Allergic rhinitis and asthma: The link further unraveled

Abstract

Allergic asthma and rhinitis are manifestations of the atopic syndrome. Although the diseases commonly occur together, it is still unclear why some allergic patients develop only asthma and others only rhinitis. The reason for the variety in clinical expression of allergic airway disease is not known. Besides a genetic predisposition, environmental factors contribute to the development of the allergic phenotype. Local and systemic inflammatory processes also seem to be involved, however, their exact contribution to the clinical picture of airway allergy still remains to be elucidated. Although it is clear that the condition of the upper airways has an impact on lower airway physiology, the mechanisms underlying this relation are far from being resolved. To date, most data point towards a systemic link between upper and lower airways, involving bloodstream and bone marrow. In this article, the latest developments with regard to nasobronchial interaction in allergic airway disease will be reviewed. Epidemiologic, experimental and clinical data underline the importance of a global approach in allergic rhinitis and asthma.

Full text

Allergic rhinitis and asthma: the link further unraveled
Gert-Jan Braunstahl, MD,PhD,* and Peter W. Hellings, MD,PhD
†
Allergic asthma and rhinitis are manifestations of the atopic
syndrome. Although the diseases commonly occur together, it
is still unclear why some allergic patients develop only asthma
and others only rhinitis. The reason for the variety in clinical
expression of allergic airway disease is not known. Besides a
genetic predisposition, environmental factors contribute to the
development of the allergic phenotype. Local and systemic
inflammatory processes also seem to be involved, however,
their exact contribution to the clinical picture of airway allergy
still remains to be elucidated. Although it is clear that the
condition of the upper airways has an impact on lower airway
physiology, the mechanisms underlying this relation are far
from being resolved. To date, most data point towards a
systemic link between upper and lower airways, involving
bloodstream and bone marrow. In this article, the latest
developments with regard to nasobronchial interaction in
allergic airway disease will be reviewed. Epidemiologic,
experimental and clinical data underline the importance of a
global approach in allergic rhinitis and asthma. Curr Opin Pulm Med
2003, 9:46–51 © 2003 Lippincott Williams & Wilkins, Inc.
Although the relation between allergic rhinitis and
asthma has been recognized for more than a century, it
has only been studied seriously for the last 10 to 15 years.
Anatomical and physiologic differences between nose
and lungs may account for the traditional division in up-
per and lower airways. The upper airways, from the nos-
trils to the vocal cords, have been the domain of the
otorhinolaryngologist for many years, while the airways
below the vocal cords have been the terrain of the pul-
monologist. This arbitrary dichotomy has contributed to
the fact that asthma and allergic rhinitis were always
considered two separate entities. Although allergists
treat atopic rhinitis and asthma, treatment strategies may
lack a combined approach.
The recent publication of the “Allergic rhinitis and its
impact on asthma” article has definitely made this idea
an outdated concept [1••]. The evidence of epidemio-
logic, pathophysiologic, and clinical data is so compel-
ling, that the concept of “one airway, one disease” is
becoming generally accepted. However, many questions
still remain unanswered. Which factors play a role in the
development of certain allergic phenotypes? Which
mechanisms are involved in nasobronchial crosstalk?
What is the place of novel treatments in the therapy of
allergic rhinitis and asthma?
Epidemiologic factors
Prevalence rates of atopic diseases, such as asthma, rhi-
nitis, and eczema, vary all over the world [2]. In Europe,
the prevalence of asthma has increased more than two-
fold during the last two decades and now affects up to
15% of the adult population [3]. The prevalence of rhi-
nitis closely follows that of asthma, but is approximately
three times higher [2]. Patients with allergic rhinitis have
a three times greater chance than healthy subjects to
develop asthma, regardless of the atopic status of the
patient [4]. The presence of atopy can be assessed with
a positive skin-prick test or radioallergosorbent test for a
specific allergen.
A family history of atopic disease is recognized as a major
risk factor for asthma and rhinitis [5,6]. Also, environ-
mental factors have an unmistakable effect on the de-
velopment of atopic disorders. The European Commu-
nity Respiratory Health Survey (ECRHC), which was
conducted during the early 1990s, collected data on the
prevalence, risk factors and disease management of
atopy and asthma [7]. Apart from the fact that there were
large geographical differences in the prevalence of
*Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, the
Netherlands;
†
Department of Otorhinolaryngology, University Hospitals, Leuven,
Belgium.
Correspondence to Gert-Jan Braunstahl, MD, PhD, Department of Pulmonary
Medicine, Erasmus Medical Center, lokatie Dijkzigt, Dr. Molewaterplein 40, 3015
GD Rotterdam, the Netherlands; e-mail: gj.braunstahl@wanadoo.nl
Current Opinion in Pulmonary Medicine 2003, 9:46–51
Abbreviations
BHR bronchial hyperresponsiveness
ECRHC European Community Respiratory Health Survey
IL interleukin
LTRAs leukotriene receptor antagonists
mAb monoclonal antibody
NS nasal steroids
PDE4 phosphodiesterase 4
SIT specific immunotherapy
VCAM vascular cell adhesion molecule
ISSN 1070–5287 © 2003Lippincott Williams & Wilkins, Inc.
46

