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Aspirin-sensitive rhinosinusitis asthma: A double-blind crossover study of treatment with aspirin
Aspirin-sensitive rhinosinusitis asthma: A doubte-blind crossover study of treatment with aspirin Donald D. Stevenson, M.D., Warren W. Pleskow, M.D.* Ronald A; Simon, M.D., David A. Mathison, M.D., William R. Lumry, Michael S&ha% M.D.,* and Robert S. Zeiger, M.D., Ph.D.* La Jolla and San Diego, Calif.
M.D.,
Twenty-jive ASA-sensitive patients with rhinosinusitis asthma underwent oral ASA challenges followed by desensitization to the adverse respiratory effects of ASA. We then compared the eficacy of continuous ASA treatment for their respiratory tract disease to that of a placebo treatment during a double-blind crossover study. For this group of 25 patients, there was significant improvement in nasal symptoms and a reduction in use of nasal beclomethasone during the months when they received ASA treatment. Lower respiratory tract symptoms, values of FEV,, and the use of antiasthmatic medications including prednisone were not significantly changed during ASA treatment. Desensitization to ASA followed by ASA treatment appears to signijcantly alleviate symptoms of rhinosinusitis. However, only half the patients experienced improvement in their asthma symptoms during ASA treatment. (J ALLERGY CLIN hMUNOL
73:500-507, I984 .)
ASA desensitization, the induction of tolerance to ASA by repeated ingestion of ASA, has been carried out successfully in ASA-sensitive rhinosinusitis asthmatic patients. Beginning with the work of Widal et al.,’ and continuing with the reports of Zeiss and Lackey,* Bianco et al.,3 Stevenson et al.,4 Pleskow et a1.,5 and Stevenson et al .,6 the phenomenon of ASA desensitization has been established. Furthermore, once ASA-sensitive patients have been desensitized and are able to ingest 650 mg of ASA without adverse respiratory responses, they can consume many times more ASA without further reactions or loss of the desensitized state.4, 5* g As demonstrated in our previous publications,5* g this state of refractoriness to the adverse effects of From the Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, Calif. and *Department of Allergy and Clinical Immunology, Kaiser Permanente Medical Center, San Diego, Calif. Supported by National Institute of Allergy and Infectious Diseases grants AI-10386 and RR 00833. Publication number 3027BCR from the Research Institute of Scripps Clinic, La Jolla, Calif. Received for publication June 6, 1983. Accepted for publication Nov. 2, 1983. Reprint requests: Donald D. Stevenson, M.D., Division of Allergy and Immunology (206W-A), Scripps Clinic and Research Foundation, 10666 North Torrey Pines Rd., La Jolla, CA 92037.
500
ASA persists for 2 to 5 days after ASA is discontinued. Cross-desensitization using other nonsteroidal anti-inflammatory drugs, has also been achieved.5 We have previously described two patients who underwent ASA desensitization and then long-term treatment with ASA, who reported improvement in their clinical courses.4 However, both patients, despite ASA desensitization and daily ingestion of ASA, continued to experience bronchospasm when they were inhaling standard methacholine solutions in the laboratory or during natural exposures to viral respiratory tract infections in association with purulent sinusitis attacks or when they were exposed to irritants inhaled during smog alerts. To test the hypothesis that ASA desensitization, followed by daily ingestion of ASA, improves the clinical course of rhinosinusitis or asthma in ASAsensitive subjects, a double-blind crossover study comparing ASA to placebo therapy was constructed. The following report presents the results. MATERIAL Patients
AND METHODS
Asthmatic patients with known or suspectedASA sensitivity were selected from the practices of the authors or referred by other specialists. All patients were admitted to the GCRC, Scripps Clinic
Aspirin-sensitive
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Abbreviations used ASA: Aspirin FEV,: Forced expiratory volume in 1 set GCRC: General Clinical Research Center q.d.: Every day q.i.d.: Four times a day
Admission CCRC Desensitization ASA +1
rhinosinusitis
asthma
501
Admission CCIC Desensitization ASA +2
Months:
and Research Foundation. Informed consent for procedures approved by the Human Subjects Committee was obtained. Standard historical information was collected, including their age, sex, duration of rhinitis and asthma, previous polypectomy , or sinus surgery. Previous history of ASAsensitivity reactions was noted. The medications taken by each patient at the point of entry into the study was recorded.
Laboratory
tests
Complete blood counts, nasal cytogram, sinus radiographs, flow/volume spirometry, and cutaneous tests for immediate hypersensitivity to extracts of common aeroallergens were obtained. Recording serial changes in values of FEV, demonstrated patients who had asthma. A 20% or more increase in FEV, values after inhalation of a bronchodilator or a 20% or more decrease in FEV, values after inhalation of gradually increasing dosages of methacholine up to five inhalations of 25 mglml was considered diagnostic of reversible obstructive airway disease.
Oral challenges On day 1, single-blind placebo challenges were conducted beginning in the morning. Baseline FEV, values were recorded before and at hourly intervals after ingesting identical opaque capsules containing lactose. On day 2, single-blind oral challenges with ASA were initiated as described in a previous publication.5 Incrementally increasing dosages of aspirin, beginning with 3 or 30 mg and thereafter 60, 100, 150, 325, and 650 mg were administered at 2- or 3-hr intervals while patient’s symptoms were being monitored, eyes, noses, chests were being examined, and flow/ volume spirometry at intervals of 1 hr or less was being recorded. Respiratory responses were observed and categorized. The only patients admitted to this study were those patients who developed a bronchospastic reaction to ASA, with FEV, values declining 25% or more from baseline, and with FEV, values during placebo challenges changing <15%. Concordant nasal and ocular symptoms and signs were noted. All these patients then underwent ASA desensitization.6 After the patients reacted to an administered dosage of ASA, recovery occurred within 2 to 24 hr. The same provoking dosage of ASA was given repeatedly at intervals of 3 to 24 hr until reactions disappeared. Thereafter, increasing dosages of ASA were administered until the patient could ingest 650 mg of ASA without adverse effect.
Double-blind
crossover
study design
All volunteers who experienced a positive bronchospastic response to ASA were desensitized to ASA. They were
*Study
drug:
ASA
or Placebo
FIG. 1. Design of double-blind crossover study is illustrated. Admission to GCRC with ASA challenge and desensitization occurs before months 1 and 5. Study drug of Phase I is crossed over in Phase II (aspirin (Ascriptin; William H. Rorer, Inc.) versus placebo therapy).
