Atopic dermatitis: Current standards of diagnosis and treatment, including the latest methods of management

Atopic dermatitis (AD) is one of the most common childhood skin conditions. It is a chronic, relapsing disease with eczematous skin lesions, pruritus, and accompanying inflammation involving Th2 helper lymphocytes [1]. The typical symptoms are persistent itching and dryness of the skin. The lesions have a typical localization and appearance that change with the patient’s age. The skin lesions usually appear on the cheeks and the trunk in infants, and with increasing age they localize mainly on the elbows and popliteal folds. Because of its persistence and recurrence, as well as the intense pruritus that accompanies the disease, AD affects the patient’s quality of life and disrupts family functioning [2]. The pathophysiology of AD is complex and multifactorial. It includes elements of epidermal barrier dysfunction, changes in cellular immune response, IgE hypersensitivity, and environmental factors [3].

Most commonly, AD is diagnosed in early childhood. During the first five years of life, symptoms appear in up to 90% of patients, with more than 50% of the symptoms occurring during the child’s first year of life. In most cases, we observe resolution of symptoms with age and remission in adults. However, in recent years, there has been a rise in the incidence of AD with so-called late onset. According to data reported by Korean researchers, 26.5% of infants under the age of two were diagnosed with AD, and this percentage dropped with age from 11.6% at age three to 4.6% at age 19 [4]. There has been a considerable upsurge in incidence over the past 25 years, and the number of diagnosed cases of AD has more than doubled, as revealed by the International Study of Asthma and Allergies in Childhood (ISAAC) Phase III study [5]. The prevalence of AD according to the ISAAC in Korea, which has been carried out every five years since 1995, showed that the cumulative prevalence of AD in Korean elementary school children has been steadily increasing from 19.7% in 1995 to 35.6% in 2010 [4]. The incidence of the disease in the pediatric population is estimated to be between 10% and 30%, while in adult patients it is estimated to be between 1% and 3%. The number of people suffering from AD is growing every year [6]. Symptoms of AD can worsen due to IgE-mediated hypersensitivity, as well as the epidermal barrier defect, which is associated with exacerbation of the disease with all the factors responsible for aggravation of skin dryness (e.g., air conditioning, central heating, poor airflow, and exposure to detergents); hence AD can have the status of a civilization disease. Many patients have a family history of atopic diseases. AD is often comorbid with other atopic diseases and is associated with the term “allergic march.” Studies show that between 35% and 66% of people with AD will develop allergic rhinitis, and between 30% and 60% will suffer from bronchial asthma [7, 8].

The pathogenesis of AD is complex, with many factors being considered: genetic, environmental, non-immunological, and immunological with overlapping epidermal barrier dysfunction [9, 10, 11].

Patients with AD are diagnosed with a defective epidermal barrier. It is genetically determined and connected with many abnormalities in the structure and function of the epidermis, not only of dead skin, but also of apparently healthy skin [24]. The primary barrier between the external and the internal environment, the stratum corneum is the main obstacle in the absorption of different substances. It consists of corneocytes and inter-cellular substance, which is made up of lipids (sterols, ceramides, phosphoglycerols, and fatty acids). In AD-affected skin, the amount of lipids is considerably diminished, both in lesional and nonlesional areas. The production of stratum corneum lipid coat is impaired, mainly due to abnormal enzymatic activity [25]. Skin affected by the epidermal barrier defect is more prone to the penetration of environmental allergens and haptens, which may lead to atopic and contact allergy. The chief symptom linked to a defect in the epidermal barrier is dryness of the skin and, what follows, increased TEWL. It has been shown that TEWL increases fourfold in the area of eczematous lesions, and twofold on non-lesional skin compared to healthy subjects [26]. TEWL has been found to be elevated in both dry skin without eczema and in clinically normal skin in patients with AD [24]. Xerosis has been linked to an increase in pruritus and consequent scratching, which causes skin irritation and excoriated skin. As a consequence, contact of environmental substances and allergens with the immune system is facilitated, so skin infections can occur. Dry skin also presents as flaky scaling or even lichenification. Disturbances of stratum corneum homeostasis are also associated with mutations in the filaggrin gene in patients with atopic dermatitis. Filaggrin has a vital function in maintaining a normal epidermal barrier. Mutations in the filaggrin gene cause disorders in the arrangement of lipid lamellae, decrease of natural moisturizing factor (NMF), and increase of TEWL [14, 26].

