New clinical and immunological aspects of acute urticaria in children

Introduction

Urticaria is characterized by global prevalence and is a significant burden in the medical, social, and economic spheres throughout the world. According to a study by Peck et al. (2021), in 2017, the incidence of urticaria covered 86 million people; specifically, women and children were affected more often than men and adults in accordance with comparison categories [1]. In particular, the prevalence of acute urticaria in pediatric patients in the world reached 6.7%¹.

Concurrently, the immunological mechanisms of the formation of various forms of urticaria in children have been practically not examined. It is important to note that the identification of aspects of the involvement of the immune system in the pathogenesis of urticaria would contribute to the optimization of the disease diagnosis and early prescription of targeted therapy to prevent the chronification of the pathological process. The concept of personalized medicine implies the selection of adequate therapy based on the comprehension of the mechanisms of the disease and the individual characteristics of the patient in order to meliorate the efficacy of healthcare delivery and its safety, as well as to minimize the cost of treatment to the state and the patient.

The purpose of the study was to investigate the characteristics of the clinical picture and innate immune response in pediatric patients with variations in the course of acute urticaria.

Materials and methods

During the investigation, 236 children with acute urticaria were examined. The control group included 30 boys and girls of the same age from health groups I and II (Order of the Ministry of Health of the Russian Federation dated December 30, 2003 No. 621 “On a comprehensive assessment of the health status of children”) who did not have a history of atopic diseases. The patients were examined on the first day of their admission to the hospital before the start of therapy. The anamnestic criterion for the inclusion of patients in the investigation was revealing episodes of urticaria lasting no more than 6 weeks².

Clinical investigation methods included an analysis of anamnestic data and an objective examination of the child with determining the severity of acute urticaria by calculating the urticaria activity scores for 7 days (UAS7) of hospital stay (Table 1) [2].

In the practice of pediatricians and allergists, doubts constantly arise about the advisability of assessing the severity of acute urticaria in accordance with the principles used in the treatment of chronic urticaria. Current international documents do not indicate the need to determine the severity of acute urticaria. However, the involvement of a questionnaire for calculating UAS7 in pediatric patients specifically with acute urticaria may turn out to be a modern, non-invasive, and reliable method for determining the severity of the disease. The implementation of this research methodology in pediatric practice was presented and approved at a meeting of the local independent ethics committee of the Federal State Budgetary Educational Institution of Higher Education Rostov State Medical University.

Immunological methods for the investigation of the humoral component of the innate immune response included the quantification of lactoferrin, interleukins IL-4, IL-6, IL-17, interferon-gamma (IFN-γ), transforming growth factor (TGF-β), the active form of vascular endothelial growth factor (VEGF-A) in blood serum by ELISA using appropriate test systems produced by Cytokin LLC (Vector-Best CJSC, Russia), Orgentec (Germany), and Bender VtdSystems GmbX (Austria). Informed consent was obtained from the children’s parents to conduct clinical examinations and collect blood samples out of a vein.

Descriptive statistics for the quantitative indicators of the samples were presented by the calculated median and quartiles. Comparisons of the median in the variable groups were made using the Mann-Whitney test, and the differences were considered statistically significant at p<0.05. Statistical analysis and processing of the collected data were performed in R version 3.2, R Foundation for Statistical Computing, Vienna, Austria.

Results

In accordance with the results of the assessed UAS7 score, all patients with acute urticaria were divided into 3 groups: group I consisted of 36 children with mild acute urticaria who exhibited UAS7 score from 7 to 15 points; group II included 139 children with moderate acute urticaria who exhibited UAS7 score from 16 to 27 points; group III was formed from 61 children with severe acute urticaria who exhibited UAS7 score from 28 to 42 points. The control group consisted of 30 boys and girls of similar age from health groups I and II without manifestations of atopic diseases at the time of examination and in history.

An analysis of clinical and anamnestic data of urticaria of various severities in pediatric patients made it possible to identify the features of the course of acute urticaria in children. In particular, it was revealed that acute urticaria most often developed in boys of primary school age, with the exception of severe acute urticaria, which predominated among girls of older school age (Table 2).

In the severe course of acute urticaria, food and drug hypersensitivities were more often recorded as effectors of pathology, while mild and moderate forms of the disease were caused in many cases by an unidentified causative allergen. Severe forms of acute urticaria were often burdened by hereditary allergic history in the form of atopic diseases in parents and older probands. Personal allergy history, manifested as atopic dermatitis, bronchial asthma, and allergic rhinitis before the development of urticaria symptoms, was also aggravated significantly more often in children with severe acute urticaria (Table 3).

The general symptomatology of urticaria in the form of asthenovegetative symptoms including weakness, dizziness, and cephalgia as well as gastrointestinal symptoms such as nausea, vomiting, and diarrhea were more typical and significantly more often recorded in severe cases of acute urticaria. According to the modern conception of the problem of food and drug anaphylaxis, the severe course of acute urticaria in some patients may be presumably a component of anaphylaxis of various geneses [3]. Coverage by urticaria over most of the skin surface (face + trunk + extremities) was observed in the majority of pediatric patients with severe acute urticaria. Urticarias of large size (more than 10 mm) with a tendency to merge were recorded in all patients with moderate and severe courses of acute urticaria. Angioedema predominantly developed in children with severe acute urticaria (Table 4).