admitted to the treatment phases of the study if they were willing to participate and if they were available for followup evaluations and repeat ASA desensitization. Ascriptin tablets (ASA 325 mg and Maalox 150 mg) and identical Ascriptin placebo tablets (Maalox 475 mg) were supplied by William H. Rorer, Inc. The treatment period consisted of two separate 3-month treatment phases, separated by a l-month washout period (Fig. 1). During the first 3 mo of the study, patients ingested daily dosages of either one, four, or eight study tablets in divided dosages. During the fourth month (washout period) study pills were discontinued. At the end of the washout period, the patients were readmitted to the GCRC and underwent another ASA challenge and desensitization. Study pills were then restarted but “crossed over” to the opposite drug for the last 3 mo of the study. A Scripps Clinic pharmacist assigned either Ascriptin placebo or Ascriptin to each patient at entry into the study by use of a random number system. The dosages (one, four, or eight tablets per day) were chosen by the investigator. Confidential records of dispensed Ascriptin and Ascriptin placebo were kept in the pharmacy, and the codes were broken only after the study was completed. The following information was recorded each day by all patients: degree (1 = no symptoms through 5 = severe symptoms) of rhinorrhea, nasal congestion, postnasal drainage, sinus pain, sense of smell, chest tightness, wheezing, coughing, shortness of breath, and chest congestion. Daily medications consumed, including study pills, were recorded. However, prednisone and beclomethasone were preferentially reduced if improved symptoms warranted such action. Dosages of other medications were not changed during the 7-month study. With few exceptions, patients were examined monthly, and FEV, values were recorded at that time. All data were entered into CLINFO (Scripps CLINFO GCRC, La Jolla, Calif.) computer. Graphs were generated by CLINFO with ASA treatments to left and placebo therapy treatment to the right, even though half the time ASA treatment followed placebo treatment in Phase II. Statistical studies were carried out by use of the CLINFO computer and included one-tailed student’s t test, linear regression analysis, and chi square.
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TABLE I. Consumption of entry
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et al.
into the study
of medications (25 patients)
at the time
No. Medication
Mean dosage per day
patients
Prednisone (q.d.) Prednisone (q.o.d.) Oral beclomethasone Nasal beclomethasone Theophylline Oral beta agonists Antihistamine/decongestant Antibiotics Cromolyn sodium
20 mg 9 mg* 361 pug 188 m 656 mg 19 mg 4 tablet -
8 8 14 12 19 6 13 1 0
*q.o.d. = 18 mg. TABLE II. Results of ASA challenges desensitization (25 patients)
and
Range
PEV, decline (%) ASA cumulative dosage (mg) to produce first reaction No. of challenges to produce desensitized state
Mean
25 30
78 1083
1
15
38 364 2.2
RESULTS
Between 1979 and 1982,91 patients with suspected ASA sensitivity underwent oral ASA challenges in the Scripps Clinic GCRC, and 54 patients (60%) experienced respiratory reactions. Of these 54 patients, 6 (11%) experienced pure nasoocular reactions without associated bronchospasm, and 48 patients (89%) experienced bronchospasm with FEV, values declining by 25% or more from baseline values. These 48 patients were eligible for entry into the study. However, 10 patients elected not to participate in the study. The remaining 38 patients entered the doubleblind crossover study. Gf these 38 patients, 13 dropped out of the study for the following reasons: three patients experienced gastrointestinal pain (all three were in the ASA phase of study when the code was broken), three patients experienced increased asthma symptoms during the first few weeks of Phase I and elected to stop the study (all three were taking ASA when the code was broken), one patient experienced increased nasal congestion (received placebo therapy), one patient developed uterine bleeding, ‘and her surgeon requested discontinuation of the study to allow hysterectomy (received placebo therapy), and five patients were uncooperative and did not complete or adequately participate in the study for a variety of psychosocial reasons (two received ASA and three received placebo therapy).
TABLE III. Differences between treatment
in mean symptom scores 3 mo of placebo and 3 mo of ASA
Symptom mean
diary score
Running nose Nasal congestion Postnasal discharge Sinus pain Sense of smell All nasal symptoms Chest tightness Wheezing Coughing Shortness of breath Chest congestion All chest symptoms Nasal beclomethasone Prednisone
Differences IplacebolASA)
T test
N - 25
N - 25
0.056 0.248 0.041 0.152 0.310 0.161 -0.149 -0.106 -0.005 -0.117 0.043 -0.067 0.411 -0.044
N.S. 0.032 N.S. 0.005 0.057 0.031 N.S. N.S. N.S. N.S. N.S. N.S. 0.030 N.S.
Analysis of all other medications, listed in Table I, did not show any significant changes.
Twenty-five patients completed the 7-month double-blind crossover study. There were eight male and 17 female patients. Their mean age was 45 yr, ranging from 18 to 71 yr. The mean duration of their respiratory tract disease was 15 yr. Twenty patients (80%) had nasal polyps, and 18 patients (72%) had undergone sinus-drainage surgery in the past. Table I lists the medications consumed by these 25 patients at the time of entry into the study and also lists the number of patients receiving each medication and the mean daily dosages. Laboratory
studies
Eosinophils were found on nasal cytograms of 18 patients (72%). Sinus radiographs were abnormal for 23 (92%) of the patients and with mucoperiosteal thickening in eight and complete opacification or airfluid levels in 17 patients. Cutaneous tests for immediate hypersensitivity were carried out in 14 of the 25 patients. Positive wheal-and-flare responses were recorded for extracts of pollen in 10 of the 14 patients (71%), danders/mite in nine of the 14 patients (64%), and fungi in three of the 11 patients (28%). Oral challenges
Placebo challenges were conducted in all 25 patients, and FEV, values varied between 0% and 15% from baseline. Nasal or ocular symptoms and signs did not occur during or after oral placebo challenges. Table II depicts the percent decrease in FEV, values after ASA ingestion and the cumulative dosages of ASA required to induce the first bronchospastic
VOLUME 73 NUMBER 4
Aspirin-sensitive
wash
~s~----,out
rhinosinusitis
asthma
503
out -Plrccbc I--ASA---’ wash
*Placebo+
I
t
3.9 Mean
2.o
daily symptom scores
‘sQ 1.8.
Mean
3.8 i
dally rymptom scoccs
3-7
1.7.
3.6 3.s
1.8 -
3.4
1.5.
3.3 2
4
3
Months
6
Score =
1.8
symptom of 7 mo
7.
scores of study.
‘a5
dally symptom scores
‘a4 1.3 1.2 1.1
1
2
3
Months
FIG. 3. Nasal symptom scores corded on vertical axis for each
Score D (Sinus pain) P e 0.05 for sinus pain of 7 mo of study.
D are rep = 0.05.
reactions. Of the 25 patients, 23 experienced nasoocular symptoms and signs at the time of the bronchospastic reaction. The total number of ASA challenges before desensitization to ASA was completed ranged from one to 15 with a mean of 2.2. Differences in mean symptom (placebo-ASA phases)
5 Months
FIG. 4. Nasal recorded on p = 0.057.
1
Mean
3.1
8 are recorded p = 0.05.
Wash out-Placebo+
--ASA-
3.2
B ;;;3cstion) .
(:asi FIG. 2. Nasal congestion on vertical axis for each
8
scores
In Table III are the results of analyzing the symptoms of 25 patients during 3 mo of ASA versus placebo therapy treatment. Differences between ASA and placebo therapy symptom scores were known to vary either in a positive or negative direction. One-
symptom vertical
scores axis for
Score $ey8 =
8
1’
E $;mcll) .
for sense of smell each of 7 mo of
E are study.
tailed student’s t test demonstrated significant differences in a positive direction (improved) for individual and combined nasal symptom scores (N = 25). The mean use of nasal beclomethasone (milligrams per day) and prednisone (milligrams per day) are also presented and demonstrate a significant reduction in use of beclomethasone . The subgroups receiving one, four, or eight study tablets per day were too small for analysis by this method. Although not depicted, the differences in other medications consumed during ASA versus placebo treatment phases were also subjected to statistical analysis by the one-tailed t test, and the null hypothesis could not be rejected. In Figs. 2, 3,4, and 5 are the mean daily symptom scores of the 25 patients for four different nasal symptoms by use of a bar graph display. Significant differences are noted for individual and combined nasal symptom scores. In Fig. 6 chest scores were not significantly different. Linear regression analysis (medication dosage versus symptom scores) was calculated by use of x = prednisone or beclomethasone dosages and y = mean symptom scores. There was no significant correlation. In assessing the effects of ASA versus placebo treatment on individual patients, we subtracted the mean scores of accumulated symptoms during 3 mo of ASA treatment from those during 3 mo of placebo treatment and determined whether or not concomitant
564
Stevenson
J. ALLERGY CLIN. IMMUNOL. APRIL 1984
et al.
