Practical Insights into Atopic Dermatitis

This book is a comprehensive, practical guide to the latest developments in the understanding and management of atopic dermatitis. Detailed information is provided on age-specific clinical symptoms, features, and diagnostic methods. Current theories on the pathogenesis of atopic dermatitis are closely examined, with attention to the roles played by genetic, allergic, immunologic, and skin barrier dysfunctions. In the second half of the book, the scientific background to and the practical use of the full range of treatment methods are described, covering topical agents, systemic agents, phototherapy, allergen-specific immunotherapy, and the most recently developed biologics and small molecules. This textbook will be an excellent guide to diagnosis and treatment for not only dermatologists but also practitioners in allergy and general medicine, including pediatricians, allergists, and primary care physicians. In addition, it will be of value for all scientists interested in developing new drugs for atopic dermatitis.

• Language: English
• Publisher: Springer
• Release date: Apr 30, 2021
• ISBN: 9789811581595

Book preview

Part IIntroduction

© Springer Nature Singapore Pte Ltd. 2021

K. H. Lee et al. (eds.)Practical Insights into Atopic Dermatitishttps://doi.org/10.1007/978-981-15-8159-5_1

Introduction to Atopic Dermatitis

Kwang Hoon Lee¹  

(1)

Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea (Republic of)

Kwang Hoon Lee

Email: [e-mail]

Keywords

AtopyAtopic dermatitisEczemaDefinition

Atopic dermatitis is one of the most common chronic, recurrent eczematous disorders. It often begins in infancy or early adolescence, and is accompanied by severe itching and various skin symptoms. Moreover, there is an increasing number of atopic dermatitis patients worldwide [1].

Although atopic dermatitis has various epidemiological factors, such as region, age, gender, and sociocultural characteristics, the incidence of atopic dermatitis has been increasing all over the world due to environmental changes, such as the changes in eating habits, clothing, residential environment, and urbanization. In case of children under 6 years old, the incidence rate of atopic dermatitis has been reported to be about 3%. Furthermore, its incidence rate has been estimated to be over 20% in children, and 1–3% in adults for the last 20–30 years [2]. The symptoms usually improve in around the first birthday, kindergarten age, or just before puberty; however, they may persist until adulthood. According to recent clinical studies, there is a steadily increasing number of adults with acute atopic dermatitis even after their twenties. Since an increasing number of adults who experience the development of atopic dermatitis for the first time in their life, it is likely to be a serious social issue [3, 4].

Patients with chronic and intractable itching, especially on their faces or hands, would be difficult to keep social relationships with others. Atopic dermatitis not only significantly damages quality of life by causing sleep deprivation, fatigue, or decrease in a sense of achievement, but also put burden on patients themselves and their families. Clinically, its symptoms vary depending on the age of patients. The progression of atopic dermatitis is classified into three phases based on the patient’s age: infancy, childhood, adolescence and adulthood [1, 5, 6]. Infancy is a period that refers to babies from 2 or 3 months to 2 years. During childhood, from 3 years to before adolescence, patients experience redness around joint areas of legs, necks, ankles, and other flexural areas. On these parts of the skin, atopic dermatitis first develops as a form of acute eczema, which makes skin red, rugged, flaky, hard. At the same time, skin around the forehead and eyes becomes red, dark, hard, and flaky. Atopic dermatitis during adolescence and adulthood display symptoms like skin redness around the upper part of the body, such as face, neck, head. Then, as in the earlier phases, the affected skin gets dark, swollen, and hard. Various types of acute or chronic eczema develop around trunk, hands, feet, arms, legs, and other parts.

It is not difficult for most physicians to diagnose atopic dermatitis; however, it gets sometimes confusing to diagnose because atopic dermatitis is accompanied by various clinical symptoms and signs [4]. Thus, it becomes complicated to define characteristic clinical symptoms of atopic dermatitis. For example, since skin diseases like psoriasis, lichen planus, or herpes are distinguishable by inspection of primary skin lesions, they are easy to be diagnosed by doctors, especially by dermatologists. On the other hand, atopic dermatitis does not provoke prototypical eczematous skin lesions in most cases. While the patients scratch their skins, the skin lesions are aggravated and resulted in a number of secondary changes. Furthermore, even experts have some difficulties in diagnosing atopic dermatitis due to a lack of definitive examinations to decide upon. Many physicians also do not regard this disease as to be curable completely. Unfortunately, since there are not many appropriate treatments available for atopic dermatitis, it is liable to abuse alternative therapies, resulting in the economic damage to the atopic dermatitis patients. Recently, numerous adverse reactions have been reported to occur because of prevalent inaccurate and unverified information based on personal experiences throughout the Internet.

