Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation.

RATIONALE: Asthma phenotyping requires novel biomarker discovery. OBJECTIVES: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). METHODS: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. RESULTS: In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-ß and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. CONCLUSIONS: The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.

Lung function fluctuation patterns unveil asthma and COPD phenotypes unrelated to type 2 inflammation.

BACKGROUND: In all chronic airway diseases, the dynamics of airway function are influenced by underlying airway inflammation and bronchial hyperresponsiveness along with limitations in reversibility owing to airway and lung remodeling as well as mucous plugging. The relative contribution of each component translates into specific clinical patterns of symptoms, quality of life, exacerbation risk, and treatment success. OBJECTIVE: We aimed to evaluate whether subgrouping of patients with obstructive airway diseases according to patterns of fluctuation in lung function allows identification of specific phenotypes with distinct clinical characteristics. METHODS: We applied the novel method of fluctuation-based clustering (FBC) to twice-daily FEV1 measurements recorded over a 1-year period in a mixed group of 134 adults with mild-to-moderate asthma, severe asthma, or chronic obstructive pulmonary disease from the European BIOAIR cohort. RESULTS: Independently of clinical diagnosis, FBC divided patients into 4 fluctuation-based clusters with progressively increasing alterations in lung function that corresponded to patterns of increasing clinical severity, risk of exacerbation, and lower quality of life. Clusters of patients with airway disease with significantly elevated levels of biomarkers relating to remodeling (osteonectin) and cellular senescence (plasminogen activator inhibitor-1), accompanied by a loss of airway reversibility, pulmonary hyperinflation, and loss of diffusion capacity, were identified. The 4 clusters generated were stable over time and revealed no differences in levels of markers of type 2 inflammation (blood eosinophils and periostin). CONCLUSION: FBC-based phenotyping provides another level of information that is complementary to clinical diagnosis and unrelated to eosinophilic inflammation, which could identify patients who may benefit from specific treatment strategies or closer monitoring.

Prevalence and Population-Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Tuberculosis transmission in the population of patients from the Krakow Region (Poland) based on the epidemiological and molecular methods.

BACKGROUND: The transmission of tuberculosis may affect the incidence rate of the disease in Poland. Genetic methods are of assistance in tracing the infection transmission, identifying its sources, determining the risk groups, and focusing on the preventive actions. OBJECTIVES: The objectives of this study lie in an assessment of tuberculosis transmission by genetic methods with the assistance of the standard epidemiologic interview. METHODS: The genome DNA of 275 Mycobacterium tuberculosis (Mtb) strains from tuberculosis patients, inhabitants of the city of Krakow, was subjected to a genetic analysis via the spoligotyping method and the IS6110-Mtb1-Mtb2 polymerase chain reaction (PCR) method. If the DNA profiles were identical in both of the PCRs, they were considered identical and classified within one molecular family. RESULTS: Among 275 strains, 104 genetic patterns (spoligotypes) were identified. Two hundred and three strains were divided into 66 molecular families (clusters) and analyzed with the IS6110- Mtb1-Mtb2 PCR method. Eighteen clusters were separated. In the Mtb1-Mtb2 clusters, 21 patients were in the risk groups (the homeless, prisoners, and nursing home residents). We did not confirm any direct or temporary contacts between the patients constituting the Mtb1-Mtb2 clusters (apart from the risk groups). However, the patients in these clusters often lived in the same parts of Krakow. CONCLUSIONS: The standard epidemiologic interview in tuberculosis patients should be combined with genetic methods. Active transmission of tuberculosis occurs largely among the individuals maintaining probably periodic contacts. The patients who are in the risk groups may play an important role in the transmission of tuberculosis.

Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper.

NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future.

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.

Dietary Intake of Flavonoids and Ventilatory Function in European Adults: A GA²LEN Study.

