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Oral desensitization to aspirin (see 1999 International Symposium pre-announcement) see 1998 symposium at eicosanoids98.html (see 1996 symposium at eicosanoids.html ) The general rules concerning treatment of AIA do not differ from the published guidelines on management of asthma. There are, however, two important differences. First, in order to prevent life threatening reactions, AIA patients should avoid aspirin and all analgesics that inhibit cyclooxygenase. Second, they may be subjected to aspirin desensitization treatment. Here we present opinions of world experts on aspirin desensitization. Dr Donald D. Stevenson discusses oral desensitization, while Drs. Giampiero Patriarca and Michael Schmitz present alternative approaches, using intrabronchial and intranasal routes. European Network on Aspirin-Induced-Asthma (AIANE) Newsletter July '99 Table of content Oral desensitization to aspirin  Donald D. Stevenson, M.D. Introduction Oral challenges to induce ASA desensitization ASA cross-sensitivity and desensitization Treatment with ASA after ASA desensitization Pathogenesis of ASA desensitization Desensitization to aspirin by nasal route  G. Patriarca, E. Nucera, D. Schiavino, M. Del Ninno, A. Buonomo, C. Misuraca, Sun Jingyu Aspirin desensitization by inhalation route   M. Schmitz-Schumann MD, FCCP

Introduction

Since IgE-mediated mechanisms have not been established as being responsible for ASA induced respiratory reactions and are considered by most investigators to be unlikely perpetrators of this disease or ASA induced reactions ^{[1] [2]}  desensitization is used here in its broadest sense and refers to reducing the reactions to ASA by repeated and increasing exposure to ASA until all reactions cease ^[3].

In 1922, Widal et al. published the first report of successful aspirin desensitization ^[4]. In a patient previously shown to react to ASA with a documented respiratory reaction, the authors administered small and then increasing daily doses of ASA until their patient could tolerate full therapeutic doses. In 1976, Zeiss and Lockey ^[5]  reported a 72 hour refractory period to ASA after an indomethacin induced respiratory reaction in a known ASA sensitive asthmatic patient. In 1977, Bianco et al.^[6]  reported tolerance to ASA in a known ASA sensitive asthmatic patient, after repeated bronchial inhalation challenges with ASA-lysine. In 1980, Stevenson et al.^[7]  reported two ASA sensitive asthmatic patients who became refractory to ASA after oral ASA challenges. Both patients were then treated with daily ASA over the ensuing months and experienced improvement in their respiratory disease.

Oral challenges to induce ASA desensitization

All ASA sensitive asthmatics can be successfully desensitized to ASA during oral ASA challenges.^{[3] [8]}  An example of an oral ASA challenge, followed by ASA desensitization is presented in table.

Between 1979 and 1999, we have conducted 500 oral ASA challenges with positive respiratory reactions. ASA desensitization was then successfully completed in 500/500 attempts. After ASA desensitization, in the absence of further exposure to ASA, the desensitized state persists for two to five days with full sensitivity returning after seven days.^[3]

ASA cross-sensitivity and desensitization

All NSAIDs, which inhibit cyclooxygenase (COX 1 and 2) in vitro, cross-react with ASA, producing respiratory reactions.^[9-12]  Furthermore, in ASA sensitive asthmatics, cross-reactions occur upon first exposure to the newly exposed NSAID.^[11]  In 1971, Vane^[9]  reported that ASA and NSAIDs inhibit formation of prostaglandins. In 1977, Szczeklik et al.^[12]  reported in vitro experiments demonstrating that ASA and NSAIDs inhibit COX in vitro at different concentrations for each drug and that this predicts cross-reactivity. NSAIDs and ASA not only share the pharmacologic effect of cross-reactivity but also share the phenomenon of cross-desensitization.^{[3] [13] [14]}

Based on the experimental findings of Vane^[10], one would assume that weak inhibitors of COX would either not cross-react with ASA or would cross-react poorly and only after challenges with large doses of the suspected analgesic. Based on this same reasoning, one would predict that cross-desensitization with weak COX inhibitors, after establishing an ASA desensitized state with ASA, would also occur. The prediction is that weak inhibitors of COX are not likely to be able to induce the desensitized state in dose ranges consistent with recommended therapeutic doses. The reason for this is that if COX inhibition and induction of respiratory reactions requires large doses of a weak COX inhibitor, even larger doses would be required to induce desensitization. Such doses would be expected to be above standard recommended doses of the drug.

