ALERGENOWO SWOISTA IMMUNOTERAPIA (ASIT): KORZYŚCI I DZIAŁANIA NIEPOŻĄDANE. DOŚWIADCZENIA WŁASNE I PRZEGLĄD LITERATURY
Olesya M. Besh, Dmytro I. Besh, Olena O. Sorokopud, Marta O. Kondratiuk, Oksana R. Slaba
Danylo Halytskiy Lviv National Medical University, Lviv, Ukraine
Introduction: Allergy is an important medical, social and economic problem nowadays, as it causes disability and patients’ quality of life decreases. According to the update data all the existing therapeutic options haven’t been used in huge majority of patients. Allergen-specific immunotherapy (ASIT) underuse in particular. One of the reasons for the low frequency of this treatment method using is the fear of systemic and local allergic.
The aim of the study was to find out the incidence and severity of adverse reactions in patients receiving subcutaneous and sublingual ASIT.
Materials and methods: In conducted research we compared peculiarities of adverse reactions using sublingual and subcutaneous ASIT methods. Criteria for inclusion in the research were age from 18 to 50 years, diagnosed intermittent or persistent BA. The investigation involved 51 patients with combined basic drug therapy and ASIT, which was performed with injected allergens for 38 patients and sublingual allergens – for 13 individuals.
Results: Local reactions were recorded in five patients (13.16%), who received injected ASIT. In four patients (10.52%), dry rales were observed for a short period after injection of the allergen. Local side effect was observed in one patient (7.69%) during sublingual ASIT.
Conclusions: Adverse reactions, that occur during ASIT, do not pose a threat to patients’ lives. However, the therapeutic effect after the year of treatment was significantly better than in patients who used medications only. Modern drugs are safe and, if all the rules are followed, the risk of adverse effects is very low.
Wiad Lek 2018, 71, 2 cz. I, -345
Allergy is a disease of the 21st century. According to the data of European association of specialists in allergology, the level of morbidity in different countries of Europe ranges from 25% to 40% [1, 2, 3]. In Ukraine, there are no exact data on the incidence of allergic pathology, however, according to results of some investigations, approximately 25% of the population suffer from allergy . The most common allergic diseases are urticaria, insect sting allergy, allergic rhinitis, bronchial asthma, drug allergy, which can be manifested as both urticaria and Quincke’s edema or bronchospasm.
Prevalence of some allergic manifestations at certain ages and progression of some allergic diseases to other ones is called “allergic (or atopic) march” . Schematically atopic march can be presented as atopic dermatitis (often in combination with food allergy) → allergic rhinitis → bronchial asthma . At each stage, the number of “causative” allergens increases and clinical picture is complicated.
Annually, thousands of people worldwide die of allergic diseases. The main causes are anaphylactic reactions to drugs and food, severe exacerbations of asthma [4, 6, 7]. Thus, the basic goal in allergy treatment is control and prevention of disease progression. According to European recommendations, general principles of allergy prevention and treatment of exacerbations are following hypoallergenic diet and elimination measures, drug therapy, which includes antihistamines, antileukotrienes, bronchodilators, intranasal or inhaled glucocorticosteroids.
Nowadays, allergen-specific immunotherapy is the only method of treatment for allergic pathology, which not only helps alleviate symptoms, but also prevents disease progression. In the second half of the 21st century, national and regional recommendations on ASIT administration were being elaborated for the treatment of patients with bronchial asthma, allergic rhinitis, as well as insect sting and food allergy [8, 9, 10, 11]. Recommendations published under WHO supervision were an important step in popularization of this hyposensitization method [7, 12]. According to recommendations on allergic rhinitis treatment (document ARIA), administration of ASIT has the highest level of evidence (level Ia). In most recommendations on bronchial asthma treatment , this method is advised only in case of ineffective drug therapy. However, there are confirming data about increase in ASIT efficacy if it is used in the first years after diagnosis of atopic disease. An important benefit in comparison with drug therapy is achieving remission, which may last up to 10 years .
