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Individual Monitoring of Aspirin Desensitization
Jan Gosepath, MD;
Dirk Schaefer, MS;
Ronald G. Amedee, MD;
Wolf J. Mann, MD
Arch Otolaryngol Head Neck Surg. 2001;127:316-321.
ABSTRACT
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Background Patients with aspirin-sensitive rhinosinusitis, which is frequently
associated with intrinsic bronchial asthma, can be desensitized by long-term
treatment with oral aspirin. The exact mechanisms of this desensitization
remain obscure, but modulations of the eicosanoid pathway occur and can be
monitored with the help of a practicable in vitro assay on mixed leukocyte
cultures.
Objective To monitor the effect of low-dose aspirin desensitization therapy, 100
mg/d, objectively by an in vitro assay.
Design In a prospective study, 30 patients with aspirin intolerance, who were
treated following a desensitization protocol with a dose of oral aspirin of
only 100 mg/d were followed up for 1 year and reassessed every 3 months clinically
and in vitro.
Results Twenty-five patients showed a normalization of in vitro eicosanoid levels
during this period, 4 showed some improvement, and 1 showed no therapeutic
effect on eicosanoid release. Clinical follow-up revealed a low recurrence
rate of nasal polyposis, with recurrent disease only in 4 individuals who
also showed no normalization of eicosanoid release levels. Furthermore, a
reduction of the average incidence of purulent episodes of sinusitis was seen
after 1 year. Of 12 patients with asthma, 9 experienced marked improvement
in pulmonary function. Of 16 individuals with a marked impairment of nasal
breathing, 14 felt an increase of nasal patency, and 7 of 11 patients with
pretreatment hyposmia had an improved sense of smell after 1 year.
Conclusions Desensitization therapy in patients with aspirin-sensitive rhinosinusitis
can be successfully performed with low oral doses of aspirin, and the individual
course throughout the desensitization can be monitored with the help of an
in vitro analysis of eicosanoid release from mixed leukocyte cultures.
INTRODUCTION
ASPIRIN INTOLERANCE (AI) in patients with chronic rhinosinusitis has
been recognized as one possible reason for recurrent nasal polyps and certainly
should be considered as a pathogenic mechanism in patients in whom nasal polyposis
is combined with intrinsic bronchial asthma.1, 2
Since the onset of the different clinical symptoms in the development of AI
is variable, sometimes by a number of years, the diagnosis of AI is not always
associated with the full clinical picture of the aspirin triad, which consists
of (1) nasal polyposis; (2) intrinsic bronchial asthma; and (3) aspirin-induced
worsening of asthmatic symptoms, often associated with naso-ocular symptoms.3, 4 However, in sensitive individuals,
even small, single doses of aspirin may cause rhinorrhea, bronchiolar constriction,
and shock symptoms related to a non–IgE-mediated pharmacological hypersensitivity
reaction.5
After recently published data pointed out an imbalance of prostaglandin
E2 (PGE2) and peptidoleukotrienes (pLTs) in aspirin-intolerant
individuals with asthma,6 2 further studies7, 8 were initiated. The results of these
studies supported the hypothesis that this assay can be used as an alternative
method to establish the diagnosis of AI as opposed to the use of oral, nasal,
or bronchial aspirin challenge tests. It is known that not only aspirin but
most other nonsteroidal anti-inflammatory drugs interact with the arachidonic
acid pathway. They are known to cause inhibition of the cyclooxygenases (mainly
isoenzyme cyclooxygenase 1), which metabolize arachidonic acid to prostaglandins.
