121
Nasal polyposis
NIELS MYGIND AND VALERIE J LUND
Introduction 1549
Definition and characteristics 1549
Epidemiology 1550
Aetiology and associated diseases 1550
Pathology and pathogenesis 1551
Clinical presentation 1552
Diagnosis and staging 1553
SEARCH STRATEGY
The data in this chapter are supported by a PubMed search using the key words nasal polyps, intranasal corticosteroids,
systemic corticosteroids and surgery.
INTRODUCTION
The ear, nose and throat (ENT) surgeon may consider
nasal polyps to be a trivial disease, as the diagnosis is easy
to make by endoscopy and the treatment consists of
corticosteroids and surgery. The patient will experience
nasal polyps to be an unpleasant disease, which severely
interferes with the quality of life.1 The scientist will find
nasal polyps to be a challenge because the aetiology, in the
large majority of cases, is unknown and because the
pathogenesis of polyp formation is poorly understood.
Why do polyps often develop in some types of
inflammatory airway diseases and not in others? Why
do polyps only develop in a few square centimetres of a
generally inflamed airway mucous membrane?
Even the name is problematic. Polyp is derived from
Greek, meaning many footed (poly, many; pous, footed),
but a polyp has only one foot (stalk). Finally, a disease
characterized by the occurrence of multiple polyps is most
correctly named nasal polyposis and, strictly speaking, it
is not a nasal but a sinonasal disease.
Treatment 1554
Summary 1556
Key points 1556
Best clinical practice 1556
Deficiencies in current knowledge and areas for future
research 1556
References 1557
DEFINITION AND CHARACTERISTICS
A polyp presents in the nasal cavity with a grape-like
appearance, having a body and a stalk. The surface is
smooth and the colour is more yellow than the pink
mucous membrane. Nasal polyps originate in the upper
part of the nose around the openings to the ethmoidal
sinuses. The polyps protrude into the nasal cavity from
the middle and superior meatus, resulting in nasal
blockage and abolishing airflow to the olfactory region.
Nasal polyposis, consisting of multiple, bilateral polyps, is
part of an inflammatory reaction involving the mucous
membrane of the nose, the paranasal sinuses and often
the lower airways. Polyps are easily accessible for
histological and immunological studies and an increasing
number of publications have appeared in recent years.2, 3
The relationship between nasal polyposis and chronic
rhinosinusitis is much debated but in its broadest sense
nasal polyposis should probably be regarded as one form
of chronic inflammation in the nose and sinuses, i.e. part
of the spectrum of chronic rhinosinusitis.4
1550 ] PART 13 THE NOSE AND PARANASAL SINUSES

EPIDEMIOLOGY NSAID intolerance is typically associated with polyp

The prevalence rate of nasal polyposis is about 2 percent.5
It increases with age, reaching a peak in those aged 50
years and older. The male:female ratio is about 2:1.
Nasal polyposis occurs with a high frequency in groups
of patients having specific airway diseases (Table 121.1).
It is noteworthy that nasal polyps are very rare in allergic
children in contrast to children with cystic fibrosis and
that the disease is more frequent in nonallergic than in
allergic adult patients with rhinitis and asthma.
Although the disease, nasal polyposis, is rare, isolated
nasal polyps occur in one third of examined nasoethmoi-
dal blocks from cadavers.6
There are few studies of the natural history of nasal
polyposis. In a follow up of patients in an otology
practice, the median time from the first to the second
polypectomy was six years, indicating that many cases of
nasal polyposis are mild.7 In another study, 85 percent of
patients referred to a hospital ENT clinic for nasal
polyposis had visible polyps 20 years after the first visit,
showing that nasal polyposis is a chronic disease.8
The polyp recurrence rate depends upon the type of
disease. It is low in cystic fibrosis and high in patients
with nonsteroidal antiinflammatory drug (NSAID) intol-
erance and asthma. [***]
AETIOLOGY AND ASSOCIATED DISEASES
The aspirin triad
A triad of nasal polyposis, asthma and aspirin (acetyl-
salicylic acid) intolerance was described many years ago
and represents the most aggressive form of the disease. It
is a nonallergic entity and the intolerance is not confined
to acetylsalicylic acid, as the patients react to other
NSAIDs, acting as cyclooxygenase inhibitors. While
formation, intake of NSAIDs is not the cause of polyp
formation. [****]
Allergic fungal sinusitis
Nasal polyps occur in almost all patients with allergic
fungal rhinosinusitis (see Chapter 114, Fungal rhinosi-
nusitis). In this disease, the tissue inflammation is
typically eosinophil-dominated,9 as in the aspirin triad.
[****]
Allergy?
As most polyps are characterized by tissue eosinophilia, it
has been the belief for decades that allergy is a significant
cause of nasal polyposis. However, this view has been
challenged because most studies have failed to show a
higher occurrence of positive skin tests to inhaled
allergens in patients with polyps than in the general
population.5, 10, 11, 12 In addition, diseases associated with
a high prevalence of polyposis (Table 121.1) are not based
on IgE-mediated allergy.
In striking contrast to nasal polyposis, which is a
disease of middle-aged people, allergic rhinitis occurs
with its highest prevalence in children and young adults.
Children with perennial allergic rhinitis, who can have
markedly swollen nasal mucous membranes, almost never
develop polyps (Table 121.1).
Even the pathogenic contribution of allergic reactions
in patients with coincidental occurrence of the two
conditions can be questioned. Keith and coworkers13 were
unable to show any deterioration of nasal symptoms or
eosinophilia during the pollen season in polyp patients
having a positive skin test to pollen. Thus, it appears that
allergy is not a well-documented cause or aggravating
factor in nasal polyposis. [**]

Table 121.1 Frequency of nasal polyps in various diseases.

Cystic fibrosis
Disease Group %
Nasal endoscopy demonstrated polyps in 45 percent of
Allergic rhinitis In children 0.1 adults with cystic fibrosis (CF).14 In the majority of
In adults 1.5 patients, the disease was staged as mild and the polyps did
Nonallergic rhinitis 5 not extend beyond the middle turbinate.15 Mucosal
Asthma in adults Allergic 5 abnormalities in the sinuses consistent with polypoid
Nonallergic 13 hyperplasia are demonstrated on computed tomography
NSAID intolerance 3672 (CT) scans in almost all patients with CF.15 [****]
NSAID intolerance and asthma 80 Histology results of CF polyps are controversial. Three
Allergic fungal rhinosinusitis 480 studies, comparing polyps from children with CF and
ChurgStrauss syndrome 50 adults with non-CF polyps, showed a strikingly lower
Cystic fibrosis In children 10 number of eosinophils in the CF polyps.16, 17, 18 However,
In adults 40 in a study of adult patients, there was a considerable
Primary ciliary dyskinesia 40 overlap in the number of eosinophils between the two
Adapted from Ref. 2. groups.19

