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Absence of Nasal Mucosal Atrophy With Fluticasone Aqueous Nasal Spray
Fuad M. Baroody;
Cheng-Chou Cheng, MD;
Birgitta Moylan, BSc;
Marcy deTineo, RN;
Lauran Haney, BS;
Kenneth D. Reed, BS;
Cindy K. Cook, MS;
Ronald E. Westlund, MS;
Elizabeth Sengupta, MD;
Jacquelynne P. Corey, MD;
Alkis Togias, MD;
Robert M. Naclerio, MD
Arch Otolaryngol Head Neck Surg. 2001;127:193-199.
ABSTRACT
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Objective To evaluate whether 1 year of continuous treatment with intranasal fluticasone
propionate would lead to atrophy in the nasal mucosa compared with an active
control, oral terfenadine.
Design Prospective, randomized, multicenter, open-label, parallel-group study.
Setting Two tertiary care academic institutions.
Patients Seventy-five subjects older than 18 years with perennial allergic rhinitis.
Interventions Patients received either fluticasone propionate aqueous nasal spray,
200 µg once daily, or terfenadine, 60 mg twice daily, for 1 year. Nasal
biopsy specimens were obtained before and after 1 year of treatment and were
evaluated for evidence of atrophy.
Main Outcome Measures Epithelial and collagen layer thickness of the nasal mucosa as assessed
by light microscopy and the presence and degree of edema, and regularity of
collagen fibrils as assessed by electron microscopy. Analyses were performed
without knowledge of subject identity or treatment assignment.
Results Neither fluticasone nor terfenadine treatment led to atrophy in the
nasal mucosa by clinical or histologic observation. No significant changes
from baseline were observed for any assessment of atrophy. In contrast to
what would have been expected if atrophy were to occur, mean epithelial layer
thickness in the fluticasone group significantly increased compared with terfenadine
treatment (P = .03).
Conclusions Treatment with intranasal fluticasone for 1 year increases the thickness
of the nasal epithelium as compared with a year's treatment with terfenadine
and does not lead to atrophy in the nasal mucosa. The increased thickness
in the fluticasone treatment may represent repair from epithelial damage caused
by chronic allergic inflammation.
INTRODUCTION
ALLERGIC RHINITIS affects more than 40 million Americans and costs society
more than $3 billion each year.1 A major characteristic
of allergic rhinitis is inflammation.2 The
inflammatory process stimulates the glands, blood vessels, and nerves of the
nasal mucosa, creating the symptoms of the disease. Whether this inflammation
causes changes to matrix structures, such as the epithelium, the basement
membrane, and the collagen matrix, is not known.
Intranasal corticosteroids are among the most commonly prescribed and
effective medications used to treat this disease.3, 4
The safety and efficacy of intranasal corticosteroids have been well established
in multiple clinical trials. Furthermore, the widespread clinical use of these
compounds during the past 25 years has not been associated with substantial
untoward adverse events.3 Intranasal corticosteroids
exert a potent topical anti-inflammatory effect.3, 5
They inhibit the recruitment of inflammatory cells and prevent the release
of inflammatory mediators, resulting in a decrease in symptoms and the blocking
of both the early- and late-phase allergic reactions.3, 4, 5, 6
Appropriate treatment options must be evaluated over the long term for
potential adverse sequelae. This is particularly true for patients with perennial
allergic rhinitis who may require long-term treatment over several years to
control their disease. Long-term use of oral corticosteroids and topical dermatologic
corticosteroids (ie, creams and ointments) have been observed to lead to atrophic
changes in the skin.7, 8, 9, 10, 11
Although there is no clinical or histologic evidence that intranasal corticosteroid
treatment leads to atrophy of the nasal mucosa, we undertook this comparative
nasal biopsy study to investigate the effects of 2 treatment options for allergic
rhinitis. We compared the structural characteristics of nasal mucosal biopsy
specimens from subjects allergic to dust mites who were treated with either
fluticasone propionate aqueous nasal spray or oral terfenadine, the active
control. Nasal mucosal atrophy was assessed qualitatively and quantitatively
by means of light and electron microscopy. Thus, this study was designed to
examine whether 1 year of treatment with a topical corticosteroid (fluticasone)
causes atrophic nasal mucosal changes when compared with an oral antihistamine
(terfenadine).
