Aspirin-exacerbated Respiratory Disease Research Articles

Patient-reported therapeutic experiences with biologic agents in aspirin-exacerbated respiratory disease

Respiratory biologics are FDA approved for the treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). However, there is limited data regarding patterns of utilization and efficacy of respiratory biologics in aspirin-exacerbated respiratory disease (AERD), a chronic disease characterized by asthma, CRSwNP, and hypersensitivity reactions to cyclooxygenase-1 inhibitors. We sought to characterize the patient experience with respiratory biologics for the treatment of AERD.

Characterization Of Alcohol Induced Respiratory Symptoms In Aspirin Exacerbated Respiratory Disease (AERD): The Happy Hour Study

AERD patients have high rates of upper and lower airway reactions with alcohol ingestion. I We hypothesized that alcohol ingestion will cause upper and lower airway reactivity that is diminished with montelukast and cetirizine pretreatment.

Prevalence Of Acetaminophen Intolerance Among Patients With Aspirin Exacerbated Respiratory Disease At A Tertiary Care Institution

Aspirin Exacerbated Respiratory Disease (AERD) is the clinical triad of chronic rhinosinusitis with nasal polyps, asthma, and intolerance to medications that inhibit the cyclooxygenase-1 enzyme. Historically, acetaminophen has been recommended as a safe alternative analgesic but clinically, some AERD patients cannot tolerate acetaminophen. This study examined the prevalence and clinical characteristics associated with acetaminophen intolerance among a cohort of AERD patients.

Phase 3b randomized controlled trial of fevipiprant in patients with nasal polyposis with asthma (THUNDER)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with asthma, particularly of late onset. Current treatment options for CRSwNP have limitations, and there is an unmet need for other safe and effective therapies. The aim of the THUNDER study was to determine the efficacy and safety of the prostaglandin D2 receptor 2 (DP2) antagonist fevipiprant in patients with CRSwNP and concomitant asthma, measured by improvement in nasal polyp score (primary end point), nasal congestion score, Sinonasal Outcome Test 22 score, and University of Pennsylvania Smell Identification Test score. THUNDER was a phase 3b, randomized, multicenter, double-blind, placebo-controlled, parallel-group, 16-week study of fevipiprant 150 mg or 450 mg once daily versus placebo. All patients received intranasal mometasone furoate 200 μg daily. Ninety-eight patients were randomly assigned to fevipiprant 150 mg (n= 32), fevipiprant 450 mg (n= 34), or placebo (n= 32). Mean (SE) change from baseline in nasal polyp score at week 16 was 0.20 (0.224) for fevipiprant 150 mg, -0.10 (0.216) for fevipiprant 450 mg, and 0.14 (0.233) for placebo. Mean treatment difference was 0.05 (95% confidence interval, -0.59, 0.70; adjusted P= .979) for fevipiprant 150 mg versus placebo and -0.25 (95% confidence interval, -0.88, 0.39; adjusted P= .656) for fevipiprant 450 mg versus placebo. There was no meaningful difference in the secondary end points for fevipiprant versus placebo. THUNDER provided no evidence of a role for fevipiprant in the treatment of patients with CRSwNP and asthma; future studies may establish a role for other DP2 antagonists, specifically in patients with aspirin-exacerbatedrespiratory disease.

Steroid affected cytokines in aspirin-exacerbated respiratory disease.

Patients with aspirin-exacerbated respiratory disease (AERD) are among the most challenging rhinologic patients to treat. AERD has a complex inflammatory milieu of lipid mediators and cytokines. In this study we evaluated cytokine differences in the complex AERD environment at the mucus, epithelial, and tissue levels. Samples were acquired at the time of sinus surgery from 21 patients (seven steroid-treated, 14 untreated) with aspirin challenge-confirmed AERD. Three methods (sponge adsorption, epithelial brushing, tissue biopsy) were used to acquire samples from the respective sinus sampling sites (mucus, polyp epithelium, and full-thickness polyp) of each patient. We measured and compared 16 cytokine concentrations in AERD patients with or without prednisone treatment using the Luminex platform. In most sampling sites, IL-5, IL-6, IL-10, IL-13, IL-33, CCL20, and TNF-α were detected at higher concentrations than IFN-γ, IL-1β, IL-17A, IL-4, IL-22, IL-17E/IL25, and GM-CSF. Each sampling site had a different pattern of cytokine levels, and except for IL-5 and IL-25 there was no correlation among sampling methods for each cytokine tested. The most notable and significant decreases in cytokines from those treated with prednisone were observed in the epithelium for IL-5, IL-10, IL-33, and IFN-γ. In the epithelial samples, type 2-associated cytokines IL-5 and IL-33, the anti-inflammatory cytokine IL-10, and IFN-γ were lower in AERD patients treated with prednisone. This work serves as a basis to assess therapeutic-induced mucosal cytokine responses in AERD and indicates that the site of cytokine measurement is an important consideration when assessing results.

