UK Respiratory Research Collaborative (UKRCC) -Research Opportunities

BSACI Council member Professor Johnston is the BSACI representative on the umbrella committee for respiratory research in the UK which has been set up by professional bodies and lung charities to look at how best to take forward respiratory research. 

There is a process (at an early stage for prioritising respiratory research) which will be discussed at future UKRRC meetings.  Professor Johnston said severe asthma had figured in some suggestions to date, but that any research identified as a priority would still need to obtain funds through usual channels such as National Institute for Health Research/Medical Research Council (NIHR/MRC), charities or other sources. National Institute for Health/ Medical Research Council (NIH/MRC). 

Professor Durham suggested that BSACI members with suggestions for research proposals (that were in line with the society’s reaserch priorities below) could send suggestions to  This e-mail address is being protected from spam bots, you need JavaScript enabled to view it   for inclusion in the UKRRC prioritising process. For further details either contact Fiona Rayner on 0207 808 7135  or email This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

Research Priorities for Prevention, Treatment and Improved Service Delivery for Allergic Diseases.

The following BSACI members contributed to the list of research priorities:

Dr C Brightling, Dr A Clark, Dr C Corrigan, Prof S Durham, Prof A Frew, Dr R Gore, Dr Y Karim, Prof.T H Lee, Dr S Nasser, Prof. DS Robinson, Dr G Scadding, Dr A Simpson and Dr S Walker .  

1. Identification of provoking causes Genes. Many genetic polymorphisms have been identified that are associated with allergy, but these do not necessarily translate into allergic disease. Additional genetic factors contribute to organ specific allergy, for example, independent genes for asthma risk. Studies must identify how these interact with other genetic factors and the environment, in populations that are well characterised phenotypically.  Intrauterine environment-further study is required into the influence of maternal health, nutrition, environmental exposure, pregnancy related factors, e.g. placental function, and genetic diversity on the development of allergy in the offspring. Postnatal environment-research should focus on nutrition and exposure to allergens, infection, and pollutants in infancy. 

The hygiene hypothesis proposes allergy risk is influenced by early life exposure to infectious agents. The timing of exposure, nature of the agents, how they interact with the immune system and host genetic variability is unclear. Data suggest that the dose and route of allergen exposure, amongst other factors such as genetic predisposition are important in determining offsprings’ allergic risk.  Studies have been limited by small numbers of subject studied and heterogeneous populations.

The lack of definitive conclusions have prevented clinicians from providing effective public health advice on allergy reduction measures or identifying high risk individuals. Identification and characterisation of genetic, environmental and gene by environment interactions in early life which provoke or protect against allergy will require study of large birth cohorts.  This is urgently required to identify susceptible individuals in whom cost-effective public health interventions may reduce the allergy burden. 

2. Measurement of provoking factors (indoor, outdoor aeroallergens and pollutants).Acute episodes of rhinitis and asthma can be caused by exposure to inhalant allergens (e.g. pollen, dust mite, animal dander etc). Prior exposure to air pollutants such as ozone, nitrogen oxides or fine particulate matter (PM) reduces the threshold for response and at higher levels, can trigger attacks of asthma in its own right.

There is some evidence that exposure to PM (especially PM from diesel exhaust) can drive the immune response toward making allergic-type antibodies (IgE). Measuring environmental levels of allergens and pollutants is difficult. Most allergens are contained on or within small particles, which vary in their biological impact depending on where they impact (in the nose, the lung or both). Particle size is a critical issue, as only particles with specific aerodynamic properties will impact in any given area. Studies of the effects of allergen exposure on disease severity must take into account the level of personal exposure, but current methods often rely on fixed samplers, which are affected by disturbance of the air, the movement of pets around the house, changes of bedding, or fluctuations in humidity and temperature, all of which will cause variation in the measurement of allergen concentrations, and may not reflect to true allergen burden experienced by the patient. Some newer methods are being developed to measure smaller numbers of particles in air as it is breathed in.

However, much work remains to be done to validate these tools and apply them to individuals going about a range of representative daily tasks. We also need exposure information for other allergens which may be important, but about which little is known (e.g. mould and fungal allergens) and on the effects of allergen transfer from one place to another. Once epidemiological surveys have identified possible triggers and interactions, these will need to be explored in mechanistic studies work to provide a plausible biological explanation for any observations made in survey work. 

3. Interventional studies-Primary prevention.Clinicians and researchers have been designing studies to prevent the development of asthma and allergies for many years – so called primary prevention studies, which start at or before birth. Ideas for prevention strategies come from observational studies of (modifiable) risk factors for the development of asthma and allergies.

