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Food Allergy, Atopic March and United Airway

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Das_AC_v1_EU Resp 15/03/2012 17:05 Page 51

Allergies

Food Allergy, Atopic March and United Airway Diseases

Rashmi Ranjan Das
Senior Resident, Department of Paediatrics, All India Institute of Medical Sciences (AIIMS)

Abstract
The atopic march refers to a typical sequence of atopic features appearing during a certain age period and persisting over several years.
In general, the clinical features of atopic dermatitis (AD) occur first, and precede the development of asthma and allergic rhinitis (AR). AR
is an independent risk factor for the subsequent development of asthma, and the diagnosis of AR often precedes that of asthma. Clinical
and experimental studies suggest a similar immunopathology between the upper and lower airways in allergic subjects. In patients with
asthma, presence of concomitant AR is associated with higher total annual medical costs, increased risk of hospitalisations and
emergency visits. Treating AR results in a lowered risk of asthma-related hospitalisations and emergency visits, and improved quality of
life. The concomitant presence of AR indicates difficult-to-control asthma, with poor asthma-related outcomes. This concept of united
airways disease or allergic rhino-bronchitis has recently received attention, with some of the novel therapeutic approaches targeting
both of conditions simultaneously, rather than separately. In this paper, the author discusses current evidence for the clinically relevant
effects that allergic conditions, from food allergies to atopic march, united airways disease and AR, can have on asthma.

Keywords
Allergic rhino-bronchitis, immunoglobin E (IgE) antibody, atopic march, co-morbidity, inflammation
Disclosure: The author has no conflicts of interest to declare.
Received: 31 October 2011 Accepted: 6 December 2011 Citation: European Respiratory Disease, 2012;8(1):515
Correspondence: Rashmi Ranjan Das, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi-110029, India. E: rrdas05@gmail.com

The atopic or allergic march refers to the typical sequence of clinical

manifestations and immunoglobulin E (IgE) antibody responses that
appear during a particular age period and persist over the years
that follow. Some manifestations become more prominent with time,
whereas others diminish or disappear completely.1 In general, the
clinical features of atopic dermatitis (AD) occur first, followed by
the development of asthma and allergic rhinitis (AR). The risk of
developing all atopic diseases is complex and the temporal pattern
described in the atopic march might not be a simple progression, as
the development of these diseases is strongly influenced by both
genetic and environmental factors.
The prevalence of AD, AR and asthma has increased worldwide over
recent decades. Increasing attention has been devoted to the
relationship between AR and asthma, which was first noted in
epidemiological studies. The nasal and bronchial mucosa present with
similarities, with AR present in up to 80 % of patients with asthma, and
asthma present in 2050% of patients with AR.2,3 AR has been found
to be an independent risk factor for the subsequent development of
asthma, not only in atopic subjects, but also in non-atopic subjects.4,5
In fact, patients with AR (even without asthma) show a higher
frequency of bronchial hyper-reactivity (BHR) and altered airway
smooth muscle function.6 This could be linked to the duration of AR
and the number of sensitisations of the patient.7 Furthermore, AR can
be considered a risk factor for asthma exacerbation, with more
frequent asthma attacks and admission to the emergency room. It has
been proposed that the prevention or early treatment of AR might
help to prevent the occurrence of asthma or the severity of bronchial
symptoms. In 1999, a workshop was held at the WHO to develop

TOUCH BRIEFINGS 2012

evidence-based guidelines to highlight the impact of AR on asthma

(ARIA). The aim of this ongoing program is to manage and prevent AR,
to better assess the interactions between AR and asthma, and to
increase awareness of AR worldwide.8 In this review, the author
discusses food allergy and atopic march, the link between the upper
and lower airways, and the resultant impact of AR on asthma.