asthma and atopy, it confirmed that environmental fac-
tors play an important role in the development of allergic
lower airway disease. Living on a farm in childhood ap-
peared to be associated with a reduced risk of developing
atopy and hay fever during adulthood. However, no pro-
tective effect was observed for the development of
asthma in this study [8]. In contrast, Riedler et al. [9]
found that exposure to a farming environment in the first
year of life also protected against asthma, independently
of allergic sensitization. Reduction of exposure to indoor
allergens in infancy reduces some—but certainly not
all—respiratory symptoms in a high-risk population [10].
Exposure to allergens was related to specific sensitiza-
tion in a dose-dependent way. Environmental tobacco
smoke exposure is another important risk factor for
wheezing in infancy. Janson et al. [11] showed that there
was a significant relation between passive smoking and
the presence of asthma, which was not the case in allergic
rhinitis. Therefore, factors such as type, duration and
severity of allergen exposure early in life, as well as mi-
crobial load and chemical agents, could possibly affect
the clinical manifestation of allergic upper and lower air-
ways disease.
Pathophysiologic factors
The nose and lungs are anatomically and physiologically
closely related organs. The nose plays an important role
in the filtering and conditioning of inhaled air. In allergic
rhinitis, these functions are impaired, which also has con-
sequences for the lower airways. Oral breathing of cold,
dry air was associated with a reduction in FEV
1
in asth-
matic patients, while this effect could be prevented as
long as nasal breathing was maintained [12]. Asthmatic
patients are known to have a reduced ability to condition
air, based on an increased swelling of the nasal mucosa.
However, the decrease in nasal airway patency is not
always related to airway symptoms [13•,14]. The poor
perception of nasal [14] and bronchial symptoms [15] in
some patients may explain why allergic rhinitis and
asthma remain undiagnosed in several patients with air-
way allergy. Indeed, in a population of mostly asymp-
tomatic subjects with occupational allergy, increased
bronchial hyperresponsiveness (BHR) was present not
only in the self-reported asthmatics, but also in self-
reported allergic rhinitis patients without lower airway
symptoms [16]. Other upper airway conditions that are
known to influence lower airway function are nasal pol-
yposis [17] and chronic sinusitis (Fig. 1) [18•]. Although
not explicitly related to the atopic syndrome, they
have been identified as factors involved in asthma
exacerbation.
Interaction mechanisms
The pathophysiologic mechanisms that could explain
the interaction between the nose and the lung are: pul-
monary aspiration, neural reflex mechanisms and sys-
temic induction of inflammatory mediators and cells.
Studies with a radiolabeled allergen have shown no de-
position of allergen in the lungs after nasal allergen ap-
plication [19]. Although postnasal drainage of inflamma-
tory mediators into the lower airways cannot be
excluded, it is not likely to play a role in vivo [20]. Ex-
posure of the nasal mucosa to cold, dry air may result in
immediate bronchoconstriction in some asthmatic pa-
tients [21]. However, no direct effect on FEV
1
could be
detected after nasal allergen challenge [19,22,23]. Nasal
provocation with methacholine in asthmatic patients
with rhinitis resulted in an increase in lower airway re-
sistance. Interestingly, this phenomenon could be
blocked by premedication of nasal mucosa with phenyl-
ephrine and therefore suggests a role for systemic me-
diators in the induction of lower airway resistance [24].
Immunopathologic mechanisms
Allergic asthma and allergic rhinitis are characterized by
a similar inflammatory process in which mast cells and
eosinophils appear to be major effector cells [25,26]. Eo-
sinophils in airway mucosa are regarded as the hallmark
of allergic rhinitis and asthma [27]. Of note, eosinophilic
inflammation has been found in the lower airways [28–
31] of allergic rhinitis patients without asthma and in the
upper airways of asthmatic patients without nasal com-
plaints [32]. Although it is clear that the condition of the
upper airways influences the lower airways, the mecha-
nisms underlying this relation are still not completely
understood.
The primary response to an allergic [33] or irritating [34]
stimulus takes place in the target organ and is generally
more severe in patients with allergic rhinitis and asthma
than in patients with only rhinitis [33]. The primary re-
sponse is initially local, but followed by a more general-
ized airway reaction. The latter includes nasal and pul-
Figure 1. Relation between sinus CT scan score and number of
eosinophils in induced sputum
Log sputum eosinophils,
%
2.0
1.0
1.5
0.5
0.0
0 5 10 15
CT scan score (0–30)
20
Rs = 0.40
P
= 0.007
25
30
Relation between sinus CT scan score and number of eosinophils in induced
sputum in patients with severe asthma. Published with permission [18•].
Allergic rhinitis and asthma Braunstahl and Hellings 47

