RU2533845C1 - Method for differentiated immunomodulatory therapy of chronic tonsillitis and/or hypertrophy of palatine tonsils in preschool children - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: pathogenetic treatment of chronic tonsillitis and/or hypertrophy of palatine tonsils in preschool children suffering from lymphoproliferative syndrome is ensured by the palatine tonsils debridement. An interleukin-1β(IL-1β) level is measured in the palatine tonsils washing. If the measured value is less than 5.8 pg/ml, recombinant interleukin-1β (IL-1β) is to be administered orally by phonophoresis with the use of the Tonsillor MM apparatus. Two courses of 10 procedures every 14 days are performed. The clinical effectiveness is assessed if observing a positive dynamics of IL-1β measured in the palatine tonsils washing 17 and 41 days after the beginning of the immunomodulatory therapy.

EFFECT: higher clinical effectiveness ensured by the differentiated selection of children for carrying out the immunomodulatory therapy, reducing a rate of infectious involvements of the palatine tonsils in the declared group of patients by the pathogenetically reasoned application of recombinant IL-1β.

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Description

The invention relates to medicine, namely to otorhinolaryngology and immunology, and is intended for the pathogenetic treatment of chronic tonsillitis and / or hypertrophy of the tonsils in preschool children.

More than 80% of all respiratory diseases in children are accompanied by damage to the mucous membrane of the pharynx and lymphoproliferative ring. Chronic inflammation of the tonsils is accompanied by inhibition of nonspecific factors of the body's natural resistance, a violation of both the humoral and cellular parts of the immune system.

In outpatient practice with the aim of increasing the body's resistance, non-specific immunostimulating herbal products based on echinacea, ginseng, lewzea, chamomile, garlic, propolis and pantocrine are widely used. However, the use of systemic immunomodulatory drugs in pediatrics without taking into account the points of application of the drug and the pathogenetic basis of the disease can lead to an imbalance of the immune system and worsen the course of the disease.

As alternative methods of immunomodulating therapy for chronic tonsillitis, methods of local exposure to the tissue of the lymphoid ring using various physical and instrumental methods, including rectangular high-frequency pulses, as well as the delivery of drugs to the tissue of the tonsils using phonophoresis, have been acquired.

So known is a method of treating chronic tonsillitis, based on the introduction into the tissue of the tonsils with ultrasound of the drug "Malavit" (Pat. 2152773 Russian Federation: IPC A61H 23/00, A61N 1/30. Method for the treatment of chronic tonsillitis. - No. 99102873/14 ; Declared Feb. 18, 1999; Pub. Jul. 20, 00). The known method allows you to combine both physical factors - low-amplitude effects on the tissue of the tonsils, and the pharmacological effects of "Malavita" on the lymphoid tissue of the tonsils. The main disadvantage of this method is the lack of criteria for selecting patients for this procedure, which severely limits the effectiveness of the method.

There is a method of treating chronic tonsillitis using ultrasound debridement of the tonsils with the Tonsillor apparatus, where a solution of 0.1% hydrogen peroxide is used as a medicine followed by phonophoresis with interferon-1α ointment (Mishenkin N.V. et al. Use of an ultrasound device "Tonsillor" for the treatment of chronic tonsillitis. - M., 1984.). The method is based on debridement and local delivery of an anti-inflammatory cytokine into the tissue of the tonsils. The disadvantage of this method is its low efficiency and short-term effect.

Recent studies have shown that in children with lymphoproliferative syndrome and chronic tonsillitis in the palatine tonsil mononuclear cells, the level and / or functional activity of interleukin-1 beta (IL-1β) is reduced. This condition is due to the predominance of mutant homozygous and heterozygous genotypes for the SNP polymorphism of interleukin-1β (+3953, C-> T).

