Clinical and anamnestic differences between acute and chronic urticaria in children

Introduction

During the past decades, there were numerous studies that showed a constant increase in the rate of allergic diseases in all age groups. This refers not only to such nosologic entities as atopic bronchial asthma, atopic dermatitis, allergic rhinitis, etc. but also to some syndromes, in particular, urticaria [1][2][3].

According to epidemiological data, 15–25% of the population had at least one urticaria episode in life. In 49% of patients, a combination of urticaria and Quincke’s edema is observed. In 70–75% of patients, the disease is acute, and in 25–30%, it is chronic [1][2][3][4]. Chronic urticaria is registered in 0.1–1% of the population and requires one of the most expensive therapies, which is a major problem for the system of healthcare and patients and their families [5][6][7].

Thus, a high morbidity rate, various causes and pathogenetic mechanisms, and peculiarities of diagnostics and treatment make urticaria one of the most acute problems in modern medicine.

The study aimed to evaluate anamnestic, clinical, and laboratory parameters in children with acute and chronic urticaria.

Materials and Methods

A total of 55 children were examined that were admitted to the all-day and day-time inpatient pediatric department of the policlinics of the State Children’s Clinical Hospital No. 17 in Ufa in January-December 2019.

The diagnosis was made according to the federal Clinical Recommendations on medical care for children with urticaria (Moscow, 2019) [1].

The authors analyzed medical records of inpatient department patients (form No. 003/u), history of a child’s development (form 112/u), and data obtained from parents (time of onset, presence and spectrum of sensibilization, family burden anamnesis including allergies, disease development, peculiarities of laboratory and immunological parameters obtained earlier). All children underwent clinical and laboratory-immunological tests with further analysis of the obtained results.

The criteria of study entry included 1) children aged 1 to 18 years old; 2) verified clinical diagnosis urticaria; 3) lack of helminthiasis and protozoal infection, inherited diseases, associated chronic diseases in the acute period; 4) agreement of patients for hospitalization, examination, and treatment of patients.

Criteria of study exclusion were 1) patients older than 18 years old; 2) lack of verified urticaria diagnosis; 3) presence of helminthiasis and protozoal infection, hereditary diseases, associated chronic disease in the acute period; 4) parents’ refusal for hospitalization, examination, and treatment of a child.

Patients were divided into two groups by the character of the process development: Group I included 44 patients with acute urticaria (80.0%), and Group II included 11 patients with chronic urticaria (20.0%). There were more patients with acute urticaria because the authors included only those patients that applied to the hospital. For a correct analysis of a hemogram, patients from Group I were divided into two subgroups depending on their age. Subgroup Ia included children up to 5 years old (n=13). Subgroup Ib included children older than 5 years old (n=31). The median age, 25% and 75% quartile in children from two subgroups with acute urticaria were 3.1 [ 1.9; 4.2] and 9.8 [ 6.4; 13.3] years old, respectively. The group of patients with chronic urticaria included only older children. Median age, 25% and 75% quartile, was 12.7 [ 8.1; 14.5] years old.

Statistical processing of the obtained data was performed with the statistical software package Statistica 10.0. The check of the sampling for normal distribution was made with the Kolmogorov-Smirnov, Lilliefors, and Shapiro-Wilk tests (for small samplings). The mentioned tests confirmed the hypothesis on the significant differences in the distribution of normal values (p < 0.05) of the majority of parameters, except for age, serum JgG, the absolute number of erythrocytes, leukocytes, and thrombocytes, and a relative number of monocytes.

Considering this condition, for the evaluation of the study results, a non-parametric Spearman rank test, Gamma, and Kendall’s tau were used. The comparison between the groups was performed using Mann-Whitney and Kolmogorov-Smirnov tests. Inconsistent variables are presented as a median of the interquartile range (25% and 75% quartile): Me [Q1; Q3]. The differences were considered statistically significant at p < 0.05.

Results

General and demographic data. The number of children that applied for medical care at the all-day and day-time pediatric department of the policlinics the State Children’s Clinical Hospital No. 17 in 2019 varied by months. The distribution was as follows: 8 patients (January), 0 (February), 5 (March), 2 (April), 6 (May), 5 (June), 5 (July), 4 (August), 5 (September), 8 (October), 4 (November), 3 (December) (Fig. 1).

Median age, 25% and 75% quartile, in all the studied children with urticaria was 8.8 [ 5; 13.1] years old. There were more male patients than female: 58.18% (n = 32) versus 41.82% (n = 23), respectively.

