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THE ATOPIC MARCH

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Received: 18.06.2015 - Accepted: 01.07.2015

THE ATOPIC MARCH

Rajat Das Gupta

Dhaka Medical College Hospital, Dhaka, BANGLADESH

ABSTRACT
The progression of atopic diseases, such as atopic dermatitis, asthma, allergic rhinitis and food allergies are
generally seen during childhood and they are known as ‘the atopic march’. There are various risk factors for deve-
loping atopic diseases including genetics, food allergens, late food introduction to the infant, life style and hygiene.
There are some immunologic contributors to this disease. Different therapeutic procedures and newer methods have
been introduced.
In this article, the author explains the definition of atopic march, pathophysiology, clinical features, epidemiology
and therapeutic approaches.

Keywords: Dermatitis, atopic, asthma, hypersensitivity

INTRODUCTION EPIDEMIOLOGY

   Ulrich Wahn explains the term “atopic march” as     Normally there are three proposed pathways of ato-
“the natural history of atopic manifestations, which is pic march. Firstly atopic dermatitis can lead to asthma
characterized by a typical sequence of immunoglobulin and allergic rhinitis. Secondly, asthma can lead to ato-
E (IgE) antibody responses’ and clinical symptoms that pic dermatitis. Thirdly, asthma can lead to rhinitis wit-
appear early in life, persist over years or decades and of- hout atopic dermatitis. Food allergy is also associated
ten remit spontaneously with age” (1). Asthma, atopic with these disorders (2). However in 2008 Barberio et al.
dermatitis (AD), allergic rhinitis and food allergies are reported a possibility of a reverse atopic march. In this
the atopic diseases (2). These diseases affect nearly 20% proposal asthma develops first and atopic dermatitis fol-
of the population in the developed countries (3). These lows (7).
diseases commonly progress first from atopic dermatitis
to asthma, then to allergic rhinitis. But this is not always     Atopic Dermatitis is associated with increased total
the way of progression (2). Atopy can be defined as the IgE serum levels in 70-80% of patients (8).Its prevalence
natural tendency (personal/familial) to develop IgE an- is 7% to 30% in children and 2% to 10% in adults (9).
tibodies and subsequent sensitization in response to en- The highest level of sensitization in Atopic Dermatitis
vironmental stimuli (4). It is considered that underlying and asthma occurs in first two years of life and in late
atopy is critical in asthma, AD and allergic rhinitis (4, childhood the prevalence of these diseases decrease. On
5).Both genetic and environmental factors are respon- the other hand, the prevalence of asthma and allergic
sible for development of these diseases. These diseases rhinitis increases with time. Sensitization to inhalant al-
may develop sequentially along a common atopic pat- lergens rises with age (10).
hway. There may be a relationship between eczema and
atopic respiratory disorders. Different cross sectional     Kulig et al. reported that half of the children with
and longitudinal studies support the atopic march. Ex- atopic dermatitis developed allergic respiratory disea-
perimental findings of mouse models also support the ses at the age of five (11). Shen et al. (12) classified the
evidence of atopic march (3). eczema into preschool and late-onset.While following a
    birth cohort for seven years, they reported that late-on-
   set group had higher risk of developing asthma or aller-
gic rhinitis five years later. Ricci et al. (13) found that the

Adress for Correspondence: Rajat Das Gupta, Dhaka Medical College Hospital, Dhaka, BANGLADESH - e-mail: rajat89.dasgupta@gmail.com
158

