Vol 19, No 1 (2022)

Russian science has suffered a heavy loss.

On March 11, 2022, Rakhim Musaevich Khaitov died. Rakhim Musaevich Khaitov was an Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Honored Scientist of the Russian Federation, Scientific Director of the National Research Center — Institute of Immunology Federal Medical-Biological Agency of Russia, Chief Allergist-Immunologist of the Ministry of Health of Russia, member of the Bureau of the Department of Physiology and Fundamental Medicine RAS, Head of the Department of Clinical Allergology and Immunology, Moscow State Medical University named after A.I. Evdokimov of the Ministry of Health of Russia.

The participation of an allergic reaction and its main constituent elements (IgE, mast cells/basophils, and eosinophils) in maintaining various types of homeostatic function is becoming increasingly obvious. This is illustrated by the example of such evolutionary acquisitions as antiparasitic and antitumor types of resistance of the organism of highly organized animal species. All three participants in the allergic reaction are involved in the preservation of the mechanisms of these forms of homeostasis, from which follows the frequently expressed fear that prolonged maintenance of the blockade of the activity of these participants. Even more so, their elimination may be accompanied by undesirable consequences in the form of suppression of specific homeostasis mechanisms, which should be taken into account when introducing into clinical practice of new groups of antiallergic drugs focused on long-term and even lifelong use.

The appeal to the development and use of antiallergic agents that eliminate the participants in the allergic response, acquired in the course of evolution and performing homeostatic functions, rather stems from the hopelessness of the situation in the treatment of patients with a severe course of the disease who are resistant to other methods of antiallergic therapy. Understanding and acceptance of such a concept in the scientific community can serve as an impetus for the improvement of existing and the creation of fundamentally new and strategically justified methods of preventing not the very possibility but the need for the development of an allergic response. Today, such methods are the restoration of the usefulness of barrier systems, allergen-specific immunotherapy, and use of natural methods to limit, stop, and reverse development (resolution) of an allergic reaction.

BACKGROUND: Hereditary angioedema due to C1-inhibitor deficiency is a rare disease caused by deficiency and/or low functional activity of C1-inhibitor. The main symptom of hereditary angioedema is recurrent angioedema in various localizations, which can lead to temporary incapacity or even death.

AIM: To study the features of the clinical course of the disease in patients with hereditary angioedema from the registry of the National Research Center (NRC) “Institute of Immunology” of the FMBA of Russia, identify the predictors of life-threatening angioedema and the need for long-term therapy, and compare the features of the course of the disease in different groups of patients.

MATERIALS AND METHODS: A total of 194 patients from NRC Institute of Immunology FMBA of Russia registry from 124 unrelated families with a diagnosis of hereditary angioedema with C1-inhibitor deficiency, confirmed in accordance with accepted diagnostic standards, were enrolled in the retrospective descriptive study.

RESULTS: Overall, 194 patients were included in the analysis (70% female and 30% male). The mean age of patients was 35±17 years. Moreover, 89% and 11% of patients had hereditary angioedema types I and II, respectively. The mean age of clinical onset was 11±9 years. Ninety-eight percent of participants had a history of at least one episode of peripheral angioedema, 86% experienced abdominal attacks, 86% experienced facial swellings, and 49% experienced laryngeal attacks. The mean diagnostic delay was 17.5±11.24 years. The older the patient is, the more possible laryngeal attacks (p <0.001), facial and neck swellings (p <0.001), and abdominal attacks are (p=0.031). No significant differences in clinical features were noted between men and women.

CONCLUSIONS: There is a problem of a long diagnostic delay of hereditary angioedema in Russia. As a consequence of the study, we have identified a number of warning criteria of hereditary angioedema: the presence of a family history, a combination of recurrent angioedema and abdominal attacks, and the onset of angioedema and/or abdominal attacks in early childhood. The existence of such criteria will make it possible to optimize the diagnosis of hereditary angioedema. Moreover, we have identified the risk factors for the development of life-threatening angioedema: the patient’s age (the older the patient, the higher the risk) and a history of angioedema of the face and neck.

BACKGROUND: Bronchial asthma is a chronic inflammatory disease of the airways, the development of which is based on genetic predictors associated with the differentiation and functioning of T-helper (Th) cells. Polymorphisms in the genes of cytokines involved in the regulation of the direction of the Th cell-mediated immune response are risk factors for the development of the disease and the realization of various phenotypes of bronchial asthma.

AIM: To study of the structure and frequency of occurrence of single nucleotide polymorphisms of cytokine genes with an assessment of the risk of various phenotypes of bronchial asthma in children.

MATERIALS AND METHODS: In this case–control study, 250 children were examined, including 150 children with a verified diagnosis of bronchial asthma (including 75 children with virus-induced and 75 children with allergen-induced disease phenotypes) and 100 sexually comparable healthy peers. The children underwent a comprehensive general clinical and allergological examination, genotyping, structure analysis, frequency of occurrence of cytokine gene polymorphisms, and calculation of the odds ratio of the risk of developing different bronchial asthma phenotypes. DNA samples isolated from peripheral venous blood were used as material for molecular genetic analysis. The following mutation points were selected: IFN-γ (T-874A), IL-4 (C-589T), IL-6 (C-174G), IL-17A (G-197A), and TNF-α (G-308A).

When processing digital data, we used the methods of descriptive, parametric, and nonparametric statistics of the Statistica 10 program, comparison of unrelated groups by qualitative characteristics, and assessment of the correspondence of the distributions of genotypes to the expected values at the Hardy–Weinberg equilibrium. The frequency distributions of genotypes and alleles in two subpopulations were analyzed using the chi-square test (χ2).

