Surfactant protein D alleviates eosinophil-mediated airway inflammation and remodeling in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Surfactant protein D (SPD) is a member of the collectin family that lines the airway epithelial cells with host defense. However, the role of SPD in the pathogenesis of aspirin-exacerbated respiratory disease (AERD) is still unclear. METHODS: The serum SPD level was measured in patients with AERD (n = 336), those with aspirin-tolerant asthma (ATA, n = 442), and healthy controls (HC, n = 104). Polymorphisms of SFTPD in the study subjects were analyzed. The effect of LTE4 on SPD production through eosinophil infiltration was investigated in BALB/c mice. The protective function of SPD against eosinophils inducing inflammation and remodeling was assessed in vitro/vivo. The potential efficacy of nintedanib against airway remodeling through the production of SPD was evaluated. RESULTS: The serum SPD level was significantly lower (P < .001) in AERD compared with ATA patients, and negatively correlated with fall in FEV1 (%) after lysine-aspirin bronchoprovocation test and/or the urinary LTE4 level. In addition, polymorphism of SFTPD at rs721917 was significantly different in the study subjects (odds ratio, 1.310; 95% confidence intervals, 2.124-3.446; P = .002). LTE4-exposed mice showed an increased eosinophil count with a decreased SPD level in bronchoalveolar lavage fluid. Eosinophils increased α-smooth muscle actin expression in airway epithelial cells, which was attenuated by SPD treatment. Furthermore, nintedanib protected the airway epithelial cells against eosinophils by enhancing the production of SPD. CONCLUSION: The decreased level of SPD in AERD was associated with airway inflammation/remodeling under the eosinophilic condition, suggesting that modulation of SPD may provide a potential benefit in AERD.

The utility of biomarkers in diagnosis of aspirin exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a distinct eosinophilic phenotype of severe asthma with accompanying chronic rhinosinusitis, nasal polyposis, and hypersensitivity to aspirin. Urinary 3-bromotyrosine (uBrTyr) is a noninvasive marker of eosinophil-catalyzed protein oxidation. The lack of in vitro diagnostic test makes the diagnosis of AERD difficult. We aimed to determine uBrTyr levels in patients with AERD (n = 240) and aspirin-tolerant asthma (ATA) (n = 226) and to assess whether its addition to urinary leukotriene E4 (uLTE4) levels and blood eosinophilia can improve the prediction of AERD diagnosis. METHODS: Clinical data, spirometry and blood eosinophilis were evaluated. UBrTyr and uLTE4 levels were measured in urine by HPLC and ELISA, respectively. RESULTS: Both groups of asthmatics (AERD, n = 240; ATA, n = 226) had significantly higher uBrTyr, uLTE4 levels, and blood eosinophils than healthy controls (HC) (n = 71) (p < 0.05). ULTE4 levels and blood eosinophils were significantly higher in AERD as compared to ATA (p = 0.004, p < 0.0001, respectively). whereas uBrTyr levels were not significantly different between both asthma phenotypes (p = 0.34). Asthmatics with high levels of uBrTyr (> 0.101 ng/mg Cr), uLTE4 levels (> 800 pg/mg Cr) and blood eosinophils (> 300 cells/ul) were 7 times more likely to have AERD.. However, uBrTyr did not increase the benefit for predicting AERD when uLTE4 and blood eosinophils were already taken into account (p = 0.57). CONCLUSION: UBrTyr levels are elevated both in AERD and ATA as compared to HC, but they could not differentiate between these asthma phenotypes suggesting a similar eosinophilic activation. The addition of uBrTyr to elevated uLTE4 levels and blood eosinophils did not statistically enhance the prediction of AERD diagnosis.

Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by tissue eosinophilia and mast cell activation, including abundant production of prostaglandin D2 (PGD2). Group 2 innate lymphoid cells (ILC2s), which promote tissue eosinophilia and mast cell responses, undergo chemotaxis and cytokine production in response to PGD2, but it is unknown whether ILC2s are active in patients with AERD. OBJECTIVE: We sought to determine whether ILC2 numbers change in peripheral blood and the nasal mucosa during COX-1 inhibitor-induced reactions in patients with AERD. METHODS: Blood and nasal scrapings were collected at baseline, during reactions, and after completion of ketorolac/aspirin challenge/desensitization in 12 patients with AERD. ILC2s and eosinophils were quantitated by means of flow cytometry. Urine was also collected, and quantification of PGD2 metabolite and leukotriene E4 levels was done by using ELISA. Baseline and nonsteroidal anti-inflammatory drug reaction clinical data were correlated with cell changes. RESULTS: ILC2 numbers significantly increased in nasal mucosal samples and decreased in blood at the time of COX-1 inhibitor reactions in 12 patients with AERD. These changes were not observed in 2 patients without AERD. Furthermore, eosinophil numbers decreased in blood concurrently with significant increases in urinary PGD2 metabolite and leukotriene E4 levels. The magnitude of increases in nasal mucosal ILC2 numbers positively correlated with maximum symptom scores during challenges. Furthermore, blood ILC2 numbers during the reaction correlated with time for the reaction to resolve, possibly reflecting reaction severity. CONCLUSIONS: ILC2s are recruited to the nasal mucosa during COX-1 inhibitor-induced reactions in patients with AERD, correlating with enhanced production of prostaglandins and leukotrienes.

Metabolomic analysis identifies potential diagnostic biomarkers for aspirin-exacerbated respiratory disease.

BACKGROUND: To date, there has been no reliable in vitro test to diagnose aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: To investigate potential diagnostic biomarkers for AERD using metabolomic analysis. METHODS: An untargeted profile of serum from asthmatics in the first cohort (group 1) comprising 45 AERD, 44 patients with aspirin-tolerant asthma (ATA), and 28 normal controls was developed using the ultra-high-performance liquid chromatography (UHPLC)/Q-ToF MS system. Metabolites that discriminate AERD from ATA were quantified in both serum and urine, which were collected before (baseline) and after the lysine-aspirin bronchoprovocation test (Lys-ASA BPT). The serum metabolites were validated in the second cohort (group 2) comprising 50 patients with AERD and 50 patients with ATA. RESULTS: A clear discrimination of metabolomes was found between patients with AERD and ATA. In group 1, serum levels of LTE4 and LTE4 /PGF2 α ratio before and after the Lys-ASA BPT were significantly higher in patients with AERD than in patients with ATA (P < 0.05 for each), and urine baseline levels of these two metabolites were significantly higher in patients with AERD. Significant differences of serum metabolite levels between patients with AERD and ATA were replicated in group 2 (P < 0.05 for each). Moreover, serum baseline levels of LTE4 and LTE4 /PGF2 α ratio discriminated AERD from ATA with 70.5%/71.6% sensitivity and 41.5%/62.8% specificity, respectively (AUC = 0.649 and 0.732, respectively P < 0.001 for each). Urine baseline LTE4 levels were significantly correlated with the fall in FEV1 % after the Lys-ASA BPT in patients with AERD (P = 0.008, r = 0.463). CONCLUSIONS AND CLINICAL RELEVANCE: Serum metabolite level of LTE4 and LTE4 /PGF2 α ratio was identified as potential in vitro diagnostic biomarkers for AERD using the UHPLC/Q-ToF MS system, which were closely associated with major pathogenetic mechanisms underlying AERD.

Potential Biomarkers for NSAID-Exacerbated Respiratory Disease.

Asthma is a common chronic disease with several variant phenotypes and endotypes. NSAID-exacerbated respiratory disease (NERD) is one such endotype characterized by asthma, chronic rhinosinusitis (CRS) with nasal polyps, and hypersensitivity to aspirin/cyclooxygenase-1 inhibitors. NERD is more associated with severe asthma than other asthma phenotypes. Regarding diagnosis, aspirin challenge tests via the oral or bronchial route are a standard diagnostic method; reliable in vitro diagnostic tests are not available. Recent studies have reported various biomarkers of phenotype, diagnosis, and prognosis. In this review, we summarized the known potential biomarkers of NERD that are distinct from those of aspirin-tolerant asthma. We also provided an overview of the different NERD subgroups.

Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Prostaglandin (PG) D2 is the dominant COX product of mast cells and is an effector of aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in patients with AERD. METHODS: Urinary eicosanoid levels were measured in aspirin-tolerant control subjects and patients with AERD. Nasal polyp specimens from patients with AERD and chronic rhinosinusitis were analyzed by using quantitative PCR, Western blotting, and immunohistochemistry. Human cord blood-and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation. RESULTS: Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in control subjects and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function and increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hematopoietic PGD2 synthase) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hematopoietic PGD2 synthase (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r = 0.74). Levels of the cleaved active form of TSLP were increased in nasal polyps from patients with AERD relative to those in aspirin-tolerant control subjects. Recombinant TSLP induced PGD2 generation by cultured human mast cells. CONCLUSIONS: Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.