Activation of platelet-adherent basophils in chronic rhinosinusitis with alcohol hypersensitivity

BackgroundAlcohol hypersensitivity (AH), an exacerbation of respiratory symptoms in response to alcohol consumption, is common in aspirin-exacerbated respiratory disease and other forms of chronic rhinosinusitis (CRS). We speculated that these reactions relate to the activation of innate immune cells including basophils and, in particular, platelet-adherent basophils by polyphenolic compounds contained within eliciting alcoholic beverages. ObjectiveWe investigated the absolute numbers of these cells in patients with AH and the ability of relevant polyphenolic compounds to cause cellular activation. MethodsData were collected from 412 consecutive adults presenting to a tertiary care sinonasal clinic in whom the presence of AH was elicited. The CRS phenotype was determined and results from complete blood cell count and differential were analyzed. A subset of patients was invited to donate blood samples that were used to explore the ability of relevant compounds associated with alcohol consumption to activate platelet-nonadherent and platelet-adherent basophils. Activation was quantified by flow cytometry as up-regulated expression of CD63 and as secretion of lipid metabolites. ResultsOf the 412 patients enrolled, 69 (16.7%) endorsed having AH. Significantly higher platelet counts were seen in patients reporting AH. Red wine extract and several polyphenolic compounds produced basophil activation and this was primarily observed among platelet-adherent basophils. Platelet activation was further established as the release of thromboxane B2. ConclusionThe presence of AH is associated with significantly higher platelet levels and compounds present in alcoholic beverages can directly mediate both their activation and the activation of platelet-adherent basophils.

Mediator production and severity of aspirin-induced respiratory reactions: Impact of sampling site and body mass index

Patients with aspirin-exacerbated respiratory disease can experience severe reactions during aspirin challenge that are associated with high levels of mast cell mediators. The tissue source and clinical factors contributing to systemic mediator levels are unknown. We sought to determine the concordance between respiratory tract and systemic inflammatory mediator levels and identify clinical factors associated with these mediators. We performed an oral aspirin challenge in 30 subjects with aspirin-exacerbated respiratory disease. Respiratory symptoms and function, nasal mucosal fluid, blood, and urine were collected at baseline, at the onset of a respiratory reaction, and over a 3-hour observation period. Changes in nasal and systemic mediator levels were compared. Neither tryptase nor leukotriene E4 levels in nasal fluid correlated with serum tryptase or urinary leukotriene E4 levels at baseline or during reactions. We observed no association between the baseline or aspirin-induced change in nasal versus urinary leukotriene E4 and serum tryptase levels. Body mass index inversely correlated with baseline and aspirin-induced urinary leukotriene E4, prostaglandin D2 metabolite, and serum tryptase levels, as well as with aspirin-induced symptoms and respiratory function, but not with nasal mediators. The levels of nasal and systemic aspirin-induced mast cell products are discordant in aspirin-exacerbated respiratory disease. Systemically detected levels are likely derived from mast cells outside of the sinonasal cavity and do not accurately reflect upper respiratory tract production. Increased body mass index decreases systemic mast cell mediator production and reaction severity, supporting a contribution of metabolic regulation in aspirin-induced systemic reactions.

Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count

In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP. We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC). SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory. Analyses included 407 patients (289 with asthma; 108with AERD; 371 and 278 with BEC counts ≥150 or ≥300 cells/μL, respectively). The proportion of patients with greater than or equal to 1-point improvement from baseline in NP score was higher with mepolizumab versus placebo across comorbid diseases (asthma: 52.9% vs 29.5%; AERD: 51.1% vs 20.6%) and baseline BEC subgroups (<150 cells/μL: 55.0% vs 31.3%; ≥150 cells/μL: 49.5% vs 28.1%; <300 cells/μL: 50.7% vs 29.0%; ≥300 cells/μL: 50.4% vs 28.1%). Asimilar trend was observed in patients without comorbid asthma or AERD. More patients had more than 3-point improvement in nasal obstruction VAS score with mepolizumab versus placebo across comorbid subgroups. Mepolizumab reduced polyp size and nasal obstruction in chronic rhinosinusitis with NP regardless of the presence of comorbid asthma or AERD.

Controversies in Allergy: Aspirin Desensitization or Biologics for Aspirin-Exacerbated Respiratory Disease—How to Choose

Aspirin-exacerbated respiratory disease (AERD) can be a frustratingly complex syndrome to treat. Until recently, standard medical and surgical therapies for patients' asthma and chronic rhinosinusitis with nasal polyposis were the primary treatment modalities available, combined with either complete avoidance of all aspirin and nonsteroidal anti-inflammatory medications, or aspirin desensitization and initiation of high-dose aspirin therapy. There are now several targeted respiratory biologics added to the available armament for patients with AERD and choosing between this ever-growing list of options can be daunting for both patients and their clinicians. This review includes our understanding and interpretation of the existing data for each option, along with our own approach to weighing the pros and cons of each treatment for individual patients.

Clinical safety of ibuprofen in pediatric practice

The article presents a review of the literature on the side effects of ibuprofen in children. The international guidelines recommend ibuprofen as an antipyretic and analgesic drug in pediatrics. The drug is characterized by a high profile of efficacy and safety in the treatment of children with fever, mild to moderate pain. Ibuprofen in over-the-counter doses has a low probability of serious side effects from the gastrointestinal tract and kidneys. Side effects of ibuprofen are transient and resolve after discontinuation of treatment. Circumstances associated with a higher risk of adverse events are highlighted. The use of ibuprofen is contraindicated in children with dehydration, which is associated with a risk of acute kidney damage. Caution should be exercised when prescribing ibuprofen to children with community-acquired pneumonia due to the risk of purulent complications. Ibuprofen should not be prescribed to patients with chickenpox to avoid bacterial superinfections. Ibuprofen should be used with caution in children with diseases of the gastrointestinal tract, liver, renal failure, hemorrhagic syndrome, anticoagulant therapy. Ibuprofen is allowed in children with bronchial asthma unless a personal or family history of aspirin-induced asthma. Caution should be exercised when treating premature infants or low birth weight infants due to the reduction in nephron mass and, therefore, the increased risk of renal damage. Ibuprofen should not be used in patients who are sensitive to this drug or other non-steroidal anti-inflammatory drugs. Ibuprofen should be taken in the minimum effective dose and discontinued as soon as possible — no more than 3 days for fever and 5 days for pain.

NSAID-exacerbated respiratory disease: a population study.

BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) may exacerbate respiratory symptoms. A recent European Academy of Allergy and Clinical Immunology position paper recommended the use of an acronym, N-ERD (NSAID-exacerbated respiratory disease), for this hypersensitivity associated with asthma or chronic rhinosinusitis with or without nasal polyposis. Our aim was to estimate the prevalence of N-ERD and identify factors associated with N-ERD.MethodsIn 2016, a cross-sectional questionnaire survey of a random adult population of 16 000 subjects aged 20–69 years was performed in Helsinki and Western Finland. The response rate was 51.5%.ResultsThe prevalence was 1.4% for N-ERD, and 0.7% for aspirin-exacerbated respiratory disease (AERD). The prevalence of N-ERD was 6.9% among subjects with asthma and 2.7% among subjects with rhinitis. The risk factors for N-ERD were older age, family history of asthma or allergic rhinitis, long-term smoking and exposure to environmental pollutants. Asthmatic subjects with N-ERD had a higher risk of respiratory symptoms, severe hypersensitivity reactions and hospitalisations than asthmatic subjects without N-ERD. The subphenotype of N-ERD with asthma was most symptomatic. Subjects with rhinitis associated with N-ERD, which would not be included in AERD, had the fewest symptoms.ConclusionWe conclude that the prevalence of N-ERD was 1.4% in a representative Finnish adult population sample. Older age, family history of asthma or allergic rhinitis, cumulative exposure to tobacco smoke, secondhand smoke, and occupational exposures increased odds of N-ERD. N-ERD was associated with significant morbidity.