Further, during the investigation, the indicators of the functioning of the humoral component of the innate immune response were intercompared among various patient groups with variations in the course of acute urticaria (Table 5). Scientific databases describe the properties of serum lactoferrin, which belongs to the transferrin protein family and participates in the transport and metabolism of iron, as one of the leading antimicrobial peptides [4]. No data have been found on the involvement of lactoferrin in the pathogenesis of urticaria in pediatric patients. The results of this study revealed an increase in its level in children with all types of acute urticaria courses but the most pronounced effect was attributed to severe cases of the inflammatory process. Therefore, the level of lactoferrin can be proposed as a simple and accessible marker and predictor of the severity of acute urticaria in pediatric patients.

The results of the investigation of the cytokine spectrum revealed overproduction of IFNγ in patients with acute urticaria, regardless of its severity. Overproduction of IFNγ in children with acute urticaria may be associated with its functions in ensuring a switch of the immune response to Th1 cells. It should be noted that the level of IFNγ hyperproduction did not depend on the severity of acute urticaria, and even on the contrary, in severe cases, there was a tendency to a decrease in its level (Table 5). The decrease in the level of IL-4 in the blood serum, which was revealed in all variations of the course of acute urticaria in children, indicated the depletion or suppression of this cytokine synthesis. Moreover, the degree of drop in IL-4 levels practically did not depend on the severity of acute urticaria in pediatric patients (Table 5). It is important to note that the level of the pro-inflammatory cytokine IL-6 exceeded the control group only in severe cases of acute urticaria. Concurrently, the level of IL-17 was increased in children with various severity levels of acute urticarial, which may indicate the activation of the Th17 variant of the immune response. It is worth noting that the concentration level of IL-17 turned out to be significantly higher at the moderate and severe degrees of acute urticaria in pediatric patients relative to the mild course of the disease (Table 5). The conducted investigations revealed that the cytokine TGF-β level was elevated at all types of disease severity but its increase was exhibited to a greater extent at severe acute urticaria. This fact is presumably associated with its ability to suppress the synthesis of proinflammatory cytokines. If the effect of TGF-β1 is weakened, a person may develop a generalized inflammatory reaction; therefore, in urticaria in children, an increase in the level of the cytokine TGF-β can be considered as an element of the feedback regulation of the immune response and inflammatory reaction. The results of assessing the level of the vascular endothelial growth factor (VEGF-A) in pediatric patients with acute urticaria showed a gradual increase in the content of this mediator in accordance with the clinical severity of the disease with the most significant overproduction at severe acute urticaria (Table 5). This result indicates the activation of the production of mediators, which promote the process of vasodilation [5].

Discussion

An analysis of the results of the investigations has shown that the urticaria activity score for 7 days (UAS7) is an effective indicator in pediatric practice and has proven itself as a simple and convenient way of ranking pediatric patients with acute urticaria into groups according to the severity of the disease.

In the authors’ opinion, children with systemic manifestations of severe acute urticaria affecting the nervous and digestive systems should be supervised as potential patients with food and drug anaphylaxis that will require ImmunoCAP molecular allergy diagnostics to identify the causative allergen and cross-type allergies, as well as early administration of epinephrine as the preventive treatment of anaphylactic shock.

In pediatric patients with acute urticaria, the activation of the humoral component of the immune response was revealed upon assessing the indicators of innate immunity. In this regard, the levels of lactoferrin, IL-6, IL-17, TGF-β1, and VEGF-A can be considered as criteria/predictors of a severe course of acute urticaria, and IL-6 and IL-17 can be taken as targets for targeted anti-cytokine therapy with already existing biological molecules such as tocilizumab and secukinumab, as well as a goal to synthesize new genetically engineered drugs.

Conclusion

1. The Urticaria Activity Score for 7 days (UAS7) is an effective tool for ranking pediatric patients with acute urticaria into groups according to the severity of the disease.
2. A severe course of acute urticaria with systemic exhibitions can be considered a manifestation of food and/or drug anaphylaxis and requires molecular allergy diagnostics, as well as early administration of epinephrine to prevent the development of anaphylactic shock.
3. The identified changes indicate an imbalance in the functioning of the innate immune response and activation of the inflammatory cytokine cascade in pediatric patients with acute urticaria, which leads to the launch of regulatory mechanisms of the inflammatory process. Moreover, pediatric patients have a clear dependence of the severity of acute urticaria on the exhibition of the imbalance of the immune response.
4. Comprehension of immunological mechanisms will allow active us4 of targeted therapy in the near future to relieve severe manifestations of acute urticaria in children at the early stages of the disease and prevent the chronification of the process.