Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study.

BACKGROUND: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We aimed to derive and validate a blood transcriptional signature to detect viral infections, including COVID-19, among adults with suspected infection who presented to the emergency department. METHODS: Individuals (aged ≥18 years) presenting with suspected infection to an emergency department at a major teaching hospital in the UK were prospectively recruited as part of the Bioresource in Adult Infectious Diseases (BioAID) discovery cohort. Whole-blood RNA sequencing was done on samples from participants with subsequently confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes that met additional filtering criteria were subjected to feature selection to derive the most parsimonious discriminating signature. We validated the signature via RT-qPCR in a prospective validation cohort of participants who presented to an emergency department with undifferentiated fever, and a second case-control validation cohort of emergency department participants with PCR-positive COVID-19 or bacterial infection. We assessed signature performance by calculating the area under receiver operating characteristic curves (AUROCs), sensitivities, and specificities. FINDINGS: A three-gene transcript signature, comprising HERC6, IGF1R, and NAGK, was derived from the discovery cohort of 56 participants with bacterial infections and 27 with viral infections. In the validation cohort of 200 participants, the signature differentiated bacterial from viral infections with an AUROC of 0·976 (95% CI 0·919-1·000), sensitivity of 97·3% (85·8-99·9), and specificity of 100% (63·1-100). The AUROC for C-reactive protein (CRP) was 0·833 (0·694-0·944) and for leukocyte count was 0·938 (0·840-0·986). The signature achieved higher net benefit in decision curve analysis than either CRP or leukocyte count for discriminating viral infections from all other infections. In the second validation analysis, which included SARS-CoV-2-positive participants, the signature discriminated 35 bacterial infections from 34 SARS-CoV-2-positive COVID-19 infections with AUROC of 0·953 (0·893-0·992), sensitivity 88·6%, and specificity of 94·1%. INTERPRETATION: This novel three-gene signature discriminates viral infections, including COVID-19, from other emergency infection presentations in adults, outperforming both leukocyte count and CRP, thus potentially providing substantial clinical utility in managing acute presentations with infection. FUNDING: National Institute for Health Research, Medical Research Council, Wellcome Trust, and EU-FP7.

Incidence, healthcare-seeking behaviours, antibiotic use and natural history of common infection syndromes in England: results from the Bug Watch community cohort study.

BACKGROUND: Better information on the typical course and management of acute common infections in the community could inform antibiotic stewardship campaigns. We aimed to investigate the incidence, management, and natural history of a range of infection syndromes (respiratory, gastrointestinal, mouth/dental, skin/soft tissue, urinary tract, and eye). METHODS: Bug Watch was an online prospective community cohort study of the general population in England (2018-2019) with weekly symptom reporting for 6 months. We combined symptom reports into infection syndromes, calculated incidence rates, described the proportion leading to healthcare-seeking behaviours and antibiotic use, and estimated duration and severity. RESULTS: The cohort comprised 873 individuals with 23,111 person-weeks follow-up. The mean age was 54 years and 528 (60%) were female. We identified 1422 infection syndromes, comprising 40,590 symptom reports. The incidence of respiratory tract infection syndromes was two per person year; for all other categories it was less than one. 194/1422 (14%) syndromes led to GP (or dentist) consultation and 136/1422 (10%) to antibiotic use. Symptoms usually resolved within a week and the third day was the most severe. CONCLUSIONS: Most people reported managing their symptoms without medical consultation. Interventions encouraging safe self-management across a range of acute infection syndromes could decrease pressure on primary healthcare services and support targets for reducing antibiotic prescribing.

Antibiotic prescribing in UK care homes 2016-2017: retrospective cohort study of linked data.

BACKGROUND: Older people living in care homes are particularly susceptible to infections and antibiotics are therefore used frequently for this population. However, there is limited information on antibiotic prescribing in this setting. This study aimed to investigate the frequency, patterns and risk factors for antibiotic prescribing in a large chain of UK care homes. METHODS: Retrospective cohort study of administrative data from a large chain of UK care homes (resident and care home-level) linked to individual-level pharmacy data. Residents aged 65 years or older between 1 January 2016 and 31 December 2017 were included. Antibiotics were classified by type and as new or repeated prescriptions. Rates of antibiotic prescribing were calculated and modelled using multilevel negative binomial regression. RESULTS: 13,487 residents of 135 homes were included. The median age was 85; 63% residents were female. 28,689 antibiotic prescriptions were dispensed, the majority were penicillins (11,327, 39%), sulfonamides and trimethoprim (5818, 20%), or other antibacterials (4665, 16%). 8433 (30%) were repeat prescriptions. The crude rate of antibiotic prescriptions was 2.68 per resident year (95% confidence interval (CI) 2.64-2.71). Increased antibiotic prescribing was associated with residents requiring more medical assistance (adjusted incidence rate ratio for nursing opposed to residential care 1.21, 95% CI 1.13-1.30). Prescribing rates varied widely by care home but there were no significant associations with the care home-level characteristics available in routine data. CONCLUSIONS: Rates of antibiotic prescribing in care homes are high and there is substantial variation between homes. Further research is needed to understand the drivers of this variation to enable development of effective stewardship approaches that target the influences of prescribing.

