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

BACKGROUND: 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. OBJECTIVE: We sought to determine the concordance between respiratory tract and systemic inflammatory mediator levels and identify clinical factors associated with these mediators. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study.

Rationale: New approaches are needed to guide personalized treatment of asthma.Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping.Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma.Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11ß-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers.Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).

Omalizumab for Aspirin Hypersensitivity and Leukotriene Overproduction in Aspirin-exacerbated Respiratory Disease. A Randomized Controlled Trial.

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.

Survey of Mast Cell Mediator Levels from Patients Presenting with Symptoms of Mast Cell Activation.

INTRODUCTION: Although 4 mast cell mediators can be routinely measured, the results of initial testing to evaluate symptoms of mast cell activation have not been widely reported. OBJECTIVE: We examined the results of mast cell mediator tests used to assess patients with mast cell activation symptoms during a 5-year time span. METHODS: After excluding patients with alternative diagnoses, records of 108 patients were reviewed for initial mediator test results. Mediators included serum tryptase plus urinary N-methyl histamine (N-MH), leukotriene (LT)E4, and 11ß-prostaglandin (PG) F2α or 2,3-dinor-11ß-PGF2α (BPG). RESULTS: Most commonly, either a single measured elevation of 1 mediator (48.1%) or elevations of 2 (33.3%) mediators was found at baseline, during symptoms or at both time points. Elevated levels of a single mediator in order of frequency were: BPG > tryptase > LTE4 > N-MH, and for two mediators: BPG + tryptase (n = 16 cases) > BPG + LTE4 (n = 9) > BPG + N-MH (n = 6). Elevations in 3 mediators (n = 8) or 4 mediators (n = 2) were much less frequent. Monoclonal mast cell activation syndrome (n = 6), and systemic and cutaneous mastocytosis (n = 4) were also infrequent. Baseline plus symptom-associated tryptase values were obtained in only 7 patients. CONCLUSIONS: This survey suggests that elevations of 1 or 2 mediators are the most common (total 81.4% of cases) findings from initial tests for mast cell activation. Elevated levels of BPG were most commonly found both singly and in combination with other mediators, followed by the finding of elevated levels of tryptase. Baseline plus symptom-associated tryptase levels were measured in only a minority of patients.

Molecularly imprinted nanoparticles-based assay (MINA) - detection of leukotrienes and insulin.

A novel molecularly imprinted polymer nanoparticle-based assay (MINA) performed in magnetic microplates was developed as an improved high-quality alternative to existing antibody-based immunoassays. MINA is a generic technology that can be adapted for biomarker detection in biological samples. Herein, we demonstrate the applicability of the MINA assay for the detection of leukotrienes and insulin in biological samples. MINA, used in a competition format, has allowed the detection of LTE4 in urine in a concentration range from 0.45 to 364 pM, with a LOD of 0.73 pM. MINA, used in a competition format, has allowed the detection of insulin in plasma in a concentration range from 25 to 2500 pM, with a LOD of 27 pM. This assay has shown comparable performance for LTE4 and insulin detection to existing chromatographic techniques (LC-MS/MS) and immunoassays in clinically relevant concentrations. The main advantages of this assay are the efficient and low cost fabrication, preparation of synthetic binders without the use of animals, and fewer steps used in the assay protocol as compared to traditional immunoassays.

Preschoolers with recurrent wheezing have a high prevalence of sleep disordered breathing.

