Effectiveness, study situation, implementation

ASIT is effective for hymenopteran venom allergies and the inhalant allergies, especially to pollen. In the case of inhalant allergies, SKIT and SLIT provide a spectrum of therapeutic modalities that allows each affected patient to receive a causal therapy tailored to his or her needs. Nevertheless, attention must be paid to adherence and compliance, especially in the first year of therapy.

The therapy of allergies is based on the three pillars of allergen avoidance, treatment of symptoms (antihistamines, steroids) and allergen-specific immunotherapy (syn. hyposensitization, desensitization). In the case of aeroallergens, be it seasonal pollen or perennial house dust mites, allergen clearance cannot be achieved due to their ubiquitous occurrence, in contrast to animal epithelia, so that allergen-specific immunotherapy comes to the fore in order to reduce the consumption of symptomatically effective drugs and to be able to prevent a possible progression of the disease in the sense of a floor change with the development of bronchial asthma in addition to allergic rhinitis. In this context, ASIT is a causal immunomodulatory therapy.

Allergic diseases and among them allergic rhinoconjunctivitis have a great economic importance – on the one hand because of the direct costs of illness, on the other hand because of the resulting inability to work. In addition to the benefit for the individual patient, ASIT has a cost-reducing effect in the long term compared with purely symptomatic therapy.

Allergies to the venoms of hymenoptera – especially bees and wasps – represent a special case, as these can lead to severe anaphylactic reactions with a corresponding risk to the patient, so that ASIT is indicated to protect against the same.

Effectiveness

In the times of evidence-based medicine, studies are required for proof of efficacy. This is clearly given for pollen allergy in adulthood. Significantly fewer studies exist in children, but evidence of efficacy has been provided here as well. Patients benefit from an early start of therapy while the disease is still short (overview 1).

The study situation is less good for house dust mite allergy, in which ASIT is used as a complementary measure after remediation and insufficient symptom control by symptomatic therapy. The recent report of the Global Initiative for Asthma (GINA), which has been rather cautious regarding recommendations for immunotherapy, now recommends the consideration of additional SLIT (sublingual immunotherapy) in adult patients with dust mite allergy with allergic rhinitis who have exacerbations despite inhaled corticosteroids. Prerequisite is FEV1 >70% of predicted lung function.

Few studies exist for animal dander allergy, especially feline epithelial. In this case, however, allergen clearance is much more achievable. In molds, there are studies on Alternaria alternata and Cladosporium herbarum extracts, although the causal relationship between sensitization and symptomatology is generally more difficult to prove for molds.

The mechanism of action of ASIT has not yet been conclusively clarified. Essentially, there is a shift from a Th2 immune response to a Th1 type immune response. The currently known mechanisms read like a history of immunology (overview 2).

Implementation of allergen-specific immunotherapy for hymenopteran venom allergy.

The efficacy of ASIT in hymenoptera venom allergy is very well established by prospective randomized studies. In this context, the ASIT is carried out for at least three years, but more likely for five years. At the standard maintenance dose of 100 μg, 75-85% of bee venom-allergic and 90-95% of wasp venom-allergic patients are protected from systemic reactions after re-sting, so ASIT with bee venom is slightly less effective than that with wasp venom. At most, a dose increase up to 200 μg may provide improved protection. The indication for ASIT bee or wasp venom allergy is anaphylactic reactions of severity ≥II, if evidence of sensitization (skin test, specific serum IgE) to the respective venom can be provided.

Since the maintenance dose, but not the method of initiation, is primarily decisive for efficacy, rapid hyposensitization with achievement of the maintenance dose after hours (Ultra-Rush), or if necessary within a few days (Rush) under inpatient conditions (or in the intensive care unit in the case of the Ultrarush procedure) has proven effective in order to achieve protection for the patient as quickly as possible. Once the maintenance dose has been reached, the intervals between injections are gradually extended to the interval of maintenance therapy. If an aqueous allergen extract was used in the increase phase, a switch to a depot extract can be made later. Therapy is continued at 4-weekly intervals during the first year of treatment, and later at 4-6-weekly intervals. Maximum can still be injected after 8-week interval.

After discontinuation of ASIT, protective efficacy is lost in up to 15% of patients over the next 5-10 years. Reliably lasting protection can only be expected from continuous therapy. Nevertheless, in the spirit of a pragmatic approach, ASIT can be terminated after 5 years in most patients. In individual cases, treatment must be continued until loss of skin test reactivity and specific IgE antibodies in serum. Lifelong treatment is given to patients with mastocytosis and particularly severe anaphylactic reactions.

