Research Progress in Atopic March

Abstract

The incidence of allergic diseases continues to rise. Cross-sectional and longitudinal studies have indicated that allergic diseases occur in a time-based order: from atopic dermatitis and food allergy in infancy to gradual development into allergic asthma and allergic rhinitis in childhood. This phenomenon is defined as the “atopic march”. Some scholars have suggested that the atopic march does not progress completely in a temporal pattern with genetic and environmental factors. Also, the mechanisms underlying the atopic march are incompletely understood. Nevertheless, the concept of the atopic march provides a new perspective for the mechanistic research, prediction, prevention, and treatment of atopic diseases. Here, we review the epidemiology, related diseases, mechanistic studies, and treatment strategies for the atopic march.

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published: 27 August 2020
doi: 10.3389/fimmu.2020.01907
Frontiers in Immunology | www.frontiersin.org 1August 2020 | Volume 11 | Article 1907
Edited by:
Christiane Hilger,
Luxembourg Institute of
Health, Luxembourg
Reviewed by:
Jarmila Celakovska,
Charles University, Czechia
Simon Blank,
Technical University of
Munich, Germany
*Correspondence:
Yufeng Zhou
yfzhou1@fudan.edu.cn
Specialty section:
This article was submitted to
Immunological Tolerance and
Regulation,
a section of the journal
Frontiers in Immunology
Received: 07 May 2020
Accepted: 15 July 2020
Published: 27 August 2020
Citation:
Yang L, Fu J and Zhou Y (2020)
Research Progress in Atopic March.
Front. Immunol. 11:1907.
doi: 10.3389/fimmu.2020.01907
Research Progress in Atopic March
Lan Yang1, Jinrong Fu 1and Yufeng Zhou 1,2
*
1Institute of Pediatrics, Children’s Hospital of Fudan University, The Shanghai Key Laboratory of Medical Epigenetics,
International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of
Biomedical Sciences, Fudan University, Shanghai, China, 2National Health Commission (NHC) Key Laboratory of Neonatal
Diseases, Fudan University, Shanghai, China
The incidence of allergic diseases continues to rise. Cross-sectional and longitudinal
studies have indicated that allergic diseases occur in a time-based order: from atopic
dermatitis and food allergy in infancy to gradual development into allergic asthma
and allergic rhinitis in childhood. This phenomenon is defined as the “atopic march”.
Some scholars have suggested that the atopic march does not progress completely
in a temporal pattern with genetic and environmental factors. Also, the mechanisms
underlying the atopic march are incompletely understood. Nevertheless, the concept
of the atopic march provides a new perspective for the mechanistic research, prediction,
prevention, and treatment of atopic diseases. Here, we review the epidemiology, related
diseases, mechanistic studies, and treatment strategies for the atopic march.
Keywords: atopic dermatitis, asthma, food allergy, allergic rhinitis, atopic march
INTRODUCTION
In recent decades, the incidence of allergic diseases has continued to increase, affecting ∼20%
of the worldwide population, especially children (1). Cross-sectional and longitudinal studies
have suggested that allergic diseases occur following a time-based order: from atopic dermatitis
(AD) and food allergy in infancy to gradual development into allergic asthma (AA) and allergic
rhinitis (AR) in childhood. In terms of anatomic structure, it follows the spatial evolution of skin–
gastrointestinal tract–respiratory tract, and this phenomenon is defined as the “atopic march” (2).
Among the allergic diseases mentioned above, some resolve gradually to disappear with age,
whereas others continue for many years (3). Some studies have shown that the atopic march does
not progress completely in a temporal pattern with genes and the environment (4). Nevertheless,
the concept of the atopic march provides a new perspective for the mechanistic research, prediction,
prevention, and treatment of allergic diseases.
Here, we review the epidemiology, related diseases, mechanism of action, and treatment
strategies of the atopic march.
EPIDEMIOLOGY OF THE ATOPIC MARCH
AD: The First Manifestation of the Atopic March
AD is a chronic recurrent skin disease. Its clinical manifestations are chronic inflammation of the
skin, itching, and an impaired skin barrier. AD affects 3% of adults and ∼30% of children, and its
prevalence tends to increase with age (5). AD occurs in the early years of life. Some epidemiology
studies have shown that 45% of affected children had the condition before 6 months of age, 60%
before 1 year of age, and up to 85% before 5 years of age (6,7).

