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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an outdated concept [1••].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?
Prevalence rates of atopic diseases, such as asthma, rhi-
nitis, and eczema, vary all over the world . 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 . The prevalence of rhi-
nitis closely follows that of asthma, but is approximately
three times higher . Patients with allergic rhinitis have
a three times greater chance than healthy subjects to
develop asthma, regardless of the atopic status of the
patient . The presence of atopy can be assessed with
a positive skin-prick test or radioallergosorbent test for a
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 . Apart from the fact that there were
large geographical differences in the prevalence of
*Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, the
Department of Otorhinolaryngology, University Hospitals, Leuven,
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: email@example.com
Current Opinion in Pulmonary Medicine 2003, 9:46–51
BHR bronchial hyperresponsiveness
ECRHC European Community Respiratory Health Survey
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.
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 . In contrast, Riedler et al. 
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 .
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.  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-
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
matic patients, while this effect could be prevented as
long as nasal breathing was maintained . 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  and bronchial symptoms  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 . Other upper airway conditions that are
known to influence lower airway function are nasal pol-
yposis  and chronic sinusitis (Fig. 1) [18•]. Although
not explicitly related to the atopic syndrome, they
have been identified as factors involved in asthma
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 . Although postnasal drainage of inflamma-
tory mediators into the lower airways cannot be
excluded, it is not likely to play a role in vivo . Ex-
posure of the nasal mucosa to cold, dry air may result in
immediate bronchoconstriction in some asthmatic pa-
tients . However, no direct effect on FEV
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 .
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 . 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 . 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
The primary response to an allergic  or irritating 
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 . 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,
0 5 10 15
CT scan score (0–30)
Rs = 0.40
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  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 . 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 .
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•].
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 . 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 . 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.  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
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
Asthma Odds ratio = 2.52
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 .
philia in mice . 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.
 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).
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 . Another report demonstrated
a beneficial effect of bronchial treatment with inhaled
corticosteroids on nasal symptoms and inflammation
. 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 . 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.
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.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
•Of special interest
•• Of outstanding interest
1Bousquet J, Van Cauwenberge P, Khaltaev N: Allergic rhinitis and its impact
on asthma. J Allergy Clin Immunol 2001, 108:S147–334.
State-of-the-art work based on a extensive review of over 2700 papers. This review
provides an evidence-based guideline for diagnosis and therapy in allergic rhinitis.
Moreover, it emphasizes the importance of a global approach in allergic rhinitis and
2The International Study of Asthma and Allergies in Childhood (ISAAC) Steer-
ing Committee. Worldwide variation in prevalence of symptoms of asthma,
Allergic rhinitis and asthma Braunstahl and Hellings 49
allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998,
3Upton MN, McConnachie A, McSharry C, et al.: Intergenerational 20 year
trends in the prevalence of asthma and hay fever in adults: the Midspan family
study surveys of parents and offspring. BMJ 2000, 321:88–92.
4Guerra S, Sherrill DL, Martinez FD, et al.: Rhinitis as an independent risk factor
for adult-onset asthma. J Allergy Clin Immunol 2002, 109:419–425.
5Aberg N: Familial occurrence of atopic disease: genetic versus environmental
factors. Clin Exp Allergy 1993, 23:829–834.
6Aberg N, Sundell J, Eriksson B, et al.: Prevalence of allergic diseases in
schoolchildren in relation to family history, upper respiratory infections, and
residential characteristics. Allergy 1996, 51:232–237.
7Janson C, Anto J, Burney P, et al.: The European Community Respiratory
Health Survey: what are the main results so far? European Community Re-
spiratory Health Survey II. Eur Respir J 2001, 18:598–611.
8Leynaert B, Neukirch C, Jarvis D, et al.: Does living on a farm during childhood
protect against asthma, allergic rhinitis, and atopy in adulthood? Am J Respir
Crit Care Med 2001, 164:1829–1834.