BACKGROUND: Flavonoids exert anti-inflammatory properties and modulate oxidative stress in vitro, suggesting a protective effect on lung function, but epidemiological studies examining this association are scarce. METHODS: A stratified random sample was drawn from the GA²LEN screening survey, in which 55,000 adults aged 15 to 75 answered a questionnaire on respiratory symptoms. Post-bronchodilator spirometry was obtained from 2850 subjects. Forced vital capacity (FVC), the ratio between the forced exhaled volume in 1 second (FEV1) and FVC (FEV1/FVC), FVC below lower limit of normal (FVC < LLN), and FEV1/FVC < LLN were calculated. Intake of the six main subclasses of flavonoids was estimated using the GA²LEN Food Frequency Questionnaire. Adjusted associations between outcomes and each subclass of flavonoids were examined with multivariate regressions. Simes' procedure was used to test for multiple comparisons. RESULTS: A total of 2599 subjects had valid lung function and dietary data. A lower prevalence of FVC < LLN (airway restriction) was observed in those with higher total flavonoid (adjusted odds ratio (aOR), higher vs. lowest quintile intake 0.58; 95% Confidence Interval (CI) 0.36, 0.94), and pro-anthocyanidin intakes (aOR 0.47; 95% CI 0.27, 0.81). A higher FEV1/FVC was associated with higher intakes of total flavonoids and pro-anthocyanidins (adjusted correlation coefficient (a ß-coeff 0.33; 0.10, 0.57 and a ß-coeff 0.44; 95% CI 0.19, 0.69, respectively). After Simes' procedure, the statistical significance of each of these associations was attenuated but remained below 0.05, with the exception of total flavonoids and airway restriction. CONCLUSIONS: This population-based study in European adults provides cross-sectional evidence of a positive association of total flavonoid intake and pro-anthocyanidins and ventilatory function, and a negative association with spirometric restriction in European adults.

Diagnostic Accuracy of Urinary LTE4 Measurement to Predict Aspirin-Exacerbated Respiratory Disease in Patients with Asthma.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) are distinguished from patients with aspirin-tolerant asthma (ATA) by significantly higher baseline concentrations of urinary leukotriene E4 (uLTE4). However, an overlap between the individual values of the groups exists. OBJECTIVE: The objective of this study was to estimate the discriminative value of uLTE4 concentration in differentiating between patients with AERD and patients with ATA and evaluate the diagnostic accuracy of uLTE4 measurement alone and added to clinical parameters to predict AERD diagnosis in patients with asthma. METHODS: Clinical data were collected from questionnaires. Spirometry, skin prick tests, total IgE, and blood eosinophilia were evaluated. ULTE4 concentrations were measured in morning urine samples by enzyme-linked immune assay (ELISA). RESULTS: Patients with AERD (n = 247) had significantly higher uLTE4 concentrations than those with ATA (n = 239). The uLTE4 concentration of 800.0 pg/mg creatinine as measured by ELISA on a spot sample best discriminated the 2 groups (area under the curve 0.7; 95% confidence interval 0.66-0.74, sensitivity 49%, specificity 81%). The positive predictive value and negative predictive value (NPV), after considering the prevalence of AERD in the population of asthmatics, were 16% and 96%, respectively. Nasal polyps, upper airway symptoms, nasal corticosteroid treatment, asthma exacerbations, forced expiratory volume in the 1 second predicted, and age of asthma onset were independent predictors of AERD diagnosis. The addition of elevated uLTE4 concentration to the set of clinical parameters enhanced slightly the prediction of AERD diagnosis beyond the level predicted by clinical parameters (P = .036). CONCLUSIONS: A set of typical clinical parameters has a superior accuracy in prediction of AERD diagnosis than the measurement of uLTE4 concentration alone. The addition of uLTE4 concentration to clinical parameters slightly enhances the prediction of AERD diagnosis, especially due to a high NPV.

Prevalence and burden of chronic bronchitis symptoms: results from the BOLD study.

We studied the prevalence, burden and potential risk factors for chronic bronchitis symptoms in the Burden of Obstructive Lung Disease study.Representative population-based samples of adults aged ≥40 years were selected in participating sites. Participants completed questionnaires and spirometry. Chronic bronchitis symptoms were defined as chronic cough and phlegm on most days for ≥3 months each year for ≥2 years.Data from 24 855 subjects from 33 sites in 29 countries were analysed. There were significant differences in the prevalence of self-reported symptoms meeting our definition of chronic bronchitis across sites, from 10.8% in Lexington (KY, USA), to 0% in Ile-Ife (Nigeria) and Blantyre (Malawi). Older age, less education, current smoking, occupational exposure to fumes, self-reported diagnosis of asthma or lung cancer and family history of chronic lung disease were all associated with increased risk of chronic bronchitis. Chronic bronchitis symptoms were associated with worse lung function, more dyspnoea, increased risk of respiratory exacerbations and reduced quality of life, independent of the presence of other lung diseases.The prevalence of chronic bronchitis symptoms varied widely across the studied sites. Chronic bronchitis symptoms were associated with significant burden both in individuals with chronic airflow obstruction and those with normal lung function.