Atopic or Allergic March

Relationship between Atopic Dermatitis and
Airway Allergies
AD is a chronic skin disease seen in paediatric age groups. The
prevalence among affected children are as follows first six
months of life (45%); first year of life (60%); and before five years
of age (up to 85 %). 9,10 The resolution rate is less in different age
groups as follows, indicating the chronic nature of the diseases
complete resolution by seven years of age (<50%); and resolution
by adulthood (60%). 1,9,11 Those patients with eczema and specific IgE
antibodies to common environmental allergens present at an
earlier age (usually two to four years), and are at a higher risk for
progressing in the atopic march to AR and asthma, than are those
without IgE sensitisation. 12 The severity of AD also directly
correlates with the future risk of developing asthma or AR. The
large Multicentre atopy study (MAS) has thrown further light on
the atopic march. 13 In this study, most infants (69%) in the high-risk
group who had developed AD by three months of age were
sensitised to aeroallergens by the age of five years. The rate of
aeroallergen sensitisation increased to 77% in all high-risk children.
At five years, 50 % of children with early AD and a positive family
history of allergy had developed either asthma or AR, compared

51

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Allergies
Figure 1: The Relative Prevalence of Atopic Symptoms
According to Age

6m
Rhinitis

1yr

3yr
Asthma

7yr
Food allergy

15yr
Eczema

Many children also exhibit these atopic symptoms of simultaneously.

with only 12% of children without AD or a positive family history of

allergy. In another large study, the authors examined the
prevalence of AR and asthma in children with physician-confirmed
AD and found that, by three years of age, nearly 66 % reported to
have AR or asthma or both, and the presence of these correlated
with poor AD control. 14 A study that strongly suggested that the
atopic march progresses well past childhood was a longitudinal
health study investigating the influence of atopic eczema on the
development of asthma from childhood to adult life. 15 This study
found that childhood eczema was significantly associated with
new-onset asthma over the life-span from the ages of 8 to 44 years
hazard ratio [HR] 1.73; 95 % confidence interval [CI] 1.422.12).
However, it is still unclear why some infants with AD outgrow the
disease with increasing age, whereas others still march to develop
other atopic diseases in later life (see Figure 1).

Pathophysiology of Atopic March

Previously, it was thought that the mechanism of the atopic march
involves defects in the adaptive immune system, often with an
emphasis on the T-helper (Th)-1/Th2 paradigm. Recently, the focus
has increasingly shifted towards a primary defect in the epithelial
barrier (promoting easy entry for pathogens, allergens, other
environmental insults) as a threshold event in AD, and consequent
later sensitisation in the airways.16 The tight junctions in airway
epithelium might also be damaged by peptidases released from
several types of pollen, facilitating an increase in epithelial
permeability and promoting allergen delivery across epithelia. A
primary epithelial barrier defect resulting from filaggrin gene mutation
(acquired and/or genetic) has lately received some attention.17 Recent
studies show that patients with AD who carry filaggrin mutations are
significantly associated with IgE-mediated sensitisation to inhalant or
food allergens, persistence of disease into adulthood and the
development of AR and/or asthma. 18,19 The filaggrin mutations
predisposing an individual to all of the above 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.