-ASA-
Wean daily symptom
Wash out *laccbo+ Mean daily symptom scores
*a1 *so
1.8 1.7
ct: A. P. Conblned Combined
3.0 2.9 2.8
chest nasal
m 0
HGsb -ASA-
out -Placebo-,
*s7 2.6 2.5 2.4 2.3 2.2 2.1
L
1.8 Mean daily prednirone dosagc(mg.)
Months &Lad nasal symptoms) r=
6 _ 1 1
234567 Montbr
FIG. 7. Mean FIG. 5. Combined vertical
axis
for
nasal symptom scores are recorded each of 7 mo of study. p = 0.05.
on
Wash out +PIaccbo+
I-ASA1.71 Mean daily symptom scores
l-8 , 5 * 1.4 1.3 I!!
h
1 2 Months
Score
(Combined chest symptoms) P= N.S. FIG. 6. Combined the
vertical
axis
for
chest symptom each of 7 mo
scores are recorded of study, p = N.S.
on
prednisone consumption was more or less during these phases. An example of data from one patient illustrating these points is presented in the form of a bar graph (Fig. 7). In Table IV, the results are recorded. Group I consists of patients who experienced improvement in their rhinitis symptoms without change in their asthma symptoms. Gf these six patients, two were not taking prednisone, three took the same dosage, and one took less prednisone during ASA-treatment phase. In Group II, two patients re-
combined nasal and chest symptom scores for patient A. P. for each of 7 mo of study are demonstrated in fop panel. Corresponding mean daily prednisone dosages are demonstrated in bottom panel.
ported improvement in asthma symptoms and took less prednisone. In Group III, eight patients reported improvement in both rhinitis and asthma symptoms. Two were not taking prednisone, one was taking the same amount, and five were taking less. In Group IV, four patients had unknown responses to ASA treatment . Although the tirst patient reported improvement in both rhinitis and asthmatic symptoms, she took more prednisone during the ASA-treatment phase. The same can be said for the next two patients who reported improvement in nasal symptoms but took more prednisone. The last patient reported worsening of both rhinitis and asthmatic symptoms during ASA treatment but had reduced prednisone therapy at the same time. In Group V, three patients experienced worsening of both rhinitis and asthmatic symptoms during ASA-treatment phase, and two of these patients took more prednisone concurrently. Two patients experienced more nasal symptoms without asthmatic symptoms: one patient took the same amount of prednisone , and the other patient took more prednisone . In Table V, those patients who experienced improvement in rhinitis, asthma, or both are analyzed with respect to whether they took ASA 325 mg/q.d., 325 mg/q.i.d., or 650 mg/q.i.d. On a percent basis, improvement occurred as follows: 325 mg/q.d. (57%), 325 mg/q.i.d. (600/o), and 650 mg/q.i.d. (6%). Al-
VOLUME 73 NUMBER 4
TABLE
IV.
Responses
Improved
Aspirin-sensitive Differences
Group
Worsened Total
Total
I II
Unknown
in symptom
No. of patients
6 2 8
and prednisone
%
4
2
1
24 8 32 4 8 4
5
3 2 25
12 8 100
16
III IV
V
scores
1
dosages
Symptom (placebo/ASA
scofes phase)
Rhinitis
Asthma
+
0 + + + -
- or 0 + + + -
rhinosinusitis
asthma
565
for 25 patients Change in prednisone dosage (during ASA phase) Not taking prednisone
same
less
3 1 -
1 2 5 -
2 2 -
L 5
3
1 2 2 1 6
1 9
1 0
more
+ = placebo scores > ASA scores; 0 = placebo scores = ASA scores; - = placebo scores < ASA scores.
though there was a trend suggesting greater improvement with larger dosages of ASA, &i-square analysis found the differences not to be significant. DlSCUSSloiu This study demonstrates that ASA treatment of ASA-desensitized patients with combined rhinosinusitis/asthrna is associated with significant improvement in upper airway symptoms but ,not in lower airway symptoms. Furthermore, as a group, these 25 patients were able to significantly reduce their use of nasal beclomethasone . Other medications, including prednisone, were not significantly less (or more) during the ASA-treatment phase. As shown in Table IV, there was heterogeneity in this population of patients with respect to their response to treatment with ASA. In Table IV, 16 patients (76%) experienced less severe symptoms of either rhirtitis alone, asthma alone, or both. Of the 12 patients receiving prednisone therapy, four took the same amount of prednisone, and eight took less prednisone during ASA treatment, suggesting decreased severity of their disease. It is interesting and probably significant that most, 14 of the 21 patients (67%) who could be analyzed for improvement in nasal symptoms enjoyed improvement while they were taking ASA. This percent improvement is similar to that previously reported by Lumry et al7 for the treatment with ASA of ASA-sensitive rhinosinusitis (without asthma) in an open study. In our results 10 of the 21 patients (48%) experienced fewer asthma symptoms during their treatment phase with ASA. For the group as a whole, a 50150 improved or worsened ratio indicates that ASA treatment had no effect. However, we continue to be im-
TABLE
V.
improved
ASA-sensitive responders
rhinosinusitislasthma (16 patients) Tablets
Improvement
Rhinitis Asthma Both Total Responders/total %
1 tab.
of AM/placebo
per
day
4 tab.
8 tab.
Total
2 2 - 5 9 9/13 69
6 2 8
2
2
0
0
- 2 4 4/l 57
- 1 3 315 60
P = N.S.
pressed by the clinical courses of a subset of these patients. For instance, one patient whose symptoms were only asthmatic, took ASA during Phase I in which she became asymptomatic and discontinued prednisone. During washout and Phase II (placebo therapy), she again had significant asthma symptoms and restarted prednisone therapy 10 to 20 mg/day. When the code was broken at the end of the study, she elected to return, undergo redesensitization, and has now enjoyed 2% asymptomatic yr while she was taking one aspirin (Ascriptin; William H. Rorer, Inc.) tablet twice a day as her only medication. The results in Table V suggest that the greater the dosage of ASA treatment up to eight tablets per day, the higher the number of patients who improved. However, chi-square statistical analysis does not support a significant difference in response relative to
dosage of ASA treatment. Nevertheless, the populations are small, and there is a suggestion of a doseresponse relationship. Since the eight ASA per day treatment group has nine responders and only four
505
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et al.