Yang et al. Research Progress in Atopic March
AD etiology is a combination of various factors involving
genes and the environment (8). Once external allergens contact
a damaged skin barrier, keratinocytes are stimulated to secrete
thymic stromal lymphopoietin (TSLP) and other factors in
conjunction with Langerhans cells (LCs) to stimulate T-helper
type 2 (Th2) immune responses. Then, the body is stimulated
to produce non-specific immunoglobulin (Ig)E (if children are
exposed to allergens such as mites for a long time, specific IgE
may appear). Subsequently, T cells, eosinophils, macrophages,
mast cells, and type 2 innate lymphoid cells (ILC2s) infiltrate to
secrete cytokines, resulting in local inflammation of the skin (9).
AD patients can be classified into two types based on whether
the IgE level is increased: intrinsic (normal IgE and non-allergic)
and extrinsic (high IgE level associated with increased disease
severity). Studies have shown that extrinsic AD increases the risk
of developing the atopic march (10,11).
AA and AR: The End Progression of the
Atopic March
AA is a common chronic airway disease characterized by
the inflammation, hyperresponsiveness, and remodeling of
airways (12–15). With modernization and industrialization, AA
incidence has increased year by year. This may be because
of lifestyle alterations, changes in environmental factors (e.g.,
increase in indoor dust mites and outdoor pollution), changes in
dietary habits, and many other factors. AR involves inflammation
of the nasal mucosa (16) and diminishes the quality of life of
sufferers (17).
Epidemiologic evidence has revealed a link between AA and
AR. A retrospective follow-up study reported the incidence of
AR to be higher in AA patients than in non-AA persons (18). In
another cohort study, Leynaert et al. demonstrated that 74–81%
of AA patients reported AR. Also, they found that AA occurred
in 2% of non-AR persons, but in 18.8% of AR patients upon
exposure to pollen or animal dander (19).
AR may lead to changes in the function of the lower airways
through three main mechanisms. Firstly, stimulation of the
nasal mucosa contracts bronchial smooth muscle through the
nasal–tracheal reflex. Secondly, various chemical mediators and
cytokines released by antigenic stimulation causing nasal mucosa
allergy are absorbed into blood, are transported to the lung
through circulation, and then act on the trachea and bronchi,
causing smooth muscle spasm. Thirdly, nasal inflammatory
mediators and secretions are discharged through the nasal
passage to the lower airways, resulting in a reduced β-adrenergic
receptor functional response (20).
Epidemiology of the Atopic March: Linking
AD With AA or AR
Dharmage et al. found, in infants who have AD within 2 years
of age, that the incidence of AA and AR increased significantly
during age 6–7 years. In particular, early-onset, persistent, and
IgE-positive AD led to a higher risk of developing AA and AR (9).
A longitudinal study on a Canadian birth cohort (2,311 children)
has shown that AD with sensitization at 1 year of age increased
the prevalence of AA and AR at 3 years of age more than 11- and
7-fold, respectively (21). In a recent report from Thailand, 102
children with AD (diagnosed at 1.5 years of age) were reviewed,
and subsequently, AR and AA were diagnosed in 61.8 and 29.4%,
respectively. Concomitantly, 67% of the AA patients also suffered
AR (22). A prospective cohort study (3,124 children aged 1–2
years) reported that, compared with children with no history
of AD, those once having AD, particularly moderate-to-severe,
early, and persistent AD, were more inclined to develop AA and
AR (23).
The discoveries mentioned above strongly support the natural
process of the atopic march.
Roles of Food Allergy
IgE-positive food allergy commonly coexists with AD in early
childhood as the earliest manifestation of the atopic march. In
2011, Japanese scholars conducted a retrospective questionnaire
survey on freshmen, and they found that AD occurred earlier
in those with accompanying food allergy. Also, having food
allergy was regarded as the biggest risk factor for the atopic
march (24). A family-based cohort study from Chicago revealed
that symptomatic food allergy, especially severe or multiple food
allergies, was closely related to AA in children aged ≥6 years.
Children with food allergy developed AA earlier than those
without food allergy (25). A survey of 2,222 infants with AD
aged 11.5–25.5 months showed that 64% of children diagnosed
with AD within 3 months of birth exhibited an IgE-mediated
sensitivity to milk, peanuts, or eggs. Also, in infants <12 months
of age, the proportion of infants with sensitivity to eggs, milk,
or peanuts increased with AD severity, but this phenomenon
was not manifested in children with AD after 1 year of age
(26). Among adults with AD, food allergy is relatively rare
(27–31). In addition, studies have shown that children sensitive
to milk in infancy subsequently exhibited aggravated airway
inflammation and increased airway responsiveness to histamine
(32,33). Remarkably, food allergy commonly exists together with
AD in infants. Therefore, it is worth exploring whether the link
between food allergy and AA or AR is related to AD or is a direct
consequence of the food allergy itself.