52

Role of Food Allergy in the Atopic March

During the past 10 years, the significant increase in food
allergy-related hospitalisations for anaphylaxis has led to the idea that
food allergy might form a second epidemic of allergic disease.2022
Children with a history of food allergy are also at greater risk of having
other atopic diseases. In a population-based birth cohort, egg allergy
increased the subsequent risk of asthma, AR and sensitisation, and an
IgE-mediated reaction to cows milk increased the risk for subsequent
atopic diseases. 2325 AD and food allergy commonly coexist,
particularly in those with early onset, severe and persistent atopic
eczema. In a most recent prospective study, which included 118
children with cows milk allergy (CMA), the authors found that children
with a history of IgE-positive CMA diagnosed at a mean age of seven
months exhibited increased airway inflammation (higher exhaled
nitric oxide) and higher bronchial responsiveness (BHR) to histamine
at eight years of age than either those who did not have food allergy
or those with non-IgE mediated CMA.25,26 These associations remained
significant after adjustment for some potential confounders. History
of wheeze in the first year of life and parental smoking were also
factors independently associated with the increased exhaled nitric
oxide and BHR at school age. Considering this and other factors, it is
unclear whether the progression from IgE-mediated food allergy to
atopic march is causal or a result of shared environment and/or
shared genetics. Because AD and food allergy can coexist in infants,
it is also unclear whether the observed association is related to
co-manifestation of other allergic conditions (e.g. eczema and AR)
that predict asthma or is a consequence of CMA itself. Therefore,
larger study cohorts are urgently needed to explore further whether
food allergy truly represents an earlier manifestation of the atopic
march or whether it is an independent predictor. In addition to the
above, methodologically sound population-based cohort studies (with
either a high prevalence of challenge-proven food allergy or with a
lower prevalence of food allergy) will provide the appropriate power
to address the above issues in future.

United Airways Disease Relationship of

Allergic Rhinitis with Bronchial Hyper-reactivity
and Asthma
There exists a temporal relationship between the onset of AR and
asthma, with AR frequently preceding the development of asthma. AR
and positive allergy skin tests are significant risk factors for the
development of newly diagnosed asthma.27 AR developing in the first
years of life is an early manifestation of an atopic predisposition,
which can be triggered by early environmental exposures and genetic
factors.28 The association between the upper and lower respiratory
airways (the united airways disease hypothesis) has been confirmed
by numerous epidemiological studies.24,2932 Although the studies have
some methodological limits, the data from the literature are
consistent. The united airways disease hypothesis proposes that any
disease process that affects the upper airway is likely to affect the
lower airway, and vice versa. At the lower end, AR might occur alone;
in the middle range, AR and BHR might be present; and at the upper
end, AR and asthma might both be present, with each affecting the
severity of the other.33 This hypothesis might hold true for both allergic
and non-allergic manifestations.

Inflammatory Changes in the Upper and Lower

Airways in Response to an Allergic Stimulus
The enhanced regenerating and protecting ability that is present in the
nose makes nasal mucosa more resistant to inflammation and able to

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Das_AC_v1_EU Resp 13/03/2012 16:57 Page 53

Food Allergy, Atopic March and United Airway Diseases

Figure 2: Impact of the Nose on the Bronchus under Normal and Pathological (Inflammatory) Conditions

Normal
circumstances

Inflammation
(rhinitis)

Cytokines (IL-5)

Bone marrow
(systemic inflammatory
response)
Physical function
(air filtration, humidification
and conditioning)

Normal airway
structure and
function

withstand environmental injuries without permanent scarring;34 this

has been supported by animal models of airway inflammation
(although most allergens are deposited in the nose, more
inflammation occurs in the lower airway).35 A large number of studies
have shown that the inflammation of nasal and bronchial mucosa
involves a similar inflammatory infiltrate (being represented by
eosinophils, mast cells, T lymphocytes and cells of the monocytic
lineage).36,37 This has also been supported by a recent study in which
the authors compared the bronchial inflammatory response following
allergen-specific challenge in patients suffering from asthma or AR
alone, and found no morphological difference between the two
groups, confirming that atopic subjects have a common inflammatory
response.38 The same pro-inflammatory mediators (histamine and
cysteinyl leukotriene [CysLT]), Th2 cytokines (interleukin [IL]-4, IL-5, IL13, granulocyte-macrophage colony-stimulating factor [GM-CSF] and
intercellular adhesion molecule 1 [ICAM-1]),36,3941 chemokines (RANTES
and eotaxin)4244 and adhesion molecules4547 appear to be involved in
the nasal and bronchial inflammation of patients with AR and asthma.
There exist some similarities and differences between the
inflammatory changes in the upper and lower airways in response to
an allergic stimulus. The similarities include increase in eosinophils,
basophils, mast cells, Th2 lymphocytes, early and late allergic
responses, and vasculature (much more in the nose than in the
bronchi).48 The differences include basement membrane thickening,
epithelial disruption and an increase in smooth muscle in bronchi.48

