UA144439U - METHOD OF TREATMENT OF PATIENTS WITH BRONCHIAL ASTHMA WITH NEUTROPHILIC TYPE OF INFLAMMATION - Google Patents

Abstract

A method of treating patients with bronchial asthma with neutrophilic inflammation is to prescribe inhaled glucocorticosteroids and long-acting beta-2 agonists according to the severity of the disease. Apply ultrafine glucocorticosteroid, tiotropium bromide through Respimat in standard therapeutic doses and inhalation with a nebulizer 10% acetylcysteine solution once a day for 10 days.

Description

A useful model belongs to medicine, namely pulmonology, and can be applied to the treatment of patients with bronchial asthma with neutrophilic type of inflammation.

Bronchial asthma (BA) is a chronic inflammatory disease of the respiratory tract caused by a significant number of cells and inflammatory mediators. Chronic inflammation is combined with bronchial hyperreactivity, manifested by recurrent symptoms of wheezing, wheezing, chest tightness, cough, especially at night and early in the morning. These episodes are usually associated with widespread but variable broncho-obstruction, which is reversible spontaneously or under the influence of therapy. On the approval and implementation of medical and technical documents on the standardization of medical care for bronchial asthma // Order of the Ministry of Health of Ukraine dated October 8, 2013.

Mo. 868. Kyiv, 2013. - 71 p.|.

The main criteria for a violation of the function of external respiration (FPR) in patients with BA are: the presence of signs of bronchial obstruction - the value of the peak volumetric velocity of exhalation (PEV) and the volume of forced exhalation in the first second (EEM:) - 80 95 of the appropriate values; pronounced reversibility of bronchial obstruction (a rapid increase in the level of HEMi"12 95 (or 2200 ml) or POSHvid"20 95 (or 260 l/min), which is measured within 15-30 minutes after inhalation of a short-acting beta-2 agonist (200-400 mcg of salbutamol) - according to the results of a pharmacological test or a more pronounced improvement after a few days or weeks after the appointment and administration of an effective control drug - inhaled glucocorticosteroid (ICS); daily variability (improvement or worsening of symptoms and FZD over time) - POshSVID and RGEMi"20 95 Variability can be determined during the day (daily variability), from day to day, from month to month, or seasonally.

of Ukraine dated 08.10.2013 Mo 868. Kyiv, 2013. - 71 p...

BA is a heterogeneous chronic inflammatory disease of the respiratory tract. At the heart of this heterogeneity, among other factors, the type of airway inflammation (eosinophilic, neutrophilic, or microgranulocytic) plays a significant role. In this regard, it is proposed to distinguish individual endotypes of the disease. An endotype is a subtype of the disease characterized by a unique pathophysiological mechanism that largely determines the response to treatment. Despite the successes in the treatment of BA, there remains a proportion of patients who cannot achieve a controlled course of the disease. Such patients include patients with BA with a neutrophilic type of inflammation, which is associated with a more severe course of the disease, with the presence of obstruction of small bronchi (maximum volume expiratory velocity at the level of 25 95 of the vital capacity of the lungs remaining before exhalation (MER25 95) "50 95) and fixed bronchial obstruction (the ratio of the forced expiratory volume in 1 second (REM) to the forced vital capacity of the lungs (EMO) - EEM1/EMOS "70 95), and the probability of hormone resistance (see Features of bronchial asthma with neutrophil by the type of inflammation / Yu.Y. Feshchenko and others / Asthma and Allergy. 2019. Mo 3. - P. 35-40. The use of ultrafine-dispersed glucocorticosteroid in the basic therapy of patients with bronchial asthma with neutrophilic type of inflammation: information sheet / Yu.I. Feshchenko and others, NIFP NAMNU.

Kyiv, 2019. - 4 p.|.

As the closest analogue, the order of the Ministry of Health of Ukraine of 08.10.2013 Mo. 868 "On the approval and implementation of medical and technical documents on the standardization of medical care for bronchial asthma" was selected | see On the approval and implementation of medical and technical documents on the standardization of medical care for bronchial asthma // Order of the Ministry of Health of Ukraine dated 08.10.2013 Mo 868. Kyiv, 2013. - 71 p.), according to which the basic therapy for asthma is the inhalation form of a fixed combination glucocorticosteroid and long-acting beta-2 agonist (budesonidnformoterol), which is used in a standard therapeutic dose according to the severity of the disease. Due to the rapid onset of action, this combination can also be used as needed, which reduces the frequency of severe exacerbations and improves asthma control at relatively low doses of ICS.

According to the order, the inhalation route of drug administration is preferred in the treatment of BA, as the drug is delivered directly to the target organ (respiratory tract), the systemic effect of the drug is minimized, drug interactions are excluded, and inhalation therapy includes the appointment of short-acting beta-2 agonists, beta- 2-agonists of long-term action, inhaled corticosteroids, cholinolytics, nebulizer therapy. Inhalation drugs for the treatment of asthma are presented in the form of metered-dose aerosol inhalers (MAIs), which are activated by the breath of the MAIs, metered-dose dry powder inhalers (MDIs), and nebulizers. Nebulizer therapy is recommended for asthma exacerbations. At the outpatient stage of treatment, a solution of 60 bronchodilators is used through a nebulizer.

Thus, the prescription of inhaled corticosteroids (ICS) should be considered in patients with any symptom related to asthma, in doses according to the severity of the patient's disease. It is necessary to titrate doses of ICS to the lowest dose at which effective asthma control is maintained. ICS have been proven to reduce asthma symptoms, improve quality of life, lung function, reduce bronchial hyperreactivity, control airway inflammation, reduce the frequency and severity of asthma exacerbations, and asthma mortality.

