Abstract 

The progression of allergic diseases with the development of atopic dermatitis and food allergy in infancy and subsequent asthma and allergic rhinitis in the later childhood is known as 'atopic march'. There have been many arguments in favour of and against this concept. This article reviews the latest epidemiology, immunological mechanisms and translational implications in clinical practice and research, which is relevant to the dermatologists. The role of skin as a site of initiation and the potential for interventions on skin that may prevent subsequent allergic diseases is also highlighted.

Keywords: Allergic march, atopic dermatitis, atopic march, skin barrier

How to cite this article:
Dhar S, Jagadeesan S. Atopic March: Dermatologic perspectives. Indian J Dermatol 2022;67:265-72
   Introduction 

A sequence of progression of allergic diseases typically beginning with early onset of atopic dermatitis and food allergy and later, allergic asthma and allergic rhinitis has been termed 'atopic march'/'allergic march'.[1] The concept of atopic march has been put forward based on clinical evidence, epidemiological data and immunological mechanisms. These allergic conditions developing sequentially are found to have common genetic and environmental predisposing factors and are characterised by a 'type 2' effector response.[2] Atopic dermatitis, which is the earliest manifestation of 'atopic march', is strongly linked with other forms of allergic diseases including food allergies and allergic respiratory disease and might actually be a 'cause' for the ensuing increased risk of allergic diseases.[3]

However, the concept of atopic march has also received criticism and counter-arguments raising concerns that the concept may be over-simplified and the prevalence overstated. Some researchers have refuted the concept of atopic march, pointing out inadequacies in data collection and even reported a 'reverse atopic march'.[4]

We herein attempt to review this concept as per the current understanding; the epidemiology, immunological mechanisms and translational implications in clinical practice and research, particularly from a dermatologist's perspective. The role of skin as a site of initiation and particularly potential interventions on skin as a target for prevention of subsequent allergic diseases is also explored.

   Atopic Dermatitis and the Role of Skin in Food Allergy and Atopic March 

It is known that the epidermal barrier in neonates is weak, and the epidermal barrier is permeable with reduced barrier function (low levels of ceramides could be a contributing factor, which increase in the weeks following birth).[5],[6] Impaired skin barrier has been found to be associated with innate immune activation which result in dysregulated immune responses, which may further deteriorate the barrier function, thus feeding a loop of ongoing inflammation and injury.[7],[8],[9]

Various studies have reported interesting findings regarding epicutaneous sensitisation of allergens via an impaired skin barrier. In infants who developed food allergy at 2 years of age, increased transepidermal water loss (impaired barrier) could be demonstrated as early as 2 days of life.[10] Animal models, particularly mouse models have shown that epicutaneous disruption followed by exposure to peanut and egg allergens can induce sensitisation.[8],[11] In another mouse model, exposure to egg allergens epicutaneously induced not only atopic dermatitis-like skin lesions, but also asthma-like airway hyperresponsiveness.[11]

For atopic dermatitis too, a lot of evidence has surfaced regarding the role in allergic sensitisation. Children with early-onset atopic dermatitis before 6 months of age without concurrent food allergy had an increased risk of developing new-onset food and inhalant allergen sensitisation by 1 and 2 years of age, respectively.[12] Also, the link between the severity and age of onset of AD and development of food allergy is well established. Martin et al.[13] reported that infants with earlier onset and more severe atopic dermatitis were more likely to develop food allergy. Early-onset and persistent AD was also associated with a higher risk of developing allergic asthma (AA) and allergic rhinitis (AR) by 18 years of age.[14]

Taken together, this body of evidence points toward the role of deranged skin barrier and atopic dermatitis being starting points towards further allergic sensitisation and the progression of 'atopic march'.

Filaggrin and atopic march

Filaggrin (FLG) being the epidermal protein that plays an integral role in the regulation and the constitution of the skin barrier, the role of loss of function FLG mutations in the development of atopic march was explored. It was found that without AD, FLG mutant alleles were not associated with an increased risk of developing asthma. The studies indicate that the FLG mutations increase the risk for developing AD which then increases the risk of developing asthma, but not directly.[15],[16]

Thymic stromal lympho protein—A linking factor in atopic march?