Settipane and Stevenson^[15] studied three ASA sensitive asthmatics, who also gave an associated history of respiratory reactions occurring two hours after ingesting 500-1000 mg acetaminophen (paracetamol). Double-blind, placebo controlled oral challenges were undertaken and none of 3 reacted to acetaminophen 500 mg. However, all 3 experienced bronchospastic reactions after ingesting acetaminophen, 1000 mg. Two patients were temporarily desensitized to 1000 and 1500 mg of acetaminophen, but desensitization to 2000 mg could not be sustained and higher doses were not administered because of concern about liver toxicity. Two patients were then desensitized to ASA (650 mg) and were then able to immediately ingest 1000 mg of acetaminophen without adverse effect, demonstrating cross-desensitization.

Treatment with ASA after ASA desensitization

In 1980, Stevenson et al.^[7] reported two ASA sensitive asthmatic subjects who were successfully desensitized to ASA and then treated with daily ASA continuously. Both patients rapidly experienced improvement in nasal patency and one regained her sense of smell. Furthermore, when daily ASA treatment continued over a number of months, nasal airway patency was maintained, re-growth of nasal polyps ceased and asthma activity diminished. At the same time, systemic corticosteroids were reduced to half their pre-treatment levels. These observations raised some interesting questions. Was it possible to treat the underlying respiratory tract inflammation of ASA disease, using the same drug which, prior to ASA desensitization, induced respiratory reactions? If this were true what biomolecular events might explain the mechanisms by which this occurred?

Taking into consideration variations in study design, doses of ASA employed, length of treatment with ASA and criteria for successful clinical outcomes, efficacy has been reported in most studies where treatment with daily ASA was instituted after ASA desensitization.^{[7] [16-20]}  One study by Naeije et al.^[21] did not show efficacy of ASA treatment in ASA sensitive asthmatic subjects. However, the usefulness of this study was hampered by small sample size and reliance upon improvement in lung function as the only criteria for improvement. This study was also less comparable to other studies because of low treatment doses of ASA and short duration of ASA treatment. Furthermore, their protocol did not allow adjustment of corticosteroid doses downward during treatment with ASA to determine whether or not lung function could be maintained while systemic steroids were reduced or removed. Lumry et al.^[17], demonstrated that ASA treatment of patients with ASA sensitive rhinosinusitis, without asthma, after ASA desensitization, was associated with clearing of hypertrophic rhinitis in 77% of the patients studied.

Stevenson et al.^[22], conducted the only double blind cross-over study of treatment with ASA, after ASA desensitization, in 25 ASA sensitive asthmatics. During the three month treatment arm with daily ASA therapy, patients experienced significant improvement in nasal symptom scores and a reduced use of nasal beclomethasone. However, only half the patients experienced improvement in asthma symptom scores and systemic corticosteroid doses were not significantly reduced during the ASA treatment period. This short term study employed variable doses of ASA and recruitment of study subjects was less than projected. Thus the multiple dose patient samples were of insufficient size to compare subgroups based on treatment doses and outcomes. Retrospectively, it would have been ideal if all 25 patients had been treated with 1300 mg of ASA each day, rather than dividing the 25 patients into treatment subgroups, particularly low dose ASA at only 325 mg per day. Furthermore, the time frame of 3 months was insufficient to asses rate of polyp regrowth or need for additional sinus or nasal polyp surgery.

Between 1986-1988, we conducted a long term double blind placebo controlled study of ASA desensitization treatment. After 2 years of recruitment, only two patients volunteered to participate. They both underwent ASA oral challenges, followed by successful ASA desensitization. As usually occurs, they immediately noted improvement in their nasal patency at the time of completion of ASA desensitization. Both started daily treatment with the study drug but disenrolled from the study several weeks later, when nasal congestion returned. In both patients placebo treatment had been randomly assigned by the pharmacist. Thus, both patients could distinguish between placebo and ASA therapy because of the return of nasal congestion while taking placebo. Furthermore, ASA as a "study drug" is available over-the-counter and not controlled by the investigators, allowing patients the option of not enrolling in a study where placebo treatment would be expected 50% of the time. Finally, the human study committee required full disclosure of therapeutic options, including the opportunity for patients to enroll in an open treatment with ASA using adjusted dosages. Essentially patients elected this last option, except for the two patients referred to earlier.

