Syndromic case definitions for Lower Respiratory Tract Infection (LRTI) are less sensitive in older age: an analysis of symptoms among hospitalised adults (preprint)

Background Lower Respiratory Tract Infections (LRTI) pose a serious threat to older adults but may be underdiagnosed due to atypical presentations. Here we assess LRTI symptom profiles and syndromic (symptom-based) case ascertainment in older (≥65y) as compared to younger adults (<65y). Methods We included adults (≥18y) with confirmed LRTI admitted to two acute care Trusts in Bristol, UK from 1st August 2020- 31st July 2022.  Logistic regression was used to assess whether age ≥65y reduced the probability of meeting syndromic LRTI case definitions, using patients’ symptoms at admission. We also calculated relative symptom frequencies (log-odds ratios) and evaluated how symptoms were clustered across different age groups. Results Of 17,620 clinically confirmed LRTI cases, 8,487 (48.1%) had symptoms meeting the case definition. Compared to those not meeting the definition these cases were younger, had less severe illness and were less likely to have received a SARS-CoV-2 vaccination or to have active SARS-CoV-2 infection. Prevalence of dementia/cognitive impairment and levels of comorbidity were lower in this group. After controlling for sex, dementia and comorbidities, age ≥65y significantly reduced the probability of meeting the case definition (aOR=0.67, 95% CI:0.63-0.71). Cases aged ≥65y were less likely to present with fever and LRTI-specific symptoms (e.g., pleurisy, sputum) than younger cases, and those aged ≥85y were characterised by lack of cough but frequent confusion and falls. Conclusions LRTI symptom profiles changed considerably with age in this hospitalised cohort. Standard screening protocols may fail to detect older and frailer cases of LRTI based on their symptoms.

The Agile Co-production and Evaluation (ACE) framework for developing public health interventions, messaging and guidance (preprint)

A lesson identified from the COVID-19 pandemic is that we need to extend existing best practice for intervention development by establishing better methods of rapidly coproducing public health interventions and messaging to support all population groups to protect themselves and their communities, together with better methods of rapidly evaluating interventions to determine which are acceptable and effective. This paper describes the Agile Co-production and Evaluation (ACE) framework, which is intended to provide a focus for investigating new ways of rapidly developing effective interventions and messaging by combining co-production methods with large-scale testing and/or real-world evaluation. We briefly review some of the participatory, qualitative and quantitative methods that could potentially be combined and propose a research agenda to further develop, refine and validate packages of methods in a variety of public health contexts to determine which combinations are feasible, cost-effective and achieve the goal of improving health and reducing health inequalities.

Understanding adherence to self-isolation in the first phase of COVID-19 response (preprint)

Objective: To gain a better understanding of decisions around adherence to self-isolation advice during the first phase of the COVID-19 response in England. Design: A mixed-methods cross sectional study. Setting: England Participants COVID-19 cases and contacts who were contacted by Public Health England (PHE) during the first phase of the response in England (January-March 2020). Results: Of 250 respondents who were advised to self-isolate, 63% reported not leaving home at all during their isolation period, 20% reported leaving only for lower risk activities (dog walking or exercise) and 16% reported leaving for potentially higher risk, reasons (shopping, medical appointments, childcare, meeting family or friends). Factors associated with adherence to never going out included: the belief that following isolation advice would save lives, experiencing COVID-19 symptoms, being advised to stay in their room (rather than just inside), having help from outside and having regular contact by text message from PHE. Factors associated with non-adherence included being angry about the advice to isolate, being unable to get groceries delivered and concerns about losing touch with friends and family. Interviews highlighted that a sense of duty motivated people to adhere to isolation guidance and where people did leave their homes, these decisions were based on rational calculations of the risk of transmission; people would only leave their homes when they thought they were unlikely to come into contact with others. Conclusions: Measures of adherence should be nuanced to allow for the adaptations people make to their behaviour during isolation. Understanding adherence to isolation and associated reasoning during the early stages of the pandemic is an essential part of pandemic preparedness for future emerging infectious diseases.