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived IL-7-like cytokine which is involved in type 2 immune responses and is significantly associated with AD, AA, food allergies and AR.[17] Many studies have found TSLP to be a key factor in the pathogenesis of AD. Studies have proven that TSLP expressed by keratinocytes due to barrier impairment leads to epicutaneous sensitization and a subsequent aggravation of allergic asthma. Demehri et al.[18] have worked with mice models and have shown that TSLP was sufficient to induce allergen-induced sensitisation in the lungs even in the absence of epicutaneous sensitisation. Given the fact that variations in TSLP are independently associated with AD and asthma, this could be a genetic linking factor in the development of atopic march.

Altered cutaneous microbiome in AD

Interactions between the microbiota in the various compartments like the skin, intestines, lung, etc., have been shown to be significant in the development of allergic diseases. Alterations in the skin microbiome have been documented in AD patients when compared with healthy controls, particularly the increased growth of staphylococcus aureus. A reduction in the richness of the microbial diversity in the gut has also been seen but has not been proven to be causal for atopic march. The diet-microbiome hypothesis underlines that an increased consumption of Western diet (less fibre, more fat) may lead to altered microbial flora of the gut including change in the mileu of the immunomodulatory molecules like reduced production of short chain fatty acids (SCFA), which, in turn, may modulate the allergic responses.[19]

Dual allergen exposure hypothesis

Put forward by Gideon Lack, this hypothesis states that there is an increased risk of allergic sensitisation and induction of food allergy if there is exposure to environmental food allergens with impaired skin barrier or inflamed skin as seen in AD.[20] However, the risk is reduced if there is early exposure to oral food allergens as this may lead to the development of immune tolerance to food allergens. This has also been demonstrated in The Learning Early About Peanut (LEAP) trial where early exposure to peanut allergens in children who were at high risk of developing peanut allergy resulted in a reduction in the cumulative incidence of peanut allergy.[21] There is also evidence suggesting that early oral introduction of egg results in a reduction in the incidence of egg allergy[22]; however, the evidence does not seem to be consistent in the case of an early introduction of cow's milk.[21] Also, the protection seems to be allergen-specific and other than a food allergy, the effect on the development of other allergic diseases is not clear, till now.[23]

Atopic dermatitis with asthma and allergic rhinitis: Epidemiological evidence

The temporal association between atopic dermatitis and allergic asthma has been explored in various longitudinal and cross-sectional studies [Figure 1]. The population-based studies viz. Tasmanian Longitudinal Health study and Prevention of Allergy among Children in Trondheim (PACT) found that the odds of developing allergic asthma increased in children with early onset AD (within first 2 years of life).[23],[24] Also, AD occurring before 1.5 years of age was associated with persistent wheeze as per the findings of the Tucson Children's Respiratory Study (TCRS).[25]

Figure 1: Age at diagnosis showing the temporal sequence of atopic diseases.[2] Reproduced with permission from Ann Allergy Asthma Immunol 2018;120:131-7.4

Click here to view

As allergic rhinitis develops later in the sequence, the direct evidence linking longitudinal progression of AD to AR is less when compared with AD and AA. A Swedish birth cohort found that infantile onset AD was associated with development of AR at the age of 12.[26] Also, in the Dampness in Building and Health (DBH) study, children with physician-diagnosed AD had a nearly three-fold increased risk of developing AR.[27]

There have been also a certain number of studies which have looked at the sequential progression from AD to AA and then AR.[28],[29],[30],[31] A study by Dharmage et al.[32] found significantly increased incidence of AA and AR in the age 6–7 years, in children who developed AD by the age of 2 years.[33] A reduction in Eczema Area Severity Index (EASI) scores was seen to coincide with an increase in physician-diagnosed bronchial obstruction in the previous year in a prospective follow-up study of AD children.[29] Development of allergic rhinitis followed the same pattern as asthma, but was delayed compared to asthma. The evidence from the German mass allergen study also supports the temporal progression from AD to AA and then AA to AR along with a decline in the prevalence of the preceding allergic disease.[30],[31]

Immunological explanation of the atopic march

As discussed earlier, allergen exposure through the inflamed skin or impaired skin barrier seems to be the initial event of atopic march, resulting in specific T and B-cell responses. This could be facilitated by genetic disruptions (e.g. filaggrin mutations) or skin inflammation or disruption by other means.[2] It is noteworthy that protease allergens can induce sensitisation even when exposed to 'healthy' skin and also act as adjuvants to facilitate allergic sensitisation to other allergens.[2],[11]