This inhibition leads to an up-regulation of the alternative pathway, with
lipoxygenases metabolizing arachidonic acid to leukotrienes. However, this
cannot be the sole cause of AI, since this effect of nonsteroidal anti-inflammatory
drugs occurs in healthy individuals as well. Several additional factors have
been discussed, like alterations in cyclooxygenase inhibition and in the kinetics
of enzymes like leukotriene synthase or an increased sensitivity of respiratory
mucosal tissue to leukotrienes in sensitive individuals.9, 10
While the exact causative mechanisms have to be further elucidated, the individual
chronologic sequence of symptoms is known to be considerably variable. First
symptoms usually occur within the fourth decade of life, with recurrent rhinitis
followed by nasal polyposis. Intrinsic bronchial asthma can develop some years
later and often it takes years again for the clinical sensitivity to nonsteroidal
anti-inflammatory drugs to occur. This is the reason why an in vitro assay,
like the one applied in this study, can be valuable in establishing the diagnosis
of AI. The alteration of arachidonic acid metabolism and eicosanoid release
can be detected in patients with an incomplete manifestation, in whom the
clinical picture of the aspirin triad has not yet fully developed as in patients
with the full triad.
Different researchers11, 12, 13, 14, 15
described the possibility of a desensitization therapy by oral administration
of aspirin for a longer period. The present study was designed to investigate
the effects of an aspirin desensitization therapy with a low oral dose of
100 mg/d, and the role of the in vitro assay in verifying and monitoring the
effect of this therapy over time based on the eicosanoid release of isolated
blood cells. The focus of this investigation is (1) to monitor the clinical
course and especially the recurrence rate of nasal polyps under oral aspirin
desensitization and (2) to correlate the clinical course to the development
seen in the eicosanoid release of isolated blood cells.
PATIENTS AND METHODS
In a prospective study, 30 patients (16 men and 14 women; average age,
47.9 years; age range, 28-65 years) underwent aspirin desensitization therapy
and were followed up for 1 year. Twenty were local residents and available
for close monitoring at our institution at 3-month intervals (group 1), while
10 from other parts of the country were only reassessed after completion of
9 months of desensitization and at 12 months after the initiation of treatment
(group 2). Patients who experienced multiple recurrences of nasal polyposis
or presented with at least 2 of the 3 criteria of the AI triad were included
in this study. On their first visit to our institution, only 6 patients were
aware of their aspirin hypersensitivity, as either they had experienced clinical
reactions like severe asthmatic symptoms after taking aspirin or their referring
physician had made them aware of this condition due to the constellation of
symptoms observed. All 30 individuals had experienced nasal polyposis for
a prolonged period and had undergone one or more endonasal sinus surgical
procedures. Before starting the desensitization, patients were assessed clinically
for recurrent polypoid disease, number of episodes of purulent rhinosinusitis
in the previous year, nasal patency, the presence and severity of asthmatic
symptoms, and their sense of smell, using the "sniffing sticks" (Sniffin Sticks;
Burghardt, Wedel, Germany). This olfactory screening test contains 8 sticks,
each of which represents a characteristic smell. The degree of hyposmia is
determined separately for each side of the nose by the number of correctly
identified sticks. Of the 30 patients, 12 were using a topical nasal corticosteroid
spray, 9 were using corticosteroid sprays as needed for control of asthmatic
symptoms, and 2 were taking systemic corticosteroids for asthma control.
Screening for inhalant allergies, using skin testing, a radioallergosorbent
test, and nasal provocation tests, was performed. Three patients with seasonal
symptoms due to their sensitization to grain and trees, who had not been treated
with immunotherapy, were scheduled for antiallergic hyposensitization, which
was performed simultaneously to the aspirin desensitization protocol.