Diagnostic uncertainty and urinary tract infection in the emergency department: a cohort study from a UK hospital.

BACKGROUND: Suspected urinary tract infection (UTI) syndromes are a common reason for empirical antibiotics to be prescribed in the Emergency Department (ED), but differentiating UTI from other conditions with a similar presentation is challenging. We investigated how often an ED diagnosis of UTI is confirmed clinically/microbiologically, and described conditions which present as UTI syndromes. METHODS: Observational study using electronic health records from patients who attended the ED with suspected UTI and had a urine sample submitted for culture. We compared the ED diagnosis to diagnosis at discharge from hospital (ICD-10 codes), and estimated the proportion of cases with clinical/microbiological evidence of UTI. RESULTS: Two hundred eighty nine patients had an ED diagnosis of UTI syndrome comprising: lower UTI (191), pyelonephritis (56) and urosepsis (42). In patients admitted to hospital with an ED diagnosis of lower UTI, pyelonephritis or urosepsis, clinical/microbiological evidence of UTI was lacking in 61/103, 33/54 and 31/42 cases respectively. The ED diagnosis was concordant with the main reason for admission in less than 40% of patients with UTI syndromes, and antibiotics were stopped within 72 h in 37/161 patients. CONCLUSIONS: Clinical/microbiological evidence of UTI was lacking in 60-70% of patients, suggesting scope to revise empirical prescribing decisions for UTI syndromes in light of microbial culture and clinical progression.

Nosocomial transmission of influenza: A retrospective cross-sectional study using next generation sequencing at a hospital in England (2012-2014).

BACKGROUND: The extent of transmission of influenza in hospital settings is poorly understood. Next generation sequencing may improve this by providing information on the genetic relatedness of viral strains. OBJECTIVES: We aimed to apply next generation sequencing to describe transmission in hospital and compare with methods based on routinely-collected data. METHODS: All influenza samples taken through routine care from patients at University College London Hospitals NHS Foundation Trust (September 2012 to March 2014) were included. We conducted Illumina sequencing and identified genetic clusters. We compared nosocomial transmission estimates defined using classical methods (based on time from admission to sample) and genetic clustering. We identified pairs of cases with space-time links and assessed genetic relatedness. RESULTS: We sequenced influenza sampled from 214 patients. There were 180 unique genetic strains, 16 (8.8%) of which seeded a new transmission chain. Nosocomial transmission was indicated for 32 (15.0%) cases using the classical definition and 34 (15.8%) based on genetic clustering. Of the 50 patients in a genetic cluster, 11 (22.0%) had known space-time links with other cases in the same cluster. Genetic distances between pairs of cases with space-time links were lower than for pairs without spatial links (P < .001). CONCLUSIONS: Genetic data confirmed that nosocomial transmission contributes significantly to the hospital burden of influenza and elucidated transmission chains. Prospective next generation sequencing could support outbreak investigations and monitor the impact of infection and control measures.

Symptom reporting, healthcare-seeking behaviour and antibiotic use for common infections: protocol for Bug Watch, a prospective community cohort study.

INTRODUCTION: Antimicrobial resistance is a significant worldwide problem largely driven by selective pressure exerted through antibiotic use. Preserving antibiotics requires identification of opportunities to safely reduce prescriptions, for example in the management of mild common infections in the community. However, more information is needed on how infections are usually managed and what proportion lead to consultation and antibiotic use. The aim of this study is to quantify consultation and prescribing patterns in the community for a range of common acute infection syndromes (respiratory, gastrointestinal, skin/soft tissue, mouth/dental, eye and urinary tract). This will inform development of interventions to improve antibiotic stewardship as part of a larger programme of work, Preserving Antibiotics through Safe Stewardship. METHODS AND ANALYSIS: This will be an online prospective community cohort study in England. We will invite 19 510 adults who previously took part in a nationally representative survey (the Health Survey for England) and consented to be contacted about future studies. Adults will also be asked to register their children. Data collection will consist of a baseline registration survey followed by weekly surveys sent by email for 6 months. Weekly surveys will collect information on symptoms of common infections, healthcare-seeking behaviour and use of treatments including antibiotics. We will calculate the proportions of infection syndromes that lead to General Practitioner consultation and antibiotic prescription. We will investigate how healthcare-seeking and treatment behaviours vary by demographics, social deprivation, infection profiles and knowledge and attitudes towards antibiotics, and will apply behavioural theory to investigate barriers and enablers to these behaviours. ETHICS AND DISSEMINATION: This study has been given ethical approval by the University College London Research Ethics Committee (ID 11813/001). Each participant will provide informed consent upon registration. We will disseminate our work through publication in peer-reviewed academic journals. Anonymised data will be made available through the UK Data Service (https://www.ukdataservice.ac.uk/).