Primary ciliary dyskinesia (Kartageners
syndrome)
Absent mucociliary clearance and recurrent bacterial
infections result in nasal polyposis in about 40 percent
of the patients.20 The recurrence rate is low after surgery.
[****]
Youngs syndrome
The cause of this syndrome is unknown. It consists of
recurrent respiratory disease with chronic rhinosinusitis,
nasal polyps, bronchiectasis and azoospermia. [***]
As we are reluctant to expose our ignorance to
patients, some physicians still call nasal polyps allergic.
This is misleading and may result in futile attempts at
identifying a causative allergen in air, food or beverages. It
is more correct to tell the patient that polyps are caused
by an allergy-like inflammation, but that the cause is
unknown. [**]
Chronic urticaria is a nonallergic disease, having many
similarities to allergy. It was recently shown that, in a
number of cases, it is caused by IgG autoantibodies to the
receptor for IgE on mast cells. Although tempting to
hypothesize, a similar process has not been identified in
nasal polyposis.
PATHOLOGY AND PATHOGENESIS
Site of polyp formation
Nasal endoscopy of a large number of patients with nasal
polyposis21 and a detailed anatomic examination of
autopsy specimens22 have shown that nasal polyps are
mainly situated in the middle meatus and that they
originate from the mucous membrane of the outlets
(ostia, clefts, recesses) from the paranasal sinuses. This
area, so critical for sinus pathology, is also referred to as
the ostiomeatal complex.
It is remarkable that polyps exclusively develop from a
few square centimetres of an airway mucous membrane
which often is universally inflamed. The reason for this is
unknown and one can only speculate about the nature of
a localization factor. One possibility is that touching
mucous membranes in the narrow ostiomeatal complex
results in the release of proinflammatory cytokines from
epithelial cells. Another possibility is an influence of
special airflow, air current and pressure in the upper part
of the nose. Finally, it may be of significance that the
nerve endings near the borderline between the nose and
paranasal sinuses are thin23 and may easily become
damaged by cytotoxic proteins, released by eosinophils.24
[****]
Chapter 121 Nasal polyposis ] 1551
Surface epithelium
TYPE OF EPITHELIUM
The major part of the polyp surface is covered by a
ciliated pseudostratified epithelium, but, in addition,
transitional and squamous epithelia are found, especially
in anterior polyps, influenced by the inhaled air
currents.25
EPITHELIAL DEFECTS
There is experimental evidence that cytotoxic proteins
from eosinophils can damage the respiratory epithelium
and induce bronchial hyperreactivity in asthma. Epithelial
defects have also been described in nasal polyps.26
However, this may be due to cutting artefacts during
processing, as the polyp epithelium appears well pre-
served without defects when polyps are removed carefully,
and gentle methods are used for fixation, dehydration and
cutting.
ROLE IN INFLAMMATION
There is increasing evidence that the airway epithelium
may play an important role in airway inflammation, as
disturbance of the epithelium, such as may occur on
exposure to chemical, physical and immunological
stimuli, can lead to the release of proinflammatory
cytokines.
Innervation
Sensory nerves, autonomic secretory and vasomotor
nerves, invariably found in normal and abnormal nasal
mucosa, cannot be identified within the stroma of polyps.23
It is assumed, therefore, that denervation of nasal
polyps causes a decrease in secretory activity of the glands
and induces an abnormal vascular permeability, leading
to tissue oedema. As mentioned, nasal polyps develop in
areas where the lining of the nasal cavity joins that of the
sinuses, and these marginal zones contain thin nerve
fascicles,23 which may have increased sensitivity to
damaging factors.
While the exact cause and mechanism of the denerva-
tion of the nasal polyps is unknown, there is little doubt
that the complete loss of autonomic innervation is an
important pathogenetic factor in the formation of polyps.24
Goblet cells
The number of goblet cells in polyps vary considerably
between and within polyps. However, the average density
is much lower than in the nasal mucous membrane.25
1552 ] PART 13 THE NOSE AND PARANASAL SINUSES
Submucosal glands
The glands of nasal polyps differ markedly from normal
nasal glands. While nasal mucosa glands are small
branched tubuloalveolar glands, those in the polyps are
long, tubular and of varying shape, size and type. The
nasal glands are evenly distributed over the mucous
membrane, while the glands in the polyps are very
unevenly distributed. Their density is more than ten times
less than in the nasal mucosa.27 All glands in the polyps
are abnormal, showing signs of cystic degeneration with
stagnation of mucus within the distended tubules.16, 27
Blood vessels, plasma exudation and oedema
formation
The vascularity of polyps is minimal as compared to
normal nasal mucosa and neither venous sinusoids nor
arteriovenous anastomoses are found.23 The venules of
the polyps show unusual organization with respect to
their endothelial cell junctions and the basement
membrane. Many cell junctions have the appearance of
a web of villous processes and are incompletely sealed,
while others are wide open,23 promoting oedema
formation.
Inflammation
Nasal polyposis is the ultimate form of inflammation of
the upper airways, which, for unknown reasons, prefer-
entially develops in subtypes of inflammatory diseases.
Although IgE-mediated allergy is not an important
aetiological factor, recent data indicate that both mast
cells and histamine are involved in the inflammation and
in the pathogenesis of polyps.
MAST CELLS AND HISTAMINE
There is an increased number of epithelial mast cells in
nasal polyps.28 Electron microscopic studies have shown
marked and widespread mast cell degranulation in all
polyps studied.29
It is in accordance with the ultrastructural changes that
total histamine levels in polyps are far higher than in
other tissues (1001000 times that of plasma).30 The
release of histamine may be an important factor in
causing plasma exudation. This is highly characteristic of
polyps, which are oedema-filled sacks.
LYMPHOCYTES
There is accumulating evidence that the inflammatory
reaction in nasal polyposis is at least in part driven by T
lymphocytes and their humoral products, the cytokines. T
lymphocytes predominate over B cells and there are
more T supressor (CD8 1 ) than T-helper cells (CD4 1 ),
the number of which are reduced by corticosteroid
treatment.31
EOSINOPHILS
Eosinophils comprise the most prevalent inflammatory
cell in most types of nasal polyps. They show signs of
activation and have markedly prolonged survival.
ADHESION MOLECULES AND CYTOKINES
Eosinophil infiltration and activation is caused by
cytokines, chemokines and adhesion molecules. Polyp
epithelial cells produce IL-1, IL-3, IL-4 and TNFa, and
these cytokines can upregulate the adhesion molecule,
VCAM-1 in endothelial cells.32, 33 The interaction be-
tween VCAM-1 and VLA-4 plays an important role for
extravasation of eosinophils into polyps. In addition, the
chemokines, eotaxin and RANTES are probably involved
as eosinophil attractants.32
The finding of high amounts of IL-5 in the majority of
nasal polyp specimens, but in none of the normal control
or sinusitis samples, indicates that IL-5 plays a key role in
the pathophysiology of eosinophil-dominated polyps.34
As activated eosinophils generate IL-5, which promote
further eosinophil accumulation and activation, nasal
polyps can be considered as a self-perpetuating eosino-
phil-dominated inflammation.35
CLINICAL PRESENTATION
Rhinosinusitis
Patients, as a rule, have suffered from perennial
nonallergic rhinitis (idiopathic rhinitis) with profuse
watery rhinorrhea for some years, then nasal blockage
gradually develops and becomes persistent. Simulta-
neously, secretions become more viscous and are removed
by noisy sniffing as postnasal drip. Involvement of the
paranasal sinuses, the mucosa of which has many goblet
cells but few seromucous glands, contributes to the
viscosity of the discharge. It is most important that
impaired airflow in the upper part of the nose is followed
by a reduced or abolished sense of smell, and with that
taste. This symptom is very annoying as it mars the
pleasure of eating and drinking.
The disease can vary in severity from a single episode
of nasal blockage, relieved by a short course of treatment,
to a life-long disease, requiring continuous and combined
treatment.
Patients often believe that they are allergic because
inhaled irritants, certain food and alcoholic beverages can
 Chapter 121 Nasal polyposis ] 1553

provoke symptoms. They should be told that these factors
are not the cause of the disease, although they can
provoke symptoms from an irritable mucous membrane.
Nasal polyps are always associated with paranasal sinus
pathology. There is hyperplasia of the maxillary mucous
membrane and the ethmoidal cells are filled with
polypoid mucous membrane. This pathology may not
necessarily result in symptoms, but it can cause a feeling
of congestion and may also increase the tendency to
bacterial infection, especially following a common cold.
When polyps develop in children, it can cause
widening of the ethmoidal cells, and flattening and
broadening of the nasal bridge (frog nose).
medical and surgical treatment, and for staging of the
disease (Table 121.2).
Imaging
While a plain x-ray examination is not very helpful, a CT
scan of the nose and paranasal sinuses gives an excellent
demonstration of the anatomy and pathology. It is
indicated when there is a suspicion of malignancy or
meningocoele, and also in all cases before endoscopic
surgery. In addition, it is used for staging of the disease
(Table 121.3).

Asthma and NSAID intolerance Other examinations

Patients with severe nasal polyposis and blood eosino- Any child with nasal polyps needs an evaluation for cystic
philia often have, or will develop, asthma (30 percent) fibrosis. In general, allergy testing is not indicated but it is
and/or NSAID intolerance (15 percent). These three often expected by the patient.
disease manifestations usually start within months or a
few years in 40- to 50-year-old patients. Most patients
develop asthma before polyps. Asthma patients have Differential diagnosis
polyps which are sensitive to corticosteroid treatment, but
they usually require continuous intranasal therapy and Nasal polyps are typically multiple and bilateral. Nasal
surgery as well. As a rule, the asthma is chronic, severe bleeding, pain and unilateral polyps should alert the
and persistent, requiring continuous inhaled corticoster- physician to other conditions, such as malignant
oid treatment. tumours, inverted papillomata and, in a child, meningo-
Questioning about adverse reactions to acetylsalicylic coeles, all of which may masquerade as simple polyps. For
acid is obligatory in patients with nasal polyps. When that reason, microscopy is always necessary when polyps
ingestion of an NSAID within minutes to a few hours has are removed for the first time, and when polyps are
resulted in rhinitis, asthma, skin itching or urticaria, then unilateral.
the diagnosis is made. In case of doubt, a challenge test
with acetylsalicylic acid may be necessary. It starts with a
low dosage (10 mg) and it must be performed by a Table 121.2 Endoscopic staging of nasal polyposis.
specialist in a hospital setting. Endoscopic appearance Score
It is important to inform NSAID intolerant patients
that they must avoid not only acetylsalicylic acid, but all No polyps 0
NSAIDs, for life. Usually, patients tolerate paracetamol Restricted to middle meatus 1
and salicylic acid. Below middle turbinate 2
Massive polyposis 3
Reprinted from Ref. 36, with permission.
DIAGNOSIS AND STAGING
Table 121.3 CT scan staging of nasal polyposis.
Rhinoscopy, endoscopy
Right Left
Large polyps can be identified by simple rhinoscopy. In
contrast to a hyperplastic turbinate, a polyp can be made Maxillary 02 02
to move by touching with a probe. Endoscopy with a rigid Anterior ethmoid 02 02
scope is the preferred examination, as it can diagnose Posteriod ethmoid 02 02
small polyps in the middle meatus and give a superior Sphenoid 02 02
assessment of the extent of the disease and of anatomical Frontal 02 02
abnormalities. The examination is performed after simple Ostiomeatal complex 0/2 0/2
spraying of the nose with a local anaesthetic and a Total 012 012
vasoconstrictor. Endoscopy is useful, not only for the 0, no opacity; 1, some opacity; 2, total opacity.
diagnosis, but also for follow-up examination after Reprinted from Ref. 37, with permission.
1554 ] PART 13 THE NOSE AND PARANASAL SINUSES

A single choanal polyp, arising from the maxillary

sinus, can present in the nose. The aetiology is unknown
and treatment consists of surgical removal, which cures
the disease. Thus, it is not part of nasal polyposis.
3

TREATMENT

Score
Treatment can be either medical and/or surgical. Medical
treatment consists of intranasal and systemic corticoster- 2
oids. Possibly, leukotriene antagonists may have an
additional effect in selected patients.