This treatment method is usually performed with domestic and dust allergens; however, hyposensitization with food allergens and essential medicines, epidermal allergens exists as well. ASIT involves regular administration of allergens gradually increasing the dose [3, 14]. At present, there are also medicines containing allergoids, which do not need dose increasing and following of certain schemes .
After treatment with high doses of allergen, the condition of allergen-specific anergy in peripheral T-cells is established. It is characterized by reduction of cell proliferation and secretion of cytokines, simultaneously, the level of IL-10 production increases, which inhibits specific T-cells, decreases IgE production and increases IgG4 index. Anergic T-cells can be reactivated by cytokines from tissue environment. If ASIT effect is positive, anergic T-cells are activated by IL-2 and/or IL-15 and stimulate synthesis of Th0/Th1-cytokines – ІgG4. ASIT efficacy in insect sting allergy is approximately 85-95%, in pollinosis – 80-90%, year-round rhinitis – 70-80%, bronchial asthma – 70-75% [2, 16, 17].
Indications for ASIT administration are confirmed IgE-mediated feature of allergic reaction, determined “causative” allergen (scratch test, molecular diagnostics), if the disease is characterized by marked symptoms, complete elimination of the allergen is impossible, and a patient’s age is from 5 to 50 years [8, 18, 19]. Contraindications for ASIT are pregnancy, acute and chronic infectious diseases in exacerbation period, tumors, mental diseases, decompensative diseases of the liver and the kidneys. The treatment starts in remission period. If sensitivity to pollen and insect sting allergens is high, it is recommended to commence hyposensitization from December to February. In case of sensitivity to epidermal, domestic or food allergens, treatment can start in any period .
Depending on the route of allergen introduction, ASIT is divided into subcutaneous and oral (drops, sprays, tablets). Each method has its advantages and disadvantages . A significant benefit of oral allergens is easy application, no need in daily injections and visits to an allergist’s office. A disadvantage of these drugs is a higher price. To achieve a permanent remission, treatment should last approximately 3-5 years [1, 19].
To perform hyposensitization, curative allergens are used – these are purified aqueous salt extracts of allergens or certain components isolated from allergic substances [3, 21]. The first allergens, which were used for ASIT, were chemically unmodified substances, stabilized by means of aluminum hydroxide, calcium phosphate or tyrosine. These substances promoted slow absorption of an allergen from an injection site .
Since then, scientific investigations have been conducted to improve the efficacy of vaccines for ASIT and decrease the number of systemic and local reactions. Native allergens were used before the 1980th. Such vaccines should contain stable proper allergenic proteins in ample amount. In fact, it was often different, since the content and quality of vaccines depend on the resulting material, which can be changeable. This problem remained unsolved until recombinant allergens appeared . For the first time these allergens were used for ASIT in the end of the 1980th. They were obtained by means of gene engineering in vitro and it became an important step in allergology history. The first clinical trials of recombinant allergens were conducted for patients with anaphylactic reactions to insect venom in anamnesis. The main benefit of these vaccines was reduction of the number of severe systemic and local adverse effects .
Discovery of allergoids was one of the steps in the process of improvement of treatment efficacy. These are chemically modified proteins of allergens, which show the same immunogenicity, however they had a significantly lower risk for the development of IgE-dependant adverse reactions of immediate type . So far, allergoids have been the base in allergen-specific immunotherapy and can be introduced in rather high therapeutic doses. Recently, carbamylated allergoids have been synthesized, which are resistant to digestion by proteolytic enzymes and are rapidly absorbed through oral mucosa. They are used for sublingual immunotherapy in patients with high sensitivity to domestic dust mites .
Despite a positive therapeutic effect, allergens, as well as other medicines, can have side effects. According to literature data, allergic reactions on average occur in 4-10% of patients. Most of them do not require intake of additional medicines [1, 23]. Adverse effects can be local and systemic. Appearance of side reactions is possible during administration of the first dose, in the period of dosage increase or during administration of supporting medicines. It is important to differentiate between safe local reactions, reaction of a shock organ (rhinitis, conjunctivitis, reaction of the bronchi) and systemic reactions, which are life threatening (they develop in 5-20% of patients) [11, 23, 24]. Patients who have anaphylactic reaction in their case histories are at high risk for the development of anaphylactic reaction . Local reactions in 2-15% of patients can be precursors of systemic reactions to allergen administration . About 30-40% of systemic reactions occur in 35-60 minutes after administration of medications .
