Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease: diagnosis and current management.

Nonsteroidal anti­inflammatory drug-exacerbated respiratory disease (N­ERD) is a unique and often clinically severe disease affecting a subgroup of adults with asthma, chronic rhinosinusitis with nasal polyposis, and respiratory reactions with exposure to all cyclooxygenase 1-inhibiting nonsteroidal anti­inflammatory drugs. N­ERD has a high disease burden and is estimated to affect 7% of adults with asthma and 30% of patients who have both asthma and nasal polyps. The disease is underdiagnosed and underrecognized by physicians on a routine basis, which leads to a delay in appropriate management. The goal of this review is to focus on the disease recognition, diagnosis, and different modes of up­to­date therapies, including medical management, surgical intervention, aspirin desensitization, and biologic therapy.

Updates on treatment options in aspirin exacerbated respiratory disease.

PURPOSE OF REVIEW: The aim is to describe why this review is timely and relevant. Acetylsalicylic acid exacerbated respiratory disease (AERD) is a clinically significant disease affecting approximately 7% of all asthmatics or around 1,400,000 persons in the United States alone. A large portion of these patients remain undiagnosed. This review summarizes up to date knowledge on the pathophysiology, treatment opinions and provides an expert opinion on how to approach the AERD patient. RECENT FINDINGS: Findings describe the main themes in the literature covered by the article. Review of the current knowledge in terms of the key cells, cytokines/chemokines contributing to the acquired disease state of AERD. It also provides clinical approach toward the AERD patient with regards to current treatment options. SUMMARY: Summary describes the implications of the findings for clinical practice or research. This is an up-to-date review of the current literature, with insight into how to approach the management of an AERD patient.

Chronic Rhinosinusitis with Nasal Polyps and Asthma.

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) characterized by a type 2 immune signature often have severe and recurrent disease. Lower airway conditions such as asthma are common comorbidities and share similar pathophysiology. CRSwNP with asthma is characterized by tissue eosinophilia and high local IgE levels. Clinically, CRSwNP with comorbid asthma is associated with more severe sinonasal symptoms and worse quality of life, and it is more difficult to treat both medically and surgically. Asthma in the presence of nasal polyposis is also more difficult to control, being more exacerbation prone, with increased airway obstruction and more extensive eosinophilic inflammation. Aspirin/nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (AERD) is a recognized phenotype of CRSwNP with comorbid asthma. Patients with CRSwNP with comorbid AERD are among those with the most severe and difficult-to-treat disease, and tend to have severe NP. The shared pathophysiology of the upper and lower airways has important implications for both the diagnosis and management of respiratory comorbidities. However, in clinical practice, the nose and lungs are often treated as separate entities. The underlying systemic inflammatory link between CRSwNP and asthma provides a compelling rationale for systemic treatment with novel biologics targeting shared underlying type 2 inflammatory pathways.

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.

Aspirin and Nonsteroidal Antiinflammatory Drugs Hypersensitivity and Management.

Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) are widely used in the United States and throughout the world for a variety of indications. Several unique hypersensitivity syndromes exist to this class of medications, making them one of the common reasons for consultation to the allergist. The lack of any laboratory-based diagnostic studies to assist in identifying the culprits in these reactions make evaluation of aspirin and NSAID hypersensitivity challenging. Identifying patients appropriate for oral challenge and/or desensitization protocols is the standard pragmatic approach to this issue when it arises.

Effect of misoprostol on patients with aspirin-exacerbated respiratory disease undergoing aspirin challenge and desensitization.