1
Intranasal corticosteroids

Intranasal corticosteroids are by far the best documented

type of treatment for nasal polyposis.38, 39, 40, 41, 42 [****]
There are at least 16 placebo-controlled studies and they Entry 1 2 3
have all shown a significant clinical effect. [Grade A] Months

RESPONSIVENESS TO NASAL CORTICOSTEROIDS
Apparently, some patients do not respond to topical steroids.
This may be due to inadequate intranasal distribution of the
spray in a very blocked nose. Responsiveness can then be
achieved after a short course of systemic steroids.
There is a close connection between eosinophilia and
steroid responsiveness, and it is dubious whether nasal
steroids are of value in primary ciliary dyskinesia and CF,
although a small placebo-controlled study has shown
efficacy in CF.43
POLYP SIZE
Intranasal steroids will not eliminate polyps, but the treat-
ment clearly reduces their size (Figure 121.1).44, 45, 46, 47, 48
On the other hand, an effect on polyps in the middle
meatus cannot be expected as only a small fraction of the
spray reaches the middle meatus.49
NASAL AIRWAY PATENCY
Nasal breathing is a required outcome from therapy and
studies have clearly shown a significant effect of topical
treatment on blockage symptom scores and on objective
measures of nasal patency.44, 45, 48, 50, 51, 52, 53, 54 However,
a patent nasal airway is not necessarily a normal airway.
Pressure from polyps may have changed the normal slit-
like cavity to a wide tube in the lower part of the nose, at
the same time as there may be considerable pathology and
blockage in the upper part of the nose.
RHINITIS SYMPTOMS
While all studies have shown an effect on nasal blockage,
the effect on sneezing and secretion has varied, probably
Budesonide aerosol
Budesonide aqua
Placebo
Figure 121.1 Mean score for polyp size in patients before and
after three months of treatment with budesonide aerosol
400 mg/day (white bars), budesonide aqua 400 mg/day (pale blue
bars) or placebo (dark blue bars). Redrawn from Ref. 44.
because many patients predominantly suffer from blockage
with little sneezing and rhinorrhoea. The overall symptom
reduction is about 50 percent (Figure 121.2).44, 54, 55
An open, one-year study has shown that the anti-
rhinitis effect is maintained and that symptoms only
slowly recur when the treatment is discontinued.56
Although steroids do not cure the disease, long-term
therapy may break vicious circles and have a long-lasting
efficacy, especially in mild cases.
SENSE OF SMELL
Loss of the sense of smell, and with that taste, caused by
polyp obstruction of the upper part of the nasal cavity, is
a very annoying symptom for most patients. Clinical
experience indicates that the effect of topical steroids, in
contrast to systemic administration, is poor.45, 46, 47, 48, 57
This is probably because a spray will not reach the
olfactory epithelium due to airway obstruction by polyps.
RECURRENCE OF POLYPS
Controlled studies have shown that topical steroids can
delay the recurrence of polyps after surgery and with that
postpone the need for new surgery.58, 59, 60 However, the
 Chapter 121 Nasal polyposis ] 1555

2 for 30 years without any report of serious adverse

events.40
1.5

Systemic corticosteroids
Score

1.0

Systemic steroids can be given as tablets (prednisolone)

0.5
and as a depot-injection, probably having similar
therapeutic indices. The total glucocorticoid dose in a
0 depot-injection corresponds to about 100 mg predniso-
0 1 2 3 4 5 6 7 8 9 10 11 12
lone. When treatment is given orally, a higher total dose is
(a) Weeks
probably necessary, e.g. 25 mg prednisolone daily for
2 1014 days. However, controlled doseeffect studies are
not available. [Grade B]
Although systemic steroid treatment has not yet been
1.5
studied in placebo-controlled trials, there is no doubt that
within a few days it can reduce all nasal symptoms
Score

1.0
considerably, including the sense of smell.57, 61 A depot-
injection releases glucocorticoid for two to three weeks
0.5 and oral treatment is often given for a similar period of
time. Clinical experience confirms that the beneficial
0 effect, in many cases, will outlast the medication for a
0 1 2 3 4 5 6 7 8 9 10 11 12 variable period.
(b) Weeks A short course of systemic steroid is equally effective as
simple polypectomy with a snare57 and it may serve as a
2
medical polypectomy. In severe disease, requiring
endoscopic surgery, preoperative use of a systemic steroid
1.5 will considerably facilitate surgery.
Only a single, two- to three-week course of systemic
Score

1.0 steroids has been given in the few published studies.

However, it seems likely that some patients with severe
0.5 recurrent polyposis may benefit from repeated use of
short-term systemic steroids. Adverse effects from this
0
therapy cannot be expected to be severe and may be
0 1 2 3 4 5 6 7 8 9 10 11 12 outweighed by increased quality of life in patients with
(c) Weeks severe disease and abolished olfaction. [***]
Placebo
Budesonide aerosol
Budesonide aqua
Surgical treatment
Figure 121.2 Effect of nasal steroid (budesonide) as the only
Due to the nature of nasal polyposis as an inflammatory
treatment in patients treated with budesonide aerosol
disease of the mucous membrane, surgery cannot be
400 mg/day (open circles), budesonide aqua 400 mg/day (open
expected to cure the disease. However, in some mild cases
squares) or placebo (filled circles). (a) Blocked nose, (b) runny
presenting for the first time with large polyps, poly-
nose, (c) sneezing. Redrawn from Ref. 44.
pectomy can have a long-lasting effect. In more severe
effect is merely partial, in particular in cases of cases with persistent symptoms, surgery is added to
pronounced inflammatory activity. medical treatment in order to reduce the amount of
inflammatory tissue, open up the nasal airway and
improve ventilation of the paranasal sinuses. [Grade C]
SINUS PATHOLOGY
A few large polyps can be removed under local
There is no reason to believe that intranasal steroids have anaesthesia by a snare. While simple polypectomy was
any effect on sinus pathology.58 formerly performed repeatedly in severe cases, such
patients are nowadays referred to a rhinosurgeon for
SAFETY endoscopic sinonasal surgery, preceded by a CT scan
examination.
One should emphasize that intranasal steroids are Recently, Blomqvist and coworkers62 performed a
the best studied form of nasal treatment, extensively used controlled study by taking advantage of the bilateral
1556 ] PART 13 THE NOSE AND PARANASAL SINUSES
nature of the disease. Following intranasal corticosteroid
treatment for one month and orally for ten days, patients
had a unilateral endoscopic surgery performed. Compar-
ison of the two sides post-operatively showed that surgery
had an additional effect on nasal blockage and on polyp
score, but not on the sense of smell. Twenty-five percent
of the patients were willing to undergo a further
operation on the unoperated side at the end of the study.
The authors concluded that medical treatment is
sufficient to treat most cases of nasal polyposis. If nasal
obstruction remains a main problem after medical
treatment then surgical treatment is indicated.
The choice of surgical approach will depend upon the
individual surgeons experience. Whether a more con-
servative or more radical approach offers the better long-
term results remains to be determined.63 [***/**]
SUMMARY
Nasal polyposis, occurring in about 2 percent of the
general population, is the ultimate form of inflammation
of the upper airways. For unknown reasons, polyps
preferentially develop in subtypes of inflammatory
diseases and they are associated with perennial nonallergic
rhinitis, asthma and intolerance to acetylsalicylic acid
(NSAIDs), allergic fungal rhinosinusitis, cystic fibrosis
and primary ciliary dyskinesia. In contrast to common
belief, IgE-mediated allergy does not seem to play an
aetiological role.
The polyps originate from the mucosa around the
ostiomeatal complex. The factors determining the loca-
lization of the disease to a few square centimetres of the
airways are not known. Polyps are oedematous sacks
covered by a normal airway epithelium and containing
very few nerves, blood vessels and glands which have
undergone cystic degeneration. Polyps contain degranu-
lated mast cells and they have a very high concentration of
histamine. Polyps are characteristically infiltrated by
eosinophils, which accumulate due to release of cytokines
(in particular IL-5) and upregulation of adhesion
molecules (VCAM-1). As eosinophils generate IL-5,
attracting more eosinophils, nasal polyps can be con-
sidered as self-perpetuating inflammatory processes.
Preceded by some years with rhinitis symptoms, nasal
blockage becomes severe and persistent and, typically, the
sense of smell is seriously impaired, when polyps develop.
The diagnosis is based on anterior rhinoscopy, or
preferably, endoscopy. A CT scan is necessary when
malignancy is suspected (bleeding, pain, unilateral
polyps) and before endoscopic surgery.
Treatment consists of corticosteroids and in severe
cases surgery. Intranasal corticosteroids reduce rhinitis
symptoms, improve nasal breathing, reduce the size of
polyps and prevent, in part, their recurrence, but it has
little effect on the sense of smell. Intranasal steroids can,
as basic long-term therapy, be used alone in mild cases,
and together with systemic steroids and/or surgery in
severe cases. Systemic steroids for two to three weeks have
an effect on all types of symptoms and pathology,
including the sense of smell. This type of treatment can
serve as medical polypectomy. When blockage is a
problem in spite of medical treatment, surgery is
recommended. Simple polypectomy is still performed,
but in the more severe and persistent cases, endoscopic
surgery is recommended.
KEY POINTS
! The aetiology to nasal polyps is in most cases
unknown but they are associated with a
number of conditions, such as asthma,
aspirin sensitivity and cystic fibrosis.
! Symptomatic nasal polyposis occurs in about
2 percent of the general population.
! The ostiomeatal complex is the most
common site.
! Nasal polyps are suspected in patient with
perennial rhinitis, persistent nasal blockage
and reduced sense of smell.
! The diagnosis is made by rhinoscopy, ideally
with a rigid endoscope.
! Unilateral nasal polyps should always be
regarded with suspicion and histology is
needed in order to exclude malignancy.
Best clinical practice
[ Primary treatment consists of intranasal
corticosteroids in the majority of cases.
[ A short course of systemic corticosteroid treatment
can serve as medical polypectomy and it can
improve olfaction.
[ In more severe cases, surgery is required. In moderate
cases, this is simple polypectomy, and in more
severe cases intranasal endoscopic surgery, preceded
by a CT scan examination of the nose and paranasal
sinuses.
Deficiencies in current knowledge and
areas for future research
$ Nasal polyposis resembles an autoimmune disease
and this possibility needs further examination.
$ The suggestion that environmental fungi may
be an initiating factor needs further investigation.

