The Influence of Skin Microbiocenosis on the Clinical Course of Atopic Dermatitis and the Rationale for Its Antibacterial Therapy in Children

The dissertation is devoted to the study of the role of skin microbiocenosis, primarily colonization by Staphylococcus aureus (St. aureus), in the clinical course of atopic dermatitis in children. The relationship between the degree of skin colonization, the excretion of exotoxins, and the severity of the disease is investigated, and the effectiveness of various options of combined antibacterial and anti-inflammatory therapy is evaluated. The work has practical significance for optimizing approaches to the treatment of children with atopic dermatitis, including sanitation of chronic infection foci and the individualized selection of antibacterial agents taking into account antibiotic resistance.

Relevance of the Problem

Population studies in recent years indicate a significant increase in the prevalence of AD. This disease affects 10–12% of the population worldwide [127]. The prevalence of AD in children ranges from 10% to 20% [137]. The onset of AD occurs in most cases in early childhood: symptoms appear during the first year of life in 60–70% of children [17]. The relevance of AD in pediatrics is determined not only by the early onset of the disease but also by the rapid development of chronic forms, leading to reduced social adaptation and disability in the child. Acquiring a chronic course with frequent relapses, the disease maintains its clinical features over many years. In most cases, AD is accompanied by respiratory manifestations of atopy: bronchial asthma and allergic rhinitis [21]. N. Williams et al. [137] note that 80% of children who developed AD in early childhood subsequently develop respiratory allergy. The pathogenesis of AD is based on genetically determined features of the immune response characterized by a shift toward a Th2-type response. IgE-mediated immunological reactions play a key role in the development of AD in children, although other types of immune responses are also encountered [47]. Specific triggers of AD include food and aeroallergens, allergens of certain bacteria and fungi. Non-specific triggering factors that provoke exacerbations of AD include irritants (clothing made of wool and synthetic fabrics, detergents, tobacco smoke), emotions, climatic factors (cold season, sharp climate changes), pollutants, and certain other factors [85]. One of the factors capable of triggering a cascade of immunological reactions in AD is the microorganisms inhabiting the skin [85, 88, 115, 122]. Among them, the most significant influence is exerted by St. aureus, which colonizes the skin of patients with AD [92]. According to G. Ricci et al., the rate of skin colonization with St. aureus in children with AD is 64% [120]. In healthy children, St. aureus is detected in only 0.5–3.5% of cases when cultures are taken from different skin sites [29]. A number of researchers have demonstrated a direct correlation between skin colonization with St. aureus and the severity of AD [68, 105, 109, 138]. Thus, E. Szakos et al. [132] obtained an increase in the SCORAD index in patients with a high degree of skin colonization with St. aureus. Currently, the main factor involved in the exacerbation and maintenance of inflammation in AD is considered to be the exotoxins secreted by St. aureus [85, 89, 106, 133]. Seven main serological types of St. aureus exotoxins are known: enterotoxins A (SEA), B (SEB), C (SEC), D (SED), E (SEE), exfoliative toxin, and toxic shock syndrome toxin 1 (TSST1). Enterotoxins, exfoliative toxin, and TSST1, like certain other bacterial and viral proteins, possess superantigen properties and are capable of stimulating T-cells in a non-specific manner, causing their polyclonal activation. It has been shown that St. aureus superantigens can influence T-lymphocyte proliferation, directly stimulate keratinocytes, Langerhans cells, and macrophages, cause infiltration of the skin by cutaneous-associated (CLA+) T-lymphocytes, reduce apoptosis of cutaneous-associated T-lymphocytes, suppress interferon-γ production by leukocytes, inhibit the immunosuppressive activity of T-regulatory lymphocytes, and also acquire the properties of classical allergens [61, 64, 69, 117, 129]. According to data obtained by R. Bunikowski et al. [61] and T. M. Zollner et al. [140], the severity of AD is more pronounced in patients from whose skin surface St. aureus secreting exotoxins has been isolated. Moreover, it has been demonstrated that the severity of AD is significantly higher in the presence of specific class E antibodies to staphylococcal enterotoxins [60]. According to data from Y. Nomura et al. [114], the severity of AD in children did not depend on the presence on the skin of only toxin-producing strains of St. aureus, or only specific IgE antibodies to staphylococcal enterotoxins in the blood. Whereas, in patients who had both toxin-producing strains of St. aureus and specific IgE antibodies to them, severe manifestations of AD were observed. St. aureus is the most frequent cause of infectious complications of AD. This microorganism is detected in cultures from foci of pyoderma in 90% of patients with AD [41]. Forms of AD complicated by pyoderma are observed in 25–34% of affected children [27] and present certain difficulties for diagnosis and therapy. Skin infections in children with AD often run a severe course, are sluggish in response to administered etiotropic therapy, and tend to recur. Processes initiated by St. aureus lead to a significant intensification of cutaneous inflammation and may contribute to further colonization of the skin by the staphylococcus. This is supported by data on the improvement of the clinical picture of the disease after the administration of antibacterial therapy [25, 90, 96]. The reasons for the susceptibility of AD patients to high colonization with St. aureus and the development of cutaneous bacterial infection, on the one hand, and the selective ability of St. aureus to colonize the skin of AD patients, on the other hand, remain not fully elucidated. Despite the in vitro data obtained on the action of superantigens, the clinical significance of skin colonization with St. aureus and the superantigens it secretes in AD in children remains not fully studied.

