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Review Article
Open Access
The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and
Asthma
Selene K. Bantz, Zhou Zhu and Tao Zheng*
Section of Allergy and Clinical Immunology, Yale University, School of Medicine, New Haven, 06520, USA
*Corresponding author: Tao Zheng, The Section of Allergy and Clinical Immunology, Yale University School of Medicine, 300 Cedar Street, TAC-S469a, New Haven
CT, USA, E-mail: tao.zheng@yale.edu
Received date: Jan 21, 2014, Accepted date: Mar 31, 2014, Published date: Apr 07, 2014
Copyright: 2014 Bantz SK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The development of atopic dermatitis (AD) in infancy and subsequent allergic rhinitis and asthma in later
childhood is known as the atopic march. This progressive atopy is dependent on various underlying factors such as
the presence of filaggrin mutations as well as the time of onset and severity of AD. Clinical manifestations vary
among individuals. Previously it was thought that atopic disorders may be unrelated with sequential development.
Recent studies support the idea of a causal link between AD and later onset atopic disorders. These studies suggest
that a dysfunctional skin barrier serves as a site for allergic sensitization to antigens and colonization of bacterial
superantigens. This induces systemic Th2 immunity that predisposes patients to allergic nasal responses and
promotes airway hyperreactivity. While AD often starts early in life and is a chronic condition, new research signifies
that there may be an optimal window of time in which targeting the skin barrier with therapeutic interventions may
prevent subsequent atopic disorders. In this review we highlight recent studies describing factors important in the
development of atopic disorders and new insights in our understanding of the pathogenesis of the atopic march.
Introduction
Atopic diseases, including atopic dermatitis, allergic rhinitis, and
asthma have increased in frequency in recent decades and now affect
approximately 20% of the population worldwide. The concept of the
atopic march was developed to describe the progression of atopic
disorders from atopic dermatitis (AD) in infants to allergic rhinitis and
asthma in children [1]. Patients with AD may develop a typical
sequence of AD, allergic rhinitis and asthma at certain ages. Some may
have disease that persists for several years, whereas others may see
improvement or resolution with increasing age [2]. Atopy is defined as
a personal or familial propensity to produce IgE antibodies and
sensitization in response to environmental triggers [3]. Underlying
atopy has been considered to be critical in linking AD, allergic rhinitis
and asthma [1,4]. The risk of developing atopic diseases is complex
and the temporal pattern described in the atopic march may not be a
simple progression. The development of these diseases is strongly
influenced by both genetic and environmental factors. While these
disorders share risk factors, the nature and development of disease can
vary among individuals. Atopic diseases can be unrelated disorders
that develop sequentially along an atopic pathway or there may be a
causal link between eczema and the later-onset atopic respiratory
disorders. However, the concept of the atopic march has been
supported by cross-sectional and longitudinal studies [5-14] and is
further confirmed when examining data on the prevalence of each
atopic disease across population life spans as well as by experimental
evidence from mouse models.
Allergy
Citation:
Bantz SK, Zhu Z, Zheng T (2014) The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma. J Clin Cell
Immunol 5: 202. doi:10.4172/2155-9899.1000202
Page 2 of 8
clinical and biophysical parameters of patients with AD. Long-term
studies would be important to evaluate whether lipid barrier
replacement therapy reduces bacterial colonization or prevents
progression of the atopic march [21].
Allergy
Citation:
Bantz SK, Zhu Z, Zheng T (2014) The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma. J Clin Cell
Immunol 5: 202. doi:10.4172/2155-9899.1000202
Page 3 of 8
children without hay fever is unlikely to be causal or familial, but
rather the result of individual-specific covariates such as respiratory
tract infections. The study also showed that the contribution of eczema
to hay fever and asthma in childhood varies for different phenotypes
and is unlikely to be completely explained by familial confounding.
This suggested that infantile eczema is causal for some hay fever in
childhood, especially in asthmatic children (about 30%), compared to
about 10% of hay fever in children without asthma. This provides
further credence that it might be possible to prevent hay fever in
children with eczema by controlling their eczema and improving skin
barrier function [35].
Allergy
Citation:
Bantz SK, Zhu Z, Zheng T (2014) The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma. J Clin Cell
Immunol 5: 202. doi:10.4172/2155-9899.1000202
Page 4 of 8
importance of the dermal microbiome in the development of allergy
and asthma [61].
Although it has become evident that the mechanisms by which
allergen exposure occurs through impaired skin barriers can initiate
systemic allergy and predispose individuals to AD, allergic rhinitis,
and asthma, the cause of AD remains incompletely understood, and
the mechanisms of the atopic march are still largely unknown.