In 1990, our experience with ASA desensitization treatment at Scripps Clinic was retrospectively analysed.^[23] We reported the clinical courses of 107 known ASA sensitive rhinosinusitis asthmatic patients treated with ASA between 1975 and 1988. Forty-two patients avoided aspirin and served as the control group. Thirty five patients were desensitized to ASA and treated continuously with ASA daily for as long as eight years. Thirty patients were initially desensitized to ASA and treated with ASA but discontinued ASA after a mean of two years. Retrospective analysis of the three groups showed that the patients treated with ASA enjoyed statistically significant reductions in hospitalizations, emergency room visits, outpatient visits, need for additional sinus surgery, need for additional nasal polypectomies, number of upper respiratory infections requiring antibiotics, and improved sense of smell. ASA desensitized and treated patients were also able to significantly reduce systemic corticosteroid maintenance doses, corticosteroid bursts per year and in the group treated continuously, were able to reduce inhaled corticosteroids when compared to the control group. In the patients who had to discontinue ASA treatment after several years, respiratory disease improved while being treated with daily ASA, but reverted back toward pre-treatment status after discontinuing ASA treatment. This study showed that ASA desensitization, followed by long term ASA treatment improved the clinical courses of ASA sensitive asthma rhinosinusitis, prevented regrowth of nasal polyps while at the same time allowing significant reduction in systemic and inhaled corticosteroids. Side effects from gastritis occurred in 20% of patients treated with ASA. Unfortunately, 30/65 patients who started ASA desensitization therapy discontinued ASA, mostly for misperceived reasons, shrinking the active treatment group to only 35 patients. This made it impossible to subdivide patients into short and long term treatment groups to determine whether therapeutic effects were concentrated in the early or later years of treatment.

In 1996, Stevenson et al.^[24] analyzed the clinical courses of an additional 65 ASA sensitive asthmatics who underwent oral ASA challenges, followed by ASA desensitization between 1988 and 1994. These patients, after ASA oral challenges and standard oral desensitization to ASA, were then treated with daily doses of ASA (650 mg BID) and followed for an average of 3.3 years (range 1-6 years). The following clinical parameters were significantly improved after long term ASA desensitization treatment: number of sinus infections/yr., number of hospitalizations for asthma/yr., number of sinus operations/yr., improvement in sense of smell, reduction in use of both nasal topical corticosteroids and systemic corticosteroids. Unchanged after ASA desensitization treatment were number of emergency room visits for asthma/yr. and use of inhaled corticosteroids. There was a down side with 10 patients discontinuing ASA Rx because of gastritis in 9 and pregnancy in one. This study showed that the main components of ASA disease, namely aggressive nasal polyp formation and sinusitis, were significantly reduced during long term ASA desensitization treatment. Concomitantly, nasal and systemic corticosteroids could be successfully reduced or discontinued without the expected increase of inflammatory respiratory disease. Also important, when the 65 patients were subdivided into treatment groups receiving ASA daily for < or >3 years, the results were essentially the same, indicating that therapeutic escape did not occur during long term treatment with ASA up to 6 years. These data further suggested that early reduction in systemic corticosteroids during the first year of ASA treatment is also not associated with disease escape. For the total group of 65 patients, the need for sinus surgery declined from a pretreatment interval of one operation every 3 years to one every 9 years during treatment with daily ASA.

Although studies which include leukotriene modifying drugs, along with ASA desensitization treatment and corticosteroid therapy have not been conducted, there is reason to be optimistic that therapeutic effects from these multiple interventions will be additive. Certainly, early clinical observation would suggest that his is true.

Pathogenesis of ASA desensitization

During ASA induced respiratory reactions, peripheral monocytes from ASA sensitive asthmatic patients undergoing induced respiratory reactions, synthesize increased amounts of leukotrienes. By contrast, after acute ASA desensitization, defined as three hours after first ingestion of ASA 650 mg without any adverse effects, peripheral blood monocytes synthesized significantly less thromboxane B2 and LTB4, the preferential 5-LO product of peripheral monocytes.^[25]25 Additionally, nasal LTC4 and histamine, which had been increased in nasal secretions during ASA induced respiratory reactions, disappeared at the point of acute desensitization.^[26] Similarly, serum histamine and tryptase levels, which were elevated during ASA induced respiratory reactions, returned to low baseline levels following acute desensitization.^[27] During respiratory reactions induced by either oral or inhalation ASA challenges, LTE4 urine levels were found to be significantly elevated when compared to baseline concentrations.^[28-30] However, after acute desensitization, urinary LTE4 concentrations returned to baseline levels.^[31] Arm, et al.^[32], on the first day following ASA desensitization, demonstrated a 20 fold decrease in bronchial airway responsiveness to inhaled LTE4, compared to pre-desensitization responses to inhalation of LTE₄ in ASA sensitive asthmatics. Responses to inhaled histamine were unchanged.