SUBJECTS AND METHODS
SUBJECTS
Men and nonpregnant, nonlactating women 18 years of age or older were
recruited from The Johns Hopkins University Hospital, Baltimore, Md, and the
University of Chicago Hospitals, Chicago, Ill, to participate in this study.
All subjects had to have a diagnosis of perennial allergic rhinitis and a
skin test positive for dust mites. Eligible subjects also had to have nasal
symptoms for more than 1 hour per day on most days for which they used at
least 1 antirhinitis medication during the 12 months before the study. Subjects
with a marked ( 50%) physical obstruction in the nose, previous nasal septal
surgery or perforation, or viral or bacterial infection within 30 days of
screening were excluded. Medications that could affect rhinitis symptoms or
allergic inflammation, such as topical and systemic glucocorticoid therapy,
intranasal cromolyn sodium, and antihistamines, were not permitted for at
least 1 month before or during the study. None of the subjects was taking
immunotherapy during the study, and those who had received previous immunotherapy
had to have stopped taking it at least 2 years before participation. Before
initiation of the study, the protocol and informed consent document were reviewed
and approved by the institutional review board governing research at each
site. All subjects provided written informed consent before participation.
DESIGN
This was a randomized, open-label, parallel-group study in 75 subjects
with perennial allergic rhinitis that compared the effects on the nasal mucosa
of 1 year of treatment with fluticasone propionate aqueous nasal spray, 200
µg once daily, vs an active control, oral terfenadine, 60-mg tablet
twice daily. At the time this study was conducted in the mid-1990s, terfenadine
was a commonly prescribed medication for the treatment of allergic rhinitis
and was considered a suitable therapeutic alternative to intranasal corticosteroid
therapy.
The study consisted of a 21-day screening phase and a 12-month randomized,
open-label treatment phase. During the screening phase, eligibility for the
study was confirmed and baseline rhinoscopy and nasal biopsy were performed.
After healing of the nasal biopsy site (approximately 1 week later), subjects
were randomly assigned to receive 1 of the following study treatments for
1 year: intranasal fluticasone propionate once daily (2 sprays of 50 µg
per spray in each nostril in the morning) or terfenadine, 60-mg tablet orally
twice daily. Subjects were allowed to take only pseudoephedrine as needed
for the relief of breakthrough symptoms during the study and were allowed
to take other medications that did not interfere with allergic inflammation,
such as analgesics. Subjects returned to the clinic at monthly intervals to
reinforce medication adherence, receive additional medication, and assess
their clinical status. After 12 months of treatment, another nasal biopsy
specimen was obtained from the opposite nostril to avoid the confounding effects
of scar formation at the site of the first biopsy specimen.
NASAL BIOPSY
After local anesthesia was induced with 1% lidocaine hydrochloride with
epinephrine 1:100 000, biopsy samples were obtained with punch forceps
from the anterior tip of the inferior turbinate by standard methods.12 This biopsy site was selected because it is the expected
site of drug impact with aqueous nasal spray medications and a major site
for allergen deposition. Each biopsy specimen was divided into sections to
enable light and electron microscopic evaluation of atrophy and labeled such
that subject identity, treatment, and date of biopsy were not apparent to
those evaluating the specimens. Biopsy samples were prepared as follows:
1. Section 1 of the biopsy specimen was fixed in formalin, embedded
in paraffin, sectioned into 5-µm sections, and stained with hematoxylin-eosin.
These samples were evaluated by means of light microscopy.
2. Section 2 of the biopsy specimen was fixed in 2.5% glutaraldehyde
in Millonig buffer (1.7% monobasic sodium phosphate + 0.3% sodium hydroxide
in distilled water with pH 7.3-7.4) at 4°C for 24 hours, then transferred
and stored in Millonig buffer at 4°C until postfixing in 1% osmium tetroxide,
dehydrating, infiltrating, and embedding in epoxy resin. The epoxy resin–embedded
tissue was then sectioned into 50- to 70-nm sections, placed on copper grids,
and contrast stained with 1.5% uranyl acetate aqueous solution and Reynold
lead citrate solution and examined by transmission electron microscopy (Philips
CM-10; Philips Inc, Mahway, NJ).
