Linking epidemiological and genomic data in cases of enteric fever in England to inform clinical management and public health action.

OBJECTIVES: To explore the feasibility of linking data from enhanced surveillance patient questionnaires from each enteric fever case in England with genome sequencing data, including antimicrobial resistance (AMR) profiles, from the corresponding isolate of typhoidal salmonellae. METHODS: After linking data we interrogated the merged dataset and assessed the utility of passive surveillance data to match and monitor antimicrobial treatment regimens in enteric fever patients with the AMR profiles of the infectious agent. RESULTS: A high proportion of cases were given antibiotics (n = 1230/1415; 86.9%); half of the cases stated the class of antibiotic they were given (n = 630/1239) and half were prescribed cephalosporins (n = 316/630). Reported treatment with a combination of antibiotics increased with symptom severity. Nearly half of isolates (n = 644/1415; 45.5%) had mutations conferring resistance to ciprofloxacin. Based on genome-derived AMR profiles, typhoidal salmonellae isolates inferred to be susceptible to the recommended first-line antimicrobials were twice as likely to be isolated from individuals residing in the least deprived areas compared with the most deprived (n = 26/169; 15.4% versus n = 32/442; 7.2%). CONCLUSIONS: Due to the high proportion of missing data obtained from patient interviews, we recommend a more transparent and systematic approach to recording the antibiotic prescription details by healthcare professionals in primary and secondary care. A more robust approach to data capture at this point in the care pathway would enable us to audit inconsistencies in the prescribing algorithms across England and ensure equitable treatment across all sections of society. Integrating prescribing data with the genome-derived AMR profiles of the causative agent at the individual patient level provides an opportunity to monitor the impact of treatment on clinical outcomes, and to promote best practice in real time.

Socioeconomic and ethnic inequalities in incidence and severity of enteric fever in England 2015-2019: analysis of a national enhanced surveillance system.

There is limited research on whether inequalities exist among individuals from different ethnicities and deprivation status among enteric fever cases. The aim of the study was to investigate the association between the enteric fever incidence rates, ethnicity and deprivation for enteric fever cases in England. Additionally, it was assessed if ethnicity and deprivation were associated with symptom severity, hospital admission and absence from school/work using logistic regression models. Incidence rates were higher in the two most deprived index of multiple deprivation quintiles and those of Pakistani ethnicity (9.89, 95% CI 9.08-10.75) followed by Indian (7.81, 95% CI 7.18-8.49) and Bangladeshi (5.68, 95% CI 4.74-6.76) groups: the incidence rate in the White group was 0.07 (95% CI 0.06-0.08). Individuals representing Pakistani (3.00, 95% CI 1.66-5.43), Indian (2.05, 95% CI 1.18-3.54) and Other/Other Asian (3.51, 95% CI 1.52-8.14) ethnicities had significantly higher odds of hospital admission than individuals representing White (British/Other) ethnicity, although all three groups had statistically significantly lower symptom severity scores. Our results show that there are significant ethnic and socioeconomic inequalities in enteric fever incidence that should inform prevention and treatment strategies. Targeted, community-specific public health interventions are needed to impact on overall burden.

Association between socioeconomic deprivation and incidence of infectious intestinal disease by pathogen and linked transmission route: An ecological analysis in the UK.

Infectious intestinal disease (IID) studies conducted at different levels of the surveillance pyramid have found heterogeneity in the association of socioeconomic deprivation with illness. The aim of this study was to analyse the association between socioeconomic deprivation and incidence of IID by certain gastrointestinal pathogens reported to UKHSA. Data were extracted from 2015 to 2018 for Salmonella, Campylobacter, Shigella, Giardia species, and norovirus. Rates were calculated per 100,000 person-years by the index of multiple deprivation quintile, and an ecological analysis was conducted using univariant and multvariable regression models for each pathogen. Incidence of Campylobacter, and Giardia species decreased with increasing deprivation. Conversely, the incidence of norovirus, non-typhoidal Salmonella, Salmonella typhi/paratyphi, Shigella species increased with increasing deprivation. Multivariable analysis results showed that higher deprivation was significantly associated with higher odds of higher number of cases for Shigella flexneri, norovirus and S. typhi/paratyphi. Infections most associated with deprivation were those transmitted by person-to-person spread, and least associated were those transmitted by zoonotic contamination of the environment. Person-to-person transmission can be contained by implementing policies targeting over-crowding and poor hygiene. This approach is likely to be the most effective solution for the reduction of IID.