Broncholytics of long-acting beta-2-agonists (TDB) are not used in monotherapy, without ICS.

They have been shown to be most effective when combined with ICS, and such a combination has advantages when moderate doses of ICS in monotherapy fail to achieve asthma control.

The addition of long-acting beta-2 agonists to ICS reduces the number of symptoms and their severity, reduces nocturnal symptoms, improves lung function, reduces the need for short-acting bronchodilators, reduces the number of exacerbations, does not increase the risk of asthma-related hospitalizations, and allows achieving disease control in a larger number of patients faster and with the use of lower doses of ICS than ICS in monotherapy.

To relieve acute symptoms of asthma, it is recommended to use short-acting bronchodilators (used as needed). Such drugs include: short-acting beta-2-agonists (KDBA) - salbutomol, fenoterol (4-6 hours of action), short-acting cholinolytic (KDHL) - ipratropium bromide and combined drugs (short-acting beta-2-agonists, short-acting anticholinergic ). KDHL - less effective than KDBA, are recommended as an alternative bronchodilator in patients with tachycardia, arrhythmias, tremors, if they occur when using KDBA.

In the medical algorithm of patients with combined pathology (joining of chronic obstructive pulmonary disease (COPD) to asthma), complex treatment with the use of basic therapy - ICS in high doses - TDB, a long-acting acholinolytic, and a long-acting theophylline - comes to the fore. An oral drug with an antioxidant effect (M-acetylcysteine) is recommended.

However, the order does not contain data on the clinical and functional characteristics of BA patients with neutrophilic type of inflammation and their treatment.

And data from literary sources regarding the effectiveness of basic inhalation therapy in

The treatment of BA patients with neutrophilic type of inflammation is quite controversial. Inadequate response to standard corticosteroid therapy in patients with neutrophilia is associated with activation of interleukin 17 | see Mespapivtv Tog Mop-eoziporpiys Abvipta /Kapepyigo A. /Admapsev ip Aviyta. 2019. Mo 2. R. 41-52), in connection with which patients are forced to increase the doses of bronchodilators. When daily doses of bronchodilators are increased, adverse reactions from the cardiovascular and nervous systems may occur. One of the factors underlying neutrophilia - tobacco smoking also reduces the effectiveness of anti-inflammatory therapy (see Bronchial asthma and tobacco smoking: treatment difficulties and problem solving prospects! / Yu. V. Prosvetov et al.

Ukraine pulmonol. journal 2019. Mo. 1. P. 63-67|Y. High activity of the inflammatory process and bacterial colonization of sputum are characteristic of neutrophilic inflammation in asthma (|see

Mystoriote-iosized aviita tapadetepi zigaieediee /5.0. ZpyKIa ei ai. //Sshtepi Oripiop ip

Ripaptasiod. 2019. Mo 46. R. 143-149), which often requires the use of antibacterial therapy | see Capepiigo A. Mespapibtv5 og Mop-eovziporpiis Abvipta //Admapsez ip Abvipta. 2019. Mo. 2. R. 41-52). With neutrophilic inflammation of the respiratory tract, there is hyperplasia of goblet cells with hyperproduction of mucus, which aggravates the degree of bronchial obstruction and increases the bacterial load. Sobriei seiYi puregriazia az a iyeaishtge oi pecizorpiiis azipta /K. AIadna ey a!. //Siipisa! 5 Ehregitepia! APegdu 2019. Mo 49 (6). R. 781-788). Among the reasons for the poor control of neutrophilic asthma, it is worth noting the possibility of some subpopulations of neutrophils to provoke bronchial hyperreactivity (see Oimidipd peshtorniie ip 5!rv5eiv5 geuea!5 a zidpitisapi goYe Tog asiimaiei peshgornpii5 ip ee demeiortepi oi aiglau Nuregteasiimnu /5.

Equities of her ai. //Siipisai 5 Ehregptepia! APegdu 2019. Mo 49 (3). P. 285-291), and when dexamethasone is used, this hyperreactivity may paradoxically increase | see Eppapsey raise soteiaibe5 m/y aipmau pesphornii5 apa aiigmau-eriiiteiiiya! ipishtu ip avziytais tise iMeafey my dekhateiNnazope /Snao M. eyi ai. / Loitai o Aegypta. 2019. Mo 56 (1). R. 1-81.

Thus, according to the obtained data: the use of standard basic inhalation therapy in patients with BA with neutrophilic type of inflammation does not allow to achieve control over the disease, which requires additional use of bronchodilators and leads to side effects; there is a high frequency of exacerbations; small bronchial obstruction and fixed bronchial obstruction develop; because it negatively affects the activity of neutrophilic inflammation.

Therefore, the development, substantiation and introduction into wide clinical practice of the treatment technology for BA with neutrophilic type of inflammation with the use of available registered in

available drugs in Ukraine is relevant.

The basis of a useful model is the task of developing a method of treatment for patients with bronchial asthma with neutrophilic type of inflammation, in which by prescribing an inhaled ultrafine-dispersed glucocorticosteroid, tiotropium bromide through Respimat in standard therapeutic doses and inhalation using a nebulizer of 10 95 acetylcysteine solution for 10 days, an improvement in clinical conditions is achieved symptoms of bronchial asthma, reduction of exacerbations, improvement of indicators of the function of external breathing and tolerance to physical exertion, improvement of quality of life, as a result of which the effectiveness of treatment of this category of patients increases.

