Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA-MeDALL hypothesis.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.

Dynamics and proliferative capacities of CD8+CD28+TCRαß+CD62Lhigh T-cell subsets in healthy and asthmatic subjects.

Adhesion molecules, as such, play essential roles in T-cell transendothelial extravasation during inflammation. A better understanding of the mechanisms underlying this process may be of value in the management of asthma. The present study employed Magnetic-Activated Cell Sorting (MACS) to isolate human CD8+ T lymphocytes from peripheral blood of asthma patients and controls. The cells were flow cytometrically assessed to evaluate surface expression of an adhesion molecule, L-selectin (CD62L) on the surface of CD8FoxP3-/bright T cell subsets and its response to inflammatory cytokines. We showed that CD8+CD28+TCRαß+CD62LhighFoxP3bright T cells were deficient in blood of some asthma patients but abundant in others. After co-stimulation of CD8+ T cells with anti-CD3/CD28 in combination with IL-2 and IL-10 or TGF-ß, the frequencies of CD8+CD28+TCRα/ß+CD62Lhigh T cells in the group of patients were lower than at baseline. Our data indicate that L-selectin expression is regulated by inflammatory cytokines. Overall, these data reveal that asthma phenotypes may be further stratified into micro subtypes with distinct cellular and molecular characteristics, supporting the concept of asthma endotypes.

Interleukin-2-mediated stat-5 expression levels in CD8+CD25+ regulatory T cells: the relevance for asthma.

Preliminary studies demonstrated the potential role of CD8+CD25+ T regulatory cells (Tregs) in asthma. However, published data with regard to the relevance of signaling pathways that govern Tregs homeostasis are limited and conflicting. The first aim of this study was to characterize the phosphorylation of STAT-5 in CD8+CD25+ Tregs. The second aim was to investigate the ability of CD8+CD25+ Tregs from patients and controls to respond to interleukin (IL)-2 treatment in vitro. Twenty-five healthy subjects (NC) and 50 patients with either severe (SA) or mild-moderate (MA) asthma were enrolled in the study. STAT-5 phosphorylation was detected in purified CD8+CD25+ Tregs from healthy and asthma subjects, indicating that STAT-5 has a role in their pathobiology. At baseline, asthmas had either significantly lower [(SA=4.5±5% vs NC=26±25%, P < 0.001) and (MA=10±7.5% vs NC=26±25%, P < 0.001)] or higher [(SA=54±58.5% vs 26±25%, P < 0.01) and (MA=71±74.5% vs 26±25%, P < 0.01) proportion of Tregs expressing pSTAT-5 than controls. In contrast to healthy subjects, CD8+CD25+ Tregs from asthma subjects had either increased (pSTAT-5high) or decreased (pSTAT-5low) phosphorylated STAT-5 levels within individual cells. These data suggest that the alteration in STAT5 phosphorylation level might be associated with asthma and is a potential molecular basis of skewed CD8+CD25+ Treg differentiation. IL-2 treatment of cells from severe asthma subjects increased the proportion of cells expressing high level of pSTAT-5 while it decreased the proportion of those expressing low level of pSTAT-5. Strikingly, IL-2 increased the proportions of both subsets from mild-moderate asthma subjects. These findings demonstrate that altered IL-2-mediated STAT-5 phosphorylation within individual circulatory CD8+CD25+ Tregs may be associated with asthma and disease severity.

Daily allergic multimorbidity in rhinitis using mobile technology: A novel concept of the MASK study.

BACKGROUND: Multimorbidity in allergic airway diseases is well known, but no data exist about the daily dynamics of symptoms and their impact on work. To better understand this, we aimed to assess the presence and control of daily allergic multimorbidity (asthma, conjunctivitis, rhinitis) and its impact on work productivity using a mobile technology, the Allergy Diary. METHODS: We undertook a 1-year prospective observational study in which 4 210 users and 32 585 days were monitored in 19 countries. Five visual analogue scales (VAS) assessed the daily burden of the disease (i.e., global evaluation, nose, eyes, asthma and work). Visual analogue scale levels <20/100 were categorized as "Low" burden and VAS levels ≥50/100 as "High" burden. RESULTS: Visual analogue scales global measured levels assessing the global control of the allergic disease were significantly associated with allergic multimorbidity. Eight hypothesis-driven patterns were defined based on "Low" and "High" VAS levels. There were <0.2% days of Rhinitis Low and Asthma High or Conjunctivitis High patterns. There were 5.9% days with a Rhinitis High-Asthma Low pattern. There were 1.7% days with a Rhinitis High-Asthma High-Conjunctivitis Low pattern. A novel Rhinitis High-Asthma High-Conjunctivitis High pattern was identified in 2.9% days and had the greatest impact on uncontrolled VAS global measured and impaired work productivity. Work productivity was significantly correlated with VAS global measured levels. CONCLUSIONS: In a novel approach examining daily symptoms with mobile technology, we found considerable intra-individual variability of allergic multimorbidity including a previously unrecognized extreme pattern of uncontrolled multimorbidity.