$ At present, the immune inflammatory process is
undergoing detailed analysis, which is needed in order
to study whether, for example, treatment with IL-5
antibodies can be a future treatment.
$ It is worth studying whether intranasal corticosteroids
can be given in a more efficient way, e.g. as nose
drops.
$ The effect of systemic corticosteroid treatment needs
to be investigated in placebo-controlled,
doseresponse studies.
$ The possibility that a long-term treatment with a low
dose of systemic corticosteroid in selected patients
has a beneficial effect which outweighs the risk of
side effects needs a thorough investigation.
$ It is possible that leukotriene antagonists can have a
beneficial effect in subgroups of polyp patient, for
example in those who are intolerant to NSAIDs.
$ Controlled studies of surgery are required.
$ It is necessary in long-term controlled studies to
analyse what is the optimal combined medical and
surgical management.
REFERENCES
1. Radenne F, Lamblin C, Vandezande L-M, Tillie-Leblond I,
Darras J, Tonnel A-B et al. Quality of life in nasal polyposis.
Journal of Allergy and Clinical Immunology. 1999; 103:
7984.
2. Settipane GA, Lund VJ, Bernstein JM, Tos M (eds). Nasal
polyps: Epidemiology, pathogenesis and treatment. The
New England and Regional Allergy Proceedings,
Providence, Rhode Island, 1997.
3. Mygind N, Lildholdt T (eds). Nasal polyposis: An
inflammatory disease and its treatment. Copenhagen:
Munksgaard, 1997.
! 4. European Academy of Allergology and Clinical
Immunology. European position paper on rhinosinusitis
and nasal polyps. EAACI Task Force. Rhinology
Supplement. 2005; 18: 187.
5. Settipane GA. Nasal polyps: pathology, immunology and
treatment. American Journal of Rhinology. 1987; 1:
11926.
6. Larsen PL, Tos M. Anatomic site of origin of nasal polyps.
American Journal of Rhinology. 1996; 10: 2116.
7. Larsen K, Tos M. Clinical course of patients with primary
nasal polyps. Acta Otolaryngologica. 1994; 114: 5569.
8. Vento SI, Ertama LO, Hytonen ML, Wolff CHJ, Malmberg
CHO. Nasal polyposis: Clinical course during 20 years.
Annals of Allergy, Asthma and Immunology. 2000; 85:
20914.
9. Cody DT, Neel HB, Ferreiro JA, Roberts GT. Allergic fungal
sinusitis: The Mayo Clinic experience. Laryngoscope. 1994;
104: 10749.
Chapter 121 Nasal polyposis ] 1557
10. Caplin I, Haynes TJ, Spahn J. Are nasal polyps an allergic
phenomenon? Annals of Allergy. 1971; 29: 6314.
11. Drake-Lee AB, Lowe D, Swanston A, Grace A. Clinical
profile and recurrence of nasal polyps. Journal of
Laryngology and Otology. 1984; 98: 78393.
12. Braun JJ, Haas F, Conraux C. Polyposis of the nasal sinuses.
Epidemiology and clinical aspects of 350 cases. Treatment
and results with a follow-up over 5 years on 93 cases.
Annales dOtolaryngologie et de Chirurgie Cervico Faciale.
1992; 109: 18999.
13. Keith PK, Conway M, Evans S, Wong S, Jordana G, Pengelly
D et al. Nasal polyps: effects of seasonal allergen
exposure. Journal of Allergy and Clinical Immunology.
1994; 93: 56774.
14. Hadfield PJ, Rowe-Jones JM, Mackay IS. The prevalence of
nasal polyps in adults with cystic fibrosis. Clinical
Otolaryngology. 2000; 25: 1922.
15. Brihaye P, Clement PAR, Dab I, Desprechin B. Pathological
changes of the lateral nasal wall in patients with cystic
fibrosis. International Journal of Pediatric
Otorhinolaryngology. 1994; 28: 1417.
16. Srensen H, Mygind N, Tygstrup I, Flensborg EW. Histology
of nasal polyps of different etiology. Rhinology. 1977; 15:
1218.
17. Oppenheimer EA, Rosenstein BJ. Differential pathology of
nasal polyps in cystic fibrosis and atopy. Laboratory
Investigation. 1979; 40: 4459.
18. Henderson Jr. WR, Chi EY. Degranulation of cystic fibrosis
nasal polyp mast cells. Journal of Pathology. 1992; 166:
395404.
19. Rowe-Jones JM, Shembekar M, Trendell-Smith N, Mackay
I. Polypoidal rhinosinuitis in cystic fibrosis: a clinical and
histopathological study. Clinical Otolaryngology. 1997; 22:
16771.
20. Pedersen M, Mygind N. Rhinitis, sinusitis and otitis media
in Kartageners syndrome. Clinical Otolaryngology. 1982;
7: 37380.
21. Stammberger H. Functional endoscopic sinus surgery. The
Messerklinger technique. Toronto: BC Decker, 1991.
22. Larsen PL, Tos M, Baer S. En block removal of the ethmoid
and ostiomeatal complex in cadavers, with a practical
application. Rhinology. 1994; 32: 623.
23. Cauna N, Hinderer KH, Manzetti GW, Swanson EW. Fine
structure of nasal polyps. Annals of Otology, Rhinology
and Laryngology. 1972; 81: 418.
! 24. Mygind N. Nasal polyposis. Editorial. Journal of Allergy and
Clinical Immunology. 1982; 86: 8279.
25. Larsen PL, Tos M. Nasal polyps. Epithelium and goblet cell
density. Laryngoscope. 1990; 99: 127480.
26. Wladislavosky-Wasserman P, Kern EB, Holley KE, Eisenbrey
AB, Gleich GJ. Epithelial damage in nasal polyps. Clinical
Allergy. 1984; 14: 2417.
27. Tos M, Mogensen C. Mucous glands in nasal polyps.
Archives of Otolaryngology. 1977; 103: 40713.
28. Ruhno J, Howie K, Anderson M, Andersson B,
Vanzieleghem M, Hitch D et al. The increased number of
epithelial mast cells in nasal polyps and adjacent
1558 ] PART 13 THE NOSE AND PARANASAL SINUSES
turbinates is not allergy-dependent. Allergy. 1990; 45:
3704.
29. Drake-Lee A, Price J. Mast cell ultrastructure in the
inferior turbinate and stroma of nasal polyps. Journal of
Laryngology and Otology. 1997; 111: 3405.
30. Drake-Lee AB, McLauhlan P. Clinical symptoms, free
histamine and IgE in nasal polyps. International Archives
of Allergy and Applied Immunology. 1982; 69: 26871.
31. Liu CM, Shun CT, Hsu MM. Lymphocyte subsets and
antigen-specific antibody in nasal polyps. Annals of
Allergy. 1994; 72: 1924.
32. Beck L, Stellato C, Beall D, Schall TJ, Leopold D, Bickel CA
et al. Detection of chemochine RANTES and endothelial
adhesion molecules in nasal polyps. Journal of Allergy and
Clinical Immunology. 1996; 98: 76680.
33. Tingsgaard PK, Bock T, Larsen PL, Tos M. Topical
budesonide treatment reduces endothelial expression of
intercellular adhesion molecules (VCAM-1 and P-selectin)
and eosinophil infiltration in nasal polyps. Acta
Otolaryngologica. 1999; 119: 3628.
! 34. Bachert C, Gevaert P, Holtappels G, Cuvelier C, van
Cauwenberge P. Nasal polyps: From cytokine to growth.
American Journal of Rhinology. 2000; 14: 27990.
35. Denburg J. Nasal polyposis: Cytokines and inflammatory
cells. In: Mygind N, Lildholdt T (eds). Nasal polyposis: An
inflammatory disease and its treatment. Copenhagen:
Munksgaard, 1997: 7887.
! 36. Lund VJ. Diagnosis and treatment of nasal polyps. British
Medical Journal. 1995; 311: 14114.
37. Lund V, Mackay I. Staging of rhinosinusitis. Rhinology.
1993; 31: 1834.
38. Drake-Lee AB. Medical treatment of nasal polyps.
Rhinology. 1994; 32: 14.
39. Holmberg K, Karlsson G. Nasal polyps: Surgery or
pharmacological intervention? European Respiratory
Review. 1994; 4:20: 2605.
40. Mygind N, Lund V. Topical corticosteroid therapy of
rhinitis. Clinical Immunotherapy. 1996; 5: 12236.
41. Lildholdt T, Mygind N. Effect of corticosteroids on nasal
polyps. In: Mygind N, Lildholdt T (eds). Nasal polyposis: An
inflammatory disease and its treatment. Copenhagen:
Munksgaard, 1997: 1609.
42. Badia L, Lund V. Topical corticosteroids in nasal polyposis.
Drugs. 2001; 61: 5738.
43. Hadfield PJ, Rowe-Jones JM, Mackay IS. A prospective
treatment trial of nasal polyps in adults with cystic
fibrosis. Rhinology. 2000; 38: 635.
44. Johansen LV, Illum P, Kristensen S, Winther L, Petersen SV,
Synnerstad B. The effect of budesonide (Rhinocort) in the
treatment of small and medium sized nasal polyps. Clinical
Otolaryngology. 1993; 18: 5247.
! 45. Lildholdt T, Rundcrantz H, Lindqvist N. Efficacy of topical
corticosteroid powder for nasal polyps: A double-blind,
placebo-controlled study of budesonide. Clinical
Otolaryngology. 1995; 20: 2630.
46. Tos M, Svendstrup F, Arndal H, Orntoft S, Jakobsen J,
Borum P et al. Efficacy of an aqueous and a powder
formulation of nasal budesonide compared in patients
with nasal polyps. American Journal of Rhinology. 1998;
12: 1839.
47. Filiaci E, Passali D, Puxeddu R, Schrewelius C. A
randomized controlled trial showing efficacy of once daily
intranasal budesonide in nasal polyposis. Rhinology. 2000;
38: 18590.
! 48. Jankowski R, Schrewelius C, Bonfils P, Saban Y, Gilain L,
Prades JM et al. Efficacy and tolerability of budesonide
aqueous nasal spray treatment in patients with nasal
polyps. Archives of Otolaryngology Head and Neck
Surgery. 2001; 127: 44752.
49. Weber R, Keerl R, Radziwill R, Schick B, Jaspersen D,
Dshambazov K et al. Vidioendoscopic analysis of nasal
steroid distribution. Rhinology. 1999; 37: 6973.
50. Drettner B, Ebbesen A, Nilsson M. Prophylactic treatment
with flunisolide after polypectomy. Rhinology. 1982; 20:
14958.
51. Rhuno J, Andersson B, Denburg J, Anderson M, Hitch D,
Lapp P et al. A double-blind comparison of intranasal
budesonide with placebo for nasal polyposis. Journal of
Allergy and Clinical Immunology. 1990; 86: 94653.
52. Holopainen E, Grahne B, Malmberg H, Makinen J, Lindqvist
N. Budesonide in the treatment of nasal polyposis.
European Journal of Respiratory Disease. 1982; 63: 2218.
53. Deuschl H, Drettner B. Nasal polyps treated with
beclomethasone dipropionate aerosol. Rhinology. 1977;
15: 1723.
54. Elbrnd O, Felding JU, Gustavsen KM. Acoustic
rhinometry used as a method to monitor the effect of
intramuscular injection of steroid in the treatment of
nasal polyps. Journal of Laryngology and Otology. 1991;
105: 17880.
55. Mygind N, Pedersen CB, Prytz S, Srensen H. Treatment of
nasal polyps with intranasal beclomethasone dipropionate
aerosol. Clinical Allergy. 1975; 5: 15964.
56. Pedersen CB, Mygind N, Srensen H, Prytz S. Long-term
treatment of nasal polyps with beclomethasone
dipropionate aerosol. Acta Otolaryngologica. 1976; 82:
2569.
57. Lildholdt T, Fogstrup J, Gammelgaard N, Kortholm B, Ulse
C. Surgical versus medical treatment of nasal polyps. Acta
Otolaryngologica. 1988; 105: 1403.
58. Dingsor G, Kramer J, Olsholt R, Sodersstrom T. Flunisolide
nasal spray 0.025% in the prophylactic treatment of nasal
polyposis after polypectomy. A randomized double-blind
parallel, placebo-controlled study. Rhinology. 1985; 23:
4958.
59. Karlsson G, Rundcrantz H. A randomized trial of intranasal
beclomethasone dipropionate after polypectomy.
Rhinology. 1982; 20: 1448.
! 60. Rowe-Jones J, Medcalf M, Durham S, Richards D, Mackay
I. Functional endoscopic sinus surgery: 5 year follow up
and results of a prospective, randomised, stratified,
double-blind, placebo controlled study of postoperative
fluticasone propionate aqueous nasal spray. Rhinology.
2005; 43: 210.

