Allergy as a specialty does not exist in Ireland to a level that an effective service is provided to patients in a consistent and equitable fashion. The main reasons for this are historical fears about the safety of subcutaneous allergen immunotherapy (SCIT) (or ‘allergy shots’), coupled with the efficacy of short-term ‘symptomatic’ treatments. The practice of SCIT in primary care ended in 1986 in the UK and Ireland as a result of a report of the Committee on Safety of Medicines (CSM) published in the BMJ in 1986. 

Prior to this, SCIT was one of the commonest modalities used in the management of allergic rhinitis (AR) (both seasonal and perennial) and in allergic asthma (AA). Therapy was usually initiated in hospital and thereafter administered by GPs. The CSM advice was effectively that GPs should no longer give allergen injections, that patients with asthma should not be treated by SCIT, and that there should be adequate monitoring and post-injection observation (initially for two hours). This effectively ended SCIT as a primary care-delivered treatment in the UK and Ireland.  

There were also serious accompanying effects for service development for the existing, but less well known, allergic diseases. These include allergies to bee and wasp venom, drugs, peanut and other food allergy in children in particular, and the new issue of health care-related latex allergy. These now represent a huge unmet need with few, if any, centres in Ireland offering structured services for adults and children. This is in sharp contrast to other jurisdictions, such as the US and mainland Europe, where allergy is a major medical specialty (eg. 100 paediatric allergists in Finland, population 5.2 million) and where SCIT has continued to be widely practised for the past 100 years. 

Associated with this is the fact that symptomatic therapies for AA and AR, such as corticosteroids, anti-leukotrienes and anti-histamines, are remarkably effective for symptom control and are relatively free from serious side effects. These treatments by definition improve symptom control but unfortunately do not affect the natural history of these diseases, with the disease recurring soon after treatment is stopped. In Ireland and the UK, this has been the predominant therapeutic approach to the management of asthma and rhinitis in the latter part of the 20th century and up to recently. The obvious short term efficacy of these therapies has resulted in there being less focus on their allergic mechanisms and so less focus on therapies directed at the cause of these diseases, rather than symptom control. The evidence, however, is now available and provides a compelling argument that treatment of the underlying allergic diathesis with allergen-specific immunotherapy (AIT) in AR, not only improves symptoms during and for at least three years post-treatment, but may prevent the development of de novo asthma in these patients. Now, a century after SCIT was first administered to patients with grass pollen hay fever in the UK, the landscape is changing internationally in the management of allergy and its related diseases which is having immediate implications for such management in Ireland. This has resulted for two reasons: 

• The efficacy of the monoclonal antibody anti-IgE in asthma
• The recent commercial availability of safe oral sublingual allergy vaccines – sublingual immunotherapy (SLIT).

History of allergy, IgE and its role in asthma

The history of allergy is informative to this debate. In the 19th and early 20th century it was noticed that certain individuals developed hypersensitivity after administration of foreign proteins then used in contemporary treatments (eg. antisera) or to innocuous substances such as grass pollen. The more immediate of these manifestations, eg. asthma, rhinitis and anaphylaxis, became known as the allergic diseases which, in the 1920s, were found to be associated with a transmissible agent. 

For example, a previously asymptomatic individual developed transient asthma to horse hair a few days after receiving a blood transfusion from a patient who had horse asthma. In addition, when serum from donor allergic individuals was injected into the skin of non-allergic recipients, it was possible to elicit a transient positive skin reaction at this recipient dermal site to injected allergen in the non-allergic individual. This became known as the eponymous Prausnitz-Kustner reaction (the P-K reaction) which was soon replaced by the more convenient (and safer!) skin prick test. This transmissible agent was known as ‘reagin’ and was subsequently identified in 1966 as being the antibody, IgE. 

