Allergen Immunotherapy for allergic rhinitis and asthma: A Synopsis
Updated: October 2016
Originally Posted: August 2011
Professor G. Walter Canonica, MD
Professor of Medicine
University of Genova DIMI
Professor Stephen R. Durham, MA MD FRCP
Professor of Allergy and Respiratory Medicine
Imperial College School of Medicine/NHLI and Royal Brompton Hospital London
London, United Kingdom
Allergen immunotherapy is the repeated administration of allergen extracts 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 (1 or 2) of allergies. Immunotherapy is indicated in allergic rhinoconjunctivitis and allergic asthma due to seasonal pollinosis and in patients with perennial disease and sensitivity to house dust mite and animal danders. In patients who develop systemic anaphylactic reactions to wasp/bee stings, immunotherapy may be life-saving and has a major impact on quality of life of venom-allergic subjects. Unlike anti-allergic drugs, immunotherapy has been shown to modify the underlying cause of the disease, with proved long term benefits. Allergen immunotherapy may be combined with appropriate allergen avoidance strategies. Immunotherapy is not competitive with the conventional use of pharmacotherapy and should be administered in the context of general advice regarding overall disease management (1).
Subcutaneous (injection) immunotherapy using high dose standardized vaccines (in general, containing 5-20 mcg of the major allergen in monthly maintenance injections) are of proved value. In view of the risk of occasional severe allergic side effects, subcutaneous 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 is around 3-5 years. In view of the remote risk of serious side effects, the risk/benefit ratio should be carefully considered in all cases.
Sublingual immunotherapy has emerged as an effective and safer alternative to the subcutaneous route for both seasonal and perennial disease. Sublingual immunotherapy has also been shown to have long-term benefits has the big advantage of self-administration in the patient’s home.
In this overview, subcutaneous immunotherapy is considered in relation to efficacy, long-term benefit, and safety. Recent advances in sublingual immunotherapy are reviewed. There follows a brief guide on practical issues concerning immunotherapy. Finally, limitations and future strategies are highlighted.
Systematic reviews have shown that subcutaneous injection immunotherapy is highly effective in allergic rhinitis, in patients with seasonal pollinosis (3) and also in patients with perennial allergy and sensitivity to house dust mites (4). Clinical efficacy is accompanied by a marked reduction in requirements for anti-allergic medication during the pollen season. For example one randomized controlled trial of 410 patients with grass pollen allergy showed a 30% decrease in seasonal symptoms, a 44% reduction in need for anti-allergic medication and a marked improvement in quality of life during the pollen season (5). Subcutaneous immunotherapy is also effective in allergic asthma. A Cochrane review (6, 7) demonstrated significant improvements in symptoms, reduction in rescue medication, and improvements in allergen-specific bronchial hyperresponsiveness. Immunotherapy was particularly effective in seasonal asthma (8), whereas immunotherapy is less effective in perennial asthma and, in one study, where mixtures of 5-7 allergens were administered to polysensitized asthmatic children, no differences from placebo were observed (9).
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 (10). Other studies have confirmed long term benefit in relation to cat allergy, ragweed, and venom allergy. There is some evidence that immunotherapy may reduce the onset of new allergen sensitivities in children (11, 12). In a prospective randomized controlled trial of pollen immunotherapy in children with seasonal allergic rhinitis, development of asthma was followed up over a period of 10 years. 2-7 years following cessation of immunotherapy, there was a persistent 2-3 fold reduction in the risk of development of physician-diagnosed asthma compared to controls (13). Taken together, these studies illustrate the important prophylactic value of injection immunotherapy, which is in contrast to anti-allergic medications where relapse of symptoms occurs immediately following their 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.
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 (14). Similar reports from the USA (15) 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
Subcutaneous 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 centers 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.
At each immunotherapy visit, a record should be made of the date, dose, and 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 immunization. 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 (fig. 1). 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 recognized 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 (16, 17). Systemic side effects should be recorded according to the World Allergy Organisation Grading scale (18) that enables standardization and comparison of reaction rates among different centers. Clinics should supply patient information sheets which detail the benefits and risks of immunotherapy and detailed information on practical aspects of immunotherapy.
Sublingual immunotherapy involves the administration of drops of allergen extracts or allergen tablets under the tongue with advice to retain for 2 minutes before swallowing (Fig.2). A Cochrane systematic review and meta-analysis of 60 studies of which 49 (4589 participants) were suitable for pooled analysis (19) showed that sublingual treatment was effective for seasonal and perennial rhinitis, whereas the evidence was less convincing in children than in adults. Recent well-powered randomized controlled trials of sublingual tablet IT have provided consistent evidence of efficacy with decreases in symptoms and rescue medication during the season, resulting in registration of two sublingual tablet vaccines in the USA (20-22).