nonresponders and the 1 ASA per day treatment group has four responders and three nonresponders or unknowns, it is logical to deduce that some of the nonresponders in the smaller dosage groups might have received a dose insufficient to treat their underlying disease. In clinical practice, we have been increasing the dosage of ASA up to eight tablets per day when nasal congestion persisted during treatment with smaller dosages of ASA, and we have observed improvement after such changes. In this study, Figs. 2 to 4 suggest that a partial escape of drug effect occurred in the third month of ASA treatment. Study design did not allow us to increase the dosage of ASA in the third month. However, increasing symptoms in the third month of ASA treatment occurred regularly when dosages of one or four study drugs (ASA) were used. By comparison, only one of nine responders consuming eight tablets per day appeared to “escape” in the third month of ASA treatment. Further evaluation of dose response to ASA is appropriate. Of the 38 patients who started the study, 13 dropped out. Three patients experienced symptoms of gastritis while they were taking ASA and discontinued their study tablets. In those patients experiencing an increase in either nasal or asthma symptoms, either the ASA treatment, underlying disease, or another provoking factor was responsible for their increasing symptoms. There is a tendency to assume that a tablet is causing one’s problem, even when another provoking factor is actually responsible. Nevertheless, these patients elected to discontinue the study even though one was taking placebo tablets. One of three patients with increasing asthma symptoms during the first weeks of Phase I treatment with ASA returned at a later date and underwent ASA desensitization and open treatment of ASA. She has subsequently experienced improvement rather than worsening in her clinical course. Retrospectively, we feel that she probably had a coincidental viral upper respiratory infection just as she was starting Phase I treatment. The uncooperative group contained some patients whose circumstances changed such that they could not return or participate in this relatively complicated study. Except for the three patients with gastrointestinal intolerance to ASA, there is no convincing evidence in the remaining 10 patients that ASA treatment caused any adverse effects. Whether or not the elimination of these 13 patients created a bias in our study could not be controlled and is not known. Further studies will be needed to determine whether or not there is a subset of patients worsened by ASA therapy who are likely to drop out of the type of study which we conducted. Such individuals should be few in number but difficult to identify, since the effects of
J. ALLERGY CLIN. IMMUNOL. APRIL 1984
natural provoking factors are not easily differentiated from a theoretical ASA-provoked adverse effect on nasal or bronchial function. Any explanations for benefit from ASA treatment in these ASA-desensitized patients are only speculative. ASA is an anti-inflammatory drug that prevents formation of cyclooxygenase-dependent prostaglandins. Perhaps a decrease in nasal congestion and a return of a sense of smell are end-organ effects of ASA as an anti-inflammatory drug. Once the original ASA-induced respiratory reaction has passed, ASA may have different or additional effects on arachidonic acid metabolism, particularly inhibition of intrapathway enzymes in the formation or diversion of lipoxygenase products. If ASA treatment is mainly or exclusively directed at the nasal membranes, mechanisms or provoking factors that influence associated asthma might be exceedingly difficult to unravel. For instance, Slavin et al.8 and Friedman and Slaving ‘have demonstrated that ASA-sensitive asthmatic patients have a high prevalence of nasal polyps and purulent sinusitis. After sphenoidethmoidectomy, with or without antral windows, 85% of their patients experienced fewer symptoms of asthma and required less systemic corticosteroids. If this were true in our study population, patients with persisting intraethmoid microabscesses might continue to have asthmatic symptoms, even during ASA treatment, because their secondary sinusitis was never cleared. Operative intervention to extirpate paranasal sinuses was not a part of this study. At the time of entry into the study, abnormal sinus roentgenograms were found in 23 of the 25 patients (92%). Of these, 17 patients (68%) had air fluid levels or complete opacification of the maxillary, ethmoids, and, frequently, sphenoid and frontal sinuses. Therefore, there is a high degree of probability that an uncontrolled variable, purulent sinusitis, was present in some of these patients. It is interesting and perhaps significant that of the five patients who worsened during ASA-treatment phase, all five had opacification or air fluid levels in their sinus radiographs and sheets of polymorphonuclear leukocytes and bacteria in their nasal cytograms. Since this study was completed, three out of five patients have undergone sinus surgery (sphenoidethmoidectomies with or without frontal or maxillary surgery) after which all three experienced marked remissions in their rhinitis and asthmatic symptoms. Two discontinued and one significantly decreased intake of prednisone therapy. The future treatment of rhinosinusitis asthma in ASA-sensitive patients cannot be stated at this time. However, careful evaluation and study of a two-stage treatment plan deserves our consideration. This would
,
VOLUME 73 NUMBER 4
consist of sphenoidethmoidectomy with or without antral or frontal sinus surgery followed by ASA desensitization and daily ASA treatment to prevent recurrence of the inflammatory rhinitis and polyps. Even with this combined approach, the use of other antiasthmatic drugs to block additional asthmagenic pathways not influenced by either presumed sinobronchial reflexes or ASA will continue to be a necessary part of treatment for many of these patients. We acknowledge the invaluable effort of the nurses in the General Clinical Research Center: Kathleen Lee, R.N., Kaye J. Smith, R.N., Dorothy Archer, L.V.N., Marilyn Kneepkens, R.N., Raechel A. Katzin, R.N., Margaret E. Floyd, R.N., Nancy F’uariea, R.N., and Mary Kelly, R.N. We express our appreciation to Shari Brewster for her expert assistance in the preparation of this manuscript and to Aparna Ewing for her advice and assistance with operation of the Clinfo computer system. REFERENCES 1. Widal MF, Abramin P, Lermoyez J: Anaphylaxie et idiosyncrasie. Presse Med 30:189, 1922 2. Zeiss CR, Locky RF: Refractory period to aspirin in a patient with aspirin-induced asthma. J ALLERGY CLIN IMMUNOL 57:440, 1976
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asthma
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3. Bianco S, Robuschi M, Petrini G: Aspirin induced tolerance in aspirin-asthma detected by a new challenge test. IRCS J Med Sci 5:129, 1977 4. Stevenson DD, Simon RA, Mathison DA: Aspirin-sensitive asthma: tolerance to aspirin after positive oral aspirin challenges. J ALLERGY CLIN IMMUNOL 66:82, 1980 5. Pleskow WW, Stevenson DD, Mathison DA, Simon RA, Schatz M, Zeiger RS: Aspirin desensitization in aspirinsensitive asthmatic patients: Clinical manifestations and characterization ofthe refractory period. J ALLERGY CLIN IMMUNOL 6911, 1982 6. Stevenson DD, Pleskow WW, Curd JG, Simon RA, Mathison DA: Desensitization to acetyl salicylic acid (ASA) in ASAsensitive patients with rhinosinusitis/asthma. In Dukor P, Kal10s P, Schlumberger I-ID, West GB, editors: PAR pseudoallergic reactions. Involvement of drugs and chemicals. Basel, 1982, vol 3, S. Karger, pp 133-156 7. Lumry WR , Curd JG , Zeiger RS , Pleskow WW , Stevenson DD: Aspirin sensitive rhinosinusitis: The clinical syndrome and effects of aspirin administration. 3 ALLERGY CLIN IMMUNOL 72:580, 1983 8. Slavin RG, Cannon RB, Friedman WH, Palitang E, Sundaram M: Sinusitis and bronchial asthma. J ALLERGY CLIN IMMUNOL 66:250, 1980 9. Friedman WH, Slavin RG: Sphenoidethmoidectomy: its role in the asthmatic patient. Otolaryngol Head Neck Surg 90:171, 1982
M.D.,
Twenty-jive ASA-sensitive patients with rhinosinusitis asthma underwent oral ASA challenges followed by desensitization to the adverse respiratory effects of ASA. We then compared the eficacy of continuous ASA treatment for their respiratory tract disease to that of a placebo treatment during a double-blind crossover study. For this group of 25 patients, there was significant improvement in nasal symptoms and a reduction in use of nasal beclomethasone during the months when they received ASA treatment. Lower respiratory tract symptoms, values of FEV,, and the use of antiasthmatic medications including prednisone were not significantly changed during ASA treatment. Desensitization to ASA followed by ASA treatment appears to signijcantly alleviate symptoms of rhinosinusitis. However, only half the patients experienced improvement in their asthma symptoms during ASA treatment. (J ALLERGY CLIN hMUNOL
73:500-507, I984 .)
