Allergen Immunotherapy: A Synopsis
Posted: August 2004
Professor G. Walter Canonica, MD
Professor of Medicine
University of Genova DIMI
Allergen immunotherapy is the repeated administration of allergen vaccines to allergic individuals in order to provide long term relief of symptoms and improvement in quality of life during subsequent natural allergen exposure. Allergen immunotherapy is highly effective in IgE-mediated disease in patients with a limited spectrum with a limited spectrum (1 or 2) of allergies. Immunotherapy is effective in allergic rhinoconjunctivitis and allergic asthma and in patients who develop systemic anaphylactic reactions to wasp/bee venom. Allergen immunotherapy may be combined with appropriate allergen avoidance strategies. Immunotherapy is not competitive with conventional use of pharmacotherapy and should be administered in the context of general educational advice regarding overall disease management (1). High dose standardised vaccines (in general, containing 5-20 mcg of the major allergen in monthly maintenance injections) should be employed. In view of the risk of occasional systemic allergic reactions, sub-cutaneous (injection) immunotherapy should only be administered by trained persons in specialist clinics and with immediate access to adrenaline and other resuscitative measures. All patients should be observed in the clinic for at least 30 minutes following injections. The optimum duration of immunotherapy is around 3-5 years. In view of the remote risk of serious systemic side effects, the risk/benefit ratio should be carefully considered in all cases.
In this overview, immunotherapy is considered in relation to issues of efficacy, long term benefit and safety. There follows a brief guide on practical issues concerning immunotherapy. Alternative routes of immunotherapy are considered. Finally, limitations and future strategies are highlighted.
Subcutaneous injection immunotherapy is highly effective in seasonal allergic rhinitis, in particular, in patients with seasonal pollinosis due to grass, tree, and weed pollens and patients with a limited spectrum of sensitivities. Narrative review of 43 double blind placebo controlled trials confirmed efficacy (greater than 30% when compared to placebo in 75-80% of studies) (2). In general, clinical efficacy is accompanied by a marked reduction in requirements for anti-allergic medication during the pollen season and, at least in one study, a marked improvement in patients' quality of life.
Allergen injection immunotherapy is also effective in allergic asthma. A Cochrane meta-analysis of 62 randomised controlled trials performed between 1954 and 1998 demonstrated highly significant improvements in symptoms, reduction in rescue medication, and improvements in both allergen specific and non-specific bronchial hyperresponsiveness (3). Immunotherapy was particularly effective in seasonal asthma (4,5), whereas immunotherapy is less effective in perennial asthma and, in one study, where mixtures of 5-7 allergens were administered to polysensitised asthmatic children, no differences from placebo were observed (6).
Allergen immunotherapy has been shown, in several studies, to confirm long term benefit following discontinuation. For example, in one double blind placebo-controlled withdrawal study, 3-4 years grass pollen immunotherapy was shown to result in sustained reduction in symptoms and rescue medication for at least 3 years following discontinuation (7). Other studies have confirmed long term benefit in relation to cat allergy, ragweed, tree pollen allergy, and venom allergy. Immunotherapy has also been shown to reduce the onset of new allergen sensitivities in children (8,9). In a prospective randomised controlled trial of pollen immunotherapy in children with seasonal allergic rhinitis, development of asthma was followed up over a period of 5 years. 2 years following cessation of immunotherapy, there was a marked reduction in the risk of development of physician-diagnosed asthma (odds ratio 2.7 95% confidence intervals 1.3-5.6), compared to controls (10). Taken together, these studies emphasise the important prophylactic value of injection immunotherapy, which is in contrast to pharmacotherapy where relapse of symptoms occurs immediately following discontinuation.
A limitation of the subcutaneous injection route of immunotherapy is the risk of potential side effects, which include systemic allergic reactions, occasional anaphylaxis and, even, fatalities. Risk factors for systemic reactions include extremely high sensitivity, co-seasonal allergen exposure, a history of previous systemic reactions, and, importantly, the presence of bronchial asthma. In one study reporting 26 fatalities over a 30 year period within the United Kingdom, in 16 of 17 patients in whom the indication for immunotherapy was known, the patients had bronchial asthma (11). Similar reports from the USA (12) highlight the increased risk of side effects and occasional fatalities in asthmatic subjects.