Even though there were not many basic or clinical studies about atopic dermatitis going on actively about 40 years ago, as atopic dermatitis prevalence rates have been rapidly increasing for the past 10 years, now there is a great number of both qualitatively and quantitatively excellent researches about atopic dermatitis due to a splendid development in genetics and immunology [7–11].

History and Definition of Atopic Dermatitis Terms

The description of atopic eczema is thought to have started when Robert Willan wrote the term, eczema, in 1808. Indeed, the term ‘eczema’ itself began to be used by the Greek scholar Aetios, who used the term as the meaning of boiling and bubbling (eczeo or ekzein = to bubble up) in the sixth century AD [6].

Later, Wilson depicted the disease with similar skin symptoms as infantile eczema. Hebra also named prurigo, which is considered to be a subtype of atopic dermatitis nowadays, as constitutional prurigo. Hebra further explained that the major symptom of prurigo is itching, and prurigo is characterized by frequent outbreaks in infants, erythematous lesions, papule and lichenoid lesions increase with age, chronic progressive course, seasonal fluctuations, and association with hay fever and asthma. The concept of constitution that prurigo begins during early childhood and continues to the rest of the life has become a critical part of dermatology. Brocq later invented the concept of neurodermatitis [6, 12].

With advancement of immunology and allergology in the early 1900s, a condition of hypersensitivity associated with asthma began to be referred as ‘atopy’. In 1923, Coca and Cook [13] defined atopy as a tendency to run in families like hay fever or asthma, and to display hypersensitive reactions to foreign antigens. The word, atopy, means not located in the right place and not in order in Greek. In 1933, Wise and Sulzberger [5] included development of skin symptoms with atopic tendency as a characteristic of atopic dermatitis and named it atopic dermatitis or atopic eczema. Since it has been proved that IgE is a mediator of immediate-type hypersensitivity by Ishizaka [14], atopy has been equated with various IgE-mediated diseases by many people. However, it is controversial to simplify atopic dermatitis as an IgE-mediated disease, because IgE-mediated penicillin hypersensitivity or hypersensitive reactions to insect bites do not often run in families. Bruynzeel-Koomen et al. [15] first identified that IgE is attached to Langerhans cells, which are antigen-presenting cells, in skin lesions of atopic dermatitis patients, and this attachment has been further verified by other researchers since then. Klubal et al. [16] also observed that these IgE molecules described above adhere to Fc epsilon RI, a high-affinity receptor for IgE, on the surface of Langerhans cells in active skin lesions of atopic dermatitis patients. Consequently, these results demonstrated that inhalant allergens, such as house dust mites, might be able to penetrate directly into the skin and cause Th2 immune responses.

In 1983, Wuthrich [17] proposed the classification of extrinsic and intrinsic atopy by analogy with respiratory atopy. However, this classification system evoked controversy about nomenclature in around 2000, so it was discussed by the Task Force Teams of the European Academy of Allergology and Clinical Immunology (EAACI) and the World Allergy Organization (WAO) [18].

Those teams initially described that atopy has an individual or familial tendency, and begins in infancy or adolescence mainly after being exposed to protein antigens, which are then sensitized to produce IgE antibodies. As a result, these patients show typical symptoms such as asthma, rhinitis, or eczema. Based on the above definition, if patients have asthma, rhinitis, or eczema, which do not have IgE detected, they can be determined to have no atopic diseases. For that reason, the WAO Task Force Team redefined eczema. Since then, they have confirmed the adjective, atopy, only when IgE antigens are found in patient’s serum. Unfortunately, this classification also led to the division of atopic diseases into atopic and non-atopic eczema [6]. Up until 50 years ago, many researchers believed that allergies would not be involved in the pathogenesis of atopic dermatitis, but rather that dry skin and psychological factors were the main causes. Nevertheless, according to the research results and achievements of all pathophysiological mechanisms or responses to treatments today, atopic dermatitis and allergy are absolutely relevant and inseparable from each other.

