**1. Introduction**

Allergic diseases are the most common chronic condition in childhood. Epidemiological studies observed increase in the prevalence of allergic diseases from the middle of the twentieth century, which is explained by environment and lifestyle changes and improvements in modern Westernized societies. At the beginning of the twenty-first century, stagnation in the prevalence of asthma while increase in the prevalence of food allergy was noticed, which announced the second wave of allergy epidemics [1–3]. The first atopic phenotype that starts in early infancy is atopic dermatitis (AD). It is estimated that it affects up to 20% of children. Disrupted integrity of the skin barrier contributes to the development of sensitization to food and aeroallergens and also increases the risk for the development of food allergy. It is considered that 30% of children with AD have food allergy, and 30% develop asthma and 75% allergic rhinitis [4]. About 3–5% of children have been diagnosed with food allergy, and up to 50% of them have AD [1]. AD and food allergy can coexist and can also appear independently in infancy and in the first years of life. In the following years, wheezing induced by viruses like respiratory syncytial virus or rhinovirus and sensitization to inhalational allergens can be observed. As the child grows up, respiratory symptoms are more common and occur outside of the infection; introduction of anti-inflammatory drugs is needed, i.e., the signs of asthma occur. Preschool and school age are the time of

appearance of allergic sensitization to pollen of grass, weed and tree pollen, and the beginning of allergic rhinoconjunctivitis which persists in adolescence and the young adult age.

At the same time, remission of atopic dermatitis and food allergy is noticed, while asthma and rhinitis symptoms continue. Sensitizations to pollen and cross-reactions to nuts, fresh fruits and vegetables may induce oral allergy syndrome, the type of food allergy that occurs in the school age. Asthma may disappear in teenage years, but after some period of remission, skin and respiratory symptoms can appear once again. In early adulthood, skin and lung symptoms are related to tobacco smoking, occupational exposures and lifestyle, and they manifest like contact dermatitis or asthma-chronic obstructive pulmonary disease overlap syndrome [5].

Atopic dermatitis, food allergy, asthma and allergic rhinitis in childhood share the common genetic, epigenetic and environmental risk factors, while the underpinning pathogenesis is marked with disrupted skin, lung and gut barriers, altered microbiome and local and systemic Th-2-driven immunological pathways. Those allergic conditions can comanifest or occur in temporal sequence. The hypothesis that has been proposed to clarify time sequence and associations of allergic disease is called allergic march. This concept means that allergic disorder starts in early infancy with the first hallmark of atopy and atopic dermatitis and then appears food allergy, and later in childhood comes asthma and allergic rhinitis. Some investigators presumed that the underlying allergic inflammation of the skin could progress from atopic dermatitis to asthma. In addition, some preventive measures like improving skin barrier before skin disease onset can reduce the risk for respiratory allergy. Those observations support the causal link between atopic dermatitis and asthma. Although described longitudinal appearance of all allergic diseases was noticed only in small proportion (~7%) of children [6, 7], others had different trajectories of one or more allergic diseases which can occur in different point of time in childhood. Last explanations are talking about a cluster of coexistence-related allergic diseases rather than a progression.

### **2. Atopic dermatitis, disrupted skin barrier and allergic sensitization: is it the beginning?**

Atopic dermatitis is the most common chronic skin disorder in childhood. It appears in early childhood with dry, itchy skin and eczema on the cheeks, wrists and other parts of the body. Up to 20% of children experience AD in childhood. The majority outgrows eczema, but one proportion of them continues to have symptoms into adulthood [8]. According to the recently published cohort, six latent classes representing subphenotypes of AD were identified. These classes can be summarized in four classes as follows: unaffected individual or transient AD (61.9%); early-onset-persistent AD (10.7%); early-onset late resolving, early-onset early resolving and mid-onset resolving by age 11 years of age (16.5%); and later-onset AD after age 3.5 years (10.9%) [9].

AD is a systemic disorder characterized by disrupted skin barrier. It is considered that factors associated with damage of skin barrier are complex and influenced by a combination of structural, genetic, environmental and immunological factors. Structural changes are caused by altered lipid composition, decreased structural proteins, increased skin pH and reduced skin microbiome diversity. Cutaneous permeability defects can be assessed by measuring transepidermal water loss (TEWL) which correlates with disease severity. Several genetic defects encoding skin barrier proteins contribute to the breakdown of skin barrier. Inherited loss-of-function mutations in filaggrin gene, which encodes structural epidermis proteins, are

**5**

asthma [28].