ASA desensitization, the induction of tolerance to ASA by repeated ingestion of ASA, has been carried out successfully in ASA-sensitive rhinosinusitis asthmatic patients. Beginning with the work of Widal et al.,’ and continuing with the reports of Zeiss and Lackey,* Bianco et al.,3 Stevenson et al.,4 Pleskow et a1.,5 and Stevenson et al .,6 the phenomenon of ASA desensitization has been established. Furthermore, once ASA-sensitive patients have been desensitized and are able to ingest 650 mg of ASA without adverse respiratory responses, they can consume many times more ASA without further reactions or loss of the desensitized state.4, 5* g As demonstrated in our previous publications,5* g this state of refractoriness to the adverse effects of From the Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, Calif. and *Department of Allergy and Clinical Immunology, Kaiser Permanente Medical Center, San Diego, Calif. Supported by National Institute of Allergy and Infectious Diseases grants AI-10386 and RR 00833. Publication number 3027BCR from the Research Institute of Scripps Clinic, La Jolla, Calif. Received for publication June 6, 1983. Accepted for publication Nov. 2, 1983. Reprint requests: Donald D. Stevenson, M.D., Division of Allergy and Immunology (206W-A), Scripps Clinic and Research Foundation, 10666 North Torrey Pines Rd., La Jolla, CA 92037.
500
ASA persists for 2 to 5 days after ASA is discontinued. Cross-desensitization using other nonsteroidal anti-inflammatory drugs, has also been achieved.5 We have previously described two patients who underwent ASA desensitization and then long-term treatment with ASA, who reported improvement in their clinical courses.4 However, both patients, despite ASA desensitization and daily ingestion of ASA, continued to experience bronchospasm when they were inhaling standard methacholine solutions in the laboratory or during natural exposures to viral respiratory tract infections in association with purulent sinusitis attacks or when they were exposed to irritants inhaled during smog alerts. To test the hypothesis that ASA desensitization, followed by daily ingestion of ASA, improves the clinical course of rhinosinusitis or asthma in ASAsensitive subjects, a double-blind crossover study comparing ASA to placebo therapy was constructed. The following report presents the results. MATERIAL Patients
AND METHODS
Asthmatic patients with known or suspectedASA sensitivity were selected from the practices of the authors or referred by other specialists. All patients were admitted to the GCRC, Scripps Clinic
Aspirin-sensitive
VOLUME 73 NUMBER 4
Abbreviations used ASA: Aspirin FEV,: Forced expiratory volume in 1 set GCRC: General Clinical Research Center q.d.: Every day q.i.d.: Four times a day
Admission CCRC Desensitization ASA +1
rhinosinusitis
asthma
501
Admission CCIC Desensitization ASA +2
Months:
and Research Foundation. Informed consent for procedures approved by the Human Subjects Committee was obtained. Standard historical information was collected, including their age, sex, duration of rhinitis and asthma, previous polypectomy , or sinus surgery. Previous history of ASAsensitivity reactions was noted. The medications taken by each patient at the point of entry into the study was recorded.
Laboratory
tests
Complete blood counts, nasal cytogram, sinus radiographs, flow/volume spirometry, and cutaneous tests for immediate hypersensitivity to extracts of common aeroallergens were obtained. Recording serial changes in values of FEV, demonstrated patients who had asthma. A 20% or more increase in FEV, values after inhalation of a bronchodilator or a 20% or more decrease in FEV, values after inhalation of gradually increasing dosages of methacholine up to five inhalations of 25 mglml was considered diagnostic of reversible obstructive airway disease.
Oral challenges On day 1, single-blind placebo challenges were conducted beginning in the morning. Baseline FEV, values were recorded before and at hourly intervals after ingesting identical opaque capsules containing lactose. On day 2, single-blind oral challenges with ASA were initiated as described in a previous publication.5 Incrementally increasing dosages of aspirin, beginning with 3 or 30 mg and thereafter 60, 100, 150, 325, and 650 mg were administered at 2- or 3-hr intervals while patient’s symptoms were being monitored, eyes, noses, chests were being examined, and flow/ volume spirometry at intervals of 1 hr or less was being recorded. Respiratory responses were observed and categorized. The only patients admitted to this study were those patients who developed a bronchospastic reaction to ASA, with FEV, values declining 25% or more from baseline, and with FEV, values during placebo challenges changing <15%. Concordant nasal and ocular symptoms and signs were noted. All these patients then underwent ASA desensitization.6 After the patients reacted to an administered dosage of ASA, recovery occurred within 2 to 24 hr. The same provoking dosage of ASA was given repeatedly at intervals of 3 to 24 hr until reactions disappeared. Thereafter, increasing dosages of ASA were administered until the patient could ingest 650 mg of ASA without adverse effect.
Double-blind
crossover
study design
All volunteers who experienced a positive bronchospastic response to ASA were desensitized to ASA. They were
*Study
drug:
ASA
or Placebo
FIG. 1. Design of double-blind crossover study is illustrated. Admission to GCRC with ASA challenge and desensitization occurs before months 1 and 5. Study drug of Phase I is crossed over in Phase II (aspirin (Ascriptin; William H. Rorer, Inc.) versus placebo therapy).
admitted to the treatment phases of the study if they were willing to participate and if they were available for followup evaluations and repeat ASA desensitization. Ascriptin tablets (ASA 325 mg and Maalox 150 mg) and identical Ascriptin placebo tablets (Maalox 475 mg) were supplied by William H. Rorer, Inc. The treatment period consisted of two separate 3-month treatment phases, separated by a l-month washout period (Fig. 1). During the first 3 mo of the study, patients ingested daily dosages of either one, four, or eight study tablets in divided dosages. During the fourth month (washout period) study pills were discontinued. At the end of the washout period, the patients were readmitted to the GCRC and underwent another ASA challenge and desensitization. Study pills were then restarted but “crossed over” to the opposite drug for the last 3 mo of the study. A Scripps Clinic pharmacist assigned either Ascriptin placebo or Ascriptin to each patient at entry into the study by use of a random number system. The dosages (one, four, or eight tablets per day) were chosen by the investigator. Confidential records of dispensed Ascriptin and Ascriptin placebo were kept in the pharmacy, and the codes were broken only after the study was completed. The following information was recorded each day by all patients: degree (1 = no symptoms through 5 = severe symptoms) of rhinorrhea, nasal congestion, postnasal drainage, sinus pain, sense of smell, chest tightness, wheezing, coughing, shortness of breath, and chest congestion. Daily medications consumed, including study pills, were recorded. However, prednisone and beclomethasone were preferentially reduced if improved symptoms warranted such action. Dosages of other medications were not changed during the 7-month study. With few exceptions, patients were examined monthly, and FEV, values were recorded at that time. All data were entered into CLINFO (Scripps CLINFO GCRC, La Jolla, Calif.) computer. Graphs were generated by CLINFO with ASA treatments to left and placebo therapy treatment to the right, even though half the time ASA treatment followed placebo treatment in Phase II. Statistical studies were carried out by use of the CLINFO computer and included one-tailed student’s t test, linear regression analysis, and chi square.