Utility of whole-genome sequencing during an investigation of multiple foodborne outbreaks of Shigella sonnei.

In April 2018, Public Health England was notified of cases of Shigella sonnei who had eaten food from three different catering outlets in England. The outbreaks were initially investigated as separate events, but whole-genome sequencing (WGS) showed they were caused by the same strain. The investigation included analyses of epidemiological data, the food chain and microbiological examination of food samples. WGS was used to determine the phylogenetic relatedness and antimicrobial resistance profile of the outbreak strain. Ultimately, 33 cases were linked to this outbreak; the majority had eaten food from seven outlets specialising in Indian or Middle Eastern cuisine. Five outlets were linked to two or more cases, all of which used fresh coriander although a shared supplier was not identified. An investigation at one of the venues recorded that 86% of cases reported eating dishes with coriander as an ingredient or garnish. Four cases were admitted to hospital and one had evidence of treatment failure with ciprofloxacin. Phylogenetic analysis showed that the outbreak strain was part of a wider multidrug-resistant clade associated with travel to Pakistan. Poor hygiene practices during cultivation, distribution or preparation of fresh produce are likely contributing factors.

Syndromic surveillance: two decades experience of sustainable systems - its people not just data!

Syndromic surveillance is a form of surveillance that generates information for public health action by collecting, analysing and interpreting routine health-related data on symptoms and clinical signs reported by patients and clinicians rather than being based on microbiologically or clinically confirmed cases. In England, a suite of national real-time syndromic surveillance systems (SSS) have been developed over the last 20 years, utilising data from a variety of health care settings (a telehealth triage system, general practice and emergency departments). The real-time systems in England have been used for early detection (e.g. seasonal influenza), for situational awareness (e.g. describing the size and demographics of the impact of a heatwave) and for reassurance of lack of impact on population health of mass gatherings (e.g. the London 2012 Olympic and Paralympic Games).We highlight the lessons learnt from running SSS, for nearly two decades, and propose questions and issues still to be addressed. We feel that syndromic surveillance is an example of the use of 'big data', but contend that the focus for sustainable and useful systems should be on the added value of such systems and the importance of people working together to maximise the value for the public health of syndromic surveillance services.

A standardized methodology for the surveillance of antimicrobial prescribing linked to clinical indications in primary care.

Background: A key component of strategies to reduce antimicrobial resistance is better antimicrobial prescribing. The majority of antibiotics are prescribed in primary care. While many existing surveillance systems can monitor trends in the quantities of antibiotics prescribed in this setting, it can be difficult to monitor the quality of prescribing as data on the condition for which prescriptions are issued are often not available. We devised a standardized methodology to facilitate the monitoring of condition-specific antibiotic prescribing in primary care. Methods: We used a large computerized general practitioner database to develop a standardized methodology for routine monitoring of antimicrobial prescribing linked to clinical indications in primary care in the UK. Outputs included prescribing rate by syndrome and percentages of consultations with antibiotic prescription, for recommended antibiotic, and of recommended treatment length. Results: The standardized methodology can monitor trends in proportions of common infections for which antibiotics were prescribed, the specific drugs prescribed and duration of treatment. These data can be used to help assess the appropriateness of antibiotic prescribing and to assess the impact of prescribing guidelines. Conclusions: We present a standardized methodology that could be applied to any suitable national or local database and adapted for use in other countries.

Socioeconomic status and infectious intestinal disease in the community: a longitudinal study (IID2 study).