Plasma apolipoprotein H levels are different between aspirin induced respiratory diseases and aspirin tolerant asthma.

Aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with increased asthma severity. To identify plasma biomarkers for the prediction of AERD, the six most abundant plasma proteins (albumin, IgG, antitrypsin, IgA, transferrin, and haptoglobin) in pooled plasma samples were removed using a multiple affinity removal system column. Two-dimensional gel electrophoresis (2DE) was used for differential display proteomic analysis of the pooled plasma. Proteins were identified by matrix assisted laser desorption ionization time-of-flight (MALDI-TOF)/TOF. Enzyme-linked immunosorbent assay (ELISA) was performed to identify and quantify apolipoprotein H (Apo H) in plasma from subjects with AERD and aspirin-tolerant asthma (ATA). Eight protein spots showed differences in relative intensity between pooled plasma from subjects with AERD (n = 8) and those with ATA (n = 8). MALDI-TOF/TOF analysis showed decreases in the levels of alpha-fibrinogen precursor, Apo H, fibrin beta, and proapolipoprotein in AERD as compared with ATA, and increases in chain A human complement component C3, 90-kDa heat shock protein, complement component C4a, and kininogen-1 isoform 2. Apo H concentrations were significantly increased in plasma from subjects with ATA than those with AERD and normal controls, as measured by ELISA (P < 0.01). AERD is characterized by changes in the levels of proteins involved in the coagulation and complement pathways. In addition, Apo H is up-regulated in ATA compared to AERD and normal controls, suggesting that Apo H may be involved in different pathogenesis of ATA from AERD.

Association of serum periostin with aspirin-exacerbated respiratory disease.

BACKGROUND: Recent studies recommend periostin as a systemic biomarker of eosinophilic airway inflammation to predict responses to novel treatments that targets eosinophilic TH2-driven inflammation in asthmatic patients. OBJECTIVE: To investigate the clinical implications of serum periostin levels in patients with aspirin-exacerbated respiratory disease (AERD) based on its overlapping TH2-mediated pathogenesis with the eosinophilic asthma. METHODS: Serum periostin levels were measured by human periostin enzyme-linked immunosorbent assay (ELISA) in serum samples from 277 adults with asthma. Serum periostin levels were compared between patients with AERD and aspirin tolerant asthma (ATA) with other asthma phenotypes, such as severe or nonsevere asthma and eosinophilic or noneosinophilic asthma. The association of serum periostin levels with clinical parameters (including disease severity and comorbid condition) was analyzed. RESULTS: Serum periostin levels were significantly higher in patients with AERD vs ATA, patients with severe asthma vs nonsevere asthma, and patients with eosinophilic asthma vs noneosinophilic asthma (P=.005, P=.02, and P=.001, respectively). Multivariate regression analysis revealed serum periostin levels as a significant parameter to predict AERD phenotype (P=.006) together with severe asthma phenotype (P=.04). In addition, serum periostin levels correlated with blood eosinophil counts (Spearman ñ = 0.244, P<.001) and sputum eosinophil counts (Spearman ñ = 0.261, P < 0.001). Higher serum periostin levels were noted in comorbid AERD patients with more severe chronic rhinosinusitis (Lund-Mackay stages 3 and 4) than those with less severe chronic rhinosinusitis (Lund-Mackay stages 1 and 2) (P = .03). CONCLUSION: Serum periostin levels are significantly elevated in AERD patients and associated with AERD phenotype and disease severity.

Upregulation of CD11b on eosinophils in aspirin induced asthma.