The task is solved by the fact that in the method of treating patients with bronchial asthma with a neutrophilic type of inflammation, which consists in prescribing an inhaled glucocorticosteroid and a long-acting beta-2-agonist, according to the severity of the disease, according to a useful model, ultrafine-dispersed glucocorticosteroid, tiotropium bromide through

Respimat in standard therapeutic doses and inhaled using a nebulizer 10 95 acetylcysteine solution once a day for 10 days.

Taking into account the fact that there are currently no clear diagnostic criteria for neutrophilic BA, which does not allow timely detection of such patients and pathogenetically justified treatment, to determine the phenotype of the disease, it is advisable to use the criterion of dividing the neutrophil content in the blood into low and high - "x" or "4000/ mkl, which is presented in the research program of severe BA (Dreams of Bemege Aviita Vezeagsi Rgodgatte (5АРВР) (see

Zrisht Apa Viosy EoziporpiY apa Meshgornii A5zosiaiope M/y A Moge bemege Azipta RNepoiure ip

She MNIBi bZemege Avipta Nezveagsi Rgodgatte (ZAVR) /A. Name her. // At. 9. Vezrig Stia Sage

Mea. 2017. Mine. 195. R. 695).

Modern standard methods of treatment of BA do not take into account the pathomorphological and functional features of patients with a neutrophilic inflammation phenotype (different endotypes are possible, including the presence of small bronchial obstruction, fixed bronchial obstruction). It is for such patients that it is advisable to use currently known ultrafine-dispersed glucocorticosteroids, which have a mass-median aerosol diameter (MMA) of particles of 1.1 μm, which allows the drug to penetrate through the largest narrowings of the tracheobronchial tree and into the small bronchi and remain in them (see .

Such a drug available in Ukraine today is beclomethasone Eco, in the form of a dosed aerosol based on a solution.

It is known that in patients with neutrophilic BA with obstruction of small bronchi and fixed bronchial obstruction, a positive effect is also observed with the use of long-acting cholinolytics (see Is it possible to improve control of bronchial asthma without increasing doses of glucocorticosteroids? / O.M. Kurbacheva, K.S. Pavlova //Practical pulmonology, 2017.

Mo 2. - pp. 14-20). Such a drug is tiotropium bromide, which belongs to the group of M-cholinergics and is characterized by an ultra-long (more than 24 hours) broncholytic effect, thanks to which tiotropium can be prescribed once a day.

The determination of violations at the level of small bronchi leads to the appointment of anti-inflammatory drugs in delivery devices that are capable of creating a high concentration of drugs in peripheral departments (for example, Respimat, breath-controlled inhalers, fine-dispersed aerosols) | see Yu.I. Feshchenko Actual problems of modern pulmonology / Ukr. pulmonol. journal 2018. Mo 4. - C 8-12). Respimat is a device that allows you to obtain an ultrafine "soft" aerosol. The Respimat inhaler functions due to mechanical energy generated by a compressible spring, does not require a power source and does not contain a propellant. This device combines the best qualities of a metered-dose aerosol inhaler (MAI): simplicity, compactness, the ability to quickly perform inhalation and the positive properties of a nebulizer: the inhaler releases aerosol slowly (about 1.5 seconds). Thus, in the process of inhalation, patients do not have problems with breathing coordination | see Arkhipov V.V., Abrosimov A.G., Arkhipova D.E.

Spiriva Respimat is a new direction in the treatment of COPD. ONVI:

Nerz / Lymly. pt) gy/apisiev/boYegpi dukpayieipuki ryieu/Zrigma Nezritai pomoe pargamiepie m

LIespepii NEW /yaikh226Euzvriri|.

Thus, compared to other currently available inhalers, Respimat has a number of advantages. It provides: the generation of an aerosol cloud that moves slowly and exists in the air for a long time, 60 which allows to improve coordination with breathing;

a high fraction of small particles (65-95 doses are particles with a size of "5.8 microns); the possibility to refuse the use of propellant; high level of deposition of the drug in the lungs and its insignificant deposition in the oropharynx; the possibility of reducing the dose of the drug by improving its delivery to the body; stable delivery of the same doses to the body during the entire shelf life; decrease in the frequency of paradoxical bronchospasm caused by excipients | see Avdeev S.N. New opportunities for using tiotropium bromide with the help of an aerosol delivery device - Respimat inhaler / Lulmonology. 2013. Mo. 5. - P. 70-80).

It is also known that even against the background of regular intake of basic inhalation therapy, some patients still complain of cough with difficult sputum production. This hypersecretion is explained by an increase in the number of goblet cells and submucosal glands in response to chronic irritation of the mucous membrane of the respiratory tract by tobacco smoke and other harmful agents. Additional use of mucoactive drugs is advisable for this category of patients. Mucolytics disrupt the structure of the mucus gel, thereby reducing its viscosity and elasticity and, thus, improving the viscoelastic properties of sputum, which facilitates the cleaning of the respiratory tract and contributes to the targeted delivery of bronchodilators and anti-inflammatory agents to the small bronchi. Codeg5 O.R. Mysoasiime Adepiv Tog