ASSESSMENT OF ATROPHY
Atrophy was assessed by means of 4 objective and quantitative measures
based on light and transmission electron microscopy (Table 1). In addition, qualitative evaluations including the presence
of squamous and respiratory epithelium, elastin, basal lamina duplication,
and collagen type were performed with electron microscopy. Specimens were
visualized at x1000 to examine the epithelium and underlying stroma
(Figure 1), x8000 to evaluate
the superficial vessels, x10 000 for high-power views of the basal
lamina and the epithelium, and x14 000 for evaluation of collagen.
Prints at each of these magnifications were unidentified as to subject name
and treatment received and were examined by 2 investigators (C.C.C. and E.S.).
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Table 1. Assessment of Atrophy
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Figure 1. Low-power transmission electron
micrograph of the nasal mucosa demonstrating, from top to bottom, the epithelium,
collagen layer, lamina propria, and the glandular layer (original magnification
x1200).
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The thickness of the collagen and epithelium was measured in the hematoxylin-eosin–stained
sections under x400 magnification with a microscope with a computer-controlled
stage (Axioplan; Zeiss Inc, Thornwood, NY) coupled to an image analysis program
(Neurolucida; Microbrightfield Inc, Colchester, Vt). The thickness of the
collagen layer was measured in micrometers at 5 points along the specimen
and that of the epithelium at 3 points along the specimen. The average value
of these respective measurements was used for analysis.
The presence of edema (presence of lucent spaces) and regularity of
collagen fibrils were graded on the scoring system described in Table 1. Micrographs representative of the low and high ends of
these scales are provided in Figure 2
and Figure 3, respectively. Figure 2 shows the electron-lucent spaces
between the collagen fibrils. Figure 2A
(x15 500) demonstrates the lack of lucent spaces (0 or none) between
the collagen fibrils, and Figure 2B (x14 500) demonstrates a large number of electron-lucent spaces
(3 or severe). Figure 3A and Figure 3B show low (+1, least regular) and
high (+3, most regular) regularity, respectively, of collagen fibrils observed
at x11 500 magnification.
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Figure 2. Transmission electron micrographs
of the collagen layer showing the presence of electron-lucent spaces between
the collagen fibrils. A, Lack of lucent spaces between the collagen fibrils,
scored 0 (original magnification x15 500). B, Large number of electron-lucent
spaces between the collagen fibrils, scored 3. The epithelium is seen above
the collagen layer (original magnification x14 500).
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Figure 3. Transmission electron micrographs
of the collagen layer (immediately beneath the epithelium) showing regularity
of the collagen fibrils (original magnification x11 500). A, Low
regularity, scored +1. B, High regularity, scored +3.
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STATISTICAL ANALYSES
Atrophy of the nasal mucosa was assessed by the evaluation of epithelial
and collagen layer thickness, presence of edema (lucent spaces), and the regularity
of collagen fibrils. Treatment groups were compared in data sets that included
all subjects who had both baseline and end-of-treatment biopsy data available.
Small sample size and distributional properties required that nonparametric
statistical tests be used for within- and between-treatment comparisons for
both light and electron microscopy data. Two analyses were conducted: a main-effects
analysis using a Wilcoxon rank sum test and a rank analysis of covariance.
Within treatment group, changes from baseline to study end were also analyzed
with a Wilcoxon signed rank test.
RESULTS
SUBJECT DISPOSITION AND DEMOGRAPHICS
Seventy-five subjects (38 in the fluticasone group and 37 in the terfenadine
group) were enrolled in the study (Table
2). The treatment groups were similar with respect to age, sex distribution,
ethnic origin, and number of subjects withdrawn early. The most common reason
for attrition during the 12-month study period was that subjects failed to
return to the clinic. Four subjects were withdrawn from the study because
of nonserious adverse events: 3 in the fluticasone group (epistaxis, nasal
dryness, and exacerbation of asthma) and 1 in the terfenadine group (exacerbation
of uveitis). The adverse event profile was similar to that observed in previous
studies. There were no serious or unusual events.
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Table 2. Subject Demographics and Disposition
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BIOPSY RESULTS
All evaluable nasal biopsy specimens from subjects with both baseline
and study end biopsy samples were included in the analyses of atrophy (n =
52). This included samples from the 51 subjects who completed the study and
1 subject who was discontinued from the study after 8 months of treatment
because of relocation.