Allergen immunotherapy is indicated in the following circumstances:
- IgE-mediated disease (symptoms on exposure to relevant allergen supported by a positive SPT/RAST to that allergen)
- Inability to avoid allergen
- Inadequacy of drug treatment
- Limited spectrum of allergies
- Patients who understand risks and limitations of treatment
- Co-existent uncontrolled asthma (within the UK, presence of asthma is considered a relative contraindication).
- Patients taking beta blockers
- Patients with other medical/immunological disease
- Small children (less than 5 years)
- Pregnancy (maintenance injections may be continued during pregnancy)
- Patients unable to comply with the immunotherapy protocol
Immunotherapy should only be performed by trained staff in an allergy clinic facility with an appropriate observation area, facilities for vaccine storage at 4ºC, and access to resuscitation facilities. An out of hours telephone contact number should be provided. Injections should only be given in the immediate presence of a physician.
Immunotherapy protocols, in general, involve weekly injections 8-16 weeks during an updosing phase, followed by monthly maintenance injections (empirically this has been extended in some centres to 6-8 weeks) for a period of 3-5 years. “Cluster” immunotherapy updosing schedules may involve repeated injections at each clinic visit. “Rush” protocols which may involve repeated updosing injections in order to achieve maintenance doses within several hours are applicable to venom sensitive patients, although are unsuitable for patients with inhalant allergies in view of the marked increased occurrence of side effects. In general, manufacturers' recommendations should be carefully followed, although tailored to individual patients' circumstances.
Figure: Allergen injection immunotherapy: technique of deep subcutaneous injection in the upper arm.
At each immunotherapy visit, a record should be made of the date, dose, volume of allergen vaccine given. Peak flow should be recorded before and after injections and any immediate (0-30 minutes) local or systemic reactions recorded. Also, any delayed local or systemic reactions following the previous injection should be recorded at the next visit. At every visit, adrenaline should be immediately available. The patient should confirm availability for at least 30 minutes following injections. The patient should be well, without concomitant allergen exposure on the suspected viral illness or recent immunisation. The time interval since the last immunotherapy injection, any reaction to previous injections and, if indicated, premedication with antihistamine should also be checked. Peak flow should be recorded and the dose of immunotherapy selected and double checked. In general, injections are given in the upper outer surface of the arm (figure). A sterile technique should be ensured. Injections should be by the deep subcutaneous route.
Injections should be postponed in the presence of respiratory infection, intercurrent illness, current asthma, or symptoms due to concomitant allergen exposure. Dosage reduction according to standard guidelines should be performed in relation to previous systemic or large local reactions, during increased allergen exposure and if there is an extended time interval since the previous injections.
In general, local swelling following injections is to be expected. No treatment is required other than reassurance, although occasionally or use of an antihistamine may be indicated. Systemic reactions should be recognised and treated promptly, according to recommended guidelines. In general, mild rhinitis or wheezing may be treated by an antihistamine or bronchodilator with continued observation. More severe reactions, including moderate asthma, urticaria, or angio-oedema require intravenous hydrocortisone and antihistamine. Adrenaline 0.5 mg by the intramuscular route is indicated in rapidly evolving systemic reactions which do not respond to these measures and in all patients where there is associated moderate/severe respiratory impairment or hypotension. In general, if in doubt, give adrenaline which is more effective when administered early during a systemic reaction. Delayed systemic reactions are almost always mild, involving mild urticaria or asthma and respond to antihistamines and/or inhaled bronchodilator therapy. Patients should be supplied with a contact telephone number of the clinic nurse/doctor and advised that if reactions do not respond to these measure, that they should attend their local accident and emergency department.
All immunotherapy clinics should have detailed standard operating procedures and regular review of practice and staff training in immunotherapy procedures and the early recognition and treatment of adverse events (13). Clinics should supply patient info rmation sheets which detail the benefits and risks of immunotherapy and detailed info rmation on practical aspects of immunotherapy.