For example, having an allergy to house dust mite is a major risk factor for asthma as is having parents with asthma. There is nothing that can be done about the latter, but it is possible (although difficult) to design changes to the home to reduce exposure to house dust mite.  There are six ongoing studies around the world that have looked at modifying the home environment to reduce exposure to mite allergens in children at high risk because of parental disease. However these studies have produce mixed and, at times, confusing results and based on current evidence it is not possible to recommend a single strategy for prevention or to define a clear public health message. What is emerging from current observational studies is that to understand the development of asthma and allergies, one needs to study both the genes and the environment and look for interactions.

Future primary prevention studies will likely assign risk based on genotype and target the intervention accordingly. It is likely as a consequence of such studies that public health messages will emerge. 

4. Interventional Studies-Secondary prevention.Sensitization to allergens (such as house dust mite, cat and dog) is associated with asthma and exposure to allergens in those asthmatics who are sensitized is associated with more severe symptoms. Investigators have therefore studied the effect of changing the environment to reduce exposure to allergens on the severity of asthma – so called secondary prevention. Although some studies in children have shown a benefit, studies in adults have generally been too small or have been aimed at practical approaches such as changing only 1 facet of the environment (eg fitting mite proof encasings) and have shown no benefit. There is an urgent need for a large adequately powered study of a multifaceted intervention in adults to definitively examine the effect of a comprehensive mite avoidance program on asthma control in adults. 

5. Prevention of occupational allergies and asthma. Asthma and allergic dermatitis arising as a direct consequence of exposures in the workplace are common in UK industry; for example approximately 10% of UK supermarket bakers (a workforce of around 8000) have bakers’ asthma and a similar proportion of those engaged in pharmaceutical research develop an allergy to laboratory animals.  A recent report by the HSE estimates that the total lifetime costs to society of the c.600 cases of occupational asthma reported each year range from  £71.7 to £100.1 million; since recognised cases are believed to represent only  a third of the true incidence, the real costs could be as high as £133.5 million (http://www.hse.gov.uk/RESEARCH/rrpdf/rr474.pdf). 

The pattern of these cost burdens suggests that employers are imposing a large ‘external’ cost on the rest of society. There are in addition high individual ‘costs’ of occupational disease including, frequently, unemployment and reduction in income.  The causes of these diseases are, by and large, well understood and experience in a small number of settings (eg latex in NHS workplaces) suggests that, with sufficient and appropriate effort, primary preventive interventions are feasible.  Extending the breach in this ‘application gap’ will require close collaboration between industry, occupational health and safety services (where these exist) and clinical researchers.  This at present can be very difficult to achieve; and is increasingly so given that there is now virtually no available external funding for such work. This clearly represents an urgent unmet  need. 

6. Inflammation and remodelling. Research into basic mechanisms of rhinitis and asthma, much of which has been pioneered in the UK, has led to the identification of potential therapeutic targets for intervention and the development of several novel and effective therapies that include anti-IgE monoclonal antibody (Omalizumab), anti-leukotrienes and the testing and introduction of known immunomodulatory treatments in asthma including Cyclosporin A and anti TNF-alpha. The role of aberrant repair and remodelling processes in the progression of asthma is increasingly recognised.

There is an urgent need to address why some atopic (skin test positive) individuals develop asthma whereas others do not. It is also important to understand the differences between mild and moderate-severe asthma, the similarities and differences between childhood and adult asthma and why some asthmatics progress to severe, progressive and ultimately irreversible disease whereas others do not. These questions may only be addressed through multi-centre studies with adequate funding for research clinicians and scientists working in collaboration and with access to well-characterised patients via adequately resourced NHS allergy clinics.  

7. Immunomodulation and immunotherapy. Asthma represents a spectrum from mild to potentially life-threatening disease. Rhinitis, although frequently trivialised represents a common cause of morbidity, with impairment of quality of life and work/school performance for over 12 million people, a quarter the UK population, Whereas intranasal corticosteroids and antihistamines are effective for rhinitis, and  inhaled corticosteroids and bronchodilators for asthma, there remains a proportion of patients who fail to respond to these treatments. Furthermore these medications do not influence the underlying progression of disease such that  relapse occurs within days of their discontinuation. 