The most dangerous systemic reaction to allergen administration is anaphylactic shock. According to literature data, most frequently it develops in patients who receive subcutaneous ASIT. On average, it occurs in 0.5-1% of patients . Lethal cases after allergen administration are also possible. Although, no cases have been recorded in the last 70 years on the territory of the former Soviet Union , there are literature data that several cases were recorded in Great Britain in 20-30th years of the 20th century . In the USA, the incidence of lethal cases during ASIT is one per 2.5 million injections. In Europe, no cases have been recorded in the last decades . Prevalence of serious systemic reactions is approximately one per million injections. Headache, arthralgia, bronchospasm, urticaria and Quincke’s edema are also referred to systemic reactions. The only method for prevention of allergic reactions in patients of the risk group is intake of antihistamines and antileukotrienes .
The most common local reaction to injected allergens is redness, itching and swelling at an injection site . In sublingual application of an allergen, itching under the tongue, numbness of the tongue and aforementioned systemic reactions are possible. According to Feliziani V. еt al. (1995), Groselaude M. Et al. (2004), most unfavorable reactions were associated with the violation of ASIT regimen by patients and were easily eliminated .
In the recent decades, many investigations have been conducted, where the efficacy and safety of different ASIT methods have been compared. In the review, published in 2008, results of 66 investigations were presented, where clinical efficacy of sublingual medicines for ASIT was studied . In 49 investigations, which provided information about total number of patients with adverse reactions, 12% of patients (529 out of 4378) reported about any side effects. The incidence of systemic reactions constituted only 0.056% (169/314 959) of cases from total number of received allergen doses .
In post-marketing research concerning ASIT, side effects were observed in less than 10% of patients, with the incidence being less than one dose per thousand (1:1000) (G.Possalacqua et al., 2006). Other investigations, conducted among children, showed that side effects were observed in 6% of cases with the incidence 0.15:1000 doses (Pajono G., et al. 2003).
According to placebo data in controlled investigations, conducted in France, Greece and Italy, adverse effects were observed in 39% of patients who received sublingual ASIT and 29% who received placebo. No cases of life threatening reactions were recorded. The authors explain dyspeptic and local reactions in the oral cavity (itching, redness) by the fact that these organs are in close contact with an allergen .
In Ukraine, several investigations were also performed, where the incidence of development of adverse reactions was compared in different ASIT methods. For example, I.V. Korytska (2006) mentions that comparing the incidence of adverse reactions in typical subcutaneous and oral routes, the incidence of local ones constituted 17.5% and 4.8%, respectively, and systemic – 1.15% and 0.47%, respectively. Throughout 12 years of monitoring, the incidence of local allergic reactions in patients due to subcutaneous ASIT constituted 4.5%, systemic reactions were observed only in 0.5% of patients, and no lethal cases were recorded [1, 18].
In 2011, B.M. Pukhlyk presented results of investigation, which involved 1194 patients with respiratory forms of allergy (575 children and 619 adults). The goal of the research was to study the efficacy and safety of oral medicines for ASIT. Based on the obtained results, deterioration of a clinical course of allergic diseases was not recorded in any case. Adverse reactions were observed only in 0.75% of cases, which was manifested by exacerbation of chronic maxillary sinusitis, sore throat and itching in the oral cavity . According to I.P.Kaydashev, H.M.Drannyk (2007), currently there are many evidences to support a considerable safety of sublingual SIT (SLIT). For over 20 years of clinical use of SLIT, no records have been made about severe or life threatening consequences of its administration. Side effect was observed in less than 10% of patients, and it is fewer than 1 case per 1000 doses of allergen.
In the last 30 years, many investigations have been conducted, which compared safety of different ASIT methods. The highest incidence of appearance of systemic reactions (including severe reactions with necessary adrenaline injection) was described in the investigations, in which native allergens were used in the treatment [29, 30]. Safer and more effective are the vaccines, which contain recombinant allergens or allergoids .