Background: Infectious intestinal diseases (IID) are common, affecting around 25% of people in UK each year at an estimated annual cost to the economy, individuals and the NHS of £1.5 billion. While there is evidence of higher IID hospital admissions in more disadvantaged groups, the association between socioeconomic status (SES) and risk of IID remains unclear. This study aims to investigate the relationship between SES and IID in a large community cohort. Methods: Longitudinal analysis of a prospective community cohort in the UK following 6836 participants of all ages was undertaken. Hazard ratios for IID by SES were estimated using Cox proportional hazard, adjusting for follow-up time and potential confounding factors. Results: In the fully adjusted analysis, hazard ratio of IID was significantly lower among routine/manual occupations compared with managerial/professional occupations (HR 0.74, 95% CI 0.61-0.90). Conclusion: In this large community cohort, lower SES was associated with lower IID risk. This may be partially explained by the low response rate which varied by SES. However, it may be related to differences in exposure or recognition of IID symptoms by SES. Higher hospital admissions associated with lower SES observed in some studies could relate to more severe consequences, rather than increased infection risk.

Whole genome sequencing reveals an outbreak of Salmonella Enteritidis associated with reptile feeder mice in the United Kingdom, 2012-2015.

Analysis of whole genome sequencing data uncovered a previously undetected outbreak of Salmonella Enteritidis that had been on-going for four years. Cases were resident in all countries of the United Kingdom and 40% of the cases were aged less than 11 years old. Initial investigations revealed that 30% of cases reported exposure to pet snakes. A case-control study was designed to test the hypothesis that exposure to reptiles or their feed were risk factors. A robust case-definition, based on the single nucleotide polymorphism (SNP) profile, increased the power of the analytical study. Following univariable and multivariable analysis, exposure to snakes was the only variable independently associated with infection (Odds ratio 810 95% CI (85-7715) p < 0.001). Isolates of S. Enteritidis belonging to the outbreak profile were recovered from reptile feeder mice sampled at the retail and wholesale level. Control measures included improved public health messaging at point of sale, press releases and engagement with public health and veterinary counterparts across Europe. Mice destined to be fed to reptiles are not regarded as pet food and are not routinely tested for pathogenic bacteria. Routine microbiological testing to ensure feeder mice are free from Salmonella is recommended.

Use of an ingredient-based analysis to investigate a national outbreak of Escherichia coli O157, United Kingdom, July 2016.

Public Health England was alerted to a national outbreak of Shiga toxin-producing Escherichia coli O157 PT34 in July 2016. Early investigations suggested that the likely source was a salad item consumed outside of the home. A number of cases reported consuming meals at a staff canteen (Venue A) and a garden café (Venue B). Both venues shared a common salad supplier. An investigation was undertaken to measure associations between salad items and illness using an 'ingredient-based analysis'. A retrospective case-control study was conducted using an online questionnaire to collect information on menu items consumed at each venue. Chefs at both venues were interviewed to identify ingredients contained within each menu item. Both venues were pooled together for multivariable analysis measuring associations at the ingredient level. Among 203 responses, 24 cases were identified (13 confirmed, two probable and nine possible). Case onsets ranged between 7 and 25 June 2016. Multivariable analysis identified strong evidence that only baby mixed-leaf salad from the common supplier was a vehicle of infection (adjusted odds ratio = 13.1; 95% confidence interval: 1.6-106.5). Identifying the specific salad ingredient associated with illness was made possible by using an ingredient-based analysis. We recommend the increased use of ingredient-based analyses.

National outbreak of Shiga toxin-producing Escherichia coli O157:H7 linked to mixed salad leaves, United Kingdom, 2016.

We investigated a large outbreak of Escherichia coli O157 in the United Kingdom (UK) with 165 cases between 31 May and 29 July 2016. No linked cases were reported in other countries. Cases were predominately female (n = 128) and adult (n = 150), 66 attended hospital and nine had features of haemorrhagic uraemic syndrome. A series of epidemiological studies (case-control, case-case, ingredients-based and venue-based studies) and supply chain investigations implicated mixed salad leaves from Supplier A as the likely outbreak vehicle. Whole genome sequencing (WGS) indicated a link with strains from the Mediterranean and informed the outbreak control team to request that Supplier A cease distributing salad leaves imported from Italy. Microbiological tests of samples of salad leaves from Supplier A were negative. We were unable to confirm the source of contamination or the contaminated constituent leaf although our evidence pointed to red batavia received from Italy as the most likely vehicle. Variations in Shiga toxin-producing E.coli surveillance and diagnosis may have prevented detection of cases outside the UK and highlights a need for greater standardisation. WGS was useful in targeting investigations, but greater coverage across Europe is needed to maximise its potential.

