Title: Reducing the burden of paediatric respiratory tract infections to the NHS
Funder: Department of Health and Social Care

Abstract: Programme 1 – Reducing the Transmission of Infectious Disease to Primary and Secondary Care Communities, primary and secondary care services are frequently overwhelmed by children and adults with infectious illnesses, most commonly respiratory and gastro-intestinal.(Hay 2005) Children appear to play a key role in infection transmission to both other children and adults. US evidence demonstrates that children’s pneumococcal vaccination leads to benefits not only for the children themselves, (Grijalva 2006) but also in reductions in pneumonia in the elderly. (Poehling 2006) Similarly, the routine vaccination of all Japanese children against influenza is thought to be responsible for reductions in influenza in other age groups. The annual cost of respiratory and gastro-intestinal infections to societies and healthcare systems worldwide is enormous, with costs including: primary care consultations; hospital attendances; hospital ward closures and disruption (e.g. due to infections such as respiratory syncytial virus (RSV) and norovirus); and parental absenteeism from work (both when they are unwell and to care for unwell children). While substantial progress has been made in the prevention of some infections through vaccination programmes, a large number of microbes (such as RSV and norovirus), are not prevented by existing or planned immunisation schedules. And large scale community based epidemiology research of respiratory and gastro-intestinal infections has not been undertaken since the 1970s in the US. (Monto 1974) Although some research is underway to assess interventions such as hand-washing in schools (Campbell 2010) and website based education to reduce transmission in the home (Little 2011), little attention has been given to improving our wider understanding of, or developing interventions to reduce, the transmission of ‘non-vaccine preventable’ respiratory or gastro-intestinal infectious diseases within our communities or understand the dynamics of infected individuals as they access primary and secondary care health services. The aim of Programme 1 is to identify where, which and by how much, interventions will reduce the community and health service burden of respiratory and gastro-intestinal tract infections. Specific objectives will be to: 1. Systematically review the literature for evidence regarding (i) the high risk locations for infection transmission and (ii) the effectiveness of existing interventions to reduce infectious diseases transmission 2. Describe the epidemiology and transmission of the microbes associated with acute respiratory and gastro-intestinal infections 3. Describe the movement through time and space of infected individuals as they access primary and secondary health care and other public services 4. Use objectives 2 and 3 to identify specific ‘pinch points’ where interventions to prevent transmission can be targeted 5. Use qualitative evidence synthesis and interviews to evaluate the lay and professional understanding of infection transmission and assess the acceptability of potential community, primary and secondary care based interventions 6. Use results from objectives 1 to 5 to inform the design and implementation of controlled studies to evaluate the effectiveness of interventions to reduce the burden of community and health service infections. These objectives are ambitious but achievable given our existing excellent collaborative links with: epidemiology; qualitative methods; microbiology; and health psychology, and our substantial success of previous and current community, primary and secondary care research (see PART C (2)” for descriptions of the, TARGET, DUTY and PCAAR studies). Moreover, this experience will be complemented by the addition of new collaborating disciplines and groups (including a new international collaboration): infectious diseases modelling (Trotter and Turner et al, University of Bristol); paediatric infectious diseases (Finn et al, University of Bristol); public health research (Campbell et al, University of Bristol), public health protection (Oliver et al, Health Protection Agency/Health Protection England); and community surveillance research (Monto et al, University of Michigan School of Public Health, first new collaboration). The quantitative work will involve community, primary and secondary care symptom, illness and microbiological transmission monitoring within a 10km perimeter of Bristol’s two acute hospital Trusts. As with Programme 2, two illustrative, highly transmissible, syndromic illnesses will be selected for the main focus of attention: (i) acute cough associated with respiratory tract infection (RTI) and (ii) diarrhoea/vomiting associated with acute gastroenteritis. Community, primary