Objective: Sleep-disordered breathing (SDB) is highly prevalent in school children with poorly-controlled asthma. However, this association has not been assessed in preschoolers with recurrent wheeze, nor in those at risk for asthma. We hypothesized that preschoolers with asthma risk (positive asthma predictive index [API]) have a higher prevalence of SDB and higher inflammatory biomarkers (blood-hsCRP and urinary-LTE4) levels than those with negative API.Method: Children 2 to 5 years of age with recurrent wheezing were classified as positive or negative API. SDB was determined by the pediatric sleep questionnaire (PSQ) and its subscale (PSQSub6). Demographic characteristics, spirometry, blood hsCRP and urinary LTE4 were assessed.Results: We enrolled 101 preschoolers: 70 completed all measurements, 55.4% were males, mean age 4.07 ± 0.87 years, 45% overweight or obese, 70% had positive API, 87.5% had rhinitis. The prevalence of SDB measured by PSQ was 40.8% and by PSQSub6 was 29.6%. However, the proportion of SDB was similar between positive and negative API groups. The hsCRP (mean ± SD) was higher in the positive than in negative API (3.58 ± 0.58 and 1.32 ± 0.36 mg/L, p = 0.69, respectively); moreover, no differences in urinary LTE4 were found between groups. No correlation of PSQ (+) or PSQSub6 (+) with hsCRP and uLTE4 was found. However, preschoolers with positive API had significantly more post-bronchodilator percentage change in FEF25-75 than negative API (24.14 ± 28.1 vs. 4.13 ± 21.8, respectively, p = 0.01).Conclusions: In preschoolers with recurrent wheezing, we should be investigating for the coexistence of SDB, using early screening methods for detecting those conditions.

Eicosanoid mediator profiles in different phenotypes of nonsteroidal anti-inflammatory drug-induced urticaria.

BACKGROUND: The role of arachidonic acid metabolites in NSAID-induced hypersensitivity has been studied in depth for NSAID-exacerbated respiratory disease (NERD) and NSAID-exacerbated cutaneous disease (NECD). However, no information is available for NSAID-induced urticarial/angioedema (NIUA), despite it being the most frequent clinical entity induced by NSAID hypersensitivity. We evaluated changes in leukotriene and prostaglandin metabolites for NIUA patients, using patients with NECD and single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) for comparison. METHODS: Urine samples were taken from patients with confirmed NSAID-induced urticaria and healthy controls, at baseline and at various time intervals after ASA administration. Eicosanoid measurement was performed using high-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. RESULTS: No differences were found between groups at baseline. Following ASA administration, LTE4 and 9α,11ß-PGF2 levels were increased in both NIUA and NECD patients compared to baseline, rising initially, before decreasing toward initial levels. In addition, the levels of these metabolites were higher in NIUA and NECD when compared with the SNIUAA and control groups after ASA administration. No changes were found with respect to baseline values for SNIUAA and control groups. CONCLUSIONS: We present for the first time data regarding the role of COX-1 inhibition in NIUA. Patients with this entity show a similar pattern eicosanoid levels following ASA challenge to those with NECD. Further studies will help ascertain the cell populations involved and the underlying molecular mechanisms.

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.

Prostaglandin E2 decrease in induced sputum of hypersensitive asthmatics during oral challenge with aspirin.

BACKGROUND: A special regulatory role for prostaglandin E2 (PGE2 ) has been postulated in nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD). OBJECTIVE: To investigate the effect of systemic aspirin (acetylsalicylic acid) administration on airway PGE2 biosynthesis in induced sputum supernatant (ISS) among subjects with NERD or aspirin-tolerant asthma with chronic rhinosinusitis with nasal polyposis (ATA-CRSwNP), as well as healthy controls (HC). METHODS: Induced sputum (IS) was collected from patients with NERD (n = 26), ATA-CRSwNP (n = 17), and HC (n = 21) at baseline and after aspirin challenge. Sputum differential cell count and IS supernatant (ISS) levels of prostanoids, PGE2 , 8-iso-PGE2 , tetranor-PGE-M, 8-iso-PGF2 α, and leukotriene C4 , D4 , and E4 , were determined using mass spectrometry. Urinary excretion of LTE4 was measured by ELISA. RESULTS: NERD subjects had elevated sputum eosinophilic count as compared to ATA-CRSwNP and HC (median NERD 9.1%, ATA-CRSwNP 2.1%, and HC 0.4%; P < 0.01). Baseline ISS levels of PGE2 were higher in asthmatics as compared to HC at baseline (NERD vs HC P = 0.04, ATA-CRSwNP vs HC P < 0.05). Post-challenge ISS levels of PGE2 compared to baseline significantly decreased in NERD and HC (P < 0.01 and P = 0.01), but not in ATA-CRSwNP. In NERD, a similar decrease in PGE2 as in HC resulted from 2.8 times lower dose of aspirin. CONCLUSION: Aspirin-precipitated bronchoconstriction is associated with a decrease in airway PGE2 biosynthesis. These results support the mechanism of PGE2 biosynthesis inhibition as a trigger for bronchoconstriction in NERD.

