens-and a larger group of syndromic surveillance general practices (SSGPs). We report changes to our sampling strategy that brings the RSC into alignment with European Centre for Disease Control guidance and then compare our cohort's sociodemographic characteristics with Office for National Statistics data. We further describe influenza and COVID-19 vaccine coverage for the 2020-2021 season (week 40 of 2020 to week 39 of 2021), with the latter differentiated by vaccine brand. Finally, we report COVID-19-related outcomes in terms of hospitalization, intensive care unit (ICU) admission, and death. RESULTS: As a response to COVID-19, the RSC grew from just over 500 PCSC practices in 2019 to 1879 practices in 2021 (PCSC, n=938; SSGP, n=1203). This represents 28.6% of English general practices and 30.59% (17,299,780/56,550,136) of the population. In the reporting period, the PCSC collected >8000 virology and >23,000 serology samples. The RSC population was broadly representative of the national population in terms of age, gender, ethnicity, National Health Service Region, socioeconomic status, obesity, and smoking habit. The RSC captured vaccine coverage data for influenza (n=5.4 million) and COVID-19, reporting dose one (n=11.9 million), two (n=11 million), and three (n=0.4 million) for the latter as well as brand-specific uptake data (AstraZeneca vaccine, n=11.6 million; Pfizer, n=10.8 million; and Moderna, n=0.7 million). The median (IQR) number of COVID-19 hospitalizations and ICU admissions was 1181 (559-1559) and 115 (50-174) per week, respectively. CONCLUSIONS: The RSC is broadly representative of the national population; its PCSC is geographically representative and its SSGPs are newly supporting UKHSA syndromic surveillance efforts. The network captures vaccine coverage and has expanded from reporting primary care attendances to providing data on onward hospital outcomes and deaths. The challenge remains to increase virological and serological sampling to monitor the effectiveness and waning of all vaccines available in a timely manner.

Assessing the Clinical and Socioeconomic Burden of Respiratory Syncytial Virus in Children Aged Under 5 Years in Primary Care: Protocol for a Prospective Cohort Study in England and Report on the Adaptations of the Study to the COVID-19 Pandemic.

BACKGROUND: Respiratory syncytial virus (RSV) commonly causes lower respiratory tract infections and hospitalization in children. In 2019-2020, the Europe-wide RSV ComNet standardized study protocol was developed to measure the clinical and socioeconomic disease burden of RSV infections among children aged <5 years in primary care. RSV has a recognized seasonality in England. OBJECTIVE: We aimed to describe (1) the adaptations of the RSV ComNet standardized study protocol for England and (2) the challenges of conducting the study during the COVID-19 pandemic. METHODS: This study was conducted by the Oxford-Royal College of General Practitioners Research and Surveillance Centre-the English national primary care sentinel network. We invited all (N=248) general practices within the network that undertook virology sampling to participate in the study by recruiting eligible patients (registered population: n=3,056,583). Children aged <5 years with the following case definition of RSV infection were included in the study: those consulting a health care practitioner in primary care with symptoms meeting the World Health Organization's definition of acute respiratory illness or influenza-like illness who have laboratory-confirmed RSV infection. The parents/guardians of these cases were asked to complete 2 previously validated questionnaires (14 and 30 days postsampling). A sample size of at least 100 RSV-positive cases is required to estimate the percentage of children that consult in primary care who need hospitalization. Assuming a swab positivity rate of 20% in children aged <5 years, we estimated that 500 swabs are required. We adapted our method for the pandemic by extending sampling planned for winter 2020-2021 to a rolling data collection, allowing verbal consent and introducing home swabbing because of increased web-based consultations during the COVID-19 pandemic. RESULTS: The preliminary results of the data collection between International Organization for Standardization (ISO) weeks 1-41 in 2021 are described. There was no RSV detected in the winter of 2020-2021 through the study. The first positive RSV swab collected through the sentinel network in England was collected in ISO week 17 and then every week since ISO week 25. In total, 16 (N=248, 6.5%) of the virology-sampling practices volunteered to participate; these were high-sampling practices collecting the majority of eligible swabs across the sentinel network-200 (43.8%) out of 457 swabs, of which 54 (N=200, 27%) were positive for RSV. CONCLUSIONS: Measures to control the COVID-19 pandemic meant there was no circulating RSV last winter; however, RSV has circulated out of season, as detected by the sentinel network. The sentinel network practices have collected 40% (200/500) of the required samples, and 27% (54/200) were RSV positive. We have demonstrated the feasibility of implementing a European-standardized RSV disease burden study protocol in England during a pandemic, and we now need to recruit to this adapted protocol. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/38026.

Sociodemographic disparities in COVID-19 seroprevalence across England in the Oxford RCGP primary care sentinel network.

