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

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

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 trajectories that form clusters [62].

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

to pollen. These children develop a systemic IgE sensitization to grass pollens in the second or third pollen season following the onset of their rhinitis symptoms [66, 67]. If patients with LAR have AR over time, this supports atopic march.

### **5. Can we prevent and/or stop atopic march?**

Better understanding of underpinning mechanisms of atopic dermatitis and atopic comorbidities as well as environmental risk factors induces further researches of preventive interventions aimed at stopping atopic march. Those interventions could be started during pregnancy and early life among healthy or high-risk infants before onset of disease (primary prevention) or among children with one atopic disease in order to prevent appearance of other atopic comorbidities (secondary prevention).

Disrupted skin barriers promote sensitizations and increase the risk for allergic disease. Improvement in skin barrier through regular application of emollients beginning in the neonatal period can prevent AD among high-risk children. Protective effect was observed if treatment lasted up to 6–8 months of age [68–70]. There was favorable effect at the 12 months of age, even after treatment was ceased [69]. These researches support original hypothesis of skin barrier dysfunction as a beginning of atopy march, but it is still unclear if this protective effect is longlasting or onset of AD is delayed. The effect of emollients on food allergy was unclear. Only one research showed a trend for decreased food sensitization at 6 and 12 months of age [69], while two other were not powered to measure food sensitization [68, 70]. Some of undergoing studies aim to investigate the effect of emollients in prevention of AD among general population.

Local and system inflammatory response is a hallmark of AD, and anti-inflammatory therapy is effective in control of exacerbations, but study of Schneider et al. showed ineffectiveness of pimecrolimus in stopping atopic march [71]. Skin microbiome dysbiosis can increase the risk for onset or exacerbation of AD and comorbidities [72]. Recent researches showed that topical application of skin commensal bacteria can improve lesions in AD [73, 74]. Apart from local use of bacteria, the great interest of researchers is the role of probiotics in protection of allergy. Several studies have shown positive effect of probiotics like that adding *Lactobacillus rhamnosus* in diet of pregnant women can reduce the risk of AD [75]. Adding probiotics like *Bifidobacterium lactis*, *Lactobacillus salivarius* or *Lactobacillus GG* to the infant formula reduced the severity of AD [76]. But recent randomized control trial has shown opposite result. The study concluded that early supplementation with LGG in the first 6 months of life does not appear to prevent eczema at 2 years of age [77]. However, systematic reviews and meta-analyses report protective effect of the probiotics for the primary prevention of atopic dermatitis [78–80]. Probiotics are ineffective in prevention of asthma, food allergy and allergic rhinitis. Medical societies like the American Academy of Pediatrics, the European Academy of Allergy and Clinical Immunology and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition do not recommend the use of probiotics for primary prevention of allergic disease [49, 81–83]. The World Allergy Organization recommends the use of probiotics in diet of mothers of high-risk infants during pregnancy and lactation and in diet of those infants in order to prevent AD [84]. There is no consensus for the most effective specific strain of probiotics. The strain, dosage, timing of introduction and duration of probiotics usage are still uncertain. These questions are the aim of the future investigations.

Early introduction of allergenic food like peanut and egg can prevent food allergy, but the effect on other allergic diseases is not known. Exposure to furry pets

**9**

*Allergic March*

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

vitamin D in allergy [86, 87].

not clear [92, 93].

**6. Conclusion**

coexistence of allergic disease.

in home like dogs and cats in early life can prevent sensitization, but this protective effect can be modified by endotoxin exposure [85]. Deficiency of vitamin D has been associated with onset and exacerbation of allergy. According to this immunomodulatory effect, it has been assumed that supplementation of vitamin D might protect against allergy. But recent researches does not support protective role of

In the prevention of allergic diseases, protective effect was observed for antihistamines. In infants with atopic dermatitis or with high risk for allergy, ketotifen treatment was associated with lower incidence of asthma [88], while the use of cetirizine decreased the risk for asthma in grass pollen-sensitized children [89]. Allergen immunotherapy (AIT) has been used over the last 100 years and is the only therapy with disease-modifying effect. The role of AIT in primary and secondary prevention was investigated in several studies. Sublingual AIT applied for the primary prevention of allergy among high-risk infants has no protective effect on the developing of first allergic disease [90]. Oral AIT decreased the risk of asthma, among children with grass pollen allergic rhinitis [91]. Recent systematic review and meta-analysis found no evidence that AIT decreased the risk for developing a first allergic disease. However, AIT reduced the risk of asthma among patients with allergic rhinitis. This effect was observed 2 and more years after the AIT was completed. AIT can reduce the onset of new sensitizations, but the evidence was

Allergic diseases like atopic dermatitis, asthma and allergic rhinitis have sequential appearance with typical peaks of incidence during childhood. This temporal association is observed in the whole children population, and it starts with atopic dermatitis and food allergy in infancy, followed with asthma in the preschool age and finishes with allergic rhinitis. During growing up, the remission of atopic dermatitis and asthma was noticed, while symptoms of allergic rhinitis persist through adolescence and young adult age. The occurrence of all allergy diseases among the same child in temporal appearance was noticed only in smaller proportion of children in which causal link between AD, asthma and AR can be presumed; while, among others, common occurrence of allergic diseases follows different trajectories, without typical allergic sequence. For those children, complex interplay of allergic predisposition, systemic and local immunological responses and environmental influences during maturation of immune system triggers the appearance of those

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

*Rhinosinusitis*

(secondary prevention).

to pollen. These children develop a systemic IgE sensitization to grass pollens in the second or third pollen season following the onset of their rhinitis symptoms [66, 67].

