Geographical variation in hepatitis C-related severe liver disease and patient risk factors: a multicentre cross-sectional study.

Despite promising steps towards the elimination of hepatitis C virus (HCV) in the UK, several indicators provide a cause for concern for future disease burden. We aimed to improve understanding of geographical variation in HCV-related severe liver disease and historic risk factor prevalence among clinic attendees in England and Scotland. We used metadata from 3829 HCV-positive patients consecutively enrolled into HCV Research UK from 48 hospital centres in England and Scotland during 2012-2014. Employing mixed-effects statistical modelling, several independent risk factors were identified: age 46-59 y (ORadj 3.06) and ≥60 y (ORadj 5.64) relative to <46 y, male relative to female sex (ORadj 1.58), high BMI (ORadj 1.73) and obesity (ORadj 2.81) relative to normal BMI, diabetes relative to no diabetes (ORadj 2.75), infection with HCV genotype (GT)-3 relative to GT-1 (ORadj 1.75), route of infection through blood products relative to injecting drug use (ORadj 1.40), and lower odds were associated with black ethnicity (ORadj 0.31) relative to white ethnicity. A small proportion of unexplained variation was attributed to differences between hospital centres and local health authorities. Our study provides a baseline measure of historic risk factor prevalence and potential geographical variation in healthcare provision, to support ongoing monitoring of HCV-related disease burden and the design of risk prevention measures.

Genomic epidemiology of SARS-CoV-2 in a university outbreak setting and implications for public health planning.

Whole genome sequencing of SARS-CoV-2 has occurred at an unprecedented scale, and can be exploited for characterising outbreak risks at the fine-scale needed to inform control strategies. One setting at continued risk of COVID-19 outbreaks are higher education institutions, associated with student movements at the start of term, close living conditions within residential halls, and high social contact rates. Here we analysed SARS-CoV-2 whole genome sequences in combination with epidemiological data to investigate a large cluster of student cases associated with University of Glasgow accommodation in autumn 2020, Scotland. We identified 519 student cases of SARS-CoV-2 infection associated with this large cluster through contact tracing data, with 30% sequencing coverage for further analysis. We estimated at least 11 independent introductions of SARS-CoV-2 into the student population, with four comprising the majority of detected cases and consistent with separate outbreaks. These four outbreaks were curtailed within a week following implementation of control measures. The impact of student infections on the local community was short-term despite an underlying increase in community infections. Our study highlights the need for context-specific information in the formation of public health policy for higher educational settings.

Comparing the age and sex trajectories of SARS-CoV-2 morbidity and mortality with other respiratory pathogens.

Comparing age and sex differences in SARS-CoV-2 hospitalization and mortality with MERS-CoV, seasonal coronaviruses, influenza and other health outcomes opens the way to generating hypotheses as to underlying mechanisms driving disease risk. Using 60-year-olds as a reference age group, we find that relative rates of hospitalization and mortality associated with the emergent coronaviruses are lower during childhood and start to increase earlier (around puberty) as compared with influenza and seasonal coronaviruses. The changing distribution of disease risk by age for emerging pathogens appears to broadly track the gradual deterioration of the immune system (immunosenescence), which starts around puberty. By contrast, differences in severe disease risk by age from endemic pathogens are more decoupled from the immune ageing process. Intriguingly, age-specific sex differences in hospitalizations are largely similar across endemic and emerging infections. We discuss potential mechanisms that may be associated with these patterns.

Severe Acute Respiratory Syndrome Coronavirus 2 Serosurveillance in a Patient Population Reveals Differences in Virus Exposure and Antibody-Mediated Immunity According to Host Demography and Healthcare Setting.

Identifying drivers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure and quantifying population immunity is crucial to prepare for future epidemics. We performed a serial cross-sectional serosurvey throughout the first pandemic wave among patients from the largest health board in Scotland. Screening of 7480 patient serum samples showed a weekly seroprevalence ranging from 0.10% to 8.23% in primary and 0.21% to 17.44% in secondary care, respectively. Neutralization assays showed that highly neutralizing antibodies developed in about half of individuals who tested positive with enzyme-linked immunosorbent assay, mainly among secondary care patients. We estimated the individual probability of SARS-CoV-2 exposure and quantified associated risk factors. We show that secondary care patients, male patients, and 45-64-year-olds exhibit a higher probability of being seropositive. The identification of risk factors and the differences in virus neutralization activity between patient populations provided insights into the patterns of virus exposure during the first pandemic wave and shed light on what to expect in future waves.