Exploring the impact of shielding advice on the health and wellbeing of individuals identified as extremely vulnerable and advised to shield in Southwest England amid the COVID-19 pandemic: A mixed-methods evaluation (preprint)

Objective: Explore the impact and responses to public health advice on the health and wellbeing of individuals identified as clinically extremely vulnerable (CEV) and advised to shield (not leave home for 12 weeks at start of the pandemic) in Southwest England during the first COVID-19 lockdown. Design: Mixed-methods study; structured survey and follow-up semi-structured interviews. Setting: Communities served by Bristol, North Somerset & South Gloucestershire Clinical Commissioning Group. Participants: 204 people (57% female, 54% >69 years, 94% White British, 64% retired) in Southwest England identified as CEV and were advised to shield completed the survey. Thirteen survey respondents participated in follow-up interviews (53% female, 40% >69years, 100% White British, 61% retired). Results: Receipt of official communication from NHS England or General Practitioner (GP) was considered by participants as the legitimate start of shielding. 80% of survey responders felt they received all relevant advice needed to shield, yet interviewees criticised the timing of advice and often sought supplementary information. Shielding behaviours were nuanced, adapted to suit personal circumstances, and waned over time. Few interviewees received community support, although food boxes and informal social support were obtained by some. Worrying about COVID-19 was common for survey responders (90%). Since shielding had begun, physical and mental health reportedly worsened for 35% and 42% of survey responders respectively. 21% of survey responders scored 10 or more on the PHQ-9 questionnaire indicating possible depression and 15% scored 10 or more on the GAD-7 questionnaire indicating possible anxiety. Conclusions: This research highlights the difficulties in providing generic messaging that is applicable and appropriate given the diversity of individuals identified as CEV and the importance of sharing tailored and timely advice to inform shielding decisions. Providing messages that reinforce self-determined action and assistance from support services could reduce the negative impact of shielding on mental health and feelings of social isolation.

Learning about COVID-19 across borders: Public health information and adherence among international travellers to the UK (preprint)

ObjectivePublic health control measures at borders have long been central to national strategies for the prevention and containment of infectious diseases. Travel was inevitably associated with the rapid global transmission of COVID-19. In the UK, public health authorities took action to reduce risks of travel-associated spread by providing public health information at ports of entry. This study aims to understand individual risk assessment processes, decision making, and adherence to official advice among international travellers; to provide evidence to inform future policy on the presentation of public health information to facilitate safer international travel. Study designThis study is a qualitative study evaluation. MethodSemi-structured interviews were conducted to investigate risk assessment processes, decision making, and adherence to official Public Health England (PHE) advice among travellers. ResultsParticipants regarded official advice as adequate at the time, despite observing differences between the intervention measures implemented in the countries of departure. Participants however also described adopting precautionary measures including self-isolation and the use of face coverings that went beyond official advice, and variability in the extent to which they adhered to guidance on contacting health authorities. Adherence to official guidance was informed by the perceived salience of specific transmission possibilities and containment measures assessed in relation to participants social and institutional environments. ConclusionAnalysis of travellers reported motivations demonstrates that responses to public health advice constitute a proactive process of risk assessment and rationalised decision-making that incorporates consideration of living situation, trust in information sources, correspondence with cultural logics, and willingness to accept potential risk to self and significant others in guiding preventive action. Our findings concerning international passengers understanding of, and compliance with, official advice and mitigation measures provide valuable evidence to inform future policy and we provide recommendations on the presentation of public health information to facilitate safer international travel. Access to a central source of regularly updated official information would help minimise confusion between different national guidelines. Greater attention to the differentiated information needs of diverse groups in creating future public-facing guidance would help to minimise the uncertainties generated by receipt of generic information.