The diagnosis of AD is based on the clinical picture. For years, Hanifin and Rajka’s diagnostic criteria have been most common (Table 1) [27]. The presence of three major and three minor criteria is sufficient for the diagnosis of AD. Pruritus is an inherent feature of AD, as is the chronic and relapsing course of the disease. A family history of AD is reported in about 60% of patients.

To evaluate the localization of the lesions, it is necessary to take into account the stage of the disease and the age of the patient. The typical features of atopic dermatitis are papules, which are often clustered and present on an erythematous, sometimes exudative surface. The lesions have different shapes and are not sharply demarcated from the surrounding tissue. In the acute phase, we can observe papules and erythema, edema, sometimes vesicles and oozing. When the entire or nearly the entire skin surface is inflamed, erythroderma may occur, accompanied by lymphadenopathy and a rise in body temperature. Scratching and the formation of excoriated wounds promote skin infection, in which case honey-yellow scabs may appear (infections caused by staphylococci and/or streptococci). In the chronic phase of the disease, skin lesions are drier, scaly, and often lichenified. Lichenification on the face makes the patient look significantly older.

The pattern of skin lesions in AD is different in different age groups. In infants, the skin is dry and rough (the diaper area is often spared), and the lesions may also be oozing. They are located predominantly on the face, cheeks, and forehead. Itchy dry patches are also reported, usually on the outer surfaces of the limbs but also on the abdomen, chest, and back.

In the next stage of the disease, the so-called pediatric phase, which begins at the age of two and lasts until adolescence, the oozing lesions like those in infants are less prevalent. The most frequently occurring lesions are typical of chronic disease with papules and patches with lichenification. They may be localized on hands, feet, in the volar region of wrists and ankles, as well as in elbow and knee joints. The Dennie-Morgan line, which is symmetrical single or double skin folds under the lower eyelid, may also occur. Cracking and oozing in the lower part of the ear-lobes and eczema behind the ears can present as well. Enlarged peripheral lymph nodes may be found on examination. In addition, cheilitis caused by licking the lips, perioral eczema, and inflammation of the corners of the mouth can also be observed. In a flare-up, due to intensive pruritus, scabs and excoriations are often present. About 70% of children also develop hand eczema with hyperkeratosis and fingertip cracks (pulpitis sicca).

In adulthood (adolescents and adults), lesions are mainly seen in the flexural folds, on the face and neck, upper arms and back, and on the dorsal surfaces of the hands and feet, including the fingers. In adults, they usually manifest as dry, scaly papules and flakes on an erythematous surface. Because of the long-lasting, chronic nature of these lesions, lichenification frequently occurs. Hand eczema may be a symptom of AD, but a higher frequency of allergic or non-allergic contact eczema is noted in patients with AD due to easier penetration of irritants and contact allergens through the insufficient epidermal barrier. In adults with chronic AD, the so-called dirty neck symptom, that is, a discolored (brown) ring around the neck, may be seen. Nipple eczema occurs in about 12% to 23% of patients as symmetric involvement of the nipple areola, often in the form of papular and vesicular lesions [28].

The diagnosis of AD relies on the clinical picture, and for many years the most commonly used criteria have been the Hanifin and Rajka diagnostic guidelines. In the majority of cases, the diagnosis is not very difficult. Differentiation is necessary in patients with less typical course and clinical picture.

In infants, AD should be differentiated from seborrheic dermatitis, irritant contact eczema, psoriasis, ichthyosis, tinea cruris, and sarcoptosis. It is also important to take into account metabolic disorders and primary immunodeficiencies. In older children, adolescents, and adults, AD should be differentiated mainly from contact dermatitis, symptomatic scabies, sarcoptosis, and Duhring’s disease. A secondary parasitic, viral, fungal, or bacterial infection causing a flare-up also requires proper diagnosis because it entails causal treatment.