Aiglau Mysyv Nuregzesteyugu ORiveazev5. Nezrigatu Sage. 2007. Mine. 52. R. 1176-1197). Acetylcysteine and carbocysteine are among the most effective mucolytics with the best evidence base in patients with broncho-obstructive lung diseases. As evidenced by the research results | see C1obai ipyiaime og spgopis obzigisiime Ishpa divvazez (СО 0). Good luck! zigagiedu iog aiadpozi5, tapadetepi apa rgemepiip oi spgopis obzigisiime Ishpu diseasezez5. MNI VL/NO mok5por teroi. ShVA: /pyrz//doidsora.oga/doia-2017-dioba!-5igatedu-diadpo5iz-tapadetepi-rhemepiop-sora/; Sa?27oia M. yei ai. Itrasi oi Mysoiuiis Adepi5 op SORO Ekhasegbayiyope: A Raig-mize apa Meimok Meia-apaiuviz. SORO. 2017. Mine. 14, Mo. 5. R. 552-563| oral intake of acetylcysteine or carbocysteine allows to reduce the severity and frequency of exacerbations, see

Sa?20ia M. ei ai. IpYamepse oi M-aseiuIsuziveyipe op spgopis Bgopspyiz og SORO ehasegbaiyyopve: a teia- apaiuviv. Yeshg Vezrig Neu. 2015. Mine. 24. R. 451-461; Rooiie R., Spopa 9., Saie5 S.). Mysoiuiys adepiv megzyv riasero og spgopis Bgopenyiyv og spgopis orvigysiime ryitopagu disease. Sosngape Oaiaraze oi Zuvietaiiis Nemiemuv. 20151. 7. Ai.Mo SO0012871.

But there are no data in the literature on the complex use of inhaled ultrafine glucocorticosteroid according to the severity of the disease, tiotropium bromide through the modern technical device Respimat, formoterol and acetylcysteine using a nebulizer in the basic inhalation therapy of BA with neutrophilic type of inflammation.

The method is carried out as follows:

In patients with uncontrolled BA, which cannot be treated with standard therapy, the phenotype of inflammation is determined by performing a blood test by microscopy with the determination of the number of neutrophils in 1 μl of blood and at a level of neutrophils of 24,000 in 1 μl of blood - the type of inflammation is considered neutrophilic | see. Madii A. Viosa dgapiiosuiee racegp5 av rgedisiog5 oi azipta rnpepoiurez ip adiyv pot She ESEA zshshau /V. Madiya her ai. //Epigoreap Vezrigayugu Uoishgpai. 2016. Mine. 48. R. 1040-1051.

Patients with BA with a neutrophilic type of inflammation are prescribed as basic therapy inhaled 250 mcg of ultrafinely dispersed beclomethasone dipropionate according to the severity of the disease and 12 mcg of formoterol twice a day, tiotropium bromide in a standard therapeutic dose (5 mcg of tiotropium) in the form of two inhalations through a delivery device

Respimat once a day (at the same time of the day) and inhaled through a nebulizer acetylcysteine at 3 ml of 1095 solution once a day in the morning (inhalation session duration 10 minutes) for 10 days.

We give concrete examples of the implementation of the method.

Example 1 (according to the closest analog method)

Patient Ya., 69 years old, was undergoing outpatient treatment in the department of differential diagnosis of tuberculosis and non-specific lung diseases of the State Institution "F.G. Yanovsky National Institute of Phthisiology and Pulmonology of the National Academy of Medical Sciences of Ukraine" due to uncontrolled bronchial asthma. He complained about attacks of hay fever, including at night, shortness of breath during physical exertion, dry cough. He has been sick for 2 years.

On examination, the general condition is satisfactory. The skin and mucous membranes are pale pink, without rashes. In the lungs, vesicular breathing is heard during auscultation, isolated dry wheezes during forced exhalation. Tones of the heart are sonorous, rhythmic.

Questionnaire data of AKT - 10 points, ASO - 2.5 points. According to the 5INO questionnaire, the symptom score is 56.9, activity limitation is 41.3, activity limitation is 50.0, the total score is 48.5 points.

The study of the function of external breathing revealed ventilation disorders according to the obstructive type: EEM: was 66.6 95, EMO - 78.7 95, ratio EEM:/EMS - 65.0 95, MO - 78.2 95, RERE - 51.5 95 , and the patency indicators of small bronchi were: MERE75" - 51.9 95,

MAYOR about"; - 32.5 9o and MERg»g5 »; - 34.2 9o from the proper values.

During the b-minute gait test, shortness of breath before the test was 3 points, blood oxygen saturation - 96 95. The patient walked 190 meters, after which the level of shortness of breath was 4 points, blood oxygen saturation - 95 95.

For 3 months, the patient received a combined drug - 320 mcg of budesonide and 9 mcg of formoterol twice a day, salbutomol as needed.

After carrying out the treatment according to the method-the closest analogue at the control visit, the data of the objective examination did not change. Questionnaire data of ACT - 10 points (unchanged), ASO - 2.83 points (deterioration). According to the 5С218О questionnaire, the quality of life did not improve (symptom score - 88.5, activity limitation - 42.6, activity limitation - 35.3, total score - 46.4 points).

The study of the function of external breathing did not reveal positive dynamics: REM: - 65.2 95, EMO - 80.6 95, ratio REMI/EMSO - 62.2 95, MO - 77.6 95, REE - 61.9 95. Patency indicators of small bronchi were: ME E75 5 - 42.8 96, MEREvog - 32.9 95 and MER"5 "; - 31.5 95 from the proper values. During the test with a b-minute gait, shortness of breath before and after the test was compounded

C and 4 points, respectively, blood oxygen saturation - 97 and 96 95, respectively. The patient walked 210 meters.

Thus, it was not possible to control the disease, improve the function of external breathing and the patient's quality of life using the closest analog method.