Allergy
Citation:
Bantz SK, Zhu Z, Zheng T (2014) The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma. J Clin Cell
Immunol 5: 202. doi:10.4172/2155-9899.1000202
Page 5 of 8
time periods with symptom-free skin, with an odds ratio of 0.54. In
particular, those with the R501X variant were unlikely to achieve
symptom-free skin without topical treatment and were about two
times more likely to use topical steroids during any 6-month interval
as compared to all others in the cohort [94]. These studies not only
demonstrate that FLG mutations increase the risk of eczema and
sensitization, but also that clinical outcomes may vary by location of
the FLG mutation and influence of other factors.
One study showed a significant association of two filaggrin gene
mutations with asthma and allergic rhinitis, but this association was
only seen in subjects with the co-existence of AD and was not
apparent in subjects without concomitant AD [67]. In addition,
filaggrin has not been found to be expressed in the human bronchial
epithelium nor beyond the inferior turbinates [95,96]; hence, filaggrin
mutations appear not to exert effects in the upper airway, suggesting
that the association of filaggrin mutations with other atopic disorders
is likely due to the common feature of allergen sensitization through
the skin. One study did find an association of FLG mutations with
peanut allergy [97]. Although it is possible that some patients with
peanut sensitization rather than true clinical allergy were included, this
strong association persisted despite multiple variations in peanut
allergy diagnostic criteria [98]. The association remained despite
asthma status, and the presence of eczema strengthened the
association though eczema did not seem to fully account for the
association. This study acknowledges that a dysfunctional skin barrier
may play a role in the pathogenesis of peanut allergy, and thus
supports the theory that sensitization in food allergy occurs in the skin
in some patients [97,98]. Peanut protein in household dust is
biologically active and related to household peanut consumption,
serving as a risk factor for the development of peanut allergy and as a
possible nidus for transcutaneous peanut exposure to a young child
with AD [99]. It is also possible that cross-sensitization with
aeroallergens such as birch protein that share homology with peanut
protein play a role in peanut sensitization in AD patients [98]. Oral
exposure to allergen, versus transcutaneous exposure, is thought to be
more tolerogenic. However, intestinal permeability is increased in
some patients with AD. It is unclear if this implies an additional route
of allergen penetration. The extent of filaggrin expression in the
gastrointestinal tract is currently unknown [97,98].
There is experimental evidence to support the hypothesis that
allergen penetration transcutaneously leads to systemic atopic
response [100,101]. The fact that asthma is found only in a subset of
filaggrin mutation carriers with AD supports the hypotheses that
asthma is secondary to allergic sensitization that occurs after
epidermal skin barrier impairment. Filaggrin mutations seem likely to
play a role in chronicity of disease and IgE sensitization in patients
with AD. Studies show that patients with early-onset AD and filaggrin
mutations have a tendency to have persistent disease into adulthood
[102]. AD patients carrying filaggrin mutations are significantly
associated with the extrinsic form of the disease (IgE-mediated
sensitization to inhalant or food allergens), and the development of
allergic rhinitis and asthma [91,103,104]. The filaggrin mutations
predisposing to asthma, allergic rhinitis, and allergic sensitization only
in the presence of AD strongly support the role of filaggrin in the
pathogenesis of AD and in the subsequent progression along the
atopic march. Expression of filaggrin gene is down-regulated in AD
skin by Th2 cytokines (IL-4 and IL-13) [105] and normal human
keratinocytes
by
sphingosylphosphorylcholine,
which
is
proinflammatory and proprurigenic in AD [106,107], suggesting that
filaggrin defects can develop as an acquired and/or genetic defect.
Allergy
Conclusion
Multiple lines of evidence (clinical, genetic and experimental
studies) suggest that previous expression of AD is a prerequisite for the
development of allergic rhinitis and asthma and specific sensitization,
highlighting the importance of the epidermal barrier in the
pathogenesis of these disorders. Whether AD in the atopic march is
necessary for progression to other atopic disorders remains to be
defined. To establish a causal relationship from AD to airway allergic
diseases, evidence of immunological mechanisms accounting for the
association and randomized controlled trials demonstrating an
effective intervention for AD with reduced subsequent asthma
incidence are still needed. It also is important to identify infants at risk
for developing lifelong chronic atopic diseases and utilize the critical
window of opportunity early in life for therapeutic intervention.
Therapy targeting the maintenance and repair of the epidermal barrier
in infants with AD may prevent the subsequent development of
asthma.
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Immunol 5: 202. doi:10.4172/2155-9899.1000202
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Immunol 5: 202. doi:10.4172/2155-9899.1000202
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Immunol 5: 202. doi:10.4172/2155-9899.1000202
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This article was originally published in a special issue, entitled: "Allergy", Edited
by Dr. Hong Wei Chu, National Jewish Health, USA
Allergy