9Riedler J, Braun-Fahrlander C, Eder W, et al.: Exposure to farming in early life
and development of asthma and allergy: a cross-sectional survey. Lancet
10 Custovic A, Simpson BM, Simpson A, et al.: Effect of environmental manipu-
lation in pregnancy and early life on respiratory symptoms and atopy during
first year of life: a randomized trial. Lancet 2001, 358:188–193.
11 Janson C, Chinn S, Jarvis D, et al.: Effect of passive smoking on respiratory
symptoms, bronchial responsiveness, lung function, and total serum IgE in the
European Community Respiratory Health Survey: a cross-sectional study.
Lancet 2001, 358:2103–2109.
12 McLane ML, Nelson JA, Lenner KA, et al.: Integrated response of the upper
and lower respiratory tract of asthmatic subjects to frigid air. J Appl Physiol
13 Assanasen P, Baroody FM, Naureckas E, et al.: The nasal passage of subjects
with asthma has a decreased ability to warm and humidify inspired air. Am J
Respir Crit Care Med 2001, 164:1640–1646.
This elegant study compares several phenotypes of the allergic spectrum in their
ability to condition air.
14 Hellgren J, Toren K, Balder B, et al.: Increased nasal mucosal swelling in
subjects with asthma. Clin Exp Allergy 2002, 32:64–69.
15 van den Toorn LM, Overbeek SE, de Jongste JC, et al.: Airway inflammation is
present during clinical remission of atopic asthma. Am J Respir Crit Care Med
16 De Meer G, Heederik D, Postma DS: Bronchial responsiveness to adenosine
5⬘-monophosphate (AMP) and methacholine differ in their relationship with
airway allergy and baseline FEV(1). Am J Respir Crit Care Med 2002,
17 Lamblin C, Gosset P, Salez F, et al.: Eosinophilic airway inflammation in nasal
polyposis. J Allergy Clin Immunol 1999, 104:85–92.
18 ten Brinke A, Grootendorst DC, Schmidt JT, et al.: Chronic sinusitis in severe
asthma is related to sputum eosinophilia. J Allergy Clin Immunol 2002,
This study in patients with severe bronchial asthma describes the influence of sinus
disease on the lower airways by using several parameters: CT scans of the sinuses,
various lung function tests, sputum eosinophilia and exhaled NO concentration.
19 Corren J, Adinoff AD, Irvin CG: Changes in bronchial responsiveness follow-
ing nasal provocation with allergen. J Allergy Clin Immunol 1992, 89:611–
20 Bardin PG, Van Heerden BB, Joubert JR: Absence of pulmonary aspiration of
sinus contents in patients with asthma and sinusitis. J Allergy Clin Immunol
21 Nolte D, Berger D: On vagal bronchoconstriction in asthmatic patients by
nasal irritation. Eur J Respir Dis Suppl 1983, 128:110–115.
22 Rosenberg GL, Rosenthal RR, Norman PS: Inhalation challenge with rag-
weed pollen in ragweed-sensitive asthmatics. J Allergy Clin Immunol 1983,
23 Schumacher MJ, Cota KA, Taussig LM: Pulmonary response to nasal-
challenge testing of atopic subjects with stable asthma. J Allergy Clin Immu-
nol 1986, 78:30–35.
24 Littell NT, Carlisle CC, Millman RP, et al: Changes in airway resistance fol-
lowing nasal provocation. Am Rev Respir Dis 1990, 141:580–583.
25 Bousquet J, Vignola AM, Campbell AM, et al.: Pathophysiology of allergic
rhinitis. Int Arch Allergy Immunol 1996, 110:207–218.
26 Busse WW, Calhoun WF, Sedgwick JD: Mechanism of airway inflammation
in asthma. Am Rev Respir Dis 1993, 147:S20–24
27 Djukanovic R, Roche WR, Wilson JW, et al.: Mucosal inflammation in asthma.
Am Rev Respir Dis 1990, 142:434–457.