Example 2 (according to the claimed method)

Patient Yu., 63 years old, was undergoing outpatient treatment in the Department of Differential Diagnosis of Tuberculosis and Non-Specific Lung Diseases of the State Institution "F.G. Yanovsky National Institute of Phthisia and Pulmonology of NAMA of Ukraine" due to an uncontrolled course of bronchial asthma. She complained of shortness of breath, dry

From cough, wheezing and attacks of dyspnea. He has been ill for 20 years, the disease progresses with frequent exacerbations.

On examination, the general condition is satisfactory. The skin and mucous membranes are pale pink, without rashes. In the lungs during auscultation, vesicular breathing is heard, single whistling rales on the right and left. Tones of the heart are sonorous, rhythmic.

Questionnaire data of AKT - 14 points, ASO - 1.83 points. According to the 502NO questionnaire, the symptom score is 46.5, activity limitation is 47.2, activity limitation is 45.8, and the total score is 46.3 points.

The study of the function of external breathing revealed ventilation disorders according to the obstructive type: volume of forced exhalation in the first second, EEM': - 70.6 95, EMO - 88.6 95, ratio REM:/EMO - 67.1 96, MO - 98 ,3 Fo, REBE - 93.3 95, and the parameters of patency of small bronchi were: МЕР75 95 - 46.6 95, МЕРevoye - 24.0 95 and МЕРg5 bo - 20.0 95 from the appropriate values.

During the b-minute gait test, shortness of breath before the test was 3 points, blood oxygen saturation - 97 95. The patient walked 240 meters, after which the level of shortness of breath was 5 points, blood oxygen saturation - 96 95.

To determine the phenotype of the patient's inflammation, a blood test was performed by microscopy to determine the number of neutrophils in 1 μl of blood, the level of which was 5304 in 1 μl, that is, the type of inflammation was defined as neutrophilic. The patient was prescribed inhalation of 250 mcg of ultrafinely dispersed beclomethasone dipropionate and 12 mcg of formoterol twice a day, 5 mcg of tiotropium bromide in the form of two inhalations through the Respimat delivery device once a day. In the complex treatment, acetylcysteine is additionally prescribed by inhalation through a nebulizer at the rate of 3 ml of 10 95 solution once a day in the morning (the duration of the inhalation session is 10 minutes) for 10 days. Salbutomol is also prescribed as needed.

After the treatment according to the claimed method, at the follow-up visit three months later, the data of the objective examination showed positive dynamics: no wheezing was heard during auscultation of the lungs. Questionnaire data indicate a significant improvement in asthma symptom control: ACT - 20 points, ASO - 0.83 points. According to the 5INO questionnaire, an improvement in the quality of life is noted (symptom score - 38.4, activity limitation - 41.8, activity limitation - 21.9, total score - 30.6 points). Research on the function of external respiration revealed a significant improvement in bronchial patency: volume of forced exhalation in the first second, REM: -

84.0 95, EMO - 88.6 95, ratio REM/EMO - 79.7 96, MO - 85.0 95, REE - 80.5 95, indicators of patency of small bronchi were: MERE" 95 - 87.8 96 , MER»vo is - 72.5 95 and MER» 2 - 48.3 Uo from the proper values. During the test with b-minute gait, shortness of breath before and after the test was 2 and C points, respectively, blood oxygen saturation - 98 95 and 97 95, respectively. The patient walked 310 meters.

Thus, according to the claimed method, it was possible to achieve control over the disease, improvement of the function of external breathing and the patient's quality of life.

The effectiveness of treatment of BA patients with neutrophilic type of inflammation was studied in 30 patients. The first (control) group consisted of 15 patients (5 men and 10 women, average age (53.2:24.9) years, EEM: after the trial with a bronchodilator (50.6:-16.3) 95, BEM/EMS ( 66.4517.8), who in complex treatment received as standard therapy a combined drug - 320 mcg of budesonide and 9 mcg of formoterol twice a day. The II (main) group consisted of 15 patients (9 men and 6 women, average age (53.6 :53.8) years, REM: (51.5:24.7) U6, EEMI/EMC (67.2х3.5), who were prescribed treatment according to the claimed method. Taking into account that almost all patients complained of cough with with difficult sputum secretion, patients of the II group at the first visit in complex treatment were additionally prescribed inhalation of 1095 acetylcysteine solution using a nebulizer once a day for 10 days.

Thus, the studied groups of patients did not differ in age, sex, and degree of bronchial obstruction. All patients additionally received salbutomol as needed.

The diagnosis of BA with a neutrophilic type of inflammation was established in patients whose neutrophil level was 24,000 in 1 μl during blood examination by microscopy.

To determine the severity of the course of asthma and assess control over the disease, patients were asked to fill out: asthma control test (AST), asthma control questionnaire (ASO)

went Bronchial asthma. Chronic obstructive pulmonary disease in the light of modern recommendations of SIMA (2017), BISM 153 (2016), SOI O (2017), MISE (2010): doctor's practice / Yu.1.

Feshchenko and others. Kyiv: "Doctor-Media-Group", 2018. 219 p.; Avipta Sopigo!i Oyeviioppaige (Meazitgipa

Avipyta Sopigoi) /R. Heyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy //(At. U. Nezrig. Sii Sage Mei. 2000. Moi. 162. R. 1330-1334;

Adapted evidence-based clinical guideline "Unified clinical protocol of primary, secondary (specialized), tertiary (high-tech specialized) medical care and medical rehabilitation. Bronchial asthma. Kyiv: "National Academy of Medical Sciences of Ukraine", 2016. - 190 p.| .