As would be expected because of the location of the biopsy (anterior
tip of the inferior turbinate), all specimens but 1 had nonciliated squamous
epithelium present at baseline. In 2 specimens, both respiratory and squamous
epithelium were seen, and in 1 specimen, only respiratory epithelium was seen
in the areas examined. The nasal biopsy specimens taken at the end of the
study similarly included squamous epithelium, although 2 specimens contained
both respiratory and squamous epithelial cells. At both baseline and study
end, the collagen was type I, basal lamina duplication was rare, and no elastin
fibers were seen, providing reassurance that severely damaged nasal mucosa
had not been observed.
Biopsy results for epithelial layer thickness, collagen layer thickness,
lucent spaces score, and regularity of collagen score are summarized in Table 3. At baseline, the mean epithelial
layer thicknesses in the fluticasone group (27.77 µm) and the terfenadine
group (28.55 µm) were not significantly different. After 1 year of treatment,
the mean epithelial layer thickness had increased to 35.17 µm (+7.40
µm) in the fluticasone group whereas it had decreased to 20.91 µm
(-7.64 µm) in the terfenadine group. These changes did not represent
a significant change from baseline for either group as tested by the Wilcoxon
signed rank test (for fluticasone, P = .37; for terfenadine, P = .23). However, when the treatment groups were compared
at study end, significant differences were observed for both the main-effects
analysis based on the Wilcoxon rank sum test (P =
.05) and when baseline effects were included as a covariate in the model (P = .03, rank analysis of covariance). This was a significantly
higher epithelial thickness at the end of treatment in the fluticasone group
(35.17 µm) compared with the terfenadine group (20.91 µm).
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Table 3. Light and Electron Microscopic Evaluations of Atrophy
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Mean collagen layer thickness was not significantly different before
or after 1 year's treatment with either fluticasone (P
= .68) or terfenadine (P = .47). At baseline, the
mean collagen layer thickness was 11.45 µm in the fluticasone group
and 11.71 µm in the terfenadine group. At study end, mean collagen layer
thickness values remained essentially unchanged (11.97 µm in the fluticasone
group and 12.46 µm in the terfenadine group).
A lucent spaces score, graded on a 4-point scale of 0 (none), 1 (mild),
2 (moderate), and 3 (severe), was created to quantify the degree of tissue
edema observed. The mean scores at baseline were similar: 1.19 for the fluticasone
group and 1.09 for the terfenadine group, indicating mild edema. No significant
within– or between–treatment group differences were observed after
1 year of treatment. The mean score at study end was essentially unchanged
for both treatment groups (1.05 for the fluticasone group and 1.14 for the
terfenadine group).
The regularity of collagen was graded on a 3-point scale of +1 (least
regular) to +3 (most regular). The mean scores at baseline were not significantly
different: 1.83 for the fluticasone group and 1.75 for the terfenadine group,
indicating a midrange level of regularity. After 1 year of treatment, the
regularity scores increased slightly in both groups (2.05 in the fluticasone
group and 1.85 in the terfenadine group). No significant within–treatment
group changes were observed, and no significant differences were observed
when the treatment groups were compared.
COMMENT
The primary objective of this study was to evaluate the effect of fluticasone
on the nasal mucosa and determine whether atrophy would be observed after
continuous treatment for 1 year. The presence of atrophy was primarily based
on 4 objective evaluations, including epithelial and basement membrane (collagen
layer) thicknesses, the degree of edema (lucent spaces), and the regularity
of the collagen fibrils, as well as clinical observation of the nasal mucosa
during the monthly visits.
Our results showed that there was no evidence that treatment with fluticasone
propionate aqueous nasal spray, 200 µg once daily, caused nasal mucosal
atrophy as compared with oral terfenadine, the active control. None of the
expected quantitative changes that could have indicated atrophy were observed,
and qualitative assessments confirmed that elastin was not present, type I
collagen was not replaced, and basal lamina duplication did not increase.
Furthermore, clinical observations during the monthly visits showed no abnormalities
on rhinoscopy.
When the treatment groups were compared, no significant differences
between treatment groups were observed with the exception of epithelial layer
thickness, which showed a significant difference between treatments. The fluticasone
group experienced a mean increase in the epithelial layer thickness at study
end, while the terfenadine group experienced a mean decrease. This result,
coupled with the qualitative assessments based on visualization of nasal mucosal
tissue, suggests that the integrity of the nasal mucosa was not affected adversely
during treatment with fluticasone in subjects with perennial allergic rhinitis.