EoE: A New Manifestation of the Atopic
March?
Eosinophilic esophagitis (EoE) is a chronic esophageal
inflammatory disease induced by pollens or food allergens
(34). EoE patients are sensitive to allergen avoidance and
glucocorticoid therapy. Genome-wide association study
(GWAS) data have indicated that EoE shares some susceptible
genetic loci with other manifestations of the atopic march,
including polymorphisms in the signal transducer and activator
of transcription 6 gene (STAT6) and TSLP (35). In addition,
epidemiology studies have demonstrated EoE to be associated
with other allergic diseases. For example, Mohammad et al.
found that, of 449 EoE patients, the prevalence rates of AR, AA,
and AD were 61.9, 39, and 46.1%, respectively, and that up to
21.6% of EoE patients developed these three atopic diseases (36).
Another study involving 35,528 people reported that those with
IgE-positive food allergy were at a higher risk of EoE (37). A birth
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Yang et al. Research Progress in Atopic March
cohort study involving 130,435 children determined a positive
association between EoE and other allergic manifestations (34).
The studies mentioned above suggest the potential of EoE as
the fifth “member” of the atopic march, but this hypothesis is
controversial. For example, EoE occurs not only in childhood but
also after childhood. In addition, EoE can occur in individuals
without a history of atopy. Therefore, larger cohorts are
needed to study the epidemiologic relationship of EoE with
other manifestations of the atopic march and the mechanisms
involved (38).
POSSIBLE MECHANISMS UNDERLYING
THE ATOPIC MARCH
Dysfunction of the Skin Barrier
The skin is the foremost barrier for defense against external
stimuli, such as pathogens, environmental pollutants, and
ultraviolet light. As a component of the innate immune
system, the skin has several defensive functions, including
microbial, chemical, physical, and immune barrier. These
different functions of the skin barrier coordinate with each other
to resist external stimuli and maintain skin homeostasis.
Allergens can enter the body through damaged skin
to cause sensitization, which is defined as “transcutaneous
sensitization” (39). Transcutaneous sensitization can cause AD
and, subsequently, AA and AR (5). Studies have shown that
epicutaneous disruption induces sensitization after exposure to
peanut and egg allergens (40,41). Spergel et al. demonstrated that
repeated cutaneous exposure to egg allergens induced AD-like
skin inflammation and AA-like bronchial hyper-responsiveness
in a mouse model (41). Emerging studies now suggest that the
skin barrier protein filaggrin and epithelial cell-derived cytokines
such as TSLP, IL-25, and IL-33 might be related to the progression
of the atopic march.
Filaggrin
Filaggrin, a barrier protein, has important roles in the integrity
of the stratum corneum in terms of structure and composition.
Mutations in the filaggrin gene (FLG) can impair the barrier
function of the skin and induce an allergic response (42,43).
Several studies have shown patients with impaired or reduced
levels of filaggrin to be more susceptible to food sensitization
(44–46). Moreover, FLG mutations increase the risk of early and
severe AD and of AA in individuals who have had AD (47–49).
Thymic Stromal Lymphopoietin
TSLP is an interleukin (IL)-7-like epithelial cell-derived cytokine
which regulates the Th2 response (50). Zhang et al. found
that TSLP overexpression in keratinocytes aggravated AA-like
airway inflammation in mice subjected to ovalbumin (OVA)
sensitization intraperitoneally and OVA challenge intranasally
(51). Another in vivo study demonstrated that keratinocytic TSLP
was essential to induce a Th2 response in the skin and to trigger
aeroallergen-challenged AA phenotypes (52). In addition, Noti
et al. found that the effect of TSLP was enough to develop
experimental EoE-like phenotypes in mice (53). Also, they found
that TSLP in skin facilitated food allergy (54).
Interleukin-33
IL-33 is derived from epithelial cells and acts on macrophages,
ILC2s, Th2 cells, mast cells, and basophils through the
suppression of tumorigenicity 2/IL-1 receptor accessory protein
heterodimer (ST2/IL1RL1) (55–60). Several studies have explored
the roles of IL-33 in allergic diseases and found high expressions
of IL-33 in the skin or airway epithelial cells in AD or airway
inflammation (61–63). Blockade of ST2 expression can alleviate
food allergy in peanut- and OVA-challenged models (64,65).