Laboratory diagnostics makes it possible to identify existing disturbances in immunological processes. Approximately 80% of adults with AD have elevated serum immunoglobulin E values (> 150 kU/l). High IgE levels are usually associated with sensitization to aeroallergens, food allergens, allergic rhinoconjunctivitis, and bronchial asthma. In some people (about 20% of patients) with typical symptoms of AD, IgE-mediated allergy cannot be documented. In children, this form of the disease is defined as intrinsic or non-allergic type of AD (IAD). However, due to the defect of the epidermal barrier about 80% of patients will usually develop IgE-mediated sensitization to environmental allergens in the future. Patients with the so-called allergic, extrinsic type of AD (EAD) exhibit higher tissue eosinophilia, increased release of proinflammatory cytokines and expression of FcɛRI on the surface of dendritic cells, compared to patients with non-allergic AD. Through activation of mast cells and dendritic cells, allergen-specific IgE plays a crucial role in the progression of skin inflammation. The effect of histamine receptors on lymphocytes, antigen-presenting cells, and keratinocytes may further worsen skin inflammation [19].

Skin prick tests (SPT), which are done by puncturing the epidermis with a lancet containing common inhalatory and food allergens, are used to diagnose IgE-dependent allergy. The tests are performed on uninjured skin, usually on the forearm, and less commonly on the upper back. Antihistamines, glucocorticosteroids, and phototherapy should be discontinued before the procedure. Positive SPT reactions are not always clinically significant. They may be the result of tolerance to an allergen, such as food allergens causing symptoms in childhood, but without clinical significance in adulthood. A positive skin reaction for a negative control may be due to its overreactivity (dermographism). A negative reaction for a positive control (histamine) indicates inadequate skin reactivity. Serum concentration of allergen-specific immunoglobulin class E is also used in diagnosis. This test is safe, does not depend on the skin reactivity or treatment (it does not require discontinuation of drugs), is not influenced by skin condition and may be also performed in patients with inflammatory lesions, which would exclude the possibility of skin prick tests [29]. For inhalatory allergy, the sensitivity and specificity of skin prick tests are estimated at 80–90% and 70–95%, respectively. In cases of symptoms suggestive of food allergy, the results of such tests are not conclusive about the absence or presence of allergy to a particular food; the outcomes should be interpreted with caution. Only a minority of patients with positive skin prick tests develop clinical symptoms during oral provocation with food containing the allergen that produces a positive SPT result. The results can be verified by testing allergen-specific IgE or by using molecular diagnostic options [30].

CRD (component-resolved diagnostics), a molecular test based on the detection of antibodies to allergen compounds, is a new tool in allergy diagnostics that is performed in specialist centers. By means of commercial tests, this diagnostic method has become available for a wider group of patients (the Faber, ALEX, ISAC tests). However, the relatively high cost of this method is still a limitation. CRD allows prediction of cross-reactivity in a patient. Cross-reactivity is a common issue, due to the high affinity of proteins that are part of a given allergen (the so-called allergen components) to proteins from other allergen sources, even to distant species. Allergen-specific IgE antibodies that are originally produced against one allergen may cross-react with many other similar allergens. A cross-reaction is very likely to occur when the identity of the protein sequence is 80%, and is rare when the similarity is 50%. One example of cross allergy is the coexistence of allergic rhinitis caused by pollen allergy and food allergy: oral allergy syndrome (OAS), also known as pollen-food syndrome (PFS, pollen food syndrome, or PFAS, pollen food allergy syndrome). The term PFAS better illustrates the cross-reactivity between pollen and food. The syndrome of oral allergic symptoms occurs mainly in adolescents and young adults; however, the frequency of its occurrence in Polish children has not been established [31, 32].

