Platelets in patients with aspirin-exacerbated respiratory disease.
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ABSTRACT:
SUBMITTER: Laidlaw TM
PROVIDER: S-EPMC4559084 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
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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:BackgroundA large percentage of patients with aspirin exacerbated respiratory disease (AERD) report the development of alcohol-induced respiratory reactions, but the true prevalence of respiratory reactions caused by alcoholic beverages in these patients was not known.ObjectiveWe sought to evaluate the incidence and characteristics of alcohol-induced respiratory reactions in patients with AERD.MethodsA questionnaire designed to assess alcohol-induced respiratory symptoms was administered to patients at Brigham and Women's Hospital and Scripps Clinic. At least 50 patients were recruited into each of 4 clinical groups: (1) patients with aspirin challenge-confirmed AERD, (2) patients with aspirin-tolerant asthma (ATA), (3) patients with aspirin tolerance and with chronic rhinosinusitis, and (4) healthy controls. Two-tailed Fisher exact tests with Bonferroni corrections were used to compare the prevalence of respiratory symptoms among AERD and other groups, with P ≤ .017 considered significant.ResultsThe prevalence of alcohol-induced upper (rhinorrhea and/or nasal congestion) respiratory reactions in patients with AERD was 75% compared with 33% with aspirin-tolerant asthma, 30% with chronic rhinosinusitis, and 14% with healthy controls (P < .001 for all comparisons). The prevalence of alcohol-induced lower (wheezing and/or dyspnea) respiratory reactions in AERD was 51% compared with 20% in aspirin-tolerant asthma and with 0% in both chronic rhinosinusitis and healthy controls (P < .001 for all comparisons). These reactions were generally not specific to one type of alcohol and often occurred after ingestion of only a few sips of alcohol.ConclusionAlcohol ingestion causes respiratory reactions in the majority of patients with AERD, and clinicians should be aware that these alcohol-induced reactions are significantly more common in AERD than in controls who are aspirin tolerant.
| S-EPMC4018190 | biostudies-literature
Project description:BackgroundAspirin-exacerbated respiratory disease (AERD) is distinguished from aspirin-tolerant asthma/chronic sinusitis in large part by an exuberant infiltration of eosinophils that are characterized by their overexpression of metabolic pathways that drive the constitutive and aspirin-induced secretion of cysteinyl leukotrienes (CysLTs).ObjectiveWe defined the inflammatory milieu that in part drives CysLT overproduction and, in particular, the role of IFN-? in the differentiation of eosinophils.MethodsQuantitative real-time PCR was performed for TH1 and TH2 signature cytokines on tissue from control subjects, patients with chronic hyperplastic eosinophilic sinusitis, and patients with AERD, and their cellular source was determined. The influence of IFN-? on maturation, differentiation, and functionality of eosinophils derived from hematopoietic stem cells was determined.ResultsGene expression analysis revealed that tissue from both aspirin-tolerant subjects and patients with AERD display a TH2 cytokine signature; however, AERD was distinguished from chronic hyperplastic eosinophilic sinusitis by the prominent expression of IFN-?. Intracellular and immunohistochemical cytokine staining revealed that the major sources of these cytokines were the eosinophils themselves. IFN-? promoted the maturation of eosinophil progenitors, as measured by increased mRNA and surface expression of CCR3 and sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8). Additionally, IFN-? increased the expression of genes involved in leukotriene synthesis that led to increased secretion of CysLTs. IFN-?-matured eosinophil progenitors were also primed, as demonstrated by their enhanced degranulation.ConclusionsHigh IFN-? levels distinguish AERD from aspirin-tolerant asthma and underlie the robust constitutive and aspirin-induced secretion of CysLTs that characterize this disorder.
