Aspirin challenge and desensitization for aspirin-exacerbated respiratory disease: a practice paper.

Aspirin desensitization is indicated for patients who have aspirin-exacerbated respiratory disease and whose asthma and/or rhinosinusitis is suboptimally controlled with inhaled corticosteroids and leukotriene-modifying drugs. In this practice paper, the general requirements for aspirin desensitization are presented, the locations where desensitizations can be safely performed are outlined, prechallenge patient preparation is discussed, an oral aspirin challenge protocol is presented, treatment of adverse reactions is reviewed, and maintenance of aspirin desensitization is discussed.     

Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease

BACKGROUND: Aspirin desensitization treatment is an option to decrease disease activity and reduce the need for systemic corticosteroids in patients with aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: This study was designed to determine whether the clinical courses of patients with AERD improved as early as 6 months after starting aspirin desensitization and to compare this with follow-up evaluations after at least a year. METHODS: Between 1995 and 2000, 172 patients with AERD were admitted to our General Clinical Research Center, were desensitized to and treated with aspirin, were discharged to their home communities, and participated in follow-up interviews and written assessments of their clinical courses. RESULTS: By the first 6 months of aspirin treatment, there were significant reductions in sinus infections and numbers of short courses of prednisone and improvements in sense of smell and general assessment of nasal-sinus and asthma symptoms (P <.0001). These results persisted for 1 to 5 years (P <.0001). Mean prednisone doses decreased from 10.8 mg/d to 8.1 and 3.6 mg/d at 6 months and greater than 1 year, respectively. Of the 172 patients, 24 (14%) discontinued aspirin treatment because of side effects, and 115 (67%) responded to aspirin treatment. After eliminating those who discontinued aspirin treatment because of side effects, the improvement rate was 115 (78%) of 148 patients. Of the 126 patients who completed a year or more of aspirin treatment, 110 (87%) experienced improvement. CONCLUSION: Aspirin desensitization followed by daily aspirin is efficacious by at least the first 6 months of treatment and continues to be effective for up to 5 years of follow-up.     

Selection of aspirin dosages for aspirin desensitization treatment in patients with aspirin-exacerbated respiratory disease

BACKGROUND: Aspirin desensitization followed by daily aspirin therapy is effective add-on treatment for patients with aspirin-exacerbated respiratory disease. Prior studies used 650 mg of aspirin twice daily, but studies at lower dosages were inconclusive. OBJECTIVE: We sought to determine the optimal daily dosage of aspirin treatment. METHODS: We studied 137 patients who had undergone successful aspirin desensitization and randomized them into 2 groups, 650 mg twice daily versus 325 mg twice daily. After 1 month, patients either increased or decreased their dosage based on their symptom control and continued that dosage for the remainder of the year. RESULTS: Patients taking either 650 mg twice daily or 325 mg twice daily showed significant improvements in number of sinus infections, sinus operations, and hospitalizations for asthma (all P < .0001). Anosmia, nasal/sinus symptoms, and asthma symptoms also improved in both groups (all P < .03). Systemic corticosteroid dosages decreased by 3- and 4-fold in the 325 mg twice daily and 650 mg twice daily groups, respectively. Of the 137 patients, 32 had adverse effects from or discontinued aspirin therapy: 14 (44%) of 32 from the group randomized to taking 650 mg twice daily and 18 (56%) of 32 from the group randomized to 325 mg twice daily. The most common adverse effect was dyspepsia. CONCLUSION: Both dosages were efficacious, and side effects occurred in both groups at similar frequencies. Some patients initially taking 325 mg twice daily required an increase to 650 mg twice daily for optimal symptom control. CLINICAL IMPLICATIONS: We recommend that patients begin daily aspirin therapy with 650 mg twice daily and subsequently decrease to the lowest effective dosage (usually 325 mg twice daily).     

Early effects of aspirin desensitization treatment in asthmatic patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin (ASA)-exacerbated respiratory disease (AERD) is characterized by aggressive inflammation of the respiratory tract and often requires topical and/or systemic corticosteroids to maintain partial control of this disease. Previous studies have revealed that ASA desensitization and subsequent treatment with ASA is associated with clinical improvement in AERD. OBJECTIVE: The aim of the present study was to determine the effect of daily ASA treatment for the first 4 weeks after ASA desensitization. METHODS: Thirty-eight patients underwent ASA oral challenge followed by ASA desensitization and daily ASA therapy. Changes in nasal and asthma symptoms, combined with changes in oral prednisone, were recorded daily during 4 weeks before and after desensitization. Severity of symptoms ranged from a scale of 1 to 5 (1 = asymptomatic and 5 = most severe symptoms). For statistical analyses the sum of nasal symptoms and asthma symptoms was calculated. Olfactory scores were also analyzed. RESULTS: Nasal and asthma symptom scores, as well as olfactory scores, improved significantly (P < 0.0001). For the 15 patients taking prednisone, their mean doses decreased from 10.7 to 5.9 mg daily (P = 0.0003). CONCLUSIONS: Our study suggests that ASA desensitization treatment is effective during the first 4 weeks of daily treatment with ASA.     