The controversies surrounding this terminology have started with the motivation to understand the etiology of atopic dermatitis. Earlier terms were based on the clinical studies and symptoms of the disease, whereas the presence of IgE antibodies has become more important when defining the term nowadays. According to the definition made by WAO, WAO initially focused on IgE which is measured in patients, rather than on visible symptoms. They subsequently included the clinical symptoms when defining atopic dermatitis [6]. In the light of research and clinical experiences to date, atopic dermatitis is a disease that belongs to IgE-mediated diseases from one angle of perspectives. On the other hand, it covers a broader scope. With the above definition, we can understand atopic diseases present at both ends of spectrum, which refer to two phenomena, IgE antibody production, and nonspecific immune responses. It is likely to suspect that there is atopy disease where the two phenomena overlap. However, it may still cause some confusion because there exists a condition that does not have latent atopy (IgE is detected in blood but does not display clinical symptoms) or intrinsic atopy (IgE is not detected but shows clinical symptoms) on the margins of the spectrum.

Terms of Eczema and Atopic Dermatitis

Being a synonym for various types of dermatitis as well as atopic dermatitis, the term eczema has been used historically in numerous regions worldwide by many medical specialties. Eczema means boiling in Greek and was introduced in the medical literature to refer to a small group of skin diseases that show vesicular or bullous lesions by Robert Wilan [6].

As mentioned previously, Atopic dermatitis was initially called porrigo larvalis, lichen agrius, and prurigo Besnier. The term atopy itself was introduced by Coca and Cooke [13] in 1923, establishing a new definition of hypersensitivity, one of the abnormal immunological reactions. In 1933, Sulzberger and Wise [5] first documented atopic dermatitis in a footnote of 1933 Year Book of Dermatology and Syphilogy. Since then, dermatitis and eczema have actually been used as synonyms to describe a subset of distinct clinical symptoms of patients. Some doctors also refer general eczema as atopic dermatitis.

There have been repeated and active discussions for centuries about the accurate meaning of eczema to determine whether eczema accompanies itching or not, whether it includes acute lesions with oozing and chronic ones like lichenification, and whether the cause is extrinsic or intrinsic. The word ‘eczema’ has not only been used continuously, but has also remained to be a demanding challenge for the American dermatology literatures. Since it is vague to determine what other diseases are included in eczema or to grasp an accurate definition of eczema, increasing number of people have desired to eliminate the term entirely [19]. Although some authors have agreed with this claim, many dermatologists have been opposed to the argument. Bear [20] said, Rational doctors still use these irrational and incorrect terms because those terms are already well known and helpful. Even if it is possible to assign better names, misleading old words are not always discarded. This is because there still remain some purposes to use the term, and besides it is difficult to learn new terms quickly throughout the world.

According to the recent meta-analysis and review papers, atopic dermatitis and eczema are the most common nomenclatures for atopic dermatitis [21]. It is not easy to describe the characteristics of atopic dermatitis due to its broad spectrum. Eczema is the most universal term preferred by the public rather than physicians. Many clinicians often select the word eczema to explain some morphological changes. Other clinicians may consider eczema and atopic dermatitis as synonyms according to nomenclature methods specified by the World Allergy Society. Thus, heterogeneous use of these terms can be confusing for patients to understand their diseases.

Diagnosis of Atopic Dermatitis

Georg Rajka and Jon Hanifin [22] brought the most significant change in the words of atopic dermatitis by proposing diagnostic criteria for atopic dermatitis in 1979. Simultaneously, Scoring System for Atopic Dermatitis (SCORAD) was first introduced to assess a degree of atopic dermatitis severity and it led to the development of objective tools for evaluating conditions of patients with atopic dermatitis. In other words, this is when the concept of atopic dermatitis has begun to take shape and numerous new diagnostic criteria have been proposed. Nonetheless, atopic dermatitis still lacks accurate biomarkers and displays a variety of clinical presentations. Thus, it is difficult to make 100% satisfactory diagnostic criteria or definitions for atopic dermatitis.

Treatment of Atopic Dermatitis

Prior to the introduction of antibiotics and steroids, atopic dermatitis was mainly treated with internal medications, dietary habit change and topical therapies. Sulzberger recommended tar ointment as the most effective drug for treating eczema on the face of infants when there were no steroids out in the medical fields [5]. Current debate on atopic dermatitis has shifted from harmful fluids discussed in the past to inflammatory cytokines and disorder of hereditary barrier disruptions. When looking at from the outside-in (corneocentric) and inside-out (immunocentric) perspectives, there are new treatments for repairing skin barriers and some magical biologics for terminating persistent inflammation [10]. Besides, Arsenic was replaced by cyclosporine, tar by topical steroids and topical calcineurin inhibitors, and roentgen therapy by narrowband ultraviolet (UV) UVB and UVA1.