We now know that allergic individuals produce allergen-specific IgE in response to such innocuous allergens as pollen, mould, animal dander and dust mites. The IgE thus produced can bind to circulating basophils; however, in the main, they dock on to the surface of the abundant tissue mast cells found in the submucosa and dermis. On subsequent exposure to allergen by either the inhaled, oral, subcutaneous or IV routes, the allergen binds to its specific binding site on the ‘docked’ IgE, so leading to mast cell (basophils in the case of in vitro exposure) activation and release of pro-inflammatory mediators such as histamine and leukotrienes. 

Long considered a marker of allergy, IgE is now regarded as pathogenic. Indeed, this has now been established beyond all doubt since 2003 when the monoclonal IgG1 anti-IgE molecule, omalizumab became available for clinical use. Omalizumab binds to free serum IgE with which it forms complexes that cannot subsequently bind to its IgE receptors on mast cells, so preventing their activation. This leads to marked down regulation of these now redundant receptors within a few weeks. Therefore, omalizumab neutralises IgE-mediated effects. This treatment is currently indicated for selected patients with severe allergic asthma (GINA 5) and can be extraordinarily effective in such patients. 

Our own experience of 34 such patients has shown reductions of 73% in exacerbation frequency, 75% in use of rescue medication and 91% reduction in hospitalisations, after only four months of therapy. In addition, there is evidence that this improved asthma control persists up to three years post treatment cessation, ie. omalizumab may have a disease modifying effect. In terms of duration of therapy, and in the absence of evidence to the contrary, our practice is to treat for a three year period and to thereafter wean treatment for an additional year, ie. a total of four years therapy. Therefore, there is now irrefutable proof of concept that allergic mechanisms, and its central molecule IgE, underpin the pathogenesis of diseases such as asthma and rhinitis. 

The annualised costs of omalizumab therapy, however, can be as high as €30,000 per patient depending on IgE levels and BMI and, therefore, at present it is only indicated in those patients with the severest allergic asthma, estimated at about 350-400 patients nationally. The most recent information from the National Asthma Programme (NAP) suggests that c.460,000 patients actually have some degree of asthma in the country, ie. 21% of children and 8% of adults, of which at least 80% will have an underlying allergic mechanism. Thus, because of the high costs associated with omalizumab, and the lack of alternatives, < 0.001% of allergic asthmatics currently receive a potential disease-modifying agent. 

The treatment of asthma as currently practised in Ireland is as a result, largely symptomatic and based on international GINA guidelines and includes glucocorticoids, beta-2 agonists, anti-leukotrienes and theophyllines, administered in a step-up/step-down fashion, depending on disease severity. Other than some evidence for early and aggressive management of asthma in the paediatric population, there is little evidence that any of these symptomatic treatments can alter the natural history of the condition.

Allergic rhinitis and allergen-specific immunotherapy 

In the UK, the current indications for AIT are:

• IgE-mediated seasonal pollen-induced rhinitis from the age of five. Asthma, if present, must be stable with FEV1 > 80% predicted (thus asthma is not a contraindication but it must be recognised and stable)
• Selected patients with AR secondary to animal dander or house dust mite allergy from the age of five
• Systemic reactions to bee and wasp venom (which is not the subject of this review).

AR, both seasonal and perennial, affects at least 25% of the adult population, is a major cause of morbidity and is a precursor for asthma development, particularly in children. Indeed, AR often constitutes an early stage in the natural history of asthma, with up to 40% of AR patients developing asthma in later life. The evidence is now compelling that the inclusion of AIT in the management of AR can improve asthma control and may even decrease the ‘allergic march’ along its journey from eczema, AR to asthma if treated early enough in children. 