Interleukin-25
IL-25 is also an epithelial cell-derived cytokine (66–68). Kim
et al. found that IL-25 inhibited filaggrin expression in the skin
and aggravated skin inflammation by coordinating with Th2
cytokines (69). Lee et al. reported OVA/alum-sensitized allergic
diarrhea to be inhibited in mice lacking IL-17RB, the receptor of
IL-25, whereas IL-25 overexpression in the intestine accelerated
the development of allergic diarrhea (70). Kang et al. found that
the mRNA expression of IL-25 was upregulated in rat lungs in a
TiO2-induced model of airway inflammation (71).
In conclusion, allergens (including food and aeroallergens)
enter the skin through the damaged skin barrier. Then, they
stimulate skin epithelial cells to release TSLP, IL-25, and IL-
33. This action activates some immune cells in the dermis [e.g.,
basophils, mast cells, dendritic cells (DCs), eosinophils, ILC2]
to secrete cytokines, and subsequently, Th2 cells are generated
and IgE production in local lymph nodes occurs. Th2 cells can
secrete more type 2 cytokines (e.g., IL-4) to activate more ILC2
and eosinophils, and IgE can act on mast cells and basophils.
This positive feedback causes skin inflammation and AD (72).
Furthermore, IgE, Th2, TSLP, IL-25, and IL-33 might enter
the digestive and respiratory tracts through blood circulation
to facilitate the development of AA, AR, and food allergy if
allergens are re-encountered (73,74) (Figure 1). Therefore, skin
barrier dysfunction might be a potential mechanism underlying
the atopic march.
Microbiome Alteration
Many microorganisms are colonized in the intestine, skin, and
respiratory tract (75) and influence health and disease. Several
studies have suggested that microbiome alteration plays roles in
atopic diseases locally or peripherally.
Kennedy et al. observed the skin microbiome dysbiosis in
early life of AD patients, and they also found that colonization
with commensal Staphylococci at 2 months was related to a lower
risk of AD at 1 year of age (76). Forno et al. and Abrahamsson
et al. reported that children who had AD at 6 months (77) and 2
years (78) of age had decreased intestinal microbial diversity at 1
month of life. A study of the KOALA birth cohort demonstrated
that infants with Clostridium difficile colonization in the gut at
1 month of life were inclined to develop AD and other atopic
diseases (79). Azad et al. demonstrated that infants who had a
positive skin prick test for food sensitization at 1 year had lower
gut microbial richness at 3 months (80). Abrahamsson et al.
reported that infants with low diversity in intestinal flora at 1
month of age were inclined to develop AA at school age (81).
In addition, Teo et al. determined that microbiome alteration
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Yang et al. Research Progress in Atopic March
FIGURE 1 | A possible model of the contribution of skin barrier dysfunction to the atopic march. Allergens (including food allergens and aeroallergens) enter the skin
through the damaged skin barrier. Then, they stimulate epithelial cells in the skin to release thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33. This
action activates some immune cells in the dermis (e.g., basophils, mast cells, DCs, eosinophils, and ILC2) to secrete cytokines, followed by the generation of T-helper
type 2 (Th2) cells and immunoglobulin E (IgE) production in local lymph nodes. Th2 cells can secrete more type 2 cytokines (e.g., IL-4) to activate more ILC2 and
eosinophils, and IgE can act on mast cells and basophils. This positive feedback causes skin inflammation and atopic dermatitis (AD). Furthermore, IgE, Th2 cells,
TSLP, IL-25, and IL-33 might enter the digestive tract and respiratory tract through blood circulation to facilitate the development of allergic asthma (AA), allergic
rhinitis (AR), and food allergy if allergens are re-encountered.
following respiratory infections during infancy might contribute
to the development of AA (82).
Moreover, some studies have shown that microbes regulate
atopic diseases by secreting metabolites. Furusawa et al. reported
that the short-chain fatty acids produced by several intestinal
microorganisms induced the proliferation of colonic regulatory
T cells (Tregs) and further ameliorated colitis and allergic
responses (83). Dysbiosis of Faecalibacterium prausnitzii, as
observed in AD, was found to reduce the production of butyrate
and propionate and further destroyed the intestinal mucosa.