61. Lildholdt T, Rundcrantz H, Bende M, Larsen K.
Glucocorticoid treatment for nasal polyps. A study of
budesonide powder and depot-steroid injection. Archives
of Otolaryngology Head and Neck Surgery. 1997; 123:
595600.
62. Blomqvist EH, Lundblad L, Anggard A, Haraldsson PO,
Stjarne P. A randomized controlled study evaluating
Chapter 121 Nasal polyposis ] 1559
medical treatment versus surgical treatment in addition to
medical treatment of nasal polyposis. Journal of Allergy
and Clinical Immunology. 1991; 107: 2248.
63. Browne JP, Hopkins C, Slack R, Topham J, Reeves BR, Lund
V et al. Health-related quality of life after polypectomy
with and without additional surgery. Laryngoscope. 2006;
116: 297302.
 122
The relationship between the upper and lower
respiratory tract

JEAN BOUSQUET AND ANTONIO M VIGNOLAy

Introduction 1560 Therapeutic consequences 1564

Epidemiological evidence 1560 Best clinical practice 1565
Key points 1561 Costs 1565
Nasal and sinusal inflammation in asthma and chronic Rhinitis and asthma: a continuum of disease? 1565
obstructive pulmonary disease 1561 Best clinical practice 1565
Bronchial inflammation in rhinitis 1562 Deficiencies in current knowledge and areas for future
Key points 1563 research 1566
Quality of life in asthma and rhinitis 1564 References 1566
Key points 1564

SEARCH STRATEGY

A Medline search was carried out using the key words rhinitis-asthma-epidemiology; rhinitis-nonspecific bronchial
hyperreactivity; rhinitis-asthma-occupational; rhinitis-asthma-allergens; rhinitis-asthma-nasal mucosa; rhinitis-asthma-
bronchial mucosa; rhinitis-asthma-biospsies; asthma-sinus-CT scans; rhinitis-remodelling; rhinitis-bronchial challenge
(endobronchial); asthma-nasal challenge; allergy-systemic; virus-nasal-bronchial; quality-of-life-asthma; quality-of-life-
rhinitis; (all drugs) rhinitis-asthma; immunotherapy-rhinitis-asthma; anti-IgE (omalizumab)-rhinitis or asthma.