Cysteinyl-leukotriene pathway as a new therapeutic target for the treatment of atherosclerosis related to obstructive sleep apnea syndrome.

AIMS: Obstructive sleep apnea (OSA) characterized by nocturnal intermittent hypoxia (IH) is associated with atherosclerosis and cysteinyl-leukotrienes (CysLT) pathway activation. We aimed to identify the determinants of CysLT pathway activation and the role of CysLT in OSA-related atherosclerosis. METHODS AND RESULTS: Determinants of the urinary excretion of LTE4 (U-LTE4) including history of cardiovascular events, polysomnographic and biological parameters were studied in a cohort of 170 OSA patients and 29 controls, and in a subgroup of OSA patients free of cardiovascular event (n = 136). Mechanisms linking IH, the CysLT pathway and atherogenesis were investigated in Apolipoprotein E deficient (ApoE-/-) mice exposed to 8-week IH. In the whole cohort, U-LTE4 was independently influenced by age, minimal oxygen saturation, and a history of cardiovascular events, and correlated significantly with intima-media thickness. In the subgroup of OSA patients free of cardiovascular event, increased U-LTE4 was increased compared to controls and independently related to hypoxia severity and traditional risk factors aggregated in the 10-year cardiovascular risk score of European Society of Cardiology. In IH mice, atherosclerosis lesion size and mRNA levels of 5-lipoxygenase, 5-lipoxygenase activating protein (FLAP) and CysLT1 receptor were significantly increased. This transcriptional activation was associated with the binding of HIF-1 to the FLAP promoter and was strongly associated with atherosclerosis lesion size. CysLT1 receptor antagonism (montelukast) significantly reduced atherosclerosis progression in IH mice. CONCLUSIONS: IH-related CysLT pathway activation contributes to OSA-induced atherogenesis. In the era of personalized medicine, U-LTE4 may be a useful biomarker to identify OSA patients for whom CysLT1 blockade could represent a new therapeutic avenue for reducing cardiovascular risk.

Omalizumab can inhibit respiratory reaction during aspirin desensitization.

BACKGROUND: Aspirin desensitization has been associated with benefit in management of aspirin-exacerbated respiratory disease (AERD). An intervention that would encourage aspirin desensitization to be performed more frequently has substantial potential for improving outcomes and quality of life in patients with AERD. OBJECTIVE: We investigated whether omalizumab administration would be associated with attenuation of aspirin-provoked bronchospasm in patients with AERD undergoing aspirin desensitization. METHODS: We carried out a randomized, double-blind, placebo-controlled study in which subjects with AERD who fulfilled label criteria for omalizumab received omalizumab or placebo for 16 weeks, and then underwent aspirin desensitization. RESULTS: Eleven subjects completed aspirin desensitization. Of the 7 who were randomized to omalizumab, 5 had no respiratory reaction during aspirin desensitization. Compared with placebo, omalizumab was associated with a significantly greater likelihood for subjects with AERD to have no respiratory reaction during desensitization (P = .04, Fisher exact test). There was an overall difference in urinary leukotriene E4 (LTE4) levels in subjects who received omalizumab and did not have a respiratory reaction during desensitization compared with subjects randomized to placebo (P = .035, mixed model with interaction). Urinary LTE4 levels were significantly higher with respiratory reaction in placebo subjects compared with levels obtained after the 100-mg dose in AERD subjects who had no respiratory reaction (P < .001, mixed model with interaction). CONCLUSION: In atopic AERD subjects, omalizumab administration for 16 weeks was associated with "clinically silent" desensitization. Further studies to investigate the therapeutic utility of omalizumab in patients with AERD who are candidates for aspirin desensitization are warranted based on these findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00555971.

Exposure to volatile organic compounds and airway inflammation.