Is fruit and vegetable intake associated with asthma or chronic rhino-sinusitis in European adults? Results from the Global Allergy and Asthma Network of Excellence (GA2LEN) Survey.

BACKGROUND: Fruits and vegetables are rich in compounds with proposed antioxidant, anti-allergic and anti-inflammatory properties, which could contribute to reduce the prevalence of asthma and allergic diseases. OBJECTIVE: We investigated the association between asthma, and chronic rhino-sinusitis (CRS) with intake of fruits and vegetables in European adults. METHODS: A stratified random sample was drawn from the Global Allergy and Asthma Network of Excellence (GA2LEN) screening survey, in which 55,000 adults aged 15-75 answered a questionnaire on respiratory symptoms. Asthma score (derived from self-reported asthma symptoms) and CRS were the outcomes of interest. Dietary intake of 22 subgroups of fruits and vegetables was ascertained using the internationally validated GA2LEN Food Frequency Questionnaire. Adjusted associations were examined with negative binomial and multiple regressions. Simes procedure was used to control for multiple testing. RESULTS: A total of 3206 individuals had valid data on asthma and dietary exposures of interest. 22.8% reported having at least 1 asthma symptom (asthma score ≥1), whilst 19.5% had CRS. After adjustment for potential confounders, asthma score was negatively associated with intake of dried fruits (ß-coefficient -2.34; 95% confidence interval [CI] -4.09, -0.59), whilst CRS was statistically negatively associated with total intake of fruits (OR 0.73; 95% CI 0.55, 0.97). Conversely, a positive association was observed between asthma score and alliums vegetables (adjusted ß-coefficient 0.23; 95% CI 0.06, 0.40). None of these associations remained statistically significant after controlling for multiple testing. CONCLUSION AND CLINICAL RELEVANCE: There was no consistent evidence for an association of asthma or CRS with fruit and vegetable intake in this representative sample of European adults.

Systemic prostacyclin and thromboxane production in obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea increases the risk of cardiovascular diseases. Alternations in prostacyclin and thromboxane concentrations and balance could constitute one of mechanisms linking sleep apnea and cardiovascular events. Thus we aimed to assess the concentrations of 6-keto-prostaglandin F1α (6-keto-PGF1α) (metabolite of prostacyclin) and thromboxane B2 (TXB2) (metabolite of thromboxane A2) in urine and blood of obstructive sleep apnea patients and controls (snoring subjects with otherwise normal polysomnogram). MATERIAL AND METHODS: Overnight urine and morning blood samples were taken from subjects and controls at baseline and in sleep apnea group during continuous positive airway pressure (CPAP) treatment. Samples were analyzed using mass chromatography/gas spectrometry. RESULTS: We analyzed data from 26 obstructive sleep apnea subjects (mean apnea-hypopnea index 45.4±17.3) and 22 well-matched controls. At baseline sleep apnea patients, when compared to controls, have higher 6-keto-PGF1α in urine (0.89±0.15 vs 0.34±0.06, p=0.01) and blood (24.49±1.54 vs 19.70±1.77, p=0.04). TXB2 levels in urine and blood were not different across groups. CPAP treatment significantly decreased 6-keto-PGF1α in urine (0.92±0.17 vs 0.22±0.10, p=0.04), but not in blood. TXB2 levels during CPAP treatment did not change significantly. CONCLUSIONS: These results suggest augmented systemic prostacyclin production in obstructive sleep apnea patients, which potentially could constitute a protective mechanism against detrimental effects of sleep apnea.

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.

Arterial and venous thromboembolism in chronic obstructive pulmonary disease: from pathogenic mechanisms to prevention and treatment.

Chronic obstructive pulmonary disease (COPD) affects approximately 10% of adults older than 40 years and is an important causes of disability and death in elderly subjects. A large proportion of COPD patients suffer from cardiovascular comorbidities. Thromboembolic events contribute considerably to morbidity and mortality in these subjects. This review summarizes the current evidence regarding the association of COPD with increased thromboembolic risk. We discuss multiple mechanisms potentially linking these conditions and available pharmacological interventions reducing the risk of thrombotic arterial and venous events with special attention paid to new oral anticoagulants.