Once the allergen enters the skin, it interacts with the immune components in the epidermis or the dermis; in AD, there is increased production of IL-4, IL-25, IL-33 and TSLP which recruit IL-5 and IL-13 producing type 2 cells which result in the development of type 2 inflammation (B cells undergo isotype class switching to become Immunoglobulin E producing cells). The dendritic cells and other immune cells also migrate from the skin to the draining lymph nodes and naïve T cells are stimulated to differentiate into allergen-specific TH2 cells which can lead to systemic inflammation. Also, the presence of allergen-specific TH2 response to one allergen could potentiate additional TH2 responses by a 'bystander' effect. Basophils, which are rich sources of IL-4, are recruited to the draining lymph node early in case of allergic stimuli (related to serum Immunoglobulin E levels, independent of antigen exposure) and can contribute to the bystander effect by promoting TH2 responses.[2],[11],[34],[35],[36],[37]

Atopic march: The criticisms

One of the main contentions against the framework of atopic march has been that its universality may be overestimated. The validity of the longitudinal and cross-sectional studies supporting the progression of atopic march has been questioned; many studies used loose 'yes' or 'no' questionnaires for diagnosing the conditions, without confirmation by physician; recall bias was not excluded, etc.[4] Moreover, this argument was given further strength by the findings of the Childhood Origins of Asthma cohort study where rigorous criteria (confirmed by 4 separate blinded investigators) were applied and AD within the first year of life was not found to be associated with asthma at 6 years of age.[38],[39]

Another important argument used to shoot down the atopic march hypothesis has been the use of 'umbrella terms' to describe allergic diseases and not allowing for the heterogeneity or the subsets in the population which may not progress in the classical fashion.[4] Martinez et al.[40] had reported that AD was a risk factor for transient early and persistent wheezers alone and not late-onset wheezers. Only a small proportion of AD patients seem to progress through the classic atopic march model.[41]

Some authors have also argued that the definition of atopic march is overly restrictive and have made a case for broadening the definition to include any allergic disease developing after AD.[4],[42] Another discrepancy cited is the case of adult-onset AA, which does not fit the traditional atopic march model and hints at alternate mechanisms.[4],[25],[42]

Strategies for prevention of atopic march

With the increasing prevalence and severity of allergic diseases, many researchers have tried several approaches in preventing the onset and progression of atopic march.

As per the current body of evidence, skin does appear a promising target for intervention in the prevention of allergic diseases. Taking into account the dual exposure hypothesis,[20] a combination of early oral introduction of food allergens and skin barrier repair interventions could help in a big way in primary prevention of atopic diseases.

The LEAP study that was published in 2015 was a landmark trial that looked at 640 infants of age 4-11 months, with a high risk of developing peanut allergy who were randomized to various treatment arms. The study led to the findings that early introduction of peanuts could prevent allergies in high-risk infants (contrary to the previous recommendations).[21] Later, the findings of the EAT study also supported the strategy of early introduction of oral food allergens as a route to tolerance. The narrow window of time allowed for tolerance induction and the need to introduce multiple food allergens are challenges in adopting this strategy.[43],[44]

The PEBBLEs pilot study in 2018 which studied the role of emollients in preventing AD and food sensitisation showed a promising non-significant trend in reducing food-sensitisation at the age of 6 and 12 months and AD at 12 months.[45] However, a large study by Dissanayake et al.[46] and two other large randomized controlled studies—the BEEP[47] and the Prevent ADALL[48] study in 2020, did not find differences between the control group and the emollient intervention group in decreasing incidence of AD (BEEP study also did not find differences in rates of food sensitisation and food allergy), which is disappointing. A major factor in the varying efficacy of the barrier repair interventions in various studies could be the type of emollients used. It is now known that tri-lipid based creams are the most effective in repairing barrier and reducing TEWL when compared with petrolatum-based creams[49] (both the BEEP and Prevent ADALL studies used petrolatum-based creams in their intervention arms). The pilot study by Lowe et al.[45] was the only one that used a tri-lipid cream and it showed a trend towards reduced risks of AD and food sensitization in infants at 6 and 12 months. Therefore, we need more well-designed studies taking care of the possible discrepancies to get a clearer verdict on the role of barrier repair interventions in preventing atopic march.[50]