Then, some toxins permeated into the circulation and induced
a Th2 immune response to facilitate skin inflammation and AD
development (84). Johnson et al. found that the polysaccharides
derived from Bacteroides fragilis induced CD4+Foxp3−T cell
activation and further prevented AA onset (85).
The studies mentioned above strongly suggest that
microbiome alteration may be involved in the atopic march.
However, further studies are needed to determine whether
microbiome shifts are a cause or a consequence of the
atopic march.
Epigenetic Factors
Epigenetic mechanisms can regulate gene expression and
constitute the cause of diseases. Several epigenome-wide
studies have revealed DNA methylation in blood to be
related to food allergy (86,87) and AA (88). Recently, Peng
et al. undertook DNA methylation analyses on the cohorts
of the Generation R Study (343 at mid-childhood and
839 newborns) in the Netherlands and Project Viva (396
at mid-childhood and 232 newborns) in the USA. Meta-
analyses linked the differential methylation profiles of the
peripheral blood of mid-childhood children with food allergens,
environmental/inhalant allergens, and atopic sensitization.
Multiple methylation site-related genes were enriched to
AA pathways, including eosinophil peroxidase (EPX), IL4,
interleukin 5 receptor A (IL5RA), and proteoglycan 2 (PRG2).
Furthermore, Peng et al. identified several methylation sites of
cord blood to be related to allergic phenotypes in mid-childhood
and that some methylation sites of cord blood were also
present in mid-childhood (89), which suggested a longitudinal
time trend.
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The findings mentioned above suggest that epigenetics may
have roles in allergic diseases. However, these studies show only a
correlation between epigenetics and the atopic march. Whether
epigenetic change is a cause or a result of the atopic march
warrants large and detailed longitudinal studies.
“Social” Dysfunction of Cells and
Molecules
Allergic reactions occur not only in the regions where allergens
are in contact directly but also in long-distance, non-contact
sites. This may be a systemic reaction of the body, and the
mechanisms are incompletely understood. Through literature
search, Luo et al. proposed a model of “social events” of cells
and molecules to explain the atopic march (90). Epithelial cells,
such as epidermal keratinocytes and airway epithelial cells, are
the first line of defense against allergen exposure and initiate the
inflammatory response by releasing proinflammatory cytokines.
Thus, epithelial cells are considered to be key participants in
allergic diseases. In this model, Luo and colleagues considered
that it is the atopic factors produced by epithelial cells locally,
not in the circulation, that drive allergy at different sites and
that certain allergens are the irritants that trigger the release of
atopic factors at different sites. Zhang et al. reported that TSLP
overexpression in keratinocytes induced AD-like symptoms
and also aggravated OVA-induced AA manifestations in mice.
However, they also found that increased TSLP expression in the
skin and, subsequently, peripheral blood was not sufficient to
induce lung inflammation (51). The atopic reaction in the lung
might be induced by the TSLP derived from the lung epithelia
themselves. Therefore, the atopic reaction in the skin and the
lung might be the consequence of the “social dysfunction” of
homologous epithelia and molecules such as TSLP. Despite its
rationality and interpretability, the theory of social events needs
sufficient evidence from in vivo and in vitro studies.
Interference of Other Predicted Genes
Marenholz et al. performed GWAS on 2,428 cases with AD
in infancy and AA in childhood and on 17,034 controls. They
identified seven susceptible sites associated with the atopic
march: FLG [1q21.3], AP5B1/OVOL1 [11q13.1], IL4/KIF3A
[5q31.1], IKZF3 [17q21], C11orf30/LRRC329,EFHC1 [6p12.3],
and rs99322 [12q21.3] (91).
Bioinformatics analyses by Gupta et al. revealed that the
atopic march involved 16 common pathogenic genes: IL4,IL5,
TSLP,RNASE3,IL13,IL10,IGHG4,IFNG,CCL11,FCER2,
RNASE2,FOXP3,KCNE4,CD4,IL4R, and CCL26 (92). These
genes were predicted through large-scale and high-throughput
bioinformatics analyses, and their roles in the atopic march need
to be determined through further experimentation.
Summarily, Paller et al. have reviewed the multifactorial
etiology of the atopic march, including skin barrier damage,
microbiome alteration, and epigenetic factors (93), and we
consider that “social” dysfunction of cells and molecules, and the
interference of other predicted genes, may also contribute to the
atopic march (Figure 2). However, further studies are required to
detail the relevant mechanisms.