Novel application of the matched case-control design to compare food supply chains during an Escherichia coli O157 outbreak, United Kingdom, 2016.

There is a need for innovative methods to investigate outbreaks of food-borne infection linked to produce with a complex distribution network. The investigation of a large outbreak of Escherichia coli O157 PT34 infection in the United Kingdom in 2016 indicated that catering venues associated with multiple cases had used salad leaves sourced from one supplier. Our aim was to investigate whether catering venues linked to cases were more likely to have used salad leaves from this supplier. We conducted a matched case-control study, with catering venues as the units of analysis. We compared venues linked to cases to those without known linked cases. We included 43 study pairs and obtained information on salad leaf products received by each venue. The odds of a case venue being supplied with salad leaves by Supplier A were 7.67 times (95% confidence interval: 2.30-25.53) those of control venues. This association provided statistical evidence to support the findings of the other epidemiological investigations undertaken for this outbreak. This is a novel approach which is labour-intensive but which addresses the challenge of investigating exposures to food across a complex distribution network.

Socioeconomic status is associated with symptom severity and sickness absence in people with infectious intestinal disease in the UK.

BACKGROUND: The burden of infectious intestinal disease (IID) in the UK is substantial. Negative consequences including sickness absence are common, but little is known about the social patterning of these outcomes, or the extent to which they relate to disease severity. METHODS: We performed a cross-sectional analysis using IID cases identified from a large population-based survey, to explore the association between socioeconomic status (SES) and symptom severity and sickness absence; and to assess the role of symptom severity on the relationship between SES and absence. Regression modelling was used to investigate these associations, whilst controlling for potential confounders such as age, sex and ethnicity. RESULTS: Among 1164 cases, those of lower SES versus high had twice the odds of experiencing severe symptoms (OR 2.2, 95%CI;1.66-2.87). Lower SES was associated with higher odds of sickness absence (OR 1.8, 95%CI;1.26-2.69), however this association was attenuated after adjusting for symptom severity (OR 1.4, 95%CI;0.92-2.07). CONCLUSIONS: In a large sample of IID cases, those of low SES versus high were more likely to report severe symptoms, and sickness absence; with greater severity largely explaining the higher absence. Public health interventions are needed to address the unequal consequences of IID identified.

Novel public health risk assessment process developed to support syndromic surveillance for the 2012 Olympic and Paralympic Games.

Background: Syndromic surveillance aims to provide early warning and real time estimates of the extent of incidents; and reassurance about lack of impact of mass gatherings. We describe a novel public health risk assessment process to ensure those leading the response to the 2012 Olympic Games were alerted to unusual activity that was of potential public health importance, and not inundated with multiple statistical 'alarms'. Methods: Statistical alarms were assessed to identify those which needed to result in 'alerts' as reliably as possible. There was no previously developed method for this. We identified factors that increased our concern about an alarm suggesting that an 'alert' should be made. Results: Between 2 July and 12 September 2012, 350 674 signals were analysed resulting in 4118 statistical alarms. Using the risk assessment process, 122 'alerts' were communicated to Olympic incident directors. Conclusions: Use of a novel risk assessment process enabled the interpretation of large number of statistical alarms in a manageable way for the period of a sustained mass gathering. This risk assessment process guided the prioritization and could be readily adapted to other surveillance systems. The process, which is novel to our knowledge, continues as a legacy of the Games.

Recurrent seasonal outbreak of an emerging serotype of Shiga toxin-producing Escherichia coli (STEC O55:H7 Stx2a) in the south west of England, July 2014 to September 2015.

The first documented British outbreak of Shiga toxin-producing Escherichia coli (STEC) O55:H7 began in the county of Dorset, England, in July 2014. Since then, there have been a total of 31 cases of which 13 presented with haemolytic uraemic syndrome (HUS). The outbreak strain had Shiga toxin (Stx) subtype 2a associated with an elevated risk of HUS. This strain had not previously been isolated from humans or animals in England. The only epidemiological link was living in or having close links to two areas in Dorset. Extensive investigations included testing of animals and household pets. Control measures included extended screening, iterative interviewing and exclusion of cases and high risk contacts. Whole genome sequencing (WGS) confirmed that all the cases were infected with similar strains. A specific source could not be identified. The combination of epidemiological investigation and WGS indicated, however, that this outbreak was possibly caused by recurrent introductions from a local endemic zoonotic source, that a highly similar endemic reservoir appears to exist in the Republic of Ireland but has not been identified elsewhere, and that a subset of cases was associated with human-to-human transmission in a nursery.

Two Linked Enteroinvasive Escherichia coli Outbreaks, Nottingham, UK, June 2014.

Enteroinvasive Escherichia coli (EIEC) outbreaks are uncommon in Europe. In June 2014, two EIEC outbreaks occurred in Nottingham, UK, within 2 days; outbreak A was linked to a takeaway restaurant and outbreak B to a wedding party. We conducted 2 analytical studies: a case-control study for outbreak A and a cohort study for outbreak B. We tested microbiological and environmental samples, including by using whole-genome sequencing. For both outbreaks combined, we identified 157 probable case-patients; 27 were laboratory-confirmed as EIEC O96:H19-positive. Combined epidemiologic, microbiological, and environmental findings implicated lettuce as the vehicle of infection in outbreak A, but the source of the organism remained unknown. Whole-genome sequencing identified the same organism in cases from both outbreaks, but no epidemiologic link was confirmed. These outbreaks highlight that EIEC has the capacity to cause large and severe gastrointestinal disease outbreaks and should be considered as a potential pathogen in foodborne outbreaks in Europe.

Cyclospora infection linked to travel to Mexico, June to September 2015.

Cyclospora cayetanensis was identified in 176 returned travellers from the Riviera Maya region of Mexico between 1 June and 22 September 2015; 79 in the United Kingdom (UK) and 97 in Canada. UK cases completed a food exposure questionnaire. This increase in reported Cyclospora cases highlights risks of gastrointestinal infections through travelling, limitations in Cyclospora surveillance and the need for improved hygiene in the production of food consumed in holiday resorts.

Trends in antibiotic prescribing in primary care for clinical syndromes subject to national recommendations to reduce antibiotic resistance, UK 1995-2011: analysis of a large database of primary care consultations.

OBJECTIVES: To measure trends in antibiotic prescribing in UK primary care in relation to nationally recommended best practice. PATIENTS AND METHODS: A descriptive study linking individual patient data on diagnosis and prescription in a large primary care database, covering 537 UK general practices during 1995-2011. RESULTS: The proportion of cough/cold episodes for which antibiotics were prescribed decreased from 47% in 1995 to 36% in 1999, before increasing to 51% in 2011. There was marked variation by primary care practice in 2011 [10th-90th percentile range (TNPR) 32%-65%]. Antibiotic prescribing for sore throats fell from 77% in 1995 to 62% in 1999 and then stayed broadly stable (TNPR 45%-78%). Where antibiotics were prescribed for sore throat, recommended antibiotics were used in 69% of cases in 2011 (64% in 1995). The use of recommended short-course trimethoprim for urinary tract infection (UTI) in women aged 16-74 years increased from 8% in 1995 to 50% in 2011; however, a quarter of practices prescribed short courses in ≤16% of episodes in 2011. For otitis media, 85% of prescriptions were for recommended antibiotics in 2011, increasing from 77% in 1995. All these changes in annual prescribing were highly statistically significant (P < 0.001). CONCLUSIONS: The implementation of national guidelines in UK primary care has had mixed success, with prescribing for coughs/colds, both in total and as a proportion of consultations, now being greater than before recommendations were made to reduce it. Extensive variation by practice suggests that there is significant scope to improve prescribing, particularly for coughs/colds and for UTIs.

Multiple outbreaks of Salmonella braenderup associated with consumption of iceberg lettuce.