Another major area of study with regard to prevention of the atopic march has been with the interventions directed at the microbiome.[19] The role played by commensal and pathologic microorganisms and repeated antibiotic exposures in leading to a type 2 inflammation have been studied. However, the efficacy of prebiotic- or probiotic- or synbiotic-based interventions in prevention of development of allergic diseases has yielded mixed findings so far.[19],[51]

Studies have also looked at the effects of optimal immunotherapy for AD in preventing atopic march, but by and large, no conclusive evidence in favour of this strategy has been obtained.[2],[52] Prophylactic antihistamines also do not seem to have a big role in prevention. A large trial that looked at 817 children with AD treated with high-dose cetirizine or placebo did not show any significant difference with regard to development of asthma.[53],[54]

Translation into clinical outcomes and avenues for further research

Allergen-specific immunotherapy has been postulated to change the natural course of allergic diseases besides alleviating the symptoms. Oral, sublingual, subcutaneous and epicutaneous routes of immunotherapy have been found to be effective in various studies.[55],[56] However, in the presence of documented serious adverse events,[57],[58] further research on allergen-specific immunotherapy should also explore the safety concerns besides the efficacy.

A recent nation-wide study from Taiwan also demonstrated that influenza vaccination was associated with lower incidental asthma risk in people with AD; however, more evidence is required to confirm this finding.[59]

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a type of cell-surface receptors that are expressed on immune cells and certain antibodies developed against Siglecs have been found to have pro-apoptotic effect on eosinophils. The use of humanized mouse models has been recommended to further explore the therapeutic role of these molecules in atopic diseases.[60]

   Conclusions 

The increasing incidence of atopic diseases world-wide which have a significant impact on the quality of life of the affected individuals makes it imperative that there is a better understanding of their genetic, immunological and epidemiological aspects. The concept of atopic march has been supported by longitudinal and cross-sectional studies and gives a framework to understand the pathophysiological mechanisms of these diseases and also offer opportunities for early therapeutic interventions. The many criticisms of this concept, however, necessitate studies which are better designed with better methods of data collection and which take into account the heterogeneity of the disease. From India, there is a paucity of data on atopic march as this would require studies with a long follow-up which is difficult to execute even in the premier institutes. As far as skin is concerned, the evidence for a strong link between impaired skin barrier and atopic diseases is accumulating. The present evidence on using emollients to prevent atopic disease progression shows mixed results though, and further research in this area is warranted. The same is true for the use of probiotics, prebiotics and synbiotics in the prophylaxis and treatment of AD. We need more controlled clinical trials to prove their efficacy conclusively.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Multiple Choice questions

Which of the following statements is not true regarding Thymic stromal lymphopoietin (TSLP)?TSLP is involved in type 2 immune responsesTSLP is an IL-5 type cytokineAssociated with AD, AR, AA and food allergiesCan cause allergen-induced sensitisation in the lungs in the absence of epicutaneous sensitisation.Which was the landmark study that led to the finding that early introduction of certain foods (peanuts) could prevent allergy in the high-risk infants?LEAP studyPEBBLE studyPACT studyBEEP studyIn the immunopathogenesis of atopic march, which among the following cells can contribute to the bystander effect by promoting TH2 responses?Dendritic cellsLangerhans cellsBasophilsB cellsDual allergen exposure hypothesis was put forward byDemehriDissanayakeMartinezLackWhich of the following statements is not true regarding filaggrin mutations?Plays an integral role in the regulation and the constitution of the skin barrierFLG mutations increase the risk for developing ADFLG mutant alleles associated with increased risk of developing asthma, independent of skin involvement.Role of FLG mutations in atopic march is being explored.Which of the following cannot be taken as a criticism of atopic march?Use of umbrella termsQuestionnaire- based studiesLack of confirmation by physiciansCommon genetic and environmental predisposing factorsThe varying efficacy of barrier repair interventions as a preventive strategy for atopic march could be most attributed toType of emollient usedMeasurement parametersFlawed study designNone of the aboveThe following strategies have been explored in the prevention of atopic marchProphylactic antihistaminesInterventions directed at the microbiomeOptimal immunotherapySkin barrier repairAll of the aboveDirect evidence linking longitudinal progression is less for which sequence?AD to AAAD to ARAD to food allergyNone of the aboveWhich of the following is being discussed in this article as being starting points towards further allergic sensitisation and the progression of 'atopic march'?Food allergyImpaired skin barrierAltered immune responsesAirway hyperresponsiveness

Answers to Multiple-choice Questions

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