References

1.

Bieber T. Atopic dermatitis. N Engl J Med. 2008;358:1483–94.Crossref

2.

Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66(Suppl 1):8–16.Crossref

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Kim J, Chao LX, Simpson EL, Silverberg JI. Persistence of atopic dermatitis (AD): a systematic review and meta-analysis. J Am Acad Dermatol. 2016;75(4):681–7.Crossref

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Chu H, Shin JU, Park CO, Lee H, Lee J, Lee KH. Clinical diversity of atopic dermatitis: a review of 5,000 patients at a single institute. Allergy Asthma Immunol Res. 2017;9(2):158–68.Crossref

5.

Wise F, Sulzberger MB. Editor’s remarks. In: Yearbook of dermatology and syphilology. Chicago: Year Book Medical; 1933.

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Ring J. Atopic dermatitis: eczema. Switzerland: Springer; 2016.

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Novak N, Leung DY. Advances in atopic dermatitis. Curr Opin Immunol. 2011;23:778–83.Crossref

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Kim HJ, Shin JU, Lee KH. Atopic dermatitis and skin barrier dysfunction. Allergy Asthma Respir Dis. 2013;1(1):20–8.Crossref

9.

Park CO, Noh S, Jin S, Lee NR, Lee YS, Lee H, Lee J, Lee KH. Insight into newly discovered innate immune modulation in atopic dermatitis. Exp Dermatol. 2013;22(1):6–9.Crossref

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Paller AS, Kabashima K, Bieber T. Therapeutic pipeline for atopic dermatitis: end of the drought? J Allergy Clin Immunol. 2017;140(3):633–43.Crossref

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Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis Primers. 2018;4(1):1.Crossref

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Rudikoff D, Cohen SR, Scheinfeld N. Atopic dermatitis and eczematous disorders. Boca Raton, FL: Taylor & Francis Group; 2014.Crossref

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Coca AF, Cooke RA. On the classification of the phenomena of hypersensitiveness. J Immunol. 1923;8:163–82.

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Ishizaka K, Ishizaka T. Identification of gE antibodies as carrier of reaginic activity. J Immunol. 1967;99:1187–98.PubMed

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Bruynzeel-Koomen C, van Wichen DF, Toonstra J, Berrens L, Bruynzeel PL. The presence of IgE molecules on epidermal Langerhans cells in patients with atopic dermatitis. Arch Dermatol Res. 1986;278:199–205.Crossref

16.

Klubal R, Osterhoff B, Wang B, Kinet JP, Maurer D, Stingl G. The high-affinity receptor for IgE is the predominant IgE-binding structure in lesional skin of atopic dermatitis patients. J Invest Dermatol. 1997;108:336–42.Crossref

17.

Wuthrich B, Schmid-Grendelmeier P. The atopic eczema/dermatitis syndrome. Epidemiology, natural course, and immunology of the IgE-associated (extrinsic) and the nonallergic 8 (intrinsic) AEDS. J Invest Allergol Clin Immunol. 2003;13:1–5.

18.

Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use. Allergy Clin Immunol Int J World Allergy Org. 2004;17:4–8.Crossref

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Ackerman AB, Ragaz A. A plea to expunge the word ‘eczema’ from the lexicon of dermatology and dermatology and dermatopathology. Arch Dermatol Res. 1982;272:407–20.Crossref

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Baer RL. No-the word ‘eczema’ should not be expunged but be retained for the time being. Am J Dermtopathol. 1982;4(4):327–8.Crossref

21.

Siverberg JI, Thyssen JP, Paller AS, Drucker AM, Wollenberg A, Lee KH, Kabsshima K, Todd G, Schmid-Grenelmeier P, Bieber T. What’s in a name? Atopic dermatitis or atopic eczema, but not eczema alone. Allergy. 2017;72(12):2026–30.Crossref

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Hanifin IM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 1980;92(suppl):44–7.