INTRODUCTION
Asthma and allergies, including rhinoconjunctivitis and
atopic dermatitis, are common throughout the world,
with a high burden of morbidity and cost. Nasal and
bronchial mucosa present similarities and most patients
with asthma also have rhinitis1 suggesting the concept of
one airway, one disease. However, not all patients with
rhinitis present with asthma and there are some
differences between rhinitis and asthma.
EPIDEMIOLOGICAL EVIDENCE
Epidemiologic relationship between rhinitis and
asthma
Epidemiologic studies have consistently shown that
asthma and rhinitis often coexist in the same patients.2
The majority of patients with asthma present with
seasonal or perennial allergic rhinitis symptoms. How-
ever, it has been shown that perennial rhinitis is a factor
independent of allergy in the risk for asthma. Rhinitis
usually happens in over 65 percent of patients with
allergic asthma and in over 80 percent of patients with
nonallergic asthma (for review, see Ref.1). However, in
many instances, symptoms predominate in one organ and
may be hidden in the other although they exist. The
Copenhagen Allergy Study3 investigated the frequency of
asthma and rhinitis related to exposure to pollens, animal
dander or mites. Between 42 and 52 percent of patients
with rhinitis had asthma and more than 99 percent of
subjects with allergic asthma also had allergic rhinitis. The
risk of asthma among subjects with allergic rhinitis was
calculated to be up to 300 times that among subjects
without allergic rhinitis. However, the results observed in
developing countries may differ from those in western
 Chapter 122 The relationship between the upper and lower respiratory tract
populations. A recent study showed that allergic rhinitis is
far less common among asthmatic subjects in rural China
than in asthmatic subjects in industrialized countries with
a western lifestyle.4 [****]
The age of onset of atopy may be an important
confounding factor for the development of asthma and
rhinitis or rhinitis alone. In an Australian study, it was
found that atopy acquired at an early age (before the age
of six years) is an important predictive factor for asthma
continuing into late childhood, whereas atopy acquired
later was only strongly associated with seasonal allergic
rhinitis.5, 6
Rhinitis and nonspecific bronchial
hyperreactivity
Many patients with allergic rhinitis have a unique
physiologic behaviour separating them from patients
with asthma or normal subjects. They have increased
bronchial sensitivity to methacholine or histamine,7
especially during and slightly after the pollen season,8
but there are large differences in the magnitude of airway
reactivity between asthmatics and rhinitics which are not
explained by the allergen type or degree of reactivity.
[****]
Causative agents in rhinitis and asthma
Among the causative agents inducing asthma and rhinitis,
some (e.g. allergens and aspirin9) are well known to affect
both the nose and the bronchi. Most inhaled allergens are
associated with nasal10 and bronchial symptoms, but in
epidemiologic studies differences have been observed.
Although there have been some recent concerns, the
prevalence of immunoglobulin (Ig)E sensitization to
indoor allergens (house dust mites and cat allergens) is
positively correlated with both the frequency of asthma
and its severity. Alternaria and insect dusts have also been
found to be linked to asthma, however, pollen sensitivity
has not been found to be associated with asthma in
epidemiological studies.1 [****]
Occupational disease represents an interesting model
to study the relationships between rhinitis and asthma.
All of the most common triggers of occupational asthma
can induce occupational rhinitis. Subjects with occupa-
tional asthma may often report symptoms of rhinocon-
junctivitis. Rhinitis is less pronounced than asthma with
low molecular weight agents. On the other hand, rhinitis
more often appears before asthma in the case of high
molecular weight agents such as small mammals.1 In
addition, rhinitis caused by some occupational agents
often develops into occupational asthma, highlighting the
importance of cessation of allergen exposure in occupa-
tional allergic rhinitis, in order to prevent asthma. [****]
] 1561
Allergic rhinitis as a risk factor for asthma
Asthma develops more commonly in patients with
perennial rhinitis. The Childrens Respiratory Study11
showed that the presence of physician-diagnosed allergic
rhinitis in infancy was independently associated with a
doubling of the risk of developing asthma by 11 years of
age. In adults, allergic rhinitis as a risk factor for asthma
was shown in a 23-year follow-up of college students.12
Significantly more (10.5 percent) of the students origin-
ally diagnosed with allergic rhinitis went on to develop
asthma compared with 3.6 percent of those who did not
have rhinitis.
This study was recently confirmed by two other studies
in Sweden13 and the USA.14 In both studies the onset of
asthma was associated with allergic rhinitis, and in the US
study, after stratification, rhinitis increased the risk of
development of asthma by about three times both among
atopic and nonatopic patients and by more than five
times among patients in the highest IgE tertile. Patients
with rhinitis with persistent and severe nasal symptoms
and a personal history of physician-confirmed sinusitis
had an additional increased risk of asthma development.
The authors concluded that rhinitis is a significant risk
factor for adult-onset asthma in both atopic and
nonatopic subjects. [****]
It is, however, not clear whether allergic rhinitis
represents an earlier clinical manifestation of allergic
disease in atopic subjects who will later go on to develop
asthma or if the nasal disease itself is causative for asthma.
KEY POINTS
! Most if not all asthmatics present rhinitis.
! Many patients with rhinitis present asthma.
! Allergy is associated with rhinitis and asthma.
! Occupational agents can cause rhinitis and
asthma.
! Nonallergic rhinitis is associated with asthma.
! Allergic and nonallergic rhinitis are risk
factors for asthma.
! Rhinitis may be associated with nonspecific
bronchial hyperreactivity.
NASAL AND SINUSAL INFLAMMATION IN
ASTHMA AND CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
Similarities and differences between nasal and
bronchial inflammation in asthma
In normal subjects, the structure of the airways mucosa
presents similarities between the nose and the bronchi.
1562 ] PART 13 THE NOSE AND PARANASAL SINUSES
Both nasal and bronchial mucosa are characterized by a
pseudostratified epithelium with columnar, ciliated cells
resting on a basement membrane. Underneath the
epithelium, in the submucosa, vessels and mucous glands
are present with structural cells (fibroblasts), some
inflammatory cells (essentially monocytic cells, lympho-
cytes and mast cells) and nerves. [****]
There are also differences between the nose and the
bronchi. In the nose, there is a large supply of
subepithelial capillary and arterial system and venous
cavernous sinusoids. The high degree of vascularization is
a key feature of the nasal mucosa and changes in the
vasculature may lead to severe nasal obstruction. On the
other hand, smooth muscle is present from the trachea to
the bronchioles explaining bronchoconstriction in
asthma.
The recent progress achieved in the cellular and
molecular biology of airways diseases has clearly docu-
mented that inflammation plays a critical role in the
pathogenesis of asthma and rhinitis. The same inflam-
matory cells appear to be present in the nasal and
bronchial mucosa. A growing number of studies show
that the inflammation of nasal and bronchial mucosa is
sustained by a similar inflammatory infiltrate, which is
represented by eosinophils, mast cells, T lymphocytes and
cells of the monocytic lineage. The same proinflammatory
mediators (histamine, CysLT), T helper (Th)2 cytokines
(interleukin (IL)-4, IL-5, IL-13 and granulocyte
macrophage colony-stimulating factor), chemokines
(RANTES and eotaxin) and adhesion molecules appear
to be involved in nasal and bronchial inflammation of
patients with rhinitis and asthma. [***]
However, there are major differences between both
sites. Although the nasal and bronchial mucosa are
exposed to the same noxious environment (and even
more so the nose), epithelial shedding is more pro-
nounced in the bronchi than in the nose of the same
patients suffering from asthma and rhinitis.15 The
magnitude of inflammation may not be identical. In
patients with moderatesevere asthma, eosinophilic
inflammation is more pronounced in the bronchi than
in the nose,15 whereas in patients with mild asthma
inflammation appears to be similar in both sites. More-
over, eosinophilic inflammation of the nose exists in
asthmatics with or without nasal symptoms.16 On the
other hand, features of airways remodelling appear to be
less extensive in the nasal mucosa than in the bronchial
mucosa. [****]
Sinus involvement in asthma
For more than 70 years, the coexistence of asthma and
rhinosinusitis has been noted in the medical literature.17
The debate still remains as to whether rhinosinusitis is a
precipitating factor for bronchial asthma. In the light of
current knowledge, it seems that rhinosinusitis and
asthma are linked by a common process that is mainly
inflammatory, and central to the pathogenesis is the role
of eosinophils and airway epithelium. Chronic rhinosi-
nusitis associated with asthma and allergy appears to be
restricted to the asthmatic population with an extensive
sinonasal disease and the presence of peripheral eosino-
philia in patients with rhinosinusitis indicates a high
likelihood of extensive disease.18 In a study comparing
mildmoderate asthmatics with corticodependent asth-
matics, the proportion of patients with symptoms of
rhinosinusitis was similar in both groups (74 percent in
corticosteroid-dependent asthma and 70 percent in
mildmoderate asthma).19 All corticosteroid-dependent
asthmatics versus 88 percent of the mildmoderate
asthmatics had abnormal computed tomography (CT)
scans. The clinical and CT scan scores were higher in the
corticosteroid-dependent asthmatics. In both groups, the
CT scan scores were correlated to the clinical scores and
the absolute number of blood eosinophils.19 [****]
Nasal and sinus inflammation in chronic
obstructive pulmonary disease
In order to determine whether nasal inflammation in
asthma was related to asthma or was found commonly in
other bronchial diseases, nasal inflammation and sinus
involvement were studied in patients with chronic
obstructive pulmonary disease (COPD). Less than 10
percent of patients with COPD have nasal symptoms.
Nasal inflammation assessed by nasal mucosal biopsies
differs from that of patients with asthma, but similarities
can be observed between nasal and bronchial mucosa in
COPD patients. In particular, there is a common
epithelial metaplasia, and the presence of CD8 and
elastase-positive cells. Computed tomography scans show
few abnormalities in COPD. Thus, sinonasal inflamma-
tion seen in asthmatics is related to asthma and is not a
feature of all bronchial diseases. [****]
BRONCHIAL INFLAMMATION IN RHINITIS
Bronchial inflammation and remodelling in
rhinitis
Some studies have examined the bronchial mucosa in
atopic nonasthmatic patients or in patients with allergic
rhinitis. They all combined to indicate that there was a
slight increase of the basement membrane size20 and a
moderate eosinophilic inflammation.21
Natural exposure to pollen during the season provokes
an increase in airway responsiveness in nonasthmatic
subjects with seasonal allergic rhinitis and also induces
inflammatory cell recruitment and IL-5 expression,
leading to bronchial inflammation.22
 Chapter 122 The relationship between the upper and lower respiratory tract
Bronchial challenge of rhinitis patients leads to
bronchial symptoms and inflammation
Endobronchial allergen challenge was carried out in
patients with seasonal rhinitis who had never presented
with asthma before. These patients developed a broncho-
constriction, and lavage carried out serially after challenge
demonstrated the occurrence of proinflammatory med-
iators and cytokines, as well as the recruitment of
inflammatory cells.23 [****]
Pulmonary inflammation after segmental ragweed
challenge was examined in allergic asthmatic and
nonasthmatic subjects.24 A total of 46 ragweed-allergic
subjects took part in these studies. Subjects had normal or
nearly normal pulmonary function, were on no chronic
medication, and were characterized as to their skin
sensitivity to intradermal ragweed injection, their non-
specific responsiveness to methacholine, and the presence
(or absence) of a late asthmatic response after whole-lung
antigen challenge. In both groups, a marked inflamma-
tory response measured in bronchoalveolar lavage fluid
(total cells per millilitre, macrophages per millilitre,
lymphocytes per millilitre, eosinophils per millilitre,
neutrophils per millilitre, total protein, albumin, urea or
eosinophil cationic protein) 24 hours after challenge was