Sublingual grass tablet IT was effective for all nasal and ocular symptoms, equally effective for hayfever in polysensitized compared to mono sensitized patients, in those with or without associated seasonal asthma and was accompanied by an improvement in quality of life. Sublingual tablet treatment for 3 years was shown to have disease-modifying effects resulting in clinical benefit that persisted for at least 2 years after stopping the treatment (23, 24). Whether or not long-term sublingual IT in children with grass pollen rhinitis will prevent progression from rhinitis to asthma, as previously observed for subcutaneous IT [the Preventive Allergy Treatment study (PAT)], is being addressed in the GAP study (25), scheduled to report in 2016/7.
Three large trials of sublingual tablet IT have been performed that included a total of 4022 participants with perennial rhinitis and IgE sensitivity to house dust mites (26-28). Tablets were taken daily for 12 months. Participants were adults and comprised a high proportion of subjects who were polysensitized and had comorbid mild asthma, neither of which impacted on efficacy or safety readouts. All 3 trials showed evidence of efficacy in rhinitis with a clear dose response and an 18% to 28% reduction in combined symptom-medication scores compared with placebo-treated groups. A study in adults showed that mite tablet sublingual immunotherapy was able to reduce the requirement for inhaled corticosteroids (29) and frequency of exacerbations in mite allergic patients with moderately severe asthma (30).
In general sublingual IT is well-tolerated. Minor local symptoms of itching, lip and tongue swelling are common, occurring in up to 50% of participants but largely self-limiting and resolving within 1-2 weeks of initiation of treatment. More bothersome local symptoms occasionally occur (reported in 5-8% of subjects) and in one recent large study in children and adults (22), local side effects resulted in withdrawal from the study in 5% of participants. A recent WAO initiative has provided a grading system for local reactions after sublingual IT (31), a basis for standardized reporting in the future. Systemic reactions are extremely rare although worldwide, several episodes of anaphylaxis have been reported in the literature, and no fatalities.
Sublingual IT v pharmacotherapy
A recent meta-analysis (32) compared the effect sizes for changes in daily total nasal symptom scores for grass and house dust mite allergen tablets of proven value v placebo with the corresponding effect sizes compared to placebo for anti-allergic drugs that included an antihistamine (desloratidine), a leukotriene antagonist (montelukast) and an intranasal steroid (mometasone furoate nasal spray). Although comparisons were limited by heterogeneity between studies, the effects on nasal symptoms with timothy grass and ragweed sublingual tablets for seasonal rhinitis were nearly as great as with mometasone and numerically greater than with montelukast and desloratadine. For perennial rhinitis, treatment effects for house dust mite sublingual tablet were numerically greater than for all 3 pharmacotherapies.
Sublingual v subcutaneous IT
Although some systematic reviews have shown greater effect sizes in seasonal pollen allergy for subcutaneous IT v placebo compared to trials of sublingual IT v placebo, there appears to be a time order effect, with more recent large studies (33, 34) that have been performed to more rigorous standards that question this conclusion. Recent meta-analyses have been inconclusive and there have been few head-to-head comparisons of sublingual IT v subcutaneous IT, all involving small studies (35). A comparison of key features of sublingual and subcutaneous immunotherapy are shown in Table 1 (35). The main conclusion is that both treatments are effective in adults and children for seasonal and perennial disease. Allergen vaccines of proven efficacy should be used and in the absence of definitive head to head trials, the patient is in equipoise. Where facilities and vaccines are available, choice of route may depend mainly on patient preference.
Table 1. A comparison of key features of Subcutaneous v sublingual immunotherapy
(reproduced with permission from J Allergy Clin Immunol 2016, ref 35)
Critical view about systematic reviews
A revisited perspective to draw clinical recommendations should be approached about AIT; since we should talk about single product and not anymore about AIT in general. This consideration derives from a more correct evaluation of the Metalanysis or Systematic Review interpretations, whose conclusions always confirmed the efficacy of AIT, as otherwise reported in this article. Nonetheless, we wish to underline that the conclusions of the Metanalysis are concerning selected studies performed with a restricted number of products, compared to the huge number of products used in clinical practice in several countries. In this context, the conclusion reported in the Metanalysis studies: “AIT is effective” is not correct (36). A more precise and correct conclusion should have been: “the studies with the products evaluated in the review analysis sustain the efficacy of them”. This would protect our patients from receiving a prescription for an AIT product that has never tested in any clinical trial. This consideration is also true in terms of safety of the same products. Accordingly—a WAO statement” (37). The WAO criteria to recommend an AIT product are consistent with the EMA requests for a claim about a product (38).