Patch testing (PT) should be carried out in every patient with chronic or recurrent eczema, irrespective of the suspected etiology. PT is the gold standard in the diagnosis of eczema and is important in the differential diagnosis. Patients with AD may also have contact allergy. Patch testing is a classical method for the detection of contact allergy, for example, type IV immune reactions in the Gell-Coombs classification to haptens: small molecule chemical compounds of natural or synthetic origin (plants, metals, fragrances, drugs, and textile dyes, etc.). The miniscule haptens penetrate into the dermis as the epidermal barrier is no obstacle for them. In the skin, these substances bind with the body’s own proteins, and the products of this interaction are usually tolerated by the immune system. However, tolerance may be compromised and type IV hypersensitivity may develop. In patch testing, suspected haptens are placed on the subject’s skin surface in appropriate concentrations and media. PT is performed without age restrictions: the indications are the same for children as for adults. Routine patch tests include the Polish Basic Series comprising 30 most allergenic substances; however, this number is the minimum and may be expanded to incorporate additional suspected substances [30].

Atopy patch tests (APT) have been suggested to investigate the relationship between exposure to proteinaceous airborne allergens (house dust mites, pollen) and the onset or flare-up of atopic eczema. These tests have not been introduced into general allergological practice, and are mainly used in clinical research. The diagnostic relevance of the atopy patch test with aeroallergens in AD is still disputed, but new reports indicate that they may be useful as an adjunctive tool in routine clinical examinations in patients with AD and/or respiratory allergy [33]. APTs with food allergens in the diagnosis of AD are a subject of considerable controversy [30].

When we suspect that food allergens exacerbate the course of AD, it is essential to take a repeated history, in order to identify the food component causing hypersensitivity reactions. The first diagnostic goal is the identification of specific hypersensitivity, regardless of its allergic or non-allergic pathogenesis. A flare-up of AD which occurs each time and in a recurrent manner after the ingestion of a specific food, other possible causes excluded, makes it possible to demonstrate hypersensitivity. The diagnostic value of medical history is usually high for immediate type I reactions in the Gell and Coombs classification, but low for delayed reactions.

In addition to repeated history taking, food and symptom diary keeping, diagnostic elimination or provocation diets also play an important role. Diagnostic diets can be especially useful in children with AD, but also in people with urticaria who identify food as a trigger for flare-ups. The common term “food” also covers food ingredients with no intrinsic nutritional value (additives used by the food industry, salicylates, essential oils, natural pharmacoactive food components such as histamine or tyramine, or drugs taken orally). The simplest solution is an open provocation test, which has a high negative predictive value. An alternative is a diet consisting in the gradual introduction of suspected foods until the appearance of the expected symptoms. It should be kept in mind that the above-mentioned tests, as well as single or double-blind oral provocation tests, do not serve to diagnose food allergy but to identify the factor that triggers hypersensitivity symptoms. A double-blind, placebo-controlled oral provocation test is optimal for the diagnosis of food hypersensitivity because it is independent of the psychological factors affecting the patient and the researcher. Caution is always required with any provocation trial, as there is a risk of adverse or even serious symptoms (anaphylaxis). Provocation with a suspected food is recommended when it is not possible to clearly identify the food causing symptoms on the basis of the patient’s history. The provocation test helps to confirm the cause-effect relationship between the stimulus (consumption of a suspected food) and the reaction: occurrence of hypersensitivity symptoms. These tests are used both for immediate reactions (IgE-dependent food allergies) and delayed reactions to foods in children with AD (e.g., milk, chicken egg, soy, and wheat). It is well known that in patients with AD the same foods may be the source of both IgE-dependent and delayed allergenic reactions. Non-nutritious, non-allergenic food components may also exacerbate the patient’s skin condition [30, 34].