seen only in the subgroup of subjects who demonstrated a
late airway reaction after whole-lung antigen challenge,
regardless of disease classification.
These studies combine to indicate that although
patients with nasal symptoms can only react if the
allergen is properly administered into the airways, it may
be argued that the doses of allergen inducing these
bronchial reactions are far greater than those naturally
happening during allergen exposure. This situation seems
to exist in thunderstorm-induced asthma25 which has
been associated with grass pollen allergy.26 The aero-
dynamic size of pollen grains ranges from 10 to 100 mm
and only a fraction of them can be deposited into the
bronchi, thus most patients only present rhinitis without
asthma. However, when exposed to water, pollen allergens
are released in submicronic particles, the starch granules,
which can reach the lower airways and induce asthma.27
Bronchial challenge of rhinitis patients leads to
nasal inflammation
In a recent study, endobronchial allergen challenge
induced nasal and bronchial symptoms as well as
reductions in pulmonary and nasal function.28 In this
study, the number of eosinophils increased in the
challenged bronchial mucosa, in the blood and in the
nasal mucosa 24 hours after bronchial challenge. More-
over, eotaxin-positive cells in the nasal lamina propria
and enhanced expression of IL-5 in the nasal epithelium
were found 24 hours after bronchial challenge. Braunstahl
] 1563
et al.29 found that nasal challenge increased eosinophils in
the bronchial mucosa. [***]
Allergy as a systemic disease
In patients with allergic diseases, allergen provocation can
activate a systemic response that provokes inflammatory
cell production by the bone marrow.30 After release and
differentiation of progenitor cells, eosinophils, basophils
and mast cells are typically recruited to tissues in atopic
individuals. An understanding at the molecular level of
the signalling process that leads to these systemic
responses between the target organ, especially the airways,
and the bone marrow may open up new avenues of
therapy for allergic inflammatory disease.31 Studies that
support the critical involvement of the bone marrow in
the development of eosinophilic inflammation of the
airways point to the systemic nature of these conditions.
A second important mechanism may be involved in
the systemic origin of airway inflammation. In situ
haemopoiesis32 depends on the production of haemo-
poietic cytokines by inflamed tissues from patients with
allergic rhinitis33 and nasal polyposis,34 which, generating
a particular local microenvironment, promote the
differentiation and maturation of eosinophil progenitors
that populate the nasal or the bronchial mucosa.35
It is therefore likely that a truly systemic response to
the application of inflammatory stimuli to the nasal (or
bronchial) mucosa should be associated with an activa-
tion of the aforementioned mechanisms. [****]
Viral infection of the nose induces asthma and
bronchial inflammation
A large number of asthma exacerbations are due to nasal
viral infections both in children and adults. Rhinoviruses are
the major cause of the common cold and a trigger of acute
asthma exacerbations.36 Experimental rhinovirus upper
respiratory infection increases airway hyperreactivity and
late asthmatic reactions following allergen challenge. How-
ever, rhinoviruses can also infect the lower airways during
natural and experimental exposure raising the possibility
that asthma exacerbations may be induced through direct
enhancement of lower airway inflammation. [****]
KEY POINTS
! Most asthmatics present sinusitis
demonstrated by CT scans.
! Severe asthmatics have more severe sinusitis
than patients with mild asthma.
! Eosinophilic inflammation is present in nasal
and bronchial mucosa of asthmatics.
1564 ] PART 13 THE NOSE AND PARANASAL SINUSES
! Epithelium and basement membrane differ in
nasal and bronchial mucosa of asthmatics.
! Bronchial and nasal mucosa of COPD
patients is similar.
! Endobronchial challenge in rhinitis patients
induces asthma.
! Bronchial challenge induces nasal
inflammation.
! Nasal challenge induces bronchial
inflammation.
! Allergic inflammation has a systemic
component.
! Nasal viral infection induces asthma
exacerbations and bronchial inflammation.
QUALITY OF LIFE IN ASTHMA AND RHINITIS
Quality of life (QOL) has been found to be impaired both
in patients with asthma and in patients with allergic
rhinitis, and the relative burden of these diseases has been
recently studied using the generic SF-36 questionnaire in
the European Community Respiratory Health Survey
(ECRHS), a population-based study of young adults.37
Patients with both asthma and allergic rhinitis experi-
enced more physical limitations than patients with
allergic rhinitis alone, but no difference was found
between these two groups for concepts related to social/
mental health. Subjects with asthma without rhinitis
could not be studied since their number was too low.
However, it seems that impairment in social life in
asthmatics may be attributable to nasal symptoms. [****]
KEY POINTS
! QOL is impaired in asthma.
! QOL is impaired in rhinitis.
! The physical component of QOL is impaired
in asthma.
! The social component of QOL is impaired in
rhinitis.
THERAPEUTIC CONSEQUENCES
Although asthma and allergic rhinitis commonly appear
together, treatments for one condition could potentially
alleviate the coexisting condition.
Medications for asthma and rhinitis can be adminis-
tered via local (intranasal, intraocular or inhaled (intrab-
ronchial)), oral and parenteral routes. There are advantages
(and some drawbacks) to administering the drug directly
into the target organ.1 Moreover, some drugs, such as
cromoglycate or nedocromil, are not absorbed when given
orally and are only effective when administered locally. In
patients suffering from asthma and rhinitis, local admin-
istration of drugs requires that they are given both nasally
and bronchially and this may decrease compliance to
treatment which is low in asthma and rhinitis.
Drugs administered topically
Glucocorticosteroids are the most effective drugs when
used topically in the nose and the bronchi for the
treatment of rhinitis and asthma. The intranasal treatment
of rhinitis using glucocorticosteroids was found to
improve asthma, at best, moderately in some but not all
studies.38 Symptoms and pulmonary function tests were
improved.39 These data suggest that treating nasal
inflammation may help to control asthma. However, a
number of aspects, such as the extent to which the
pathophysiology of the two diseases overlaps and whether
treating one will affect the other, still remain to be clarified.
Less is known about the effects on nasal disease by
inhaled (intrabronchial) treatment with glucocorticoster-
oids. One study examined effects on nasal allergic disease
of inhaled budesonide (avoiding nasal deposition of the
drug) in patients with seasonal allergic rhinitis, but
without asthma.40 During the birch pollen season,
budesonide reduced the seasonal eosinophilia both in
the circulation and in the nose along with an attenuation
of seasonal nasal symptoms. Nasal and systemic anti-
eosinophil actions are produced at commonly employed
dose levels of orally inhaled budesonide.
Drugs administered orally
Drugs administered by the oral route may have an
effect on both nasal and bronchial symptoms. Oral
H1-antihistamines represent the first-line treatment
of allergic rhinitis and although some studies have found
a modest effect on asthma symptoms, these drugs are
not recommended for the treatment of asthma.41 The
association of oral H1-antihistamines and decon-
gestants was found to be more effective on asthma
symptoms.42 Leukotriene modifiers were shown to be
effective in controlling symptoms of mild to moderate
asthma and seasonal allergic rhinitis.43 Oral glucocorticos-
teroids are highly effective in the treatment of rhinitis and
asthma but side effects after long-term use are common.
Specific immunotherapy
The indications of specific immunotherapy in allergic
asthma and rhinitis have been separated in some guide-
lines. This artificial separation has led to unresolved issues
possibly because the allergen-induced IgE-mediated
 Chapter 122 The relationship between the upper and lower respiratory tract
reaction has not been considered to be a multiorgan
disease. It is therefore important to consider specific
immunotherapy based on the allergen sensitization rather
than on the disease itself since most patients with allergic
asthma also present rhinitis or rhinoconjunctivitis.1
Immunotherapy can also alter the atopic phenotype by
restoring the normal equilibrium between Th1 and Th2
lymphocytes. This form of therapy is currently under
investigation in subjects with allergic rhinitis as a means of
prevention of secondary asthma, and initial results are
encouraging.44
Anti-immunoglobulin E monoclonal antibody
The anti-IgE antibody, omalizumab,45 has been shown to
be safe and effective in separate populations of patients
with seasonal and perennial allergic rhinitis, and in
children and adults with moderatesevere allergic asthma.
Studies are ongoing to assess its effectiveness in patients
with comorbid allergic airways disease, and to investigate
whether a course of treatment could reduce the risk of
developing asthma. Its systemic activity and ability to
reduce levels of IgE regardless of allergen specificity may
be especially advantageous in these respects.
Treatment of rhinitis reduces asthma severity
Two very recent studies showed that treating allergic
rhinitis reduces health care utilization for comorbid
asthma. In a first study, a retrospective cohort study was
carried out in 4944 patients with both allergic rhinitis and
asthma, aged 12 to 60 years, who were continuously
enrolled and had no evidence of COPD.46 The risk of an
asthma-related event (hospitalization and emergency
department visit) for the treated group was about half
that for the untreated group. In another retrospective
cohort study carried out in 13,844 asthmatics of a
managed care organization aged greater than five years,47
patients who received intranasal corticosteroids had a
reduced risk for emergency department visits by compar-
ison with those who did not receive this treatment.
Best clinical practice
[ Oral H1-antihistamines are effective in rhinitis.
[Grade A]
[ Oral H1-antihistamines are poorly effective in
asthma. [Grade A]
[ Intranasal corticosteroids are inconstantly effective in
asthma. [Grade A]
[ Intranasal corticosteroids reduce asthma
exacerbations. [Grade B]
] 1565
[ Intrabronchial corticosteroids are effective in rhinitis
(single study). [Grade A]
[ Oral leukotriene receptor antagonists are often
effective in rhinitis. [Grade A]
[ Allergen-specific immunotherapy is effective in both
rhinitis and asthma. [Grade A]
[ Anti-IgE monoclonal antibody is effective in both
rhinitis and asthma. [Grade A]
COSTS
Rhinitis inceases the costs of asthma and it was found in a
large population that yearly medical care charges were on
average 46 percent higher for those with asthma and
concomitant allergic rhinitis than for persons with
asthma alone.48
RHINITIS AND ASTHMA: A CONTINUUM OF
DISEASE?
There are similarities and differences between the nasal
and bronchial mucosa in rhinitis and asthma. It appears
that most asthmatics present rhinitis, whereas only a
fraction of rhinitis patients present clinically demon-
strable asthma even though a greater number of patients
has nonspecific bronchial hyperreactivity. It seems that
the epithelialmesenchymal trophic unit exists from the
nose to the bronchiolaralveolar junction and that the
same inflammatory cells are present throughout the
airways suggesting a continuum of disease.
However, there are differences in terms of exposure to
allergens and noxious agents, the nose being more
exposed than the lower airways. There are also major
structural differences between the nasal and the bronchial
mucosa since in the former there is a large vascular supply
whereras in the latter there is smooth muscle. Airway
smooth muscle is of paramount importance in asthma
due to its contractile properties, but in addition, it may
contribute to the pathogenesis of the disease by increased
proliferation and the expression and secretion of proin-
flammatory mediators and cytokines.
It is therefore possible that the difference between
rhinitis and asthma is that in the fomer there is an
epithelialmesenchymal trophic unit,49 whereas in the
latter there is an epithelialmesenchymalmuscular
trophic unit.
Best clinical practice
These studies strongly support the 1999 World Health
Organization workshop Allergic rhinitis and its impact on
asthma1 which recommended that:
1566 ] PART 13 THE NOSE AND PARANASAL SINUSES
[ patients with persistent allergic rhinitis should be
evaluated for asthma by history, chest examination
and, if possible and when necessary, assessment of
airflow obstruction before and after bronchodilator;
[ history and examination of the upper respiratory tract
for allergic rhinitis is performed in patients with