Implementation of allergen-specific immunotherapy for pollen allergy

The prerequisite for any ASIT against inhaled allergens is a proven connection between seasonally or geographically related symptoms and the corresponding sensitization via the detection of specific IGE in prick tests and/or serology (overview 3) . In the meantime, detection methods are available for the relevant main allergens of the leading pollens (Tab. 1).

These can be used to determine whether the patient is sensitized to a major allergen as contained in the therapeutic extract and thus actually benefits from the therapy. Accordingly, the determination of these components is only useful if an ASIT is planned. The presence of contraindications (overview4) should be excluded. The need for interpretation of the test results requires an indication by the allergist, while the therapy itself is usually performed by the primary care provider.

Since subcutaneous injection and sublingual immunotherapy are two different routes of application, the modality of therapy must first be determined together with the patient. Patient preference is understandably for sublingual therapy with drops or tablets, as no painful injections and significantly fewer physician consultations are required. Although there is evidence of efficacy for both routes of application, the two forms of therapy, like preparations and extracts from different manufacturers, can hardly be compared with each other, so that ultimately an individual decision must always be made. Since, in addition to a high cumulative dose, the patient’s compliance and adherence are also decisive for the success of the therapy (overview 1), the form of therapy must be selected in such a way that it can be carried out by the patient over the required period of three years. Both sublingual and subcutaneous immunotherapies show poor patient persistence in this regard. In most cases, ASIT is stopped early (41-93% for SLIT, 40-77% for SCIT). These figures also reflect our own experience. One explanation could be the frequency of appointments, with patients being contacted quickly by us if they miss an appointment in SKIT, whereas with the ~4 appointments/year in SLIT, even calling the patient in if they miss an appointment makes little difference if therapy was discontinued months earlier by the patient. The initial weekly appointments of SKIT especially in the initial phase, in which the therapy is discontinued particularly frequently, tend to lead to a habituation of the patient, so that it is often possible to continue the therapy for the entire duration even in patients with low compliance. In addition to a viable doctor-patient relationship, it is also helpful to provide the patient with precise information regarding the allergy and its possible consequences. If treatment is nevertheless discontinued, the reasons range from change of residence to pregnancy to comorbidities. In Switzerland, the cost of treatment is often a reason for starting therapy later, as patients want to wait until the turn of the year and the accompanying opportunity to change their deductible.

The beginning of sublingual therapy takes place in the office, already the next doses can be taken at home. Despite good tolerability in terms of systemic reactions, local side effects such as itching and burning in the mouth to stomach pain can occur, which in turn can have a diminishing effect on compliance.

If the patient and allergist decide on SKIT, there is again a choice between preseasonal and seasonal therapy. In this regard, the boundaries are beginning to blur, as it makes sense to continue administering extracts that were originally designed for preseasonal therapy throughout the year due to the high cumulative dose required. In addition, the increase is often faster with such extracts. This may also be an advantage as pollen season approaches and there is less time to begin therapy. It has already been shown that an increase can also be possible during the season without additional risk for the patient, but in principle it is advisable in practice to follow the manufacturer’s instructions or the drug compendium exactly. If the start of therapy still seems desirable despite the advanced time of year, there is the possibility of more rapid initiation by the allergist in the context of cluster or rush immunotherapy. Cluster immunotherapy in particular is suitable for shortening the initial therapy with 3-4 injections on one day in 30-minute intervals to a few weeks with weekly treatment. In addition to the increased time per consultation, patients must expect increased local side effects in the form of a swollen arm. The risk for systemic reactions is only slightly increased with an incidence per injection of 0.06% compared to 0.01% with standard administration.

The choice in therapy forms is again reduced by the sometimes limited availability of therapy extracts. As a result of increased regulations regarding the approval of therapeutic extracts, there has already been a reduction in supply. While this was a step towards improving quality, the suspension of deliveries of allergy medicines from STALLERGENES Greer SAS, which was ordered by the French Medicines Agency in the fall of 2015, was more drastic. Due to a new IT system put into operation in 2015, incorrectly labeled preparations were delivered. Although Switzerland was not affected by the incorrect delivery, it has not received any new preparations since then. The supply freeze is ongoing, so patients under ASIT with an appropriate preparation had to be switched to products from other manufacturers, which usually required a new boost. Since the end of 2016, there has also been a supply shortage for ash and olive pollen extracts from Allergopharma AG. These should be available again from fall 2017. It is to be hoped that there will not be any further bottlenecks as a result of a domino effect caused by a shift to the few other providers. This is all the more important as we have to make do with this therapeutic armamentarium until new therapeutic approaches such as epicutaneous immunotherapy (EPIT) or intralymphatic immunotherapy (ILIT) are available for broader clinical application. In addition to better tolerability, it is hoped that this will also lead to a shorter duration of therapy.