Low-dose aspirin desensitization in individuals with aspirin-exacerbated respiratory disease

Authors

  • K. Fruth,

    Corresponding author
    • Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • B. Pogorzelski,

    1. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • I. Schmidtmann,

    1. Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • J. Springer,

    1. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • N. Fennan,

    1. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • N. Fraessdorf,

    1. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • A. Boessert,

    1. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • D. Schaefer,

    1. Medical Clinic III, Friedrich-Alexander-University Erlangen-Nuremberg, Germany
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  • J. Gosepath,

    1. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • W. J. Mann

    1. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • Edited by: Wytske Fokkens

Correspondence

Kai Fruth, Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany.

Tel.: +49-6131/177361

Fax.: +49-6131/176637

E-mail: kai.fruth@unimedizin-mainz.de

Abstract

Background

Nasal polyposis frequently occurs within the clinical picture of aspirin-exacerbated respiratory disease (AERD).

A derailed arachidonic acid metabolism is regarded to be part of the pathophysiology of AERD, and aspirin desensitization is the only causal therapeutic option, so far. The optimal maintenance dose of aspirin desensitization to prevent nasal polyp recurrence on the one hand and to minimize aspirin-related side-effects, on the other hand, is still a matter of debate. The aim of this trial was to investigate the efficacy and safety of a low-dose aspirin desensitization protocol.

Methods

After sinus surgery, 70 individuals with AERD were randomly allocated to a prospective double-blind placebo-controlled aspirin desensitization protocol with a maintenance dose of 100 mg daily. The primary outcome was polyp relapse after 36 months. Nasal endoscopy status, quality of life, and patients' symptom score as well as aspirin-related side-effects were monitored.

Results

Due to the high dropout rate, only 31 individuals were evaluated. After 36 months, nasal polyp relapse was less frequent (P = 0.0785) and the polyposis score was lower (P = 0.0702) in the therapy group. Quality of life obviously improved (P = 0.0324), clinical complaints (P = 0.0083) were significantly reduced, and no severe aspirin-related side-effects were observed.

Conclusion

Aspirin desensitization with a maintenance dose of 100 mg daily has a positive impact on nasal polyp relapse and seems to be a safe and suitable therapy to improve clinical complaints and the quality of life of individuals with AERD.

Chronic rhinosinusitis (CRS) is frequently associated with recurrent nasal polyps, intrinsic bronchial asthma, and nonsteroidal anti-inflammatory drugs (NSAIDs) triggered hypersensitivity, known as Samter's triad or aspirin-exacerbated respiratory disease (AERD) [1-3]. Individuals with AERD are thought to be characterized by genetic polymorphisms that lead to a reduced activity of the constitutively expressed cyclooxygenase 1 (cox) isoenzyme and by an increased leukotriene receptor affinity. Due to these changes in the arachidonic acid metabolism, the measurable prostaglandin (PG)/leukotrienes (LT) imbalance in these patients has a decisive impact on the inflammatory changes of both the upper and lower airway [4-7].

In addition to drawing the diagnosis from clinical appearance, aspirin challenge is a diagnostic option; however, severe adverse bronchial reactions can occur [8].

The development of the full clinical picture of AERD can take years and can make the diagnosis of AERD challenging, and patients with a less pronounced airway hyperreactivity to aspirin intake might not be diagnosed adequately by aspirin challenge.

Even if AERD is solely partially clinically expressed, the disease defining PG/LT imbalance is already detectable in the early and incomplete stage of AERD by the functional in vitro eicosanoid test (FET) [9-11].

The resulting individualized dynamic eicosanoid pattern of the FET is classified in groups, which represent the severity of the disease and symptoms [11].

In a synopsis of patients' clinical symptoms, FET can be seen as a helpful diagnostic tool to confirm AERD adequately in clinical practice without side-effects.

Several researchers have described diverse adaptive aspirin desensitization protocols and their clinical results and impact on LT and PG release [12, 13]. In 1996, Stevenson et al. [14] could demonstrate the efficacy of aspirin desensitization with a daily aspirin dose of up to 1300 mg; however, severe side-effects were reported.