Epidemiology of Seasonal Coronaviruses: Establishing the Context for the Emergence of Coronavirus Disease 2019.

Public health preparedness for coronavirus (CoV) disease 2019 (COVID-19) is challenging in the absence of setting-specific epidemiological data. Here we describe the epidemiology of seasonal CoVs (sCoVs) and other cocirculating viruses in the West of Scotland, United Kingdom. We analyzed routine diagnostic data for >70 000 episodes of respiratory illness tested molecularly for multiple respiratory viruses between 2005 and 2017. Statistical associations with patient age and sex differed between CoV-229E, CoV-OC43, and CoV-NL63. Furthermore, the timing and magnitude of sCoV outbreaks did not occur concurrently, and coinfections were not reported. With respect to other cocirculating respiratory viruses, we found evidence of positive, rather than negative, interactions with sCoVs. These findings highlight the importance of considering cocirculating viruses in the differential diagnosis of COVID-19. Further work is needed to establish the occurrence/degree of cross-protective immunity conferred across sCoVs and with COVID-19, as well as the role of viral coinfection in COVID-19 disease severity.

Virus-virus interactions impact the population dynamics of influenza and the common cold.

The human respiratory tract hosts a diverse community of cocirculating viruses that are responsible for acute respiratory infections. This shared niche provides the opportunity for virus-virus interactions which have the potential to affect individual infection risks and in turn influence dynamics of infection at population scales. However, quantitative evidence for interactions has lacked suitable data and appropriate analytical tools. Here, we expose and quantify interactions among respiratory viruses using bespoke analyses of infection time series at the population scale and coinfections at the individual host scale. We analyzed diagnostic data from 44,230 cases of respiratory illness that were tested for 11 taxonomically broad groups of respiratory viruses over 9 y. Key to our analyses was accounting for alternative drivers of correlated infection frequency, such as age and seasonal dependencies in infection risk, allowing us to obtain strong support for the existence of negative interactions between influenza and noninfluenza viruses and positive interactions among noninfluenza viruses. In mathematical simulations that mimic 2-pathogen dynamics, we show that transient immune-mediated interference can cause a relatively ubiquitous common cold-like virus to diminish during peak activity of a seasonal virus, supporting the potential role of innate immunity in driving the asynchronous circulation of influenza A and rhinovirus. These findings have important implications for understanding the linked epidemiological dynamics of viral respiratory infections, an important step towards improved accuracy of disease forecasting models and evaluation of disease control interventions.

Estimation of temporal covariances in pathogen dynamics using Bayesian multivariate autoregressive models.

It is well recognised that animal and plant pathogens form complex ecological communities of interacting organisms within their hosts, and there is growing interest in the health implications of such pathogen interactions. Although community ecology approaches have been used to identify pathogen interactions at the within-host scale, methodologies enabling robust identification of interactions from population-scale data such as that available from health authorities are lacking. To address this gap, we developed a statistical framework that jointly identifies interactions between multiple viruses from contemporaneous non-stationary infection time series. Our conceptual approach is derived from a Bayesian multivariate disease mapping framework. Importantly, our approach captures within- and between-year dependencies in infection risk while controlling for confounding factors such as seasonality, demographics and infection frequencies, allowing genuine pathogen interactions to be distinguished from simple correlations. We validated our framework using a broad range of synthetic data. We then applied it to diagnostic data available for five respiratory viruses co-circulating in a major urban population between 2005 and 2013: adenovirus, human coronavirus, human metapneumovirus, influenza B virus and respiratory syncytial virus. We found positive and negative covariances indicative of epidemiological interactions among specific virus pairs. This statistical framework enables a community ecology perspective to be applied to infectious disease epidemiology with important utility for public health planning and preparedness.