*Allergic March*

*DOI: http://dx.doi.org/10.5772/intechopen.85553*

epithelium of asthma patients [14].

associated with early-onset AD that is more often persistent and closely related with asthma and food allergy [10]. Polymorphisms in the thymic stromal lymphopoietin (TSLP) gene, SPINK5 gene and corneodesmosin have also been linked to AD and the development of food allergy [11–13]. The inflammatory responses induced by AD are manifested by increased production of Th2 cytokines such as IL-4, IL-13, IL-25, IL-33 and TSLP. TSLP is one of the major inductors of systemic Th2 response, and it is considered that it could be the link between skin and respiratory allergy. It is expressed in skin keratinocytes, pulmonary airway and intestinal epithelium, while increased expression was observed in the skin of AD patients and respiratory

Skin microbiome dysbiosis is characterized by the dominance of *Staphylococcus aureus* which through various mechanisms worsens chronic skin inflammation [15]. Skin barrier dysfunction is associated with innate immune activation that results in dysregulated immune response to environmental antigens (like allergens and bacteria) and skin inflammation leading to the evolution of allergic sensitization [16]. Several studies on animals and humans support the concept that damaged skin promotes sensitizations. In mouse, exposure to egg and peanuts through disrupted skin induces sensitization [17] and, after exposure to egg aerosol, could induce asthma-like airway hyperresponsiveness [18]. In children, applications of peanut oil to inflamed skin were positively associated with the development of peanut food allergies [19], and the use of wheat-containing facial soap was positively associated with the development of wheat food allergy [20]. Application of oat-based creams on the skin of children with AD can induce oat sensitization in one third of children [21]. The concept of allergic march has been supported by cross-sectional and longitudinal birth cohort studies. Several birth cohorts have shown associations between early-onset AD and development of asthma and allergic rhinitis in school age [22, 23]; risk is greater in children with early-onset persistent AD phenotype [24]. Children with AD and allergic sensitization had increased risk of food allergy, asthma and allergic rhinitis compared to non-sensitized children without AD [25]. Food sensitizations in the first 2 years of life were associated with increased risk of asthma and allergic rhinitis in school age [26]. Peanut, milk and egg food allergy also increased the risk of developing asthma and rhinitis later in childhood [27]. Meta-analyses of birth cohort studies which investigated atopic march observed that early-life food sensitization was associated with an increased risk of infantile eczema, childhood wheeze/asthma, eczema and allergic rhinitis and young adult

The development of sensitization is complex, and except skin barrier defect and environmental allergen exposure, the presence of other factors is important because they may function as adjuvants, and some of them are bacterial colonization of the skin, allergens with intrinsic protease activity and exogenous adjuvants [29].

Allergic diseases of the skin, gut and lung are complex disorders with multiple phenotypes and underlying genotypes. They occur as a result of environmental exposures during early life in individuals with genetic susceptibility to allergy. Gene-environment interactions are accountable for different influences of the environment on individual level. There are several hypotheses of allergy increase in the twentieth century. According to the *hygiene hypothesis*, decreased exposure to microorganisms in modern society, through increased hygiene and decreased prevalence of infection in early life, disrupts immune tolerance and directs immu-

**3. Why is allergy increasing? Hypothesis-driven strategy**

nological reaction toward Th2 direction [30].

#### *Allergic March DOI: http://dx.doi.org/10.5772/intechopen.85553*

*Rhinosinusitis*

young adult age.

appearance of allergic sensitization to pollen of grass, weed and tree pollen, and the beginning of allergic rhinoconjunctivitis which persists in adolescence and the

asthma-chronic obstructive pulmonary disease overlap syndrome [5].

allergic diseases rather than a progression.

**it the beginning?**

AD after age 3.5 years (10.9%) [9].

At the same time, remission of atopic dermatitis and food allergy is noticed, while asthma and rhinitis symptoms continue. Sensitizations to pollen and cross-reactions to nuts, fresh fruits and vegetables may induce oral allergy syndrome, the type of food allergy that occurs in the school age. Asthma may disappear in teenage years, but after some period of remission, skin and respiratory symptoms can appear once again. In early adulthood, skin and lung symptoms are related to tobacco smoking, occupational exposures and lifestyle, and they manifest like contact dermatitis or