Low uptake of COVID-19 lateral flow testing among university students: a mixed methods evaluation (preprint)

BackgroundUniversity populations offer a unique opportunity to quantify COVID-19 lateral flow testing (LFT) uptake. MethodsMixed methods evaluation of LFT among University of Bristol students comprising an analysis of testing uptake using logistic regression analyses; a survey; and qualitative interviews to explore experiences of testing and subsequent behaviour. Results12,391 LFTs were conducted on 8025/36,054 (22.3%) students. Only one in 10 students had the recommended two tests. There were striking demographic disparities in uptake with those from ethnic minority groups having lower uptake (e.g. 3% of Chinese students were tested vs. 30.7% of White students), and variations by level and year of study (ranging from 5.3% to 33.7%), place of residence (29.0% to 35.6%) and faculty (15.2% to 32.8%). Barriers to engagement with testing included a lack of awareness, knowledge and understanding, and concerns about the accuracy and safety. Students understood limitations of LFTs but requested further information about test accuracy. Tests were used to inform behavioural decisions, often in combination with other information, such as the potential for exposure to the virus and perceptions of vulnerability. ConclusionsThe low uptake of testing brings into question the role of mass LFT in university settings.

Accuracy of four lateral flow immunoassays for anti SARS-CoV-2 antibodies: a head-to-head comparative study (preprint)

BackgroundSARS-CoV-2 antibody tests are used for population surveillance and might have a future role in individual risk assessment. Lateral flow immunoassays (LFIAs) can deliver results rapidly and at scale, but have widely varying accuracy. MethodsIn a laboratory setting, we performed head-to-head comparisons of four LFIAs: the Rapid Test Consortiums AbC-19 Rapid Test, OrientGene COVID IgG/IgM Rapid Test Cassette, SureScreen COVID-19 Rapid Test Cassette, and Biomerica COVID-19 IgG/IgM Rapid Test. We analysed blood samples from 2,847 key workers and 1,995 pre-pandemic blood donors with all four devices. FindingsWe observed a clear trade-off between sensitivity and specificity: the IgG band of the SureScreen device and the AbC-19 device had higher specificities but OrientGene and Biomerica higher sensitivities. Based on analysis of pre-pandemic samples, SureScreen IgG band had the highest specificity (98.9%, 95% confidence interval 98.3 to 99.3%), which translated to the highest positive predictive value across any pre-test probability: for example, 95.1% (95%CI 92.6, 96.8%) at 20% pre-test probability. All four devices showed higher sensitivity at higher antibody concentrations ("spectrum effects"), but the extent of this varied by device. InterpretationThe estimates of sensitivity and specificity can be used to adjust for test error rates when using these devices to estimate the prevalence of antibody. If tests were used to determine whether an individual has SARS-CoV-2 antibodies, in an example scenario in which 20% of individuals have antibodies we estimate around 5% of positive results on the most specific device would be false positives. FundingPublic Health England. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched for evidence on the accuracy of the four devices compared in this study: OrientGene COVID IgG/IgM Rapid Test Cassette, SureScreen COVID-19 Rapid Test Cassette, Biomerica COVID-19 IgG/IgM Rapid Test and the UK Rapid Test Consortiums AbC-19 Rapid Test. We searched Ovid MEDLINE (In-Process & Other Non-Indexed Citations and Daily), PubMed, MedRxiv/BioRxiv and Google Scholar from January 2020 to 16th January 2021. Search terms included device names AND ((SARS-CoV-2) OR (covid)). Of 303 records assessed, data were extracted from 24 studies: 18 reporting on the accuracy of the OrientGene device, 7 SureScreen, 2 AbC-19 and 1 Biomerica. Only three studies compared the accuracy of two or more of the four devices. With the exception of our previous report on the accuracy of the AbC-19 device, which the current manuscript builds upon, sample size ranged from 7 to 684. For details, see Supplementary Materials. The largest study compared OrientGene, SureScreen and Biomerica. SureScreen was estimated to have the highest specificity (99.8%, 95% CI 98.9 to 100%) and OrientGene the highest sensitivity (92.6%), but with uncertainty about the latter result due to small sample sizes. The other two comparative studies were small (n = 65, n = 67) and therefore provide very uncertain results. We previously observed spectrum effects for the AbC-19 device, such that sensitivity is upwardly biased if estimated only from PCR-confirmed cases. The vast majority of previous studies estimated sensitivity in this way. Added value of this studyWe performed a large scale (n = 4,842), head-to-head laboratory-based evaluation and comparison of four lateral flow devices, which were selected for evaluation by the UK Department of Health and Social Cares New Tests Advisory Group, on the basis of a survey of test and performance data available. We evaluated the performance of diagnosis based on both IgG and IgM bands, and the IgG band alone. We found a clear trade-off between sensitivity and specificity across devices, with the SureScreen and AbC-19 devices being more specific and OrientGene and Biomerica more sensitive. Based on analysis of 1,995 pre-pandemic blood samples, we are 99% confident that SureScreen (IgG band reading) has the highest specificity of the four devices (98.9%, 95% CI 98.3, 99.3%). We found evidence that all four devices have reduced sensitivity at lower antibody indices, i.e. spectrum effects. However, the extent of this varies by device and appears to be less for other devices than for AbC-19. Our estimates of sensitivity and specificity are likely to be higher than would be observed in real use of these devices, as they were based on majority readings of three trained laboratory personnel. Implications of all the available evidenceWhen used in epidemiological studies of antibody prevalence, the estimates of sensitivity and specificity provided in this study can be used to adjust for test errors. Increased precision in error rates will translate to increased precision in seroprevalence estimates. If lateral flow devices were used for individual risk assessment, devices with maximum specificity would be preferable. However, if, for an example, 20% of the tested population had antibodies, we estimate that around 1 in 20 positive results on the most specific device would be incorrect.