Intranasal ketorolac,diagnosis, and desensitization for aspirin-exacerbated respiratory disease

BackgroundIntranasal ketorolac has been proposed as a diagnostic test for aspirin-exacerbated respiratory disease (AERD) and a faster, safer, and reliable addition to facilitating aspirin (ASA) desensitization.ObjectiveWe conducted the first prospective study to dissect the impact of intranasal ketorolac incorporation during ASA desensitization vs standard oral protocols in concert with evaluating its diagnostic use for AERD.MethodsPatients with AERD were enrolled in a prospective open-label observational study between November 2006 and August 2013. Participants selected either one of the following desensitization protocols: intranasal ketorolac 1 day before oral ASA (group 1, combined) or ketorolac challenge with greater than 2 weeks elapsing until oral ASA (group 2, washout). All patients were on a leukotriene-modifying drug (montelukast) for at least 1 week before the challenge.ResultsA total of 20 patients were enrolled: 13 in group 1 and 7 in group 2. No significant differences were seen for baseline symptom scores or forced expiratory volume in 1 second. Group 1 exhibited significant increases for the threshold dose of ASA (P = .009), the likelihood of having silent ASA desensitization (P = .01), and decreased reaction severity to oral ASA (P = .04). There were no significant differences in reaction forced expiratory volume in 1 second, the incidence of extrapulmonary symptoms, limited nasoocular reactions, rescue treatment requirements, or time to symptom resolution. There was 100% concordance between reactions to intranasal ketorolac and oral ASA for group 2, supporting its use as a diagnostic test for AERD.ConclusionIntranasal ketorolac is a useful diagnostic test and adjunct within the combined ketorolac/ASA protocol to achieve effective, efficient, and perhaps safer desensitization to ASA for patients with AERD.     

Safety of high-dose rofecoxib in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by progressive sinusitis, nasal polyposis, and asthma that begins and continues in the absence of exposure to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Cross-sensitivity to all NSAIDs that inhibit cyclooxygenase-1 (COX-1) occurs in these individuals. Reactions to aspirin and NSAIDs in patients with AERD are largely due to inhibition of COX-1. Despite accumulating data on the safety of COX-2 selective inhibitors in AERD, concern still remains that high doses of a COX-2 inhibitor may be sufficient to induce a cross-reaction. OBJECTIVE: To determine whether high-dose rofecoxib cross-reacts in patients with AERD and asthma. METHODS: Sixty asthmatic patients underwent blinded placebo-controlled oral challenges with 50 mg of rofecoxib. Aspirin sensitivity was subsequently confirmed in all patients with the use of single-blinded aspirin challenges. RESULTS: None of the 60 patients experienced any symptoms, changes in nasal examination results, or declines in lung function during rofecoxib challenge. All 60 patients experienced respiratory reactions to aspirin challenge, with a mean provoking dose of 57 mg. The exact 1-sided 95% confidence interval for the underlying probability of 50 mg of rofecoxib inducing respiratory cross-reactions in patients with AERD is 0 to 0.05, or 0% to 5%. CONCLUSIONS: These results confirm the lack of cross-reactivity of aspirin and the highly selective COX-2 inhibitors in AERD. We suggest that it is time for the labeling of highly selective COX-2 inhibitors to reflect these data and for the warning that patients with AERD in particular and asthmatic patients in general avoid selective COX-2 inhibitors to be removed.     

Pathogenesis of aspirin-exacerbated respiratory disease

The underlying respiratory disease is activated by unknown mechanism and results in an intense infiltration of mast cells and eosinophils into the entire respiratory mucosa. These cells synthesize leukotrienes (LTs) at a very high rate and mast cells also release histamine and tryptase and synthesize PGD₂ a vasodilator and bronchoconstrictor. Furthermore, AERD patients under synthesize from arachidonic acid (AA) a peculiar product called lipoxins, which opposes inflammation generated by leukotrienes. Finally, cysLT₁ receptors are over expressed and highly responsive to LTE₄, further augmenting the underlying inflammatory disease. This inflammatory condition is partly inhibited by synthesis of PGE₂ through COX-1. PGE₂ partially inhibits 5-lipogygenase conversion of AA to LTA₄ and blocks release of histamine and tryptase from mast cells. When COX-1 is inhibited by ASA or NSAIDs, PGE₂ synthesis stops and an enormous release of histamine and synthesis of LTs occurs. The upper respiratory reaction is mediated by both histamine and LTs but the bronchospastic reaction is mediated by LTs. The systemic effects of flush, gastric pain and hives are mediated by histamine. Aspirin desensitization can not be explained by disappearance of LT synthesis since urine LTE₄ levels are still elevated at acute ASA desensitization. However, mast cell products such as histamine, tryptase and PGD₂ are no longer released or synthesized at acute desensitization. It is more likely that a diminution in number or function of cysLT receptors accounts for the diminished inflammatory response found in ASA desensitization.     

