Impact case study database

A more personalised approach to clinical management is part of the ‘silent revolution’ unfolding within the NHS and worldwide. The novelty of the research led by Mukhopadhyay is evidenced by Sir Stephen Holgate, an internationally respected expert in asthma, who stated that these results constitute ‘ one of the first demonstrations of the application of personalised medicine to the clinical management of asthma’ [Source 5.1]. The impact of the research on treatment response and genetic variation has affected diverse beneficiaries (patients and carers, clinicians, trainees and regulatory bodies) locally, nationally and internationally. The evidence provided through the body of research has been used to create a notable shift in awareness of alternative treatment options, which is now improving clinical practice, informing GP training (UK), and is formalised within international treatment guidelines (Australia). Life-changing care is now being provided for the patients and families undergoing alternative treatment.

4.1 Developing new personalised clinics for allergy-related disease care management

New paediatric personalised medicine clinics, in operation from 2016, and supported by the NHS and Rockinghorse, a Sussex-based charity, constitute a unique development at the Royal Alexandra Children’s Hospital in Brighton (Royal Alex). These clinics have treated over 60 children with severe, often multi-system disease through repeat visits. The clinics draw on the deeper scientific understanding of the uniqueness of each child with regard to allergy-related diseases, and clinical problems that affect children according to their individual genetic traits and environmental exposures. This is in stark contrast to the way dermatology clinics were run previously, ie on the basis that allergy and eczema were separate entities. Leading paediatric dermatologist, Dr Jess Felton, attributes the shift in clinical practice at the Royal Alex to the research undertaken by Mukhopadhyay’s team [5.2]. This shift directly influences practice by placing greater emphasis on allergy testing and the use of emollients from a very early age in children with eczema and related conditions. As a result, children under the age of 6 months, presenting with eczema are treated more proactively as the research showed that infants with these skin barrier defects develop more severe atopic disease. These clinics focus more on understanding the role of external allergens, performing skin prick testing for allergies in the dermatology outpatient clinic to help with diagnosis of selected type 1 allergies that may be adding to the severity of eczema. This joint clinic where dieticians, dermatologists and asthma specialists devise a care plan in collaboration with the child’s parents has dramatically improved patient experience. NHS consultants and trainees report benefit from this innovative approach [5.2]. The carers interviewed in a 2019 survey (n=30) reported 100% satisfaction following treatment due to their changed care plan, their involvement in treatment decisions and the united approach of their clinicians [5.3]. [text removed for publication] [5.4].

4.2 Increasing awareness of the benefits of a patient-centred approach to the treatment of allergy-related diseases (healthcare professionals and the public)

To extend the clinical impact the research team disseminated their key research findings across a series of events in 2015-2016. This included study days for 43 trainee GPs in Sussex [5.5a], 44 attendees of the National Medical Students Paediatric Conference [5.5b] and presentations to 48 child health professionals in India through links with the Indian Academy of Paediatrics [5.5c]. Feedback from these events indicates that at least 124/135 (92%) of the professional audience had better awareness of how a poor response to asthma medicine could result from genetic variation in patients. All GPs in attendance confirmed they were now more likely to check whether asthma medicines were working in individual patients [5.5a-c]. The team tailored their findings to a health professional audience and disseminated them via presentations and commentary pieces in key UK health channels: Royal College of General Practitioners (RCGP), websites for the journals Pulse and Nursing in Practice. To build on this impact, the RCGP has made this material available through its website and the research into genetic predisposition and its implications for patient care has been incorporated into the RCGP’s online and in person CPD. The research underpins key guidance in the RCGP’s e-learning module on allergy, developed in partnership with Thermo Fisher Scientific [5.6]. This course is designed to educate GPs about the various presentations of allergic disease, how to assess an atopic patient and when to investigate in primary care or refer to secondary care. This course has been completed by 5,489 healthcare practitioners across the UK since its launch [5.6].

In collaboration with the arts group Same Sky, the team organised and presented their work at a public participation event (May 2016) as part of the Brighton Fringe Festival (approximately 250 attendees). The views of the public, captured on video, indicate an increased understanding of a personalised approach to treatment and an interest in participating in the debate around this subject [5.7a]. Similar results were seen at the New Scientist Science Festival, London (2018) where 331 members of the public found the ‘Personalised Medicine’ stand to be important and educational, with 280 reporting a substantial increase in their understanding of how genes affect the way we respond to medicines and how genes affect diseases [5.7b]. The research findings were also presented to two primary schools in rural Portugal (52 children) and three schools in rural and urban West Bengal, India (239 children). As a result of this engagement a change in awareness of the potential of personalised medicine was recorded [5.7c].

4.3 Improving asthma management through genotype-based prescribing

New treatments for severely affected children have proved to be life changing for individual patients. One patient, Ewan Mackintosh, has declared that having faced multiple ineffective courses of treatment, the research-led decision to prescribe montelukast based on his individual genotype, caused his severe breathlessness to disappear virtually overnight [5.8]. Similarly, this has caused other children undergoing the new treatment regime to eradicate problems faced with every day activities including climbing stairs and playing sports [5.8]. The research findings led directly to the first large-scale comparison of genotype-based personalised care with standard care in asthma anywhere in the world. This was the first time that grant funding of this scale (Action Medical Research (AMR), grant GN2203, GBP277,375) was awarded to a precision medicine randomised controlled trial in the field of children’s asthma (2015). Within the trial Mukhopadhyay and colleagues demonstrated the significant benefit of prescribing according to a patient’s genotype. Of the 241 patients recruited from across England and Scotland, the 121 patients randomised to the ‘personalised care’ group, experienced a significant improvement in their quality of life as assessed on a wide range of activities, including physical activities, school work and sleep quality in comparison to the 120 patients randomised to the ‘standard NHS care’ group [reference 3.6]. Completed in 2019, the AMR have noted that the successful findings of this trial, the first of its kind in children and teenagers, are helping ‘t he charity to make a difference’ with children affected by disabling conditions. The AMR selected the project as an Action ‘Steps Forward’ for 2020 and included it in their 2020 Research Review for supporters and trustees due to positive results and its potential to provide a model for other diseases. These publications are used by the charity to demonstrate the value of donors’ giving, and to inspire, motivate and help with communications and fundraising to encourage potential future supporters of the charity [5.9].

4.4 Changes to Australian healthcare guidelines on asthma

In a 2015 review of childhood mortality, doctors in Australia were cautioned that the adverse gene-medicine interaction described in Mukhopadhyay and colleagues’ research may have contributed to multiple asthma-related deaths in children in New South Wales between 2004 and 2013. The review revealed that a large number of children had been prescribed inhaled corticosteroids in combination with regular long-acting beta2 agonist (LABA; eg salmeterol). Citing the team’s findings on the link between β receptor gene polymorphism and LABA adverse effects, the review drew the hypothesis that ‘ LABA use in the children who died from asthma may have, theoretically, put these children at risk of severe exacerbation and […] it might, therefore, explain the increase in asthma deaths seen in recent years’ [5.10].

In the 2015 version of the Asthma Australia Handbook, the national asthma guideline for health professionals in Australia, Mukhopadhyay’s research is one of the key pieces of research evidence cited as part of the recommended stepwise approach to asthma management in children, warning clinicians about the adverse gene-LABA medication interaction [5.11a-b]. As part of this approach, the guideline specifically states that response to treatment partly depends on genetics, referencing the team’s finding that due to the child’s genotype, only a proportion of children will respond to individual asthma treatments [5.11c]. This is to our knowledge the first example of genotype-based advice in any national guideline for asthma.