502
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TABLE I. Consumption of entry
J. ALLERGY CLIN. IMMUNOL. APRIL 1994
et al.
into the study
of medications (25 patients)
at the time
No. Medication
Mean dosage per day
patients
Prednisone (q.d.) Prednisone (q.o.d.) Oral beclomethasone Nasal beclomethasone Theophylline Oral beta agonists Antihistamine/decongestant Antibiotics Cromolyn sodium
20 mg 9 mg* 361 pug 188 m 656 mg 19 mg 4 tablet -
8 8 14 12 19 6 13 1 0
*q.o.d. = 18 mg. TABLE II. Results of ASA challenges desensitization (25 patients)
and
Range
PEV, decline (%) ASA cumulative dosage (mg) to produce first reaction No. of challenges to produce desensitized state
Mean
25 30
78 1083
1
15
38 364 2.2
RESULTS
Between 1979 and 1982,91 patients with suspected ASA sensitivity underwent oral ASA challenges in the Scripps Clinic GCRC, and 54 patients (60%) experienced respiratory reactions. Of these 54 patients, 6 (11%) experienced pure nasoocular reactions without associated bronchospasm, and 48 patients (89%) experienced bronchospasm with FEV, values declining by 25% or more from baseline values. These 48 patients were eligible for entry into the study. However, 10 patients elected not to participate in the study. The remaining 38 patients entered the doubleblind crossover study. Gf these 38 patients, 13 dropped out of the study for the following reasons: three patients experienced gastrointestinal pain (all three were in the ASA phase of study when the code was broken), three patients experienced increased asthma symptoms during the first few weeks of Phase I and elected to stop the study (all three were taking ASA when the code was broken), one patient experienced increased nasal congestion (received placebo therapy), one patient developed uterine bleeding, ‘and her surgeon requested discontinuation of the study to allow hysterectomy (received placebo therapy), and five patients were uncooperative and did not complete or adequately participate in the study for a variety of psychosocial reasons (two received ASA and three received placebo therapy).
TABLE III. Differences between treatment
in mean symptom scores 3 mo of placebo and 3 mo of ASA
Symptom mean
diary score
Running nose Nasal congestion Postnasal discharge Sinus pain Sense of smell All nasal symptoms Chest tightness Wheezing Coughing Shortness of breath Chest congestion All chest symptoms Nasal beclomethasone Prednisone
Differences IplacebolASA)
T test
N - 25
N - 25
0.056 0.248 0.041 0.152 0.310 0.161 -0.149 -0.106 -0.005 -0.117 0.043 -0.067 0.411 -0.044
N.S. 0.032 N.S. 0.005 0.057 0.031 N.S. N.S. N.S. N.S. N.S. N.S. 0.030 N.S.
Analysis of all other medications, listed in Table I, did not show any significant changes.
Twenty-five patients completed the 7-month double-blind crossover study. There were eight male and 17 female patients. Their mean age was 45 yr, ranging from 18 to 71 yr. The mean duration of their respiratory tract disease was 15 yr. Twenty patients (80%) had nasal polyps, and 18 patients (72%) had undergone sinus-drainage surgery in the past. Table I lists the medications consumed by these 25 patients at the time of entry into the study and also lists the number of patients receiving each medication and the mean daily dosages. Laboratory
studies
Eosinophils were found on nasal cytograms of 18 patients (72%). Sinus radiographs were abnormal for 23 (92%) of the patients and with mucoperiosteal thickening in eight and complete opacification or airfluid levels in 17 patients. Cutaneous tests for immediate hypersensitivity were carried out in 14 of the 25 patients. Positive wheal-and-flare responses were recorded for extracts of pollen in 10 of the 14 patients (71%), danders/mite in nine of the 14 patients (64%), and fungi in three of the 11 patients (28%). Oral challenges
Placebo challenges were conducted in all 25 patients, and FEV, values varied between 0% and 15% from baseline. Nasal or ocular symptoms and signs did not occur during or after oral placebo challenges. Table II depicts the percent decrease in FEV, values after ASA ingestion and the cumulative dosages of ASA required to induce the first bronchospastic
VOLUME 73 NUMBER 4
Aspirin-sensitive
wash
~s~----,out
rhinosinusitis
asthma
503
out -Plrccbc I--ASA---’ wash
*Placebo+
I
t
3.9 Mean
2.o
daily symptom scores
‘sQ 1.8.
Mean
3.8 i
dally rymptom scoccs
3-7
1.7.
3.6 3.s
1.8 -
3.4
1.5.
3.3 2
4
3
Months
6
Score =
1.8
symptom of 7 mo
7.
scores of study.
‘a5
dally symptom scores
‘a4 1.3 1.2 1.1
1
2
3
Months
FIG. 3. Nasal symptom scores corded on vertical axis for each
Score D (Sinus pain) P e 0.05 for sinus pain of 7 mo of study.
D are rep = 0.05.
reactions. Of the 25 patients, 23 experienced nasoocular symptoms and signs at the time of the bronchospastic reaction. The total number of ASA challenges before desensitization to ASA was completed ranged from one to 15 with a mean of 2.2. Differences in mean symptom (placebo-ASA phases)
5 Months
FIG. 4. Nasal recorded on p = 0.057.
1
Mean
3.1
8 are recorded p = 0.05.
Wash out-Placebo+
--ASA-
3.2
B ;;;3cstion) .
(:asi FIG. 2. Nasal congestion on vertical axis for each
8
scores
In Table III are the results of analyzing the symptoms of 25 patients during 3 mo of ASA versus placebo therapy treatment. Differences between ASA and placebo therapy symptom scores were known to vary either in a positive or negative direction. One-
symptom vertical
scores axis for
Score $ey8 =
8
1’
E $;mcll) .
for sense of smell each of 7 mo of
E are study.
tailed student’s t test demonstrated significant differences in a positive direction (improved) for individual and combined nasal symptom scores (N = 25). The mean use of nasal beclomethasone (milligrams per day) and prednisone (milligrams per day) are also presented and demonstrate a significant reduction in use of beclomethasone . The subgroups receiving one, four, or eight study tablets per day were too small for analysis by this method. Although not depicted, the differences in other medications consumed during ASA versus placebo treatment phases were also subjected to statistical analysis by the one-tailed t test, and the null hypothesis could not be rejected. In Figs. 2, 3,4, and 5 are the mean daily symptom scores of the 25 patients for four different nasal symptoms by use of a bar graph display. Significant differences are noted for individual and combined nasal symptom scores. In Fig. 6 chest scores were not significantly different. Linear regression analysis (medication dosage versus symptom scores) was calculated by use of x = prednisone or beclomethasone dosages and y = mean symptom scores. There was no significant correlation. In assessing the effects of ASA versus placebo treatment on individual patients, we subtracted the mean scores of accumulated symptoms during 3 mo of ASA treatment from those during 3 mo of placebo treatment and determined whether or not concomitant
564
Stevenson
J. ALLERGY CLIN. IMMUNOL. APRIL 1984
et al.
