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

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 immunological reaction toward Th2 direction [30].

The beginning of hygiene hypothesis can be found in the David Strachan study from 1989. He observed that children who grew up in large families, with large number of older siblings, have less allergy and concluded that exposure to infection in early life (prenatally and early childhood) can prevent allergy [31]. This was confirmed by subsequent studies which linked less allergies with viral, bacterial or protozoic pathogens, transmitted by the fecal-oral route [32]. In 1990 hygiene hypothesis was supported by the observation that growing up on farms, regular contact with farm animals, stables and drinking unpasteurized milk were protective against allergy [33]. Farms are microbe-rich environment. Endotoxin, lipopolysaccharide, part of the outer layer of Gram-negative bacteria, is a marker of microbe surroundings. Its protective effect on atopy is produced by stimulation of immune system in Th1 direction. Preventive effect of endotoxin was seen only for early-life exposure (prenatal and early childhood, before development of allergic sensitization) [33, 34].

In the past 20 years, hygiene hypothesis was expanded by "old friends hypothesis" and "biodiversity hypothesis" [35, 36]. According to that hypothesis, contact with natural environment and its species (included microbes and parasites) protects against allergy. Children are exposed to the environment indirectly (through mother during prenatal life) and directly through the skin, gut and lung. Changes in the microbiome of the gut, skin and nose reduced microbiome diversity, and loss of symbiotic relationship with parasites and bacteria increased the risk for allergic disease [37]. Stability and diversity of gut microbiome are developed during early life (first 1000 days of postnatal life). This process can be influenced with different factors like mode of birth, infant feeding, fiber content in the mother's and child's diet and older siblings and exposure to pets and/or farm animals during childhood. Environment and dietary habits of mother and previous generations can change microbe diversity of neonate's trough epigenetic modification [38–42].

The second hypothesis *dual-allergen exposure hypothesis* is based on observations that allergic sensitization occurs through disrupted skin in AD, while early ingestion of food (before development of sensitization) allows development of oral tolerance [43]. Delayed introduction of solid food in infancy, which were recommended at the end of the twentieth was not protective for food allergy development [44]. This hypothesis was confirmed by several randomized clinical trials like Learning Early About Peanut Allergy (LEAP) and Enquiring About Tolerance (EAT). EAT was looking at the early introduction of six common food allergens at 3 months of age alongside breastfeeding compared to exclusive breastfed infants. It found that prevalence of egg allergy was lower among infants with early introduction [45]. LEAP assessed oral tolerance induction of peanut in group of high-risk infants between 4 and 11 months of age. It compared early and regular peanut consumption, average of 6 grams of peanut protein a week, in relation to completely avoiding peanut protein until 60 months of age. Early introduction of peanut protein results in significant reduction in peanut allergy. LEAP-On study was an extension of LEAP, in which protective effect of early introduction on peanut allergy was observed, even after cessation of peanut consumption [46, 47]. According to the findings from the studies like LEAP and EAT, guidelines for complementary feeding were remarkably changed. Pediatric and allergy societies have published consensus statements about early introduction of peanuts in high-risk infants. Also, current recommendations advise against delayed introduction of allergenic food into infant diet [48, 49].

Recent researches report about the important role of vitamin D in the pathogenesis of allergy. Vitamin D has positive impact on foetal lung development and an immunomodulatory effect; it stimulates differentiation of T lymphocytes, induction of Treg, while its deficiency induces Th2 response [50]. It was observed that rise in allergy prevalence occurs with increasing *vitamin D deficiency* especially among

**7**

trajectories that form clusters [62].

*Allergic March*

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

populations less exposed to the sun [51]. Deficit of vitamin D is associated with increased risk of peanut and egg food allergy, atopic dermatitis and asthma. The severe form of the diseases was observed with higher vitamin D deficiency [52, 53].

The allergic march is a real phenomenon, but there is a great debate about underlying mechanisms. Some researchers argue that there is a causal link between AD and other allergic diseases in childhood, in which AD is the first disease with local and systemic immunological response. Systemic response could trigger multisystem allergic disease. Longitudinal, prospective population-based cohorts or cohorts of high-risk infants reported about increased risk of asthma and allergic

Meta-analysis of 13 prospective birth cohort studies reported that odd ratio of asthma among children with AD in the first 4 years of life was 2.14% (95% CI 1.67–2.75), while the prevalence of asthma at the age of 6 years in eczema cohort studies was 29.5% (95% CI, 28.2–32.7%). The conclusion was that only one in every three children with eczema develops asthma during later childhood [4]. According to the results of high-risk birth cohort, 26.7% children with AD developed AR at 7 years of age, while the risk is higher among children with persistent and late-onset AD (OR 2.68, 95% CI 0.97–7.41) [57]. Sensitization to food allergen increased the risk for AR (OR 1.2, 95% CI 0.6–2.2), but the associations is stronger among children who had co-sensitization to both food and aeroallergens (OR 3.1, 95% CI 1.2–7.8) [28]. In the PASTURE study, children with early-persistent AD phenotype and those with late phenotype had an increased risk of developing allergic rhinitis. Early AD phenotype did not associate with AR, while the risk increased among children with early AD and food allergy [60]. According to these results, there was a new question: can we predict which phenotype of AD will be linked to asthma? More information come from longitudinal cohorts which analyzed different phenotypes of AD based on disease course and determined which classes are at highest risk for other atopic diseases [9, 60, 61]. According to the results from those studies, the early-onset, severe, persistent phenotype is associated with the highest risk for allergic comorbidities. Polysensitization, atopic heredity and filaggrin loss-of-mutation contribute to increased risk [62]. Children with high-risk phenotype of AD are candidates for preventive measures, which could delay or stop the occurrence of asthma and allergic rhinitis. But, it is considered that there is not enough evidence that AD causes asthma and allergic rhinitis. Paller et al., in recent review, presumed existence of inherited predisposition to one or more atopic disorders. Occurrence of the disease is a result of complex interplay between different underlying genotypes and environmental exposures during maturation of immune system, with tissue-specific peak time of clinical manifestation. Allergic diseases have different phenotypes and different