BACKGROUND: Although a challenge test using non-steroidal anti-inflammatory drugs (NSAIDs) is crucial for diagnosis of aspirin-induced asthma (AIA), it also has drawbacks in terms of possible side effects. Therefore, alternative in-vitro diagnostic methods for AIA are awaited. METHODS: Nineteen stable non-AIA patients (9 males and 10 females; mean age, 49.4 ± 4.8 years), and 20 AIA patients (9 males and 11 females; mean age, 51.1 ± 4.8 years) were enrolled in this study. CD11b and CD16 expressions on the peripheral-blood granulocytes after administration of aspirin and different concentrations of PGE2 in vitro were examined using flowcytometry. RESULTS: Aspirin induced a significant increase in CD11b expression on eosinophils (CD16 negative granulocytes) in 19 AIA patients and one non-AIA patient. Increase in CD11b expression on eosinophils by aspirin administration was suppressed by PGE2 in a dose-dependent manner. CONCLUSIONS: The measurement of CD11b expression on peripheral-blood eosinophils showed very high sensitivity and specificity of (-95%) in diagnosing AIA. Although this method requires laboratory facilities for flowcytometry, it may be very useful in diagnosis of AIA without side effects. In addition, PGE2 may be involved in regulation of CD11b expression on eosinophils by aspirin administration.

Differential gene expression profile in PBMCs from subjects with AERD and ATA: a gene marker for AERD.

Aspirin-exacerbated respiratory disease (AERD) is associated with severe asthma and aspirin can cause asthma to worsen, often in the form of a severe and sudden attack. The oral aspirin challenge is the gold standard to confirm the diagnosis of AERD, but it is time consuming and produces serious complications in some cases. Therefore, more efficient and practical method is needed to predict AERD patients. The aim of the present study was to identify AERD-related gene expression in peripheral blood mononuclear cells (PBMCs) and examine the diagnostic potential of these candidate gene(s) for predicting AERD. To do this, RNAs from 24 subjects with AERD and 18 subjects with aspirin-tolerant asthma (ATA) were subjected to microarray analysis of ~34,560 genes. In total, 10 genes were selected as candidate gene markers by applying p ≤ 0.001(t test) and ≥8-fold change, and to correct for multiple comparisons, the false discovery rate analyses were performed. By applying multiple logistic regression analysis, among possible 1,023 models (2(10)-1), a model consisting of CNKSR3, SPTBN2, and IMPACT was selected as candidate set, because this set showed the best AUC (0.98) with 88 % sensitivity and 89 % specificity. For validation, mRNA levels by real-time PCR on PBMCs from two population sets in a gene-chip study and another replication sample, 20 AERD, 20 ATA, and 8 normal controls, were significantly different between groups with 100 % sensitivity and 100 % specificity in each of the two population sets. However, IMPACT gene did not differentiate between AERD and normal controls. The set of the two genes (CNKSR3 and SPTBN2) showed the best AUC (0.96) with 88 % sensitivity and 94 % specificity in a gene-chip study sample. In addition, this set showed perfect discriminative power with AUC (1.0, 100 % sensitivity and 100 % specificity) in each of the two population sets: the gene-chip samples and the replication samples. It also showed perfect discrimination for AERD from NC (AUC: 1.0) and ATA from NC (AUC: 1.0). In conclusion, we developed the two gene markers (CNKSR3 and SPTBN2) of PBMC which differentiate between AERD and ATA with a perfect discriminative power. These gene markers may be an efficient and practical method for predicting AERD.

Expression of melatonin in platelets of patients with aspirin-induced asthma.

BACKGROUND: The diffuse neuroimmunoendocrine system (DNIES) is a universal system of response, control and organism protection. Platelets are cells of DNIES producing and storing melatonin which plays an important role in the regulation of physiological processes in the human body, under normal conditions and in pathology. Our previous study has revealed a low basic melatonin production in patients with aspirin-induced asthma (AIA). It has been suggested that low daytime production of melatonin in patients with AIA is attributable to the reduction in its synthesis in platelets in this group of patients. The objective of this study was to investigate this hypothesis. MATERIALS AND METHODS: The melatonin expression in platelets has been studied by means of indirect immunofluorescence in nine patients with AIA and 14 healthy subjects. RESULTS: The results of the study have revealed that only 13·1 ± 1·3% of platelets in patients with AIA have shown melatonin-specific luminescence, compared to 97·7 ± 0·6% of platelets in healthy subjects (P < 0·001). No melatonin expression has been observed in the rest of platelets in patients with AIA. No significant difference between the degree of the melatonin luminescence in platelets of the patients with AIA and control group has been found. CONCLUSIONS: It can be concluded that the reduced melatonin synthesis in platelets of patients with AIA may determine a low daytime melatonin production and may lead to impairments in platelet receptors and ion channels. This results in disturbances in calcium homoeostasis, which may be a cause of platelet activation and pathological response to exogenous melatonin and acetylsalicylic acid.