-ASA-
Wean daily symptom
Wash out *laccbo+ Mean daily symptom scores
*a1 *so
1.8 1.7
ct: A. P. Conblned Combined
3.0 2.9 2.8
chest nasal
m 0
HGsb -ASA-
out -Placebo-,
*s7 2.6 2.5 2.4 2.3 2.2 2.1
L
1.8 Mean daily prednirone dosagc(mg.)
Months &Lad nasal symptoms) r=
6 _ 1 1
234567 Montbr
FIG. 7. Mean FIG. 5. Combined vertical
axis
for
nasal symptom scores are recorded each of 7 mo of study. p = 0.05.
on
Wash out +PIaccbo+
I-ASA1.71 Mean daily symptom scores
l-8 , 5 * 1.4 1.3 I!!
h
1 2 Months
Score
(Combined chest symptoms) P= N.S. FIG. 6. Combined the
vertical
axis
for
chest symptom each of 7 mo
scores are recorded of study, p = N.S.
on
prednisone consumption was more or less during these phases. An example of data from one patient illustrating these points is presented in the form of a bar graph (Fig. 7). In Table IV, the results are recorded. Group I consists of patients who experienced improvement in their rhinitis symptoms without change in their asthma symptoms. Gf these six patients, two were not taking prednisone, three took the same dosage, and one took less prednisone during ASA-treatment phase. In Group II, two patients re-
combined nasal and chest symptom scores for patient A. P. for each of 7 mo of study are demonstrated in fop panel. Corresponding mean daily prednisone dosages are demonstrated in bottom panel.
ported improvement in asthma symptoms and took less prednisone. In Group III, eight patients reported improvement in both rhinitis and asthma symptoms. Two were not taking prednisone, one was taking the same amount, and five were taking less. In Group IV, four patients had unknown responses to ASA treatment . Although the tirst patient reported improvement in both rhinitis and asthmatic symptoms, she took more prednisone during the ASA-treatment phase. The same can be said for the next two patients who reported improvement in nasal symptoms but took more prednisone. The last patient reported worsening of both rhinitis and asthmatic symptoms during ASA treatment but had reduced prednisone therapy at the same time. In Group V, three patients experienced worsening of both rhinitis and asthmatic symptoms during ASA-treatment phase, and two of these patients took more prednisone concurrently. Two patients experienced more nasal symptoms without asthmatic symptoms: one patient took the same amount of prednisone , and the other patient took more prednisone . In Table V, those patients who experienced improvement in rhinitis, asthma, or both are analyzed with respect to whether they took ASA 325 mg/q.d., 325 mg/q.i.d., or 650 mg/q.i.d. On a percent basis, improvement occurred as follows: 325 mg/q.d. (57%), 325 mg/q.i.d. (600/o), and 650 mg/q.i.d. (6%). Al-
VOLUME 73 NUMBER 4
TABLE
IV.
Responses
Improved
Aspirin-sensitive Differences
Group
Worsened Total
Total
I II
Unknown
in symptom
No. of patients
6 2 8
and prednisone
%
4
2
1
24 8 32 4 8 4
5
3 2 25
12 8 100
16
III IV
V
scores
1
dosages
Symptom (placebo/ASA
scofes phase)
Rhinitis
Asthma
+
0 + + + -
- or 0 + + + -
rhinosinusitis
asthma
565
for 25 patients Change in prednisone dosage (during ASA phase) Not taking prednisone
same
less
3 1 -
1 2 5 -
2 2 -
L 5
3
1 2 2 1 6
1 9
1 0
more
+ = placebo scores > ASA scores; 0 = placebo scores = ASA scores; - = placebo scores < ASA scores.
though there was a trend suggesting greater improvement with larger dosages of ASA, &i-square analysis found the differences not to be significant. DlSCUSSloiu This study demonstrates that ASA treatment of ASA-desensitized patients with combined rhinosinusitis/asthrna is associated with significant improvement in upper airway symptoms but ,not in lower airway symptoms. Furthermore, as a group, these 25 patients were able to significantly reduce their use of nasal beclomethasone . Other medications, including prednisone, were not significantly less (or more) during the ASA-treatment phase. As shown in Table IV, there was heterogeneity in this population of patients with respect to their response to treatment with ASA. In Table IV, 16 patients (76%) experienced less severe symptoms of either rhirtitis alone, asthma alone, or both. Of the 12 patients receiving prednisone therapy, four took the same amount of prednisone, and eight took less prednisone during ASA treatment, suggesting decreased severity of their disease. It is interesting and probably significant that most, 14 of the 21 patients (67%) who could be analyzed for improvement in nasal symptoms enjoyed improvement while they were taking ASA. This percent improvement is similar to that previously reported by Lumry et al7 for the treatment with ASA of ASA-sensitive rhinosinusitis (without asthma) in an open study. In our results 10 of the 21 patients (48%) experienced fewer asthma symptoms during their treatment phase with ASA. For the group as a whole, a 50150 improved or worsened ratio indicates that ASA treatment had no effect. However, we continue to be im-
TABLE
V.
improved
ASA-sensitive responders
rhinosinusitislasthma (16 patients) Tablets
Improvement
Rhinitis Asthma Both Total Responders/total %
1 tab.
of AM/placebo
per
day
4 tab.
8 tab.
Total
2 2 - 5 9 9/13 69
6 2 8
2
2
0
0
- 2 4 4/l 57
- 1 3 315 60
P = N.S.
pressed by the clinical courses of a subset of these patients. For instance, one patient whose symptoms were only asthmatic, took ASA during Phase I in which she became asymptomatic and discontinued prednisone. During washout and Phase II (placebo therapy), she again had significant asthma symptoms and restarted prednisone therapy 10 to 20 mg/day. When the code was broken at the end of the study, she elected to return, undergo redesensitization, and has now enjoyed 2% asymptomatic yr while she was taking one aspirin (Ascriptin; William H. Rorer, Inc.) tablet twice a day as her only medication. The results in Table V suggest that the greater the dosage of ASA treatment up to eight tablets per day, the higher the number of patients who improved. However, chi-square statistical analysis does not support a significant difference in response relative to
dosage of ASA treatment. Nevertheless, the populations are small, and there is a suggestion of a doseresponse relationship. Since the eight ASA per day treatment group has nine responders and only four
505
Stevenson
et al.