BACKGROUND: Exposure to low levels of volatile organic compounds (VOCs) in ordinary life is suspected to be related to oxidative stress and decreased lung function. This study evaluated whether exposure to ambient VOCs in indoor air affects airway inflammation. METHODS: Thirty-four subjects from the hospital that had moved to a new building were enrolled. Symptoms of sick building syndrome, pulmonary function tests, and fractional exhaled nitric oxide (FeNO) were evaluated, and random urine samples were collected 1 week before and after the move. Urine samples were analyzed for VOC metabolites, oxidative stress biomarkers, and urinary leukotriene E4 (uLTE4) levels. RESULTS: The level of indoor VOCs in the new building was higher than that in the old building. Symptoms of eye dryness and eye irritation, as well as the level of a xylene metabolite (o-methylhippuric acid) increased after moving into the new building (p = 0.012, p = 0.008, and p < 0.0001, respectively). For the inflammatory markers, FeNO decreased (p = 0.012 and p = 0.04, respectively) and the uLTE4 level increased (p = 0.005) after the move. CONCLUSION: Exposure to a higher level of VOCs in everyday life could affect airway inflammation.

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.

Identification of phenotypic clusters of nonsteroidal anti-inflammatory drugs exacerbated respiratory disease.

BACKGROUND: Clinical presentation of nonsteroidal anti-inflammatory drugs exacerbated respiratory disease (NERD) is found to be heterogeneous. This study classified phenotypic clusters to determine NERD subtypes. METHODS: We performed two-step cluster analysis using urticaria, chronic rhinosinusitis (CRS), and atopy, in a NERD cohort comprising 302 patients. Asthma exacerbation was defined as receiving at least one burst of intravenous steroid treatment and/or at least two bursts of oral steroid use (≥ 45 mg/3 days) per year. The possession rate of anti-asthmatic medications was estimated during the follow-up period. RESULTS: There were four subtypes: subtype 1 (NERD with CRS/atopy and no urticaria), subtype 2 (NERD with CRS and no urticaria/atopy), subtype 3 (NERD without CRS/urticaria), and subtype 4 (NERD with urticaria). Significant differences were found between the four subtypes in the female proportion, baseline FEV1%, serum total IgE level, and sputum/peripheral eosinophil count. A higher frequency of asthma exacerbations was noted in subtype 1 compared to subtype 3. The possession rates of medium- to high-dose inhaled corticosteroids/long-acting beta2 -agonists showed significant differences among the four subtypes. Metabolomic analysis showed that the four subtypes of NERD had a higher serum leukotriene E4 (LTE4) level than those with aspirin-tolerant asthma. The patients with subtypes 1 and 3 had a higher urine LTE4 level than those with subtype 2. CONCLUSION: We found four distinct subtypes with different clinical/biochemical findings and asthma exacerbations in a NERD cohort. These findings suggest that stratified strategies by applying subtype classification may help achieve better outcomes in the management of NERD.

Urinary cysteinyl leukotriene E4 level and therapeutic response to montelukast in children with mild obstructive sleep apnea.

BACKGROUND: Antileukotriene has been used for alleviating disease severity in children with adenotonsillar hypertrophy (ATH) and mild obstructive sleep apnea (OSA). Previous study showed the relationship between urinary cysteinyl leukotriene E4 (uLTE4) level and therapeutic response to montelukast in asthmatic adults. However, this relationship has never been investigated in pediatric OSA. OBJECTIVES: To determine the relationship between uLTE4 level and therapeutic response to montelukast in children with ATH and mild OSA. METHODS: Children aged 3-15 yrs who had ATH and mild OSA were enrolled. All had quality of life (assessed by Thai version OSA-18 QoL questionnaire) and uLTE4 levels measured prior to start a 6-week course of montelukast treatment. Overnight polysomnography (PSG) and QoL reassessment were performed after completing the treatment. Those who demonstrated a large improvement of mean total QoL score or ≥ 50% decrease of obstructive apnea-hypopnea index (OAHI) after the treatment were defined as responders. RESULTS: Twenty-six children were enrolled (mean age 7.5 ± 2.9 yrs, 38.5% male). After 6-week course of montelukast, nine (34.6%) children showed significant improvement. The mean uLTE4 level from the responders was higher comparing to the non-responders (2,952.56 ± 966.9 vs. 978.6 ± 460.8 pg/mg creatinine; p < 0.001). uLTE4 level of ≥ 1,457 pg/mg creatinine had 100% sensitivity and 88.2% specificity in identifying the responders. CONCLUSIONS: We found the association between ULTE4 and therapeutic response to monteleukast. The uLTE4 level of ≥ 1,457 pg/mg creatinine could predict the therapeutic response to montelukast in children who had ATH and mild OSA.