The relative values of CD8+CD25+Foxp3brigh Treg cells correlate with selected lung function parameters in asthma.

The study aimed to detect CD8(+)CD25(+)FoxP3(brigh) Tregs and investigate their possible association with selected lung function values. CD8(+)CD25(+)FoxP3(brigh) Tregs were detected by flow cytometry in the peripheral blood of 25 patients with severe asthma (SA), 25 patients with mild-to-moderate asthma (MA), and 25 age-matched healthy donors (NC). The percentages of CD8(+)CD25(+)FoxP3(brigh) Tregs of the patients with severe (3.4 ± 4.55), and mild-to-moderate asthma (7.5 ± 8.15), were markedly lower than those of controls (12.1 ± 13.2). The mean forced expiratory volume in 1 s (FEV1) % predicted value in severe asthma subpopulation was significantly lower (67.05 ± 15.98%) when compared with that of mild-to-moderate asthma subgroup (87.71 ± 16.12%). Interestingly, the percentages of CD8(+)CD25(+)FoxP3(brigh) Tregs correlate with mean peak expiratory flow (PEF)% predicted values in severe (r = 0.7, P <0.01) and mild-to-moderate (r = 0.73, P <0.01) asthma. In contrast, this parameter was positively correlated with FEV1% predicted values in the severe asthmatics only (r = 0.71, P <0.01). In summary, this study establishes a link between the percentage of CD8(+)CD25(+)FoxP3(brigh) Tregs and selected lung function parameters, suggesting that this parameter has potential as a marker for inflammation and airflow obstruction.

Frequent exacerbators--a distinct phenotype of severe asthma.

BACKGROUND: Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult-to-treat disease. OBJECTIVE: The goal of our study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations. METHODS: Ninety-three severe asthmatics (SA) and 76 mild-to-moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations. RESULTS: During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 µg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1 /FVC ratio (-0.07 vs. -0.01 ΔFEV1 /FVC, frequent vs. non-frequent, respectively, P < 0.05). Exhaled NO > 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively). CONCLUSION AND CLINICAL RELEVANCE: We were able to distinguish and characterize a subphenotype of asthma subjects--frequent exacerbators--who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice.

Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma.

BACKGROUND: Although asthma is characterized by variable airways obstruction, most studies of asthma phenotypes are cross-sectional. The stability of phenotypes defined either by biomarkers or by physiological variables was assessed by repeated measures over 1 year in the Pan-European BIOAIR cohort of adult asthmatics. METHODS: A total of 169 patients, 93 with severe asthma (SA) and 76 with mild-to-moderate asthma (MA), were examined at six or more visits during 1 year. Asthma phenotype clusters were defined by physiological variables (lung function, reversibility and age of onset of the disease) or by biomarkers (eosinophils and neutrophils in induced sputum). RESULTS: After 1 year of follow-up, the allocation to clusters was changed in 23.6% of all asthma patients when defined by physiological phenotypes and, remarkably, in 42.3% of the patients when stratified according to sputum cellularity (P = 0.034). In the SA cohort, 30% and 48.6% of the patients changed allocation according to physiological and biomarker clustering, respectively. Variability of phenotypes was not influenced by change in oral or inhaled corticosteroid dose, nor by the number of exacerbations. Lower stability of single and repeated measure was found for all evaluated biomarkers (eosinophils, neutrophils and FeNO) in contrast to good stability of physiological variables (FEV1 ), quality of life and asthma control. CONCLUSION: Phenotypes determined by biomarkers are less stable than those defined by physiological variables, especially in severe asthmatics. The data also imply that definition of asthma phenotypes is improved by repeated measures to account for fluctuations in lung function, biomarkers and asthma control.

Allergy-related changes in levels of CD8+CD25+FoxP3(bright) Treg cells and FoxP3 mRNA expression in peripheral blood: the role of IL-10 or TGF-beta.