The patients' quality of life was evaluated according to the quality of life questionnaire of St. George's Hospital

went Chdope5 R.MU., BGogde U., dope5 R.MU. BI Sieogde"5 gezrigaiyutgtu dieviyoppaige og SORO raiepiv (50VO-S) tapiai. I opdop: 51. Seogde"5 Opimeteyu oi Hopdop, 2008. 15 r.|.

An overview x-ray of the chest organs was performed in all patients to rule out concomitant pulmonary pathology.

In order to establish a diagnosis, determine the degree of broncho-obstruction and identify functional features in patients with BA with neutrophilic type of inflammation, spirography was performed with the analysis of the "flow-volume" curve of forced exhalation on the set for researching the respiratory system "Maviei bZstep Rpeito" and the device "Mavziveg 5step" RET" of the company "Sagaiipai!

Neatsi" (Germany). The following indicators of FZD were studied: vital capacity of the lungs (VFC), forced vital capacity of the lungs (FVC), forced expiratory volume in 1 s (EGEM', maximum expiratory volume velocity at 25, 50, 75 95 vital capacity of the lungs (MEREg25", MEREvo»g, MERE?" o), peak expiratory volume velocity (PEV). The study was carried out in the morning, after a 12-14 hour break in taking medication. The values were taken into account and recorded in the patient's individual card external respiratory function indicators, which were obtained 15-30 minutes after inhalation of a short-acting Vg2 agonist (400 μg of salbutamol). All indicators were evaluated as a percentage of the standard values developed by R.F. Klement et al.

went Instruction on the application of formulas and tables of the correct values of the main spirographic indicators / R.F. Klement et al. L., 1986. - 79 p.). When applying the hardware method of research (spirography), the reference values entered into the software of the equipment used were taken into account.

To assess the patients' tolerance to physical exertion, a 6-minute walk test (6MMUT) was performed (in accordance with the standard protocol) | see ATO 5ia (stages:

Sshideiipev Tog Te 5ih-Mipshe UMaikK Tevi //"At. 9. Vezrig. Stii. Sage Med. 2002. Moi. 166. R. 111-117).

Before the start and at the end of the test, shortness of breath was assessed on the Vog9d scale, blood oxygen saturation (5pO:g). Patients were required to stop walking if the following symptoms occurred: very severe shortness of breath, chest pain, dizziness, leg pain, and if

Air temperature up to 80.0-86.0 95. The distance covered during b min (6MMU0) was measured in meters. heart rate (HR) and heart rate were determined using a pulse oximeter.

Accumulation of data and their mathematical processing were carried out with the help of licensed software products included in the Mystozoi OPise Rgoiezziop! 2003, Kyvviap license

Asadetis OREM Mo I yeme! Mo 17016297. Statistical processing was performed with the help of mathematical and statistical capabilities of MO Ekhseyi, followed by verification of the reliability of the result using the Student's criterion. Lapach S.N., Chubenko A.V., Babych P.N.

Statistical methods in medical and biological research using Eksvi. Kyiv:

Morion, 2000. - 320 p.|.

All BA patients with neutrophilic type of inflammation were standardized according to previous treatment - before inclusion in the study, they received standard basic BA therapy according to the severity of the disease according to current treatment standards, which was carried out for 12 weeks, but had an uncontrolled course of the disease.

In patients of both groups, the main points that usually make it difficult to achieve control were excluded (patients were committed to therapy, had a good command of the inhalation technique, their accompanying pathology was under control).

The study of patients of I and I groups consisted of 2 visits - the moment of inclusion of the patient in the study (1 visit) and after 12 weeks of observation (2 visit). At the 1st and 2nd visits, the patients underwent examination methods, based on the results of which the severity of the course of BA, control over symptoms, indicators of external breathing function, quality of life of the patients were assessed, and the effectiveness and tolerability of the treatment carried out were determined (see Table 1).

Table 1

Scheme of conducting a clinical and functional study of the I-II groups of patients with BA (observation) treatment

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Assessment of tolerability of treatment (7-77 Her p.

The criteria for stabilization of clinical symptoms of BA were considered to be: cessation of sputum discharge, reduction of cough (absence of cough throughout the day and night, sometimes there was a thin cough in the morning); shortness of breath, increased tolerance to physical exertion, improved quality of life according to quality of life questionnaires of St. George's Hospital.

After the end of the treatment (after 12 weeks) at the 2nd visit, its effectiveness was assessed by both the doctor and the patient. Compliance and tolerability of the treatment, the presence of side effects, were also evaluated. The treatment was considered effective if it was evaluated as such by both the doctor and the patient, at the same time, there were positive dynamics of both clinical symptoms of BA and functional indicators according to the selected research methods.

According to the basic characteristics, the groups of patients were comparable both in terms of the severity of symptoms and the level of control. The total score of BA symptoms according to AST was (12,944.0) points in the control group and (14,341.5) points in the main group, according to the ASO questionnaire) - (1.9:0.3) and (2,320.7), respectively (see . table 2).

The uncontrolled course of the disease, its clinical and functional manifestations, to a certain extent worsened the quality of life of patients according to all scales of the 5О2ВО questionnaire - respiratory problems, their frequency and severity (domain score of symptoms was in the control group

(64.3:25.3) points and in the main group - (71,425.6) points), limitation of physical activity due to shortness of breath and the impact of the disease on psychosocial problems related to breathing (domains of activity limitation in the control group (54, 7 6.7) points and in the main group (45.7 5.1) points, the activity restriction domain - (37.755.5) and (39.4-6.0) points in the control and main groups, respectively). The total score was (44.7-44.8) points in the control group and (46.74.8) points in the main group (see Table 2).