ANIMAL MODELS FOR STUDIES ON THE
ATOPIC MARCH
The modeling process of Leyva-Castillo et al. consisted of two
phases. In the first phase, wild-type (WT) BALB/c mice were
treated with calcipotriol MC903 plus OVA through epicutaneous
sensitization. This led to increased levels of Th2 cytokines,
Th17 cytokines, and OVA-specific IgE and IgG1 in serum. In
the second phase, MC903-treated (epicutaneous) OVA-sensitized
mice underwent intranasal challenge with OVA. These mice
exhibited AA-like symptoms with increased mucus secretion,
eosinophil infiltration, and expression of Th2 cytokines (52).
In a model established by Han et al., WT BALB/c mice
were first treated with OVA plus TSLP via the intradermal
route (four times within 2 weeks). After 9 days, the mice were
challenged by OVA via the intranasal route for four consecutive
days. Consequently, the mice exhibited increased OVA-specific
IgE in serum as well as cellular and eosinophil infiltration in
the bronchoalveolar lavage fluid. Histopathology showed severe
inflammatory infiltrates in mouse lungs. In addition, periodic
acid–Schiff staining showed excessive goblet cell metaplasia and
mucus secretion (94).
Moreover, one study showed that epicutaneous exposure
to Aspergillus fumigates aeroallergens followed by intranasal
challenge with A. fumigates induced an allergic nasal response in
BALB/c mice (95).
In conclusion, the models mentioned above have one
similarity: the skin is used as a sensitization site, consistent
with the feature that AD is the initial manifestation during the
atopic march. These animal models facilitate the studies of the
mechanisms underlying the atopic march.
REFUTATIONS OF THE ATOPIC MARCH
Despite substantial epidemiologic and experimental evidence,
some scholars argued that the prevalence of the atopic march may
be overemphasized (96).
First, the methods of the data collection and disease
identification initiate one main concern. Considering the cost
and time required to make physician diagnoses, allergic disease
identification was often based on “yes” or “no” questions. In
existing epidemiologic surveys, the diagnosis of AD, AA, and
AR simply used “yes” or “no” questionnaires, and some even
lacked further physician identification (97–99). In addition,
deviations and over-reporting in questionnaire surveys from
some individuals led to an overestimation of the disease
prevalence (100). Another rebutted criticism of the atopic march
is the failure to consider disease heterogeneity or variations.
Martinez et al. found that AD patients were at a higher risk
of developing transient early AA and persistent AA, not late-
onset AA (97). This indicates that the association between
AD and AA may be restricted to specific AA subpopulations,
not universal. Moreover, some individual-level analyses did
not support the typical temporal pattern. At an individual
level rather than a large-scale population level, Belgrave et al.
demonstrated that only 3.1% of children followed the classical
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FIGURE 2 | The temporal pattern and the possible mechanisms of the atopic march. The temporal pattern of the atopic march is, in general, from atopic dermatitis
(AD) and food allergy in infancy to gradual development into allergic asthma (AA) and allergic rhinitis (AR) in childhood. Several mechanisms could underlie the atopic
march: skin barrier damage, microbiome alteration, “social” dysfunction of cells and molecules, epigenetic factors, and interference of other predicted genes.
atopic march procession (AD first, followed by AA and then
AR) and more than 90% of children with atopic manifestations
did not (101).
Unusually, a study from Italy found an evidence of a
“reverse” atopic march. The study included 745 children aged
6–9 years with AA only, without a history of food allergy or
AD. After a 9-years follow-up, 20% of the children were found
to have developed AD (102). In addition, the prevalence of the
atopic march differed in distinct countries. Colombian scholars
followed up 326 mother–infant pairs in a birth cohort study,
and they found that AA was the most common manifestation
by 24 months. The prevalence of recurrent AA was 7.1%
at 12 months and reached 14.2% at 24 months. However,
allergic symptoms induced by milk, egg, or other food allergens
were scarce, only 1.8%, and AD was not observed in any
cases (103).
Although these studies refute the concept of atopic march
to a certain extent, we cannot deny the contribution of the
theory of atopic march to the early prevention, diagnosis,
and treatment of allergic diseases. Future research on the
atopic march should improve the current data collection and
disease identification methods, not only relying on “yes” or
“no” questionnaires, take disease subtypes into account, and
perform the study in an individual level rather than only in a
group level.