In Ireland, the most common causes of seasonal allergic rhinitis (SAR) are grass and tree pollens, whereas the most common cause of perennial allergic rhinitis (PAR) is house dust mite. These patients are looked after by their GPs, paediatricians, ENT surgeons, clinical immunologists and some respiratory physicians, often without recourse to a full allergy assessment, and so treatment is largely symptomatic including H1 antihistamines, glucocorticoids, decongestants, anticholinergics and antileukotrienes. Table 1 summarises and grades the interventions available for AR. Treatment with triamcilonone (Kenalog) and other depot steroid preparations is not recommended by any international guideline. In addition, only 0.014% of the paediatric population with AR is receiving allergen immunotherapy even though there is compelling evidence that it may prevent these children from subsequently developing asthma. There is no doubt in my view that the management of AR in Ireland, particularly with the low uptake of immunotherapy, lags far behind that of the UK, which in turn lags far behind that of mainland Europe, the US and Australia. This has major implications, not just in terms of symptom control, but also potentially in terms of missing an opportunity to prevent the development of subsequent asthma.

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Evidence for AIT (SLIT or SCIT) in allergic rhinitis and asthma

Resulting from meta-analysis of double-blind placebo controlled (DBPC) randomised clinical trials, there is now Grade 1A evidence for AIT in the management of allergic rhinitis. It is currently recommended that such treatment continues for three years. AIT induces clinical and immunologic tolerance, has long-term efficacy and may prevent the progression of allergic disease. Evidence indicates an approximate 40% reduction in nasal and ocular symptoms during the three years of active therapy which persists for at least a further two years post-cessation of therapy, ie. there is a disease modifying effect not seen with conventional symptomatic therapies. There is also strong evidence that children with AR, but not AA, who receive a three-year course of grass pollen immunotherapy, demonstrate a 66% reduction in subsequent asthma incidence at seven years post-treatment follow up when compared to an untreated group. This important and paradigm-shifting question is currently the subject of a definitive large DBPC trial which will report in 2015. The benefit of AIT for perennial rhinitis triggered by house dust mite and animal dander, particularly cat, is less well established than with seasonal allergens, however, clinical trials have shown a definite benefit provided subjects are appropriately selected. 

The exact molecular mechanism of action of AIT is not known, however, there are well described physiologic changes that occur in vitro and in vivo (see Table 2). In essence, the available data indicate that AIT results in a fundamental modulation of the allergic immune system resulting inter alia in an anti-IgE effect by a mechanism different from that of omalizumab. The rapid generation of IL-10 producing T regulatory cells after commencement of treatment results in the production of allergen specific IgG4 blocking antibodies, as opposed to IgE, which competitively bind to the IgE receptor on mast cells preventing their subsequent activation by allergen. Thus, like omalizumab, AIT inhibits IgE-mediated allergy, but possibly in a more fundamental way. In any event, the centrality of IgE as a target of immunotherapy, whether by omalizumab or AIT, underpins the modern management of allergic diseases.

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There are currently two licensed oral tablet vaccines available for grass pollen allergic rhinitis in Ireland, ie. Grazax and Oralair. They are both administered sublingually. If patients have co-existing asthma, which many do, it must be controlled, with an FeV1 > 80% predicted. Patients should be advised to place the tablet under their tongue for one to two minutes and then swallow it. Grazax (Timothy grass only) should be commenced two to four months before the pollen season starts in late May/June and continued daily for a total period of three years (pre-seasonal, co-seasonal, maintenance). Oralair (five grass mix) is commenced at the same time for a treatment period of six months per year for three successive years, if there is an effect seen after the first season. 

There are currently no licensed allergen vaccines available for house dust mite or animal dander and these must be acquired directly from the supplier on a named patient basis and thus have cost implications for the patient. Patients should be supervised for one hour after the first dose of AIT; however, serious side effects are not a feature of this treatment. In our experience, some patients experience mild oropharyngeal itching or tingling, which are rarely troublesome enough to stop therapy and which can be treated with prophylactic antihistamine in any event. 