Atopic dermatitis, food allergy, asthma and allergic rhinitis in childhood share the common genetic, epigenetic and environmental risk factors, while the underpinning pathogenesis is marked with disrupted skin, lung and gut barriers, altered microbiome and local and systemic Th-2-driven immunological pathways. Those allergic conditions can comanifest or occur in temporal sequence. The hypothesis that has been proposed to clarify time sequence and associations of allergic disease is called allergic march. This concept means that allergic disorder starts in early infancy with the first hallmark of atopy and atopic dermatitis and then appears food allergy, and later in childhood comes asthma and allergic rhinitis. Some investigators presumed that the underlying allergic inflammation of the skin could progress from atopic dermatitis to asthma. In addition, some preventive measures like improving skin barrier before skin disease onset can reduce the risk for respiratory allergy. Those observations support the causal link between atopic dermatitis and asthma. Although described longitudinal appearance of all allergic diseases was noticed only in small proportion (~7%) of children [6, 7], others had different trajectories of one or more allergic diseases which can occur in different point of time in childhood. Last explanations are talking about a cluster of coexistence-related

**2. Atopic dermatitis, disrupted skin barrier and allergic sensitization: is** 

Atopic dermatitis is the most common chronic skin disorder in childhood. It appears in early childhood with dry, itchy skin and eczema on the cheeks, wrists and other parts of the body. Up to 20% of children experience AD in childhood. The majority outgrows eczema, but one proportion of them continues to have symptoms into adulthood [8]. According to the recently published cohort, six latent classes representing subphenotypes of AD were identified. These classes can be summarized in four classes as follows: unaffected individual or transient AD (61.9%); early-onset-persistent AD (10.7%); early-onset late resolving, early-onset early resolving and mid-onset resolving by age 11 years of age (16.5%); and later-onset

AD is a systemic disorder characterized by disrupted skin barrier. It is considered that factors associated with damage of skin barrier are complex and influenced by a combination of structural, genetic, environmental and immunological factors. Structural changes are caused by altered lipid composition, decreased structural proteins, increased skin pH and reduced skin microbiome diversity. Cutaneous permeability defects can be assessed by measuring transepidermal water loss (TEWL) which correlates with disease severity. Several genetic defects encoding skin barrier proteins contribute to the breakdown of skin barrier. Inherited loss-of-function mutations in filaggrin gene, which encodes structural epidermis proteins, are

**4**

associated with early-onset AD that is more often persistent and closely related with asthma and food allergy [10]. Polymorphisms in the thymic stromal lymphopoietin (TSLP) gene, SPINK5 gene and corneodesmosin have also been linked to AD and the development of food allergy [11–13]. The inflammatory responses induced by AD are manifested by increased production of Th2 cytokines such as IL-4, IL-13, IL-25, IL-33 and TSLP. TSLP is one of the major inductors of systemic Th2 response, and it is considered that it could be the link between skin and respiratory allergy. It is expressed in skin keratinocytes, pulmonary airway and intestinal epithelium, while increased expression was observed in the skin of AD patients and respiratory epithelium of asthma patients [14].

Skin microbiome dysbiosis is characterized by the dominance of *Staphylococcus aureus* which through various mechanisms worsens chronic skin inflammation [15]. Skin barrier dysfunction is associated with innate immune activation that results in dysregulated immune response to environmental antigens (like allergens and bacteria) and skin inflammation leading to the evolution of allergic sensitization [16]. Several studies on animals and humans support the concept that damaged skin promotes sensitizations. In mouse, exposure to egg and peanuts through disrupted skin induces sensitization [17] and, after exposure to egg aerosol, could induce asthma-like airway hyperresponsiveness [18]. In children, applications of peanut oil to inflamed skin were positively associated with the development of peanut food allergies [19], and the use of wheat-containing facial soap was positively associated with the development of wheat food allergy [20]. Application of oat-based creams on the skin of children with AD can induce oat sensitization in one third of children [21]. The concept of allergic march has been supported by cross-sectional and longitudinal birth cohort studies. Several birth cohorts have shown associations between early-onset AD and development of asthma and allergic rhinitis in school age [22, 23]; risk is greater in children with early-onset persistent AD phenotype [24]. Children with AD and allergic sensitization had increased risk of food allergy, asthma and allergic rhinitis compared to non-sensitized children without AD [25]. Food sensitizations in the first 2 years of life were associated with increased risk of asthma and allergic rhinitis in school age [26]. Peanut, milk and egg food allergy also increased the risk of developing asthma and rhinitis later in childhood [27]. Meta-analyses of birth cohort studies which investigated atopic march observed that early-life food sensitization was associated with an increased risk of infantile eczema, childhood wheeze/asthma, eczema and allergic rhinitis and young adult asthma [28].

The development of sensitization is complex, and except skin barrier defect and environmental allergen exposure, the presence of other factors is important because they may function as adjuvants, and some of them are bacterial colonization of the skin, allergens with intrinsic protease activity and exogenous adjuvants [29].