Long-term evaluation of nasal polyposis recurrence: A focus on multiple relapses and nasal cytology

PurposeRecurrence of chronic rhinosinusitis with nasal polyps (CRSwNP) is highly variable, reaching 55–60% of cases. Different results about clinical parameters as recurrence predictors has been reported. The aim of this retrospective study was to evaluate CRSwNP recurrence risk after a long-term follow-up (up to 20 years). Moreover, the role of nasal cytology was assessed. Materials and methodsSixty-one patients who underwent functional endoscopic sinus surgery for CRSwNP were enrolled. Clinical parameters were recorded. Nasal cytology was performed at follow-up examinations. The Kaplan-Meier method was used to obtain the recurrence-free survival curves. The median number of recurrences per year was evaluated. ResultsFive- and 10-year recurrence rates were 30.29% and 66.06%, respectively. Median recurrence-free survival was 106 months. Asthma and Aspirin-Exacerbated Respiratory Disease represented predictors of multiple recurrences (p < 0.05). Intranasal steroids were the main treatment to prevent relapses (p < 0.05). Patients with normal cytology at follow-up evaluation had a lower probability to have first recurrence within 10 years (59% of cases), compared to neutrophil or eosinophil infiltrate (100% and 88% of cases, respectively) (p < 0.05). ConclusionsCRSwNP has a high recurrence risk, also more than 10 years after surgery. Nasal cytology may identify subjects with a higher risk of early recurrence.

Dupilumab as an adjunct to surgery in patients with aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and respiratory reactions to cyclooxygenase-1 inhibitors.1 Patients with AERD have severe CRSwNP that is often refractory to standard therapies, including intranasal corticosteroids,2 and is associated with high utilization of health care resources.3 After endoscopic sinus surgery (ESS), nasal polyp regrowth occurs within 2 years for 85% of patients with AERD,4 and for many patients, surgery does not provide complete resolution of symptoms.

Demographic Variation in Chronic Rhinosinusitis by Subtype and Region: A Systematic Review.

Chronic rhinosinusitis (CRS) describes a heterogenous group of diseases including CRS with (CRSwNP) or without nasal polyps (CRSsNP), aspirin-exacerbated respiratory disease (AERD), and allergic fungal rhinosinusitis (AFRS). It affects 10 to 15% of the US population and is more common in women and White patients. However, these estimates are based on survey and database studies with innate diagnostic inaccuracy. Additionally, few studies report subtype-specific demographics. We explore the demographic differences of CRS in the U.S. by subtype and region. To characterize demographic differences between the CRS population and the overall US population, and also between different CRS subtype populations. We performed a systematic review for articles reporting on US demographics of adults with CRS. Study participants were required to have been diagnosed using consensus criteria. Data on demographics, geographic region, and CRS subtype were analyzed. Our study analyzed 31 unique studies representing 8409 patients with 50.7% females and weighted mean age of 48.0 years. Compared to the overall US population, CRS patients were predominantly White (78.5%) and non-Hispanic (94.5%) with under-representation of other races. Grouped by subtype, CRSwNP affected a significantly higher proportion of men (59.8%). AFRS affected a significantly higher proportion of Black patients (53.8%) while CRSsNP was more prevalent in White patients (84.2%). When grouped by region, the South had a significantly higher proportion of female (53%) and Black (17.8%) CRS patients. The West had a significantly higher proportion of Asian (4.5%) and Hispanic (12.3%) patients. Significant demographic differences exist in CRS patients based on subtype and region. These data provide an estimation of the demographic make-up of CRS, but further high-level demographic studies are needed.

Updates on treatment options in aspirin exacerbated respiratory disease.

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. 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 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 Outcomes of Patients With Aspirin-Exacerbated Respiratory Disease Treated With Budesonide Irrigations: A Case Series.