Factors associated with asthma control in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Effective control of asthma is the primary goal of its treatment. Despite an improved understanding of asthma pathogenesis and accessibility of novel therapies, the rate of uncontrolled asthma remains high. OBJECTIVE: To find potential factors associated with asthma control in patients with aspirin-exacerbated respiratory disease (AERD). METHODS: Clinical data were collected from a specifically structured questionnaire. Demographics, a history of upper airway symptoms, asthma course, exacerbations expressed as emergency department (ED) visits/hospitalizations, and asthma treatment were considered. Spirometry, skin prick tests, total IgE concentration, and blood eosinophil count were evaluated. Asthma control was assessed through the Asthma Control Test (ACT). RESULTS: Out of 201 AERD patients, 41 (20.4%), 69 (34.3%), and 91 (45.3%) had controlled, partially controlled, and uncontrolled asthma, respectively. A multivariate ordered logistic regression analysis revealed that hospitalizations for asthma in the previous 12 months (OR 2.88; 95%CI, 1.11-7.46), ED visits for asthma throughout its duration (OR 1.05; 95%CI, 1.004-1.10), and total IgE concentration (OR 1.28; 95%CI, 1.02-1.60) were positively associated with poor asthma control, whereas FEV1 values (OR 0.98; 95%CI, 0.96-0.99) and medical care at a referential specialty clinic (OR 0.50; 95%CI, 0.27-0.95) were positively associated with good asthma control. CONCLUSIONS: The prevalence of uncontrolled asthma in AERD patients is high and similar to that observed in different asthmatic populations. Owing both to the specificity and complexity of the disease, AERD patients should stay under regular care of well experienced referential medical centers to ensure that this asthma phenotype is dealt with effectively.

Comparison of IGRA tests and TST in the diagnosis of latent tuberculosis infection and predicting tuberculosis in risk groups in Krakow, Poland.

BACKGROUND: The objective of this study was to assess the prevalence of latent tuberculosis infection (LTBI) in risk groups in Krakow, using the QuantiFERON-TB Gold In-Tube (QFT-GIT) test and the tuberculin skin test (TST); we also sought to assess the rate of progression to active disease over 4-5 y of follow-up. METHODS: QFT-GIT tests were performed on 785 subjects and the TST on 701 subjects from the risk groups of homeless persons, close contacts, periodic contacts, and residents of long-term care facilities (LTCFs), and subjects from a low risk group. RESULTS: In homeless persons, close contacts, periodic contacts, LTCF residents, and low risk persons, a positive QFT-GIT was found in 36.7%, 27.2%, 27.0%, 21.1%, and 23.7% of subjects, respectively, while a positive TST was found in 55.8%, 47.4%, 47.6%, 43.2%, and 47.9%, respectively. Of 63 homeless subjects, 5 developed active TB over 248 person-y of follow-up (incidence rate (IR) 20 per 1000 person-y, 95% confidence interval (CI) 8.4-48.5); of 148 close contacts, 5 developed active TB over 740 person-y of follow-up (IR 7, 95% CI 2.8-16.2); of 145 periodic contacts, 2 developed active TB over 580 person-y of follow-up (IR 4, 95% CI 0.9-13.8). The IR per 1000 person-y (95% CI) among subjects with a positive QFT-GIT was 30 (9.0-86.1) for homeless subjects, 18 (5.7-54.7) for close contacts, and 13 (3.2-51.3) for periodic contacts. In Poland there is no policy for the provision of LTBI treatment to people with a positive QFT or TST; therefore, the estimated rates of disease progression were analysed amongst untreated subjects. CONCLUSIONS: The prevalence of positive QFT-GIT and TST was high in the study risk groups. The best predictor of active TB in the homeless and close contacts groups was a positive QFT-GIT together with a positive TST.

Aspirin desensitization in patients with aspirin-induced and aspirin-tolerant asthma: a double-blind study.

BACKGROUND: Numerous open trials have demonstrated the beneficial clinical effects of aspirin desensitization (AD) in patients with aspirin-induced asthma (AIA). These beneficial effects might be attributable to aspirin's potent anti-inflammatory properties, but that supposition requires further corroboration. OBJECTIVE: We sought to compare the clinical and biochemical responses to chronic oral AD in 20 patients with AIA and 14 patients with aspirin-tolerant asthma (ATA). All of the patients had chronic rhinosinusitis and nasal polyposis, and these responses were investigated in a pilot, double-blind, placebo-controlled study. METHODS: Twelve patients with AIA and 6 patients with ATA were randomly assigned to receive 624 mg of aspirin, and 8 patients with AIA and 8 patients with ATA received placebo. Both aspirin and placebo were administered once daily for 6 months. Nasal symptoms, Sino-Nasal Outcome Test (SNOT20) scores, peak nasal inspiratory flows, Asthma Control Questionnaire scores, spirometric parameters, peak expiratory flows, blood eosinophilia, and corticosteroid doses were assessed on a monthly basis. Levels of urinary leukotriene E4 and the stable plasma prostaglandin (PG) D2 metabolite 9α,11ß-PGF2 were evaluated at baseline and after 1, 3, 5, and 6 months. RESULTS: Only the patients with AIA subjected to AD reported improvements in smell and reductions in sneezing and nasal blockade. The SNOT20 and Asthma Control Questionnaire scores of these patients decreased, and their peak nasal inspiratory flows increased. The dosages of inhaled corticosteroids were reduced. There were no changes in leukotriene E(4) or 9α,11ß-PGF(2) levels after AD. CONCLUSION: The clinically beneficial effects of AD on nasal and bronchial symptoms occurred only in the patients with AIA.