Anamnesis of children showed that the median disease duration from the onset to the hospitalization and verification of urticaria diagnosis (25% and 75% quartile) was 3 [ 2; 5] days. The median hospitalization time of children with urticaria (25% and 75% quartile) was 4 [ 3; 5] inpatient days.

The evaluation of premorbid background and trigger actors of urticaria. Anamnesis of children with urticaria revealed 6 groups of trigger factors. Among them, there were nutritional (53 patients), pharmaceutical, and domestic (9 and 5 patients) trigger factors. Two patients from each group were prone to pollen, cold, and insect factors. In 3 children, trigger factors were not identified.

The analysis of comorbid background in children with urticaria showed that gastrointestinal pathology had the highest occurrence rate (56.36%). Thus, chronic gastroduodenitis was diagnosed in 18 children, gastroesophageal reflux disease was observed in 5 children, irritable bowel syndrome – in 4 children, cholecystitis – in 3 children, and gastroduodenal ulcer – in 1 child.

The evaluation of family medical history in children with urticaria. Burdened family anamnesis with allergic diseases was revealed in 12 children (21.82%) in both parents and in 12 children (21.82%) – in mothers. In parents of 31 children (56.3%), burdened family anamnesis with allergic diseases was not observed.

Intolerance of food products was revealed in 10 mothers, pharmaceuticals – in 5 women. The reaction to domestic, pollen, and epidermal allergens was observed in 4, 3, and 1 mothers, respectively. Insecticide allergy was revealed in 1 woman.

Among fathers, intolerance of food products was revealed in 6 people, pharmaceuticals – in 4 people, insects – 3 people, and pollen – in 1 father.

The evaluation of laboratory parameters. The authors evaluated the parameters of clinical and biochemical blood assays, humoral immunity, results of an enzyme immunoassay for antibodies to H. Pylori, lamblias, and helminths. Hemogram and immunogram parameters were analyzed considering age-related physiological peculiarities.

In the group of children with acute urticaria younger and older than 5 years old, all the parameters of the hemogram corresponded with the age-related norms. It should be noted that normal eosinophil count in complete blood count (CBC) was obtained in 48 children in the studied group (87.27%), and increased levels were observed in 7 children (12.73%).

The changes in the biochemical blood assay parameters were revealed in 10 children: 2 children had elevated levels of ALT, 6 children had elevated levels of AST, and 3 children had elevated levels of total bilirubin.

The evaluation of immunological parameters. The evaluation of the immunogram results was made with age-related tables with normal reference values. Considering the peculiarities of humoral immunity, immunoglobin parameters were estimated separately for children younger and older than 5 years old.

In the group of children with acute and chronic urticaria, the distribution of the results of IgA levels (n=51) was the following: normal values were observed in 47 children (92.15%), elevated levels – in 1 child (1.96%), and selective deficiency was revealed in 3 children (5.88%). The evaluation of the levels of IgM and IgG (n=51) revealed elevated values in 12 children (25.53%) and 4 children (7.84%), respectively.

In the group of children with acute urticaria younger and older than 5 years old and chronic urticaria, the mean IgA, M, G, and CIC values were within the age-related norms (Table 1).

Table 1

The level of total IgE in the studied group was evaluated in 46 children. In 25 of them (54.35%), the level of total IgE was within the age-related norms, in 21 children (45.65%), the levels were elevated.

The mean levels of IgE in children with acute urticaria younger and older than 5 years old significantly increased the age-related norms (Table 1). The mean level of IgE in children with chronic urticaria did not exceed allowed reference values (Table 1). Thus, the meal levels of total JgE did not exceed reference values only in children with acute urticaria.

Normal values of Antistreptolysin O (ASLO) in the group of children with acute and chronic urticaria were revealed in 27 children (65.85%), and elevated values – in 14 children (34.15%).

The evaluation of the results of ASLO in children with acute urticaria in the age group younger than 5 years old did not reveal any deviations from the norm (Table 1). The mean levels of ASLO in the group of children older than 5 years old exceeded the allowable levels (Table 1). In children with chronic urticaria, the level of ASLO was within the reference values (Table 1).

Comparative characteristics of patients. The authors analyzed correlations between the studied parameters in patients with acute and chronic urticaria using such non-parametric methods as Spearman’s test, Gamma, and Kendall’s tau.