The most suitable protocol to establish efficacious and well-tolerable desensitization with the lowest possible maintenance dose of oral aspirin remains to be determined. Lee et al. [15] recommend at least an aspirin intake dose of 325 mg twice daily for optimal symptom control, but current reports showed that even aspirin doses of up to 325 mg/day are associated with a considerable risk of gastrointestinal bleedings [16, 17].

For the first time, we investigated in a randomized double-blind placebo-controlled clinical trial whether an adaptive aspirin desensitization with an initial dose of up to 800 mg aspirin for one day followed by a maintenance dose of 100 mg daily is safe, efficacious in preventing nasal polyp recurrence, able to reduce clinical symptoms, and finally able to improve quality of life.

Methods

Seventy individuals (31 women and 39 men, mean age 45 years, SD 11 years) with nasal polyps and AERD underwent sinus surgery in a tertiary medical center between 2006 and 2008. Chronic rhinosinusitis (CRS) was diagnosed by nasal endoscopy and by computer tomography according to the EPOS guidelines [18]. All individuals suffered from recurrent nasal polyps and had undergone previous sinus surgery at least twice. Patients' history was taken with emphasis on clinical symptoms of intrinsic asthma or NSAID-triggered hypersensitivity (anaphylaxis, bronchospasm or urticaria) to confirm whether they meet the criteria of the proposed classification system of AERD [19].

The underlying pathologic eicosanoid profile of AERD was confirmed by the functional in vitro test (LipiDOC-AIT, Erlangen, Germany). The overall imbalance of eicosanoids, termed value of the analgesic intolerance test (AIT value), was assessed by provocation of peripheral blood leukocytes and measurement of eicosanoids (i.e., prostaglandin E2 and peptido-leukotrienes) released in vitro. Patients with an AIT value higher than 0.7 combined with recurrent nasal polyps and with the characteristic clinical symptoms were regarded as individuals suffering from AERD as proposed by Schaefer et al. [20, 21].

All individuals entered voluntarily and gave informed consent as defined in the application to the ethics committee (EudraCT no. 2005-004437-18).

Pregnant women and individuals with hemorrhagic diathesis, chronic gastric or duodenal ulcers, glucose-6-phosphate dehydrogenase deficiency, renal or liver diseases and individuals who took anticoagulant medication were excluded.

Aspirin desensitization

Six weeks after sinus surgery, block randomization was performed by the institutional center of clinical research to allocate patients to the aspirin (36 individuals, 17 women and 19 men, mean age 44.9 years, SD 11.3 years) or to the placebo group (34 individuals, 14 women and 20 men, mean age 45.9 years, SD 10.4 years) and hospitalized for desensitization. On admission, nasal endoscopy was performed to ensure re-epithelialization of the previous surgical field. Forced expiratory volume in 1 s. (FEV1) was measured before the first medication application and repeated 2 h after intake to monitor a deterioration of lung function.

On the first day, a cumulative aspirin dose of 180 mg and on the second of 800 mg was reached. The maintenance dose from the third day on was set to 100 mg daily. Study medication was produced by the institutional pharmacy. Placebo medication consisted of lactose, magnesium stearate, cellulose powder and microcrystalline cellulose.

Follow-up

Examination was performed after 6, 9, 12, 24, and 36 months.

Follow-up assessments

Endoscopic assessment

Nasal endoscopic assessment was classified based on a polyp score from zero (no polyps) to three (polyps obstruct the entire nasal cavity) for each side separately [22, 23]. The maximal possible score was six. A score of one and more was regarded as polyp recurrence.

Sense of smell testing

Sniffin' Sticks® (Burghart, Wedel, Germany) were used to monitor olfactory function [24]. Eight items were presented to each side separately. The mean sum of the correctly identified items of both sides was used for evaluation.

Quality of life

The Rhinosinusitis Disability Index questionnaire modified for German-speaking countries by Maune et al. was used. It consists of 30 questions concerning nasal and paranasal symptoms. Symptom severity was rated on a scale from 1 to 5 (1 = very rare, 2 = rare, 3 = sometimes, 4 = often, 5 = very often [25]); hence, the highest possible score was 150.