Table 2

Dynamics of questionnaire results under the influence of treatment (Mat) 00 Indicators | drlvro'na street (TV) parta VI

Indexes : : - - - :

Note 1. "statistically significant difference of the indicator before and after treatment, p0.05.

According to the results of the statistical analysis, it was established that during 12 weeks of treatment, 3 1 to 2 visits, in patients of the 1st group who received standard basic therapy, there were no changes in the clinical symptoms of BA according to the scales of AST, ASO and quality of life 502280. However, a three-month course of treatment with the use of an ultrafine aerosol of beclomethasone dipropionate, tiotropium bromide through a modern technical device Respimat, with a long-acting B2-agonist formoterol and a 10-day inhalation application / mucolytic acetylcysteine, led to the clearing of the tracheobronchial tree from thick sputum and the targeted delivery of anti-inflammatory and broncholytic drugs means in the small parts of the respiratory tract, contributed to the reduction of BA symptoms and improvement of disease control in patients of the HER group. Thus, the total amount of points for AST increased in the main group from (14.34-1.3) to (20.3:50.8) points (p«0.05), the score according to the ASO questionnaire decreased from (2.3 :2-0.2) to (1.1320.1) points (p«0.05), which indicated an improvement in the control of asthma symptoms and a reduction in exacerbations. The indicator of the symptom score according to the questionnaire of the quality of life of St. George's Hospital decreased from (71.4x55.6) points to (51.325.0) points, p«e0.05, which indicated an improvement in the quality of life of patients.

But the individual domains of the activity limitation questionnaire, activity limitation, and the total score did not reliably change.

When examining the indicators of the function of external breathing in the studied patients of both groups before the start of treatment against the background of moderate obstructive disorders (EEM;: in the control group it was (50.6:-16.3) 95 and in the main group (51.5:2-16 ,3) 95 of the appropriate) significant violations were determined at the level of medium and small bronchi: MEE5o and MERg25 were, respectively, (34.3226.1) 95 and (33.3:223.4) 95 in the control group and (28.9: 4.5) 95 and (19.1х2.9) 95 in the main group (see table

From 3). EEM growth. in the sample with a bronchodilator in the control group was (13.0--2.6) 95, and in the main group (21,024.7) 5, which met the criteria for violation of FZD in patients with BA - rapid reversibility of bronchial obstruction (EEM:»12 95 (or»200 ml)).

After 3 months, on the background of treatment according to the proposed method, during the study of spirometry indicators in patients of the main group, an improvement in patency at the level of small bronchi (MERE:ho, MERE") and the ratio of REM/EMS was determined. Thus, МЕР5о increased in the main group from (28.9:4.5) 95 to (41.64.2) 95, p«e0.05, МЕР» - from (19.15-2.9) 95 to ( 27.6:2.6) 95, p«e0.05 and REEM/EMUS from (67.23.5) 95 to (76.1x2.3) 965, p«0.05, which indicated improvement of bronchial patency at the level of small bronchi and reduction of fixed bronchial obstruction. No reliable dynamics of the studied indicators were observed in the control group.

Table C

Spirometry indicators in patients with BA before and after treatment (Met)

Control group (p-15) Main group (p-15

Indicators: I - - - I 77.5x21.3 79.0x22.0 65.9x241 69,945.5

EMC, 95 83.2526.8 80.5:522.9 57.254.6 66.7-5.2

EEM., 96 50.6-16.3 59.4522.9 51.554.7 56.5526.1

EEMI/EMC, 9o 66.41 7.8 61.4-14 6 67.253.5 76.152.37

RERG»5, up to 64.2528.7 64.2523.3 60.8-6.2 64.457.0

MAYOR »5, 90 41.8:28.5 40.4525.8 42.457.5 54.828.9

MAYOR Beau, 90 34.3526.1 32.3223.4 28.954.5 41.654.27

MER»5, 90 33.3523.4 30.9518.9 19.122.9 27.652.67

Note. " - a statistically significant difference between the indicator before and after treatment (p<0.05).

Improvement of bronchial patency contributed to increased tolerance to physical exertion and decreased shortness of breath (see Table 4).

Table 4

Results of the b-minute walk test in patients with BA before and after treatment (Mat)

Control group (n--15) Main group (n-15

Indicators I I - I - -

Assessment of shortness of breath on a scale of 2.203 2.1x0.3 2.5:0.3 1.5x0y

Debt before the test, points before the test, 95 95,320.9 95,930.5 95,930.8 97,150.3

The number of meters traveled 305.4278.8 307.6577.4 266.3516.2 312.0514.47

Assessment of shortness of breath on a scale 3.850 340.5 410.3 310.37

Debt after the test, points after the test, 95 95,120.6 95.5:20.4 95.7-0.3 95,920.3

Note 1. 7" statistically significant difference in the indicator before and after treatment, p«e0.05.

In patients of the main group, the distance covered by patients in 6 minutes increased by 45.7 meters from (266.3-16.2) m to (312.0:14.4) m, p«0.05. In the control group, the distance covered remained almost at the initial level. Shortness of breath according to the Borg scale in the main group decreased before the test from (2.5:20.3) points to (1.5:20.1) points, re«e0.05 and after the test - from (4.120.3) points to (3.1:0.3) points, p«0.05, while it remained unchanged in the control group.

Improvement in asthma control and reduction in bronchospasm led to an improvement in quality of life in patients in the main group, as evidenced by a reduction in the symptom score on the St. George's Hospital Quality of Life Questionnaire (see Table 2).