severity and good control of AD can be predicted for the     These differences may be due to differences in extent
onset of asthma. of some factors like urbanization, industrialization, life
style, latitude, disease severity, socioeconomic status and
    Ohshima et al. conducted a follow up study on 169 ethnicity (2).
Japanese children. They found that 35% of children de-
veloped asthma (14). More than half of the children with
AD develop asthma and more than three-fourth of them PATHOPHYSIOLOGY
develop allergic rhinitis during the first six years of life,
as reported by Spergel JM (9).     At first there is initial sensitization to the allergens
in the patient’s life. This triggers the activation of the
    Lowe AJ et al. in 2008 reported that eczema in early epithelial cells, which as result release chemotactic fa-
life in boys is associated with an increased risk of chil- ctors for dendritic cells thymic stromal lymphopoietin
dhood asthma. In girls, the association was weak (15). (TSLP) and tumor necrosis factor alpha (TNF-alpha),
Meanwhile other studies also reported that boys have that induce the expression of adhesion molecules at
great risk of asthma during childhood (16, 17). the endothelium (2, 33). Dendritic cells have high affi-
nity IgE receptors (FcERI) by which they internalize the
    The association between a higher BMI and symp- allergen, which lead the naive T cell activation in Th1
toms of wheeze and cough in children has been obser- (by IL-2 and IFN-alpha), and Th2 (by IL-4) cells in the
ved in different studies (18-20). lymph nodes. Then filaggrin mutations lead to a dec-
rease in Th1 response and an increase in Th2 response
    There are six times the odds of developing asthma and release of IL-5 and IL-13 which trigger eosinophi-
associated with food allergy than patients without any lic infiltration and hyperproduction of IgE. In the nasal
food allergy (21, 22). Patients with positive family his- and bronchial mucosa, the Th2 response stimulates the
tory of food allergy have a high risk of developing food allergen response. This leads to eosinophil infiltration,
allergy in subsequent period (23).Monozygotic twins IgE hypersecretion, mast cell proliferation, epithelial cell
have higher risk of developing peanut allergy than diz- activation, mucus hypersecretion and smooth muscle
ygotic twins. The sibling of an affected person of allergy spasm(5, 34).
has ten times more risk to develop allergy (24).
    Harskamp et al. describe the immune response in
   While studying about the worldwide incidence of atopic dermatitis skin. Infiltration of T cells in the skin
atopic diseases, we found that developed countries have due to microbial toxins, allergens, and mechanical tra-
reached a plateau, while in the developing countries the uma leads to IgE production (induced by IL-13), IL-4
incidence is increasing (2, 25).However a study found production. On the other hand, IFN-gamma decreases
that in Australian school children, the prevalence of ast- production of IgE (35).
hma increased from 12.9% to 38.6% from 1982 to 1997
(26).The prevalence of AD in children increased from     Dharmage SC et al. (36) proposed the mechanism of
17.3% to 27.3% from 1986 to 2001 and from 5.3% to atopic march. According to them, genetic predispositi-
12.0% from 1964 to 1986 in Denmark and Scotland res- on like filaggarin null mutation and environmental risk
pectively (27, 28). factors like infection leads to childhood eczema. Due to
trauma and defective skin barrier there is microbial and
   In developing counties, there are also similar stu- allergen entry , which lead to epicutaneous sensitization.
dies. In Colombia, a study on 5.978 patients found that, Th2 memory cells migrate into the nasal and bronchial
12% of the patients had asthma, 32% had allergic rhini- lymphoid tissue and causes airway inflammation. Aller-
tis and 14% had atopic eczema (29). In a longitudinal gen re-entry and over expression of TLSP this lead to
cohort study in Taiwan, the 8-year-prevalence of atopic bronchial asthma and allergic rhinitis.
dermatitis, allergic rhinitis and asthma was 6.7%, 26.3%
and 11.9%, respectively (30). A study conducted among     According to the “Hygiene Hypothesis” proposed by
North Indian population discovered that atopic was the David Strachan in 1989, cleaner environment decreasing
commonest dermatitis (28.46%) in children in a pediat- infections and in developed countries over the last few
ric dermatology clinic (31). In 1999, a study in Bangla- years have led to a higher prevalence of atopic diseases
desh showed 5.2% of the country’s population is suffe-
(28).
ring from asthma (32).
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CLINICAL FEATURES     Development of asthma, rhinoconjuctivitis and ec-

zema are triggered by cow milk allergy (43).
 