Better understanding of underpinning mechanisms of atopic dermatitis and atopic comorbidities as well as environmental risk factors induces further researches of preventive interventions aimed at stopping atopic march. Those interventions could be started during pregnancy and early life among healthy or high-risk infants before onset of disease (primary prevention) or among children with one atopic disease in order to prevent appearance of other atopic comorbidities

Disrupted skin barriers promote sensitizations and increase the risk for allergic disease. Improvement in skin barrier through regular application of emollients beginning in the neonatal period can prevent AD among high-risk children. Protective effect was observed if treatment lasted up to 6–8 months of age [68–70]. There was favorable effect at the 12 months of age, even after treatment was ceased [69]. These researches support original hypothesis of skin barrier dysfunction as a beginning of atopy march, but it is still unclear if this protective effect is longlasting or onset of AD is delayed. The effect of emollients on food allergy was unclear. Only one research showed a trend for decreased food sensitization at 6 and 12 months of age [69], while two other were not powered to measure food sensitization [68, 70]. Some of undergoing studies aim to investigate the effect of emollients

Local and system inflammatory response is a hallmark of AD, and anti-inflammatory therapy is effective in control of exacerbations, but study of Schneider et al. showed ineffectiveness of pimecrolimus in stopping atopic march [71]. Skin microbiome dysbiosis can increase the risk for onset or exacerbation of AD and comorbidities [72]. Recent researches showed that topical application of skin commensal bacteria can improve lesions in AD [73, 74]. Apart from local use of bacteria, the great interest of researchers is the role of probiotics in protection of allergy. Several studies have shown positive effect of probiotics like that adding *Lactobacillus rhamnosus* in diet of pregnant women can reduce the risk of AD [75]. Adding probiotics like *Bifidobacterium lactis*, *Lactobacillus salivarius* or *Lactobacillus GG* to the infant formula reduced the severity of AD [76]. But recent randomized control trial has shown opposite result. The study concluded that early supplementation with LGG in the first 6 months of life does not appear to prevent eczema at 2 years of age [77]. However, systematic reviews and meta-analyses report protective effect of the probiotics for the primary prevention of atopic dermatitis [78–80]. Probiotics are ineffective in prevention of asthma, food allergy and allergic rhinitis. Medical societies like the American Academy of Pediatrics, the European Academy of Allergy and Clinical Immunology and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition do not recommend the use of probiotics for primary prevention of allergic disease [49, 81–83]. The World Allergy Organization recommends the use of probiotics in diet of mothers of high-risk infants during pregnancy and lactation and in diet of those infants in order to prevent AD [84]. There is no consensus for the most effective specific strain of probiotics. The strain, dosage, timing of introduction and duration of probiotics usage are still uncertain. These

Early introduction of allergenic food like peanut and egg can prevent food allergy, but the effect on other allergic diseases is not known. Exposure to furry pets

If patients with LAR have AR over time, this supports atopic march.

**5. Can we prevent and/or stop atopic march?**

in prevention of AD among general population.

questions are the aim of the future investigations.

**8**

in home like dogs and cats in early life can prevent sensitization, but this protective effect can be modified by endotoxin exposure [85]. Deficiency of vitamin D has been associated with onset and exacerbation of allergy. According to this immunomodulatory effect, it has been assumed that supplementation of vitamin D might protect against allergy. But recent researches does not support protective role of vitamin D in allergy [86, 87].

In the prevention of allergic diseases, protective effect was observed for antihistamines. In infants with atopic dermatitis or with high risk for allergy, ketotifen treatment was associated with lower incidence of asthma [88], while the use of cetirizine decreased the risk for asthma in grass pollen-sensitized children [89]. Allergen immunotherapy (AIT) has been used over the last 100 years and is the only therapy with disease-modifying effect. The role of AIT in primary and secondary prevention was investigated in several studies. Sublingual AIT applied for the primary prevention of allergy among high-risk infants has no protective effect on the developing of first allergic disease [90]. Oral AIT decreased the risk of asthma, among children with grass pollen allergic rhinitis [91]. Recent systematic review and meta-analysis found no evidence that AIT decreased the risk for developing a first allergic disease. However, AIT reduced the risk of asthma among patients with allergic rhinitis. This effect was observed 2 and more years after the AIT was completed. AIT can reduce the onset of new sensitizations, but the evidence was not clear [92, 93].