Additional questions

Patients were asked three additional questions about ‘overall nasal and paranasal complaints’, ‘quality-of-life impairment by nasal and paranasal complaints’, and ‘general health condition’ during aspirin desensitization. Answers were rated on a scale from 1 to 7: 1 = rare/very good health condition, 4 = average, 7 = serious complaints/very poor health condition.

Symptom score

We used a questionnaire of main and secondary nasal and paranasal symptoms as recommended by American Academy of Otolaryngology [26, 27].

Nasal airway obstruction, postnasal drip, and cephalgia were regarded as main symptoms and rated from 0 for no symptoms to 4 for major complaints.

An impairment of olfactory function was regarded as main symptom as well and was rated from 0 to 4 with respect to the indentified items of the Sniffin' Sticks test. Seven to eight identified items were scored with 0; 5 to 6 identified items were scored with 1; 3 to 4 identified items were scored with 2; 1 to 2 identified items were scored with 3; and 0 identified items were scored with 4.

Secondary symptoms, coughing and sneezing, were rated from 0 = no symptoms to 2 = major complaints.

The sum of the score, which could reach 20 at maximum, was used for evaluation.

The clinical evaluation was carried out by ENT specialists without the knowledge about patients' allocation to aspirin or placebo treatment. The information of patients' allocation was stored in sealed envelopes until the end of the observation period.

Concomitant medication

Besides study medication, the use of inhaled steroids and nasal saline washing was allowed. All individuals took nasal corticosteroids during the study period.

Statistical analysis

Primary outcome was recurrence of nasal polyps, defined as a polyp score of 1 or more. We tested for differences between treatment groups applying Fisher's exact test. Significance level was 5 %. Sample size calculation yielded that with 70 patients a recurrence rate below 10% in the aspirin group could be established at the 5% level with power 80% assuming a base recurrence rate of 40% in the placebo group.

Secondary endpoints were sense of smell, quality of life, and symptom score.

All analyses of secondary endpoints were exploratory; however, associations with P-values ≤ 0.05 might indicate relevant differences.

Scores and ordinal variables were compared using Mann–Whitney U tests. Quantitative variables are described by mean, standard deviation, extrema, median, and quartiles. Categorical variables are described by absolute and relative frequencies. Time to relapse was analyzed using Kaplan–Meier estimates.

Analysis was performed with SAS software, version 9.3 (Cary, NC, USA).

Results

Thirty-one individuals, 18 of the aspirin (11 men and seven women) and 13 of the placebo group (five men and eight women), were evaluated after 36 months. Thirty-nine of 70 patients, 18 of the aspirin and 21 of the placebo group, discontinued aspirin intake over the 3-year period for various reasons but no one due to aspirin-related side-effects (Fig. 1). In eight patients (two of aspirin group, six of placebo group), revision sinus surgery was indicated during the observation period.

Figure 1.

Dropout reasons of the aspirin and the placebo group.

After 36 months, eight in 13 individuals (62%) of the placebo group showed nasal polyp relapse compared with five in 18 individuals (28%) of the aspirin group, but the difference was not significant (P = 0.0785) (Fig. 2). Similarly, Kaplan–Meier analysis showed that definite polyp relapse occurred earlier and more frequently in the placebo group (Fig. 3).

Figure 2.

Nasal polyp relapse after 36-month follow-up. An endoscopic polyp score of one or more was regarded as relapse. More individuals of the placebo group were suffering from nasal polyp relapse compared with the aspirin group (P = 0.0785).

Figure 3.

Time to nasal polyp relapse. All individuals who had not experienced a definite relapse were at risk. Individuals who left the study were censored.

A trend indicated that aspirin desensitization might be helpful to reduce nasal polyp recurrence. Nasal polyposis score showed a lower median sum in the therapy group (therapy group: median = 0; placebo group: median = 2; P = 0.0702) (Table 1). The median score of the Sniffin' Sticks identification score in the aspirin group was 5 compared with 1 in the placebo group, indicating a slight improvement in the aspirin group and less inflammation at the olfactory region (P = 0.3191). Comparing the differences in the Sniffin' Sticks identification score before sinus surgery and after 36 month of desensitization, we found a more pronounced improvement in the sense of smell in the aspirin group (P = 0.0748) (Table 1).