a) Atopic Dermatitis:
THERAPEUTIC APPROACHES:
    The first manifestations are intensely pruritic eryt-     Gordon BR et al. (44), proposed that supplementa-
hematous papules and vesicles on the face. There is wi- tion of dietary probiotics, exclusive breast feeding and
despread cutaneous dryness. Edema of affected areas inhalant allergen immunotherapy (Subcutaneous/Sub-
leads to oozing and crusting. There might be lymphade- lingual) are the ways of preventing allergy. It has been
nopathy in affected children. The disease is sometimes shown that high TGF-b levels in breast milk protect the
self resolving. Atopic dermatitis in adults predominantly child from development of allergies .For allergic asthma
involves the flexural folds, the face and neck, the upper and rhinitis 2013 PRACTALL has confirmed subcutane-
arms and back and the dorsum of the hands, feet, fingers ous and sublingual immunotherapy (45). Matricardi PM
and toes. As a result of superimposed Staphylococcal in- et al. in their meta analysis have shown that in control-
fection there is crusting and exudation (2, 3, 37). ling seasonal allergic rhinitis subcutaneous immunothe-
rapy is at least as potent as pharmacotherapy (46).
b) Asthma:
    In 2006, the PRACTALL consensus paper proposed
step-based algorithm for eczema therapy (depending on
    Common features of asthma are cough, chest tigh- severity) (47) (Table 1).
tness, breathlessness and wheeze. It may have diurnal   
variations and the symptoms are worse at early morning     Omalizumab, which acts by binding with free IgE
although there is a variety named nocturnal asthma (38). and preventing free IgE from attaching to high-affinity
In some patients there is low forced expiratory volume in IgE receptor, effectively reduces exacerbation rates of
1 second (FEV1) along with eosinophil and Th2 infiltra- asthma. This drug is indicated for patients who are 6 ye-
tion in bronchial tissue (2).Kumar R et al. have shown ars and older, with moderate to severe asthma (48). It
that fractional exhaled nitric oxide (FeNO) is marker of can be used in allergic rhinitis also although its high cost
lower airway inflammation and higher level of FeNO in may lower its compliance (49).
allergic rhinitis patients can be used as a predictor of the
onset of asthma (39).     Leukotriene receptor antagonists (montelukast) are
recommended for the treatment of asthma. In an open
c) Allergic Rhinitis: randomized clinical trial in Bangladesh, it has been
showed it can be used in atopic dermatitis (50).
    Watery rhinorrhea, nasal obstruction, nasal itching
   Prebiotics, probiotics and breast-feeding balance
and sneezing are the main symptoms of allergic rhinitis
improve intestinal processing of antigens ingested in the
(40). diet. By increasing the uptake of antigens by Peyer’s pat-
ches, they also reduce intestinal inflammation and IgE
d) Food Allergy: production. This prevents developing an exaggerated
Th2 immune response. Otherwise like bronchial tissue,
there would be systemic sensitization and major enhan-
    Incidence of food allergy is higher at first 2 years of cement and distribution to tissues (51).Breastfeeding
life (41). Also it has a wide variety of signs and symp- increases the number of immunoglobulin secretor cells
toms. Skin reactions are the most common which inclu- and thus protects against atopic diseases (52). By increa-
de acute urticaria, angioedema and erythema. Laryngeal sing the Bifidobacterium populations, probiotic controls
edema, rhinorrhea and bronchospasm are the symp- Clostridium/Bifidobacterium ratio. Probiotics decreases
toms of respiratory tract involvement and nausea, vomi- the risk of development of allergies by producing an-
ting, abdominal pain and diarrhea are the symptoms of ti-inflammatory cytokines and inducing the regulatory
gastro-intestinal system. Anaphylaxis is the most serious
condition. It could trigger peanuts, tree nuts and shel- cell responses (53).
lfish are the most common reason of anaphylaxis (42).
160

Table 1: Proposed eczema therapy by PRACTALL he PC, Loannidis JP et al. The PRISMA statement for re-
(PRACTical ALLergy) consensus paper (47) porting systematic reviews and meta-analyses of studies
that evaluate health care interventions: explanation and
elaboration. BMJ 2009;339:2700.

7. Barberio G, Pajno GB, Vita D, Caminiti L, Canonica

GW, Passalacqua G. Does a ‘reverse’ atopic march exist?
Allergy 2008;63:1630-2.
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8. Patrizi A, Pileri A, Bellini F, Raone B, Neri I, Ricci G.
   The beauty of science is that it has no boundary. Atopic dermatitis and the atopic march: what is new? J
Medical science cannot be an exception for this. We are Allergy (Cairo) 2011;2011:279425.
getting new information constantly which enlightens us
about atopic diseases. Atopic march is a combination of 9. Spergel JM. From atopic dermatitis to asthma: the ato-
multiple diseases and it needs multimodal therapeutic pic march. Ann Allergy Asthma Immunol 2010;54(2):99-
approaches. In spite of having promising therapies like 106.
monoclonal antibodies, sublingual therapy, immunot-
herapy, prebiotics and probiotics, more studies should be 10. Kijima A, Murota H, Takahashi A, Arase N, Yang
done to find out the exact “magic bullet” to fight against L, Nishioka M et al. Prevalence and impact of past his-
this atopic march. tory of food allergy in atopic dermatitis. Allergol Int
2013;62(1):105-12.
Ethics Committee Approval: Not applicable.
Informed Consent: Not applicable. 11. Kulig M, Bergmann R, Klettke U, Wahn V, Tacke U,
Conflict of Interest: The authors declared no conflict of in- Wahn U. Natural course of sensitization to food and in-
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Financial Disclosure: The authors declared that this study Allergy and Clinical Immunology 1999;103(6):1173-9.
received no financial support.
12. Shen CY, Lin MC, Lin HK, Lin CH, Fu LS, Fu YC.
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