Genetics of denatonium-responsive bitter receptors in aspirin-exacerbated respiratory disease.
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ABSTRACT:
SUBMITTER: Douglas JE
PROVIDER: S-EPMC9957822 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
Publications
Genetics of denatonium-responsive bitter receptors in aspirin-exacerbated respiratory disease.
Douglas Jennifer E JE Lin Cailu C Mansfield Corrine J CJ Bell Katherine K Salmon Mandy K MK Kohanski Michael A MA Adappa Nithin D ND Palmer James N JN Bosso John V JV Reed Danielle R DR Cohen Noam A NA
International forum of allergy & rhinology 20220912 3
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Project description:BackgroundAspirin-exacerbated respiratory disease (AERD) is a condition of the upper and lower respiratory tract characterized by reactions to nonsteroidal anti-inflammatory drugs. The Severe Asthma Research Program reported a strong association between perimenstrual asthma (PMA) and aspirin-sensitive asthma.ObjectiveTo evaluate the prevalence and characteristics of PMA among a cohort of patients with AERD.MethodsWomen 18 years and older enrolled in the Brigham and Women's AERD registry were surveyed about their reproductive, asthma, and sinus history. Subjects reporting the development of asthma before menopause were included. Continuous and categorical variables were compared between those reporting menstruation as a trigger for asthma symptoms and those who did not. Covariates expected a priori to have a positive effect on the odds of PMA were included in a multivariate logistic regression model to test associations between PMA and clinical factors.ResultsAmong females of childbearing potential, 369 of 695 responded to the survey and 322 met inclusion criteria. Twenty-four percent of subjects (n = 74) reported PMA. Earlier age of AERD onset, concurrent worsening of sinus symptoms the week before or during menstruation, increased emergency department visits for asthma, and a change in the severity of respiratory symptoms at menopause were more common in PMA. Earlier age at first nonsteroidal anti-inflammatory drug-induced respiratory reaction and emergency department visits increased the odds of reporting PMA.ConclusionsPMA and increased sinus symptoms with menstruation are common in females with AERD. Females with AERD should be counseled about upper and lower respiratory symptom deterioration with menstruation.
| S-EPMC7012664 | biostudies-literature
Project description:Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the exposure to aspirin or other nonsteroidal anti-inflammatory drugs. The key pathogenic mechanisms associated with AERD are the overproduction of cysteinyl leukotrienes (CysLTs) and increased CysLTR1 expression in the airway mucosa and decreased lipoxin and PGE2 synthesis. Genetic studies have suggested a role for variability of genes in disease susceptibility and the response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10, ACE, IL13, KIF3A, SLC22A2, CEP68, PTGER, and CRTH2 and a four-locus SNP set composed of B2ADR, CCR3, CysLTR1, and FCER1B. Future areas of investigation need to focus on comprehensive approaches to identifying biomarkers for early diagnosis.
| S-EPMC3151506 | biostudies-literature
Project description:BackgroundAspirin-exacerbated respiratory disease (AERD) is a mechanistically distinct subtype of chronic rhinosinusitis with nasal polyps (CRSwNP). Although frequently associated with type 2 inflammation, literature characterizing the milieu of inflammatory cytokines and lipid mediators in AERD has been conflicting.ObjectiveWe sought to identify differences in the upper airway inflammatory signature between CRSwNP and AERD and determine whether endotypic subtypes of AERD may exist.MethodsLevels of 7 cytokines representative of type 1, type 2, and type 3 inflammation, and 21 lipid mediators were measured in nasal mucus from 109 patients with CRSwNP, 30 patients with AERD, and 64 non-CRS controls. Differences in inflammatory mediators were identified between groups, and patterns of inflammation among patients with AERD were determined by hierarchical cluster analysis.ResultsAERD could be distinguished from CRSwNP by profound elevations in IL-5, IL-6, IL-13, and IFN-γ; however, significant heterogeneity existed between patients. Hierarchical cluster analysis identified 3 inflammatory subendotypes of AERD characterized by (1) low inflammatory burden, (2) high type 2 cytokines, and (3) comparatively low type 2 cytokines and high levels of type 1 and type 3 cytokines. Several lipid mediators were associated with asthma and sinonasal disease severity; however, lipid mediators showed less variability than cytokines.ConclusionsAERD is associated with elevations in type 2 cytokines (IL-5 and IL-13) and the type 1 cytokine, IFN-γ. Among patients with AERD, the inflammatory signature is heterogeneous, supporting subendotypes of the disease. Variability in AERD immune signatures should be further clarified because this may predict clinical response to biologic medications that target type 2 inflammation.
| S-EPMC8035132 | biostudies-literature
Project description:Asthma and chronic rhinosinusitis are heterogeneous airway diseases of the lower and upper airways, respectively. Molecular and cellular studies indicate that these diseases can be categorized into unique endotypes, which have therapeutic implications. One such endotype is aspirin-exacerbated respiratory disease (AERD), which encompasses the triad of asthma, aspirin (or nonsteroidal anti-inflammatory drug) hypersensitivity, and nasal polyposis. AERD has unique pathophysiological features that distinguish it from aspirin-tolerant asthma and other forms of chronic rhinosinusitis. This review details molecular and cellular features of AERD and highlights current and future therapies that are based on these insights.