and secondary care data will be collected using a range of previous successful methods including: (i) mobile phone symptom data capture (http://www.epicollect.net/); (ii) self and research nurse administered throat/ nasal swabbing in the community, primary and secondary care; (ii) QResearch and NHS Direct/HPA syndromic surveillance systems; and (iii) Hospital Episodes Statistics data. Real time qualitative work will allow individuals involved in a community, primary or secondary care outbreak of symptoms to be interviewed in depth regarding the possible origins of their symptoms as well as their perception ofinfection transmission and the acceptability of potential interventions, such as improved hand and other hygiene measures, isolation of symptomatic individuals, face masks, alternative arrangements for the care of unwell children, screening of unwell people entering public spaces (e.g. swimming pools), to interrupt infection transmission. Quantitative and qualitative data will be used to inform the development of community, primary and secondary care based interventions to reduce the transmission of infections within our communities. Where possible, effectiveness will be tested using RCT designs, but if this is not possible due to issues of scale, comparable regions of the UK will be selected for parallel before/after designs. Programme 2 – Improving Parental use of Primary Care Services Programme 2 will build on our current NIHR “TARGET” Programme for Applied Research. Results from the first two TARGET Workstreams (WS) are highlighting that: (i) parents of children experiencing acute RTI find the decision to consult difficult and they want much clearer guidance regarding specific symptoms that should/don’t need to prompt help seeking from primary care (Cabral 2012); (ii) that any information provided should be relevant, contemporaneous regarding illnesses currently circulating in their locality (these data will be provided by Programme 1 work) and include advice regarding how best to alleviate symptoms; (iii) that parental information needs should be addressed using a range of media and personnel (including the internet) and that all advice should be consistent; (Ingram 2012) and (iv) to be most effective, interventions should: engage children; occur prior to an illness episode; employ delayed prescribing; and provide guidance on specific symptoms. (Andrews 2012) The third “TARGET” WS will derive and validate a clinical rule to predict complications of acute cough in children presenting to primary care. As with Programme 1, Programme 2 will focus on two common, illustrative syndromic illnesses (acute cough and diarrhoea/vomiting), though this time in children only since primary care infection presentations are more common in this age group than any other. (McCormick 1995) In collaboration with parents, clinicians, health economists, trials methodologists and health psychologists, we will learn from, and scale up, the “TARGET” Programme intervention (currently being planned for piloting) by developing more sophisticated multi-media (complex) interventions targeted at parents and clinicians to improve awareness of symptoms that should/should not result in primary care consultations. It is likely these will include: educational sessions for clinicians on how to support parental future help-seeking (dove-tailed with improving appropriateness of antibiotic prescribing, see Programme 4) and informed by the symptoms and signs identified in TARGET WS3 as being of prognostic importance; the development of internet based support for parents that includes up to date information regarding contemporaneous circulating illnesses and moderated by experienced primary care health care professionals. Parents will have the facility to share experience of caring for their children, how they coped with specific symptoms, when and why they decided to consult their GP/NHS Direct – and what the GP/ NHS Direct advised. A range of evidence-based multi-media information packages will be developed which will provide parents with training regarding the identification of ‘red flag’ symptoms (e.g. video clips of children with respiratory distress or dehydration) with clear advice regarding when to seek help and from whom. Since parents also state they wish to know how best to alleviate their children’s symptoms (Cabral 2012), interventions will include the latest evidence regarding parent ‘self help’ measures (see Programme 3). Programme 3 – Supporting Parental Treatment of Children’s Symptoms in the Home Having published the only fully home based RCT of antipyretic strategies for the treatment of fever in pre-school children, my group has established an international reputation for research investigating the alleviation of the distressing symptoms associated with infections in children.