Understanding patterns of adherence to COVID-19 mitigation measures: A qualitative interview study. (preprint)

In an effort to reduce the spread of COVID-19, the UK government has introduced a series of mitigation measures. The success of these measures in preventing transmission is dependent on adherence, which is currently considered to be low. Evidence highlights the disproportionate impact of mitigation measures on individuals from Black, Asian and minority ethnic (BAME) communities, as well as among those on a low income, and an understanding of barriers to adherence in these populations is needed. In this qualitative study we examined patterns of adherence to mitigation measures and reasons underpinning these behaviors among people on low income and those from BAME communities. Semi-structured interviews were conducted with 20 participants from BAME and low-income White backgrounds. The topic guide was designed to explore how individuals are adhering to social distancing and self-isolation measures during the COVID-19 pandemic, and to explore in detail the reasons underpinning this behavior. Data were analyzed using thematic analysis following which charts were used to help compare concepts within and between participants and develop an understanding of patterns of adherence. Participants were confused by the constantly changing and seemingly contradictory rules and guidance. As a result, decisions were made about how best to protect themselves and their household from COVID-19, and from the detrimental impact of lockdown restrictions. This was not always in line with government advice. We identified three categories of adherence to lockdown measures 1) caution motivated super-adherence 2) risk-adapted partial-adherence and 3) necessity-driven partial-adherence. Decisions about adherence considered potential for exposure to the virus, ability to reduce risk through use of protective measures, and perceived importance of/need for the behavior. This research highlights a need for a more nuanced understanding of adherence to lockdown measures. Provision of practical and financial support could reduce the number of people who have to engage in necessity-driven partial-adherence. Information about viral transmission could help people assess the risk associated with partial-adherence more accurately. More evidence is required on population level risks of people adopting risk-adapted partial-adherence.