28 Foresi A, Leone C, Pelucchi A, et al.: Eosinophils, mast cells, and basophils in
induced sputum from patients with seasonal allergic rhinitis and perennial
asthma: relationship to methacholine responsiveness. J Allergy Clin Immunol
29 Alvarez MJ, Olaguibel JM, Garcia BE, et al.: Airway inflammation in asthma
and perennial allergic rhinitis. relationship with nonspecific bronchial respon-
siveness and maximal airway narrowing. Allergy 2000, 55:355–362.
30 Sedgwick JB, Calhoun WJ, Gleich GJ, et al.: Immediate and late airway re-
sponse of allergic rhinitis patients to segmental antigen challenge. Charac-
terization of eosinophil and mast cell mediators. Am Rev Respir Dis 1991,
31 Djukanovic R, Lai CK, Wilson JW, et al.: Bronchial mucosal manifestations of
atopy: a comparison of markers of inflammation between atopic asthmatics,
atopic nonasthmatics and healthy controls. Eur Respir J 1992, 5:538–544.
32 Gaga M, Lambrou P, Papageorgiou N, et al.: Eosinophils are a feature of
upper and lower airway pathology in non-atopic asthma, irrespective of the
presence of rhinitis. Clin Exp Allergy 2000, 30:663–669.
33 Marcucci F, Sensi LG, Migali E, et al.: Eosinophil cationic protein and specific
IgE in serum and nasal mucosa of patients with grass-pollen-allergic rhinitis
and asthma. Allergy 2001, 56:231–236.
34 Palczynski C, Walusiak J, Ruta U, et al.: Occupational asthma and rhinitis due
to glutaraldehyde: changes in nasal lavage fluid after specific inhalatory chal-
lenge test. Allergy 2001, 56:1186–1191.
35 Braunstahl GJ, Kleinjan A, Overbeek SE, et al.: Segmental bronchial provo-
cation induces nasal inflammation in allergic rhinitis patients. Am J Respir Crit
Care Med 2000, 161:2051–2057.
36 Braunstahl GJ, Overbeek SE, Kleinjan A, et al.: Nasal allergen provocation
induces adhesion molecule expression and tissue eosinophilia in upper and
lower airways. J Allergy Clin Immunol 2001, 107:469–476.
37 Brightling CE, Bradding P, Symon FA, et al.: Mast-cell infiltration of airway
smooth muscle in asthma. N Engl J Med 2002, 346:1699–1705.
Interesting article with a clearly defined hypothesis. The relationship between the
presence of mast cells in smooth muscle tissue and increased bronchial hyperre-
sponsiveness in patients with asthma sheds new light on the pathophysiology of
38 Braunstahl GJ, Overbeek SE, Fokkens WJ, et al.: Segmental bronchoprovo-
cation in allergic rhinitis patients affects mast cell and basophil numbers in
nasal and bronchial mucosa. Am J Respir Crit Care Med 2001, 164:858–
An innovative aspect of the relationship between bronchi and nose was investi-
gated using an experimental approach.
39 Hellings PW, Hessel EM, Van Den Oord JJ, et al.: Eosinophilic rhinitis accom-
panies the development of lower airway inflammation and hyper-reactivityin
sensitized mice exposed to aerosolized allergen. Clin Exp Allergy 2001,
First report on mouse model of global airway allergy, illustrating the simultaneous
induction of eosinophilic inflammation in upper and lower airways and highlighting
the systemic character of the inflammatory response following allergen inhalation in
40 Chanez P, Vignola AM, Vic P, et al.: Comparison between nasal and bronchial
inflammation in asthmatic and control subjects. Am J Respir Crit Care Med
41 Hellings PW, Vandenberghe P, Kasran A, et al.: Blockade of CTLA-4 en-
hances allergic sensitization and eosinophilic airway inflammation in geneti-
cally predisposed mice. Eur J Immunol 2002, 32:585–594.
42 Wang J, Palmer K, Lotvall J, et al.: Circulating, but not local lung, IL-5 is re-
quired for the development of antigen-induced airways eosinophilia. J Clin
Invest 1998, 102:1132–1141.
43 Tomaki M, Zhao LL, Lundahl J, et al.: Eosinophilopoiesis in a murine model of
allergic airway eosinophilia: involvement of bone marrow IL-5 and IL-5 recep-
tor alpha. J Immunol 2000, 165:4040–4050.
44 Saito H, Matsumoto K, Denburg AE, et al. Pathogenesis of murine experimen-
tal allergic rhinitis: a study of local and systemic consequences of IL-5 defi-
ciency. J Immunol 2002, 168:3017–3023.
Innovative study on the role of the IL-5-eosinophil pathway in experimental rhinitis,
depicting the important, but not crucial role of IL-5 and eosinophils in nasal symp-
toms and histamine hyperresponsiveness.
45 Saito H, Howie K, Wattie J, et al.: Allergen-induced murine upper airway in-
flammation: local and systemic changes in murine experimental allergic rhini-
tis. Immunology 2001, 104:226–234.
46 Crystal-Peters J, Neslusan C, Crown WH, et al.: Treating allergic rhinitisin
patients with comorbid asthma: the risk of asthma-related hospitalizations
and emergency department visits. J Allergy Clin Immunol 2002, 109:57–62.
Retrospective cohort study based on insurance claims data. This study clearly
demonstrates an inverse relation between allergic rhinitis treatment and asthma
47 Welsh PW, Stricker WE, Chu CP, et al.: Efficacy of beclomethasone nasal
solution, flunisolide, and cromolyn in relieving symptoms of ragweed allergy.
Mayo Clin Proc 1987, 62:125–134.
48 Foresi A, Pelucchi A, Gherson G, et al.: Once daily intranasal fluticasone
propionate (200 micrograms) reduces nasal symptoms and inflammation but
also attenuates the increase in bronchial responsiveness during the pollen
season in allergic rhinitis. J Allergy Clin Immunol 1996, 98:274–282.
49 Corren J, Adinoff AD, Buchmeier AD, et al.: Nasal beclomethasone prevents
the seasonal increase in bronchial responsiveness in patients with allergic
rhinitis and asthma. J Allergy Clin Immunol 1992, 90:250–256.
50 Lipworth BJ, White PS: Allergic inflammation in the unified airway: start with
the nose. Thorax 2000, 55:878–881.
51 Aubier M, Levy J, Clerici C, et al.: Different effects of nasal and bronchial
glucocorticosteroid administration on bronchial hyperresponsiveness in pa-
tients with allergic rhinitis. Am Rev Respir Dis 1992, 146:122–126.
52 Greiff L, Andersson M, Svensson C, et al.: Effects of orally inhaled budes-
onide in seasonal allergic rhinitis. Eur Respir J 1998, 11:1268–1273.
53 Woodcock A, Custovic A: ABC of allergies. Avoiding exposure to indoor
allergens. BMJ 1998, 316:1075–1078.
54 Durham SR, Walker SM, Varga EM, et al.: Long-term clinical efficacy of grass-
pollen immunotherapy. N Engl J Med 1999, 341:468–475.
55 Bousquet J, Demoly P, Michel FB: Specific immunotherapy in rhinitis and
asthma. Ann Allergy Asthma Immunol 2001, 87:38–42.
Evidence-based review of literature published on allergen-specific immunotherapy
(SIT) with special emphasis on the effect on asthma. The authors give clear rec-
ommendations for the use of SIT in allergic rhinitis and asthma.
56 Moller C, Dreborg S, Ferdousi HA, et al.: Pollen immunotherapy reduces the
development of asthma in children with seasonal rhinoconjunctivitis (the PAT-
study). J Allergy Clin Immunol 2002, 109:251–256.
Elegant 3-year follow-up study in children with seasonal allergic rhinitis, which in-
vestigates the preventive effect of allergen-SIT on the development of asthma.
57 Rak S, Heinrich C, Jacobsen L, et al.: A double-blinded, comparative study of
the effects of short preseason specific immunotherapy and topical steroids in
patients with allergic rhinoconjunctivitis and asthma. J Allergy Clin Immunol
A unique comparative study between allergen-SIT and nasal steroids (NS) in sea-
sonal allergic rhinitis and asthma.
58 Rakoski J, Wessner D: A short assessment of sublingual immunotherapy. Int
Arch Allergy Immunol 2001, 126:185–187.
59 Bousquet J, Godard P, Michel FB: Antihistamines in the treatment of asthma.
Eur Respir J 1992, 5:1137–1142
60 Baena-Cagnani CE: Desloratadine activity in concurrent seasonal allergic rhi-
nitis and asthma. Allergy 2001, 56 Suppl 65:21–27.
61 Henz BM: The pharmacologic profile of desloratadine: a review. Allergy 2001,
56 Suppl 65:7–13.
62 Ciprandi G, Tosca M, Passalacqua G, et al.: Long-term cetirizine treatment
reduces allergic symptoms and drug prescriptions in children with mite al-
lergy. Ann Allergy Asthma Immunol 2001, 87:222–226.
63 Horwitz RJ, McGill KA, Busse WW: The Role of Leukotriene Modifiers in the
Treatment of Asthma. Am J Respir Crit Care Med 1997, 157:1363–1371.
64 Sampson A, Holgate S: Leukotriene modifiers in the treatment of asthma.
Look promising across the board of asthma severity. BMJ 1998, 316:1257–
65 Borish L: The role of leukotrienes in upper and lower airway inflammation and
the implications for treatment. Ann Allergy Asthma Immunol 2002, 88:16–22.
An excellent review on the pathophysiologic role of leukotrienes in allergic rhinitis
and asthma and the therapeutical implications.
66 Schmidt BM, Kusma M, Feuring M, et al.: The phosphodiesterase 4 inhibitor
roflumilast is effective in the treatment of allergic rhinitis. J Allergy Clin Immu-
nol 2001, 108:530–536.
67 Yoshida N, Shimizu Y, Kitaichi K, et al.: Differential effect of phosphodiester-
ase inhibitors on IL-13 release from peripheral blood mononuclear cells. Clin
Exp Immunol 2001, 126:384–389.
68 Arshad SH, Holgate S: The role of IgE in allergen-induced inflammation and
the potential for intervention with a humanized monoclonal anti-IgE antibody.
Clin Exp Allergy 2001, 31:1344–1351.
This review gives insight into the immunopathologic functions of immunoglobulin E
in allergy and asthma. It provides the rationale for targeting IgE as one of the key
players in allergic airway disease.
69 Platts-Mills TA: The role of immunoglobulin E in allergy and asthma. Am J
Respir Crit Care Med 2001, 164:S1–5.
70 Busse W, Corren J, Lanier BQ, et al.: Omalizumab, anti-IgE recombinant hu-
manized monoclonal antibody, for the treatment of severe allergic asthma.J
Allergy Clin Immunol 2001, 108:184–190.
Randomized, double-blinded, placebo-controlled trial involving patients with se-
vere allergic asthma, who are corticoid dependent. This study clearly showed the
efficacy and safety of omalizumab in this population.
71 Holgate S, Bousquet J, Wenzel S, et al.: Efficacy of omalizumab, an anti-
immunoglobulin E antibody, in patients with allergic asthma at high risk of
serious asthma-related morbidity and mortality. Curr Med Res Opin 2001,
Meta-analysis based on three randomized trials investigating the efficacy and pub-
lic health impact of omalizumab as an add-on therapy in severe allergic asthma.
Allergic rhinitis and asthma Braunstahl and Hellings 51