There is an increasing body of evidence that alterations of regulatory T (Treg) cell numbers and functions lead to immune disorders. Accordingly, understanding the regulatory mechanisms that maintain peripheral regulatory T (Treg) cell homeostasis is key to the development of effective targeted biologic therapies. We previously demonstrated the effects of IL-10 or TGF-beta on distinct CD8+CD28- T cell subsets in vitro. Allergy-related changes of CD8+CD25+FoxP3(bright)Treg cells and FoxP3 mRNA expression in peripheral blood were assessed by means of multicolor flow cytometry and real-time polymerase chain reaction (RT-PCR). Co-stimulation of CD8+CD25+ T cells with anti-CD3/CD28 in the presence of either IL-10 or TGF-beta increased the frequency of CD8+CD25+FoxP3(bright)Treg cells in patients with asthma and controls. Likewise, CD8+CD25+ T cell activation with anti-CD3/CD28 and TGF-beta increased FoxP3mRNA expression in all groups. Anti-CD3/CD28 and IL-10 appeared to regulate FoxP3 mRNA expression in a phenotype-dependent manner. Specifically, co-stimulation by anti-CD3/CD28 and IL-10 markedly increased FoxP3 mRNA expression in the severe asthma group whereas it had opposite effects on this value in other groups. Taken altogether, these data suggest that IL-10 and TGF-beta may modulate FoxP3 expressions at the protein and mRNA levels in respect to their need for peripheral tolerance.

The effects of interleukin-10 or TGF-beta on anti-CD3/CD28 induced activation of CD8+CD28- and CD8+CD28+ T cells in allergic asthma.

The CD8+CD28- and CD8+CD28+ T cells play a primordial role in peripheral tolerance, but little is known about their implication in allergic asthma. This study was designed to determine the changes in a proportion of human circulatory CD8+ subsets before and after short term culture in the presence of anti-CD3/CD28 and IL-10 or TGF-beta. Flow cytometry analysis revealed increased percentage of CD8+CD28- T cells but decreased percentage of CD8+CD28+ T cells enriched from peripheral blood of adult allergic asthma individuals compared to controls (baseline). In comparison to the baseline, co-stimulation with anti-CD3/CD28 and IL-10 decreased the proportion of CD8+CD28- T cells in severe allergic asthma subjects, whereas it increased this value in mild to moderate asthmatic subjects and controls. Adding TGF-beta decreased the proportion of CD8+CD28- T cells from allergic asthma subjects, whereas it has opposite effects on this subset from controls. IL-10 and TGF-beta had some plethoric effects on FoxP3 expression in anti-CD3/CD28 activated CD8+CD28- T cells. Thus, these findings indicate that a control mechanism involving IL-10 and TGF-beta might be defective in allergic asthma subjects.

Comparison of changes in the percentages of CD8+CD28-TCRalpha beta+ T cell subpopulations in allergic asthma subjects vs controls before and after anti-CD3/anti-CD28/IL-2 stimulation in vitro.

Asthma is a chronic inflammatory disease characterized by the migration of activated T cells into the bronchial mucosa. TGF-beta and IL-10 have proved to regulate airway hyper-responsiveness and leukocytes recruitment to the airways of ovalbumin (OVA) sensitized mice. We examined relative changes in CD8+T cell subpopulations between fifty allergic asthma subjects and twenty five aged-matched healthy adults before and after anti-CD3/CD28 and IL-2 stimulation in the presence of IL-10 or TGF-beta, focusing on CD62L and FoxP3 expressing TCR alpha beta + cells. Severe asthma group had a significantly higher percentage of CD8+ CD28-and CD8+ CD28-TCR alpha beta + CD62L highFoxP3 bright T cells than other groups after enrichment. Compared to the baseline, co-stimulation with either IL-10 or TGF-beta increased the percentage of CD8+CD28-but decrease the percentage of CD8+CD28+T cells within anti-CD3/anti-CD28/IL-2 activated CD8+T cells in all groups. Co-stimulation with anti-CD3/anti-CD28/IL-2 in presence of either IL-10 or TGF-beta decreased the frequencies of CD8+CD28-TCR alpha beta +CD62Lhigh FoxP3 bright T cells in severe asthma subgroup but increased this parameter in other groups. We suggest that altered high level expression of CD62L and FoxP3 on CD8+ CD28-TCR alpha beta + T cell is relevant to allergic asthma. These data have implications for further characterization of CD8+ CD28-TCR alpha beta+ T cell subsets, with special emphasis on their implication in healthy or allergic immune response.

Adherence to inhaled corticosteroids and long-acting ß2-agonists in asthma: A MASK-air study.