Proposed Interaction Mechanisms between the Upper

(Nose) and Lower Airways (Bronchus)
AR can cause worsening of asthma by several different mechanisms.
Nasal challenge with allergen might cause non-specific bronchial
responsiveness, with or without airflow limitation of the lower
airways. Several mechanisms have been proposed to link AR and the
occurrence or worsening of asthma (see Figure 2). The suggested
mechanisms by which interaction occurs between the upper and
lower airways are as follows.
Bone marrow-derived systemic inflammatory response after
nasal and bronchial provocation, there are increased IL-5 levels in
the blood, and systemic IL-5 is involved in the migration of

EUROPEAN RESPIRATORY DISEASE

Increased oral breathing

Nasobronchial reflex
Minimal persistent inflammation
(ICAM-1 expression)

Inflammatory changes
and bronchial
hyper-reactivity

eosinophils toward the airway.49,50 IL-5 also has a crucial role in the
eosinopoiesis in the bone marrow.51 In experimental AR, an
increase in eosinophil progenitors in the bone marrow has been
found after allergen challenge of the nose.52 These data add to the
evidence that both the systemic release of IL-5 and stimulation of
bone marrow eosinopoiesis after allergen inhalation are important
factors involved in the process of global airway allergy.
Nasobronchial reflex a neurogenic (nasobronchial) reflex has also
been suggested (e.g. transient bronchoconstriction resulting from
irritant stimulation of nasal mucosa). To date, there little evidence
to support this concept.
Increased oral breathing AR has adverse effects on the lower
airway as a result of the promotion of breathing through the
mouth. In AR, mouth breathing is favoured, which might lead to
inflammatory changes and increase in BHR in susceptible persons,
and bronchoconstriction in patients with asthma.53,54
Aspiration of nasal contents secretions might drip or diffuse from
the upper airway to the lower airway. Under normal conditions,
however, this mechanism does not seem to have a contributory
effect on nasobronchial interaction.
Exhaled nitric oxide (eNO) concentrations in healthy subjects, eNO
originates mainly from the upper airway (with a minor contribution
from the lower airway). In patients with AR, lower airway
inflammation can be demonstrated by increased levels of eNO.
Minimal persistent inflammation (MPI) this has been demonstrated
in both mite-induced and pollen-induced AR.55 MPI involves a weak
and persistent expression of ICAM-1 (the major receptor for human
rhinoviruses). This frequently leads to exacerbation of asthma related
to upper respiratory viral infections, primarily owing to rhinoviruses.56

Functional and Immunological Impacts of

Allergic Rhinitis on Asthma
As described above, AR is an independent risk factor for the
subsequent development of asthma, not only in atopic subjects, but
also in non-atopic subjects. Non-asthmatic patients with AR and BHR
can have mild but significant changes in their small airway.57 AR in
early childhood is an independent predictor for wheezing between the
ages of 5 and 13 years, as found by MAS.58 In a prospective study,
37.7 % of children with AR showed hyper-responsiveness to