After treatment with ASA 650 mg BID for two or more weeks, during chronic desensitization, Juergens et al.^[25] showed that peripheral monocyte synthesis of LTB₄ declined substantially, to the same level found in normal controls. Nasser, et al.^[31] reported that during chronic ASA desensitization, with ASA 500 mg qd for 6 months, mean urine LTE₄ levels declined to lower values, but not to values found in normals. Daffern et al. (submitted for publication) showed that treatment with ASA 650 mg BID was associated with significant declines in urinary LTE₄ levels in the majority of patients at one year of treatment with the mean decrease statistically significant. However, urinary LTE₄ levels from a few patients did not change during long term ASA desensitization treatment. These experiments suggested that ASA desensitization, particularly long term treatment with higher doses of ASA in most AIA patients, probably inhibits both COX and other enzymes above LTE₄, possibly even at the PLA₂ level, leading to diminished synthesis of both prostanoids and LTs. Simultaneously, LTE₄ bronchial receptors remain down regulated ^[32], further reducing the effects of any available terminal LTs. Mast cells are also influenced by ASA to reduce secretion of pre-formed mediators. The effects of ASA desensitization eosinophils are unknown. Such an environment would be expected to result in a general decrease in respiratory tract inflammation with a reduction in nasal polyp formation and brochial hyperirritability.

Donald D. Stevenson, M.D.
Senior Consultant, Div. of Allergy, Asthma and Immunology
Chairman Emeritus, Dept. of Medicine
Scripps Clinic and the Scripps Research Institute, La Jolla, Calif., USA

References

1. Stevenson D.D., Lewis R.: Proposed mechanisms of aspirin sensitivity reactions. Editorial. J. Allergy Clin. Immunol., 1987; 80: 788-790 [Medline]

2. Szczeklik A.: The cyclooxygenase theory of aspirin-induced asthma. Eur. Resp. J., 1990; 3: 588-593 [review]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2115849&dopt=Abstract

3. Pleskow W.W., Stevenson D.D., Mathison D.A., Simon R.A., Schatz M., Zieger R.S.: Aspirin desensitization in aspirin sensitive asthmatic patients: clinical manifestations and characterization of the refractory period. J. Allergy Clin. Immunol., 1982; 69: 11-19  [Medline]

4. Widal M.F., Abrami P., Lermoyez J.: Anaphylaxie et idiosyncrasie. Presse Med., 1922; 30: 189-192 [Medline]

5. Zeiss C.R., Lockey R.F.: Refractory period to aspirin in a patient with aspirin-induced asthma. J. Allergy Clin. Immunol., 1976; 57: 440-448 [Medline]

6. Bianco S.R., Robuschi M., Petrini G.: Aspirin induced tolerance in aspirin-asthma detected by a new challenge test. IRCS J. Med. Sci., 1977; 5: 129-136

7. Stevenson D.D., Simon R.A., Mathison D.A.: Aspirin-sensitive asthma: tolerance to aspirin after positive oral aspirin challenges. J. Allergy Clin. Immunol., 1980; 66: 82-88 [Medline]

8. Stevenson D.D., Simon R.A.: Sensitivity to aspirin and nonsteroidal antiinflammatory drugs. In: Middleton E.J., Reed C.E., Ellis E.F., Adkinson N.F Jr, Yunginger J.W., Busse W.W., eds: Allergy: principles and practice.St. Louis, Mosby, 1993: 1747-1765
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?form=4&db=m&term=Stevenson+Simon&dispmax=50&relentrezdate=No+Limit

9. Vane J.R.: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol., 1971; 231: 232-235 [Medline]

10. Vane J.R.: The mode of action of aspirin and similar compounds. J. Allergy Clin. Immunol., 1976; 58: 691-712 [Medline]

11. Mathison D.A., Stevenson D.D.: Hypersensitivity to non-streroidal anti-inflammatory drugs: indications and methods for oral challenge. J. Allergy Clin. Immunol., 1979; 64: 669-674

12. Szczeklik A., Gryglewski R.J., Czerniawska-Mysik G.: Clinical patterns of hypersensitivity to nonsteroidal anti-inflammatory drugs and their pathogenesis. J. Allergy Clin. Immunol., 1977; 60: 276-284

13. Bosso J.V., Creighton D., Stevenson D.D.: Fluriprofen (Ansaid) cross-sensitivity in an aspirin-sensitive asthmatic patient. Chest, 1992; 101: 856-858