Public health information on COVID-19 for international travellers: Lessons learned from a rapid mixed-method evaluation in the UK containment phase (preprint)

Introduction In the containment phase of the response to the COVID-19 outbreak, Public Health England (PHE) delivered advice to travellers arriving at major UK ports. We aimed to rapidly evaluate the impact and effectiveness of these communication materials for passengers in the early stages of the pandemic. Methods In stage I (Patient and Public Involvement, PPI) we interviewed seven travellers who had returned from China in January and February 2020. We used these results to develop a questionnaire and topic guides for stage II, a cross-sectional survey and follow-up interviews with passengers arriving at London Heathrow Airport on scheduled flights from China and Singapore. The survey assessed passengers' knowledge of symptoms, actions to take and attitudes towards PHE COVID-19 public health information; interviews explored their views of official public health information and self-isolation. Results In stage II, 121 passengers participated in the survey and 15 in follow-up interviews. 83% of surveyed passengers correctly identified all three COVID-19 associated symptoms listed in PHE information at that time. Most could identify the recommended actions and found the advice understandable and trustworthy. Interviews revealed that passengers shared concerns about the lack of wider official action, and that passengers' knowledge had been acquired elsewhere as much from PHE. Respondents also noted their own agency in choosing to self-isolate, partially as a self-protective measure. Conclusion PHE COVID-19 public health information was perceived as clear and acceptable, but we found that passengers acquired knowledge from various sources and they saw the provision of information alone on arrival as an insufficient official response. Our study provides fresh insights into the importance of taking greater account of diverse information sources and of the need for public assurance in creating public health information materials to address global health threats. Keywords COVID-19, public health advice, government, policy, airport, international travel

COVID-19 transmission in a university setting: a rapid review of modelling studies (preprint)

Managing COVID-19 within a university setting presents unique challenges. At the start of term, students arrive from geographically diverse locations and potentially have higher numbers of social contacts than the general population, particularly if living in university halls of residence accommodation. Mathematical models are useful tools for understanding the potential spread of infection and are being actively used to inform policy about the management of COVID-19. Our aim was to provide a rapid review and appraisal of the literature on mathematical models investigating COVID-19 infection in a university setting. We searched PubMed, Web of Science, bioRxiv/ medRxiv and sought expert input via social media to identify relevant papers. BioRxiv/ medRxiv and PubMed/Web of Science searches took place on 3 and 6 July 2020, respectively. Papers were restricted to English language. Screening of peer-reviewed and pre-print papers and contact with experts yielded five relevant papers - all of which were pre-prints. All models suggest a significant potential for transmission of COVID-19 in universities. Testing of symptomatic persons and screening of the university community regardless of symptoms, combined with isolation of infected individuals and effective contact tracing were critical for infection control in the absence of other mitigation interventions. When other mitigation interventions were considered (such as moving teaching online, social/physical distancing, and the use of face coverings) the additional value of screening for infection control was limited. Multiple interventions will be needed to control infection spread within the university setting and the interaction with the wider community is an important consideration. Isolation of identified cases and quarantine of contacts is likely to lead to large numbers of students requiring educational, psychological and behavioural support and will likely have a large impact on the attendance of students (and staff), necessitating online options for teaching, even where in-person classes are taking place. Models were highly sensitive to assumptions in the parameters, including the number and type of individuals contacts, number of contacts traced, frequency of screening and delays in testing. Future models could aid policy decisions by considering the incremental benefit of multiple interventions and using empirical data on mixing within the university community and with the wider community where available. Universities will need to be able to adapt quickly to the evolving situation locally to support the health and wellbeing of the university and wider communities.

Self assessment overestimates historical COVID-19 disease relative to sensitive serological assays: cross sectional study in UK key workers (preprint)

Objective To measure the association between self-reported signs and symptoms and SARS-CoV-2 seropositivity. Design Cross sectional study of three key worker groups. Setting Six acute NHS hospitals and two Police and Fire and Rescue sites in England. Participants Individuals were recruited from three streams: (A) Police and Fire and Rescue services (n=1147), (B) healthcare workers (n=1546) and (C) healthcare workers with previously positive virus detection (n=154). Main outcome measures Detection of anti-SARS-CoV-2 antibodies in plasma. Results 943 of the 2847 participants (33%) reported belief they had had COVID-19, having experienced compatible symptoms (including 152 from Stream C). Among individuals reporting COVID-19 compatible symptoms, 466 (49%) were seronegative on both Nucleoprotein (Roche) and Spike-protein (EUROIMMUN) antibody assays. However, among the 268 individuals with prior positive SARS-CoV-2 tests, of whom 96% reported symptoms with onset a median of 63 days (IQR 52 to 75 days) prior to venesection, Roche and EUROIMMUN assays had 96.6% (95% CI 93.7% to 98.2%) and 93.3% (95% CI 89.6% to 95.7%) sensitivity respectively. Symptomatic but seronegative individuals had significantly earlier symptom onset dates than the symptomatic seropositive individuals, shorter illness duration and a much lower anosmia reporting frequency. Conclusions Self-reported belief of COVID-19 was common among our frontline worker cohort. About half of these individuals were seronegative, despite a high sensitivity of serology in this cohort, at least in individuals with previous positive PCR results. This is compatible with non-COVID-19 respiratory disease during the COVID-19 outbreak having been commonly mistaken for COVID-19 within the key worker cohort studied.