All 30 individuals had a positive test result for AI using a functional
in vitro assay following a recently published protocol6:
blood was drawn from all patients, and a mixed leukocyte culture was prepared
using dextran sedimentation. Thereafter, the eicosanoid release of pLTs and
PGE2 was analyzed using competitive enzyme immunoassays.16 The release of pLTs and PGE2 was assayed
simultaneously and in duplicate for each sample. The antibody directed against
pLTs recognized leukotriene C4 and the metabolites leukotriene
D4 and leukotriene E4 with equal sensitivity. The detection
limit was 3 pg per well for pLTs and PGE2. The changes in eicosanoid
release determined a positive or negative test result. A positive test result was defined as elevated pLT release and lowered
PGE2 release, while a negative test result
was defined by normal pLT and PGE2 release when compared with the
release levels in a healthy control group. The eicosanoid levels of this healthy
control group, consisting of 50 individuals who showed no clinical evidence
of any symptoms consistent with AI, were assessed by the same assay mentioned
previously, in the same laboratory, when the protocol of the assay first had
been established.6
To initiate the desensitization therapy, oral aspirin was given in increasing
dosages for 2 days (day 1, 100 mg [2 doses of 50 mg]; and day 2, 500 mg),
and patients were hospitalized for this therapy. Airway resistance and forced
expiratory volume in 1 second were closely monitored during this induction
period. On the first day after an initial lung function test, 50 mg was given
in the morning, and only after a repeated check of airway resistance and forced
expiratory volume in 1 second was the second 50 mg administered orally, usually
8 hours after the initial dose. On the second day, 500 mg was given orally
if repeated lung function testing had not revealed a decrease in forced expiratory
volume in 1 second of 25% or greater. On the third day, aspirin was reduced
to the maintenance dose of 100 mg/d, to be given for at least 9 months to
minimize the incidence of the known adverse effects of aspirin if given in
higher doses for a longer period. We did not encounter any mild or moderate
problems, such as acute asthmatic attacks or shock symptoms, gastric pain,
or ulcers, following this regimen. However, if on day 2 the patient had a
decrease of forced expiratory volume in 1 second of greater than 25%, we assumed
that the 100 mg of aspirin that was administered on day 1 was already above
the individual threshold of aspirin-related asthmatic symptoms. Therefore,
in these patients we did not increase the daily dose further, but treated
them with the maintenance dose of 100 mg immediately on day 2, skipping the
further increase to 500 mg.
Clinical reassessment and the functional in vitro assay were repeated
at each follow-up visit of every patient in an attempt to identify changes
in the release of eicosanoids over time and to correlate these with the clinical
course.
For the statistical analysis of the data obtained, a Wilcoxon signed
rank test was used and results were statistically significant if P<.05 and highly significant if P<.01.
RESULTS
A functional in vitro test for AI before starting the desensitization
therapy using mixed leukocyte cultures revealed a positive result in all 30
patients, implying that basal release of pLTs was elevated and basal release
of PGE2 was reduced, which was one of the inclusion criteria for
this study.
GROUP 1
Findings Before AI Desensitization
Before initializing the desensitization, 8 of the 20 individuals in
group 1 were free of nasal polyps. Twelve showed recurrent polyps, of which
9 had minor findings in the ethmoid region, 2 had more severe findings, and
1 had massive panpolyposis. All of these 12 patients had undergone more than
1 previous surgical intervention, with the last operation having been more
than 3 months before the beginning of the desensitization. All patients with
recurrent polyps complained about a significant impairment of nasal breathing
and a reduction of their sense of smell. Olfactory screening using the sniffing
sticks revealed various degrees of hyposmia in 8 patients and total anosmia
in those 3 with severe polyposis. Eight individuals had intrinsic asthma of
variable severity, but all achieved good symptom control with the use of a
topical inhalant or systemic corticosteroids.
Screening for inhalant allergies revealed a positive test result in
11 patients: 6 were allergic to grain and trees, 3 to mite, and 2 to animal
hair. Three of these patients had undergone immunotherapy for a minimum of
3 years, and 3 patients with seasonal symptoms due to their sensitization
to grain and trees were scheduled for antiallergic hyposensitization simultaneously
to the aspirin desensitization therapy.
Clinical Follow-up (at 3, 6, 9, and 12 Months)
The 8 individuals who had been free of polyps after revision surgery
before starting the desensitization all remained disease free for 12 months.