Pathophysiology-targeting treatments exist for aspirin-exacerbated respiratory disease (AERD) through aspirin desensitization and biologics, such as dupilumab. With increasing attention paid to these treatments, which may be associated with significant side effects and/or cost, there is little description of chronic rhinosinusitis with nasal polyps (CRSwNP) response to treatment with intranasal corticosteroids and saline irrigations in AERD. To determine the effect of intranasal budesonide irrigations for the treatment of CRSwNP in AERD. This is an observational study of 14 AERD patients presenting to a rhinology clinic for CRS who were treated with twice daily high volume, low pressure irrigations with 240 mL of saline to which a 0.5 mg/2 mL respule of budesonide was added. All participants completed a 22-item Sinonasal Outcome Test (SNOT-22) at enrollment and at follow up 1 to 6 months later. Polyp scores were also calculated at each time point. SNOT-22 scores ranged from 26 to 98 (median: 40.5) at enrollment and 3 to 85 (median: 38.5) at follow-up. Polyp scores ranged from 2 to 6 (median: 4) at enrollment at 0 to 6 (median: 2) at follow-up. Over the treatment period, change in SNOT-22 score ranged from -38 to 16 (median: -18) and change in polyp score ranged from -2 to 0 (median: -0.5). Approximately 57% of participants experienced at least 1 minimal clinically important difference in SNOT-22 score and 21% of participants had a SNOT-22 score <20 at follow-up. Medical management with intranasal corticosteroids and saline irrigations alone leads to significant improvement in sinonasal symptomatology in a subset of AERD.

New concepts for the pathogenesis and management of aspirin-exacerbated respiratory disease.

The purpose of this review is to provide a comprehensive summary of the current understanding of the pathogenesis of aspirin-exacerbated respiratory disease (AERD), and an update on its management. Elevated levels of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a newly described metabolite of arachidonic acid, have been identified in nasal polyps of AERD patients. In nasal polyps, activated basophils, and interleukin-5 -receptor-α-positive IL-5Rα+ plasma cells are associated with more severe nasal polyposis in AERD. Alveolar monocyte-derived macrophages and their persistent proinflammatory activation were suggested as putative factors contributing to AERD. Although not AERD-specific, three biological agents are now available for the management of both nasal polyposis and asthma. A newly downstream product of 15-lipoxygenase, 15-Oxo-ETE, was recently found to be significantly elevated in nasal polyps from AERD patients. This eicosanoid metabolite likely originates from an interplay between epithelial cells and mast cells. Nasal polyp basophils, IL-5Rα+ plasma cells, and alveolar macrophages were identified as important contributors to inflammation in AERD. Besides traditional aspirin desensitization and treatment for AERD management, several biologics for treatment of asthma are available, including three that have been approved for nasal polyposis. These biologic agents show variable rates of success in controlling AERD symptoms.

Anaphylaxis in a Patient Undergoing FESS for Nasal Polyposis: Revisting Samter’s Triad

Patients with nasal polyposis frequently have associated bronchial asthma and hypersensitivity to NSAIDs. When the three conditions co-exist, it is referred to as the Samter’s triad. Patients with Samter’s triad are an important subset of those with aspirin-exacerbated respiratory disease (AERD). We present a case of a young female patient undergoing endoscopic sinus surgery for nasal polyps, who although did not show any other features of AERD, went on to develop florid anaphylaxis to diclofenac administration intra-operatively. After adequate resuscitation and intensive care stay, the patient made a complete recovery. NSAIDs must be avoided in patients with nasal polyps, despite showing no other features of this syndrome. Other analgesic agents that can be used include IV paracetamol and opioids like tramadol.

Outcomes of aspirin exacerbated respiratory disease patients treated with aspirin desensitization and biologics.

Outcomes of aspirin exacerbated respiratory disease patients treated with aspirin desensitization and biologics.

Yardstick for the medical management of chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is an inflammatory condition of the paranasal sinuses defined by classic symptoms, imaging findings, or endoscopic findings. There are a growing number of emerging pharmacologic therapies being evaluated to treat patients with CRS, some of which have gained indication status in the United States. There have not been updated treatment guidelines published in the United States however since 2014. This document is meant to serve as an updated expert consensus document for the pharmacologic management of patients with CRS. We review available data focusing on prospective clinical trials on oral and intranasal corticosteroids, nasal irrigation, biologics, antibiotics, and allergy immunotherapy for CRS both with and without nasal polyposis, including specific therapies for aspirin-exacerbated respiratory disease–associated CRS and allergic fungal CRS. There are multiple options to treat CRS, and clinicians should be knowledgeable on the efficacy and risks of these available therapies. Allergists-immunologists now have various therapies available to treat patients with CRS.