| S-EPMC4790533 | biostudies-other
Project description:Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease characterized clinically by the triad of asthma, nasal polyposis, and pathognomonic respiratory reactions after ingestion of aspirin. It is a distinct syndrome associated with eosinophilic infiltration of respiratory tissues and excessive production of cysteinyl leukotrienes. Despite the consistent clinical phenotype of the respiratory disease, the underlying pathogenesis of the disease remains unclear. In addition to their role in hemostasis, platelets have the capacity to influence the activation state and function of other immune cells during inflammation and to facilitate granulocyte recruitment into the tissues. Platelets also possess a repertoire of potent preformed mediators of inflammation that are released on activation and are a rich source of newly synthesized lipid mediators that alter vascular permeability and smooth muscle tone. Accordingly, platelet activity has been linked to diverse inflammatory diseases, including asthma. Both human and animal studies strongly suggest that platelet activity is uniquely associated with the pathophysiology of AERD. This article summarizes the evidence supporting an effector role for platelets in asthmatic patients in general and in patients with AERD in particular and considers the potential therapeutic implications.
| S-EPMC4559084 | biostudies-literature
Project description: Not available
| S-EPMC6519056 | biostudies-literature
Project description:BackgroundAspirin desensitization followed by daily aspirin use is an effective treatment for aspirin-exacerbated respiratory disease (AERD).ObjectiveTo assess clinical features as well as genetic, immune, cytological and biochemical biomarkers that might predict a positive response to high-dose aspirin therapy in AERD.MethodsWe enrolled 34 AERD patients with severe asthma who underwent aspirin desensitization followed by 52-week aspirin treatment (650 mg/d). At baseline and at 52 weeks, clinical assessment was performed; phenotypes based on induced sputum cells were identified; eicosanoid, cytokine and chemokine levels in induced sputum supernatant were determined; and induced sputum expression of 94 genes was assessed. Responders to high-dose aspirin were defined as patients with improvement in 5-item Asthma Control Questionnaire score, 22-item Sino-Nasal Outcome Test (SNOT-22) score and forced expiratory volume in 1 second at 52 weeks.ResultsThere were 28 responders (82%). Positive baseline predictors of response included female sex (p = .002), higher SNOT-22 score (p = .03), higher blood eosinophil count (p = .01), lower neutrophil percentage in induced sputum (p = .003), higher expression of the hydroxyprostaglandin dehydrogenase gene, HPGD (p = .004) and lower expression of the proteoglycan 2 gene, PRG2 (p = .01). The best prediction model included Asthma Control Test and SNOT-22 scores, blood eosinophils and total serum immunoglobulin E. Responders showed a marked decrease in sputum eosinophils but no changes in eicosanoid levels.Conclusions and clinical relevanceFemale sex, high blood eosinophil count, low sputum neutrophil percentage, severe nasal symptoms, high HPGD expression and low PRG2 expression may predict a positive response to long-term high-dose aspirin therapy in patients with AERD.
| S-EPMC9292205 | biostudies-literature
Project description:Aspirin-exacerbated respiratory disease (AERD) severity and its clinical phenotypes are characterized by genetic variation within pathways for arachidonic acid metabolism, inflammation, and immune responses. Epigenetic effects, including DNA methylation and histone protein modification, contribute to regulation of many genes that contribute to inflammatory states in AERD. The development of noninvasive, predictive clinical tests using data from genetic, epigenetic, pharmacogenetic, and biomarker studies will improve precision medicine efforts for AERD and asthma treatment.
| S-EPMC5720138 | biostudies-literature
Project description:BackgroundAspirin-exacerbated respiratory disease (AERD) is characterized by 3 clinical features: asthma, nasal polyposis, and respiratory reactions to cyclooxygenase-1 inhibitors (nonsteroidal anti-inflammatory drugs). Electronic health records (EHRs) contain information on each feature of this triad.ObjectiveWe sought to determine whether an informatics algorithm applied to the EHR could electronically identify patients with AERD.MethodsWe developed an informatics algorithm to search the EHRs of patients aged 18 years and older from the Partners Healthcare system over a 10-year period (2004-2014). Charts with search terms for asthma, nasal polyps, and record of respiratory (cohort A) or unspecified (cohort B) reactions to nonsteroidal anti-inflammatory drugs were identified as "possible AERD." Two clinical experts reviewed all charts to confirm a diagnosis of "clinical AERD" and classify cases as "diagnosed AERD" or "undiagnosed AERD" on the basis of physician-documented AERD-specific terms in patient notes.ResultsOur algorithm identified 731 "possible AERD" cases, of which 638 were not in our AERD patient registry. Chart review of cohorts A (n = 511) and B (n = 127) demonstrated a positive predictive value of 78.4% for "clinical AERD," which rose to 88.7% when unspecified reactions were excluded. Of those with clinical AERD, 12.4% had no mention of AERD by any treating caregiver and were classified as "undiagnosed AERD." "Undiagnosed AERD" cases were less likely than "diagnosed AERD" cases to have been seen by an allergist/immunologist (38.7% vs 93.2%; P < .0001).ConclusionsAn informatics algorithm can successfully identify both known and previously undiagnosed cases of AERD with a high positive predictive value. Involvement of an allergist/immunologist significantly increases the likelihood of an AERD diagnosis.
| S-EPMC5266739 | biostudies-literature
Project description:Aspirin-exacerbated respiratory disease (AERD) is an adult-onset upper and lower airway disease consisting of eosinophilic nasal polyps, asthma, and respiratory reactions to cyclooxygenase 1 (COX-1) inhibitors. Management includes guideline-based treatment of asthma and sinus disease, avoidance of COX-1 inhibitors, and for some patients aspirin desensitization followed by high-dose aspirin therapy. Despite this, many patients have inadequately controlled symptoms and require multiple sinus surgeries. In this review, we discuss the current standard approaches to the management of AERD, and we introduce several therapeutics under development that may hold promise for the treatment of AERD.
| S-EPMC4853506 | biostudies-literature