Objective of the Research

To study the influence of skin microbiocenosis on the clinical course of atopic dermatitis and to improve the effectiveness of its treatment in children.

Tasks of the Research

1. To identify features of the clinical course of atopic dermatitis taking into account skin colonization with St. aureus and to assess the skin microbiocenosis in various forms of atopic dermatitis.

2. To determine the ability of St. aureus isolated from the skin surface of children with atopic dermatitis to secrete enterotoxins A, B, C, D, E, and toxic shock syndrome toxin 1, and to elucidate their influence on the course of atopic dermatitis in children.

3. To evaluate the therapeutic effectiveness of various options of combined therapy on the course of the disease and the state of skin microbiocenosis in children with atopic dermatitis.

Scientific Novelty

A relationship has been demonstrated between colonization of the skin with St. aureus in children suffering from atopic dermatitis and the severity of its clinical course, and the risk of pyoderma development.

It has been established that the severity of the course of atopic dermatitis does not depend on the ability of St. aureus strains to secrete enterotoxins and toxic shock syndrome toxin 1.

Features of the skin microflora in children with various forms of the disease have been established, and the possibility of improving the condition of patients and eradicating St. aureus through combined therapy involving systemic and topical antibacterial agents and topical corticosteroids has been demonstrated.

Practical Significance

Based on the study of the influence of combined therapy using systemic and topical antibacterial agents and topical corticosteroids in children with atopic dermatitis, the high significance of measures aimed at eradicating St. aureus from the skin of affected children has been demonstrated, which can be achieved through the use of combined topical corticosteroids for external therapy. These children require sanitation of chronic infection foci under dispensary supervision by specialists. A high frequency of antibiotic resistance has been demonstrated in St. aureus isolated from the skin of children with atopic dermatitis. Therefore, such children require an individualized approach to the prescription of antibacterial therapy.

The materials of the dissertation were presented at the I All-Russian Congress «Modern Technologies in Pediatrics and Pediatric Surgery» (Moscow, 2002), the II All-Russian Congress on Pediatric Allergology (Moscow, 2003), the III Russian Congress «Modern Technologies in Pediatrics and Pediatric Surgery» (Moscow, 2004), and the scientific-practical conference of the Federal State Unitary Enterprise «Moscow Research Institute of Pediatrics and Pediatric Surgery of Roszdrav» (2004).

10 publications have been published on the topic of the dissertation.

Practical recommendations set forth in the dissertation are used in the allergology department of the Federal State Unitary Enterprise «Moscow Research Institute of Pediatrics and Pediatric Surgery of Roszdrav», at the clinic of the Federal State Scientific Center of the Russian Federation — the Institute of Immunology.