ENGLISH VERSION: PERSONALIZED DESENSITIZATION WITH ACETYLSALICYLIC ACID IN PATIENTS WITH HYPERSENSITIVITY TO NON- STEROIDAL ANTI-INFLAMMATORY DRUGS

Aims: Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) has various mechanisms and represents different clinical syndromes from anaphylaxis to severe bronchospasm. The prevalence of aspirin hypersensitivity among patients with asthma and nasal polyps reaches 25.6%. Respiratory reactions associated with aspirin or other NSAIDs are not immunological. The basis of these reactions is non-allergic hypersensitivity of the cross-reactive type. Desensitization followed by long-term aspirin therapy is an effective method of treating hypersensitivity to aspirin or other NSAIDs. Using aspirin 600-1200 mg/day can significantly alleviate the symptoms of asthma, allergic rhinitis. Methods: We successfully applied aspirin desensitization for method of patients with hypersensitivity to NSAIDs. According to the method, an hour before the desensitization, daily montelukast 10 mg was taken orally, then aspirin every 3 hours. Results: Three patients underwent desensitization of aspirin. The dose was selected individualy depending on the clinical manifestations of drug-induced adverse reactions (AR). ARs during desensitization were treated by iv dexamethasone administration. Subsequent doses did not cause AR. Doses of aspirin were increased to a maximum of 1250 mg daily, and were continued for the long-term use. Conclusion: It is possible to conclude that the initial dose of aspirin should be 16-40mg; it is possible to increase the dose if the initial dosage is well tolerated; symptoms of moderate intolerance are treated by 4-8 mg iv dexamethasone; prior to desensitization, we recommended to use montelukast 10 mg, it is safe to practice desensitization of aspirin according to a personalized technique by a specialist in an intensive care unit.