53

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Allergies
methacholine challenge, and of these children, 19.6 % developed
asthma during a seven-year follow up.59 In another large cohort study
of a primary care population followed up for an average duration of
8.4 years, physician-diagnosed AR increased the risk almost fivefold
for a future asthma diagnosis (HR: 4.86, p-number <0.001, 95 % CI:
3.506.73). 60 There are few studies comparing the clinical
characteristics of asthma in patients with and without AR. Patients
with either perennial or seasonal AR are more at risk of developing
BHR than are healthy control subjects, with perennial AR posing a
greater risk than seasonal AR.
The relationship between the nose and bronchi has been studied from
several angles, each elucidating a different aspect of the mechanism.
In patients with AR, inflammatory cells and mediators have been
found in the lower airway, without any apparent clinical manifestation
of lower airway inflammation. In non-asthmatic subjects with AR,
subepithelial fibrosis of the bronchi is observed, suggesting the
presence of active structural remodeling in the lower airway similar in
nature to that seen in asthma, although less marked.61 In atopic
subjects, allergen-specific nasal challenge can elicit following
responses immediate bronchoconstriction, increase in airway
responsiveness and bronchial inflammation characterised by
eosinophilic infiltrates.62,63 In non-asthmatic subjects with AR, an early
and late-phase reaction was observed after bronchial segmental
allergen challenge, suggesting that the bronchial mucosa of subjects
with AR can be triggered by allergens.64 In addition, an increase in
airways inflammation was found after segmental challenge in the
above subjects. In support of this, it has been found that asthma
exacerbations frequently occur coincident with the worsening of
nasal symptoms.65

Treatment Effect of Allergic Rhinitis on

Asthma-related Outcomes
If the united airways disease hypothesis provides a functional link
between the nose and the bronchi, then it is reasonable to expect a
therapeutic link between the two, meaning that effective treatment
of AR might have some effect on the asthma or BHR.66 In support of
this, it has been reported that the treatment of AR might affect the
symptoms of asthma and BHR in both atopic and non-atopic
subjects. For example, the use of intranasal corticosteroids have
been shown to reduce concomitant BHR significantly as well as
asthma symptoms in patients with asthma, and this has been found
in several clinical trials as well as in a Cochrane review.6769 In a
retrospective study involving large number of patients with asthma,
the authors found that intranasal corticosteroid therapy reduced the
risk of emergency department visits, irrespective of the use of
inhaled corticosteroids.70 Similarly, in another study, the authors
demonstrated reduced nasal and blood eosinophilia and reduced
seasonal nasal symptoms with the use of inhaled budesonide.71
Similar results have been observed in patients with AR in many other

1.
2.

3.

4.

5.

54

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march, J Allergy Clin Immunol, 2003;112(6 Suppl):S11827.
Shaaban R, Zureik M, Soussan D, et al., Rhinitis and onset of
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studies. In one study, the use of an H1 receptor antagonist

(cetirizine) in patients with AR significantly reduced non-specific
BHR.72,73 In another multicentre study involving adult patients with
seasonal AR and asthma, therapy with a leukotriene receptor
antagonist (montelukast) improved asthma outcomes as well as
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annual medical cost is higher for patients with co-morbid AR with
asthma, rather than with asthma alone. In addition, co-morbid AR is
associated with greater prescribing frequency of asthma-related
medications, a higher number of asthma attacks and emergency
visits, greater frequencies of hospitalisations and worsened clinical
outcomes.83 Treating AR results in a lowered risk of asthma-related
hospitalisations and emergency visits, improved quality of life and low
cost-of-illness. However, in a recent study, the authors found that all
asthmatic subjects (with or without AR) had significantly greater
impairment in physical measures, whereas mental health scores in
patients with isolated AR were lower than those of asthmatic
subjects, and the impact of AR on asthma found to have a minor role
in health-related quality of life (HRQOL).84

Conclusion
AR and asthma are two different manifestations of a single disorder of
the airways. Both share common pathogenetic mechanisms, a high
prevalence in the population, negative effects on the quality of life
and certain common therapeutic approaches. Asthma and AR
frequently occur concomitantly, and the presence of AR often
precedes the development of asthma. Co-morbid AR is a marker of
difficult-to-control asthma and the greater use of asthma resources to
treat it results in better asthma-related outcomes. The united airways
disease hypothesis is clearly supported by these data, with AR having
an important effect on asthma. Therefore, diagnostic and therapeutic
approaches should target both diseases simultaneously, rather than
separately. Future directions of research in this area include the
potential for early treatment of AR to prevent progression to asthma
and the best possible strategies to treat these two co-morbidities. n

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