Table 1. Absolute values and P-values of the follow-up assessments after 36 month.
 GroupNMinimumLower quartileMedianMeanUpper quartileMaximumP-value
  1. P-values ≤ 0.05 are printed in bold; P, placebo; A, aspirin

Polyposis scoreP130.00.02.02.24.06.00.0702
A180.00.00.00.91.06.0
Sniffing scoreP130.00.01.02.56.08.00.3191
A180.00.55.03.87.08.0
Difference, sniffing score after 36 month compared with presurgeryP13−2.5−1.00.50.21.01.50.0748
A15−1.50.01.51.93.55.5
Quality-of-life scoreP1242.048.568.668.784.5101.8 0.0324
A1830.040.046.051.155.090.0
Intensity of overall nasal and paranasal complaintsP122.03.54.04.35.56.0 0.0019
A181.02.02.52.43.05.0
Quality-of-life impairment by nasal and paranasal complaintsP121.03.54.04.05.07.0 0.0083
A181.01.02.52.43.06.0
General health conditionP122.02.03.03.34.06.0 0.0290
A180.01.02.02.23.05.0
Symptom scoreP127.09.011.010.812.813.0 <0.0001
A170.03.05.05.27.09.5

Aspirin desensitization improved the quality of life with respect to nasal and paranasal complaints. The achieved score of the 30-item quality-of-life questionnaire was considerably lower in individuals who had taken aspirin (aspirin group: median = 46.0; placebo group: median = 68.6, P = 0.0324) (Fig. 4, Table 1).

Figure 4.

Results of the quality-of-life questionnaire after 36 months. The individuals of the aspirin group reported less complaints compared with individuals of the placebo group (P = 0.0324) ( = outliers). The horizontal line in the middle of each box indicates the median, while the top and bottom borders of the box mark the 75th and 25 percentiles, respectively. The whiskers above and below the box mark the maximum and minimum.

Additionally, the evaluation of the questions regarding ‘overall nasal and paranasal complaints’,quality-of-life impairment by nasal and paranasal complaints’, and ‘evaluation of the general health condition’ reflects the positive effect of aspirin desensitization with less nasal complaints and a milder life impairment due to nasal and paranasal complaints in the aspirin group. The score of ‘overall nasal and paranasal complaints’ was lower in the aspirin group (P = 0.0019), and the evaluation of ‘quality-of-life impairment by nasal and paranasal complaints’ showed less impairment in the aspirin group (P = 0.0083). Finally, ‘evaluation of the general health condition’ indicated an improvement in the general health condition in the therapy group (P = 0.0290) (Fig. 5a, b, c, Table 1).

Figure 5.

Evaluation of three questions regarding the well-being after 36 months of aspirin desensitization. The three questions were rated to a scale from 1 to 7: 1 = rare/very good health condition, 4 = average, 7 = serious complaints/very poor health condition. a) Evaluation of ‘overall nasal and paranasal complaints’. The individuals of the aspirin group reported less nasal and paranasal complaints compared with individuals of the placebo group (P = 0.0019) (= outliers). b) Evaluation of ‘quality of life impairment by nasal and paranasal complaints’.The individuals of the aspirin group reported a reduced quality-of-life impairment by nasal and paranasal complaints compared with individuals of the placebo group (P = 0.0083) (○ = outliers). c) Evaluation of ‘validation of the general health condition’. The individuals of the aspirin group reported a better general health condition compared with individuals of the placebo group (P = 0.029) ( = outliers). Graph elements are explained in the legend to Figure 4.

Aspirin desensitization contributed to a reduction in major symptoms such as nasal airway obstruction, postnasal drip, cephalgia, impairment of olfactory function, all signs of upper airway mucosal inflammation, and secondary nasal symptoms such as coughing and sneezing, indicated by an obvious reduction in the median symptom score of 5 in the aspirin group after 36 months compared with the score of 11 in the placebo group (P < 0.0001) (Table 1).

