Letter from the British Society for Allergy
& Clinical Immunology
The British Society of Allergy and Clinical
Immunology is a nonprofits professional organisation that has
450 members. The society's aims are to support its membership
in providing a high quality, NHS based service for the treatment
of people with allergic diseases.
Research is a core value of our society. Many
of our members are engaged in research into the causes of allergic
diseases and understanding the underlying mechanisms, in order
to identify and develop potential novel therapies. Other research
interests include primary and secondary prevention of allergic
diseases through allergen avoidance strategies, dietary modification
and development of novel vaccines to modify the course of allergic
diseases.
In response to your "Call for Evidence:
Allergy", the BSACI held a "Think Tank", chaired
by Professor Tak H Lee, on 30 September 2006, in order to address
research priorities in Allergy. The attached suggestions are representative
of allergists, clinical immunologists, paediatricians, rhinologists,
chest physicians and colleagues from primary care, from a wide
geographic distribution within the UK.
BSACI is a small society and unable to fund
research directly, whereas the society could and should facilitate
a network of NHS-based research centres to support DH initiatives
for research in allergy. However, without capacity building within
NHS-led allergy services and without a critical mass of well-phenotyped
NHS patients there can be no effective research into prevention
or treatment of allergic diseases, or research into optimal NHS
care pathways (at both primary and secondary care level). In this
regard, the recently published Department of Health Review of
Allergy Services gives no cause for optimism.
APPENDIX
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,
Professor S Durham, Professor A Frew, Dr R Gore, Dr Y Karim, Professor
T H Lee, Dr S Nasser, Professor 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 of the influence of
maternal health, nutrition, environmental exposure, pregnancy
related factors, eg 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 (eg 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 (eg 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
produced 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
Sensitisation to allergens (such as house dust
mite, cat and dog) is associated with asthma and exposure to allergens
in those asthmatics who are sensitised 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 per cent of UK supermarket
bakers (a workforce of around 8,000) 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 of 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 sensitisations 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 long term 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 their lives by the disease. These difficult to treat asthmatics
represent about 10 per cent of the total asthmatic population
and include both adults and children, and a recent survey identified
up to 7,000 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 1,000 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 per cent 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.
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