Effect of TGF-ß1 on eosinophils to induce cysteinyl leukotriene E4 production in aspirin-exacerbated respiratory disease.

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-ß1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-ß1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-ß1 and urinary LTE4. The function of TGF-ß1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-ß1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-ß1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-ß1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-ß1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-ß1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.

Cellular interactions in aspirin-exacerbated respiratory disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize the complex cellular interactions of aspirin-exacerbated respiratory disease (AERD) and how these interactions promote pathogenic mechanisms of AERD. RECENT FINDINGS: In addition to characteristic changes in eicosanoid levels, recent studies have identified increases in alarmin cytokines (IL-33, thymic stromal lymphopoietin) as well as activated innate lymphoid and plasma cell populations in samples from AERD patients. SUMMARY: Patients with AERD typically demonstrate high levels of proinflammatory eicosanoids including cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) and hyporesponsiveness to prostaglandin E2 (PGE2). CysLTs are released by mast cells, eosinophils, and adherent platelets and promote epithelial release of IL-33, which activates mast cells and group 2 innate lymphoid cells (ILC2s) in concert with CysLTs. TSLP induces PGD2 release from mast cells which activates and recruits eosinophils, basophils, Th2 cells, and ILC2s via CRTH2. In turn, ILC2s and other cell types produce Th2 cytokines IL-4, IL-5, and IL-13 that, along with CysLTs and PGD2, promote bronchoconstriction, eosinophilic tissue inflammation, and mucus production.

A proinflammatory marker in chronic rhinosinusitis: serum calprotectin.

INTRODUCTION: Studies have shown that calprotectin has a strong pro-inflammatory effect. Elevated calprotectin levels in the serum can be used as a strong clinical marker indicating the presence of inflammation. OBJECTIVE: To investigate serum calprotectin levels in patients with chronic rhinosinusitis (CRS) and to determine the applicability of calprotectin as a potential molecular pro-inflammatory biomarker for CRS. METHODS: The study consisted of three groups: chronic rhinosinusitis with polyps (CRSwNP group), chronic rhinosinusitis without polyps (CRSwoNP), and healthy control. CRS patients with polyps were further divided into two groups depending on the presence/absence of Samter's triad. The Nose Obstruction Symptom Evaluation (NOSE) scale score and serum calprotectin value were evaluated in all participants. RESULTS: The mean serum calprotectin value was 79.5±11.8 ng/ml for the CRSwNP group, 71.3±16 ng/ml for the CRSwoNP group, and 61.9±11.6 ng/ml for the control group (p<0.001). The Samter's triad group had a significantly higher calprotectin value than the non-Samter's triad group (p=0.03). There was a significant correlation between the NOSE scores and calprotectin levels (rho=0.734, p<0.001). CONCLUSION: Serum calprotectin values were correlated with the severity of symptoms in patients with CRS; thus, it seems to be a valuable pro-inflammatory biomarker for the diagnosis of the disease and determining its severity. Further studies with larger series are needed to evaluate the preoperative and postoperative serum calprotectin values ​​in patients undergoing surgery.

Serum level of stem cell factor and its soluble receptor in aspirin-exacerbated respiratory disease.

Aim: Stem cell factor (SCF) may be associated with inflammatory processes leading to aspirin-induced asthma. This study evaluated the relationship between serum level of SCF and its soluble receptor with aspirin-induced asthma. Methods & materials: Twenty-five patients and 25 healthy controls were enrolled in this study. The concentration of SCF and mast/stem cell growth factor receptor (C-kit) was determined in serum samples. Spirometry and rhinometry were performed to determine the severity of the disease. p < 0.05 were considered significant. Results: The serum levels of SCF and C-kit receptor were significantly higher in the case group. The serum SCF and C-kit level had a significant positive correlation with the severity of asthma, disease duration and nasal obstruction. Conclusion: Our findings suggest that SCF and C-kit receptors have a direct effect on the severity of aspirin-induced asthma.

Sinus Surgery Is Associated with a Decrease in Aspirin-Induced Reaction Severity in Patients with Aspirin Exacerbated Respiratory Disease.