One of the most common and complex forms of food allergy in early childhood is cow’s milk protein intolerance (CMPI). Cow’s milk protein, like other foods, can cause symptoms through both an IgE-dependent and an IgE-independent mechanism. An allergy to cow’s milk proteins may aggravate AD. Clinically, CMPI may also manifest with gastrointestinal symptoms such as food protein–induced enteropathy (FPE), food protein–induced enterocolitis syndrome (FPIES), or food protein–induced allergic proctocolitis (FPIAP). In 2013, the UK guidelines for the diagnosis and treatment of IgE-independent cow’s milk protein allergy in infants entitled Milk Allergy in Primary Care (MAP) were published. They discuss both forms (IgE-dependent and IgE-independent) and outline practical principles for the management of mild/moderate IgE-independent allergy, the most common clinical form of CMPI. If the clinical history suggests IgE-independent cow’s milk protein allergy and the child has not had a severe delayed reaction, trial elimination of the suspected allergen from the diet is recommended, with reintroduction to the diet thereafter. In most infants in this situation, if they are fed modified milk, the treatment should be started with the administration of extensively hydrolyzed formula (eHF); however, in some situations amino acid–based formula (AAF) may be preferable. When a breastfed infant reacts to cow’s milk proteins ingested by the mother, it is recommended to first eliminate cow’s milk from the mother’s diet, and if supplemental feeding is needed, to include a hydrolysate. If the symptoms are markedly relieved after the introduction of an elimination diet, it is necessary to reintroduce the allergen into the diet and reassess the severity of symptoms after provocation to confirm CMPI. Skipping this step leads to unwarranted continuation of an unnecessary diet in many infants, which presents a major nutritional challenge. If the clinical history suggests IgE-mediated CMPI, skin prick tests can be performed or allergen-specific IgE antibodies directed against suspected food allergens can be measured in the blood. However, care must be taken in interpreting these results. Positive results in skin prick tests or the presence of specific IgE only indicate sensitization (i.e., the presence of IgE antibodies) to food allergens, but do not confirm allergy. The final diagnosis of clinically manifest allergy depends on the interpretation of these results against the clinical history. Food allergy has a strong tendency to resolve with age due to maturation of the gastrointestinal tract and development of tolerance to sensitizing food allergens. Individuals sensitized to pollen allergens may cross-react also to food allergens [31, 32, 34, 35, 36].

There are many suggestions of non-recommended methods in diagnosing diseases, including AD, proposed by so-called alternative medicine. They can be divided into those based on rational grounds but amply proven to be of no value, and those that are utterly irrational. The first group includes, for example, the measurement of IgG4/IgG in serum or performing a blastic transformation test. The methods that are irrational but popular among a certain group of patients largely due to their promotion on the Internet include bioresonance, bioenergy therapy, homeopathy, and others. These methods should not be recommended or used [30].

AD is a difficult disease to treat, and the discomfort it causes significantly impairs the quality of life for patients and their families. In order to achieve the best possible control of the disease and to improve the patient’s comfort, the therapy should be multi-directional and comprehensive. The management also depends on the severity of the disease. Education of the patient and his/her family, prophylaxis, skin care, correct local treatment and, if appropriate, systemic therapy are important elements that we should focus on in order to control the disease. Psychological support of the patient and their family is an essential and integral part of the management.

In recent years, researchers have taken more interest in the quality of life of patients, including those with AD. The quality of life of patients with AD has received a lot of attention, with evidence found in numerous publications in the international literature [37, 38]. However, there is much less research on the quality of life of parents of children with AD. Few papers have been published on the subject so far, and this issue requires further investigation. Chronic dermatological diseases, such as AD, although not directly life-threatening, can substantially reduce the quality of life of patients and their families, to a degree comparable to that of sufferers of coronary heart disease, asthma, or diabetes [39, 40, 41, 42, 43]. Patients with AD are at higher risk for neuropsychiatric disorders such as depression, attention-deficit/hyperactivity disorder (ADHD), and headaches [44, 45]. Decreased quality of life in patients with AD is associated with the discomfort of recurrent and chronic inflammatory skin lesions, persistent pruritus, and long-term therapy. The severe deterioration of the quality of life of patients and their families affects the psychological development of children, may lead to their behavioral disorders (hyperactivity, hypersensitivity), and impacts many areas of family life such as sleep, leisure activities, and relationships between family members [46]. Parents often describe children with AD as more irritable, moody, and weepy [47]. AD sufferers have lowered self-esteem, view themselves as less attractive, and find it more difficult than healthy individuals to form social contacts [48]. The 2010 study on the quality of life in a group of children with AD under four years of age, carried out in Gdansk, showed a significant relationship between the severity of inflammatory changes and the intensity of mood disorders, the time it takes to put the child to sleep, problems during family play and activities, and during meals, therapy, and bathing. In the group of patients aged 5 to 16, a correlation was found between inflammatory lesions and increased feelings of embarrassment, shyness, sadness, or concern about the appearance of the skin, peer interactions, playing, going out, doing sports, learning problems, and sleep disturbances. The study also showed a decline in quality of life for families of patients with AD. The disease limited most areas of family life (daily activities, housework, cleaning, meals, rest, and sleep). Because of sleep disorders and the need for long-term treatment, caregivers of children with AD were disheartened and exhausted [49].