Discussion

The efficacy of aspirin desensitization in patients with AERD has been previously described with varying maintenance doses up to 1.3 g aspirin daily [14, 15]. Stevenson et al. [14] observed a significant reduction in sinus infections, necessary revision surgery per year, and a reduction in nasal corticosteroids doses during high-dose aspirin desensitization. However, severe aspirin-related side-effects such as gastric bleeding and gastric pain were observed as well. High-dose aspirin desensitization protocols hint at the incidence of side-effects such as reported by Stevenson et al. as well as the possibility of impaired renal function, nausea, blood disorders, and the risk of life-threatening asthma attacks during aspirin desensitization, affecting patients' compliance [14, 28]. These concerns led us to the prospectively evaluated desensitization protocol with 100 mg daily orally as suggested by Gosepath et al. [1] who observed a positive impact on recurrence rate of nasal polyps. In contrast to this study, we now analyzed for the first time the efficacy of low-dose aspirin desensitization in a double-blind and placebo-controlled clinical trial.

Reasons for noncompliance were manifold but similar in the placebo and aspirin group. Merely, the dropout rate due to ‘other diseases’ occurring during the trial, such as heart attacks, which required a permanent aspirin intake, was higher in the placebo compared with the aspirin group. Sex, age, quality of life, number of previous sinus surgeries, and the allocation to the aspirin or placebo group had no predictive value, no matter whether a patient completed the study or not. No one in our cohort experienced side-effects such as gastric bleeding or dropped out due to other aspirin-related side-effects.

The unawareness of ENT specialists in private practices that a short interruption of medication intake would not affect a possible long-term clinical benefit was one other reason leading to dropouts. This fact implies the necessity for a closer cooperation of all physicians who are involved in patients' treatment to guarantee a successful desensitization.

We observed a tendency toward a reduction in nasal polyp recurrence and nasal polyp extent, and an improvement in patients' nasal and paranasal symptoms as well as an improvement in quality of life.

One reason that our results showed solely a tendency but no significant reduction in nasal polyp recurrence in the aspirin group might be the high dropout rate, but another possibility might as well be the low-maintenance aspirin dose of 100 mg daily. Data known from literature are manifold and contradictory. Rozsasi et al. [29] postulated 100 mg aspirin daily not to be efficacious and recommended a maintenance dose of 300 mg daily to reduce nasal polyp recurrence and to improve sense of smell, whereas Gosepath et al. [1] could demonstrate an obvious reduction in nasal polyp recurrence, an improvement in the sense of smell with a maintenance aspirin dose of 100 mg daily. The hypothesis of a potentially better clinical benefit of 300 mg aspirin compared with 100 mg should be evaluated with a double-blind prospective dose-finding protocol as the interpretation of previously reported data is limited by the open study design [29] and should include numerous individuals as, in light of previous experience, a high dropout rate can be expected.

Furthermore, as all patients, no matter whether they were included in the aspirin or placebo group, took nasal corticosteroids, the clinical differences between the two groups resulting from aspirin desensitization might be partially levelled out by the well-known anti-inflammatory effect of topical nasal steroids.

Conclusions

Besides topical nasal steroids, low-dose aspirin desensitization with 100 mg daily might be regarded as a helpful additional therapeutic postoperative option as our data demonstrate an improvement in quality of life, a reduction in CRS-related symptoms, and a tendency to reduce nasal polyp relapse and extend.

Acknowledgments

We are gratefully indebted to Mr. Felix Jost for his statistical expertise and to Mr. Gerson Samosny, Mrs. Melanie Kaiser and Mrs. Jenny Tandel for their excellent support regarding data processing. Finally, we would like to thank Mrs. Vanessa Augello and Mrs. Dr. Annette Affolter for their help in preparing this manuscript. Supported by the research program of the University of Mainz, Germany (MAIFOR).

Author contributions

All named authors contributed to the work.

Conflict of interest

There is no conflict of interest to declare.

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