asthma;
[ proposal of a strategy combining the treatment of
both the upper and lower airway disease in terms of
efficacy and safety.
Deficiencies in current knowledge and
areas for future research
$ More prospective studies should assess the
relationship between rhinitis and asthma and confirm
that rhinitis is a risk factor for asthma.
$ In occupational diseases, the recognition of rhinitis
may detect patients early during the course of the
disease in order to prevent the onset and progression
of persistent asthma in subjects exposed to known
risk factors.
$ More studies are needed to assess nasal and
bronchial inflammation in patients with asthma and
COPD.
$ Nasal remodelling is poorly understood.
$ Mechanistic studies are needed.
$ More studies are needed to appreciate the
relationships between the upper and lower airways
and the systemic nature of allergic diseases.
$ Large pivotal clinical trials should be started to assess
whether the treatment of one target organ may
improve outcome measures of the other target organ.
These studies should be carried out in persistent and
intermittent diseases.
$ Large pivotal trials should be started to show that
oral or systemic treatments improve outcome
measures of the entire airway.
$ Prospective studies should confirm the protective role
of nasal treatment on asthma exacerbations and
emergency department visits.
REFERENCES
! 1. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic
rhinitis and its impact on asthma. Journal of Allergy and
Clinical Immunology. 2001; 108: S147334. This paper
reports a World Health Organization workshop
highlighting the relationships between asthma and
rhinitis. There are over 2700 references.
2. Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F.
Perennial rhinitis: An independent risk factor for asthma in
nonatopic subjects: results from the European Community
Respiratory Health Survey. Journal of Allergy and Clinical
Immunology. 1999; 104: 3014.
3. Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A,
Jorgensen T. Secular trends of allergic asthma in Danish
adults. The Copenhagen Allergy Study. Respiratory
Medicine. 2001; 95: 25864.
4. Celedon JC, Palmer LJ, Weiss ST, Wang B, Fang Z, Xu X.
Asthma, rhinitis, and skin test reactivity to aeroallergens
in families of asthmatic subjects in Anqing, China.
American Journal of Respiratory and Critical Care
Medicine. 2001; 163: 110812.
5. Peat JK, Salome CM, Woolcock AJ. Longitudinal changes in
atopy during a 4-year period: relation to bronchial
hyperresponsiveness and respiratory symptoms in a
population sample of Australian schoolchildren. Journal of
Allergy and Clinical Immunology. 1990; 85: 6574.
6. von Mutius E, Weiland SK, Fritzsch C, Duhme H, Keil U.
Increasing prevalence of hay fever and atopy among
children in Leipzig, East Germany. Lancet. 1998; 351:
8626.
! 7. Leynaert B, Bousquet J, Henry C, Liard R, Neukirch F. Is
bronchial hyperresponsiveness more frequent in women
than in men? A population-based study. American Journal
of Respiratory and Critical Care Medicine. 1997; 156:
141320. The first large epidemiologic survey showing an
association between rhinitis and asthma. Moreover, this
study is the first to show that nonallergic rhinitis is
strongly associated with asthma.
8. Sotomayor H, Badier M, Vervloet D, Orehek J. Seasonal
increase of carbachol airway responsiveness in patients
allergic to grass pollen. Reversal by corticosteroids.
American Review of Respiratory Disease. 1984; 130:
568.
9. Szczeklik A, Stevenson DD. Aspirin-induced asthma:
advances in pathogenesis and management. Journal of
Allergy and Clinical Immunology. 1999; 104: 513.
10. Sibbald B, Rink E. Epidemiology of seasonal and perennial
rhinitis: clinical presentation and medical history. Thorax.
1991; 46: 895901.
11. Wright AL, Holberg CJ, Martinez FD, Halonen M, Morgan
W, Taussig LM. Epidemiology of physician-diagnosed
allergic rhinitis in childhood. Pediatrics. 1994; 94:
895901.
12. Settipane RJ, Hagy GW, Settipane GA. Long-term risk
factors for developing asthma and allergic rhinitis: a 23-
year follow-up study of college students. Allergy
Proceedings. 1994; 15: 215.
13. Plaschke PP, Janson C, Norrman E, Bjornsson E, Ellbjar S,
Jarvholm B. Onset and remission of allergic rhinitis and
asthma and the relationship with atopic sensitization and
smoking. American Journal of Respiratory and Critical
Care Medicine. 2000; 162: 9204.
! 14. Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as
an independent risk factor for adult-onset asthma. Journal
 Chapter 122 The relationship between the upper and lower respiratory tract
of Allergy and Clinical Immunology. 2002; 109: 41925.
Association between rhinitis and asthma are well known
and many studies have been published within the past five
years. However, this study shows that rhinitis is an
independent risk factor for asthma.
! 15. Chanez P, Vignola AM, Vic P, Guddo F, Bonsignore G,
Godard P et al. Comparison between nasal and bronchial
inflammation in asthmatic and control subjects. American
Journal of Respiratory and Critical Care Medicine. 1999;
159: 58895. The first study in which nasal and bronchial
mucosal biopsies have been carried out in the same
patients.
16. Gaga M, Lambrou P, Papageorgiou N, Koulouris NG,
Kosmas E, Fragakis S et al. Eosinophils are a feature of
upper and lower airway pathology in non-atopic asthma,
irrespective of the presence of rhinitis. Clinical and
Experimental Allergy. 2000; 30: 6639.
17. Slavin RG. Asthma and sinusitis. Journal of Allergy and
Clinical Immunology. 1992; 90: 5347.
18. Newman LJ, Platts-Mills TA, Phillips CD, Hazen KC, Gross
CW. Chronic sinusitis. Relationship of computed
tomographic findings to allergy, asthma, and eosino-
philia [published erratum appears in Journal of the
American Medical Association 1994 Sep 21;272(11):852].
Journal of the American Medical Association. 1994; 271:
3637.
! 19. Bresciani M, Paradis L, Des Roches A, Vernhet H, Vachier I,
Godard P et al. Rhinosinusitis in severe asthma. Journal of
Allergy and Clinical Immunology. 2001; 107: 7380.
Association between sinusitis and asthma are well known
and many studies have been published. However, this
study shows that the more severe asthma, the more
extensive sinusitis.
20. Chakir J, Laviolette M, Boutet M, Laliberte R, Dube J,
Boulet LP. Lower airways remodeling in nonasthmatic
subjects with allergic rhinitis. Laboratory Investigation.
1996; 75: 73544.
21. Djukanovic R, Lai CK, Wilson JW, Britten KM,
Wilson SJ, Roche WR et al. Bronchial mucosal
manifestations of atopy: a comparison of markers of
inflammation between atopic asthmatics, atopic
nonasthmatics and healthy controls. European Respiratory
Journal. 1992; 5: 53844.
22. Chakir J, Laviolette M, Turcotte H, Boutet M, Boulet LP.
Cytokine expression in the lower airways of nonasthmatic
subjects with allergic rhinitis: Influence of natural allergen
exposure. Journal of Allergy and Clinical Immunology.
2000; 106: 90410.
23. Calhoun WJ, Jarjour NN, Gleich GJ, Stevens CA, Busse
WW. Increased airway inflammation with segmental
versus aerosol antigen challenge. American Review of
Respiratory Disease. 1993; 147: 146571.
24. Shaver JR, OConnor JJ, Pollice M, Cho SK, Kane GC, Fish JE
et al. Pulmonary inflammation after segmental ragweed
challenge in allergic asthmatic and nonasthmatic subjects.
American Journal of Respiratory and Critical Care
Medicine. 1995; 152: 118997.
] 1567
25. Anto JM, Sunyer J. Thunderstorms: a risk factor for asthma
attacks. Thorax. 1997; 52: 66970 (editorial).
26. Knox RB. Grass pollen, thunderstorms and asthma. Clinical
and Experimental Allergy. 1993; 23: 3549.
27. Suphioglu C, Singh MB, Taylor P, Bellomo R, Holmes P, Puy
R et al. Mechanism of grass-pollen-induced asthma.
Lancet. 1992; 339: 56972.
! 28. Braunstahl GJ, Kleinjan A, Overbeek SE, Prins JB,
Hoogsteden HC, Fokkens WJ. Segmental bronchial
provocation induces nasal inflammation in allergic rhinitis
patients. American Journal of Respiratory and Critical
Care Medicine. 2000; 161: 20517. The authors have
demonstrated for the first time that allergen trigger of
one site of the airways induces inflammation in the other
site of the airways.
29. Braunstahl GJ, Overbeek SE, Kleinjan A, Prins JB,
Hoogsteden HC, Fokkens WJ. Nasal allergen provocation
induces adhesion molecule expression and tissue
eosinophilia in upper and lower airways. Journal of Allergy
and Clinical Immunology. 2001; 107: 46976.
30. Denburg JA, Sehmi R, Saito H, Pil-Seob J, Inman MD,
OByrne P M. Systemic aspects of allergic disease: Bone
marrow responses. Journal of Allergy and Clinical
Immunology. 2000; 106: 2426.
31. Inman MD, Ellis R, Wattie J, Denburg JA, OByrne PM.
Allergen-induced increase in airway responsiveness,
airway eosinophilia, and bone-marrow eosinophil
progenitors in mice. American Journal of Respiratory Cell
and Molecular Biology. 1999; 21: 4739.
32. Denburg JA, Otsuka H, Ohnisi M, Ruhno J, Bienenstock J,
Dolovich J. Contribution of basophil/mast cell and
eosinophil growth and differentiation to the allergic tissue
inflammatory response. International Archives of Allergy
and Applied Immunology. 1987; 82: 3216.
33. KleinJan A, Dijkstra MD, Boks SS, Severijnen LA, Mulder
PG, Fokkens WJ. Increase in IL-8, IL-10, IL-13, and RANTES
mRNA levels (in situ hybridization) in the nasal mucosa
after nasal allergen provocation. Journal of Allergy and
Clinical Immunology. 1999; 103: 44150.
34. Bachert C, Wagenmann M, Hauser U, Rudack C. IL-5
synthesis is upregulated in human nasal polyp tissue.
Journal of Allergy and Clinical Immunology. 1997; 99:
83742.
35. Robinson DS, Damia R, Zeibecoglou K, Molet S, North J,
Yamada T et al. CD34(1)/interleukin-5R alpha messenger
RNA1 cells in the bronchial mucosa in asthma: potential
airway eosinophil progenitors. American Journal of
Respiratory Cell and Molecular Biology. 1999; 20: 913.
36. Johnston SL, Pattemore PK, Sanderson G, Smith S,
Campbell MJ, Josephs LK et al. The relationship between
upper respiratory infections and hospital admissions for
asthma: a time-trend analysis. American Journal of
Respiratory and Critical Care Medicine. 1996; 154:
65460.
37. Leynaert B, Neukirch C, Liard R, Bousquet J, Neukirch F.
Quality of life in allergic rhinitis and asthma. A
population-based study of young adults. American Journal
1568 ] PART 13 THE NOSE AND PARANASAL SINUSES
of Respiratory and Critical Care Medicine. 2000; 162:
13916.
38. Watson WT, Becker AB, Simons FE. Treatment of allergic
rhinitis with intranasal corticosteroids in patients with
mild asthma: effect on lower airway responsiveness.
Journal of Allergy and Clinical Immunology. 1993; 91:
97101.
39. Pedersen B, Dahl R, Lindqvist N, Mygind N. Nasal
inhalation of the glucocorticoid budesonide from a spacer
for the treatment of patients with pollen rhinitis and
asthma. Allergy. 1990; 45: 4516.
40. Greiff L, Andersson M, Svensson C, Linden M, Wollmer P,
Brattsand R et al. Effects of orally inhaled budesonide in
seasonal allergic rhinitis. European Respiratory Journal.
1998; 11: 126873.
41. Van-Ganse E, Kaufman L, Derde MP, Yernault JC, Delaunois
L, Vincken W. Effects of antihistamines in adult asthma: a
meta-analysis of clinical trials. European Respiratory
Journal. 1997; 10: 221624.
42. Corren J, Harris AG, Aaronson D, Beaucher W, Berkowitz R,
Bronsky E et al. Efficacy and safety of loratadine plus
pseudoephedrine in patients with seasonal allergic rhinitis
and mild asthma. Journal of Allergy and Clinical
Immunology. 1997; 100: 7818.
43. Meltzer E, Malmstrom K, Lu S, Brenner B, Wei L, Weinstein
S et al. Concomitant montelukast and loratadine as
treatment for seasonal allergic rhinitis: placebo-controlled
clinical trial. Journal of Allergy and Clinical Immunology.
2000; 105: 91722.
44. Moller C, Dreborg S, Ferdousi HA, Halken S, Host A,
Jacobsen L et al. Pollen immunotherapy reduces the
development of asthma in children with seasonal
rhinoconjunctivitis (the PAT-study). Journal of Allergy and
Clinical Immunology. 2002; 109: 2516.
45. Babu KS, Arshad SH, Holgate ST. Anti-IgE treatment: an
update. Allergy. 2001; 56: 11218.
46. Crystal-Peters J, Neslusan C, Crown WH, Torres A. Treating
allergic rhinitis in patients with comorbid asthma: the risk
of asthma-related hospitalizations and emergency
department visits. Journal of Allergy and Clinical
Immunology. 2002; 109: 5762.
! 47. Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST.
Intranasal steroids and the risk of emergency
department visits for asthma. Journal of Allergy
and Clinical Immunology. 2002; 109: 63642.
This paper delivers a new concept in the treatment of the
asthmatic patient. Patients receiving intranasal
corticosteroids have fewer emergency department visits
for asthma.
48. Yawn BP, Yunginger JW, Wollan PC, Reed CE, Silverstein
MD, Harris AG. Allergic rhinitis in Rochester, Minnesota
residents with asthma: frequency and impact on health
care charges. Journal of Allergy and Clinical Immunology.
1999; 103: 549.
49. Holgate ST, Davies DE, Lackie PM, Wilson SJ, Puddicombe
SM, Lordan JL. Epithelialmesenchymal interactions in the
pathogenesis of asthma. Journal of Allergy and Clinical
Immunology. 2000; 105: 1.