Therefore, as the closest analogue to the claimed method, the method of local treatment of chronic tonsillitis with recombinant interleukin-1β (beta-leukin) was selected (Brodovskaya OB A clinical and immunological evaluation of the effectiveness of local treatment of chronic tonsillitis with recombinant interleukin-1β (beta-leukin): Candidate of Medical Sciences, St. Petersburg, 2004 .-- 113 pp. ill.). In this case, patients underwent a clinical and laboratory examination before the appointment of immunomodulating therapy, and the level of concentration of cytokines in washes from palatine tonsils was also determined. Then, a course of treatment was prescribed with the Tonsillor apparatus with beta-leukin lasting 5-8 procedures. The disadvantages of this method include the fact that it can be used only for patients aged 14 to 42 years, while a course of immunomodulating therapy is prescribed to all patients without regard to their immunological status. In addition, the use of interleukin-1β in the form of a solution helps to quickly wash it out of the tissues of the tonsils and reduce the therapeutic effect.

The technical result of the invention is the differentiated selection of children for immunomodulating therapy, increasing the effectiveness of the treatment of chronic tonsillitis and / or hypertrophy of the tonsils in preschool children, reducing the frequency of infections of the tonsils due to the pathogenetically substantiated use of recombinant gel-based interleukin-1β.

It is known that the lack of interleukin-1β during antigenic stimulation leads to a disruption in the processing and presentation of the antigen to T-lymphocytes and, as a result, to a change in the priming of T-helpers towards the activation of allergic inflammation (Immunology and Allergology, edited by A.A. Vorobyov, A.S. Bykova, A.V. Karaulova // Moscow, Practical Medicine. - 2006. - 287 p.). Moreover, local and systemic allergic reactions determine not only the severity of chronic tonsillitis (compensation or decompensation), but also contribute to the development of hypertrophy of the tonsils, stimulating lymphoproliferation of the pharyngeal ring cells. Based on this, an increase in the local level of IL-1β in the palatine tonsil with its initial deficiency in preschool children with chronic tonsillitis and / or hypertrophy of the tonsils is a pathogenetically substantiated therapeutic approach. A recombinant gel-based interleukin-1β (“Kolegel”) was chosen as a therapeutic drug. Phonophoresis of cytokines at a frequency of ultrasonic vibrations of 26.5 ± 1.5 kHz leads to the penetration of the regulatory peptide into the tissue of the tonsils without gross violations of the structure of its molecule. These data served as a starting point for a new method of treating chronic tonsillitis and tonsil hypertrophy in preschool children.

To confirm the effectiveness of the proposed method, a survey was conducted of 121 children aged 5 to 7 years with chronic tonsillitis and / or hypertrophy of the tonsils II / III degree of severity. In addition, 109 conditionally healthy children of the corresponding age with sexual discreteness in the sample of the corresponding general population were examined.

The concentrations of interleukin-1β, receptor antagonist of interleukin-1, interleukin-4, tumor necrosis factor alpha and interferon-α in rinsing from palatine tonsils were studied by enzyme-linked immunosorbent assay (ELISA) on commercial kits of LLC Tsitokin in St. Petersburg in accordance with the attached instructions in the main group and in the comparison group. Lavage from the tonsils was obtained by washing the tonsils with 3 ml of physiological saline before treatment, as well as after the first and second courses of topical immunomodulating therapy. The cytokine concentration obtained in ELISA was analyzed in pg / ml.

On a sample of conditionally healthy children (n = 109), the norms of pro-inflammatory and pro-allergic interleukins in rinses from the tonsils were determined (Table 1).

Table 1 Norms of pro-inflammatory and pro-allergic interleukins in flushing with palatine tonsils in children of early and preschool age Cytokines Indicators Min Max Alpha TNF, pg / ml 0.00 7.06 Receptor antagonist IL-1, pg / ml 0.00 1246.12 IL-1 beta, pg / ml 5.80 57.16 IL-4, pg / ml 0.00 25.00 Alpha INF, pg / ml 0.00 15.23 Note: Min - the smallest value of the indicator in the study group; Max - the highest value of the indicator in the group; IL - interleukin; TNF - tumor necrosis factor; INF - interferon.

Thus, the level of IL-1β in rinses from palatine tonsils less than 5.8 pg / ml is the lower limit of the norm and, as a result, an indication for the appointment of topical immunomodulating therapy with recombinant interleukin. Combined treatment was carried out with the Tonsillor-MM apparatus, and crypts of the tonsils were sanitized before treatment, and the course of treatment included two stages of 10 procedures with a 14-day break.