monary symptoms, decreased airway patency and the
development of an inflammatory infiltrate, dominated by
eosinophils and T-lymphocytes [35,36]. The number of
blood eosinophils and the concentration of serum-
interleukin (IL)-5 increase in allergic subjects after natu-
ral [33] and experimental allergen exposure [35,36]. In
contrast, levels of eosinophil cationic protein are el-
evated only locally and not systemically after allergen
exposure, indicating that eosinophils become activated
in the airway mucosa [33]. The migration of eosinophils
from the blood to the tissue is facilitated by adhesion
molecules. After nasal provocation, vascular cell adhesion
molecule (VCAM)-1 and E-selectin were upregulated on
nasal and bronchial endothelium of allergic rhinitis pa-
tients without asthma [36].
Eosinophils are not the only cells involved in nasobron-
chial crosstalk. The role of the mast cell in asthma is also
subject to renewed interest. Mast cells are present in
increased numbers in the smooth muscle of asthmatic
patients and are related to BHR [37••]. Mast cells do not
only react on local stimuli. Segmental bronchial provo-
cation in allergic rhinitis patients results in mast cell de-
granulation and the influx of increased numbers of ba-
sophils in nasal mucosa [38•].
Systemic pathway
Animal models of airway allergy have also significantly
contributed to our current understanding of the allergic
airway response. Repeated allergen inhalations by sensi-
tized mice induced eosinophilic inflammation in the lu-
men and tissue of upper and lower airways simulta-
neously [39•]. In response to allergen inhalation,
swelling of the nasal mucosa developed concomitantly
with lower airway hyperresponsiveness. Finally, param-
eters of inflammation were positively correlated in the
upper and lower respiratory tract of these mice. There-
fore, murine data illustrate that allergen inhalation may
lead to the induction of allergic inflammation in upper
and lower airways, confirming the concept of global air-
way allergy. It is notable that the degree of eosinophilic
airway inflammation in these mice was more pronounced
in the bronchi than in the nose, an observation that is also
made in asthmatic patients [40]. However, it was found
that 83% of inhaled particles are retained within the na-
sal mucosa of mice, whereas only 13% reach the bronchi
[39•]. Therefore, these data suggest that, besides local
antigen deposition and induction of allergic inflamma-
tion at the site of allergen deposition, other mechanisms
must be involved in the development of severely in-
flamed lower airways in asthma.
Like in asthmatic patients, allergen inhalation by sensi-
tized mice stimulates allergen-specific IgE production
and enhances eosinophilia in the blood [41]. In addition,
it was demonstrated that allergen inhalation by sensi-
tized mice leads to a systemic increase of levels of IL-5
[39•], a well-known growth and differentiation factor for
eosinophils at the site of inflammation. Hence, this ob-
servation of systemic release of IL-5 after allergen inha-
lation fundamentally changes our idea about the involve-
ment of IL-5 in allergic disease. Apart from its paracrine
role in sustaining eosinophilic inflammation in the in-
flamed airway, IL-5 represents one of the mediators in-
volved in a systemic allergic response. Recent murine
data provide further insight into the role of systemic IL-5
in allergic airway disease. Wang et al. [42] reported that
systemic IL-5 plays a crucial role in the migration of
eosinophils towards the airway. In addition, IL-5 is in-
volved in the eosinopoiesis in the bone marrow. Indeed,
anti-IL-5 monoclonal antibody (mAb) given intraperito-
neally has inhibited bone marrow and airway eosino-
Figure 2. Nasobronchial crosstalk
Nasobronchial crosstalk
Symptoms
Function
Inflammation
Allergen
VCAM-1
IL-5, eotaxin
IL-5
Systemic circulation as an important pathway in the interaction between upper
and lower airways.
Figure 3. Children with and without asthma after 3 years of
immunotherapy
Patients,
%
100
60
80
40
20
0
SIT
No asthma
Asthma Odds ratio = 2.52
n
= 19
n
= 60
Control
n
= 32
n
= 40
The percentage of children after 3 years of immunotherapy with and without
asthma among those without asthma before treatment (N = 151). The absolute
numbers of children are shown above bars. Published with permission [56].
48 Asthma

philia in mice [43]. Moreover, IL-5-deficient mice fail to
develop eosinophilia in bone marrow and nasal tissue in
experimental rhinitis [44•]. These data illustrate that
IL-5 may represent the systemic link between antigen
deposition onto the airway mucosa, eosinopoiesis in the
bone marrow and airway eosinophilia, as well as highlight
the contribution of the bone marrow to the inflammatory
response in allergic airway disease. Recently, Saito et al.
[45] analyzed the inflammatory changes in the nasal mu-
cosa and bone marrow in experimental rhinitis, showing
an increase in eosinophil progenitors in the bone marrow
after allergen deposition in the nose. Therefore, we tend
to speculate that the systemic release of IL-5 and stimu-
lation of bone marrow eosinopoiesis after allergen inha-
lation represent factors that are involved in the genera-
tion of airway allergy throughout the entire airway.
Although other mechanisms—ie, neural reflexes, pulmo-
nary aspiration, and mouth breathing—may contribute to
nasobronchial interaction, these recent data provide
ample evidence for the existence of a systemic pathway.
Systemic signals, including IL-5, and bone marrow seem
to be relevant in allergic airway disease (Fig. 2).
Therapeutic implications
Although accumulating evidence underlines the impor-
tance of allergic rhinitis in the control of asthma [46•],
both diseases are still treated as separate disorders. Few
studies have investigated the effect of nasal treatment on
asthma. Topical treatment with intranasal corticosteroids
reduces lower airway symptoms and decreases BHR in
allergic rhinitis patients with seasonal asthma [47–50]. In
one study, delivery of beclomethasone to the nose had
an even greater effect on BHR than delivery of the same
dose via the oral route [51]. Another report demonstrated
a beneficial effect of bronchial treatment with inhaled
corticosteroids on nasal symptoms and inflammation
[52]. Avoidance of inhalant allergens [10,53] and immu-
notherapy [54,55••,56–58] may be effective for asthma
and rhinitis on a long-term basis. A 3-year course of spe-
cific immunotherapy (SIT) in children with seasonal al-
lergic rhinitis significantly reduced the risk of developing
asthma (Fig. 3) [56•]. In a comparative study between
nasal steroids (NS) and short preseason SIT in patients
with allergic rhinitis and asthma, NS appeared to be
more effective in local disease control than SIT. SIT,
however, was able to have a positive influence on sys-
temic and bronchial parameters in these patients, while
NS had no apparent effect on the lower airways [57•].
Despite the benefit of antihistamines and cromoglycates
in seasonal allergic rhinitis, their effects on lower airways
are still doubtful [59]. Novel antihistamines, however,
seem to exert some beneficial effect on lower airway
inflammation, possibly through their antiinflammatory
properties [60–62]. Leukotriene receptor antagonists
(LTRAs) proved to have an additional therapeutic effect
on asthma [63,64]. Recent data show that the leuko-
trienes may also be of importance in inflammatory upper
airway disease, which emphasizes a role for LTRAs in
the treatment of allergic rhinitis [65•]. Recently, phos-
phodiesterase 4 (PDE4) inhibitors, which exert an anti-
inflammatory effect by blocking IL-13 production, have
come to our attention. Although this drug is still in de-
velopment, it has proved to be safe and effective in
asthma and rhinitis [66,67]. Also, anti-IgE antibodies are
promising tools in asthma and rhinitis therapy. They pre-
vent IgE from binding to receptors on mast cells and
basophils, thereby eliminating allergic inflammation at
the initial step of the inflammatory cascade [68•,69].
Anti-IgE treatment has proved to be effective in asthma,
since it reduced symptoms, asthma exacerbations and
the need for steroids [70•,71••]. Its usefulness in allergic
rhinitis—particularly as a steroid-sparing agent—has yet
to be determined.
Conclusion
The idea that allergic rhinitis and asthma are related
originates from the late 19th century. The relation be-
tween allergic rhinitis and asthma has been well estab-
lished in epidemiologic studies and clinical trials. How-
ever, little is known about the immunopathologic
mechanisms that underlie the interaction between upper
and lower airways. The condition of the upper airways
can influence the lower airways and vice versa. Local al-
lergen exposure at one end of the respiratory system
induces mucosal inflammation at the other end. There-
fore, upper and lower airways need to be regarded as one
functional entity. Although physiologic mechanisms may
also contribute to nasobronchial crosstalk, most recently
published data are in favor of a systemic pathway, in-
volving bloodstream and bone marrow. This also has im-
plications for rhinitis and asthma therapy, providing a
rationale for systemic treatment. What eventually deter-
mines the clinical phenotype in allergic airway disease is
still not completely understood. Several factors, such as
the type of inhalant allergy and the duration and severity
of exposure, as well as the genetic susceptibility, may
contribute to the expression of the clinical picture. Fu-
ture studies will, hopefully, elucidate to what extent lo-
cal and systemic factors add to the development of aller-
gic airway disease.
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Allergic rhinitis and asthma Braunstahl and Hellings 51