Pruritus is an unpleasant sensation that leads to scratching. It is a bothersome symptom of atopic dermatitis that considerably lowers quality of life. Pruritus is regarded as a separate type of surface sensation that is transmitted to the central nervous system through specific neural pathways.

Despite improvement in research methods, the pathomechanism of pruritus in AD is still not fully explained. Researchers take into account stimulation of nerve endings in the skin (cutaneous pruritus), as well as some disorders in the peripheral and central nervous system (neurological pruritus) [50]. Increased secretion of nerve growth factor (NGF) by cells of the basal layer of the epidermis results in hypertrophy of nerve endings and increased number of axons [51]. It has been observed that itch can be induced more easily using provocative factors in patients with AD than in healthy subjects. A lowered pruritic sensory threshold may be associated with a rise in the number of sensory nerve fibers, neurofilaments, enhanced expression of neuropep-tide Y, substance P, and CGRP (calcitonin gene-related peptide) in the affected skin [52]. A number of possible mediators of pruritus are being considered, which include acetylcholine, bradykinin, endothelin 1, endovanilloids, histamine, interleukins 2 and 31, cannabinoids, corticotropin, leukotriene 4, vasoactive intestinal peptide (VIP), opioid peptides, prostaglandins, tryptase, kallikreins, and serotonin.

Pruritus is a subjective symptom; therefore, it is difficult to assess its severity. The tools that are most commonly used for assessment of pruritus are the well-known and approved Visual Analogue Scale (VAS) and Numeric Rating Scale (NRS) [53].

Chronic pruritus (lasting more than six weeks) usually has a detrimental effect on the patients’ mental state, and may cause sleep disorders, depression, or anxiety disorders, thus markedly reducing their quality of life [54, 55]. Sleep disorders affect not only patients with AD but also their family members. Parents of children with AD have been found to have nighttime sleep shortened by an average of 2.6 hours [56].

Pruritus is not only a symptom of dermatological diseases; it can also accompany many internal conditions (liver, hematological, and endocrinological conditions), neurological, infectious (AIDS, parasitic diseases), and psychiatric illnesses [54].

In AD, pruritus is the primary symptom and one of the four main diagnostic criteria, according to Hanifin and Rajka. The severity of pruritus correlates with the severity of the disease process and is part of the assessment of AD severity in the frequently used SCORAD scale [57]. The oSCORAD scale (objective SCORAD) is a modified version, where the assessment of subjective symptoms was excluded. Other tools used to measure the severity of AD include the Eczema Area and Severity Index (EASI), which assesses subjective symptoms and is often used in clinical trials, similarly to the Investigators’ Global Assessment (IGA) scale [58].

The prevailing view today is that every patient with AD suffers from pruritus at least during some periods of the disease [59]. A number of factors can aggravate pruritus in AD: sweating, dry skin, physical exertion, emotional stress, some fabrics (such as wool), hot water, and certain foods [60]. According to patient reports, pruritus may be reduced by the use of emollients, topical corticosteroids, antihistamines, cool air or cool bath, and rest, but these antipruritic therapies have had limited long-term effect [60].

The increase in the incidence of AD has prompted the search for effective prophylactic methods to prevent the development of the disease. Prophylaxis may involve children at risk without symptoms (primary prophylaxis), as well as those with early or advanced symptoms (secondary prophylaxis). Evidence-based measures for primary prevention include breastfeeding infants up to 3–6 months of age and not smoking during pregnancy. The goal of prophylaxis in people diagnosed with AD is to prevent further progression of the disease, to reduce the frequency of flare-ups, and to decrease the severity of symptoms.