To study the effectiveness of topical immunomodulatory therapy in swabs with palatine tonsils in children with hyperproliferative syndrome, the concentration of IL-1β was determined:

- before treatment,

- 7 days after the first course of treatment (17 days from the first analysis),

- 7 days after the second course (41 days after the first study of local interleukins).

Based on the data obtained, it was proved that before treatment, the average level of IL-1β in the sample of children with lymphoproliferative syndrome was low - 4.2 pg / ml (± 0.13), while the rest of the interleukin concentrations were determined within normal limits (Table. 2). The latter fact is explained by the fact that the levels of interleukins in flushing from the tonsils are quite polymorphic: from low to very high indicators, respectively, and the range of normal values is also wide.

table 2 Comparison of the pharynx interleukins before the start of the Kolegel treatment and after one and two courses of local immunotherapy using the Tonsillor-MM apparatus Cytokines Before treatment After 1 course After 2 courses p ₁ p ₂ M ± m M ± m M ± m Tumor necrosis factor-alpha, pg / ml 0.18 0.02 0.31 0.02 0.37 0,03 p> 0.05 p> 0.05 Interleukin 1 receptor antagonist, pg / ml 165.3 17.9 145.5 15.8 116.4 12.7 P <0.05 p <0.001 Interleukin-1 beta, pg / ml 4.22 0.13 4.83 0.14 5.95 0.11 p> 0.05 p <0.05 Interleukin-4, pg / ml 13.77 1.34 10.75 0.85 10.60 1,02 p <0.05 p <0.05 Interferon alfa, pg / ml 10.32 0.85 9.13 0.74 7.30 0.60 p> 0.05 p <0.05 Note: The table shows the average values obtained in a sample of patients (n = 121) with chronic tonsillitis, where M is the average value of the cytokine concentration, ± m is the average deviation error, p ₁ and p ₂ are the significance of differences in the compared groups of children after the first and the second course of treatment, respectively.

After the first course of local immunomodulating therapy, the values of the receptor antagonist interleukin-1 and interleukin-4 significantly decreased (for the receptor antagonist of interleukin-1: before treatment 165.29 ± 17.99 pg / ml and after treatment 145.46 ± 15.83 pg / ml; for interleukin-4: before treatment 13.77 ± 1.34 pg / ml and after treatment 10.75 ± 0.85 pg / ml). The average level of interleukin-1β in rinses from the tonsils after the first course of local immunomodulating therapy increased, but no significant differences were obtained.

After the second 10-day course of phonophoresis of recombinant IL-1β into the tissue of the tonsils, the dynamics of secretion of interleukins remained. Thus, the average level of the receptor antagonist of interleukin-1 decreased to 116.37 ± 12.67 pg / ml against 165.29 ± 17.99 pg / ml before treatment (p <0.001) and against 145.46 ± 15.83 pg / ml - after the first course of local immunomodulating therapy (p <0.01). The average level of local interleukin-4 decreased to 10.60 ± 1.02 pg / ml against 13.77 ± 1.34 pg / ml before treatment (p <0.05) and did not change relative to the average after the first course of immunomodulating therapy ( p> 0.05).

It should be noted that after two courses of local immunomodulatory therapy with recombinant interleukin-1β in preschool children with chronic tonsillitis and / or hypertrophy of the tonsils in the rinses of the tonsils, the average level of interferon-α significantly decreased (from 10.32 ± 0.85 pg / ml - before treatment, to 7.30 ± 0.60 pg / ml - after 2 courses of immunomodulating therapy, p <0.05). After two courses of topical immunotherapy, the average level of IL-1β significantly increased and began to reach 5.95 ± 0.11 pg / ml (p <0.05), which is higher than the lower limit of the normal value of this interleukin for swabs from the tonsils.

