Award Title: Use of fractional exhaled nitric oxide (FeNO) to guide monitoring of asthma treatment in primary care
Funder: Department of Health and Social Care

Abstract: Background to the research Acute exacerbations of asthma place considerable burden on health care resources, with hospitalisations accounting for 52% to 86% of total asthma-related costs. Inhaled corticosteroids are the mainstay of treatment to prevent acute exacerbations. However, standard methods of monitoring asthma in primary care, including spirometry and reversibility assessments, have limited value in predicting future exacerbations. This may result in inaccurate targeting and dosing of inhaled corticosteroids in patients with asthma. Fractional exhaled nitric oxide (FeNO) is an objective marker of steroid-responsive eosinophilic airway inflammation, which may allow for a more targeted and personalised treatment approach. Raised FeNO levels have been shown to be associated with increased risk of asthma exacerbations. However, although NICE already recognises the value of using FeNO to aid diagnosis of asthma, it has highlighted the need for more robust evidence to guide health care professionals in how to use and interpret FeNO measurements when monitoring asthma treatment in patients who have already been diagnosed. Aims of the work My proposed programme of research aims to:Establish optimal FeNO thresholds for monitoring treatment of asthma.Explore health care professionals' views and experiences of using FeNO to monitor asthma treatment in primary care.Plan of investigation To establish optimal FeNO thresholds for stepping up and stepping down treatment in patients with asthma, I propose to conduct a systematic review and individual patient data (IPD) meta-analysis of data from observational studies and randomised controlled trials. For my primary analysis, I will conduct a one-stage meta-analysis. I will use mixed effects Poisson regression to examine the association between FeNO measurements and incidence of acute asthma exacerbations, adjusting for potential baseline confounders, including age, sex, smoking status and co-morbidities. I will construct Receiver Operator Characteristic (ROC) curves and explore different strategies for determining optimal decision thresholds on the ROC curve, including weighted comparison measures and average overall costs of performing FeNO measurements. To explore health care professionals' views and experiences of using FeNO to monitor asthma treatment in primary care, I will conduct semi-structured interviews with a maximum variation sample of 15 to 20 health care professionals based on video-recorded primary care asthma monitoring consultations conducted by study participants. I will lend study participants a FeNO analyser (NIOX VERO, Aerocrine) to use during one or two video-recorded asthma clinics and train them in how to obtain and interpret FeNO measurements according to a FeNO-guided management algorithm whose decision thresholds will be informed by the findings of the systematic review and IPD meta-analysis. I will watch two or three contrasting consultations with each study participant and ask them to talk me through their thought process during each consultation. Data will be analysed using thematic analysis to allow an inductive approach, whereby emerging themes will be grounded in the data collected rather than derived from previous research or researchers' preconceptions. Data collection, analysis and coding will proceed alongside each other until data saturation is reached. Summary of potential benefits to patients and the NHS My proposed research will produce an evidence-based algorithm for FeNO-guided monitoring of asthma treatment in primary care. The systematic review and IPD meta-analysis, whose findings will be available by the end of year 3, will establish optimal FeNO decision thresholds for adjusting treatment. The qualitative study, whose findings will be available by the end of year 5, will inform strategies for implementing FeNO-guided monitoring of asthma treatment in primary care. These research findings will help inform NICE and BTS/SIGN guidance on monitoring asthma treatment and have strong potential for rapid translation into clinical practice within five years of this fellowship being completed.

Lay Abstract: BackgroundAsthma is a common condition which affects the airways of the lungs. In people with asthma, swelling (also known as inflammation) can occur in the linings of the airways. This inflammation can cause mucus (phlegm) to build up and make the airways narrower than usual. This can lead to symptoms such as wheezing, coughing, chest tightness and shortness of breath. If these symptoms flare up very badly, people may need treatment with medicines to help reduce inflammation in the airways (such as antibiotics or steroids) or even admission to hospital. To try and prevent serious 'flare-ups' from happening, health care professionals may advise people with asthma to take inhaled steroids to keep the inflammation in their airways under control.Most patients with asthma have asthma check-ups at least once a year in their GP surgery. However, the tests used during these asthma check-ups are not always helpful in predicting how likely someone is to have a serious 'flare-up' of their asthma (also known as an exacerbation). Fractional exhaled nitric oxide (FeNO) is a quick and easy breath test which measures inflammation in the airways and predicts more accurately how likely someone is to have an exacerbation of their asthma. However, at the moment, most GP surgeries do not measure patients' FeNO levels during asthma check-ups. The National Institute for Health and Clinical Excellence (NICE) already recognises the value of FeNO in helping health care professionals diagnose asthma. However, NICE has also highlighted the need for clearer guidance on how to use FeNO to make sure that the right people receive treatment with inhaled steroids, and that treatment doses are correctly adjusted in order to minimise the risk of future exacerbations. Aims and proposed methods My proposed research aims to: 1) Find out which FeNO levels should prompt health care professionals to consider adjusting a patient's asthma treatment. I will study the relationship between FeNO levels and risk of future exacerbations by combining the results of several different studies on this subject. Combining these results will help me draw more definite conclusions by allowing me to apply the same definition of exacerbations across all studies, consider the predictive value of individual FeNO measurements (rather than categories or ranges of FeNO measurements), and take into account other factors which might influence the risk of exacerbations, such as age, smoking and other medical conditions. 2) Find out how health care professionals feel about using FeNO to help them decide how to adjust patients' asthma treatment during asthma check-ups.Using the findings of my first study, I will train 15 to 20 health care professionals who perform asthma check-ups in GP surgeries in how to measure and use FeNO to adjust asthma treatment. I will then lend them a machine for measuring FeNO to use during one or two asthma clinics, which I will ask them to record on video. For each health care professional, I will select two or three different video-recorded consultations, and ask them to watch these consultations with me while talking me through their thought process during each consultation.Patient and public involvement I plan to recruit an advisory group of six patient representatives, consisting of people with asthma and carers of people with asthma. The group will meet once during year 3 to help me prepare information leaflets for patients about my proposed study with health care professionals, and ensure that procedures for seeking consent to video-record consultations are acceptable to patients. The group will meet again during year 5 to help me summarise the findings of my research in terms which patients will understand and help me find ways of informing relevant patient groups and the wider public about these findings. Between meetings, I will keep the group updated on emerging findings from my study with health care professionals. Dissemination I will aim to publish my research findings in high quality and widely read medical and scientific journals.I will also aim to present my research at national and international meetings attended by health care professionals who are mainly responsible for monitoring and adjusting treatment in patients with asthma. I will work closely with my research mentors, Professors Ian Pavord and Mike Thomas, to incorporate my research findings into national asthma management guidelines for health care professionals. I will also aim to promote uptake of my research findings into clinical practice by working with a regional network of academics and clinicians based in Oxford, which has links to patients, universities, industry, and health service providers and commissioners.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: RESPIRATORY