Cohort study protocol: Bioresource in Adult Infectious Diseases (BioAID).

Introduction: Infectious diseases have a major impact on morbidity and mortality in hospital. Microbial diagnosis remains elusive for most cases of suspected infection which impacts on the use of antibiotics. Rapid advances in genomic technologies combined with high-quality phenotypic data have great potential to improve the diagnosis, management and clinical outcomes of infectious diseases.  The aim of the Bioresource in Adult Infectious Diseases (BioAID) is to provide a platform for biomarker discovery, trials and clinical service developments in the field of infectious diseases, by establishing a registry linking clinical phenotype to microbial and biological samples in adult patients who attend hospital with suspected infection. Methods and analysis: BioAID is a cohort study which employs deferred consent to obtain an additional 2.5mL RNA blood sample from patients who attend the Emergency Department (ED) with suspected infection when they undergo peripheral blood culture sampling.  Clinical data and additional biological samples including DNA, serum and microbial isolates are obtained from BioAID participants during hospital admission.  Participants are also asked to consent to be recalled for future studies. BioAID aims to recruit 10,000 patients from 5-8 sites across England.  Since February 2014 >4000 individuals have been recruited to the study.  The final cohort will be characterised using descriptive statistics including information on the number of cases that can be linked to biological and microbial samples to support future research studies. Ethical approval and section 251 exemption have been obtained for BioAID researchers to seek deferred consent from patients from whom a RNA specimen has been collected. Samples and meta-data obtained through BioAID will be made available to researchers worldwide following submission of an application form and research protocol.   Conclusions: BioAID will support a range of study designs spanning discovery science, biomarker validation, disease pathogenesis and epidemiological analyses of clinical infection syndromes.

A cross-sectional study of blood cultures and antibiotic use in patients admitted from the Emergency Department: missed opportunities for antimicrobial stewardship.

BACKGROUND: Early review of antimicrobial prescribing decisions within 48 h is recommended to reduce the overall use of unnecessary antibiotics, and in particular the use of broad-spectrum antibiotics. When parenteral antibiotics are used, blood culture results provide valuable information to help decide whether to continue, alter or stop antibiotics at 48 h. The objective of this study was to investigate the frequency of parenteral antibiotic use, broad spectrum antibiotic use and use of blood cultures when parenteral antibiotics are initiated in patients admitted via the Emergency Department. METHODS: We used electronic health records from patients admitted from the Emergency Department at University Hospital Birmingham in 2014. RESULTS: Six percent (4562/72939) of patients attending the Emergency department and one-fifth (4357/19034) of those patients admitted to hospital were prescribed a parenteral antimicrobial. More than half of parenteral antibiotics used were either co-amoxiclav or piperacillin-tazobactam. Blood cultures were obtained in less than one-third of patients who were treated with a parenteral antibiotic. CONCLUSIONS: Parenteral antibiotics are frequently used in those admitted from the Emergency Department; they are usually broad spectrum and are usually initiated without first obtaining cultures. Blood cultures may have limited value to support prescribing review as part of antimicrobial stewardship initiatives.

Are the public getting the message about antimicrobial resistance?

Raising public awareness of the need to use antibiotics appropriately is a major focus of the UK Government's strategy to tackle antimicrobial resistance. To investigate the public's views on antibiotic use and resistance we conducted a survey of 120 people as part of patient engagement activities held at University College London Hospital in June 2015.

Incidence and recurrence of boils and abscesses within the first year: a cohort study in UK primary care.