Furthermore, the increase in epithelial thickness after fluticasone treatment
may represent repair of epithelial damage associated with the chronic inflammation
that is characteristic of perennial allergic disease.
Our findings are consistent with the existing literature and confirm
what has been the clinical experience for decades, ie, that long-term use
of intranasal corticosteroid therapy does not lead to atrophy or other severe
adverse sequelae in the nasal mucosa. Moreover, our study is the first, to
our knowledge, to use objective and quantitative assessment of the nasal mucosa
by transmission electron microscopy and in which lack of change in these objective
criteria were used to conclude that fluticasone treatment did not have deleterious
effects on the nasal mucosa. Several other intranasal biopsy studies have
similarly failed to find an atrophic effect of other intranasal corticosteroids13, 14, 15, 16, 17, 18, 19, 20
or fluticasone.21
Among the findings of interest, Sørensen et al13
in 1976 performed biopsies of polyps after treatment with beclomethasone dipropionate
aerosol for 1 year and observed decreased interstitial fluid within the tissue
by light microscopy. Furthermore, there were no consistent changes of the
surface epithelium by transmission electron microscopy. Quantitative data
or controls were not presented. In 1977, Poytner14
observed that no mucosal atrophy occurred in patients treated with beclomethasone
for 2.5 to 3.5 years. In 1978, Mygind et al15
reported that biopsy specimens of nasal polyps in patients receiving beclomethasone
treatment for 3 years showed no changes in epithelial metaplasia or ciliary
structure. In 1982, Holopainen and colleagues16
performed biopsies in 6 patients after 6 years of treatment with beclomethasone
and observed no evidence of atrophy. No quantitative data were presented.
In 1983, Knight and Kolin17 performed biopsies
in 9 patients with perennial rhinitis with or without allergy after the patients
had received beclomethasone for 48 weeks in an open, noncomparative study.
They reported no evidence of atrophy or scarring as assessed by light microscopy,
but few details were presented. In 1988, Pipkorn et al18
reported on a multicenter, open longitudinal study of 24 patients receiving
budesonide. Biopsy specimens obtained at entry and after 1 year (5 patients)
and between 2.5 and 5.5 years (5 patients) of use showed no significant change.
In a more recent study, Minshall and colleagues20
evaluated nasal biopsy specimens from an open study of 52 subjects with perennial
rhinitis before and after 1 year of treatment with mometasone furoate by light
microscopy and compared the results with those from 24 healthy subjects who
underwent biopsy at baseline and after 1 year without treatment. They found
no change in epithelial thickness, no signs of atrophy, and a decrease in
focal metaplasia.
In 1991, Orgel and colleagues19 evaluated
41 paired nasal biopsy specimens from an open-label study of fluocortin butyl.
They reported no evidence of basement membrane thinning and, similar to our
findings, observed a tendency for improvement of the epithelium toward columnar.
The authors concluded that intranasal corticosteroids improve epithelial injury
secondary to chronic inflammation.
Holm and colleagues21 performed a double-blind,
placebo-controlled biopsy study with fluticasone with the use of light microscopy
in patients with perennial allergic rhinitis. Twenty-eight sets of paired
biopsy data were able to be evaluated before and after 1 year of treatment.
No differences between the groups were observed before or after treatment.
The biopsy site in the Holm et al study (inferior edge of the inferior turbinate)
differed from that in ours (anterior tip of the inferior turbinate) but demonstrated
that a year's treatment with fluticasone did not alter the mucosa in the ciliated
epithelium.
Skin atrophy from topically applied corticosteroids can be detected
within time frames varying from 1 to 4 months of administration.7, 8, 9, 10, 11
Why the nasal mucosa acts differently from the skin is not known. There are
several possible explanations. One explanation is that, while the nose contains
only type I collagen, the skin contains elastin and type IV collagen. The
latter elements may be more glucocorticoid sensitive. Another explanation
may relate to residence time of drug at the application site. With dermatologic
preparations, the creams or ointments are applied to a specific site and left
in situ, sometimes under occluded conditions, for up to 24 hours. With an
intranasal spray, drug is removed within a few hours from the airways by mucociliary
transport.