One of the prophylactic methods that has been advocated is the use of probiotics. There are many reports in the literature on the role of probiotic bacteria in the primary prevention of AD. It has been suggested that the early gut microflora is involved in the pathogenesis of AD; therefore, it has been argued that modulating it may contribute to the prevention of allergic diseases as well as to their treatment. A review of several papers has shown that the administration of probiotics during pregnancy and in the first weeks or months of a child’s life contributes, albeit moderately, to reducing the risk of AD [61]. A recent review included 39 randomized control groups with a total of 2599 participants of both sexes, ranging from one year old to 55 years old, to investigate the use of probiotics such as Lactobacillus and Bifidobacteria taken alone or in combination with other probiotics for four weeks to six months. Analysis of SCORAD-based outcomes by age group revealed no significant difference between probiotic and control among children under two years of age. However, data in the older age groups showed a significant difference in favor of probiotics [62]. Examining the effect of probiotic supplementation over time has yielded controversial results. The choice of probiotic bacteria, the dosage, the period for which the probiotic is administered, and the presence of multiple interfering factors (diet, age, obesity, and environmental exposure) may affect the success of probiotic supplementation therapy. Differences in strain specificity, timing, and length of supplementation, and the influence of additional factors all add to the varying conclusions of meta-analyses. Probiotic use may alter the composition of children’s gut flora, modulate immune system reactivity, and likely perform an important role in the prevention of AD. The effects of probiotic administration in the prevention and treatment of allergic diseases are still disputable, and there are no clear definitive recommendations. The use of probiotics requires further research. Well-designed, double-blind randomized trials involving large groups of patients are required to conclusively evaluate the efficacy of probiotics in the prevention of AD [63].

When it comes to preventive measures, current literature also supports early, daily emollient therapy to decrease the incidence of AD in infants who are at risk [64]. In secondary prevention, appropriate skin care is the most important management strategy. One of the factors responsible for the onset, exacerbation, and persistence of eczematous lesions in AD is a defective epidermal barrier. For this reason, measures to strengthen this barrier prevent inflammatory changes. Proper care during exacerbations, but also between relapses, contributes to prolonging the remission time and shortening the duration of flare-ups. The natural skin barrier can be restored by emollient preparations, which have moisturizing and lubricating properties. They should be used continuously (if well tolerated), at least twice a day (they are effective for about six hours). Different types of emollient products are available. Some form a protective layer to prevent water loss from the skin, others contain substances that help bind water in the stratum corneum, supply water to the epidermis, or contain natural lipid components. Emollients are usually based on two types of emulsions: oil-in-water and water-in-oil, and easily soluble three-phase emulsions. They are commercially available in the form of ointments, creams, emulsions, shower gels, and bath oils. The most effective products are those containing urea (5–10%), which maintains proper hydration of the stratum corneum, as well as ceramides or other physiological epidermal lipids. A range of different emollient formulations have been described and tested against clinical data in the medical literature. Most have demonstrated beneficial effects, but there is no evidence of a clear advantage in terms of the benefits of a particular emollient in the treatment of AD. For patients, physician or nurse recommendations are the most important consideration when choosing an emollient, so medical professionals should provide evidence-based information about these care products [65].

A combination of avoiding potential aggravating factors, daily emollient therapy and proper epidermal care with anti-inflammatory medication applied as needed is the basis of treatment for AD. During the management of a chronic disease such as AD, close collaboration of the patient or their carers/parents with a nurse and a doctor is essential. It is of utmost importance to educate the patient on the nature of the disease, to explain the need for long-term skin care and to discuss the effects of different drug groups.

Regardless of the decision to initiate pharmacological treatment, efforts should be made to minimize factors that worsen disease control. It may be beneficial if a physician or nurse educates the patient about the factors that exacerbate the course of the disease. This includes proper education on how to recognize and eliminate or reduce factors such as irritants (soaps, shampoos, alkaline detergents in skin care products), clothing (such as wool or certain synthetic materials), airborne fragrances or formaldehyde, artificial dyes and preservatives in foods, micro-organisms, contact allergens, sweat, and scratching. Attention is called to foods containing large amounts of tyramine (a precursor to histamine), which is found in fish, yellow cheese, and blue cheese, for example. Awareness of these factors may, to some extent, help patients to avoid them and thus prevent flare-ups of the disease.