Of those 9 with minor findings of recurrent polyps at the beginning of the
treatment, 7 also showed no evidence of disease after 12 months of desensitization,
indicating a marked clinical improvement (2 of these 7 underwent immunotherapy
for antiallergic hyposensitization); and the other 2 remained at a steady
state without worsening of their symptoms. Two patients with more severe forms
of recurrent polyposis showed a reduction of polyps over time as their eicosanoid
release levels improved simultaneously (1 of these 2 underwent immunotherapy
for antiallergic hyposensitization). The patient who had started out with
recurrent polypoid disease even experienced some worsening during the 12 months
of follow-up and continued to be anosmic, with highly impaired nasal breathing.
This patient also experienced further worsening of asthmatic symptoms, which
had been progressing during the last 3 years.
Of the 8 asthmatic patients, 5 reported a reduction of clinical symptoms
and a decreased frequency of their need to use inhalant corticosteroids. In
those 12 individuals who had complained about an impairment of nasal breathing
due to recurrent polyps, 11 reported noticeable improvement after 1 year.
Of the 8 patients who had shown marked hyposmia, 4 experienced a marked improvement
in their sense of smell, which went along with a strong improvement in subjective
quality of life. With the exception of the individual previously mentioned,
the other 2 anosmic patients regained some sense of smell, both reporting
this subjective change at the 9-month and the 1-year visits.
In Vitro Follow-up (at 3, 6, and 9 Months)
In vitro variables correlated well with the clinical findings. During
the first 3 months of desensitization, the levels of PGE2 decreased
and those of pLTs increased in some patients, resulting in an even more pathologic
ratio of PGE2 and pLT (PGE2/pLT index). However, this
tendency was reversed after 3 months. Of the 20 patients in group 1, 9 underwent
an in vitro test at 6 months. They all showed a tendency toward normalization
of eicosanoid levels. Basal PGE2 release was higher and basal pLT
release lower than before the beginning of the desensitization therapy. However,
these eicosanoid levels were not normal when compared with those of a healthy
control group.8 At this point, eicosanoid levels
of only 3 individuals had reached levels comparable to those of healthy controls.
At 9 months, all 20 patients were tested again, and 19 showed an improvement
in the basal release levels of pLTs and PGE2, 17 had levels comparable
to those of healthy controls, and 2 still showed "shifting" toward higher
levels of pLTs (these were the 2 individuals who remained at a steady state
clinically). In the one patient with progression of polyps clinically, eicosanoid
levels remained unchanged throughout the observation period (Figure 1A-C).
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Figure 1. Data are shown before (n = 20)
and 3 (n = 20), 6 (n = 9), and 9 (n = 20) months after initiating the desensitization
therapy in group 1 (n = 20). Lines show the individual courses of the 20 patients,
and the large shaded boxes indicate mean values. A, Peptidoleukotriene (pLT)
release. B, Prostaglandin E2 (PGE2) release. C, The
PGE2/pLT index.
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GROUP 2
Findings Before AI Desensitization
Evaluation of these 10 patients showed similar results. Clinically,
while the remaining 6 were free of polyps, 4 individuals had minor recurrence
of nasal polyps before initiating the desensitization. Nasal breathing was
impaired in patients with recurrent polyps, and 3 of these 4 presented with
hyposmia. Inhalant allergies were found in 3 of these 10 individuals: 2 were
allergic to animal hair and 1 to grain and trees. None of these patients underwent
immunotherapy for antiallergic hyposensitization throughout the observation
period. Four patients had a history of intrinsic bronchial asthma and were
taking topical corticosteroids.
Clinical Follow-up (at 9 and 12 Months)
After 1 year of follow-up, none of the 4 individuals previously mentioned
showed any progression of the recurrent polyposis, 3 showing improvement in
nasal obstruction secondary to polyps on nasal endoscopy. Also, the 6 individuals
without polyposis remained free of disease. Nasal patency improved in 3 of
those 4 individuals in whom it had been impaired, and the 3 hyposmic individuals
reported an ameliorated sense of smell, which could be verified using the
sniffing sticks. The 4 asthmatic patients all reported a decreased need for
inhalant corticosteroids for symptom control.
