Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease characterized by dry skin, cutaneous inflammation and intense itching which can be exacerbated by many trigger factors such as allergens, infections, season and climate changes or psychological stress. Almost half of the cases are diagnosed by the age of 1 year and more than one third of the patients have a persistent disease throughout adulthood (1,2). Nowadays, AD is one of the most common skin diseases worldwide. However, it is often perceived as a minor dermatologic condition, for which patients have to endure symptoms over time (3). At individual level, it has been depicted that AD has a significant effect on quality of life, more important than other common skin diseases, extending its negative effects on patient's family (4,5). Being frequently associated with asthma, allergic rhinitis, contact dermatitis, food allergies, AD deserves to be analyzed in the light of possible complications (6).

The severity of the disease is assessed based on the intensity of the eczema, by the presentation of elementary lesions (erythema, edema/papule, exudate/wounds, excoriations and lichenification), and on the repercussions of subjective symptoms, such as itching and sleep loss (7,8). Furthermore, it is important to take into account the effects of AD on patients' lives, the social impact of the disease, how the patients are managing their condition and their opinion regarding how well the disease is controlled.

The main functions of the skin are protection and defense. Impairment of skin barrier affect the defense against the action of external physico-chemical agents and aggression of microorganisms. Most of the barrier defects that have been described in AD originate in the stratum corneum, a main component of skin barrier owning a ‘brick and mortar’ structure. The surface lipids of stratum corneum provides a filmogenic feature. Also, filaggrin, after hydrolyzed, is responsible for pH maintenance, moisture and skin protection against microbial agents. On the other hand, proteins of the tight junctions are essential to control the selective permeability of the epidermis (9).

There is a wide group of microorganisms that colonize the skin and influence the innate immune response. Predominance of Staphylococcus aureus in active lesions of AD, can exacerbate or contribute to persistent skin inflammation in AD by secreting toxins with antigenic properties, leading to activation of T cells and other immune cells (10). In the skin of AD patients were found specific IgE antibodies directed against the toxins and basophils are able to release histamine on exposure to the relevant toxin (11,12). Moreover, staphylococcal superantigens may induce mast cell degranulation after penetrating the epidermal barrier resulting in pruritus and acute inflammation.

Being a complex, multifactorial disease, therapeutic management of AD is directly dependent on the severity of the condition as well as the patient's compliance (13). Numerous efforts have been directed toward the development of the easiest and most reliable therapeutic strategy for this disease characterized by varied and recurrent symptoms (14). The management of AD is currently focused on avoiding triggers, improving skin hydration and reduction of skin inflammation (15).

In a simplistic note, nowadays, the therapeutic management of AD is represented primarily by emollients associated with the administration of topical steroids and oral antihistamines. This treatment offers a rapid and effective relief of AD symptoms but, it is important to take into consideration that long-term use of corticosteroids may lead to cutaneous adverse events as well as systemic side effects (16,17). Also, ultraviolet therapy may be considered, followed by immunosuppressants such as systemic corticosteroids and cyclosporine A and topical calcineurin inhibitors (18).

The poor adherence of the patient to drug therapy has made it necessary to combine different therapies in the field of alternative medicine involving the mobilization of physiological and psychological resources. Numerous studies have suggested that balanced lifestyle, healthy diet, hydration, massage, aromatherapy, leisure activities such as listening to classical music, socializing, attending cultural events, altogether could modulate the behavior of patients' immune cells, leading to a favorable evolution of the disease, with a significant decrease in frequency of exacerbations (19–22). Although there are still not enough data to be considered ‘effective’ in a conventional sense, adjuvant therapies can have promising results that could be the main subject of further research (23–25).

Already known as a field of study that analyzes the mutual influence of the nervous and immune systems, psycho-neuroimmunology has become the focus of many research studies that seek to find new treatment pathways for diseases such as AD (26,27).

Being a constant aspect of modern life and widely used as a simple term, stress, is defined as a general response of the body to external or internal factors and it has the role of intensely enlivening the physiological and psychological resources of the individual (28). However, it results in an imbalance between the requirements of the body and its ability to cope with it (29). Persistence of stress is known as chronic stress, with repercussions on various organs and systems, especially on the immune system. From the anatomical and physiological point of view, there are several links between the central nervous system (CNS) and the immune system. The most important are represented by the autonomic nervous system (ANS) composed of sympathetic (noradrenergic) and parasympathetic (cholinergic) systems, and the hypothalamic-pituitary-adrenal (HPA) axis (27).

It is well-known that stress related conditions are one of the most worrying political and economic issues in the countries of the European Union, being responsible for producing important social and health care costs (30–32).

Numerous studies have suggested the possibility of stress and neuroendocrine factors being involved in the onset, relapse or worsening of a series of dermatological disorders, such as melanoma and non-melanoma skin cancer, psoriasis, acne, rosacea, vitiligo, alopecia areata, lichen planus, seborrheic eczema, urticaria, prurigo nodularis or AD. Their actions seem to be mediated by neurohormones, neuropeptides, neurotransmitters and neuromediators that modulate the interactions between skin and nervous, immune and endocrine systems (33–38).

Although many studies have attempted to identify a clear-cut correlation between stress and allergic skin diseases, it cannot yet be stated that stress is able to induce an allergic response in any circumstance. However, certain subjects with genetic susceptibility could have a predisposition to develop such conditions.