Allergen immunotherapy (desensitisation) involves the repeated administration of allergen extracts to allergic individuals, in order to induce a state of clinical and immunological tolerance. Widely practised in US and Europe, this therapy has not been widely adopted in UK. Recent work has shown that allergen injection immunotherapy is highly effective, safe when performed by trained persons, and, unlike inhalers and nasal sprays, may induce long term remission, reduce the onset of new sensitizations and prevent the progression from rhinitis to asthma. The sublingual route of immunotherapy (under the tongue) has recently been shown to be effective and suitable for home use in adults and there is encouraging preliminary data in children. There is an urgent need for research to address whether the sublingual route may also induce longterm remission and have disease modifying properties.

Research into the mechanism of sublingual immunotherapy, the development of biomarkers to predict the clinical response to treatment, and the development of novel ‘adjuvants’ to improve the efficacy of both injectable and sublingual vaccines are urgently required.      

8. Diagnosis and monitoring disease severity. Improved diagnostic accuracy and more targeted therapy tailored for individual sufferers will help our battle to hold back the ‘allergic march’. In this regard identification of objective and practical biomarkers applicable as diagnostic and prognostic tools, as well as therapeutic targets will assist in clinical management of allergic disease. Biomarkers can be defined as measurements that are associated with the biology or physiology of a clinical disease process. It is critical that biomarkers are relevant, and reflect or predict patient-centred outcomes such as symptoms, quality of life, disability, exacerbations and death.

A wide variety of biomarkers have been associated with allergic disease, but few are well-validated and fewer still are used in routine clinical care. For example, in asthma response to certain drug treatments are associated with genetic polymorphisms (pharmacogenetics), and anti-inflammatory treatment titrated based upon markers of inflammation measured in exhaled breath, sputum composition, and measures of airway physiology have all shown benefit compared to standard therapy. Further scrutiny of these biomarkers and the development of simpler markers are required so that these can be taken from the research arena and applied to the clinical care of sufferers with allergic disease. 

9. Difficult to treat asthma. Although asthma care has improved in the last 15 years with the advent of British and International treatment guidelines and widespread use of preventive inhaled steroid therapy, a small proportion of asthmatics continue to have severe limitation of there lives by the disease.  These difficult to treat asthmatics represent about 10% of the total asthmatic population and include both adults and children, and a recent survey identified up to 7000 adults with difficult asthma reported by UK chest physicians. 

 Studies have suggested these patients are those most at risk of dying from their asthma (over 1000 deaths per year in the UK) and they account for up to half of all healthcare resource costs for asthma.  They often remain symptomatic despite treatment including oral steroids (which can produce serious side effects including osteoporosis, diabetes and hypertension).  This group remains ill defined and understudied and there are no current guidelines on management of this group in the British Guidelines on Asthma.  New treatments aimed at this group include anti-IgE antibodies which represent expensive treatment with poorly defined criteria for use.  Recent descriptive studies have suggested that such patients are a diverse group with a high rate of misdiagnosis and co-existing psychiatric disease and poor adherence with taking prescribed medication. 

However at least 50% of difficult to treat asthmatics seem to have resistant asthma and recent efforts have focussed on defining an agreed investigation and management approach to inform guidelines.  A British Thoracic Society working party has been established to form a UK national network of regional centres for difficult asthma to allow setting up of a national database for research and clinical development. 

Current research aims include defining sub groups who might respond to different biological therapies such as anti-IgE, anti-IL-5 or anti-TNF or identifying markers of inflammation (such as induced sputum eosinophil counts) that might predict (and allow prevention) of disease exacerbations.  Current research areas in this field include factorial analysis to identify disease subgroups and mapping of phenotype with genotype and patterns of inflammatory gene expression. 

10. Service delivery interventions. The majority of straightforward cases of allergic diseases including rhinitis, asthma and eczema, can be managed effectively in primary care by appropriately trained staff, although there is clear need for specialist referral pathways for many allergic conditions including drug, food and venom allergy. We have access to an armoury of evidence-based treatments for allergic diseases, although there remain significant gaps in our understanding of some of the fundamental clinical issues in relation to diagnosis, prevention and service delivery that need addressing in order to ensure evidence-based care of allergy sufferers.  In terms of diagnosis, we have no proof whether identification of a specific allergen trigger using specific IgE or skin prick testing improves the outcome of management of respiratory diseases or eczema. 

We have no proof which blood tests (if any) are useful in diagnosing chronic urticaria. We do not know what proportion of patients with a history suggestive of antibiotic allergy has measurable specific IgE to penicillin or equivalent.  In terms of service delivery, there are clear, published guidelines on the management of anaphylaxis, but we do not know how often A/E treatment of anaphylaxis complies with best evidence, or whether patients with anaphylaxis get followed up effectively and safely. We also do not yet know whether primary care-based allergy services prevent hospital admissions, or understand the extent of their contribution to cost-effective disease management.