Allergen immunotherapy is accompanied by a marked increase in “blocking” IgG antibodies and blunting of seasonal increases in allergen specific IgE concentrations in patients with seasonal pollinosis. There is inhibition of the recruitment and activation of effector cells including mast cells, eosinophils, and basophils in the allergic respiratory mucosa of the nose and bronchi. Data strongly suggest that these “effector” mechanisms are modified as a consequence of altered T-lymphocyte responses following high dose allergen exposure during immunotherapy (14). There is immune deviation from a "Th2-type" response with dominant production of IL4 and IL5 in favour of “Th1-type” responses with production of interferon gamma and IL2. Immunotherapy also has been shown to induce a subset of “T-regulatory” cells with allergen-specific increases in the production of interleukin 10 and TGF beta. These cytokines inhibit T responses and avert antibody production in favour of IgG4 and, possibly, IgA synthesis with downregulation of IgE responses (14). These events are accompanied by suppression of allergen-induced T cell-dependent late responses in the skin and lung and long term disease suppression which is apparent following discontinuation. Immunotherapy is the only treatment that has the potential to modify the course of allergic disease, which is in contrast to usual pharmacotherapy.
In order to improve safety and convenience, alternative routes of immunotherapy have been tried, of which the most promising is the sublingual-swallow (SLIT) route (15). This involves the administration of drops or rapid-dissolving tablets under the tongue for 2-3 minutes, usually followed by swallowing. A meta-analysis of 22 double blind placebo controlled trials have confirmed the efficacy of this route of therapy for seasonal and perennial rhinitis, in terms of reduction in symptom and rescue medication (16). Few comparisons with conventional antiallergic treatments or the subcutaneous route have been performed. In general, the sublingual-swallow route, although efficacious, appears less effective than the subcutaneous route. Local side effects of itching and swelling in the mouth are common although, in general, trivial and require no treatment and only rarely result in discontinuation of therapy. Systemic side effects appear extremely uncommon and no serious adverse events have been reported from across many trials. Although recommended as an alternative in international guidelines (16), further studies of potential long term benefit, comparative studies and, in particular, more studies in children, in who sublingual-swallow treatment cannot currently be recommended, is routine practice outside clinical trials.
The intranasal route has also been shown to be effective (16), although this route is less attractive for patients and local side effects may require pre-treatment with antihistamines or cromoglycate. For these reasons, the intranasal route has not been widely taken up. The oral route is not currently recommended, although there has been a recent resurgence of interest in the use of microencapsulated extracts which may avoid gastric digestion and facilitate uptake within the small bowel. The inhaled route is not recommended on account of unacceptable side effects.
New knowledge on mechanisms and reservations concerning side effects of subcutaneous allergens has prompted the development of modified vaccines. The introduction of recombinant allergens has undoubtedly allowed better standardisation of allergen extracts and affords the opportunity for individualised treatment which is tailor made according to individual sensitivities (17). However, at present, there are no published trials of recombinant allergens for immunotherapy. The use of novel adjuvants in order to delay absorption or modify T lymphocyte responses are currently under investigation. Alum is the traditional adjuvant in "depo" extracts, widely used in Europe. Alum has the effect of delaying absorption and, in contrast to murine studies, downregulates Th2 responses in humans, shown in both in vitro and in vivo studies. Bacterial adjuvants include lipopolysaccharide and DNA oligonucleotides. MPL (monophosphoryl) lipid is a modified LPS from salmonella which is widely used as an adjuvant in prophylactic vaccines for infectious diseases, induces preferential Th1 responses (18). Bacterial DNA oligonucleotides containing an abundance of CPG motifs have also been shown to promote Th1 responses and may also induce IL-10, possibly by inducing T regulatory cells (19). There is preliminary data from controlled trials which support the use of these adjuvants in allergen extracts for seasonal allergic rhinitis (18,19), although further studies are required.
The use of short T cell peptides for immunotherapy has the potential to stimulate “protective” Th1 and/or T regulatory responses whilst avoiding systemic side effects associated with cross linking of IgE on mast cells and basophils which is the risk associated with conventional whole allergen extracts. Initial studies in cat allergy are encouraging, although, again, further studies are required (20,21).
Allergen immunotherapy via the subcutaneous route is highly effective, particularly in patients with seasonal pollinosis. Clinical efficacy is accompanied by suppression of late phase responses and long term disease remission. Evidence supports the view that immunotherapy may also prevent onset of new sensitisations and progression of rhinitis to asthma in children. The sublingual-swallow route has emerged as a promising alternative, although probably less effective modality, whereas the development of novel adjuvants for improvement of the efficacy and safety profile of the conventional subcutaneous route are currently well in progress. The use of recombinant allergens and the peptide approach will be investigated in the near future. Meanwhile, the subcutaneous use of conventional allergen vaccines in carefully selected patients in specialist centres remains the gold standard for comparison of other novel approaches.
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