Systemic expression of inflammatory mediators in patients with chronic rhinosinusitis and nasal polyps with and without Aspirin Exacerbated Respiratory Disease.

BACKGROUND: Systemic reactions are related to the pathogenesis of Aspirin Exacerbated Respiratory Disease (AERD). With this work we wanted to study the changes in the systemic levels of inflammatory mediators in both baseline and after oral aspirin challenge in patients with and without AERD. METHODS: Patients with nasal polyposis and asthma with AERD (n=20) and without (n=18) were orally challenged with aspirin in a single-blind placebo controlled study. Serum samples and urine were collected before and 6h after placebo and aspirin oral challenges. Serum levels of inflammatory mediators were assayed by using the Luminex technology and ELISA. The concentrations of 9-alpha, 11-beta prostaglandin F2, and leukotriene E4 (uLTE4) were measured in urine samples by ELISA. The expression of T-cell surface markers was analyzed in peripheral blood mononuclear cells isolated before and after the challenges. RESULTS: AERD patients showed significantly higher baseline levels of s-IL-5R-alpha, uLTE4 and percentage of CD4(+)CD25(+)CD127(pos) and CD4(+)CD45RA(-)CD45RO(+) but decreased levels of TGF-ß1 and number of CD4(+)CD25(+)CD127(neg) cells. Aspirin challenge induced the release of uLTE4, IL-6 and increased the number of CD4(+)CD45RA(-)CD45RO(+) memory T-cells only in AERD patients but failed to reduce the levels of sCD40L as observed in non-AERD subjects. Further, IL-8 and sIL-5R-alpha levels directly correlated with the PD20ASA and the effects of aspirin on IL-6 and number of memory T-cells was more pronounced in subjects showing more strong reaction (bronchial and nasal). CONCLUSIONS: AERD patients have a differential baseline inflammatory pattern that supports the role inflammation as underlying mechanism of the disease. Systemic response to oral aspirin challenge was related to an increase in serum IL-6 and the number of circulating memory T-cells in AERD patients.

Utility of low-dose oral aspirin challenges for diagnosis of aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is diagnosed through graded aspirin challenges that induce hypersensitivity reactions and eicosanoid level changes. It is not known whether diagnostically useful changes also occur after low-dose aspirin challenges that do not induce hypersensitivity reactions. OBJECTIVE: To investigate the utility of low-dose oral aspirin challenges for diagnosing AERD by measuring different clinical parameters and eicosanoid changes. METHODS: Sixteen patients with AERD and 13 patients with aspirin-tolerant asthma underwent oral challenges with low-dose (20 or 40 mg) aspirin and diagnostic oral graded aspirin challenges (up to 325 mg of aspirin). Forced expiratory volume in 1 second, nasal peak flow, the fraction of exhaled nitric oxide (FeNO), and eicosanoid levels in plasma and urine were analyzed. RESULTS: In patients with AERD but not in those with aspirin-tolerant asthma, 40-mg aspirin challenges induced a significant mean (SEM) decrease from baseline in FeNO (19% [5.1%]; P = .001) without causing any hypersensitivity reaction. The FeNO decrease also occurred after higher-dose aspirin challenges (27.8% [4.9%]; P < .001). The sensitivity and specificity of 40-mg aspirin-induced FeNO changes for identifying AERD were 90% and 100% with an area under the curve of 0.98 (95% CI, 0.92-1.00). The low-dose challenge also induced a significant leukotriene E4 urine increase in patients with AERD (from 6.32 [0.08] to 6.91 [0.15] log-pg/mg creatinine; P < .001), but the sensitivity and specificity of these changes were less than for the FeNO changes. CONCLUSION: The low-dose aspirin-induced decrease in FeNO in patients with AERD may be useful for the diagnosis of aspirin allergy without inducing a hypersensitivity reaction. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01320072.