Stress may induce AD lesions by impairing the skin barrier function (39) and by favoring a switching of the immune response towards a Th2 type lymphocyte response (40–42). These changes may underpin the pathogenic pathways in the onset of the disease. Furthermore, chronic stress is able to reduce the activity of NK cells, leading to an increased vulnerability to infection, hence an aggravation of skin lesions (43).

Another hypothesis of pathogenic mechanism in AD is the increased reactivity of the sympathetic-adrenal medullary system to stress (44) which leads to an imbalance between the adrenergic and cholinergic systems, clinically expressed by paradoxical vasoconstriction to mechanical stimulation of the skin (45).

The activation of neuroendocrine systems as an initial response to stress is different in intensity or duration in any individual subject. In chronic stress, the initial adaptation or adjustment mechanisms aimed to cope with the stress agent stimulate the secretion of various neuropeptides and neurohormones with an important role on the onset and course of the disease (46,47).

For example, secretion of catecholamines and cortisol, major stress hormones, have a significant influence on the immune system. They inhibit the production of IL-12 by antigen-presenting cells (APC), responsible for stimulating the Th1 cell response (48). Moreover, corticosteroids have a direct stimulatory effect on Th2 response, by increasing the levels of interleukins IL-4, IL-10 and IL-13 (49,50). Thus, chronic stress may induce an imbalance of Th1/Th2 responses in favor of the Th2-mediated response, with impairment of neuroimmunological homeostatic mechanisms, favoring the occurrence of an allergic inflammatory response.

Moreover, stress may induce modulatory actions on cutaneous nerve fibers and their neurons of origin. An increased density of nerve fibers has been emphasized, especially those containing substance P (SP), in AD lesions (51–57). In addition, patients with AD have significant changes in plasma and tissue levels of neuropeptides such as vasoactive intestinal peptide (VIP), nerve growth factor (NGF), and SP, neuropeptide Y (NPY). Another neuropeptide that could be involved in pathogenesis of AD is calcitonin gene related peptide (CGRP). Higher levels of neuropeptides such as SP, CGRP and VIP induce vasodilation and increased vascular permeability. SP action on monocytes and macrophages increases the production of TNF-α and IL-12, while CGRP stimulates Langerhans cell function to initiate immune responses of Th2 type (58). Furthermore, SP and CRH, released at the peripheral level in inflammatory outbreaks induces mast cell degranulation, thus aggravating the symptoms (59). Mast cells can be another link between stress and exacerbation of AD lesions not only by degranulation of mast cells induced by stress factors, but also by increasing the number of mast cells in the skin (60,61). It was also emphasized that plasma levels of histamine and its concentration in the skin of patients with AD are increased (54).

Thus, there are numerous neuro-pharmacologic agents such as neuropeptides (ACTH, NPY, VIP, SP, CGRP), neurotransmitters [(acetylcholine, noradrenaline, serotonin, histamine, glutamic acid, γ-aminobutyric acid (GABA)] and hormones (adrenaline and glucocorticoids) involved in the modulation of neuronal receptors that amplify circuits of inflammation. They are all viable options for not only the treatment of AD, but also for other stress-mediated inflammatory skin diseases.

At present it is not possible to explain a direct correlation between stress and several skin diseases, but it is important to take into account the evidence obtained from different studies that support the idea that chronic stress, in genetically susceptible individuals, can favor the onset of AD on the one hand, and can impair the therapeutic control of existing skin disease on the other.

Living with a chronic condition like AD can be both challenging and frustrating. The symptoms such as itching, rash, scaly skin, dryness, bumps, and papules have periods of remission and reappearance, with AD flaring up over and over again (3). It is essential to comprehend that psychological stress affects skin through its direct and indirect effects on immune response, cutaneous neuropeptide expression, and skin barrier function (9). Even though the mechanism underlying the association of AD with psychological stress has not been fully elucidated, many new insights for understanding the role of stress in AD were provided in the field of psychoneuroimmunology (26). There is a growing knowledge about all factors that influence not only the onset, but also the course and severity of this condition, but little is still known about the coping management that may improve its symptoms. There is evidence on the significance of factors such as emotions, sleep, laughter, human interactions, mobile phones, videogames and so on, therefore it is more than relevant to emphasize the link between them and AD (91).

Several studies depicted not only the connection between the nervous and immune system but also the biochemical and cellular links between them (92). It must be taken into account that during chronic stress various hormones and neuropeptides are released leading to immunological changes with imbalance between Th1 and Th2, in favor of the latter.

In conclusion, more and more studies focus on the idea that lifestyle and day-to-day challenges significantly affect susceptible people who are prone to AD. Having all the data, can we conclude that the factors listed are not only responsible for the worsening of AD but also for the increase of its incidence?

Studies regarding lifestyle, including every modality of coping with the stress in AD, have a great potential for identifying new therapeutic targets that can improve the treatment of this chronic and relapsing skin disease that has significant impact on patient's quality of life. Even though the research in medicine is continuously undertaken, it is important to emphasize well-being, humor as potential therapeutic interventions, ameliorating atopic eczema and dermatitis. Therefore, using positive emotions as part of the therapy is an outstanding advice not only for patients with AD but also for many other areas of clinical dermatology.