Instruction on how to apply medications to the skin or how to make wet dressings, for example, is of great value. All educational approaches and techniques are useful: verbal instruction, drawings or photographs, video presentation, “live” demonstration, and individual or group training. The method of choice depends on the needs and educational capabilities of the patient. It is necessary to cleanse the atopic skin gently and thoroughly, in a bath containing emollients with lubricating and moisturizing properties. Baths should contain natural or mineral oils, without detergents. AD sufferers should avoid soaps and detergents with an alkaline reaction and replace them with special bars or syndets. Washing agents should have a low pH (close to 5.5), and should contain as little fragrances, dyes, and preservatives as possible. It is not recommended to use sponges for bathing, as fungi and bacteria contaminating the sponge may colonize the skin. The bath should not be too hot (about 36–37°C), should not exceed a few minutes, and a shower/quick bath is preferred. After the bath, the patient should gently pat the skin dry, without irritating or wiping it, and apply an emollient moisturizer for up to five minutes, when the skin contains the most moisture. Emollients are applied to the entire surface of the damp skin after the bath. Successful emollient therapy requires good collaboration with the patient, hence the importance of education and explaining the need for systematic use of well-tolerated emollients. When atopic lesions flare up, emollient therapy may be poorly tolerated, with burning and increased pruritus, in which case topical anti-inflammatory drugs should be used first. Medicated preparations should be used before emollients [66].

Many patients do not follow the recommended proper skin care, do not use medications as prescribed, do not fill prescriptions, use medications irregularly, or discontinue treatment before they achieve measurable benefits after an apparent improvement. Poor compliance with therapy sometimes results from a conscious decision by the patient or, more often, may be a consequence of cognitive or physical impairment. Complex treatment regimens and misunderstanding of treatment are not without relevance.

Food allergens are most often of concern in the youngest children. Cow’s milk protein, egg white, soy and wheat are the most common sensitizers. Typically, food allergies become irrelevant in adulthood as tolerance to foods is acquired. The introduction of elimination diets should be considered carefully and without haste, and should be based mainly on the patient’s history and observation; additional examinations (skin tests and serum allergen-specific IgE testing) play an auxiliary role [30].

Inhalant allergens, such as dust mites, may contribute to skin deterioration in some patients. Although there are still few studies on the efficacy of aeroallergen elimination measures and many authors question their effectiveness, allergen avoidance is recommended by the EAACI (European Academy of Allergy and Clinical Immunology) and WHO (World Health Organization) guidelines [67]. While elimination or avoidance of sensitizing allergens is not always possible, it should be pursued. Education by a trained nurse and/or physician about possible ways to avoid allergens is important. It also seems beneficial to provide written information to the patient on how to reduce exposure to sensitizing inhalant allergens.

Other complicating factors in atopic skin may include stress, hormonal changes (for instance, menstruation), and infection. The skin of AD patients is sensitive to various nonspecific stimuli and is prone to irritation. These stimuli include not only chemical agents (such as detergents), but also exposure to dry air, cold, abrasion, and other mechanical trauma. Cleaning should be done with suitable protective gloves, while the surfaces exposed to damage (hands, for instance) should be protected with greasy creams. For people with AD, occupational exposure to factors that may lead to symptoms is a major concern. This is important in career counseling. Professions involving exposure to wet conditions, irritants, and allergenic substances, including animals, should be discouraged for people with atopic diseases.

Proper patient education improves the course of AD and facilitates disease control. How the nurse and physician educate the patient about disease management will largely affect the success of treatment and the quality of life of the patient with AD.

Therapeutic failures in the treatment of AD are due to the multifactorial origin of the disease. Owing to the complex pathogenesis of AD, there is a greater need to customize treatment. It has been suggested that different subtypes of AD (phenotypes, endotypes, genotypes, and immunotypes) can be distinguished based on various characteristics, e.g., patient age, disease onset, symptom severity, flare-up triggers, response to therapy, biomarkers, and genetic and immunological variants. As in the approach to bronchial asthma or chronic rhinitis, phenotyping can personalize therapy, and help optimize treatment according to pathogenesis. Phenotyping can lead to the development of therapies for patients who will benefit from approaches based on targeted immune mechanisms [103].