The receptor binding domain of SARS-CoV-2 spike is the key target of neutralizing antibody in human polyclonal sera. (preprint)

Natural infection of SARS-CoV-2 in humans leads to the development of a strong neutralizing antibody response, however the immunodominant targets of the polyclonal neutralizing antibody response are still unknown. Here, we functionally define the role SARS-CoV-2 spike plays as a target of the human neutralizing antibody response. In this study, we identify the spike protein subunits that contain antigenic determinants and examine the neutralization capacity of polyclonal sera from a cohort of patients that tested qRT-PCR-positive for SARS-CoV-2. Using an ELISA format, we assessed binding of human sera to spike subunit 1 (S1), spike subunit 2 (S2) and the receptor binding domain (RBD) of spike. To functionally identify the key target of neutralizing antibody, we depleted sera of subunit-specific antibodies to determine the contribution of these individual subunits to the antigen-specific neutralizing antibody response. We show that epitopes within RBD are the target of a majority of the neutralizing antibodies in the human polyclonal antibody response. These data provide critical information for vaccine development and development of sensitive and specific serological testing.

Mental health during the COVID-19 pandemic in two longitudinal UK population cohorts (preprint)

Background: The impact of COVID-19 on mental health is unclear. Evidence from longitudinal studies with pre pandemic data are needed to address (1) how mental health has changed from pre-pandemic levels to during the COVID-19 pandemic and (2), whether there are groups at greater risk of poorer mental health during the pandemic? Methods: We used data from COVID-19 surveys (completed through April/May 2020), nested within two large longitudinal population cohorts with harmonised measures of mental health: two generations of the Avon Longitudinal Study of Parents and Children (ALPSAC): the index generation ALSPAC-G1 (n= 2850, mean age 28) and the parents generation ALSPAC-G0 (n= 3720, mean age = 59) and Generation Scotland: Scottish Family Health Study (GS, (n= 4233, mean age = 59), both with validated pre-pandemic measures of mental health and baseline factors. To answer question 1, we used ALSPAC-G1, which has identical mental health measures before and during the pandemic. Question 2 was addressed using both studies, using pre-pandemic and COVID-19 specific factors to explore associations with depression and anxiety in COVID-19. Findings: In ALSPAC-G1 there was evidence that anxiety and lower wellbeing, but not depression, had increased in COVID-19 from pre-pandemic assessments. The percentage of individuals with probable anxiety disorder was almost double during COVID-19: 24% (95% CI 23%, 26%) compared to pre-pandemic levels (13%, 95% CI 12%, 14%), with clinically relevant effect sizes. In both ALSPAC and GS, depression and anxiety were greater in younger populations, women, those with pre-existing mental and physical health conditions, those living alone and in socio-economic adversity. We did not detect evidence for elevated risk in key workers or health care workers. Interpretation: These results suggest increases in anxiety and lower wellbeing that may be related to the COVID-19 pandemic and/or its management, particularly in young people. This research highlights that specific groups may be disproportionally at risk of elevated levels of depression and anxiety during COVID-19 and supports recent calls for increasing funds for mental health services. Funding: The UK Medical Research Council (MRC), the Wellcome Trust and University of Bristol.