Thus, the topical treatment with recombinant interleukin-1β changed the composition of local interleukins in the direction of activation of processing and presentation of the antigen (increased interleukin-1β), in the direction of suppressing allergic reactions (decreased interleukin-4 and the receptor antagonist of interleukin-1) and towards the end of the inflammatory process (reduction of interferon-alpha).

Due to the fact that after 2 courses of treatment all the indicators of interleukins have changed towards normalization, we can assume that this method of treating chronic tonsillitis and hypertrophy of the tonsils has 100% signs of pathogenetic effectiveness.

Below is a method of implementing the proposed method.

In preschool children with chronic tonsillitis and / or hypertrophy of the tonsils, the level of IL-1β in the washing of the tonsils is examined. For IL-1β values below 5.8 pg / ml, topical immunomodulating therapy is carried out, for this purpose sanitation and rinsing of caseous plugs are performed using the Tonsillor-MM apparatus, after which a thin layer of gel with recombinant interleukin-1β is applied to the applicator (" Kollegel ") and conduct phonophoresis at a frequency of 26.5 ± 1.5 kHz for 30 seconds. Treatment is carried out in two courses of 10 days with a 14-day break, while after 17 and 41 days from the start of treatment, the level of pro-inflammatory and pro-allergic interleukins is monitored. At the same time, the lack of dynamics in the levels of interleukins of the tonsils indicates the lack of effect of this treatment and repeated treatment procedures - it is impractical.

Thus, the technically simple procedure of local phonophoresis “Colegel” is applied to the tonsils using the Tonsillor-MM device, a time-saving treatment method, can be used as monotherapy for chronic tonsillitis and tonsil hypertrophy.

Example 1. Child F., 5 years old, consulted an immunologist-allergist with complaints of frequent acute respiratory morbidity more than 8 times a year. Examination of the pharynx revealed hypertrophy of the tonsils of the third degree. A study of interleukins flushing from the tonsils revealed a decrease in the level of interleukin-1 beta to 4.2 pg / ml. Interleukin-4 was increased to 29 pg / ml. All other interleukin counts were normal.

After two ten-day courses of therapy with the Tonsillor-MM apparatus with Colegel, the level of interleukin-1 beta increased to 11 pg / ml, and the level of interleukin-4 decreased to 24 pg / ml.

Thus, the local immunomodulating therapy “Colegel” using the Tonsillor-MM apparatus normalized the level of local interleukins, and studies of the palatine tonsil 5 months after the therapy showed a decrease in its size. The frequency of respiratory diseases in six months did not exceed 2 times.

The method was tested on the basis of ZAO Modern Medical Technologies for 121 children of preschool age (5-7 years), suffering from hypertrophy of the tonsils and / or chronic tonsillitis. All patients received a 30-second phlegophoresis of "Kolegel" on the tonsils using the apparatus "Tonsillor-MM" course in 10 sessions. Of these, two patients received phonophoresis courses. All children underwent phonophoresis without complications. The effectiveness of local immunomodulating therapy, according to the local cytokine status, was observed in 119 children, which amounted to 98.34%. The recurrence rate of chronic tonsillitis decreased in 119 children by 2 times.

Claims (3)

1. A method of differentiated immunomodulatory therapy of chronic tonsillitis and / or hypertrophy of palatine tonsils in preschool children, including a study of the level of cytokines in swabs of crypts of the tonsils, debridement of the tonsils and local administration of recombinant interleukin-1β (IL-1β) using phonophoresis apparatus Tonsillor-MM ”, characterized in that the treatment of children with lymphoproliferative syndrome is carried out with a decrease in the level of interleukin-1β in rinses from the tonsils less than 5.8 pg / ml, while two courses of about 10 procedures with a 14-day break, and the effectiveness of therapy is evaluated on the basis of the positive dynamics of the level of IL-1β, determined in rinses from the tonsils after 17 and 41 days from the start of immunomodulating therapy. 2. The method according to claim 1, characterized in that "Kollegel" is selected as the drug from the group of recombinant interleukins-1β. 3. The method according to claim 1, characterized in that the phonophoresis "Kolegel" is carried out for 30 seconds at a frequency of ultrasonic vibrations of 26.5 ± 1.5 kHz.