After the first presentation of hypersensitivity reaction to aspirin (ASA) by Hirschberg in 1902, several types of hypersensitivity reactions to non-steroidal antiinflammatory and anti-rheumatic drugs (NSAIDs) have been described. NSAID-induced hypersensitivity reactions have different mechanisms and represent a wide range of clinical manifestations, from anaphylaxis to severe bronchospasm, developing within minutes after administration of drugs, as well as delayed reactions, developing in several days or weeks [1].
Hypersensitivity to ASA is found in 0.5-1.9% of population. The prevalence of hypersensitivity to NSAIDs in asthma patients as reported by questionnaire survey or medical record evaluation is from 4.3% to 11% and may reach 21% if provocative tests are used to clarify the diagnosis. Among patients with bronchial asthma and nasal polyps, the prevalence of hypersensitivity to ASA may be as high as 25.6%. Skin reactions to NSAIDs occur in 3.5% of population, and the prevalence of hypersensitivity to ASA can reach 27-35% among patients with chronic urticaria. NSAIDs constitute the second most frequent group of drugs responsible for the development of anaphylactic reactions [2].
Allergic reactions to NSAIDs are observed regardless of their chemical structure and / or anti-inflammatory potential. NSAIDs from the heteroaryl acetic acid group (naproxen, diclofenac, ibuprofen) cause immediate hypersensitivity reactions more frequently than other NSAIDs. Modern selective cyclooxygenase-2 inhibitors can also cause allergic reactions, although with a very low frequency of 0.008%. Hypersensitivity reactions caused by ASA or other NSAIDs (synonyms, used previously, are "aspirin triad" and "asthmatic triad") are manifested by bronchial obstruction, shortness of breath, nasal congestion or rhinorrhea, and are observed in patients with chronic respiratory diseases (asthma, rhinosinusitis and nasal polyps).
The prevalence of this group of reactions ranges from 4.3 to 20%, depending on the population of the examined subjects and diagnostic methods. The presence of chronic rhinosinusitis with nasal polyps, severe asthma and female sex are associated with a high incidence of hypersensitivity to ASA and other NSAIDs.
Respiratory system responses, caused by ASA or other NSAIDs, are not immunological, i.e. they are not based on an antigen-antibody interaction. The nonallergic hypersensitivity of the cross-reactive type underlies these reactions. The main mechanism of these reactions consists in the inhibition of COX-1 by most NSAIDs -COX-1 inhibitors. Such a change in COX-1 activity is clearly manifested under conditions of impaired arachidonic acid metabolism. The disorders of arachidonate metabolism are as follows: 1) increased levels of leukotriene E4 in urine, expired breath condensate, bronchoalveolar lavage, induced phlegm and saliva due to increased 5-lipoxygenase activity; 2) decreased production of prostaglandin E2 by the epithelium of the upper and lower respiratory tract, accompanied by the inhibition of COX-2 and reduced basal production of lipoxin A4 by peripheral blood leukocytes; 3) increased expression of type 1 leukotriene receptors by the nasal mucosa cells [3].
Inhibition of COX-1 leads to activation of mast cells and eosinophils with a release of inflammatory mediators. Therefore, such reactions are characterized by manifestations of chronic eosinophilic inflammation. COX-2 inhibitors and low doses of COX-1 inhibitors are usually well tolerated by patients. Cysteinyl-leukotrienes (LT) are one of the main mediators, causing NSAID intolerance reactions. Consequently, blockade of type 1 leukotriene receptors by pharmacological inhibitors can alleviate clinical symptoms. Viral infections may be an important factor in the persistence of respiratory tract inflammation in such patients.
Clinical manifestations of hypersensitivity as a rule are observed in 30-180 min after administration of ASA / NSAIDs: patients develop non-bronchial symptoms (rhinorrhea, nasal congestion), ocular, skin (urticaria and / or angioedema) and gastrointestinal symptoms. Usually, a patient with hypersensitivity to NSAIDs presents with past history of chronic rhinosinusitis (sometimes complicated by mucosal hypertrophy and nasal polyps) and / or asthma. However, in some patients the intake of NSAIDs may cause the first bronchial asthma attack. Anosmia is a characteristic clinical feature in such patients.
Desensitization, followed by a long-term ASA therapy, is an effective treatment for patients with respiratory diseases, exacerbated by NSAIDs. The use of ASA at a dose of 600-1200 mg per day can significantly alleviate the symptoms of asthma and affected upper respiratory tract, as well as reduce the dose of intranasal corticosteroids (recommendation level B). In some patients, desensitization with ASA leads to a decreased frequency of polyps recurrence and repeated surgeries. Along with improving the management of bronchial asthma, desensitization with ASA also reduces the need for oral glucocorticoids [6].
We have tested and successfully applied the technique of desensitization with acetylsalicylic acid for patients with hypersensitivity to NSAIDs. One hour prior to desensitization, patients were prescribed montelukast 10 mg orally, 1 tablet, and ASA every 3 hours.
We present several typical cases that demonstrate an individual approach to desensitization. Following the examination, it was found that the patient had sensitization with pollen antibodies. The patient was recommended to undergo specific immunotherapy with wormwood pollen.

Discussion
Three patients were desensitized with acetylsalicylic acid, and desensitization was personalized by nature. A dose of ASA was selected individually for each patient, depending on the anamnestic clinical manifestations of anaphylactic reactions. Two patients had an allergic reaction in the form of bronchospasm after ASA intake: one dose of 40 mg of ASA and the other dose of 37.5 mg of ASA. The 3rd patient developed rhinorrhea and sneezing on administering the 3rd dose of ASA (75 mg). In all three patients, allergic reactions were arrested by i/v administration of dexamethasone. Later on, subsequent doses did not cause allergic reactions. Doses of ASA were raised to a maximum of 1250 mg per day in 2 doses for a long-term administration.
One patient subsequently presented with clinically significant sensitization to wormwood pollen. In our opinion, this sensitization was masked by severe intolerance to ASA and revealed a seasonal allergy after desensitization. Thus: 1) The initial dose of ASA should be 16-40 mg, depending on the presence of severe reactions in case history; 2) An increase in the dose of ASA is performed in case of satisfactory dose tolerance (mild rhinorrhea symptoms are allowed); 3) The appearance of moderate intolerance symptoms to ASA is effectively arrested by i/v administration of 4-8 mg of dexamethasone; 4) Most often, the symptoms of intolerance in desensitization with ASA are manifested when receiving doses of 37-75 mg; 5) It is advisable to administer 10 mg of monteleukast before desensitization with ASA; 6) Manifestation of desensitization with ASA is a safe technology when conducted using a personalized technique by trained personnel under conditions of intensive care wards; 7) Successful desensitization with ASA can contribute to the detection of seasonal allergies, previously hidden by year-round symptoms.