BACKGROUND: Nasal polyps influence the burden of aspirin-exacerbated respiratory disease (AERD) by contributing to eicosanoid production. AERD is diagnosed through graded aspirin challenges. It is not known how sinus surgery affects aspirin challenge outcomes. OBJECTIVE: To investigate the effects of endoscopic sinus surgery (ESS) on aspirin-induced reaction severity and on the levels of eicosanoids associated with these reactions. METHODS: Twenty-eight patients with AERD were challenged with aspirin before and 3 to 4 weeks after ESS. Respiratory parameters and plasma and urine levels of eicosanoids were compared before and after challenges. RESULTS: Before ESS, AERD diagnosis was confirmed in all study patients by aspirin challenges that resulted in hypersensitivity reactions. After ESS, reactions to aspirin were less severe in all patients and 12 of 28 patients (43%, P < .001) had no detectable reaction. A lack of clinical reaction to aspirin was associated with lower peripheral blood eosinophilia (0.1 K/µL [interquartile range (IQR) 0.1-0.3] vs 0.4 K/µL [IQR 0.2-0.8]; P = .006), lower urinary leukotriene E4 levels after aspirin challenge (98 pg/mg creatinine [IQR 61-239] vs 459 pg/mg creatinine [IQR 141-1344]; P = .02), and lower plasma prostaglandin D2 to prostaglandin E2 ratio (0 [±0] vs 0.43 [±0.2]; P = .03), compared with those who reacted. CONCLUSIONS: Sinus surgery results in decreased aspirin sensitivity and a decrease in several plasma and urine eicosanoid levels in patients with AERD. Diagnostic aspirin challenges should be offered to patients with suspected AERD before ESS to increase diagnostic accuracy. Patients with established AERD could undergo aspirin desensitizations after ESS as the severity of their aspirin-induced hypersensitivity reactions lessens.

Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial.

BACKGROUND: The high levels of eicosanoid production and the clinical efficacy of leukotriene-modifying pharmacotherapies for patients with aspirin-exacerbated respiratory disease (AERD) suggest that other interventions targeting arachidonic acid dysregulation may also improve disease control. OBJECTIVE: To assess the utility of a high omega-3/low omega-6 diet for the treatment of AERD. METHODS: Prospective, nonblinded dietary intervention in 10 adult patients with AERD at Brigham and Women's Hospital in Boston, MA. The primary objective was for subjects to reduce dietary omega-6 fatty acid consumption to less than 4 g/d and increase omega-3 intake to more than 3 g/d. The primary outcome was change in urinary leukotriene E4, with changes in other eicosanoids, platelet activation, lung function, and patient-reported questionnaires also assessed. RESULTS: Of the 10 subjects who screened for the study, all 10 completed the dietary intervention. Urinary leukotriene E4 decreased by 0.17 ng/mg (95% CI, -0.29 to -0.04; P = .02) and tetranor prostaglandin D-M decreased by 0.66 ng/mg creatinine (95% CI, -1.21 to -0.11; P = .02). There was a 15.1-point reduction in the 22-item Sino-Nasal Outcome Test score (95% CI, -24.3 to -6.0; P = .01), a 0.27-point reduction in the 7-item Asthma Control Questionnaire score (95% CI, -0.52 to -0.03; P = .03), and no change in FEV1 % predicted (P = .92) or forced vital capacity % predicted (P = .74). All patients lost some weight over the 2-week intervention period, and there were no diet-associated adverse events. CONCLUSIONS: A high omega-3/low omega-6 diet may be an appropriate adjunct treatment option for patients with AERD.

Plasma 15-Hydroxyeicosatetraenoic Acid Predicts Treatment Outcomes in Aspirin-Exacerbated Respiratory Disease.

