Title: The early use of Antibiotics for at Risk CHildren with InfluEnza in primary care (the ARCHIE programme).
Funder: Department of Health and Social Care

Abstract: Aims and objectives The overall aim of the ARCHIE programme is to produce an evidence base to inform NHS policy for the use of antibiotics in at risk children with influenza/influenza-like illness (ILI). At risk children are more prone to influenza-related clinical deterioration (bacterial complications and hospitalisation) than otherwise healthy children. The programme will be delivered in five workpackages designed to: refine the definition of at risk , explore the views of GPs and parents who will be key to implementing policy, test the effectiveness of early antibiotics delivered in primary care, determine the effect of antibiotics on bacterial carriage and antibiotic resistance, and construct clinical and economic models to inform NHS policy. Background and rationale Influenza/ILI in children create a considerable burden on NHS resources each winter. Influenza immunisation is only partially effective, coverage amongst at risk children is currently low and antiviral medications are of modest clinical benefit. Because of concern about NHS capacity to manage complications during influenza epidemics and pandemics there are national government stockpiles of co-amoxiclav held for use in primary care. Research environment The programme will be co-ordinated by the University of Oxford, which has an established primary care research environment of excellence (top rated in 2008 Research Assessment Exercise and founder member of the National School of Primary Care Research). The programme will benefit from pre-agreed collaboration between the PCRN and MCRN. Research plan Workpackage A will provide a refined, evidence-based definition of at risk children through conducting a prognostic systematic review. This definition will inform a more precise definition of at risk for entry into our clinical trial (workpackage C) and for future influenza immunisation policy. Workpackage B will explore factors which influence GPs antibiotic prescribing decisions as well as parental experiences and consulting attitudes in relation to at risk children with influenza/ILI using qualitative methodology. The results will help us design materials for our clinical trial and understand the factors likely to influence the implementation of our research findings. We will also develop a website to improve public understanding of the importance of influenza and its complications. Workpackage C will determine the effectiveness of the early co-amoxiclav use for at risk children with influenza/ILI by conducting a double-blind randomised placebo-controlled trial involving 600 children in Thames Valley, Liverpool, Bristol and Southampton. We will perform exploratory subgroup analyses in children with different influenza subtypes (A, B, A/H1N1 2009), influenza and bacteria co-infections and prescribed concurrent antiviral medication. Workpackage D will determine the impact of co-amoxiclav on bacterial carriage and the development of antibiotic resistance by conducting a nested prospective longitudinal study of children participating in the trial, sampling with interval throat swabs over the course of a year. Workpackage E will conduct a systematic review, develop and validate multivariable risk scores to estimate levels of risk in at risk children with influenza/ILI and determine which children are likely to gain greatest clinical benefit from antibiotics. We will assess and compare health care resource utilisation and costs, and explore the cost-effectiveness of different potential strategies for early antibiotic use. Projected Outputs & Dissemination plans The programme will provide an evidence base to underpin NHS policy for primary care antibiotic prescribing during the influenza season. Outputs will include peer- reviewed presentations and publications in multidisciplinary fields and a website of parents experiences of children with influenza. We will disseminate our findings to the Department of Health to refine the definition of at risk children in the Green book on immunisation and to use our cost effectiveness models to guide NHS seasonal and pandemic influenza policy. Relevant expertise & experience of the research team We are a strong mulitidisciplinary team with experience of working together in the National School of Primary Care Research and established track records in childhood infection research. Drs Harnden and Semple have key advisory roles to the Department of Health in developing paediatric influenza policy. Justification of costs The main costs are for staff &ndash; research, clinical trials unit, laboratory and administrative support. The research will be co-ordinated by a full-time programme manager. Management & Governance, including Programme Management and any ethical implications The ARCHIE programme will be coordinated in Oxford and guided by a steering group with independent and lay representation. The clinical trial will be supported by the UKCRC registered Oxford Primary Care Trials Unit. The trial will be carried out according to the principles of the Declaration of Helsinki (revision 2008). Patient and Public Involvement Two patient representatives will be actively involved in the ARCHIE programme. Together with MCRN consumer representatives, they have already helped us develop the focus of our application, particularly our interview and focus group topic guide. Both patient representatives will also have key roles in designing user-friendly trial recruitment materials and disseminating our research findings. Our lay co-applicant will co-facilitate our parent focus groups.

Lay abstract: Flu (influenza) and flu-like symptoms are among the commonest reasons why parents bring their children to see a general practitioner (GP) during winter. For most children flu is a mild and relatively short illness. However, some children can become more unwell with flu. The flu virus damages the linings of the throat and lungs. This makes children feel more unwell and increases the risk of bacterial infections including ear infections and pneumonia. At risk children are those children with existing medical conditions that are more prone to becoming unwell from flu and further bacterial infections than otherwise healthy children. These can lead to more visits to a GP surgery, hospital or out-of-hours centre and cause disruption to children and parents generally, including time off school, nursery or work. Antibiotics are given to children with flu who already have a bacterial infection. However, we would like to know whether giving antibiotics to at risk children with flu at an earlier stage reduces the chances of them becoming more unwell or getting further bacterial infections. We would like to research the following: Find out which children are at greatest risk of complications of flu by looking at the previous research that has already been done. Ask GPs and parents their views and experiences in relation to flu and its treatment in at risk children by interviewing them and holding group meetings to find out their opinions. See whether giving early antibiotics to at risk children with flu-like symptoms reduces their chances of becoming more unwell and needing to see a doctor by performing a large research trial. Help medical staff and policy makers decide which children are likely to benefit most from early antibiotics by developing scoring systems. Look at how much flu in at risk children costs parents and the NHS and whether early antibiotic use might reduce these costs. See whether early antibiotic use might reduce the chances of antibiotics working against future infections or encourage growth of potentially harmful bacteria. We already have ethics approval to begin interviewing parents. We will gain the necessary approvals to begin all other aspects of our research, including Medicines and Healthcare Regulatory Agency approval for our research trial. Our team has considerable expertise in research involving children with coughs, colds, sore throats and ear infections and includes the leading UK researchers in this subject. Our findings will directly benefit patients, medical staff and policy makers in raising awareness of flu in at risk children. They will also help to inform guidelines for antibiotic use during flu seasons and to make sure that there is a good supply of antibiotics in preparation for future flu outbreaks.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION