Symposium: The Rhinitis–Asthma Connection: One Linked Airway

The upper and lower airways: The epidemiological and

pathophysiological connection
Raymond G. Slavin, M.D., M.S.

ABSTRACT
The upper and lower airways do not exist as anatomically and functionally distinct areas. There are important relationships
between both the nose and the paranasal sinuses and asthma. Both allergic rhinitis and rhinosinusitis may impact bronchial
asthma. The patient with rhinitis should be observed carefully for the development of asthma, and those with asthma should be
considered to have either rhinitis or rhinosinusitis.
(Allergy Asthma Proc 29:553–556, 2008; doi: 10.2500/aap.2008.29.3169)
Key words: Allergic rhinitis, airway hyperreactivity, asthma, connection, epidemiology, inflammation, lower
airway, pathophysiology, rhinosinusitis, upper airway

Lesions in the nose and the sinuses are so common in

asthma as to be almost a clinical characteristic, and they
may be of diagnostic importance.
Frances Rackeman, M.D., 1931

M ore than three-quarters of a century ago, a Bos-

ton allergist in private practice made the afore-
mentioned statement. Dr. Rackeman astutely observed
may be associated with several comorbidities includ-
ing allergic conjunctivitis, rhinosinusitis, and asthma.

that rather than assuming that the upper and lower

airways are anatomically and physiologically distinct,
there are important relationships between the two.
Specifically, diseases of the upper airway can impact
unfavorably on the lower airway and worsen asthma.
I would like to discuss two upper airway diseases,
viz., allergic rhinitis and rhinosinusitis, and their rela-
tionships to asthma. I will deal largely with the epide-
miological and pathophysiological connections.
ALLERGIC RHINITIS
Allergic rhinitis is an extremely common disease,
affecting ⬎40 million Americans. It has proven to be
quite costly, both directly in terms of dollars spent and
indirectly in terms of life-style impact.1 Allergic rhinitis
From the Division of Immunobiology, Section of Allergy and Clinical Immunobiology,
Department of Internal Medicine, Saint Louis University School of Medicine, St.
Louis, Missouri
Presented at the meeting of the Eastern Allergy Society, Naples, Florida, May 4, 2008
There are no financial disclosures
Raymond G. Slavin, M.D., M.S., Saint Louis University School of Medicine, 1402
South Grand Boulevard, St. Louis, MO 63106
E-mail address: slavinrg@slu.edu
Copyright © 2008, OceanSide Publications, Inc., U.S.A.
Association of Allergic Rhinitis and Asthma
There are a number of studies showing a significant
association between allergic rhinitis and asthma (Table
1). In terms of coexistence, up to 80% of asthmatic
patients have been diagnosed with rhinitis.2 Asthma
has been diagnosed in up to 58% of patients with
rhinitis.3 Rhinitis occurs simultaneously with or pre-
cedes asthma in up to 64% of patients.4 There is also
evidence that patients with asthma who deny symp-
toms of rhinitis have inflammatory changes in their
nasal mucosa. Therefore, one may argue that in most
patients with asthma, the entire respiratory tract is
involved. This has prompted the introduction of the
term chronic allergic airways syndrome.5 At the lower
end of the spectrum are patients with upper airway
diseases alone, whereas the high end consists of pa-
tients with both rhinitis and asthma. Nonallergic rhi-
nitis has also been found to be associated with asthma.6
Patients with perennial rhinitis had almost four times
the incidence of asthma as patients with no rhinitis.
Another example of comorbidity of rhinitis and
asthma occurs in patients sensitive to aspirin and non-
steroidal anti-inflammatory drugs.7 In the workplace,
symptoms of rhinitis are commonly associated with
occupational asthma. One study showed 92% of sub-

Allergy and Asthma Proceedings 553

Table 1 Interrelationships between allergic rhinitis
and asthma
Allergic rhinitis and asthma frequently coexist
Allergic rhinitis is a risk factor for developing asthma
Rhinitis makes asthma worse
Nasal dysfunction may cause changes in lower
airway function via both direct and indirect
mechanisms
jects with occupational asthma experienced rhinitis
symptoms.8 Given all of these examples, it can be
stated that both allergic and nonallergic rhinitis are
strongly associated with asthma.
Rhinitis as a Risk Factor for Asthma
One of the most convincing studies indicating that
having allergic rhinitis predisposes to asthma was per-
formed at Brown University.9 More than 1800 incom-
ing freshmen were evaluated for allergy. None of them
had asthma. Some of the group had allergic rhinitis
and were skin test positive, but the rest were negative
by history and skin testing. The 23-year follow-up
questionnaire revealed that the group who had allergic
rhinitis as freshman had developed asthma three times
more commonly than those with no history of allergic
rhinitis. Of the group who developed asthma, 86% also
had allergic rhinitis. Among the participants with both
asthma and seasonal allergic rhinitis, 44.8% experi-
enced the development of seasonal allergic rhinitis
first, 34.5% experienced the development of asthma
first, and 20.7% experienced the development of both
diseases at the same time.
Impact of Allergic Rhinitis on Asthma Severity
There appears to be evidence of increased symptom
severity, involving the entire respiratory tract, in pa-
tients with both rhinitis and asthma. In patients with
more severe rhinitis, a number of asthma parameters
are worsened including weekly attacks, nightly awak-
ening, related work loss, and asthma severity as deter-
mined by the National Asthma Education Prevention
Program designation.10
Anatomic and Physiological Similarities of Rhinitis
and Asthma
There are many similarities between the upper and
lower airways including a continuous basement mem-
brane, pseudostratified columnar epithelium, mucosal
transport, tubuloalveolar seromucous glands, goblet
cells, parasympathetic and sympathetic innervation,
and circadian rhythm response (Table 2).11 Triggers for
upper and lower airway responsiveness are the same,
including nonspecific irritants (e.g., cold air and ciga-
rette smoke) and allergens, both seasonal (pollens and
554
Table 2 Similarities between the upper and lower
airways
Anatomic
Continuous basement membrane, pseudostratified
columnar epithelium, mucosal transport, mucous
glands, goblet cells, and innervation
Circadian rhythm
Triggers
Nonspecific (cold air and cigarette smoke)
Allergens (seasonal and nonseasonal)
Patterns of inflammation
Hyperresponsiveness
Acute late-phase response
Table 3 Changes in the nose that affect the lower
airway
Filter function failure of nose: Increased allergen/
irritant burden on lower airway
Heat and humidification failure of nose: Exercise-
induced asthma
Increased lower airway responsiveness: Specific and
nonspecific
Viral upper respiratory infection
Nasal bronchial reflex
mold) and perennial (house-dust mites and animals).
The cellular mediators of inflammation for both in-
clude mast cells, eosinophils, basophils, and Th2 lym-
phocytes. The number of eosinophils in the nose has
been shown to correlate with eosinophilic infiltration
in the bronchi. Finally, both the nose and the lung
show airway hyperresponsiveness as well as an acute
and late-phase response. In patients with pure rhinitis
and no evidence of asthma, inhalation of methacholine,
a parasympathomimetic agent, results in an increase in
lower airway responsiveness that approaches that seen
in asthma.
Changes in the Nose That Affect the Lower Airway
In addition to the horizontal relationship between
rhinitis and asthma (i.e., the impressive coexistence of
rhinitis and asthma) there is also a vertical relationship,
by which changes in the nose affect the lower airway
(Table 3). One example is the important role the nose
plays in filtering, warming, and humidifying inspired
air. If the nose is bypassed, more irritants, allergens,
and colder drier air reach the lung, resulting in a wors-
ening of asthma. In one study on exercise-induced
asthma, subjects with spontaneous breathing (i.e.,
breathing through the nose and mouth) showed a
slight decrease in forced expiratory volume in 1 second
(FEV1) compared with subjects breathing exclusively
November–December 2008, Vol. 29, No. 6
through their nose. Mouth breathers showed a much
greater decline in FEV1 with exercise.12
Nasal provocation has also been shown to alter lower
airway function. Stimulation of the nose by histamine
or allergen resulted in a fall in FEV1 in patients with
pure allergic rhinitis and no evidence of asthma either
clinically and/or by pulmonary function testing.13 In
another study, nasal challenge with allergen resulted in
an influx of eosinophils in nasal epithelium and lamina
propria as well as in bronchial epithelium and lamina
propria. In addition, there was an up-regulation of
adhesion molecules ICAM-1, VCAM-1, and E-selectin.
The local expression of these adhesion molecules in the
bronchial epithelium correlated with the number of
mucosal eosinophils.14 The reverse also occurs with
allergen bronchial challenge resulting in an increase in
nasal mucosal eosinophils.15 Another example of the
upper and lower airway relationships is the effect of
viral upper respiratory infections (URI) on asthma.
Clearly, these infections are the most frequent cause of
emergency room visits and hospitalizations for
asthma. During a viral URI, the lower airway is more
responsive to both histamine and allergen inhalation.16
Nasal inoculation with strain 16 rhinovirus in allergic
asthmatic patients resulted in an increase in circulating
neutrophils 48 hours later, which correlated with an
increase in nasal concentration of IL-8 and G-CSF. An
increase in bronchial neutrophils was seen 96 hours
later.17 A clinical correlate may be that a short course
on montelukast, a leukotriene antagonist, has been
shown to improve asthma systems and health care
utilization in children experiencing a viral URI.18
Evidence for a nasal-bronchial reflex has been seen in
studies on patients with unilateral trigeminal neuralgia
who underwent nerve resection. Briefly, nasal expo-
sure to silica on both sides of the nose showed a
significant increase in lower airway resistance after
silica exposure on the intact side with no change seen
on the resected side.19
Mechanisms Underlying Rhinitis and Asthma
Connections
A number of theories have been proposed to account
for the relationship between the nose and the lung. I
have already alluded to the term chronic allergic air-
ways syndrome, sometimes referred to as the “one
airway– one disease” hypothesis. Denburg et al. found
that after nasal allergen challenge, there was an in-
crease in circulating mature basophils and eosinophils
and an increase in progenitors of eosinophils and ba-
sophiles. An increase in CD35⫹ cells was also seen,
which is indicative of punitive progenitor cells of all
linkages. Their conclusion was “that allergic inflamma-
tion involves a systemic process in which the bone
marrow actively contributes to maintain and sustain
disease and symptoms.”20
Allergy and Asthma Proceedings
Rhinosinusitis and Asthma
It has been suggested that the term sinusitis be re-
placed by rhinosinusitis, a more descriptive and accu-
rate word for the following reasons. Rhinitis typically
precedes sinusitis, sinusitis without rhinitis is rare, the
mucosa of the nose and sinuses is contiguous, and
symptoms of nasal obstruction and nasal discharge are
prominent in sinusitis.
The frequent association of paranasal sinus disease
and bronchial asthma has been noted for many years.21
A number of clinical studies in the 1920s and 1930s
emphasized the importance of rhinosinusitis as a trig-
ger for asthma. However, the relationship then seemed
to fall into disrepute and little was written about the
relationship for the next several decades. One prevail-
ing thought was that sinus changes simply reflected an
epiphenomenon, viz., a disease of the entire respiratory
membrane. Therefore, management of rhinosinusitis
per se would be expected to have little effect on the
course of lower respiratory tract disease. In the last 20
years, the relationship of rhinosinusitis and asthma has
been revived.
There is no question that a high incidence of radio-
graphic evidence of rhinosinusitis is present in patients
with asthma. A study from France22 indicated that
patients with mild-to-moderate asthma had an 87%
incidence of abnormal sinus CTs while patients with
severe steroid-dependent asthma showed 100% abnor-
mal sinus CT. In Finland23 there was an 87% abnormal
CT sinus incidence in adults with asthma exacerba-
tions. A later study in the Netherlands showed much
the same thing; severe adult asthmatic patients had an
incidence of 87% abnormal sinus CT.24
Mechanisms Relating Rhinosinusitis and Asthma
Although a number of possibilities have been sug-
gested, the precise mechanisms linking rhinosinusitis
to asthma are not known. One theory proposes that the
airway hyperresponsiveness seen in rhinosinusitis
might depend on pharyngobronchial reflexes triggered
by seeding of the inflammatory process into the phar-
ynx through postnasal drainage of mediators and in-
fected material from affected sinuses. The theory is
based on the finding that intrabronchial and particu-
larly extrabronchial reactivity were strongly associated
with the degree of pharyngitis as determined by his-
tory, physical examination, and nasal lavage. In a later
study, the authors showed actual damage of pharyn-
geal mucosa in patients with chronic rhinosinusitis
marked by epithelial thinning and a striking increase in
pharyngeal nerve fiber density.25 This would favor an
increase in excessive irritants to submucosal nerve end-
ings inducing the release of sensory neuropeptides via
axon reflexes with activation of a neural arch, resulting
in reflex airway constriction.
555
 Another possibility is the same as proposed for the
relationship between rhinitis and asthma, viz., the one-
airway hypothesis. In a study of 22 patients with re-
fractory chronic rhinosinusitis, there was a striking
similarity of features with those of bronchial asthma
including eosinophilic inflammation, epithelial shed-
ding, and basement membrane thickening.26 Finally, a
systemic process could be involved with the inflamma-
tory mucosa of rhinosinusitis releasing cytokines,
which stimulate the bone marrow to release inflamma-
tory cells, which then migrate to the lung.
CONCLUSION
Although the precise mechanisms have not been elu-
cidated, there appear to be important links between the
upper and lower airways. Physicians must be accus-
tomed to examining both parts of the respiratory tract.
Patients with rhinitis should be observed carefully for
the development or coexistence of asthma and those
with asthma should be considered to have rhinitis or
rhinosinusitis.
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