Within-microenvironment exposure to particulate matter and health effects in children with asthma: a pilot study utilizing real-time personal monitoring with GPS interface.

BACKGROUND: Most particulate matter (PM) and health studies in children with asthma use exposures averaged over the course of a day and do not take into account spatial/temporal variability that presumably occurs as children move from home, into transit and then school microenvironments. The objectives of this work were to identify increases in morning PM exposure occurring within home, transit and school microenvironments and determine their associations with asthma-related inflammation and rescue medication use. METHODS: In 2007-2008, thirty Denver-area schoolchildren with asthma performed personal PM exposure monitoring using a real-time sensor integrated with a geographic information system (GIS) to apportion exposures to home, transit and school microenvironments. Concurrently, daily monitoring of the airway inflammatory biomarker urinary leukotriene E4 (uLTE4) and albuterol usage was performed. RESULTS: Mean PM exposures each morning were relatively well correlated between microenvironments for subject samples (0.3 < r < 0.8), thus limiting use of this exposure metric to attribute health effects to PM exposure in specific microenvironments. Within-microenvironment increases in exposure, such as would be characterized by one or a series of transient spikes or a sustained increase in concentration (exposure event), however, were not strongly correlated between microenvironments (|r| < 0.25). On days when children were exposed to a ≥ 5µg/m3 exposure event during transit, they demonstrated a 24.0 % increase in uLTE4 (95 % CI: 1.5 %, 51.5 %) and a 9.7 % (-5.9 %, 27.9 %) increase in albuterol usage compared to days without transit exposure events. Associations between exposure events and health outcomes in home and school microenvironments tended to be positive as well, but weaker than for transit. CONCLUSIONS: School children with asthma moving across morning microenvironments experience spatially heterogeneous PM exposures with potentially varying health effects.

Aspirin provocation increases 8-iso-PGE2 in exhaled breath condensate of aspirin-hypersensitive asthmatics.

BACKGROUND: Isoprostanes are bioactive compounds formed by non-enzymatic oxidation of polyunsaturated fatty acids, mostly arachidonic, and markers of free radical generation during inflammation. In aspirin exacerbated respiratory disease (AERD), asthmatic symptoms are precipitated by ingestion of non-steroid anti-inflammatory drugs capable for pharmacologic inhibition of cyclooxygenase-1 isoenzyme. We investigated whether aspirin-provoked bronchoconstriction is accompanied by changes of isoprostanes in exhaled breath condensate (EBC). METHODS: EBC was collected from 28 AERD subjects and 25 aspirin-tolerant asthmatics before and after inhalatory aspirin challenge. Concentrations of 8-iso-PGF2α, 8-iso-PGE2, and prostaglandin E2 were measured using gas chromatography/mass spectrometry. Leukotriene E4 was measured by immunoassay in urine samples collected before and after the challenge. RESULTS: Before the challenge, exhaled 8-iso-PGF2α, 8-iso-PGE2, and PGE2 levels did not differ between the study groups. 8-iso-PGE2 level increased in AERD group only (p=0.014) as a result of the aspirin challenge. Urinary LTE4 was elevated in AERD, both in baseline and post-challenge samples. Post-challenge airways 8-iso-PGE2 correlated positively with urinary LTE4 level (p=0.046), whereas it correlated negatively with the provocative dose of aspirin (p=0.027). CONCLUSION: A significant increase of exhaled 8-iso-PGE2 after inhalatory challenge with aspirin was selective and not present for the other isoprostane measured. This is a novel finding in AERD, suggesting that inhibition of cyclooxygenase may elicit 8-iso-PGE2 production in a specific mechanism, contributing to bronchoconstriction and systemic overproduction of cysteinyl leukotrienes.