Simultaneously with AR, local allergic rhinitis (LAR) can appear in the preschool age. This entity of rhinitis is marked with local synthesis of specific IgE but without systemic allergy (allergic sensitizations and specific IgE). It was observed that LAR is a separate, well-defined phenotype of noninfectious rhinitis, which is stable over time [63, 64]. But, among younger patients and children, LAR can be the first step in the natural evolution to classical AR, especially when starting in the first two decades of life and in polysensitized patients [65]. In the German Multicentric Allergy Study, it was observed that over one third of the children developing a typical grass pollen-related seasonal AR had no serum-specific IgE

**4. Allergic march: causal link or cluster of related diseases**

rhinitis among children with previous or current AD [54–59].

*Rhinosinusitis*

modification [38–42].

The beginning of hygiene hypothesis can be found in the David Strachan study from 1989. He observed that children who grew up in large families, with large number of older siblings, have less allergy and concluded that exposure to infection in early life (prenatally and early childhood) can prevent allergy [31]. This was confirmed by subsequent studies which linked less allergies with viral, bacterial or protozoic pathogens, transmitted by the fecal-oral route [32]. In 1990 hygiene hypothesis was supported by the observation that growing up on farms, regular contact with farm animals, stables and drinking unpasteurized milk were protective against allergy [33]. Farms are microbe-rich environment. Endotoxin, lipopolysaccharide, part of the outer layer of Gram-negative bacteria, is a marker of microbe surroundings. Its protective effect on atopy is produced by stimulation of immune system in Th1 direction. Preventive effect of endotoxin was seen only for early-life exposure (prenatal

and early childhood, before development of allergic sensitization) [33, 34].

In the past 20 years, hygiene hypothesis was expanded by "old friends hypothesis" and "biodiversity hypothesis" [35, 36]. According to that hypothesis, contact with natural environment and its species (included microbes and parasites) protects against allergy. Children are exposed to the environment indirectly (through mother during prenatal life) and directly through the skin, gut and lung. Changes in the microbiome of the gut, skin and nose reduced microbiome diversity, and loss of symbiotic relationship with parasites and bacteria increased the risk for allergic disease [37]. Stability and diversity of gut microbiome are developed during early life (first 1000 days of postnatal life). This process can be influenced with different factors like mode of birth, infant feeding, fiber content in the mother's and child's diet and older siblings and exposure to pets and/or farm animals during childhood. Environment and dietary habits of mother and previous generations can change microbe diversity of neonate's trough epigenetic

The second hypothesis *dual-allergen exposure hypothesis* is based on observations that allergic sensitization occurs through disrupted skin in AD, while early ingestion of food (before development of sensitization) allows development of oral tolerance [43]. Delayed introduction of solid food in infancy, which were recommended at the end of the twentieth was not protective for food allergy development [44]. This hypothesis was confirmed by several randomized clinical trials like Learning Early About Peanut Allergy (LEAP) and Enquiring About Tolerance (EAT). EAT was looking at the early introduction of six common food allergens at 3 months of age alongside breastfeeding compared to exclusive breastfed infants. It found that prevalence of egg allergy was lower among infants with early introduction [45]. LEAP assessed oral tolerance induction of peanut in group of high-risk infants between 4 and 11 months of age. It compared early and regular peanut consumption, average of 6 grams of peanut protein a week, in relation to completely avoiding peanut protein until 60 months of age. Early introduction of peanut protein results in significant reduction in peanut allergy. LEAP-On study was an extension of LEAP, in which protective effect of early introduction on peanut allergy was observed, even after cessation of peanut consumption [46, 47]. According to the findings from the studies like LEAP and EAT, guidelines for complementary feeding were remarkably changed. Pediatric and allergy societies have published consensus statements about early introduction of peanuts in high-risk infants. Also, current recommendations advise against delayed introduction of allergenic food into infant diet [48, 49].

Recent researches report about the important role of vitamin D in the pathogenesis of allergy. Vitamin D has positive impact on foetal lung development and an immunomodulatory effect; it stimulates differentiation of T lymphocytes, induction of Treg, while its deficiency induces Th2 response [50]. It was observed that rise in allergy prevalence occurs with increasing *vitamin D deficiency* especially among

**6**

populations less exposed to the sun [51]. Deficit of vitamin D is associated with increased risk of peanut and egg food allergy, atopic dermatitis and asthma. The severe form of the diseases was observed with higher vitamin D deficiency [52, 53].