Investigations, in which a connection between allergen dose and the incidence of appearance of systemic and local reactions was compared, were also conducted. In the research performed by M.S. Tankersley et al., it was confirmed that reduction of allergen dose does not reduce the incidence of appearance of systemic reactions, but it diminishes the risk for the development of local reactions .
The aim of the study was to find out the incidence and severity of adverse reactions in patients receiving subcutaneous and sublingual ASIT.
Materials and methods
In conducted research we compared peculiarities of adverse reactions using sublingual and subcutaneous ASIT methods with allergens of domestic dust mites. Criteria for inclusion in the research were age from 18 to 50 years, diagnosed intermittent or persistent BA with mild or moderate course, presence of general indications for ASIT with domestic allergens, duration of BA anamnesis at least one year and absence of ASIT in anamnesis. The investigation involved 51 patients with combined basic drug therapy and ASIT, which was performed with injected allergens for 38 patients and sublingual allergens – for 13 individuals. Typical ASIT was conducted via subcutaneous injection of an allergen solution (Limited company „Immunolog” Ukraine) with increasing doses for each dilution. Sublingual treatment method was performed with standardized extracts of mite allergens („Sevapharma”, Czech Republic).
Results and Discussion
All patients tolerated ASIT well, no severe systemic reaction to allergen administration was observed during the procedure. Local reactions were recorded in five patients (13.16%), who received injected ASIT, and were manifested by hyperemia at an injection site to 6-12 mm in diameter, which is considered as being safe for a patient. In four patients (10.52%), dry rales were observed for a short period after injection of the allergen, which were relieved by one-two inhalations of short-acting bronchospasmolytic agents. We regarded these manifestations as an individual reaction to allergen administration and they were not considered contraindications for further ASIT. However, rates of increasing allergen doses in such patients slowed down. Administration of the previous dosage was repeated until local reaction disappeared, and only then an allergen dose was increased again. Local side effect, manifested by itching in the oral cavity and the lips, was observed in one patient (7.69%) during sublingual ASIT. The symptoms diminished after rinsing the oral cavity with warm water and intake of antihistamines. In this case, we returned to the previous dose for one day, and then dosage increasing was resumed.
Future perspectives for SIT include investigation of new materials for active components, such as recombinant allergens, modified allergens, hypoallergenic isoforms and tolerogenic peptides, as wells as adjuvants for efficacy improvement, such as monophosphoryl lipid A or bacterial DNA. The latter induces tolerance to allergens stimulating Toll-like receptors, which control congenital immunity.
ASIT, like any other therapy, has its own medical indications and contraindications. The presence of clinical manifestations that increase each next season, the total IgE level’s increasing, positive skin tests, and the evidence of major allergens are indications for specific treatment. Unfortunately, as any other method of treatment, there is a risk of developing systemic or local allergic reactions. During 100 years of the ASIT existence, a lot of work was done to increase the effectiveness and to reduce the adverse reactions (such as improving drugs for treatment, using different schemes of treatment, changing the methods of drug administration). The studies conducted over the past 10 years have shown that modern drugs are effective and safe for treating allergies. The risk of adverse reactions, most of which are local, does not exceed 10% on overage. During using subcutaneous method of ASIT such reactions as redness, swelling, itching at the site of injection can form. During oral ASIT such reactions are itching in the oral cavity, slight rash, redness. The frequency of severe systemic reactions does not exceed 1% today. Deaths caused by the ASIT are not registered today.
The incidence of systemic reactions in subcutaneous route of administration is significantly higher than in sublingual application of allergens. The use of allergoids in the treatment also decreases the risk for the development of allergic reactions.
Nowadays, ASIT is the only treatment method for allergy, which enables to alleviate symptoms, prevents the disease progression and helps a patient to achieve remission. Despite adverse reactions that can occur in the process of treatment, it is a highly effective treatment method. To increase its efficacy, it is necessary to use modern drugs and select individual dosage. Though the fewest systemic and local reactions, according to conducted investigations, were found in medicines containing allergoids, native allergens are often used if there is a need in individual production of a drug.