BACKGROUND: Boils and abscesses are common in primary care but the burden of recurrent infection is unknown. AIM: To investigate the incidence of and risk factors for recurrence of boil or abscess for individuals consulting primary care. DESIGN AND SETTING: Cohort study using electronic health records from primary care in the UK. METHOD: The Health Improvement Network (THIN) database was used to identify patients who had consulted their GP for a boil or abscess. Poisson regression was used to examine the relationship between age, sex, social deprivation, and consultation and to calculate the incidence of, and risk factors for, repeat consultation for a boil or abscess. RESULTS: Overall, 164 461 individuals were identified who consulted their GP for a boil or abscess between 1995 and 2010. The incidence of first consultation for a boil or abscess was 512 (95% CI = 509 to 515) per 100 000 person-years in females and 387 (95% CI = 385 to 390) per 100 000 person-years in males. First consultations were most frequent in younger age groups (16-34 years) and those with the greatest levels of social deprivation. The rate of repeat consultation for a new infection during follow up was 107.5 (95% confidence interval [CI] = 105.6 to 109.4) per 1000 person-years. Obesity (relative risk [RR] 1.3, 95% CI = 1.2 to 1.3), diabetes (RR 1.3, 95% CI = 1.2 to 1.3), smoking (RR 1.3, 95% CI = 1.2 to 1.4), age <30 years (RR 1.2, 95% CI = 1.2 to 1.3), and prior antibiotic use (RR 1.4, 95% CI = 1.3-1.4) were all associated with repeat consultation for a boil or abscess. CONCLUSION: Ten percent of patients with a boil or abscess develop a repeat boil or abscess within 12 months. Obesity, diabetes, young age, smoking, and prescription of an antibiotic in the 6 months before initial presentation were independently associated with recurrent infection, and may represent options for prevention.

Tackling the threat of antimicrobial resistance: from policy to sustainable action.

Antibiotics underpin all of modern medicine, from routine major surgery through to caesarean sections and modern cancer therapies. These drugs have revolutionized how we practice medicine, but we are in a constant evolutionary battle to evade microbial resistance and this has become a major global public health problem. We have overused and misused these essential medicines both in the human and animal health sectors and this threatens the effectiveness of antimicrobials for future generations. We can only address the threat of antimicrobial resistance (AMR) through international collaboration across human and animal health sectors integrating social, economic and behavioural factors. Our global organizations are rising to the challenge with the recent World Health Assembly resolution on AMR and development of the Global Action plan but we must act now to avoid a return to a pre-antibiotic era.

The World Health Assembly resolution on antimicrobial resistance.

Antimicrobial resistance is a global problem that can only be tackled successfully through strengthened international partnerships. A concerted political, scientific and media campaign has garnered support for the recent World Health Assembly resolution on antimicrobial resistance, mandating the WHO to develop a global action plan. This resolution has the 'One Health' approach at its core, emphasizing collaboration across human and animal health sectors at the international, national and regional levels, coupled with strong leadership and the political will to act. Key themes are communication, prevention of infection, using knowledge to guide action, sustainability and optimizing the use of antimicrobial medicines and diagnostic devices. Implementation of the global action plan will require member states to make a commitment to developing national action plans and strengthening capacity, building on collaborations between the WHO, the World Organisation for Animal Health, the World Bank, Codex Alimentarius and the Transatlantic Task Force on Antimicrobial Resistance.

Use of primary care data for detecting impetigo trends, United kingdom, 1995-2010.

Using a primary care database, we identified a major increase in impetigo in the United Kingdom during 1995-2010. Despite a doubled rate of primary care consultations, this increase was not identified by routine surveillance. Primary care databases are a valuable and underused source of surveillance data on infectious diseases.

The role of the Panton-Valentine leucocidin toxin in staphylococcal disease: a systematic review and meta-analysis.

BACKGROUND: Invasive community-onset staphylococcal disease has emerged worldwide associated with Panton-Valentine leucocidin (PVL) toxin. Whether PVL is pathogenic or an epidemiological marker is unclear. We investigate the role of PVL in disease, colonisation, and clinical outcome. METHODS: We searched Medline and Embase for original research reporting the prevalence of PVL genes among Staphylococcus aureus pneumonia, bacteraemia, musculoskeletal infection, skin and soft-tissue infection, or colonisation published before Oct 1, 2011. We calculated odds ratios (ORs) to compare patients with PVL-positive colonisation and each infection relative to the odds of PVL-positive skin and soft-tissue infection. We did meta-analyses to estimate odds of infection or colonisation with a PVL-positive strain with fixed-effects or random-effects models, depending on the results of tests for heterogeneity. RESULTS: Of 509 articles identified by our search strategy, 76 studies from 31 countries met our inclusion criteria. PVL strains are strongly associated with skin and soft-tissue infections, but are comparatively rare in pneumonia (OR 0·37, 95% CI 0·22-0·63), musculoskeletal infections (0·44, 0·19-0·99), bacteraemias (0·10, 0·06-0·18), and colonising strains (0·07, 0·01-0·31). PVL-positive skin and soft-tissue infections are more likely to be treated surgically than are PVL-negative infections, and children with PVL-positive musculoskeletal disease might have increased morbidity. For other forms of disease we identified no evidence that PVL affects outcome. INTERPRETATION: PVL genes are consistently associated with skin and soft-tissue infections and are comparatively rare in invasive disease. This finding challenges the view that PVL mainly causes invasive disease with poor prognosis. Population-based studies are needed to define the role of PVL in mild, moderate, and severe disease and to inform control strategies. FUNDING: None.