OBJECTIVES: To monitor changes in seroprevalence of SARS-CoV-2 antibodies in populations over time and between different demographic groups. METHODS: A subset of practices in the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) sentinel network provided serum samples, collected when volunteer patients had routine blood tests. We tested these samples for SARS-CoV-2 antibodies using Abbott (Chicago, USA), Roche (Basel, Switzerland) and/or Euroimmun (Luebeck, Germany) assays, and linked the results to the patients' primary care computerised medical records. We report seropositivity by region and age group, and additionally examined the effects of gender, ethnicity, deprivation, rurality, shielding recommendation and smoking status. RESULTS: We estimated seropositivity from patients aged 18-100 years old, which ranged from 4.1% (95% CI 3.1-5.3%) to 8.9% (95% CI 7.8-10.2%) across the different assays and time periods. We found higher Euroimmun seropositivity in younger age groups, people of Black and Asian ethnicity (compared to white), major conurbations, and non-smokers. We did not observe any significant effect by region, gender, deprivation, or shielding recommendation. CONCLUSIONS: Our results suggest that prior to the vaccination programme, most of the population remained unexposed to SARS-CoV-2.

Pfizer-BioNTech and Oxford AstraZeneca COVID-19 vaccine effectiveness and immune response amongst individuals in clinical risk groups.

Background COVID-19 vaccines approved in the UK are highly effective in general population cohorts, however, data on effectiveness amongst individuals with clinical conditions that place them at increased risk of severe disease are limited. Methods We used GP electronic health record data, sentinel virology swabbing and antibody testing within a cohort of 712 general practices across England to estimate vaccine antibody response and vaccine effectiveness against medically attended COVID-19 amongst individuals in clinical risk groups using cohort and test-negative case control designs. Findings There was no reduction in S-antibody positivity in most clinical risk groups, however reduced S-antibody positivity and response was significant in the immunosuppressed group. Reduced vaccine effectiveness against clinical disease was also noted in the immunosuppressed group; after a second dose, effectiveness was moderate (Pfizer: 59.6%, 95%CI 18.0-80.1%; AstraZeneca 60.0%, 95%CI -63.6-90.2%). Interpretation In most clinical risk groups, immune response to primary vaccination was maintained and high levels of vaccine effectiveness were seen. Reduced antibody response and vaccine effectiveness were seen after 1 dose of vaccine amongst a broad immunosuppressed group, and second dose vaccine effectiveness was moderate. These findings support maximising coverage in immunosuppressed individuals and the policy of prioritisation of this group for third doses.

Modelling the early expressive communicative trajectories of infants/toddlers with early cochlear implants.

For children with normal hearing (NH), early communication skills predict vocabulary, a precursor to grammar. Growth in early communication skills of infants with cochlear implants (CIs) was investigated using the Early Communication Indicator (ECI), a play-based observation measure. Multilevel linear growth modelling on data from six ECI sessions held at three-monthly intervals revealed significant growth overall, with a non-significant slower growth rate than that of children with NH (comparison age centred at 18 months). Analyses of gesture use and of nonword vocalisations revealed the CI group used significantly more of each, with more rapid growth. In contrast, the CI group used significantly fewer single words and multiword utterances, and with slower growth. Maternal education and time to achieve consistent CI use impacted significantly on growth for the CI sample. The results indicate that progression to vocabulary by young CI users can be supported by encouraging their use of prelinguistic communication.

Allied Health Clinicians' Understanding of Palliative Care as It Relates to Patients, Caregivers, and Health Clinicians: A Cross-Sectional Survey.

PURPOSE: The scope of hospice or palliative care has expanded since its inception, which has significant ramifications for the AH workforce. This study sought to elicit allied health (AH) clinicians' understanding and views about palliative care and its relevance to their clinical practice and to identify their educational needs. Results from analysis of free text survey responses to a single open-ended question from a larger survey are presented. METHODS: An online survey was distributed to AH clinicians via email lists for the CareSearch Allied Health Hub, Allied Health Professions Australia, and other groups. Descriptive statistics and content analysis of free text responses were used to analyse the data. RESULTS: A total of 217 AH clinicians responded to an email survey and 187 useable responses were analysed. Four themes were identified: 1) palliative care employs a client-centred model of care, 2) acknowledgement of living whilst dying, 3) interdisciplinary palliative care interventions provide active care in a range of domains, and 4) characteristics of palliative care teams and settings. CONCLUSION: AH clinicians plan an active role in physical, social, and psycho-spiritual care of palliative care patients and caregivers. Burgeoning numbers of palliative care patients in nonspecialist palliative care settings require AH clinicians to develop skills and competencies to work with people who have advanced disease.