An open-label study, although not generally optimal, was specifically
selected as the design for this study. Any attempt to double-blind this study,
given the differences in the formulations of the test medications (intranasal
spray vs oral tablets), would have required a double-dummy design that would
have necessitated that all subjects take both oral medication and intranasal
spray. Although not expected to have detrimental effects on the nasal mucosa,
a placebo spray or the insertion of the device into the nostrils to deliver
the nasal spray could potentially have confounded the biopsy data. To obviate
this problem, all biopsy evaluations were performed by clinicians who were
otherwise uninvolved in the care of subjects and who were blinded to the subject's
treatment and identity. This eliminated potential bias and ensured the validity
of the nasal mucosa assessments, which were the primary safety assessments
in this study.
This study was not designed to compare the efficacy of these compounds
in the treatment of allergic rhinitis. Fluticasone and terfenadine have been
compared in well-controlled clinical trials by others.22, 23, 24
However, subjects were examined in this study on a monthly basis to demonstrate
that therapeutic doses of both treatment regimens were being taken by the
subjects and to reinforce medication adherence. During the study, the treatment
groups experienced reductions from baseline in their rhinitis symptom scores
as assessed by both clinicians and subjects. Thus, it appeared from these
assessments that study medication adherence was sufficient to derive therapeutic
benefit.
Study treatments were well tolerated during this year-long study. The
adverse event profile was similar between treatments and to that observed
in numerous other studies. No serious or unusual events were observed. Only
1 subject withdrew from the fluticasone group because of localized bleeding.
Whether this patient would have shown changes on a nasal biopsy specimen consistent
with mucosal damage is unknown. Our findings, however, support the clinical
impression that, if patients are tolerating intranasal corticosteroids, they
can safely continue them. It is therefore prudent to reinforce the clinical
practice of examining patients within 2 to 4 weeks of initiation of intranasal
corticosteroid treatment with careful attention to the nasal mucosa. If bothersome
bleeding is reported by the subject and the nasal mucosa shows evidence of
injury, it is prudent to decrease the dose of administered corticosteroids
or even discontinue them.
The results of this study show that the use of intranasal fluticasone
propionate aqueous nasal spray, 200 µg once daily for 1 year, does not
lead to atrophy in the nasal mucosa. Conversely, this study shows that treatment
with fluticasone leads to a significant increase in epithelial thickness compared
with the posttreatment epithelial thickness in the terfenadine-treated group.
This suggests a positive effect of intranasal fluticasone on the nasal epithelium.
Our study has extended the previous work of others with nasal biopsy by using
quantitative objective measures of atrophy from light and electron microscopy
in a larger number of subjects and comparing the results with those of biopsy
specimens from subjects using a suitable therapeutic alternative. In compilation,
these studies all speak to the lack of histologic damage induced by intranasal
corticosteroids.
In summary, our study should make clinicians feel more secure in their
use of intranasal corticosteroids to treat allergic rhinitis. Using light
and electron microscopy, we performed a detailed and controlled investigation
of the nasal mucosa and found no evidence of structural damage after 1 year
of use. Combining these observations with the established efficacy of intranasal
corticosteroids in treating nasal symptoms argues that they should be a first-line
treatment in patients with perennial allergic rhinitis.
AUTHOR INFORMATION
Accepted for publication July 31, 2000.
This study was supported in part by grants AI45583 and DC02714 from
the National Institutes of Health, Bethesda, Md, and a grant-in-aid from Glaxo
Wellcome Inc, Research Triangle Park, NC.
From the Section of Otolaryngology–Head and Neck Surgery (Drs
Baroody, Cheng, Corey, and Naclerio and Mss deTineo and Haney) and the Department
of Pathology (Dr Sengupta), Pritzker School of Medicine, University of Chicago,
Chicago, Ill; Department of Medicine (Division of Clinical Immunology), The
Johns Hopkins University School of Medicine, Baltimore, Md (Ms Moylan and
Dr Togias); and Glaxo Wellcome Inc, Research Triangle Park, NC (Messrs Reed
and Westlund and Ms Cook).
Corresponding author and reprints: Fuad M. Baroody, MD, Section of
Otolaryngology–Head and Neck Surgery, University of Chicago, 5841 S
Maryland Ave, MC1035, Chicago, IL 60637 (e-mail: fbaroody{at}surgery.bsd.uchicago.edu).
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