(Hay 2008) Symptoms associated with infections for which parents commonly seek advice include crying, pain, rash, fever, “prolonged symptoms”, cough, vomiting and diarrhoea.(Hay 2005) Evidence suggests there is wide variation in the way European and US primary care clinicians and parents manage symptoms. Programme 3 will therefore start with a Bristol based ‘Scoping Meeting’ of European and US primary care infection researchers to learn from the variation in care strategies. I am already a member of the GRIN (General Practice Infection Network), a highly successful collaboration of European and US primary care infection researchers, who meet annually to present and discuss latest research. Thus, in conjunction with our PPI group (see below), we will invite members of the GRIN group to: 1. Map all existing strategies and treatments currently available in, and used by, European and US parents and clinicians 2. Describe the evidence for the risks and benefits of each strategy and 3. Identify candidate therapies for which further research is necessary. One candidate has already been identified for which further research is warranted and an illustrative description is given below. RCT of Anaesthetic Ear Drops for Acute Otitis Media in Children Acute otitis media (AOM) is important to parents and the NHS for three reasons. First, the infection causes pain and distress to the child, due to a rise in pressure in the middle ear, stretching the tympanic membrane. Second, parents are more likely to consult for AOM than for any other symptom of acute infection, with around 2.6M consultations at a cost to the NHS of at least £50M per annum. Finally, AOM is now the most common reason for a child to receive anantibiotic in the UK and US with three-quarters of UK general practices prescribing antibiotics to 80% or more of children with AOM. (Ashworth 2005) This is inappropriate, unnecessary and contrary to NICE Guidelines, exposing children to side effects (diarrhoea, rashes and anaphylaxis) and the risk of carrying antibiotic resistant bacteria. (Costelloe 2010) Given that children are responsible for the transmission of bacterial infections to both the young and old within their communities (see Programme 1), AOM is a key infection for which alternative management strategies are urgently needed. Anaesthetic ear drops are thought to work by directly anaesthetising the tympanic membrane, the source of a child’s pain in acute otitis media. They are a good example of the international variation in supportive care in that they are available over-the-counter in Europe, North America and Australasia, but not in the UK, potentially leaving UK parents at a disadvantage compared with their European counterparts. The three previous trials assessing analgesic effectiveness have been synthesised and the Cochrane review concluded that “the evidence from is insufficient to know whether ear drops are effective”. (Foxlee et al. 2006) No trial has previously investigated their effects on antibiotic consumption. (Ashworth 2005) We hypothesise that the use of anaesthetic ear drops in the UK will: (i) reduce children’s pain, (ii) reduce the use of antibiotics and (iii) be a cost effective alternative to existing management strategies. Since it is possible that any liquid in the outer ear could have soothing effects, we will propose a three arm, individually randomised, placebo and usual care controlled trial with allocation to: (i) anaesthetic ear drops + usual care; (ii) topical placebo drops + usual care or; (iii) usual care alone. This will be a difficult trial to conduct since children will only be eligible if they have with ear pain (an intermittent symptom) at the time of treatment administration. However, our successful ‘PITCH’ antipyretic trial (Hay 2008) had a similar, intermittent symptom (fever) eligibility criterion, demonstrating our capability to conduct this trial. Programme 4 – Improving the Use of Antibiotics in Primary Care Although reductions in overall antibiotic use would expected with reduced primary care consultations, and reducing antibiotic use is closely related to Programmes 1 to 3, improving the appropriate use of antibiotics requires a complementary approach. Many GPs regard the problem of antibiotic resistance as “minimal” (Kumar 2003) or “theoretical”, (Butler 1998) despite being responsible for over 80% of all antibiotic prescriptions. Yet, there is growing evidence (from my group (Costelloe 2010) and that of the European Surveillance of Antimicrobial Consumption (ESAC)) that primary care prescribed antibiotics leads to antibiotic resistance in bacteria causing minor infections or carried by asymptomatic adults and children. Other research has shown that enhanced communication skills training (Cals 2009) and GP practice feedback of practice specific antibiotic resistance rates (Butler 2012) can reduce the unnecessary use of