Part IIEpidemiology

© Springer Nature Singapore Pte Ltd. 2021

K. H. Lee et al. (eds.)Practical Insights into Atopic Dermatitishttps://doi.org/10.1007/978-981-15-8159-5_2

Epidemiology of Atopic Dermatitis

Jaeyong Shin¹  

(1)

Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea (Republic of)

Jaeyong Shin

Email: [e-mail]

Keywords

Atopic dermatitisEpidemiologyEnvironmental factorsHygiene hypothesis

Epidemiology of Atopic Dermatitis at a Glance

The prevalence of atopic dermatitis is on the rise, 10–20 percent of children and 1–3 percent of adults around the world.

It is assumed that environmental factors may be associated with the difference in prevalence around the world.

In the industrialized world, atopic dermatitis as a cause of increased hygiene hypothesis (Hygiene hypothesis), indoor and outdoor environments, increasing pollution, Westernized eating habits, etc. can be mentioned as the cause of everything.

Atopic dermatitis not only puts an economic burden on the patient, but also social costs.

Atopic dermatitis (AD) is one of the most common skin diseases and is on the rise worldwide [1–6]. Especially in industrialized countries, 10–20% of children and 1–3% of adults suffered from atopic dermatitis [4, 6]. One of five children have symptoms of atopic dermatitis during certain times of life. Half of the AD patients initially show symptoms within the first 12 months [7]. Even though most of them experience spontaneous relief of symptoms during the school-age or adolescence, eczema lesions can be accompanied by itching often deteriorate intermittently. In addition, 25% of children’s atopic dermatitis is thought to continue atopic dermatitis in the form of dry skin and eczema in their hands even after the symptoms of severe dermatitis have disappeared. Adult-onset AD has also been increasing. In this chapter, we look at the differences between the prevalence rate AD at home and abroad and its geographical location, the factors of the increase in AD, and the social cost of the skin disease.

Epidemiology of Atopic Dermatitis in Korea

Research on the prevalence rate of atopic dermatitis can be largely divided into methods by dermatologist’s skin examination, methods of using questionnaire, and methods of using big data such as data requested by the Health Insurance Review and Assessment (HIRA) (Table 1). First, the dermatologist’s skin examination method is the most accurate way to check the prevalence rate of atopic dermatitis in a specific population. However, skin screening requires a lot of effort and cost. Also, it takes a lot of time and resources that it is unrealistic to study on a large population. Second, the method of using questionnaires can be for the entire population. It also has an advantage to capture time trends across geographic areas. However, it is necessary to verify the validity and reliability of the survey tool. The diagnosis of atopic dermatitis depends on the subjective judgment of the respondents, and there is a risk for a recall bias. The most widely used questionnaire for epidemiological studies of atopic diseases is the ISAAC questionnaire produced by the International Study of Asthma and Allergy in Childhood Program [8–10]. ISAAC questionnaire consists of survey questions to confirm the occurrence of major atopic diseases over the past year, such as asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, food allergy, and drug allergy. The ISAAC questionnaire has been adopted to investigate the prevalence of atopic diseases internationally and has been conducted several times in Korea. Lastly, claim-based big national data by the HIRA is one of the important sources of epidemiological research. However, visits to hospitals are selective depending on individual characteristics, severity of the disease, and accompanying medical conditions. Since medical records are not designed for research, they may be medically inaccurate or incomplete. They may also include nonmedical content, especially according to salary recognition criteria.

Table 1

The prevalence rate of atopic dermatitis in Korea

Diagnosis of atopic dermatitis requires accurate medical history and skin examination [11–13]. Therefore, it is difficult to make an accurate diagnosis without examining patients in person. Therefore, it suggests that epidemiological studies by skin screening suggest the most accurate prevalence of atopic dermatitis. However, epidemiological surveys using questionnaires and big data-based research can provide new information that cannot be obtained from small-scale studies.

Epidemiology of Atopic Dermatitis by Skin Examination

Kim et al., in Jincheon County, North Chungcheong Province (Table 1), conducted the first epidemiological study of atopic dermatitis reported to the Korean Dermatological Society in 1978 [14]. They visited all families with infants in the area and conducted skin checkups of 516 children under the age of 6 and reported 11.2% (58 people) of the prevalence rate. According to this study, 67.3% of the patients had a family history of atopic diseases. Atopic dermatitis began after 2 months of birth, with the highest frequency between 18 and 24 months. It decreased after the age of 5 years.

