Donald D. Stevenson

Aspirin-induced asthma: advances in pathogenesis and management.

In some patients with asthma, aspirin (ASA) and all nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase enzymes (cyclooxygenase-1 and -2) precipitate asthmatic attacks and naso-ocular reactions. This distinct clinical syndrome, called aspirin-induced asthma (AIA), is characterized by a typical sequence of symptoms, intense eosinophilic inflammation of nasal and bronchial tissues, combined with overproduction of cysteinyl-leukotrienes (Cys-LTs). At baseline, cys-LT urinary excretion is augmented, and ASA administration leads to its further temporary increase. After ASA challenge, cys-LTs are released into nasal and bronchial secretions and can be collected in the urine. LTC4 synthase, the terminal enzyme for cys-LT production, is markedly overexpressed in eosinophils and mast cells from bronchial biopsy specimens of most patients with AIA. An allelic variant of LTC4 synthase that enhances enzyme transcription is associated with AIA. Avoiding ASA and nonsteroidal anti-inflammatory drugs does not prevent progression of the inflammatory disease. Corticosteroids continue to be the mainstay of therapy, and anti-LT drugs are also indicated for treatment of the underlying disease. After ASA desensitization, daily ingestion of high doses of ASA reduces inflammatory mucosal disease symptoms, particularly in the nasal passages, in most patients with AIA.

Aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma : Long-term outcomes

BACKGROUND Aspirin-sensitive patients with asthma experience continuous inflammation of their nasal and sinus tissues, complicated by recurrent sinusitis, which frequently leads to asthma attacks. Systemic corticosteroid therapy and sinus or polyp surgery are currently required to control underlying rhinosinusitis, and bursts of corticosteroids are used for asthma control. OBJECTIVE After aspirin desensitization therapy, objective measures of respiratory disease activity, linked to the need for systemic corticosteroids and sinus surgery, were studied to determine whether any changes occurred. METHODS Sixty-five aspirin-sensitive patients with asthma underwent aspirin challenge, followed by aspirin desensitization and daily treatment with aspirin over 1 to 6 years (mean, 3.1 years). Clinical outcome measurements before aspirin desensitization treatment and during follow-up were analyzed for the larger group of 65 patients and subgroups (29 patients receiving therapy for 1 to 3 years and 36 patients receiving therapy for 3 to 6 years). RESULTS In the larger group of 65 patients, there were significant reductions in numbers of sinus infections per year (median, 6 to 2), hospitalizations for treatment of asthma per year (median, 0.2 to 0), improvement in olfaction (median, 0 to 2), and reduction in use of systematic corticosteroids (mean, 10.2 to 2.5 mg) with p values less than 0.0001. Numbers of sinus and polyp operations per year were significantly reduced (median, 0.2 to 0; p = 0.004), and doses of nasal corticosteroids (in micrograms) were significantly reduced (mean dose, 139 to 106 micrograms, p = 0.01). Emergency department visits and use of inhaled corticosteroids were unchanged. CONCLUSIONS The results support a role for aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma.

Aspirin intolerance in asthma: Detection by oral challenge☆☆☆

Abstract Oral aspirin challenge was used to detect aspirin intolerance in selected asthmatic patients who did NOT give a history of asthma following aspirin ingestion. Forty-two asthmatic patients with either nasal polyps, sinusitis, or severe asthma requiring corticosteroid therapy were challenged with aspirin. Under carefully controlled circumstances and at a time when their asthma was stable, patients ingested 640 mg. of aspirin (Ascriptin) after taking all their usual maintenance medications. Several parameters of lung function and clinical symptomatology were followed serially over a 4 hour period. Eight of 42 challenges were positive. When these patients were combined with 14 patients who were intolerant to aspirin by history, the prevalence of aspirin intolerance in our asthmatic population was 8 per cent. Patients who were intolerant to aspirin showed a statistically significant increase in the prevalence of the hallmark criteria of nasal polyps, sinusitis, and steroid dependency when compared to all new asthmatic patients during a 2 year period. Aspirin challenge in selected patients can detect aspirin intolerance not recognized by history alone. These patients can be warned to avoid aspirin ingestion in the future. In addition, their management can be improved by recognizing this variant of the asthma syndrome.

Diagnosis, prevention, and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs

Aspirin (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) share common pharmacologic effects in the prevention of inflammation, at least in part through inhibition of prostaglandin formation. ASA and NSAIDs have predictable side effects such as gastric pain, ecchymosis, and tinnitus. They also cause anaphylactoid shock, urticaria/angioedema, nephropathy, and hepatitis in individuals who appear to be normal and in whom prediction of such reactions cannot be made. Two selected populations of patients are likely to experience hypersensitivity reactions to both ASA and NSAIDs. Patients with asthma have an 8% to 20% chance of experiencing asthmatic attacks after ingesting ASA and NSAID. If such patients have associated rhinosinusitis (polyps), prevalence increases to 30% to 40%. Patients with chronic urticaria/angioedema have a 21% to 30% chance of experiencing an urticarial flare after ingesting ASA and NSAIDs.