Among the revealed correlations in children with acute urticaria younger than 5 years old, there was a significant direct correlation between the patients’ age and low levels of JgA in the serum (rs = 0.806380 p < 0.05). The rate of the revealed gastrointestinal pathology in children younger than 5 years old was lower than in children older than 5 years old. However, there was a statistically significant correlation with the level of JgM (rs = 0.872872, p < 0.05) and JgG in the serum (rs = 0.763763, p < 0.05) and the leukocyte count in the blood (rs = 0.692820, p < 0.05). In the group of children with acute urticaria older than 5 years old, a significant direct association was observed between the age of the patient and the respective gastrointestinal pathology (rs = 0.421569, p < 0.05).

In children with chronic urticaria, no significant described correlations were revealed.

According to the Mann-Whitney (Table 2) and Kolmogorova-Smirnova tests (Table 3), the paired comparison between all the variables in children with urticaria from Groups I and II revealed statistically significant differences by the age, level of CICs (circulating immune complexes), erythrocytes, hemoglobin, and eosinophils in CBC.

Table 2

Table 3

Discussion

Among the children with urticaria, male patients prevailed over female (58.18% (n = 32) males versus 41.82% (n = 23) females). By the character of the disease development, there were more patients with acute urticaria (80.0%). Acute urticaria was observed more often in younger children, and chronic urticaria – in older children (Zcor. = -2.14665; p = 0.031822).

According to the rate of application (Fig. 1), the maximum number of children were hospitalized for urticaria in January, May, and October 2019. The authors suggested that children who had urticaria onset in January and May, had diet failure due to holiday celebrations, and in October, there is a high risk of acute respiratory viral infection and medication load.

Besides, it should be noted that food triggers (69.73%) prevailed in children with urticaria. These data were confirmed by the work of Ivanova [4] that demonstrated the highest sensibilization of children to alimentary allergens (70.6%) during scratch tests in 520 children with urticaria in the anamnesis aged 1 to 14 years old. Positive scarification tests were obtained in 400 (82.6%) out of 520 examined children.

According to some authors [1][2][3][5][7], urticaria in children can develop as a result of various pathogenetic mechanisms of two types: allergic and non-allergic. In children with allergic urticaria, the release of histamine is mediated by immunological reactions that are based on the binding of specific IgE antibodies with the respective receptors on the surface of mast cells and basophils with their degranulation and release of histamines and other vasoactive products to the surrounding tissues. In the present study, the development of acute urticaria with the expected involvement of JgE-mediated reaction was observed in 45.65% (n=21) of cases, because in children with acute urticaria, the mean levels of total JgE exceeded the reference values only in this group (Table 1).

When allergic urticaria is suspected in a patient, family anamnesis for predisposition to allergic reactions should be collected. In the present study, burdened family anamnesis was revealed in less than half of patients (43.64%), and parents had different causative allergens. In parents, intolerance to food products (14.54%) and drugs (8.18%) prevailed. The reaction to domestic, pollen, and epidermal allergens was observed rarely. More than half of the observed children (56.36%) did not have burdened family anamnesis for allergies. This can indicate that urticaria is a manifestation of both true allergy and pseudo allergy. It is known that non-allergic mechanisms with an increase in the levels of histamine provoke urticaria in children more often [1][2][3].

Allergy tests (skin scratch test and prick test, the level of allergen-specific IgE in the serum) are feasible in patients with the respective anamnesis. Allergic diseases are observed more often in patients with acute urticaria than in the overall population [1][2][3][4]. At the same time, allergic reactions of type I rarely provoke chronic urticaria [5].

According to diagnostic algorithms, patients with acute urticaria are not recommended extended examination except in cases of burdened medical history [1][2]. Patients with chronic urticaria are recommended CBC, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) tests, and exclusion of possible allergens. To reveal possible provoking factors and perform differential diagnostics, the tests should be conducted for the exclusion of infectious disease and atopia that evaluate the function of endocrine glands and autoimmune markers of the diseases [1][2].

The results of the study in the group of children with acute urticaria younger and older than 5 years old showed that all parameters of the hemogram corresponded to the age-related norms. In patients with chronic urticaria, higher levels of eosinophils were observed (Zcor. = -2.96741; p = 0.003003).

Kozel et al. [5] established the diagnostic value of different CBC parameters in 350 patients with chronic urticaria. The experts recommended the following laboratory tests: ESR, leucocyte count in the peripheral blood, leukocyte formula, and common urine test [5]. These authors did not reveal any deviations from the norm and possible causes of chronic urticaria.

The evaluation of immunogram parameters in the group of children with acute urticaria younger and older than 5 years old and children with chronic urticaria showed that IgA, M, G, and CIC were within the age-related norms (Table 1). Among possible immune mechanisms of chronic urticaria development, a pathogenetically significant increase in the CIC level should be highlighted (Zcor. = 1.98537; p = 0.047104) in comparison with children with acute urticaria.