Lee et al. [15] visited 10 elementary schools in Bucheon in 1992 and conducted skin checkups for 4018 students at the age of 7 years old. They reported a 3.78% (152/4018) prevalence of atopic dermatitis. The most common eczematous lesions are flexural areas (83.6%). It is also frequently accompanied by pityriasis alba (59.8%), perifollicular accentuation (57.8%), keratosis pilaris (56.5%), hyperlinear palms, (55.2%), and Dennie-Morgan folds (26.3%).

In 1994–1995, Kim et al. [16], conducted skin checkups on 6070 children and teenagers aged between 6 and 18 years in Seoul, Ulsan, and Chuncheon. They found that the prevalence rate of atopic dermatitis was 6.0% for all participants, 10.0% for the aged between 6 and 8 years, 5.4% for the aged 10–12 years old, and 2.5% for the aged 16–18 years old, respectively. Especially for those aged 6–8 years of the most common frequency, the prevalence of AD was 17.5% in Seoul and 9.6% in Chuncheon. It shows that the prevalence rate of atopic dermatitis was higher in large cities than in provincial cities.

Kim et al. [16] visited four kindergartens in Daegu to conduct skin examinations of 733 children aged between 3 and 6 years. They described that the prevalence of AD was 7.9% of the Korean atopic dermatitis diagnosis standards, 8.0% of the Japanese atopic dermatitis diagnosis standards, and 11.2% of Hanifin and Rajka diagnosis standards.

In 2012, Lee et al. [17] conducted skin checkups on a total of 1320 students (7–12 years old) at five elementary schools in Gwangju, with 11.3% (149/1320 years old) having atopic dermatitis.

Kim et al. [18] conducted skin checkups on healthy adults aged 19 years or older (n = 2032) who visited skin examination centers at six general hospitals in Seoul and Gyeonggi Province in 2009. They reported that the prevalence rate of adult atopic dermatitis was 2.6%. Adult patients had the highest atopic dermatitis at 4.5% in their 30s, decreasing with 1.2% in their 50s and 0.4% in their 60s or older. It also shows significantly higher prevalence rates in men (4.2%), compared to women (1.3%).

Bae et al. [19], visited a military unit in northern Gyeonggi Province in 2010 and conducted skin checkups of 1321 soldiers (19–24 years old). According to the study, atopic dermatitis (5.1%) was the third most common skin disease after acne (35.6%) and athlete’s foot (15.2%). However, AD had the greatest impact on soldiers’ quality of life in all three aspects: symptoms, function, and emotion.

Epidemiology of Atopic Dermatitis by Questionnaire

In 1995, Lee et al. [20] surveyed 40,429 children aged between 6 and 15 years. They found that 7.3% of elementary school students (6–12 years old) and 3.9% of middle school students (12–15 years old) had atopic dermatitis. It shows higher rate in Seoul (elementary school students: 8.8%; middle school: 4.9%) compared to provincial cities (elementary school students: 6.6%; middle school: 3.5%). The study was conducted again in 2000 under the same condition [21]. It shows a higher prevalence than in 1995, with 10.7% in elementary school and 6.1% in middle school. In 2010, Ahn et al., conducted a survey on the prevalence of atopic dermatitis nationwide in the same way in the same age group [22]. It also confirmed that atopic dermatitis has been steadily increasing in Korea, with 17.9% of elementary school students and 11.2% of middle school students.

In addition, many researchers studied the dynamics of atopic dermatitis under various conditions using different questionnaires. According to a survey of 30,893 children aged 8–11 years using ISAAC questionnaire in 2006 [23], Seo et al. found that atopic dermatitis had a prevalence rate of 15.3% (girls: 16.5%, boys: 13.7%). In particular, the number of cases of atopic dermatitis was high in industrialized cities (15.9% for boys and 18.7% for girls), large cities (15.4% for boys and 17.5% for girls), provincial cities (13.6% for boys and 17.0% for girls), and island areas (11.4% for boys and 14.2% for girls), respectively. According to a study conducted by Kim et al. on healthy adults who visited the skin examination centers in 2009, the prevalence of atopic dermatitis in adults was 2.6% of skin checkups and 7.1% of the ISAAC questionnaire, respectively. In 2009, Paik et al. [24] used ISAAC questionnaire for 8750 children (0–12 years old), and the prevalence rate of atopic dermatitis was 14.4% for all participants, 18.0% for preschool children (0–6 years old), and 13.9% for elementary school students (7–12 years old). According to the 7th Korea Centers for Disease Control and Prevention’s online survey of youth health behaviors (n = 75,643) in 2011 [25], the prevalence of atopic dermatitis was 23.1% in adolescents (13–18 years old). The high risk for AD is associated with the higher the income of their families and the higher the educational background of their mothers.