The aim of this study was to describe the findings from an outbreak investigation following several apparently unrelated community outbreaks of gastroenteritis. Epidemiological, environmental, laboratory and traceback investigations were used to identify the source of the outbreak. We enrolled 23 (of 29) laboratory confirmed cases and 24 neighbourhood case-nominated controls in a case-control study which revealed that illness was associated with consumption of iceberg lettuce (matched odds ratio 8.0 (95% CI 1.1-355) contaminated with Salmonella braenderup. Several eating establishments were affected and the lettuce was traced back to a single producer in Spain. This is the first UK report implicating S. braenderup in an outbreak due to lettuce. The results highlight the need to increase attention to the various stages in the farm-to-fork process to reduce produce-associated outbreaks related to the global food trade.

Outbreak of Shiga toxin-producing Escherichia coli O157 linked with consumption of a fast-food product containing imported cucumbers, United Kingdom, August 2020.

BACKGROUND: In August 2020, an outbreak of Shiga toxin-producing Escherichia coli (STEC) O157:H7 occurred in the United Kingdom. Whole genome sequencing revealed that these cases formed a genetically distinct cluster. METHODS: Hypotheses generated from case interviews were tested in analytical studies, and results informed environmental sampling and food chain analysis. A case-case study used non-outbreak 'comparison' STEC cases; a case-control study used a market research panel to recruit controls. RESULTS: A total of 36 cases were identified; all cases reported symptom onset between August 3 and August 16, 2020. The majority of cases (83%) resided in the Midlands region of England and in Wales. A high proportion of cases reported eating out, with one fast-food restaurant chain mentioned by 64% (n = 23) of cases. Both the case-case study (adjusted odds ratio (aOR) 31.8, 95% confidence interval (CI) 1.6-624.9) and the case-control study (aOR 9.19, 95% CI 1.0-82.8) revealed statistically significant results, showing that the consumption of a specific fast-food product was independently associated with infection. CONCLUSIONS: Consumption of a specific fast-food product was a likely cause of this outbreak. The only ingredient specific to the product was cucumbers. The supply of cucumbers was immediately halted, and no further cases have been identified.

Neighbourhood unemployment and other socio-demographic predictors of emergency hospitalisation for infectious intestinal disease in England: A longitudinal ecological study.

BACKGROUND: Previous studies have observed that infectious intestinal disease (IID) related hospital admissions are higher in more deprived neighbourhoods. These studies have mainly focused on paediatric populations and are cross-sectional in nature. This study examines recent trends in emergency IID admission rates, and uses longitudinal methods to investigate the effects of unemployment (as a time varying measure of neighbourhood deprivation) and other socio-demographic characteristics on IID admissions for adults and children in England. METHODS: A longitudinal ecological analysis was performed using Hospital Episode Statistics on emergency hospitalisations for IID, collected over the time period 2012-17 across England. Analysis was conducted at the neighbourhood (Lower-layer Super Output Area) level for three age groups (0-14; 15-64; 65+ years). Mixed-effect Poisson regression models were used to assess the relationship between trends in neighbourhood unemployment and emergency IID admission rates, whilst controlling for measures of primary and secondary care access, underlying morbidity and the ethnic composition of each neighbourhood. RESULTS: From 2012-17, declining trends in emergency IID admission rates were observed for children and older adults overall, while rates increased for some sub-groups in the population. Each 1 percentage point increase in unemployment was associated with a 6.3, 2.4 and 4% increase in the rate of IID admissions per year for children [IRR=1.06, 95%CI 1.06-1.07], adults [IRR=1.02, 95%CI 1.02-1.03] and older adults [IRR=1.04, 95%CI 1.036-1.043], respectively. Increases in poor primary care access, the percentage of people from a Pakistani ethnic background, and the prevalence of long-term health problems, in a neighbourhood, were also associated with increases in IID admission rates. CONCLUSIONS: Increasing trends in neighbourhood deprivation, as measured by unemployment, were associated with increases in emergency IID admission rates for children and adults in England, despite controlling for measures of healthcare access, underlying morbidity and ethnicity. Research is needed to improve understanding of the mechanisms that explain these inequalities, so that effective policies can be developed to reduce the higher emergency IID admission rates experienced by more disadvantaged communities.