BACKGROUND: Aspirin desensitization followed by daily aspirin provides therapeutic benefits to patients with aspirin-exacerbated respiratory disease (AERD). It is not well understood how eicosanoid levels change during aspirin treatment. OBJECTIVE: To investigate associations between clinical outcomes of aspirin treatment and plasma eicosanoid levels in patients with AERD. METHODS: Thirty-nine patients with AERD were offered aspirin treatment (650 mg twice daily) for 4 weeks. Respiratory parameters and plasma levels of multiple eicosanoids were recorded at baseline and after 4 weeks of aspirin therapy using the Asthma Control Test and Rhinoconjunctivitis Quality of Life Questionnaire. Respiratory function was evaluated using the FEV1 and nasal inspiratory peak flow. RESULTS: After aspirin treatment, respiratory symptoms improved in 16 patients, worsened in 12 patients, and did not change in 4 patients. Seven patients were unable to complete the desensitization protocol. Patients with symptom improvement had higher baseline plasma 15-hydroxyeicosatetraenoic acid (15-HETE) levels than did patients with symptom worsening: 7006 pg/mL (interquartile range, 6056-8688 pg/mL) versus 4800 pg/mL (interquartile range, 4238-5575 pg/mL), P = .0005. Baseline 15-HETE plasma levels positively correlated with the change in Asthma Control Test score (r = 0.61; P = .001) and in FEV1 after 4 weeks of aspirin treatment (r = 0.49; P = .01). It inversely correlated with Rhinoconjunctivitis Quality of Life Questionnaire score (r = -0.58; P = .002). Black and Latino patients were more likely to have symptom worsening on aspirin or fail to complete the initial desensitization than white, non-Latino patients (P = .02). CONCLUSIONS: In patients with AERD, low baseline 15-HETE plasma levels and black or Latino ethnicity are associated with worsening of respiratory symptoms during aspirin treatment.

Association of interleukin-25 levels with development of aspirin induced respiratory diseases.

BACKGROUND: Aspirin-exacerbated respiratory diseases (AERD) are caused by ingestion of non-steroidal anti-inflammatory drugs and are characterized by acute bronchospasms and marked infiltration of eosinophils, the latter being attributable to altered synthesis of cysteinyl leukotrienes (LT) and prostaglandins (PG). Recently, the innate Th2 response is revealed to induce eosinophil infiltration in allergic inflammation, however the role of the innate Th2 response has not been studies in AERD. Thus, we evaluated the relationship between the innate Th2 cytokines including IL-25, thymic stromal lymphopoietin (TSLP) and IL-33 and the development of AERD. METHODS AND MATERIALS: Plasma IL-25, IL-33, and TSLP levels were measured before and after aspirin challenge in subjects with AERD (n = 25) and aspirin-tolerant asthma (ATA, n = 25) by enzyme-linked immunosorbent assay (ELISA). Pre and post-aspirin challenge levels of LTC4 and PGD2 were measured using ELISA. RESULTS: Basal plasma IL-25 levels were significantly higher in AERD group than in normal controls and in ATA group (p = 0.025 and 0.031, respectively). IL-33 and TSLP levels were comparable in the AERD and ATA groups. After the aspirin challenge, the IL-25 levels were markedly decreased in the ATA group (p = 0.024), while not changed in the AERD group. The post-challenge IL-25 levels of all asthmatic subjects were significantly correlated with aspirin challenge - induced declines in FEV1 (r = 0.357, p = 0.011), but not with basal and post challenge LTC4 and PGD2 levels. CONCLUSIONS: IL-25 is associated with bronchospasm after aspirin challenge, possibly via mechanisms other than altered LTC4 and PGD2 production.

Exploration of the Sphingolipid Metabolite, Sphingosine-1-phosphate and Sphingosine, as Novel Biomarkers for Aspirin-exacerbated Respiratory Disease.

Sphingolipid (SL) metabolites have been suggested to be important inflammatory mediators in airway inflammation and asthma. However, little is known about SL metabolites in aspirin-exacerbated respiratory disease (AERD). We aimed to explore the potential AERD biomarkers by conducting lipidomics targeting SL metabolites. The levels of SL metabolites in serum and urine samples from 45 AERD patients and 45 aspirin-tolerant asthma (ATA) patients were quantified through mass spectrometry. During the lysine-aspirin bronchoprovocation test (ASA-BPT), the levels of serum sphingomyelin (SM) were significantly decreased in AERD (P < 0.05) but not in ATA. The serum SM levels were positively correlated with airway responsiveness to methacholine. At the basal status before the ASA-BPT, the levels of serum sphingosine-1-phosphate (S1P) and urine sphingosine were significantly higher in the AERD patients compared with that of ATA patients (P < 0.001) and were positively correlated with a greater decrease in FEV1 (%) values following the ASA-BPT test (P < 0.001 for each), and with serum periostin level (P < 0.05 for each). This study is the first to evaluate serum S1P and urine sphingosine as potential biomarkers of AERD as well as to examine the metabolic disturbance of SL in AERD patients.