Epidemiological Investigation of Atopic Dermatitis Based on Claims Data from the Health Insurance Review and Assessment Service

According to a survey of patients who visited hospitals more than once with the main diagnosis of atopic dermatitis (ICD-10 code: L20) using data requested by the Health Insurance Review and Assessment Service [26], the prevalence rate of atopic dermatitis nationwide was 2.2% (male 2.1%, female 2.4%) in 2008. The prevalence rate of atopic dermatitis by age group was decreasing with the increasing age group, 21.1% by 12 months of age, 26.5% by 12 months of age, 7.6% by 6 years of age, 3.4% by 12 years of age, 2.4% by 18 years of age, and 0.9% by 19 years of age, respectively. Kim et al. [27] reported that the prevalence rate of atopic dermatitis was 1.9%, 9.5% under the age of 10, and 1.2% over the age of 10 in 2014, under the same conditions.

Geographical Location According to Different Prevalence of Atopic Dermatitis

A representative study comparing prevalence rates of atopic diseases by country is the International Study on the Epidemiological Survey of Pediatric Asthma and Allergy Diseases (ISAAC) project. The ISAAC study was planned in three stages, with the aim of comparing prevalence rates among countries in Phase I, the risk factors for allergic diseases in Phase II, and the objective of repeating the first stage of investigation in Phase III to see changes in prevalence rates over time.

The first-stage ISAAC study was conducted by 155 organizations from 56 countries in 1992–1997 [28], covering a total of 715,033 children, while the third-stage ISAAC study was conducted by 233 institutions from 98 countries between 1999 and 2004 [29]. This is the largest epidemiological study ever conducted on a global scale to investigate the prevalence of atopic dermatitis, and the prevalence rate of atopic dermatitis can be compared according to geographical location. The global prevalence of atopic dermatitis in children (6–7 years old) was 6.1% in the first phase of ISAAC study (1992–1997), up 7.9% in the third phase (1999–2004), and showed a range of 0.9% (India) to 22.5% (Equator) depending on the country and institution. Even within one continent, the prevalence of atopic dermatitis showed a large deviation, generally high prevalence in Oceania, and low prevalence rates in India, the eastern Mediterranean, northern Europe, and Eastern Europe. Areas with particularly high prevalence rates of 15% or more were located in Asia-Pacific, Central and South America, Europe, and Oceania. In this study, the prevalence of atopic dermatitis in children in Korea was 11.3%, the 22nd highest among 56 countries.

The global prevalence of atopic dermatitis in adolescence (13–14 years old) increased from 7.3% in 1992–1997 to 8.8% in 1999–2004, with a range of 0.2% (China) to 24.6% (Colombia) [30]. This also has large regional deviations with generally high prevalence rates in Africa and Oceania, and with low prevalence rates in India, northern Europe, and Eastern Europe. In this study, the prevalence rate of atopic dermatitis in adolescence in Korea was 5.7%, the 65th among 98 countries.

In summary, the prevalence of atopic dermatitis was on the rise worldwide in both children and adolescence, and there was a huge difference of 60 times for each country. These large differences between regions suggest that environmental factors play an important role in the occurrence of atopic dermatitis.

Factors to Increase Atopic Dermatitis

In the ISAAC study, the global prevalence of atopic dermatitis shows an overall upward trend between 1992 and 1997 and 1999 and 2004. The change was observed in most countries except Western Europe, especially among countries in Africa, the Asia-Pacific region, South America, South Europe, and Eastern Europe. In a study using ISAAC questionnaire conducted in Korea, the prevalence rate of atopic dermatitis among elementary school students increased to 7.3% in 1995, 10.7% in 2000, 17.9% in 2010, 3.9% in 1995, 6.1% in 2000, and 11.2% in 2010. Deckers et al. [30] systematically examined literatures that reported the prevalence of atopic dermatitis between 1990 and 2010. They reported the increasing prevalence of atopic dermatitis in Africa, East Asia, Western Europe, and Northern Europe.

The prevalence rate of atopic diseases can fluctuate in a short period, depending on political and social changes. According to a study in Germany on the prevalence of atopic dermatitis in pre-unification children (5–6 years old) before and after unification, there was no significant change in West Germany [31], while East Germany saw a significant increase from 16.0% in 1991 to 23.4% in 1997. A similar phenomenon has been confirmed again in studies of other regions or immigrant groups where rapid urbanization has progressed.

Even within a country, there is a higher risk of atopic dermatitis in cities than in rural areas. According to a systematic review [32], 19 out of 26 studies comparing regional differences in atopic dermatitis show significantly higher prevalence than rural areas in cities.

Genetic predisposition and environmental factors work in the development of atopic dermatitis. The reason for the surge in atopic diseases such as asthma, allergic rhinitis, and atopic dermatitis can be explained as environmental factors stemming from industrialization. Changes in personal hygiene due to transformation to nuclear family and improvements in residential environment, the expansion of the use of hazardous chemicals, the increase in environmental pollutants resulting from industrialization, and Westernized eating habits are cited as factors for the occurrence and deterioration of atopic dermatitis (Table 2) [33].

Table 2

Hypothesis of the rise in atopic dermatitis

Hygiene Hypothesis

In the late 1980s, Strachan raised the Hygiene Hypothesis to explain the high incidence of atopic dermatitis in families with few siblings [34]. Hygiene hypothesis is that Th1 immune response is not mature while the Th2 immune system prevails, in an industrialized society because of the decrease in family members, improvement in residential environment, and personal hygiene [35, 36]. They reduce the chance of exposure to viruses and germs in infancy or to endotoxins, increasing the prevalence of atopic diseases. The hypothesis suggests that external requirements in infancy can affect the determination of future immune responses, which is able to serve as a new opportunity to understand post-birth immune responses. However, the prevalence of atopic diseases in underdeveloped countries is often high, and atopic diseases occur frequently in population groups with low socioeconomic levels. This makes it difficult to explain the increase in atopic diseases only through the hygiene hypothesis. There is another analysis that hygiene hypothesis shows a stronger link in asthma and allergic rhinitis, while atopic dermatitis is relatively less persuasive.

Indoor Air Pollution

Indoor air pollution is regarded that it is a potential cause of increased atopic dermatitis. Many environmental factors, such as house dust mites, pollen, and exposure to air pollutants, are associated with the deterioration of atopic dermatitis as well as they increase the risk of atopic dermatitis [37]. There is a high risk of atopic dermatitis if the house was remodeled or new furniture purchased within 12 months of birth, and exposure to cigarette smoke before and after childbirth [38].

Environmental Pollution

Several studies suggest that the increase in environmental pollutants due to industrialization are direct factors in the increase in atopic dermatitis. The occurrence of atopic dermatitis is associated with residences closer to the side of the road, with high nitrogen dioxide (NO2) and carbon monoxide (CO), which are harmful gases from automobiles [39]. Volatile organic compounds can also affect both the development and deterioration of atopic dermatitis, and recently, the relationship between Korea’s spring fine dust and atopic dermatitis has been proven [40].

Climate

Climate is also closely related to triggering atopic dermatitis. Weiland et al. analyzed the first stage of ISAAC study conducted in 56 countries for a total of 715,033 children and adjusted income of each country, latitude, altitude, average annual temperature, and average relative humidity [41]. According to the study, it shows that the higher the latitude, the lower the annual average temperature is associated with the increased prevalence rate of atopic dermatitis. Low temperatures and low humidity are directly related to atopic dermatitis, and it has been proven that high humidity and adequate exposure to ultraviolet rays can reduce the occurrence of atopic dermatitis. As shown in these series of studies, climatic factors such as temperature, humidity, and exposure to ultraviolet rays are thought to have a direct impact on the development of atopic dermatitis [42]. However, climate factors are thought to work in combination with many other factors, as excessive sweating may worsen atopic dermatitis.

Diet

Westernized diet, characterized by processed grains, preserved red meats, and saturated fats, is one of the reasons for the increase in atopic dermatitis. The three-stage ISAAC study shows that atopic dermatitis is less common in children who frequently consume fresh fruits [43]. According to the study, the risk of atopic dermatitis also increases when eating fast food frequently. A similar result was also found in an ecological study comparing calories per capita by country, meat, and vegetable consumption with the prevalence of atopic dermatitis [44].

Westernized diet lacks ω-3 unsaturated fatty acids, which act as anti-inflammatory molecule, while it contains rich ω-6 unsaturated fatty acids, which act as an inflammatory agent. Frequent intake of fish rich in ω-3 unsaturated fatty acids during pregnancy reduced the incidence of atopic