Modelling the impact of co-circulating low pathogenic avian influenza viruses on epidemics of highly pathogenic avian influenza in poultry.

It is well known that highly pathogenic avian influenza (HPAI) viruses emerge through mutation of precursor low pathogenic avian influenza (LPAI) viruses in domestic poultry populations. The potential for immunological cross-protection between these pathogenic variants is recognised but the epidemiological impact during co-circulation is not well understood. Here we use mathematical models to investigate whether altered flock infection parameters consequent to primary LPAI infections can impact on the spread of HPAI at the population level. First we used mechanistic models reflecting the co-circulatory dynamics of LPAI and HPAI within a single commercial poultry flock. We found that primary infections with LPAI led to HPAI prevalence being maximised under a scenario of high but partial cross-protection. We then tested the population impact in spatially-explicit simulations motivated by a major avian influenza A(H7N1) epidemic that afflicted the Italian poultry industry in 1999-2001. We found that partial cross-protection can lead to a prolongation of HPAI epidemic duration. Our findings have implications for the control of HPAI in poultry particularly for settings in which LPAI and HPAI frequently co-circulate.

Implications of within-farm transmission for network dynamics: consequences for the spread of avian influenza.

The importance of considering coupled interactions across multiple population scales has not previously been studied for highly pathogenic avian influenza (HPAI) in the British commercial poultry industry. By simulating the within-flock transmission of HPAI using a deterministic S-E-I-R model, and by incorporating an additional environmental class representing infectious faeces, we tracked the build-up of infectious faeces within a poultry house over time. A measure of the transmission risk (TR) was computed for each farm by linking the amount of infectious faeces present each day of an outbreak with data describing the daily on-farm visit schedules for a major British catching company. Larger flocks tended to have greater levels of these catching-team visits. However, where density-dependent contact was assumed, faster outbreak detection (according to an assumed mortality threshold) led to a decreased opportunity for catching-team visits to coincide with an outbreak. For this reason, maximum TR-levels were found for mid-range flock sizes (~25,000-35,000 birds). When assessing all factors simultaneously using multivariable linear regression on the simulated outputs, those related to the pattern of catching-team visits had the largest effect on TR, with the most important movement-related factor depending on the mode of transmission. Using social network analysis on a further database to inform a measure of between-farm connectivity, we identified a large fraction of farms (28%) that had both a high TR and a high potential impact at the between farm level. Our results have counter-intuitive implications for between-farm spread that could not be predicted based on flock size alone, and together with further knowledge of the relative importance of transmission risk and impact, could have implications for improved targeting of control measures.

Generating social network data using partially described networks: an example informing avian influenza control in the British poultry industry.

BACKGROUND: Targeted sampling can capture the characteristics of more vulnerable sectors of a population, but may bias the picture of population level disease risk. When sampling network data, an incomplete description of the population may arise leading to biased estimates of between-host connectivity. Avian influenza (AI) control planning in Great Britain (GB) provides one example where network data for the poultry industry (the Poultry Network Database or PND), targeted large premises and is consequently demographically biased. Exposing the effect of such biases on the geographical distribution of network properties could help target future poultry network data collection exercises. These data will be important for informing the control of potential future disease outbreaks. RESULTS: The PND was used to compute between-farm association frequencies, assuming that farms sharing the same slaughterhouse or catching company, or through integration, are potentially epidemiologically linked. The fitted statistical models were extrapolated to the Great Britain Poultry Register (GBPR); this dataset is more representative of the poultry industry but lacks network information. This comparison showed how systematic biases in the demographic characterisation of a network, resulting from targeted sampling procedures, can bias the derived picture of between-host connectivity within the network. CONCLUSIONS: With particular reference to the predictive modeling of AI in GB, we find significantly different connectivity patterns across GB when network estimates incorporate the more demographically representative information provided by the GBPR; this has not been accounted for by previous epidemiological analyses. We recommend ranking geographical regions, based on relative confidence in extrapolated estimates, for prioritising further data collection. Evaluating whether and how the between-farm association frequencies impact on the risk of between-farm transmission will be the focus of future work.