BACKGROUND: Prostaglandin E2 (PGE2) is an anti-inflammatory compound that inhibits 5-lipoxygenase activity. Diminished PGE2 regulation in aspirin-exacerbated respiratory disease (AERD) leads to respiratory reactions on cyclooxygenase 1 inhibition. In vitro studies have found that exogenous PGE2 stabilizes inflammatory mediator release. OBJECTIVE: To examine whether misoprostol (oral prostaglandin E1 analogue) use during aspirin challenge and desensitization might decrease the severity of aspirin-induced symptoms and make desensitization safer for patients with AERD. METHODS: Forty-five patients undergoing aspirin challenge and/or desensitization were randomized to misoprostol (n = 30) or placebo (n = 15) and compared with a group of historical controls (n = 31). Misoprostol (200 µg) was administered at 30 minutes, 90 minutes, and 4 hours after the first dose of nasal ketorolac. Measured end points included change in forced expiratory volume in 1 second (FEV1), peak nasal inspiratory flow rate (PNIF), number of treatments received for induced reactions, and adverse gastrointestinal effects. RESULTS: A difference in FEV1 and PNIF reduction was detected between misoprostol and placebo (P = .03) and misoprostol and historical controls (P = .01), respectively, during nasal ketorolac challenge. No difference was detected among aspirin reactors. Among all reactors, no difference in magnitude was found for FEV1 (P = .13) or PNIF (P = .07) reduction across all 3 groups. Total treatment requirement was similar (P = .14). Patients receiving misoprostol were more likely to report adverse gastrointestinal effects (P = .02). CONCLUSION: The addition of misoprostol to current aspirin challenge and/or desensitization protocols reveals no protective effect in reducing the intensity of nonsteroidal anti-inflammatory drug-induced symptoms and is not recommended based on the findings in this study.

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.

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.

Aspirin desensitization for cardiovascular disease.

PURPOSE OF REVIEW: The use of aspirin in coronary artery disease and address the unmet need of aspirin therapy in patients with history of hypersensitivity reactions to aspirin (acetylsalicylic acid; ASA) or other nonsteroidal inflammatory drugs (NSAIDs). RECENT FINDINGS: Aspirin hypersensitivity is reported in 1.5% of patients with cardiovascular disease. However, many of those labeled as allergic to aspirin had experienced side-effects and could be safely treated with aspirin. Those with true hypersensitivity reactions were often not placed on appropriate antiplatelet therapy. A number of protocols of varying complexity exist in the literature for aspirin desensitization. The focus of this review is to identify the types of aspirin reactions that can occur and provide a rational approach to oral aspirin challenge and desensitization. SUMMARY: In summary, with rare exceptions, patients with a history of 'aspirin/NSAID allergy' who need ASA for cardiovascular issues will be able to safely take aspirin either after a graded challenge or desensitization providing a central role of the allergist in the management of these patients.

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.

Cardiovascular prophylaxis and aspirin "allergy".

Aspirin is an important antiplatelet agent in the treatment of cardiovascular disease. Aspirin "allergy" often directs the physician away from this potentially life-saving modality. The majority of patients with a history of "reactions to aspirin" have aspirin/nonsteroidal anti-inflammatory drug (NSAID)-induced gastritis, easy bruisability, or other side effects. The minority of these patients has a "true allergy," referred to as a hypersensitivity reaction. The former group can be started on aspirin without the need for special challenge. Adding a proton-pump inhibitor can often mitigate the gastrointestinal side effects. Patients with aspirin hypersensitivity can be safely challenged with aspirin.

Approach to patients with aspirin hypersensitivity and acute cardiovascular emergencies.

The occurrence of an emergent need for aspirin therapy in an aspirin or nonsteroidal anti-inflammatory drug (NSAID)-"allergic" individual presents one of the more challenging situations the allergist may face. A common request is for the allergist to evaluate an acutely ill patient in a monitored hospitalized setting with a vague and remote history of a "reaction to aspirin." Because of significant diagnostic limitations, introducing aspirin can be very difficult. The concern about the potential for causing anaphylaxis in an acutely ill patient can lead to fear about performing any challenge or desensitization in these patients. The objective of this article was to review the literature regarding aspirin challenges and desensitization in the emergency setting and present a rational approach to administering aspirin to patients that require this drug.

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.

Surfer's asthma.