Long-term effects of aspirin desensitization—Treatment for aspirin-sensitive rhinosinusitis-asthma

One hundred seven known aspirin (ASA)-sensitive patients with rhinosinusitis-asthma were studied from 1975 to 1988. Forty-two of the patients avoided ASA and served as the control group. Thirty-five patients were desensitized to ASA and treated with daily ASA treatment (Rx) for as long as 8 years (mean, 3.75 years) to May 1988 and were designated the continuous group. Thirty patients, initially desensitized to ASA and treated with daily ASA, who stopped Rx permanently after a mean duration of 2 years, were designated the discontinued group. Retrospective analyses of baselines revealed that both continuous and discontinued groups during ASA Rx demonstrated statistically significant reduction in number of hospitalizations per year, emergency room visits per year, outpatient visits per year, upper respiratory infections-sinusitis-antibiotics per year, need for nasal polypectomies and additional sinus operations, and improvement in sense of smell compared to the control group. Simultaneously, the ASA-Rx groups were able to significantly reduce systemic corticosteroid dosage, corticosteroid bursts per year, and, in the continuous group only, significantly reduce inhaled corticosteroids. All three groups maintained control of respiratory symptoms. ASA desensitization followed by long-term daily ASA Rx appears to improve ASA-sensitive rhinosinusitis-asthma and concomitantly allows reduction of systemic corticosteroids.

Aspirin-sensitive rhinosinusitis asthma: a double-blind crossover study of treatment with aspirin

Twenty-five ASA-sensitive patients with rhinosinusitis asthma underwent oral ASA challenges followed by desensitization to the adverse respiratory effects of ASA. We then compared the efficacy 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 FEV1, and the use of antiasthmatic medications including prednisone were not significantly changed during ASA treatment. Desensitization to ASA followed by ASA treatment appears to significantly alleviate symptoms of rhinosinusitis. However, only half the patients experienced improvement in their asthma symptoms during ASA treatment.

Aspirin-Exacerbated Respiratory Disease: Evaluation and Management

The clinical syndrome of aspirin-exacerbated respiratory disease (AERD) is a condition where inhibition of cyclooxygenase-1 (COX-1) induces attacks of upper and lower airway reactions, including rhinorrhea and varying degrees of bronchospasm and laryngospasm. Although the reaction is not IgE-mediated, patients can also present with anaphylactic hypersensitivity reactions, including hypotension, after exposure to COX-1 inhibiting drugs. All patients with AERD have underlying nasal polyps and intractable sinus disease which may be difficult to treat with standard medical and surgical interventions. This review article focuses on the management of AERD patients with a particular emphasis on aspirin desensitization and continuous treatment with aspirin.

Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects

OBJECTIVE Cross-sensitivity between aspirin and acetaminophen in aspirin-sensitive asthmatic patients has been reported with frequencies ranging from 0% to 29%. The relationship is dose-dependent for acetaminophen challenges, ranging between 300 and 100 mg. METHODS To determine the prevalence of cross-sensitivity to high-dose acetaminophen, we performed single-blind acetaminophen oral challenges with 1000 mg and 1500 mg in 50 aspirin-sensitive asthmatic patients and in 20 non-aspirin-sensitive asthmatic control subjects. RESULTS Overall, 17 of 50 (34%) of aspirin-sensitive asthmatic patients reacted to acetaminophen in doses of 1000 to 1500 mg (95% confidence interval: 20% to 49%). By contrast, none of the 20 non-aspirin-sensitive asthmatic patients reacted to acetaminophen (95% confidence interval: 0% to 14%). This difference was highly significant (p = 0.0013), supporting the hypothesis that cross-sensitivity between aspirin and acetaminophen is unique in aspirin-sensitive asthmatic patients. CONCLUSION Although high-dose ( > 1000 mg) acetaminophen cross-reactions with aspirin were significant with respect to frequency (34%), such reactions included easily reversed bronchospasm in only 22%, and were generally mild. We recommended that high doses of acetaminophen (1000 mg or greater) should be avoided in aspirin-sensitive asthmatic patients.

Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature

BACKGROUND Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity. Previously reported prevalence rates have been widely variable based on the population studied, method of diagnosis, and definition of aspirin sensitivity. OBJECTIVE We sought to determine the prevalence of AERD among asthmatic adults. METHODS A systematic review of databases was performed to identify all clinical trials published on or before June 16, 2013, that evaluated the prevalence of AERD. The studies were clustered into 7 different groups based on underlying disease (asthma, nasal polyps or chronic rhinosinusitis, or both), as well as on the methodology of prevalence determination. RESULTS A total of 1770 articles were identified, with 27 considered appropriate for inclusion. Prevalence rates of AERD ranged from 5.5% to 12.4% based on study type. Among all studies in asthmatic patients, regardless of method, the prevalence of AERD was 7.15% (95% CI, 5.26% to 9.03%). The prevalence of AERD was highest among patients with severe asthma (14.89% [95% CI, 6.48% to 23.29%]). Among patients with nasal polyps and chronic rhinosinusitis, the prevalence was 9.69% (95% CI, 2.16% to 17.22%) and 8.7% (95% CI, -1.02% to 18.34%), respectively. CONCLUSION AERD is a distinct and important subtype of asthma and polypoid sinus disease. The prevalence of AERD is 7% in typical adult asthmatic patients and twice that number in patients with severe asthma, which underscores the importance of recognizing this disorder. Early identification of this syndrome is critical in view of the increased morbidity and costs associated with asthma exacerbations and the option to treat patients with AERD with long-term aspirin treatment after desensitization.

Aspirin-sensitive asthma: Tolerance to aspirin after positive oral aspirin challenges

Two aspirin-sensitive asthmatic patients underwent oral aspirin challenges for investigative purposes. Folowoing the expected respiratory reaction to aspirin, the patients became refractory to the further adverse effects of aspirin. Additionally they began taking 325 mg aspirin per day, and after 6 and 8 mo aspirin dosage was increased to 650 mg per day. We have noted an improvement in their rhinitis and asthma during this open drug trial. Furthermore, maintenance systemic corticosteroids have been reduced in one patient and discontinued in the other without a decline in lung function values. If these intitial observations are found in a larger number of aspirin-sensitive asthmatic patients, changes in our understanding of the pathogenesis of rhinosinusitis-asthma-aspirin syndrome would follow, and treatment for such asthmatic patients might be improved.