1. Korytska I.V. Spetsyfichna imunoterapiia yak yedynyi patohenetychnyi metod likuvannia alerhichnykh zakhvoriuvan [Specific immunotherapy as the only pathogenetic method of treatment of allergic diseases]. Klinichna imunolohiia. Alerholohiia. Infektolohiia. 2015; 2: 12-21.
2. Derkach M.I., Chopiak V.V. Alerhenspetsyfichna imunoterapiia: istoriia, suchasni pohliady ta problemy [Allergenspecific Immunotherapy: History, Modern Views and Problems]. Mezhdunarodnыi эndokrynolohycheskyi zhurnal. 2013; 6: 144-150.
5. Shumna T.Ie. Suchasni pohliady na likuvannia ta profilaktyku alerhichnykh zakhvoriuvan u ditei [Modern views on the treatment and prevention of allergic diseases in children]. 2011; 6(33): 15-19.
7. Penagos M, Passalacqua G., Compalati E. et al. Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest. 2008; 133(3): 599-609.
8. Pukhlyk B.M., Zaikov S.V., Hohunska I.V. et al. Ievropeiskyi vybir u likuvanni alerhichnykh zakhvoriuvan orhaniv dykhannia [European choice in the treatment of allergic diseases of the respiratory organs]. Asthma and allergy. 2012; 4: 37-45.
10. Dhami S., Nurmatov U., Arasi S. et al. Allergen immunotherapy for allergic rhinoconjunctivitis: a systematic review and meta-analysis. Allergy. 2017; 72: 1597–1631.
11. Penagos M., Passalacqua G., Compalati E. et al.: Meta-analysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest. 2008; 133(3): 599–609.
12. Merkulova A. GINA 2017: chto novoho? [GINA 2017: What’s new?]. Health of Ukraine. 2017; 6 (403): 64-65.
15. Hryshylo P.V., Hryshylo A.P. Zastosuvannia imunoterapii vaktsynamy v likuvanni alerhichnykh zakhvoriuvan [Application of immunotherapy with vaccines in the treatment of allergic diseases]. Asthma and Allergy. 2012; 2: 57-62.
17. Korytska I.V. Alerhiia ta alerhenspetsyfichna imunoterapiia [Allergy and allergenic-specific immunotherapy]. Klin. immunology. Allergology. Infectology. 2013; 4: 73-75.
19. Dyatytskovskaya Ye.M. Porivnialna efektyvnist parenteralnoi i peroralnoi ASIT u khvorykh na polinoz [Comparative efficacy of parenteral and oral ACIT in patients with polyneas]. Journal of the Ear, Nose and Throat Diseases. 2011; 2: 20-24.
20. Hohunska I.V., Dytiatkivska Ie. M., Pukhlyk B.M., Kholodenko T.Iu. Rezultaty retrospektyvnoho doslidzhennia efektyvnosti alerhen-spetsyfichnoi imunoterapii pry alerhiinykh zakhvoriuvanniakh orhaniv dykhannia [Results of a retrospective study of the effectiveness of allergen-specific immunotherapy in allergic respiratory diseases]. Klin. immunology. Allergology. Infectology. 2012; 2: 48–51.
21. Naumova O.O., Hohunska I.V. Zastosuvannia molekuliarnoi alerhodiahnostyky dlia prohnozu efektyvnosti ASIT i tiazhkosti perebihu perekhresnoi kharchovoi alerhii iz sensybilizatsiieiu do pylku derev [Application of molecular allergy diagnosis to predict the effectiveness of ACIT and the severity of the cross-over food allergy with sensitization to pollen of trees]. Clinical Immunology. Allergology. Infectology.
2017; 1: 12-21.
23. Sohn M. H. Efficacy and Safety of Subcutaneous Allergen Immunotherapy for Allergic Rhinitis. Allergy Asthma Immunol Res. 2018; 10(1): 1-3.
25. Cox L., Calderón M., Pfaar O. Subcutaneous allergen immunotherapy for allergic disease: examining efficacy, safety and cost-effectiveness of current and novel formulations. Immunotherapy.2012; 4(6): 601-16.
28. Brown T. Sublingual Immunotherapy May Be Useful for Asthma, Allergies. JAMA. 2013; 309: 1278-1288.
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