PREVENTION AND TREATMENT
STRATEGIES FOR THE ATOPIC MARCH
Several measures used to prevent and treat allergic diseases are
expected to interfere with, delay, and block the natural process of
the atopic march.
Food Interventions
In most studies, breastfeeding for >6 months has been
recommended because it reduces not only the incidence of AD
but also of other allergic diseases (104). A 15-years follow-up
study of the German Infant Nutritional Intervention (GINI)
cohort has shown that, if breastfeeding is not possible, compared
with standard cow’s milk formula (CMF), the interventional
use of partial whey hydrolyzate (pHF-W) formula and extensive
casein hydrolyzate (eHF-C) formula in the first 4 months of
life has significant preventive effects on AD, and the eHF-
C formula also reduced the prevalence of AA and AR (105).
However, the mechanisms underlying the preventative effects of
hydrolyzed formulas are unknown. In addition, the assessment of
the effects of hydrolyzed formulas was based on parental reports
of physicians’ diagnosis, not on the clinical examinations. These
are the criticisms against the use of hydrolyzed formulas for the
prevention of allergic conditions.
Moreover, Wickens et al. found that supplementation with
Lactobacillus rhamnosus for the first 2 years of life reduced the
prevalence of AD by about half (106). However, further studies
are required to handle the uncertainties about whether other
probiotics are equally effective and how probiotics exert their
effects on allergic diseases.
Furthermore, the Learning Early About Peanut Allergy
(LEAP) trial demonstrated that, compared with children who
avoided peanut, sustained peanut consumption, beginning in the
first 11 months of life, significantly decreased the prevalence of
peanut allergy at 60 months of age in infants with high atopic
risk (107). In addition, a large-scale population-based prospective
study showed that early introduction of cow’s milk protein
as a supplement to breastfeeding might promote tolerance,
reducing the incidence of IgE-mediated cow’s milk protein
allergy (108).
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Environmental Prevention
Exposure to several environmental factors is closely related to
having allergic diseases. Studies have shown that smoke in the
environment increases children’s risk of allergic sensitization and
AA (109). Therefore, it is strongly recommended that all parents
should stop smoking tobacco. Dust mites, pollen, cockroaches,
pet fur, and fungi are common allergens, and avoiding exposure
to these allergens can reduce the sensitization of children at
high risk. However, it has also been proposed that there was
no correlation between house dust mite (HDM) exposure and
AA (110), and keeping pets (cats or dogs) in the home in the
first year after birth reduced the risk of sensitization to multiple
allergens during childhood, but it impaired lung function once
cat or dog sensitization has occurred, particularly in children
with a family history of AA (111). These controversial views are
initiating further research to evaluate their relevance.
Medical Treatment
Symptomatic Treatment
Antihistamines are used to relieve itching in AD patients and to
prevent skin damage aggravated by scratching. Ketotifen, an H1
antihistamine, significantly lowered AA risk in infants with AD
or other pre-asthmatic conditions (112,113). A double-blind,
randomized, placebo-controlled trial showed that compared to
placebo, cetirizine significantly reduced the incidence of AA in
AD patients sensitized to grass pollen or to HDM (114). However,
considering the side effects of antihistamines, a large number of
clinical trials are needed to evaluate the security of antihistamines
and the effectiveness of interventions in the natural course of
allergic diseases.
Glucocorticoid is also an effective anti-inflammatory
treatment for allergic diseases, and inhaled glucocorticoids has
now become the first-line treatment for AA (115). Although
the symptoms of AD and AA can be significantly improved
by glucocorticoids, it is prone to relapse after withdrawal. In
addition, there are many side effects. Therefore, glucocorticoids
should be prescribed with caution by the physicians.
Allergen-Specific Immunotherapy
Allergen-specific immunotherapy (ASIT), also known as
“desensitization therapy,” can alleviate allergy symptoms for a
long time and change the natural course of allergic diseases (116).