In the pathogenesis of urticaria, infectious agents (streptococci, EBV viruses, hepatitis A, B, and C, adenoviruses, enteroviruses, lamblias, and helminths) lead to the damage of cellular membranes because of disorders in arachidonic acid metabolism. It leads to the release of histamine and other vasoactive mediators into the intercellular space [3][5]. Streptococcus infection could play a certain role in the development of acute urticaria in children of the older age group because the average ASLO value in the group of children with acute urticaria older than 5 years old exceeded the allowed values in the present study (Table 1).

Urticaria in children and adolescents can be provoked by chronic gastrointestinal infections, in particular, Helicobacter pylori [1][2][3]. Among the examined children, 31 patients (56.36%) had associated chronic gastrointestinal pathologies that were verified by the results of ultrasound imaging of the abdominal organs and esophagogastroduodenoscopy with further consultation of a gastroenterologist. The authors suggested an increased role of chronic gastrointestinal pathology in the development of acute (47.72%) and chronic (81.81%) urticaria in children older than 5 years old. As a rule, recurrent and chronic urticaria develops at this age.

Sizyakina et al. [3] noted in their review article that gastrointestinal pathology, helminth and Lamblia intestinalis invasion were the most frequent causes of acute and recurrent urticaria in children older than 3 years old. The authors suggested that gastrointestinal pathology associated with Helicobacter pylori and chronic respiratory diseases (chronic sinusitis and tonsillitis) were the most likely cause of urticaria in adolescents. In this age group, autoimmune forms of urticaria are observed more often.

The revealed correlation between the age of patients and a low level of JgA in the serum (rs = 0.806380 p < 0.05) can be associated with the allergic component in children with acute urticaria aged younger than 5 years old.

The rate of the revealed gastrointestinal pathology in children younger than 5 years old was lower than in children older than 5 years old. However, a statistically significant correlation was established between the level of JgM (rs = 0.872872, p < 0.05) and JgG in the serum (rs = 0.763763, p < 0.05) and leukocyte count in the blood (rs = 0.692820, p < 0.05). In the group of children with acute urticaria older than 5 years old, there was a significant direct correlation between the age of patient and the comorbid gastrointestinal pathology (rs = 0.421569, p < 0.05).

Heterogeneity of clinical-anamnestic and laboratory-immunological parameter values was observed in children with acute and chronic urticaria.

Conclusion

The present study revealed a clinical-anamnestic profile of children with acute and chronic urticaria.

By the character of the disease development, there were more children with acute urticaria (80.0%). Acute urticaria developed in younger children more frequently (Zcor. = -2.14665; p = 0.031822). The development of acute urticaria with a possible JgE-mediated mechanism was observed in 45.65% of cases (n=21). Among non-immune mechanisms of the development of acute urticaria, alimentary triggers prevail (82.71%), probably, due to the effect of histamine and other vasoactive mediators that are consumed in excessive amounts with food. Besides, the authors established a significant role of streptococcus infection (34.15%) and chronic gastrointestinal pathology (47.72%) in the development of acute urticaria in children older than 5 years old. Among the established correlations in children with acute urticaria younger than 5 years old, a significant direct correlation between the age and low levels of JgA in the serum should be highlighted (rs = 0.806380 p < 0.05). The rate of gastrointestinal pathology in children younger than 5 years old was lower than in children older than 5 years old. However, a statistically significant correlation was established between the level of JgM (rs = 0.872872, p < 0.05) and JgG in the serum (rs = 0.763763, p < 0.05) and leucocyte count in the blood (rs = 0.692820, p < 0.05). In the group of children with acute urticaria older than 5 years old, there was a significant direct association between the age of patients and comorbid gastrointestinal pathology (rs = 0.421569, p < 0.05).

Chronic urticaria was observed in older children (Zcor. = -2.14665; p = 0.031822). In children with chronic urticaria, the levels of eosinophils in the blood were higher (Zcor. = -2.96741; p = 0.003003). Among possible immune mechanisms of chronic urticaria development, a pathogenetically significant increase in the CIC levels (Zcor. = 1.98537; p = 0.047104) should be noted. Children with chronic urticaria did not have statistically significant associations among the studied correlations, which could be associated with a small sampling.

The results of the study revealed differences in the clinical-anamnestic and laboratory parameter values in children, which should be considered during the examination and management of patients.