nonresponders and the 1 ASA per day treatment group has four responders and three nonresponders or unknowns, it is logical to deduce that some of the nonresponders in the smaller dosage groups might have received a dose insufficient to treat their underlying disease. In clinical practice, we have been increasing the dosage of ASA up to eight tablets per day when nasal congestion persisted during treatment with smaller dosages of ASA, and we have observed improvement after such changes. In this study, Figs. 2 to 4 suggest that a partial escape of drug effect occurred in the third month of ASA treatment. Study design did not allow us to increase the dosage of ASA in the third month. However, increasing symptoms in the third month of ASA treatment occurred regularly when dosages of one or four study drugs (ASA) were used. By comparison, only one of nine responders consuming eight tablets per day appeared to “escape” in the third month of ASA treatment. Further evaluation of dose response to ASA is appropriate. Of the 38 patients who started the study, 13 dropped out. Three patients experienced symptoms of gastritis while they were taking ASA and discontinued their study tablets. In those patients experiencing an increase in either nasal or asthma symptoms, either the ASA treatment, underlying disease, or another provoking factor was responsible for their increasing symptoms. There is a tendency to assume that a tablet is causing one’s problem, even when another provoking factor is actually responsible. Nevertheless, these patients elected to discontinue the study even though one was taking placebo tablets. One of three patients with increasing asthma symptoms during the first weeks of Phase I treatment with ASA returned at a later date and underwent ASA desensitization and open treatment of ASA. She has subsequently experienced improvement rather than worsening in her clinical course. Retrospectively, we feel that she probably had a coincidental viral upper respiratory infection just as she was starting Phase I treatment. The uncooperative group contained some patients whose circumstances changed such that they could not return or participate in this relatively complicated study. Except for the three patients with gastrointestinal intolerance to ASA, there is no convincing evidence in the remaining 10 patients that ASA treatment caused any adverse effects. Whether or not the elimination of these 13 patients created a bias in our study could not be controlled and is not known. Further studies will be needed to determine whether or not there is a subset of patients worsened by ASA therapy who are likely to drop out of the type of study which we conducted. Such individuals should be few in number but difficult to identify, since the effects of
J. ALLERGY CLIN. IMMUNOL. APRIL 1984
natural provoking factors are not easily differentiated from a theoretical ASA-provoked adverse effect on nasal or bronchial function. Any explanations for benefit from ASA treatment in these ASA-desensitized patients are only speculative. ASA is an anti-inflammatory drug that prevents formation of cyclooxygenase-dependent prostaglandins. Perhaps a decrease in nasal congestion and a return of a sense of smell are end-organ effects of ASA as an anti-inflammatory drug. Once the original ASA-induced respiratory reaction has passed, ASA may have different or additional effects on arachidonic acid metabolism, particularly inhibition of intrapathway enzymes in the formation or diversion of lipoxygenase products. If ASA treatment is mainly or exclusively directed at the nasal membranes, mechanisms or provoking factors that influence associated asthma might be exceedingly difficult to unravel. For instance, Slavin et al.8 and Friedman and Slaving ‘have demonstrated that ASA-sensitive asthmatic patients have a high prevalence of nasal polyps and purulent sinusitis. After sphenoidethmoidectomy, with or without antral windows, 85% of their patients experienced fewer symptoms of asthma and required less systemic corticosteroids. If this were true in our study population, patients with persisting intraethmoid microabscesses might continue to have asthmatic symptoms, even during ASA treatment, because their secondary sinusitis was never cleared. Operative intervention to extirpate paranasal sinuses was not a part of this study. At the time of entry into the study, abnormal sinus roentgenograms were found in 23 of the 25 patients (92%). Of these, 17 patients (68%) had air fluid levels or complete opacification of the maxillary, ethmoids, and, frequently, sphenoid and frontal sinuses. Therefore, there is a high degree of probability that an uncontrolled variable, purulent sinusitis, was present in some of these patients. It is interesting and perhaps significant that of the five patients who worsened during ASA-treatment phase, all five had opacification or air fluid levels in their sinus radiographs and sheets of polymorphonuclear leukocytes and bacteria in their nasal cytograms. Since this study was completed, three out of five patients have undergone sinus surgery (sphenoidethmoidectomies with or without frontal or maxillary surgery) after which all three experienced marked remissions in their rhinitis and asthmatic symptoms. Two discontinued and one significantly decreased intake of prednisone therapy. The future treatment of rhinosinusitis asthma in ASA-sensitive patients cannot be stated at this time. However, careful evaluation and study of a two-stage treatment plan deserves our consideration. This would
,
VOLUME 73 NUMBER 4
consist of sphenoidethmoidectomy with or without antral or frontal sinus surgery followed by ASA desensitization and daily ASA treatment to prevent recurrence of the inflammatory rhinitis and polyps. Even with this combined approach, the use of other antiasthmatic drugs to block additional asthmagenic pathways not influenced by either presumed sinobronchial reflexes or ASA will continue to be a necessary part of treatment for many of these patients. We acknowledge the invaluable effort of the nurses in the General Clinical Research Center: Kathleen Lee, R.N., Kaye J. Smith, R.N., Dorothy Archer, L.V.N., Marilyn Kneepkens, R.N., Raechel A. Katzin, R.N., Margaret E. Floyd, R.N., Nancy F’uariea, R.N., and Mary Kelly, R.N. We express our appreciation to Shari Brewster for her expert assistance in the preparation of this manuscript and to Aparna Ewing for her advice and assistance with operation of the Clinfo computer system. REFERENCES 1. Widal MF, Abramin P, Lermoyez J: Anaphylaxie et idiosyncrasie. Presse Med 30:189, 1922 2. Zeiss CR, Locky RF: Refractory period to aspirin in a patient with aspirin-induced asthma. J ALLERGY CLIN IMMUNOL 57:440, 1976
Aspirin-sensitive
rhinosinusitis
asthma
507
3. Bianco S, Robuschi M, Petrini G: Aspirin induced tolerance in aspirin-asthma detected by a new challenge test. IRCS J Med Sci 5:129, 1977 4. Stevenson DD, Simon RA, Mathison DA: Aspirin-sensitive asthma: tolerance to aspirin after positive oral aspirin challenges. J ALLERGY CLIN IMMUNOL 66:82, 1980 5. Pleskow WW, Stevenson DD, Mathison DA, Simon RA, Schatz M, Zeiger RS: Aspirin desensitization in aspirinsensitive asthmatic patients: Clinical manifestations and characterization ofthe refractory period. J ALLERGY CLIN IMMUNOL 6911, 1982 6. Stevenson DD, Pleskow WW, Curd JG, Simon RA, Mathison DA: Desensitization to acetyl salicylic acid (ASA) in ASAsensitive patients with rhinosinusitis/asthma. In Dukor P, Kal10s P, Schlumberger I-ID, West GB, editors: PAR pseudoallergic reactions. Involvement of drugs and chemicals. Basel, 1982, vol 3, S. Karger, pp 133-156 7. Lumry WR , Curd JG , Zeiger RS , Pleskow WW , Stevenson DD: Aspirin sensitive rhinosinusitis: The clinical syndrome and effects of aspirin administration. 3 ALLERGY CLIN IMMUNOL 72:580, 1983 8. Slavin RG, Cannon RB, Friedman WH, Palitang E, Sundaram M: Sinusitis and bronchial asthma. J ALLERGY CLIN IMMUNOL 66:250, 1980 9. Friedman WH, Slavin RG: Sphenoidethmoidectomy: its role in the asthmatic patient. Otolaryngol Head Neck Surg 90:171, 1982