14. Stevenson D.D., Simon R.A.: Sensitivity to aspirin and nonsteroidal antiinflammatory drugs. In: Middleton E. Jr, Ellis E.F., Yunginger J.W., Reed C.E., Adkinson N.F. Jr, Busse W.W., eds: Allergy: principles and practice. St Louis, Mosby, 1998: 1225-1234

15. Settipane R.A., Stevenson D.D.: Cross sensitivity with acetaminophen in aspirin sensitive asthmatic. J. Allergy Clin. Immunol., 1989; 84: 26-33

16. Chiu J.T.: Improvement in aspirin-sensitive asthmatic subjects after rapid aspirin desensitization and aspirin maintenance (ADAM) treatment. J. Allergy Clin. Immunol., 1983; 71: 560-567

17. Lumry W.R., Curd J.G., Zieger R.S., Pleskow W.W., Stevenson D.D.: Aspirin-sensitive rhinosinusitis: the clinical syndrome and effects of aspirin administration. J. Allergy Clin. Immunol., 1983; 71: 580-587

18. Nelson R.P., Stablein J.J., Lockey R.F.: Asthma improved by acetylsalicylic acid and other non-steroidal antiinflammatory agents. N. Eng. Reg. Allergy Proc., 1986; 7: 117-121

19. Szczeklik A., Gryglewski R.J., Niľankowska E.: Asthma relieved by aspirin and by other cyclooxygenase inhibitors. Thorax, 1978; 33: 664-665

20. Lockey R.F.: Aspirin-improved ASA triad. Hosp. Pract., 1978; 13: 129-133

21. Naeije N., Bracamonte M., Michel O., et al.: Effects of chronic aspirin ingestion in aspirin-intolerant asthmatic patients. Ann. Allergy, 1984; 53: 262-264

22. Stevenson D.D., Pleskow W.W., Simon R.A., Mathison D.A., Lumry W.R., Schatz M., Zieger R.S.: Aspirin-sensitive rhinosinusitis asthma: a double-blind cross-over study of treatment with aspirin. J. Allergy Clin. Immunol., 1984; 73: 500-507

23. Sweet J.A., Stevenson D.D., Simon R.A., Mathison D.A.: Long term effects of aspirin desensitization treatment for aspirin sensitive rhinosinusitis asthma. J. Allergy Clin. Immunol., 1990; 86: 59-65

24. Stevenson D.D., Hankammer M.A., Mathison D.A., Christensen S.C., Simon R.A.: Long term ASA desensitization-treatment of aspirin sensitive asthmatic patients: clinical outcome studies. J. Allergy Clin. Immunol., 1996; 98: 751-758

25. Juergens U.R., Christiansen S.C., Stevenson D.D., Zuraw B.L.: Inhibition of monocyte leukotriene B4 production following aspirin desensitization. J. Allergy Clin. Immunol., 1995; 96: 148-156

26. Ferreri N.R., Howland W.C., Stevenson D.D., Spiegelberg H.L.: Release of leukotrienes, prostaglandins, and histamine into nasal secretions of aspirin-sensitive asthmatics during reaction to aspirin. Am. Rev. Resp. Dis., 1988; 137: 847-854

27. Bosso J.V., Schwartz L.B., Stevenson D.D.: Tryptase and histamine release during aspirin-induced respiratory reactions. J. Allergy Clin. Immunol., 1991; 88: 830-837

28. Christie P.E., Tagari P., Ford-Hutchinson A.W., Charlesson S., Chee P., Arm J.P., Lee T.H.: Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am. Rev. Respir. Dis., 1991; 143: 1025-1029

29. Christie P.E., Tagari P., Ford-Hutchinson A.W., Black C., Markendorf A., Schmitz-Schumann M., Lee T.H.: Urinary leukotriene E4 after lysine-aspirin inhalation in asthmatic subjects. Am. Rev. Respir. Dis., 1992; 146: 1531-1534

30. Sladek K., Szczeklik A.: Cysteinyl leukotrienes overproduction and mast cell activation in aspirin-provoked bronchospasm in asthma. Eur. Respir. J., 1993; 6: 391-399

31. Nasser S.M.S., Patel M., Bell G.S., Lee T.H.: The effect of aspirin desensitization on urinary leukotriene E4 concentration in aspirin-sensitive asthma. Am. J. Respir. Crit. Care Med., 1995; 151: 1326-1330

32. Arm J.P., O'Hickey S.P., Spur B.W., Lee T.H.: Airway responsiveness to histamine and leukotriene E4 in subjects with aspirin-induced asthma. Am. Rev. Respir. Dis., 1989; 140: 148-153

Table. Oral ASA desensitization in an AIA patient

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