RESULTS: A comparative analysis of the frequencies of alleles and genotypes of cytokines of various Th profiles with the definition of features in allergen-induced and virus-induced phenotypes of the disease revealed the predominance of homozygous genotypes IFN-γ (A-874A), IL-4 (T-589T), IL-6 (G-174G), IL-17A (A-197A), and TNF-α (A-308A) in children with bronchial asthma, and in healthy peers, IFN-γ (T-874T), IL-4 (C-589C), IL-6 (C-174C), IL-17A (G-197G), and TNF-α G-308G were prevalent. Heterozygous genotypes IL-4 (C-589T), IL-6 (G-174C), IL-17A (G-197A), and TNF-α (G-308A) were found in children with bronchial asthma more often than in healthy peers, with the exception of the IFN-γ genotype (T-874A). In children with the virus-induced bronchial asthma phenotype, the presence of the IL-4 (C-589T) mutant allele was found in 30.67% of cases with an odds ratio of 19.3 (95% CI, 11.23–33.31). When carrying the mutant A-genotype IFN-γ (T-874A), the odds ratio of the risk of developing the disease reflected a high degree of probability of the virus-induced bronchial asthma phenotype (OR, 5.11; 95% CI, 3.18–8.23). Carriage of homozygous genotypes IL-6 (G-174G) and IL-17A (A-197A) determined an increased risk of developing allergen-induced bronchial asthma (OR, 2.71; 95% CI, 1.73–4.18, and OR, 0.51; 95% CI, 0.32–0.71, respectively). Among children with bronchial asthma, a statistically significant increase was noted in the incidence of the functionally unfavorable genotype A308A of the TNF-α gene, and the odds ratio reflects a 2.6-fold increase in the risk of developing a virus-induced bronchial asthma phenotype (χ²=18.66; p=0.017; OR, 2.60; 95% CI, 1.67–4.01).

CONCLUSIONS: As a result of the study, significant differences were determined in the structure and frequency of occurrence of cytokine gene polymorphisms in children with allergen and virus-induced bronchial asthma, depending on the realized phenotype of the disease. Carriage of mutant alleles IFN-γ (A-874A), IL-4 (T-589T), IL-6 (G-174G), IL-17A (A-197A), and TNF-α (A-308A) can be characterized as genetic predictors of bronchial asthma, for the implementation of the virus-induced phenotype, and the odds ratio is higher in the presence of mutant alleles IFN-γ (A-874A), IL-4 (T-589T), and TNF-α (A-308A), for the allergen-induced phenotype of the disease — IL-6 (G-174G) and IL-17A (A-197A).

Allergic rhinitis is one of the most common diseases (~10%–24% of the population experience allergic rhinitis in the Russian Federation) occurring in the population regardless of sex and age. The urgency of the problem is associated with an increase in the number of patients and the fact that allergic rhinitis is considered a risk factor for the development of asthma.

The clinical allergic rhinitis guideline aimed to optimize patient care, up-to-date information about the epidemiology, and disease etiology and pathogenesis. Herein, we present the actual data about the allergic rhinitis classification and its clinical signs and modern (clinical, laboratory, and instrumental) and differential diagnostics. Studies reported allergic rhinitis treatment, rehabilitation, and prevention in the guidelines. The authors describe in detail the existing healthcare options for patients with allergic rhinitis, diagnostic features, and care in partial groups of population (children and pregnant women). The clinical guidelines are recommended for medical doctors (independently from qualification), under- and postgraduate students, universities tutors, residents, and researchers.

The seasonality of exacerbations of pollinosis, a widespread pathology in the pediatric population, depends on the timing of flowering plants in the patient's region of residence. With age, the symptoms of pollen allergy become more pronounced, pollen bronchial asthma develops, the effectiveness of symptomatic therapy decreases, the spectrum of causally significant allergens expands, which requires personalized effective treatment methods.

Cases of allergen-specific immunotherapy in patients with type 1 diabetes mellitus are rare, therefore they deserve special attention. In addition to a thorough assessment of the safety of the therapy in relation to the course of diabetes, it is necessary to pay attention to the advantages of sublingual immunotherapy, in particular, a significant reduction in the need for pharmacotherapy of exacerbations. The ultimate goal of sublingual immunotherapy is a persistent drug-free remission of an allergic disease for several years after the end of the course of treatment.

A description of a clinical case of a pediatric patient (boy, age 12 at the start of observation) with pollen allergy (allergic rhino-conjunctivitis to grass pollen) in combination with diabetes mellitus type 1 is presented. Initiation criteria of allergen-specific immunotherapy (clear seasonal peak of exacerbations, high and concordant data of allergotesting in vivo and in vitro, progredient course of pollinosis clinical signs during years before allergen-specific immunotherapy was started) discussed in case of comorbid patient. Possible risks were analyzed and absence of diabetes mellitus as contraindication for immunotherapy stated. The patient underwent 2 pre-coseasonal courses of sublingual immunotherapy with grass pollen allergens in 2020 and 2021 with a pronounced positive effect. In the second year of treatment, remission of the disease was achieved: almost complete absence of hay fever symptoms in the flowering season of 2021, no progression of the disease, a significant decrease in the need for therapy to relieve symptoms. During the course of therapy, the patient did not show any deterioration in the course of diabetes mellitus, and number of days with extra dosage of insulin not caused by dietary provocation, decreased. The patient is being monitored, and the third course of sublingual immunotherapy with grass pollen allergens is started.

Thus, allergen-specific immunotherapy with a sublingual method of administration of the drug is safe and effective in the treatment of pollen allergy, is recommended for outpatient use in patients from the age of five, is indicated especially for patients with a progressive nature of the disease when it is impossible to protect it from contact with an allergen or with insufficient effectiveness of standard pharmacotherapy.