Failure of tacrolimus to prevent aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease

BACKGROUND: In patients with aspirin-exacerbated respiratory disease (AERD), pretreatment with asthma controller medications (leukotriene modifiers, inhaled or systemic corticosteroids, and salmeterol) partially modifies the severity of aspirin-induced asthmatic reactions. OBJECTIVE: A recent study showed that pretreatment with tacrolimus completely prevented aspirin-induced respiratory reactions and might allow silent aspirin desensitization. METHODS: Ten patients with rhinosinusitis, nasal polyps, and asthma had a history of asthma attacks after ingesting aspirin and nonsteroidal anti-inflammatory drugs. All underwent baseline oral aspirin challenges and had typical respiratory reactions. They were then randomized to receive tacrolimus (0.1 mg/kg weight; 8 patients) or placebo (2 patients) in a double-blind protocol before rechallenge with aspirin using the previous provoking dose of aspirin. In addition, respiratory reactions sustained by 50 consecutive patients with AERD during 2004 were recorded, analyzed, and compared with the tacrolimus/placebo-treated patients to determine whether there were any differences. RESULTS: Tacrolimus pretreatment failed to block respiratory reactions to provoking doses of aspirin in 5 of 8 patients with AERD, and in the other 3 patients did not block higher doses of aspirin. The results of oral aspirin challenges in the control population of 50 patients were compared with either the baseline or postchallenge data from the tacrolimus-pretreated or placebo-pretreated patients with AERD, and there were no significant differences. CONCLUSIONS: Use of tacrolimus as add-on pretreatment to prevent reactions to aspirin in patients with AERD or to achieve the goal of silent aspirin desensitization could not be accomplished.     

Aspirin desensitization in patients with AERD

All patients with aspirin exacerbated respiratory disease (AERD) can be desensitized to ASA. After achieving this state, patients can then take ASA daily without adverse effect. ASA desensitization can be maintained indefinitely as long as the patient takes ASA each day. Crossdesensitization with older NSAIDs also occurs. After ASA desensitization, patients can take daily ASA in order to treat their underlying respiratory disease. In AERD patients treated with ASA 650 BID for at least a year, 115/172 (67%) improved in their clinical courses while decreasing systemic and topical corticosteroids. Sixteen failed to improve, 24 stopped ASA because of intractable side effects (gastritis or hives) and 17 patients discontinued ASA treatment in the first year of study for unrelated reasons. Therefore, treatment with daily ASA is a significant therapeutic option for patients afflicted with AERD. It should be used for AERD patients who do not respond to topical corticosteroids and leukotriene modifier drugs. Those who respond to systemic steroids or have intractable or recurrent nasal polyps are particularly well-suited for this therapeutic intervention.     

Effect of in vitro aspirin stimulation on basophils in patients with aspirin-exacerbated respiratory disease

Background Basophil activation has been implicated in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). However, a comprehensive analysis of basophil responses to aspirin in terms of mediator release, cytokine secretion and increased expression of surface activation markers has not been performed.
Objective To study the in vitro effects of aspirin on the concurrent release of histamine, leukotriene C₄ (LTC₄) and IL-4 from human basophils and to also evaluate changes in surface activation markers (CD63, CD69 and CD203c) expressed by these cells.
Methods Basophil-enriched cell suspensions from 10 patients with AERD and 10 healthy volunteers were incubated with lysine-aspirin for up to 3 h. Cells were analysed for expression of CD63, CD69 and CD203c using flow cytometry. Cell-free supernatants were evaluated for histamine, and LTC₄ release and for IL-4 secretion.
Results Aspirin-induced expression of CD63, CD69 and CD203c yielded 30%, 80% and 70% sensitivity, respectively, but with poor specificity. There was no significant difference in LTC₄ synthesis between groups. None of the patients with AERD (or controls) released IL-4 in response to aspirin. A higher dose of 5 mg/mL aspirin-mediated non-specific effects on basophils.
Conclusion Basophil responses to in vitro aspirin challenge are poor indicators of clinical sensitivity. Aspirin activates some basophils by means of mechanisms that differ from the classical IgE-mediated pathway. Our study also shows that the use of 27 m m of aspirin (5 mg/mL) by previous investigators causes non-specific basophil activation, thereby eliminating its usefulness in a cell-based diagnostic test for AERD. Evaluation of in vitro basophil activation has low clinical value in identifying aspirin-induced respiratory reactions.