| S-EPMC3788084 | biostudies-literature
Project description:BackgroundPatients widely use medical identification (ID) to indicate their food and drug allergies, and chronic medical conditions. One chronic condition for which patients are recommended to use a form of medical ID is Aspirin-Exacerbated Respiratory Disease (AERD), a disease characterized by the presence of asthma, chronic rhinosinusitis with nasal polyps and sensitivity to aspirin and other COX-1 inhibitors, including nonsteroidal anti-inflammatory drugs (NSAIDs). The uptake of medical ID use in AERD is unknown and has not been widely studied in this population.MethodsWe conducted a cross-sectional survey study to measure the perception of the need to use a medical ID and its use by patients with AERD internationally.Results245 members of an online AERD support group completed an online survey. The majority (80%, n = 198) of the participants did not use any form of medical ID. The participants reported that the lack of knowledge and awareness about the importance of using a medical ID was the most common reason for not using it.ConclusionThis international survey found that the majority of the AERD patient respondents did not use a medical ID. The most common reasons for nonuse were not knowing that it is recommended for their condition and that the patients did not consider it necessary. The results highlight the need for further patient and health care provider education.
| S-EPMC10012488 | 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:BACKGROUND:Aspirin-exacerbated respiratory disease (AERD) differs from aspirin-tolerant disease in part because of eosinophilic tissue infiltration and overexpression of arachidonic acid metabolic pathway components that lead to enhanced secretion of cysteinyl leukotrienes and prostaglandin (PG) D2 observed constitutively and paradoxically in response to aspirin and other COX inhibitors. We have previously demonstrated the capacity of IFN-? to drive cysteinyl leukotriene expression and response. OBJECTIVE:We investigated eosinophils as a source of PGD2 production in patients with AERD. METHODS:Eosinophils were enriched from tissue and peripheral blood obtained from control subjects, patients with aspirin-tolerant disease, and patients with AERD. mRNA was extracted and evaluated for expression of hematopoietic prostaglandin D synthase (hPGDS). Expression of hPGDS protein was confirmed with Western hybridization and immunofluorescence staining. Cells were stimulated with aspirin, and secretion of PGD2 was quantified. CD34+ progenitor cells were isolated and matured into eosinophils in the presence or absence of IFN-? and hPGDS mRNA, and PGD2 release was measured. RESULTS:Gene expression analysis revealed that eosinophils from tissue and blood of patients with AERD display increased levels of hPGDS compared with asthmatic and control samples. Western hybridization confirmed the increase in hPGDS mRNA translated to increased protein expression. Immunofluorescence confirmed mast cells and eosinophils from tissue of patients with AERD and asthma demonstrated hPGDS expression, with higher levels in eosinophils from patients with AERD. Incubation of eosinophils from blood and tissue with aspirin stimulated PGD2 release. IFN-?-matured eosinophil progenitors showed enhanced hPGDS expression and increased levels of PGD2 release at baseline and after aspirin stimulation. CONCLUSIONS:In addition to mast cells, eosinophils represent an important source of PGD2 in patients with AERD and identify a new target for therapeutic intervention.
| S-EPMC5056805 | biostudies-literature
Project description:BackgroundAspirin-exacerbated respiratory disease (AERD) is an inflammatory condition of the respiratory tract and is characterized by overproduction of leukotrienes (LT) and large numbers of circulating granulocyte-platelet complexes. LT production can be suppressed by prostaglandin E(2) (PGE(2)) and the cyclic AMP-dependent protein kinase A (PKA).ObjectiveTo determine if PGE(2)-dependent control of LT production by granulocytes is dysregulated in AERD.MethodsGranulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses.ResultsGranulocytes from subjects with AERD generated more LTB4 and cysteinyl LTs than did granulocytes from controls with aspirin-tolerant asthma and controls without asthma. When compared with controls, granulocytes from subjects with AERD had comparable levels of EP(2) protein expression and PGE(2)-mediated cAMP accumulation, yet were resistant to PGE(2)-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE(2)-mediated suppression of LTB(4). The PKA inhibitor H89 potentiated LTB4 generation by control granulocytes but was inactive in granulocytes from individuals with AERD and had no effect on platelet P-selectin induction. Both tonic PKA activity and levels of PKA catalytic gamma subunit protein were significantly lower in granulocytes from individuals with AERD relative to those from controls.ConclusionsImpaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE(2), whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction.
| S-EPMC4040319 | biostudies-literature
Project description: Not available
| S-EPMC8810664 | 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