As a result of the conducted studies, it was established that the use of standard basic drug therapy of BA did not affect the dynamics of clinical symptoms, improvement of quality of life, improvement of indicators of the function of external breathing, tolerance to physical exertion in patients with BA with neutrophilic type of inflammation, i.e., the treatment turned out to be ineffective, which was noted by both the doctor and the patients. At the same time, there were no compliance violations.

The appointment of inhaled ultrafine glucocorticosteroid according to the severity of the disease, tiotropium bromide through the modern technical device Respimat in standard therapeutic doses, formoterol 12 mcg twice a day and inhalation of 1095 acetylcysteine solution using a nebulizer for 10 days resulted in positive dynamics of clinical symptoms of BA, improvement of indicators of the function of external breathing and tolerance to physical exertion, improvement of quality of life, as a result of which the effectiveness of treatment of this category of patients increased.

At the end of the studied course of treatment, an assessment of the effectiveness and tolerability of both treatment regimens was carried out. Data on the assessment of the effectiveness and tolerability of treatment by both the doctor and the patient were taken into account. When evaluating the results of the complex treatment, it was determined that in the control group, 13 (86.7, 95) patients did not notice the effect of the treatment, and in the main group, only 1 patient did not notice an increase in the efficiency of the treatment. At the same time, the research doctor did not find positive dynamics of clinical symptoms of AD, as well as functional indicators according to the selected research methods in 12 (80.0 9o) patients of the control group and in 1 patient of the main group (see Table 5).

Table 5

Evaluation of effectiveness and tolerability of 2 methods of complex treatment of patients with BA (Significant improvement | 0 /|0.0323.25| 0 |0.0323.25 8 )|53,3.12,9| 7 46.7212.9 (Slight improvement | 2 )/13.3:x85.8| With |20.0510.3 6 Sh|40.0512.6| 7 46.7-12.9 improvement

Deterioration 0 002149) 0 | boho 0 |00-149| 0 (014.9

Note. " - statistically significant difference in the indicator between observation groups (re0.05).

In 14 (93.3)95 patients of the main group, the treatment was considered effective - it was positively evaluated by both the doctor and the patient, while positive dynamics of both clinical symptoms of BA and functional indicators were observed. Significant improvement was noted by 8 (53.3 Ob) patients and insignificant by 6 (40.0 95). The doctor noted significant improvement in 7 (46.7 95) patients and minor improvement in 7 (46.7 95) patients.

In the control group, the treatment was considered effective by only 2 (13.3 95) patients and was evaluated positively by the doctor in 3 (20.0 9o) patients.

No compliance violations were noted during the complex treatment.

The tolerability of treatment was evaluated positively by both patients and doctors. All patients tolerated the studied courses of therapy well, none of them experienced adverse events during the studied period.

The conducted studies established that the appointment of patients with BA with neutrophilic type of inflammation as the basic therapy of ultrafine-dispersed inhaled glucocorticosteroid according to the severity of the disease, tiotropium bromide through a modern technical device Respimat in a standard therapeutic dose, formoterol 12 mcg twice a day and inhalation use of acetylcysteine 1095 solution using nebulizer once a day for 10 days led to positive dynamics of clinical symptoms of BA, improvement of indicators of the function of external breathing and tolerance to physical exertion, improvement of quality of life, as a result of which the effectiveness of treatment of patients with BA with neutrophilic type of inflammation was 93.3 Ob.

Thus, in contrast to the closest analogue, the advantages of the claimed method are: achievement of clinical and functional efficiency in 93.3% of patients; a statistically significant increase in the value of AST from (14.3:-1.3) to (20.3:20.8) points (р«е0.05), a decrease in the ASO questionnaire score from (2.3х0.2) to ( 1.1240.1) score (p«e0.05), which indicates the improvement of control over BA symptoms and reduction of exacerbations; a clinically significant decrease in the symptom score from (71.42-5.6) points to (51.325.0) points, p«e0.05 according to the results of the quality of life questionnaire of St. George's Hospital, which indicates an improvement in the quality of life of patients;

statistically significant increase of MER»o from (28.9:4.5) 95 to (41.654.2) 95, p«0.05, MER» - from (19.122.9) 95 to (27.6:2.6) ) 96, p«0.05 and EEM/EMS from (67.2:3.5) 95 to (76.1x2.3) 95, p«0.05 after 3 months of complex treatment, which indicates an improvement in bronchial patency at the level of small bronchi and reduction of fixed bronchial obstruction; a statistically significant increase in the number of meters passed by the EMMUT from (266.3x416.2) m to (312.0214.4) m, p«0.05, a decrease in shortness of breath according to the Borg scale before the test from (2.5:-0.3 ) m to (1.5:0.1) m, p«e0.05 and after the test - from (4.1240.3) m to (3.150.3) m, p«0.05, which indicates an increase tolerance to physical activity; complex therapy according to the claimed method was well tolerated by patients and was not accompanied by the development of side effects.

The proposed method is easy to use and can be widely used in pulmonology and therapeutic practice.

Claims (1)

USEFUL MODEL FORMULA The method of treatment of patients with bronchial asthma with a neutrophilic type of inflammation, which consists in the appointment of an inhaled glucocorticosteroid and a long-acting beta-2 agonist according to the severity of the disease, which is characterized by the use of an ultrafine-dispersed glucocorticosteroid, tiotropium bromide through Respimat in standard therapeutic doses and inhaled using a nebulizer 10 95 acetylcysteine solution once a day for 10 days.