Modulation of inflammatory and hemostatic markers in obstructive sleep apnea patients treated with mandibular advancement splints: a parallel, controlled trial.

STUDY OBJECTIVE: Obstructive sleep apnea (OSA) is associated with systemic inflammation and a hypercoagulable state. The current study aim was to investigate whether mandibular advancement splint (MAS) therapy affects inflammatory and hemostatic parameters in patients with mild-to-moderate OSA. METHODS: Twenty-two patients with mild-to-moderate OSA and 16 control subjects were studied. OSA subjects were treated with a titratable MAS for 6 months. Baseline plasma C-reactive protein, interleukin-1ß, interleukin-10, interleukin-6, P-selectin, fibrinogen, D-dimer, plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex, activated thrombin-activatable fibrinolysis inhibitor (TAFIa), 6-keto-PGF1α, glucose, and fibrin clot lysis time (CLT) were measured in all subjects. After 3 months of MAS therapy, measurements were repeated for the 22 patients, and after 6 months all measurements were repeated for all study subjects. RESULTS: MAS treatment reduced significantly AHI at 3 months (24 vs 13.1/h) and further improved it at 6 months (13.1 vs 7.05/h). Compared with controls, OSA subjects had a significant higher baseline mean levels of fibrinogen, TAFIa, 6-keto-PGF1α, and glucose. MAS treatment significantly improved levels of IL-1ß, D-dimer, TAFIa, and CLT. Despite residual apneas, MAS treatment group presented similar measured homeostatic and inflammatory levels to controls except for glucose. CONCLUSION: Treatment with MAS in mild-to-moderate OSA subjects improves the inflammatory profile and homeostatic markers. CITATION: Nizankowska-Jedrzejczyk A; Almeida FR; Lowe AA; Kania A; Nastalek P; Mejza F; Foley JH; Nizankowska-Mogilnicka E; Undas A. Modulation of inflammatory and hemostatic markers in obstructive sleep apnea patients treated with mandibular advancement splints: a parallel, controlled trial.

Certain subphenotypes of aspirin-exacerbated respiratory disease distinguished by latent class analysis.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is recognized as a distinct asthma phenotype. It usually has a severe course accompanied by chronic hyperplastic eosinophilic sinusitis with nasal polyps, blood eosinophilia, and increased concentrations of urinary leukotriene E4 (LTE4). More insightful analysis of individual patients shows this group to be nonhomogeneous. OBJECTIVE: We sought to identify any likely subphenotypes in a cohort of patients with AERD through the application of latent class analysis (LCA). METHODS: Clinical data from 201 patients with AERD (134 women) were collected from questionnaires. Standard spirometry, atopy traits, blood eosinophilia, and urinary LTE4 concentrations were evaluated. LCA was applied to identify possible AERD subphenotypes. RESULTS: Four classes (subphenotypes) within the AERD phenotype were identified as follows: class 1, asthma with a moderate course, intensive upper airway symptoms, and blood eosinophilia (18.9% of patients); class 2, asthma with a mild course, relatively well controlled, and with low health care use (34.8% of patients); class 3, asthma with a severe course, poorly controlled, and with severe exacerbations and airway obstruction (41.3% of patients); and class 4, poorly controlled asthma with frequent and severe exacerbations in female subjects (5.0% of patients). Atopic status did not affect class membership. Patients with particularly intensive upper airway symptoms had the highest levels of blood eosinophilia and the highest concentrations of urinary LTE4. CONCLUSIONS: LCA revealed unique AERD subphenotypes, thus corroborating the heterogeneity of this population. Such discrimination might facilitate more individualized treatment in difficult-to-treat patients.