Mechanisms 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 (39). 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 (40, 41). Both sublingual and subcutaneous immunotherapy have been shown to inhibit seasonal activation of blood basophils (42) and innate lymphoid cells (ILC2s) (43) during the pollen season. Data strongly suggest that these “effector” mechanisms are modified as a consequence of altered T-lymphocyte responses following high dose allergen exposure during immunotherapy (44, 45). Studies of blood cells (46) and cells in the target organs (47) of allergy have shown a decrease in the number and activation status of Th2 cells following successful immunotherapy. Underlying mechanisms have been shown to include an immune deviation from a "Th2-type" response with dominant production of IL-4 and IL-5 in favor 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 (44, 48). These cytokines inhibit T responses and divert antibody production in favor of IgG4 and IgA synthesis with downregulation of IgE responses (reviewed in reference 48). 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 this potential to modify the course of allergic disease, which is in contrast to usual pharmacotherapy. The mechanisms involved in sublingual IT have been shown to be similar to those observed with subcutaneous IT, although it is highly likely that additional local mechanisms are involved in the sublingual region and draining lymph nodes which also drain the nose and upper respiratory tract (2).
Most interest has centered on sublingual immunotherapy (2) as an alternative to the subcutaneous route. The intranasal route has also been shown to be effective (49), 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 been largely discontinued. The oral route is not currently recommended for inhalant allergens. The inhaled route is not recommended on account of unacceptable side effects including bronchial asthma. The administration of allergen extracts via the ‘epicutaneous route’ (application of patches containing allergen directly to the skin surface) has been shown in early development to be effective for grass pollen allergy (50). The intra-lymphatic approach that involves injecting allergen under ultrasound control directly into lymph nodes in the region of the upper thigh (inguinal region) is a further route of interest (51). These alternative routes are currently undergoing phase I/II clinical trials.
New knowledge on mechanisms and reservations concerning side effects of subcutaneous allergens has prompted the development of purified/recombinant allergens and modified vaccines. The availability of recombinant allergens has undoubtedly allowed better standardization of allergen extracts and affords the opportunity for individualized treatment which could be tailor-made according to individual sensitivities (52). For example the availability of recombinant birch and grass allergens for in vitro detection of specific IgE allows identification of the major causal allergens (Bet v 1, Ph p 1 and phl p5) and recognition of cross-reacting allergens (Bet v 2, Phl p 12) that may give rise to ‘false positive’ IgE/skin test results when only crude extracts are used for diagnosis (53). There are now several published trials of recombinant allergens for immunotherapy. A recombinant Bet v 1 product was shown to be efficacious with numerically similar results compared to a purified Bet v 1 extract and the standardized crude Birch extract in tree pollen allergy (54). A recombinant grass extract containing a mix of 5 major grass allergens was also effective (55).
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 "depot" extracts, widely used in Europe (5). Bacterial adjuvants include lipopolysaccharide (LPS) 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 (56, 57). 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 (57). There is preliminary data from controlled trials which support the use of these adjuvants in allergen extracts for seasonal allergic rhinitis (58, 59), 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 are the risk associated with conventional whole allergen extracts. Recent studies in cat allergy are encouraging (60, 61). However for all these approaches, further adequately powered clinical trials performed to rigorous standards are required (62).
Allergen immunotherapy via the subcutaneous and sublingual routes is highly effective, particularly in patients with seasonal pollinosis. Clinical efficacy is accompanied by suppression of late phase responses and long-term disease remission. The presence of asthma and /or polysensitization does not compromise the efficacy in subjects with whom it is possible to select for immunotherapy a ‘dominant’ allergen that is responsible for symptoms. Evidence supports the view that immunotherapy may prevent progression of rhinitis to asthma in children. The development of novel adjuvants for improvement of the efficacy and safety profile of the immunotherapy are currently in progress. The use of recombinant allergens and the peptide approaches have been shown also to be effective although their efficacy and safety profile compared to currently available immunotherapy is yet to be determined. Meanwhile, the use of subcutaneous or sublingual allergen vaccines in carefully selected patients remain the gold standards for comparison of other novel approaches. The choice of either subcutaneous or sublingual vaccines where vaccines of proven value are available commercially at present can largely be decided by patient preference.
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