antibiotics. However, study related reductions remain modest and despite European initiatives (such as the annual European Antibiotic Awareness Days), overall UK prescribing rates are currently rising. Very little research has investigated links between primary care prescribed antibiotics and bacterial resistance in more serious infections warranting hospital care. Knowledge of these effects, and their associated economic impact, could have a major influence on public expectations for, and primary care use of, antibiotics. We have completed the “PCAAR-H pilot” study (see Part C (2) for background), the unadjusted logistic regression results of which show that, among adult patients who were admitted to the Bristol Royal Infirmary (one of Bristol’s two acute hospital Trusts) with urinary tract infection, those who had at least one course of antibiotics in the previous 12 months had a 3.3 greater odds of having an infection that was resistant to at least one type of antibiotic (95% CI 1.07 to 10.12, p=0.038). Therefore, in conjunction with Programmes 1 to 3, the Programme 4 objectives are to: 1. Expand the PCAAR-H pilot into a definitive study of a wider range of infections 2. Establish a new collaboration with the European Surveillance of Antimicrobial Consumption (ESAC) Group at the University of Antwerp, Belgium and 3. Build existing collaborations with NHS Bristol (PCT) Medicines Management to use the evidence from objectives 1 and 2 to refine previous interventions to improve antibiotic use. The PCAAR-H pilot will be developed into a full study by recruiting both adults and children from whom bacteria have been isolated from a wider range of microbiological samples (e.g. urine, blood, cerebro-spinal fluid, joint aspirates or skin/abscess samples) and sent to the HPA laboratory located within the Bristol Royal Infirmary Acute Trust for the assessment of suspected urinary tract, respiratory tract, bone, joint, brain or skin infections. We will request ethics approval to link and then pseudo-anonymise two databases. First, the antimicrobial susceptibility status of these isolates and second the same patients’ primary care record of antibiotic prescribing, using the same methods successfully employed in the past. (Hay 2005) This will give the group a substantial dataset in which to investigate infection and age specific relationships between resistance and primary care antibiotic use.Since the European Surveillance of Antimicrobial Consumption (ESAC) Group at the University of Antwerp is a leading international group working in this area, costs are included within this Professorship for me to travel regularly to Belgium to meet with Professors Coenen and Goossens, present results and discuss potential for interventions. These will be developed in close conjunction with Bristol NHS (the PCT, or its commissioning successor) to ensure that the research is implemented in clinical practice. Specific opportunities exist to develop and translate research into PCT medicines management policy such as: (i) providing advice and input to the annually updated Bristol NHS antibiotic guidelines; (ii) further develop existing PCT initiatives such as 'Scriptswitch' (a computer decision support tool that interacts with GP electronic medical records to provide clinicians with real time prescribing support) to provide antibiotic prescribing guidance (e.g. use of the evidence based “delayed prescribing” strategy); (iii) providing PCT pharmacy support for the aim of using the NHS IT “Spine” (that will link GP prescribing to chemists’ medicine dispensing) to monitor and evaluate adherence to prescribing interventions (e.g. “delayed prescribing”) which has been shown to effectively reduce antibiotic use in efficacy studies, but not in “real life” clinical practice; and (iv) working closely together to develop the future translational research agenda. Thus, the overall aim of this Professorship is to provide evidence that puts the NHS onto a proactive rather than reactive footing in the management of common infectious diseases. Funding for these Programmes will be sought from the NIHR, either as individual projects (e.g. the HTA for the trials), or Programme Grants and /or as an Infection Theme in a Bristol wide NIHR Biomedical Research Centre application.

Lay abstract: Community, primary and secondary care services are frequently overwhelmed by children with infectious illnesses, most commonly respiratory. Children also play a key role in the transmission of infection both to other children and adults. Presentation to primary care often results in the use of antibiotics, many of which are unnecessary, and promote illness medicalisation and bacterial resistance. The overall aim of this Professorship is to reduce the burden of respiratory tract infections in children to the NHS.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION