ASSOCIATION BETWEEN ATOPIC AND NON-ATOPIC DISEASES AT CHILDREN

SE «Dnipropetrovsk medical academy of Health Ministry of Ukraine» 1 Department of pediatrics 1 and medical genetics Manuilivsky ave., 29a, Dnipro, 49023, Ukraine SE «Dnipropetrovsk medical academy of Health Ministry of Ukraine» 2 V. Vernadsky str., 9, Dnipro, 49044 Ukraine e-mail: dsma@dsma.dp.ua MI «Dnipropetrovsk city clinical hospital N 5 of “DRC”» 3 I. Akinfeyeva str., 5, Dnipro, 49027, Ukraine MI «Dnipropetrovsk city clinical hospital N 5 of “DRC» 4 Consultation-diagnostic department Shevchenko str., 6a, Dnipro, 49044, Ukraine ДЗ «Дніпропетровська медична академія МОЗ України» 1 кафедра педіатрії 1 та медичної генетики (зав. – д. мед. н., проф. О.Є. Абатуров) пр. Мануйлівський, 29а, Дніпро, Україна ДЗ «Дніпропетровська медична академія» МОЗ України» 2 вул. Володимира Вернадського, 9, Дніпро, 49044, Україна КЗ «Дніпропетровська міська дитяча клінічна лікарня No 5 «ДОР» 3 вул. І. Акінфеєва, 5, Дніпро, 49027, Україна КЗ «Дніпропетровська міська дитяча клінічна лікарня No 5 «ДОР» 4 Консультативно-діагностичне відділення вул. Шевченка, 6а, Дніпро,49044, Україна


18/ Том XXIІI / 1 ч. 1
Atopic diseases at children (AlD) include atopic dermatitis (AD), seasonal allergic rhinoconjunctivitis (SARC), perennial allergic rhinitis (PAR) and bronchial asthma (BA). Non-atopic allergic diseases are mainly represented by acute and recurrent urticaria (AcU/RecU) and Quincke edema (QE). In recent years, the prevalence of AlD has increased and currently affects about 20% of the world's human population [9]. Recently there had been developed the concept of atopic march (AM) from early childhood to school age and adolescence [3]. The mechanism of AM development is always an individual combination of risk factors and represents a linear progression of AD-SARC/PAR-BA. The essence of the combination is the interaction of genetic and environmental factors. AM development can take place by atopic mechanisms with/or without environmental triggers that will lead to transformation AD into the respiratory forms of AlD [4]. Thus, according to van der Hulst et al., the frequency of AD that began in early childhood into BA does not exceed 30% [8]. In view of the strong family predisposition for AlD associated with the genotype, the gradual decrease in exposure to the heterogeneity of microorganisms over the past decades has led to immune dysregulation in such populations, increasing the incidence of hypersensitivity -AlD-and autoimmune diseases [5].
The main mechanism of pathogenesis of AlD in most patients is IgE-mediated allergic inflammation. At the same time, in 10-30% of patients, elevated IgE levels are not recorded. This confirms the hypothesis of the complex nature of AD and other AlD represented by other immune and non-immune (pseudoallergic) mechanisms of inflammation. Triggers of non-allergenic nature, which are most often recorded as causative of AD, are dietary abuse, uncompensated psycho-emotional stress, tobacco smoke, xenobiotics, industrial pollutants. Dietary abuse separately and in combination with uncontrolled use of xenobiotics lead to dyspepsia syndrome in the intestine, which is the trigger mechanism for the AcU/RecU and QE. The main nosological forms of the pathology of the digestive system are functional disorders of the biliary system (FDBS) and reactive pancreatitis (RP).
Despite the large number of studies on AD comorbidities that provide data for analyzing AD complications, such as neurotic disorders, sleep disturbances, bleeding gums, toothache, etc., but not there is analyzed comorbid states from the digestive system, which can be internal triggers of AD development in particular and AM in general [2,6]. Currently, the main internal factors for triggering AD with the risk of transformation in BA is food sensitization and mutation of the filaggrin gene [7]. Although some studies attempt to establish a causal relationship between AlD and the change in the qualitative and quantitative composition of the gut microbiome [10], there is still currently little data on the association between AlD, FRBS and RP.
The purpose of the study was to determine associations between atopic (AD, SARC/PAR, BA), non-atopic (AcU/RecU, QE) allergic diseases and diseases of the digestive system (FRBS and RP) at children from 0 to 18 years old.
Statistical processing was carried out using the licensed software Statistica v. 6.1 for Windóws (serial number AGAR909E415822FA). In the study of association relationships, the Spearman rank association ratios (R) were used with an estimate of their statistical significance by Student's criterion (t). The critical significance level of the association ratio (plevel) was taken as <0.05. The presence of an association between different diseases, sensitization, or other comorbid states has been evidenced by positive association ratio (direct relation), the absence of interaction -by a negative coefficient. The association strength was evaluated as weak at | R |<0.3, moderate -at 0.3≤| R |≤0.7, strong at | R |>0.7 [1].

RESULTS AND DISCUSSION
According to the results of the association analysis, the peculiarities of interactions between etiological factors, comorbid conditions and other factors within various AlD at children were established.
Atopic dermatitis. Analysis of the combination of AD with other parameters of the disease confirms the absence of correlation between the urticaria and AD as nosologies with different mechanisms of development (table 1). At the same time, a direct association between AD as the main manifestation of FA at children and digestive system (DS) diseases, in particular, FDBS and RP, had been established. This evidences the role of syndromes of dyspepsia and maldigestion, which are characteristic to FRBS and RP, and exacerbation of AD at children. Acute/recurrent urticaria Particular attention should be paid to urticaria, since combining different mechanisms of pathogenesis, it does not compose AM. Thus all AM-nosologies -AD, SARC, PAR, BA -did not have a significant association to AcU/RecU. This allows us to confirm the fact that episodes of AcU/RecU do not accelerate the course of AM, do not cause the transformation of one form AM to another. In particular, it concerns AD, which, being an allergic disease affecting the skin, originates from another mechanism of pathogenesis -a direct association to ACU/RECU, according to the results of our study, is absent (table 2). The absence of general mechanisms of pathogenesis was also confirmed within studying the etiological spectrum of AcU/RecU -a significant direct association was determined only with food, drug and/or insect venom allergens -the traditional etiological spectrum in patients with AcU/RecU. In this case, there was no direct association with the traditional AM-nosologies groups of allergenspollen, HDM and petsʼ epidermal.
We have determined the reverse association of AcU/RecU with the age of sick children, which indicates a higher incidence of urticaria at younger ages. Thus, the prevalence of ACU/RECU among children under 6 years of age is 20.87% (48 out of 230 cases), at the age of 6-11 years -9.12% (26 out of 285 cases), at the age of 12-18 years -8.73% (24 out of 275 cases) at p<0.001 compared with pre-school children. A direct association was established between AcU/RecU and QE which often interact with each other. It is necessary to note the confirmation of hypothesis of the association of disorders of the digestion process and urticaria, which demonstrate approximately identical strengths of direct associations between the FDBS, RP, and the general level of morbidity of the DS and AcU/RecU.

Quincke edema (QE)
Pathogenetically associated to AcU/RecU is a Quincke edema, which often occurs at the same time with urticaria. According to the correlation analysis, there is a positive correlation between QE and urticaria, as well as with food and insect venom senssitization which confirms the hypothesis about the non-atopic nature of QE mechanisms (table 3). The presence of QE reverse association with age points to the danger of this nosology -more often it occurs at young children (up to 6 years old). The high level of mucosal vascularization and the small diameter of the sub-vocal space of the vocal box space leads to a high risk of occurrence of QE in larynx, which is a life-threatening condition. There was no reliable direct association with pollen, HDM or epidermal sensitization. The etiological spectrum was represented by food and insect venom allergens, which confirms the emergence of QE after alimentary abuse and insect bites.

Seasonal allergic rhinoconjunctivitis (SARC)
According to the association analysis, it is established that SARC has a direct association with the age of the studied children -it`s frequency increases with age (table 4). Thus, the prevalence of SARC among children under 6 years of age is 30.43%, at the age of 6-11 years it is 55.44%, at the age of 12-18 years, it is 57.09% at p<0.001 compared with the 150 children of preschool age. A strong direct association exists between pollen sensitization and SARC (R=0.831, p<0.001), which proves the dominance of allergy to plant pollen in the etiology of SARC as the most common form of pollinosis. Unexpected there was to be determined the association between the sensitization to the HDM (n Der p1, n Der p2), the epidermal allergens of the cat, the dog and the bird feathers and SARC -its value is 10 times less than the association with pollen sensitization, but the direct nature of it indicates the presence of patients with combined forms of allergy: the pollen one that causes SARC and to mites of household dust, cats, dogs and birds that cause the PAR. Controversial data have been obtained regarding the association of BA, SARC and PAR -there was a significant negative association between them, that is, pollinosis in SARC format had been identified more often separately from the PAR and BA of a non-pollen etiology. At the same time, a direct asociation had been established between SARC of pollen etiology and the emergence of a bronchial obstruction syndrome (R=0.235, p<0.001), which indicates the transformation of the allergic rhinoconjunctivitis into BA in the course of AM at children. Concerning the combination of SARC and DS impairments, then the negative associations ratios indicate that there are no such connections.

Perennial allergic rhinitis (PAR)
Analyzing the data on the association of PAR with other factors, we have received a direct one with age -the incidence of PAR is increasing with the increase in the age of children as the form of AM progression (table 5). The etiological spectrum of the PAR was represented by reliable direct associations with HDM, the cat, dog and birds feathers allergens, and fungi of Alternaria, Aspergillus genera placed in this roster in order of decreasing the association strength.
Unlike SARC, a frequent combination with BA (R=0.145, p<0.001), as well as with inflammatoryproliferative diseases of the nasal cavity (adenoid vegetations, gaimoritis/ethmoiditis, etc.) is characteristic for PAR. Thus, it can be stated that the transformation of the PAR, as a chronic inflammation of the mucous membrane of the nose, not only into BA in the AM course, but also in the ENT pathology. The negative association between PAR and ARVI (acute rhinopharyngitis and bronchitis) and the pathology of the DS (FDBS) indicates that there is no significant association between the PAR and these nosologies at s separate patient.
Bronchial asthma is the final stage of AM, therefore, the establishment of its associations with other nosologies of AM is important for developing the methods of treatment and prevention of AM in children. The analysis of data in table 6 showed a direct association between the age of children and the incidence of asthma (R=0.284, p<0.001). That is, this diagnosis is more common in schoolchildren and adolescents -in 14.35% than at children under the age of 6 years -in 25.26% of children 6-11 years old (p<0.01) and in 42.91% of children aged 12-18 years old (p<0.001 in comparison with other age 151 18/ Том XXIІI / 1 ч. 1 groups), confirming the hypothesis of asthma as the final stage of AM development. The etiological spectrum of asthma was mostly represented by HDM-allergens. Among all the forms of AlD that we had studied at children, a reliable direct BA association was established only with the PAR (R=0.145, p<0.001), while other AM nosologies (AD, SARC) did not demonstrate a direct association with asthma. Controversial data had been found on association with other nosologies. Thus, ARVIs, which are the main trigger of asthma at preschoolers (Okhotnikova et al., 2011), did not show a significant direct association with asthma; instead, ENT pathology (tonsillitis and / tonsils hypertrophy) had a direct asso-ciation with BA. In our opinion, this is due to the sensitizing effect of bacterial cells, the concentration of which increases as a result of chronic carrying in the mucous membranes of the oral cavity within these nosologies. The study results showed different formats of associations between AM nosologies and other AlD and comorbidities. Thus, direct association between AD, FDBS and RP points to dyspepsia syndrome as the main etiopathogenetic mechanism of development of the food intolerance and, as a result, its transformation into food allergy (FA). SARC was found more frequently in older children (6-11 years old, 12-18 years old) and had a significant direct association with plants` pollen as the main etiological factor for pollinosis. At the same time, weak, but significant associations of SARC with HDM and pets` epidermal allergens appear to be interesting, indicating the association of SARC and PAR at the same patient as a consequence of co-sensitization in the course of chronic allergic inflammation with hyperproduction of general and specific IgE. The direct correlation of SARS with bronchial obstruction syndrome as a complication of acute bronchitis at children points at a tendency for the transformation of atopic disease into BA in the form of descending the inflammatory process from the mucous membranes of the upper airways and the eye bulb down to the mucous membranes of the bronchi. The continuation of AM goes on in the form of a PAR, the frequency of which increases with age, and the etiological spectrum is confirmed by sensitization to typical allergen groups -HDM, pets`epidermal allergens and fungal major allergens Alt a1(mold genera Alternaria alternata). Interestingly, the direct association of PAR had been found not only with the BA, but also with proliferative-inflammatory diseases of the nasal cavity (adenoid vegetations, ethmoiditis, gaimoritis), indicating a direct association between chronic inflammation of the mucous membrane and transformation of the inflammatory process into an allergic involving Th-2 cells and IgE. The trend of causative associations is maintained as well in BA case -more often BA occurs early schoolers and adolescents and is associated with HDM-sensitization. The presence of a direct associations between BA with chronic tonsillitis and/or tonsils hypertrophy reveals, in our opinion, a mixed mechanism of the BA pathogenesis with the involvement of the pathogenic microflora of the respiratory tract.
A separate group had been being urticaria and Quincke edema. In our study, there had been no significant direct association with atopic diseases -AD, SARC/ PAR, BA. This indicates the difference in pathogenesis mechanisms of development of those AlDs from atopic diseases, which confirms the independence of AM in children from Acu/Rec and QE. In this case, statistically significant asdociation between those nosologies and typical etiological factors was revealed. Thus, AcU/RecU had a direct association with food, drug and insect venom sensitization as well as with QE, and clinicallywith FDBS and RP. In turn, QE was reliably associated with AcU/RecU, food and, most of all, with an insect venom sensitization (insect bites). This sequence is continued by the direct association of AcU/RecU and QE with DS-disorders -FDBS and RP. Concerning the revealed interrdependance of QE with ARVI (rhinopharyngitis/bronchitis), further clinical and statistical studies are needed for itʼs explanation.

CONCLUSIONS
1. Atopic dermatitis is the first step of AM and is caused, first of all, by food allergens.
2. One of the FA and AM triggers at children are the comorbid states of the digestive system and, in particular, FDBS.
3. Within achieving by a child sick with AM the school-age disease is being transformed into SARC and/or PAR with typical sensitization spectrum -to plants`pollen (SARC), HDM, epidermal and fungal (PAR) allergens, respectively. 4. SARC and PARs have a statistically significant BA transformation trend.
5. Chronic infectious-inflammatory diseases of the upper respiratory tract have a direct association with the development of the PAR and BA. Chronic ethmoiditis and sinusitis aggravate the course of PAR, chronic tonsillitis and tonsils hypertrophy that of BA.
6. Acute and reccurent utricaria as well as Quincke edema compose a separate group of AlD that are pathogenetically and clinically interdependant and have no reliable association with AM diseases.
7. There is a direct association between nosological forms of urticaria and Quincke edema and diseases of digestive tract -FDBS and RP.