Katharine M. Woessner

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.

Use of intranasal ketorolac and modified oral aspirin challenge for desensitization of aspirin-exacerbated respiratory disease.

BACKGROUND Intranasal ketorolac challenges can induce respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD). OBJECTIVE To determine whether intranasal ketorolac challenges might be used for aspirin desensitization. METHODS One hundred patients with suspected AERD who were referred to Scripps Clinic from May 1, 2007 to December 31, 2009 were challenged with 4 increasing doses of ketorolac intranasally at 30-minute intervals. Symptoms, objective changes in the results of their nasal examination, peak nasal inspiratory flow rates, and forced expiratory volume in 1 second (FEV(1)) values were recorded. After nasal ketorolac dosing, patients were given oral aspirin as part of the challenge and desensitization. A control group consisted of 100 patients who had previously undergone our standard oral aspirin challenges and desensitization. Both groups were consecutively enrolled and had similar clinical characteristics. RESULTS Compared with the standard oral aspirin challenge and desensitization, intranasal ketorolac and modified aspirin challenge significantly attenuated the mean percentage decrease in FEV(1) values (8.5% vs 13.4%; P = .01) and decreased the percentage of extrapulmonary reactions (23% vs 45%; P = .002), particularly laryngospasm (7% vs19%; P = .02) and gastrointestinal reactions (12% vs 33%; P = .001). This new protocol was significantly shorter, lasting an average of 1.9 vs 2.6 days (P = <.001). In fact, 83% of the patients completed the new protocol in less than 48 hours compared with only 20% in the oral challenge control group (P < .001). CONCLUSIONS Intranasal ketorolac challenge and desensitization followed by rapid oral aspirin challenges is effective, safe, and less time-consuming than our standard oral aspirin desensitization protocol.

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug-related urticaria and angioedema.

Nonsteroidal anti-inflammatory drug (NSAID)-induced urticarial and angioedema reactions are among the most commonly encountered drug hypersensitivity reactions in clinical practice. Three major clinical phenotypes of NSAID-induced acute skin reactions manifesting with angioedema, urticaria, or both have been distinguished: NSAID-exacerbated cutaneous disease, nonsteroidal anti-inflammatory drug-induced urticaria/angioedema (NIUA), and single NSAID-induced urticaria and angioedema. In some patients clinical history alone might be sufficient to establish the diagnosis of a specific type of NSAID hypersensitivity, whereas in other cases oral provocation challenges are necessary to confirm the diagnosis. Moreover, classification of the type of cutaneous reaction is critical for proper management. For example, in patients with single NSAID-induced reactions, chemically nonrelated COX-1 inhibitors can be safely used. However, there is cross-reactivity between the NSAIDs in patients with NSAID-exacerbated cutaneous disease and NIUA, and thus only use of selective COX-2 inhibitors can replace the culprit drug if the chronic treatment is necessary, although aspirin desensitization will allow for chronic treatment with NSAIDs in some patients with NIUA. In this review we present a practical clinical approach to the patient with NSAID-induced urticaria and angioedema.

Evidence-based approach to aspirin desensitization in aspirin-exacerbated respiratory disease

1. Review the target audience, learning objectives and author disclosures. 2. Complete the pre-test online at www.jacionline.org (click on the Online CME heading). 3. Follow the online instructions to read the full version of the article, including the clinical vignette and review components. 4. Complete the post-test. At this time, you will have earned 1.00 AMA PRA Category 1 CME Credit. 5. Approximately 4 weeks later you will receive an online assessment regarding your application of this article to your practice. Once you have completed this assessment, you will be eligible to receive 2 MOC Part II Self-Assessment credits from the American Board of Allergy and Immunology.

Crossreacting drugs and chemicals

Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) exert their clinical effect through inhibition of prostaglandin H synthases 1 and 2, also known as cyclooxygenase. This shared effect of COX-inhibition is also the mechanism for shared adverse effects. Much of our understanding of cross-reacting drugs and chemicals with aspirin comes from studying asthmatics with aspirin-exacerbated respiratory disease (AERD). Aspirin exacerbated respiratory disease is characterized by recalcitrant sinusitis/polyposis, asthma and precipitation of asthma after ingestion of aspirin and most NSAIDs. Cross-reactions between ASA and NSAIDs occur with first exposure unlike IgE-mediated allergic drug reactions. Cross-reactions between aspirin and other drugs are dependent upon inhibition of the cyclooxygenase-1 isoenzyme. Desensitization to aspirin will result in cross-desensitization to all NSATDs that inhibit COX-1. Despite reports in the literature, there does not appear to he cross-reactions between food coloring, hydrocortisone succinate and monosodium glutamate in individuals with aspirin exacerbated respiratory disease. The new highly selective cyclooxygenase 2 inhibitors are well tolerated in AERD asthmatics who have not been desensitized to aspirin. Because low-dose ASA exerts a cardioprotective effect by irreversible inhibition of COX-1, AERD patients who are at risk for coronary artery disease should be considered for aspirin desensitization.