In Vitro Follow-up (at 9 Months)
In vitro variables also correlated well with the clinical course and
showed a normalization of the eicosanoid release levels in 8 patients and
some residual pathologic shifting in 2 patients after 9 months.
GROUPS 1 AND 2
Looking at all 30 patients, the mean number of sinus infections per
year was reduced from 4 to 2 after the initiation of therapy, while the number
of patients with more than 3 episodes of purulent sinusitis per year decreased
from 11 to 2. After 9 months of aspirin desensitization, the eicosanoid levels
were normal in 25 patients, there was residual pathologic shifting in 4, and
the levels were unchanged in 1. The development of the clinical and in vitro
variables for all 30 patients in groups 1 and 2 is summarized in
Table 1,
Table 2, and
Table 3
and in Figure 2A-C. Statistical
significance was evaluated using the Wilcoxon signed rank test.
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Table 1. Clinical Assessment of All 30 Patients Before the Initiation
of Aspirin Desensitization
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Table 2. Endoscopic Assessment of Nasal Polyposis of the 30 Patients
After 12 Months*
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Table 3. Effects of the Desensitization Therapy on Clinical Symptoms,
Other Than Polyposis, That Are Associated With Aspirin Sensitivity*
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Figure 2. Data are shown before and 9 months
after initiating the desensitization therapy in groups 1 and 2 (n = 30). Lines
show the individual courses of the 30 patients, and the large shaded boxes
indicate mean values. A, Peptidoleukotriene (pLT) release. Significant changes
(P<.05) are marked with an asterisk. B, Prostaglandin E2 (PGE2) release. Significant changes (P<.05)
are marked with an asterisk. C, The PGE2/pLT index. Highly significant
changes (P<.01) are marked with a dagger.
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COMMENT
Aspirin intolerance, since it was first described in the beginning of
the century,11, 15 has been studied
by many researchers,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29
yet the exact causative mechanisms still remain obscure. Clinically, aspirin-sensitive
rhinosinusitis is often associated with recurrent polypoid disease. However,
not all patients present with the classic clinical triad of nasal polyposis,
intrinsic bronchial asthma, and worsening of asthmatic and/or nasal symptoms
after ingestion of aspirin.7 Several researchers4, 13, 15, 19, 20, 21, 22
have demonstrated the possibility of successfully desensitizing individuals
to aspirin. The underlying mechanisms explaining this desensitization still
require further elucidation. Changes in the metabolism of arachidonic acid
and the eicosanoid pathway during desensitization have been detailed, mainly
by analyzing urinary leukotrienes23, 24
but also by measuring leukotriene release from peripheral blood monocytes25 or mixed leukocytes.17
Following a recently published protocol,6 we
were able to show that analyzing eicosanoid release in mixed leukocyte cultures
offers an alternative to oral, bronchial, or nasal challenge tests. In a recent
investigation,7 we found this in vitro analysis
reliable in establishing the diagnosis of aspirin sensitivity, especially
if patients did not present with a clear clinical picture of the aspirin triad.
This is of particular interest, since the onset of clinical symptoms in the
development of AI is known to be quite variable. Often, nasal polyps occur
years before the development of intrinsic asthma, which is then followed by
clinical intolerance to aspirin.2, 29
Early diagnosis and treatment before the manifestation of the complete triad
may be crucial for therapeutic success.
The results of the present study suggest that this functional in vitro
test is suitable for monitoring the effectiveness of a long-term aspirin desensitization
protocol and for giving a correlation for clinical improvement or stagnation.
Using a dose of as little as 100 mg/d, maintained after the induction period
of 2 days, we found effects on the eicosanoid release comparable to data we
had gathered earlier with higher doses of 300 and 500 mg/d (J.G., D.S., and
W.J.M.,unpublished data, 1998). After having correlated the clinical effectiveness
of this low dose of 100 mg with the positive development of the in vitro variables
and thus proving the effectiveness of this protocol, we think that in the
future it could be reduced to just monitoring the clinical course and, therefore,
be applied in institutions that would not have in vitro testing available.