Common asthma triggers during recreational activities include allergen exposure, concomitant viral infection, and exercise. We present the case of a 42-year-old man with a 2-year history of wheezing, chest tightness, and upper respiratory symptoms that were associated with surfing. He denied symptoms with other forms of exercise and had no personal history of asthma. His physical exam was unremarkable and his pre- and postbronchodilator spirometry was normal. After detailed history and keen observation on the patient's part, a diagnosis was made and he enjoyed good response to the therapy for this condition. Underrecognized asthma triggers and exposures in the recreational environment should be investigated.

The clinical effectiveness of aspirin desensitization in chronic rhinosinusitis.

Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease characterized by chronic rhinosinusitis, nasal polyposis, asthma, and airway reactivity to aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). For patients who have inadequately controlled rhinosinusitis and/or asthma despite treatment with topical corticosteroids and leukotriene-modifying drugs, aspirin desensitization is an important therapeutic option. This review examines the evidence supporting the effectiveness of aspirin desensitization for the treatment of chronic rhinosinusitis in patients with AERD. Practical aspects of conducting safe aspirin desensitization procedures and optimizing therapeutic benefits are also reviewed. When conducted in accordance with current guidelines, aspirin desensitization is a safe procedure that allows patients with AERD who have an indication for aspirin or other NSAIDs to safely ingest these medications. There is now strong evidence that aspirin desensitization and daily aspirin therapy is effective for treatment of the chronic inflammatory disease of the upper airway and lower airways in AERD.

Sinusitis and chronic progressive exercise-induced cough and dyspnea.

We present the case of a 47-year-old man with exercise-induced dyspnea, cough, chest tightness, and recalcitrant chronic rhinosinusitis. Evaluation revealed IgE sensitization to grass, tree, and weed pollen, no evidence of obstruction on spirometry, and a negative methacholine challenge. Diagnostic considerations included allergic and nonallergic rhinitis, asthma, aspirin-exacerbated respiratory disease, vocal cord dysfunction, extra-esophageal manifestations of acid reflux, and vasculitits. Further evaluation with sinus imaging, laryngoscopy, ambulatory pharyngeal pH testing, upper endoscopy, and bronchoscopy led to a diagnosis. Key issues surrounding the diagnostic and therapeutic approaches to this patient's condition are reviewed.

The relationship between historical aspirin-induced asthma and severity of asthma induced during oral aspirin challenges.

BACKGROUND: Historical aspirin- or nonsteroidal anti-inflammatory drug (NSAID)-induced reactions might provide predictive information about the severity of reactions in patients with aspirin-exacerbated respiratory disease (AERD) undergoing oral aspirin challenge (OAC). OBJECTIVE: We sought to assess the relationship between historical aspirin- or NSAID-induced bronchial reactions and the severity of bronchial reactions during OAC in patients with AERD. METHODS: Data regarding the provoking doses, treatments, and treatment settings of historical aspirin/NSAID-induced reactions were recorded, analyzed, and compared with the provoking doses, maintenance regimens, and observed decreases in FEV(1) that occurred during OAC in 210 consecutive patients referred with suspected AERD. RESULTS: Of 147 patients who reported seeking acute medical care for their historical aspirin/NSAID-induced asthma attacks, 101 (69%) were treated in an emergency department and released, and 46 (31%) required hospitalization. During OAC in these 147 subjects, 23 (16%) had a 20% to 29% decrease and 14 (10%) had a 30% or greater decrease in FEV(1) values from baseline. Of the 46 patients previously hospitalized for aspirin/NSAID-induced asthma attacks, 9 (20%) had a 20% to 29% decrease and 6 (13%) had a 30% or greater decrease in FEV(1) during OAC. By contrast, of the 63 patients who treated their prior aspirin/NSAID-induced reactions at home, 5 (8%) had a 20% to 29% decrease and 5 (8%) had a 30% or greater decrease in FEV(1) during OAC (P = not significant for both). CONCLUSION: The severity of the historical aspirin/NSAID-induced asthma attack was not predictive of asthma severity during OAC. CLINICAL IMPLICATIONS: These data provide further reassurance regarding the safety of outpatient aspirin desensitization.