NSAID single-drug-induced reactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are cyclooxygenase inhibitors with analgesic, anti-inflammatory, antipyretic, and antithrombotic effects. NSAIDs have been implicated in a variety of drug-induced reactions that are proved as or suspected of being mediated through a host immune response. Single-drug-induced reactions are the hallmark of these types of reactions. The types of single-drug-induced reactions are the confluence of 2 variables, the structure of the drug and the specific types of immune responses. This article identifies reactions patterns and the NSAIDs most likely to elicit each immune response.

Update on Aspirin-Exacerbated Respiratory Disease

Aspirin-exacerbated respiratory disease (AERD) is an acquired disease characterized by chronic eosinophilic airway inflammation with underlying dysregulation of arachidonic acid metabolism. The purpose of this paper is to review the latest developments in our understanding of the underlying pathophysiology including the role of eosinophils, mast cells, innate lymphoid cells (ILC2), and platelets. Clinical features such as respiratory reactions induced by alcohol, aggressive nasal polyposis, and anosmia will allow for earlier recognition of these patients in clinical practice. The current state of the art management of AERD will be addressed including the ongoing central role for aspirin desensitization and high-dose aspirin therapy.

An Overview of Nonsteroidal Antiinflammatory Drug Reactions

Nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin, are among the most commonly used drugs worldwide. They account for a large number of adverse drug reactions (ADRs). The prevalence of NSAID-induced reactions is increasing. Distinguishing between a predicted side effect of a drug and a potentially life-threatening hypersensitivity reaction is essential to manage the affected patient. However, most clinicians find it difficult to diagnose these types of reactions despite published classification schemes. In this overview, we provide an in-depth review of NSAID classification, types of NSAID reactions, diagnostic tactics, and management strategies to provide the reader with a greater understanding of NSAID-induced reactions.

Use of a composite symptom score during challenge in patients with suspected aspirin-exacerbated respiratory disease

BACKGROUND Aspirin-exacerbated respiratory disease is characterized by asthma, chronic rhinosinusitis, nasal polyposis, and sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs. Confirmation of the diagnosis requires provocation challenge with resulting upper and/or lower airways reactivity. Currently, determination of a positive challenge result is based solely on clinical judgment that synthesizes subjective symptoms and objective measures, as a concomitant increase in nasal or bronchial airways resistance is measured in only half of patients. OBJECTIVE To describe a quantitative scoring system, based on symptoms typically reported during provocation challenge, used to identify a positive challenge result. METHODS A total of 115 patients were asked to record 10 symptoms, rated on a scale from 1 (mild) to 10 (most severe), at regular intervals during intranasal ketorolac with modified oral aspirin challenge performed in our office. Composite scores, a simple sum of all individual scores, were calculated at each time point and compared with baseline, prechallenge values. RESULTS One hundred of the 115 patients were determined to have a positive challenge result. A statistically significant difference in composite scores was observed in reactors vs nonreactors. All nonreactors recorded an increase in composite score of less than 5, whereas 69% of reactors recorded an increase of 5 or more. CONCLUSION Our 10-symptom composite score provides a quantitative and comparable measure of symptoms that typically present during a challenge with a positive result. Although an external validation is needed to confirm its diagnostic performance characteristics, a change in composite score of 5 or more appears to be specific to reactors.

Long-term Clinical Outcomes of Aspirin Desensitization With Continuous Daily Aspirin Therapy in Aspirin-exacerbated Respiratory Disease

Background Aspirin-exacerbated respiratory disease (AERD), also known as Samter’s triad or aspirin (ASA)-intolerant asthma, affects 7% of asthmatics and has a higher prevalence in those with chronic rhinosinusitis and concomitant nasal polyposis. ASA desensitization with daily ASA therapy is a uniquely beneficial treatment for this disease entity and has been shown to have a significant impact on symptom scores, polyp disease, and need for systemic corticosteroids. However, no long-term studies have demonstrated whether or not ASA therapy remains safe and beneficial for these patients beyond 5–10 years. Objective This study was designed to determine the clinical course of AERD patients desensitized between 1995 and 2010. Methods A 20-question survey was distributed to patients who successfully completed ASA desensitization between January 1995 and April 2010. The questions were designed to assess ASA safety and longitudinal effects of ASA therapy in AERD. Results Of the 285 patients contacted, 92 (32%) completed the questionnaire. Average length of follow-up was 15 years. Of survey responders, 35 patients had discontinued ASA therapy. Although adverse reactions occurred, many also discontinued due to lack of efficacy or need for surgery. For those remaining on ASA (62%), significant improvement in sense of smell, asthma, sinus, and allergic rhinitis scores were noted (P ≤ .001). The majority of ASA patients (68%) had a positive response to treatment and did not require further sinus surgery. However, ASA therapy did not delay the time to next sinus/polyp surgery (P = .27) or reduce total number of sinus surgeries (P = .56) compared to those who stopped treatment. Nearly 85% of AERD patients on ASA therapy found it to be helpful in improving airway disease and quality of life. Conclusion Aspirin desensitization followed by daily maintenance ASA therapy appears to be safe and effective even after 10+ years of continuous use.