Several ASIT routes have been documented in preclinical studies,
including subcutaneous immunotherapy (SCIT), sublingual
immunotherapy (SLIT), epicutaneous immunotherapy (EPIT),
and oral immunotherapy (OIT). The recognized mechanism of
specific immunotherapy is stimulation of the secretion of IL-10
and transforming growth factor-βfrom Tregs, promotion of
the balance of Th1 cells/Th2 cells, and conversion of IgE to IgG
to block the IgE-mediated immune cascade (117,118). Zhong
et al. found that the clinical symptoms and quality of life of AD
patients with HDM sensitization could be improved after 2 years
of ASIT (119). Besh et al. demonstrated that combining basic
therapy with SCIT acquired significantly better results in AA
patients compared to basic therapy only (120). Karakoc-Aydiner
et al. found that the nasal symptom scores of children with AR
were significantly reduced after receiving dust mite allergen
vaccine through SCIT or SLIT (121). However, the lack of
security greatly limits the development of ASIT. For example,
the adverse reactions of SLIT mainly focus on local reactions,
such as oromucosal pruritus and gastrointestinal reaction
(122). In addition, almost all clinical trials related to OIT are
accompanied by one or several serious adverse reactions, such
as severe gastrointestinal reactions, systemic allergic reactions,
etc. (123). Long-term follow-up of milk OIT patients showed
that the complete immune tolerance rate after OIT treatment
was only 31% (124,125). Therefore, further research on ASIT
should be directed at the improvement of not only its efficacy but
also security.
Targeted Therapy
Omalizumab is a human monoclonal antibody against IgE.
In 2003, it was approved for the treatment of severe AA
in adolescents and adults. Esquivel et al. demonstrated that
omalizumab inhibited rhinovirus infections, illnesses, and
exacerbations of AA through specific binding to IgE (126).
Dupilumab is a human IgG4 monoclonal antibody against IL-4
receptor subunit alpha (IL-4Rα), and it can inhibit IL-4 and IL-13
signaling pathways by interacting with IL-4Rα(127). Dupilumab
has been approved by the US Food and Drug Administration
to treat infants with moderate-to-severe AD with poor results
from conventional treatment (128). Tezepelumab (AMG 157)
is a monoclonal antibody (G2λ) against TSLP. In one clinical
trial, tezepelumab treatment for 5–12 weeks blunted inhaled
allergen-induced AA attacks (129). Of note is that these targeted
therapy medicines are only licensed for use in certain allergic
diseases. Although the off-label uses or adjunct to treatment
for numerous allergic conditions have acquired encouraging
results, their potential efficacy still needs to be evaluated through
clinical trials.
BIOMARKERS OF THE ATOPIC MARCH
Although there are no reliable biomarkers to identify subjects
with high risk of atopic march, Davidson et al. have proposed
some recommendations recently for future research to explore
biomarkers, which would provide some possibilities to examine
the atopic march.
The relevant proposals are as follows: (1) to look at the
protein, RNA, and lipid signatures in infants before and after AD
using multi-omics approaches; (2) to analyze transcriptomics,
proteomics, metabolomics, and the cell types of infant blood
sequentially; (3) to perform sequential immune profiling of the
blood, including serology, cytokine profiles, and the evolution of
specific B and T cells; (4) to investigate the microbiomes in the
skin and gut from birth; and (5) to consider potential maternal
delivery effects for atopy (130).
CONCLUSION
The global increase of atopic diseases greatly lowers the quality
of life. The theory of atopic march facilitates our understandings
of the pathophysiology of atopic diseases and further promotes
the early detection, prevention, and treatment of children at
Frontiers in Immunology | www.frontiersin.org 7August 2020 | Volume 11 | Article 1907

Yang et al. Research Progress in Atopic March
risk of allergic diseases. Future studies on atopic march would
be directed at the following points. Firstly, the methods for
data collection should be improved and disease heterogeneity
or variations should be considered when performing substantial
epidemiologic surveys. Secondly, more detailed and logical
mechanisms, including genetic and environmental aspects,
should be explored to account for the temporal pattern, which
would pave the way for novel approaches for the prevention and
timely early treatment of the clinical manifestations, ultimately
reducing the allergy burden.
AUTHOR CONTRIBUTIONS
LY contributed to collection of references and manuscript
preparation. JF and YZ contributed to manuscript modifications.
All authors contributed to the article and approved the
submitted version.
FUNDING
This work was supported by grants from the National Key
R&D Program of China (2016YFC1305102 to YZ), National
Natural Science Foundation of China (81671561, 81974248 to
YZ), the International Joint Laboratory Program of National
Children’s Medical Center (EK1125180109 to YZ), Program
for Outstanding Medical Academic Leader (2019LJ19 to YZ),
and Shanghai Municipal Planning Commission of Science and
Research Fund (201740065 to YZ). Shanghai Pujiang Program
(16PJ1401600 to JF). Shanghai Committee of Science and
Technology (19ZR1406400 to JF).
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Conflict of Interest: The authors declare that the research was conducted in the
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