However, the main value of the in vitro assay will remain in establishing
the diagnosis in patients without a typical triad of symptoms and furthermore
in relating individual clinical courses and possible failures of treatment
to the individual eicosanoid levels. The question of which dose of oral aspirin
should be administered to induce tolerance to aspirin is controversially discussed
throughout the literature. Most researchers suggest daily doses to be maintained
at considerably high levels, between 500 and 1000 mg; in some studies, dosages
of even more than 2000 mg/d were used.13, 15, 20, 22, 23, 24, 25, 26, 27, 28
The 9-month course of the 30 patients described in this study, who received
a dose of 100 mg/d, shows clear positive effects on the recurrence rate for
nasal polyps, the number of episodes of purulent sinusitis, nasal patency,
and the sense of smell. These effects are positively correlated with the results
of the repeated measurements of eicosanoid release in vitro. All patients
with such positive effects on their clinical course also showed a clear tendency
toward normalization of basal release levels of pLTs and PGE2.
On the other hand, the only individual who did not benefit from desensitization
clinically and had to be scheduled for revision surgery due to massive recurrence
of polyps still showed pathologic eicosanoid release levels after 9 months
that were virtually unchanged when compared with the first measurement at
the beginning of therapy.
We are aware that in those 3 individuals who underwent aspirin desensitization
and antiallergic hyposensitization simultaneously throughout the observation
period, the observed clinical improvement could in part be contributed to
the antiallergic treatment because of IgE-related mechanisms that are being
discussed in the pathogenesis of nasal polyps and asthma.30, 31
However, the in vitro variables used in this study did not show any marked
differences between these 3 individuals and those who improved clinically
but did not undergo antiallergic hyposensitization.
The in vitro follow-up revealed an initial tendency to even more pathologic
eicosanoid release levels within the first 3 months of aspirin desensitization,
which was not accompanied by a worsening of clinical symptoms. But only after
the in vitro variables started to improve (6- and 9-month visits) did the
clinical improvement become obvious. This lack of correlation within the first
3 months cannot be fully explained by the data gathered in this investigation,
but suggests the existence of compensating mechanisms in case of a further
deterioration of already pathologic eicosanoid levels.
The use of topical corticosteroid sprays has been shown to have no impact
on the eicosanoid levels measured by immunoassay.6
However, the use of systemic corticosteroids may lead to reduced basal release
levels of PGE2. This was seen in both individuals who took systemic
corticosteroids for asthma control, as after 9 months they showed reduced
pLT levels but still had reduced PGE2 levels. This does not indicate
ineffectiveness or failure of the desensitization in these individuals. Rather,
the achieved improvement of asthmatic symptoms in both individuals, with a
cessation or reduction of corticosteroid use, may lead to a normalization
of PGE2 levels as well.
In conclusion, we believe that the results presented in this study support
the use of a low dose of aspirin (100 mg/d) in an effort to induce tolerance
in aspirin-sensitive patients. The in vitro analysis of eicosanoid release
from mixed leukocyte cultures using a functional in vitro assay offers a new
tool not only to help establish the diagnosis of AI but also to individually
monitor the effect and objectively verify the success of a desensitization
therapy over time.
AUTHOR INFORMATION
Accepted for publication August 31, 2000.
Presented at the annual meeting of the German Society of Oto-Rhino-Laryngology,
Head and Neck Surgery, Aachen, Germany, May 14, 1999.
From the Departments of Otolaryngology–Head and Neck Surgery,
Mainz Medical School, Mainz, Germany (Drs Gosepath and Mann and Mr Schaefer);
and Tulane University, School of Medicine, New Orleans, La (Dr Amedee).
Corresponding author and reprints: Jan Gosepath, MD, Department of
Otolaryngology–Head and Neck Surgery, Mainz Medical School, Langenbeckstrasse
1, 55101 Mainz, Germany (e-mail: gosepath{at}hno.klinik.uni-mainz.de).
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