Our practice is to furnish the patients with the new once-daily H1 antihistamine, bilastine 20mg two days prior to commencing treatment and to continue for three days after. This novel antihistamine has an excellent safety profile with a rapid onset and long duration of action. We have very positive one year data in adult patients with AR treated with grass pollen SLIT. On average, there was a 75% reduction in nasal and ocular symptom scores after the first year of treatment. All but one have controlled asthma on maintenance medications. Their mean age is 37 years with an equal gender balance. Minimal and transient local side effects occurred in three subjects, ie. lip itch, ear itch, tongue tingling.

Setting up an allergy service in primary care

In my view it is entirely feasible to set up a functioning allergy service in primary care. For example, AR is a simple and gratifying condition to treat with SLIT and it is well suited to a primary care setting with local support from secondary care. GPs are already familiar with the symptomatic management of asthma and rhinitis; however, would need to upskill in the area of specific allergy management as introduced in this review and references which follow. There are readily available eLearning courses whereby practitioners can enhance their knowledge in a relatively short period of time. 

Skin allergy testing kits are available commercially and take about 20 minutes to perform and interpret with the suggested recommended allergens as per Table 3. There are two grass pollens licensed for AR in adults and children from the age of five in Ireland for use as recommended by the BSACI guidelines. In less common situations, other allergens for AIT will be indicated for PAR, particularly house dust mite and animal danders. These can be obtained by the supplier on a named patient basis. It is only with practice and familiarity that a prescribing comfort zone will be established by the practitioner. 

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New dimension of management

The management of allergic diseases, in particular asthma and rhinitis, has entered a new dimension over the past five years. This has come about because of the efficacy of monoclonal anti-IgE therapy in asthma coupled to the widespread availability of oral allergens for sublingual immunotherapy (SLIT) in rhinitis. Management is now moving beyond the symptomatic as these therapies increasingly demonstrate that they can alter the natural history of these common conditions. 

Anti-IgE therapy with omalizumab in asthma shows dramatic effects in responders that can persist for three years after cessation of treatment. Likewise, grass pollen SLIT in rhinitis leads to a 40% reduction in symptoms that can persist for two years after treatment is stopped. Indeed, there is increasing evidence that SLIT in children from the age of five with rhinitis may prevent the subsequent development of asthma up to 10 years after treatment cessation. Despite these exciting developments, allergy services are rudimentary in Ireland. 

References

1. Scadding GK et al. BSACI guidelines for the management of allergic and non-allergic rhinitis. Clinical and experimental allergy: J Br Soc  Allergy and Clinical Immunology 2008; 38: 19-42
2. Walker SM et al. Immunotherapy for allergic rhinitis. Clinical and experimental allergy: J Br Soc Allergy and Clinical Immunology 2011; 41: 1177-1200
3. Scadding GK et al. BSACI guidelines for the management of rhinosinusitis and nasal polyposis. Clinical and experimental allergy: J Br Soc Allergy and Clinical Immunology 2008; 38: 260-275
4. Royal College of Physicians. Allergy the unmet need: A report of the Royal College of Physicians Working Party on the provision of allergy services in the UK. RCP
5. House of Lords; Science & Technology Committee. Allergy; 6th Report of Session 2006-7. The Stationary Office Limited, UK
6. Neary E, Hourihane JOB. Specific Allergen Immunotherapy Use In Ireland In 2012: An Irish Paediatric Surveillance Unit (IPSU) Study. Irish Med Journal (in press 2013)
7. A study into efficacy of omalizumab therapy in patients with severe persistent allergic asthma at a tertiary referral centre for asthma in Ireland. Subramaniam A, Al-Alawi M, Hamad S, O’Callaghan J, Lane SJ. QJM 2013; doi: 10.1093/qjmed/hct072
8. Costello RW, Long DA, Gaine S, Mc Donnell T, Gilmartin JJ, Lane SJ. Therapy with omalizumab for patients with severe allergic asthma improves asthma control and reduces overall healthcare costs. Ir J Med Sci 2011; 180:637-41
9. Wiley: Allergy and Allergic Diseases, 2 Volume Set, 2nd Edition. Kay AB, Kaplan AP, Bousquet J, Holt PG