INTRODUCTION: Adherence to controller medication is a major problem in asthma management, being difficult to assess and tackle. mHealth apps can be used to assess adherence. We aimed to assess the adherence to inhaled corticosteroids+long-acting ß2-agonists (ICS+LABA) in users of the MASK-air® app, comparing the adherence to ICS+formoterol (ICS+F) with that to ICS+other LABA. MATERIALS AND METHODS: We analysed complete weeks of MASK-air® data (2015-2022; 27 countries) from patients with self-reported asthma and ICS+LABA use. We compared patients reporting ICS+F versus ICS+other LABA on adherence levels, symptoms and symptom-medication scores. We built regression models to assess whether adherence to ICS+LABA was associated with asthma control or short-acting beta-agonist (SABA) use. Sensitivity analyses were performed considering the weeks with no more than one missing day. RESULTS: In 2598 ICS+LABA users, 621 (23.9%) reported 4824 complete weeks and 866 (33.3%) reported weeks with at most one missing day. Higher adherence (use of medication ≥80% of weekly days) was observed for ICS+other LABA (75.1%) when compared to ICS+F (59.3%), despite both groups displaying similar asthma control and work productivity. The ICS+other LABA group was associated with more days of SABA use than the ICS+F group (median=71.4% versus 57.1% days). Each additional weekly day of ICS+F use was associated with a 4.1% less risk in weekly SABA use (95%CI=-6.5;-1.6%;p=0.001). For ICS+other LABA, the percentage was 8.2 (95%CI=-11.6;-5.0%;p<0.001). CONCLUSIONS: In asthma patients adherent to the MASK-air app, adherence to ICS+LABA was high. ICS+F users reported lower adherence but also a lower SABA use and a similar level of control.

Identification by cluster analysis of patients with asthma and nasal symptoms using the MASK-air® mHealth app.

BACKGROUND: The self-reporting of asthma frequently leads to patient misidentification in epidemiological studies. Strategies combining the triangulation of data sources may help to improve the identification of people with asthma. We aimed to combine information from the self-reporting of asthma, medication use and symptoms to identify asthma patterns in the users of an mHealth app. METHODS: We studied MASK-air® users who reported their daily asthma symptoms (assessed by a 0-100 visual analogue scale - "VAS Asthma") at least three times (either in three different months or in any period). K-means cluster analysis methods were applied to identify asthma patterns based on: (i) whether the user self-reported asthma; (ii) whether the user reported asthma medication use and (iii) VAS asthma. Clusters were compared by the number of medications used, VAS asthma levels and Control of Asthma and Allergic Rhinitis Test (CARAT) levels. FINDINGS: We assessed a total of 8,075 MASK-air® users. The main clustering approach resulted in the identification of seven groups. These groups were interpreted as probable: (i) severe/uncontrolled asthma despite treatment (11.9-16.1% of MASK-air® users); (ii) treated and partly-controlled asthma (6.3-9.7%); (iii) treated and controlled asthma (4.6-5.5%); (iv) untreated uncontrolled asthma (18.2-20.5%); (v) untreated partly-controlled asthma (10.1-10.7%); (vi) untreated controlled asthma (6.7-8.5%) and (vii) no evidence of asthma (33.0-40.2%). This classification was validated in a study of 192 patients enrolled by physicians. INTERPRETATION: We identified seven profiles based on the probability of having asthma and on its level of control. mHealth tools are hypothesis-generating and complement classical epidemiological approaches in identifying patients with asthma.

U.S. and European severe asthma cohorts: what can they teach us about severe asthma?

Asthma is a global health problem affecting around 300 million patients of all ages and ethnic groups in all countries around the world. In the majority of subjects with persistent, mild-to-moderate asthma (MA), the disease can be relatively well controlled by the use of currently available medications; however, five to ten per cent of patients suffer from a particularly severe disease that is poorly controlled clinically and often refractory to usual treatment. Improved care of severe asthma (SA) is a major unmet medical need and several international consortia aim at improving our understanding of mechanisms in SA. To manage SA better, standardized definitions and concepts of asthma severity, risk and level of control are critical. In the following sections, we present several guidelines approaches and definitions followed by an overview of U.S. (SARP) and European (ENFUMOSA, BIOAIR, U-BIOPRED) SA networks. Key findings regarding SA phenotypes, risk factors and pathophysiology are discussed. International cooperation in the area of respiratory diseases, including SA, across the Atlantic Ocean, will lead to a better understanding of asthma pathology, especially of those severe, not well controlled or difficult-to-treat cases.

Phenotypic characterization of ex vivo CD4+CD25highCD127low immune regulatory T cells in allergic asthma: pathogenesis relevance of their FoxP3, GITR, CTLA-4 and FAS expressions.

BACKGROUND: CD4+CD25high regulatory T (Treg) cells are crucial for immune homeostasis and peripheral tolerance, but their relevance to allergic asthma has not been fully elucidated. OBJECTIVE: To assess peripheral blood CD4+ T cells, and CD4+CD25highCD127low Treg cells expressing phenotypic markers (FoxP3, GITR, CTLA-4, and FAS) in allergic asthma subjects. MATERIALS AND METHODS: Peripheral blood mononuclear cells were isolated from 60 allergic asthma (AA) subjects and 30 healthy controls (HC). We examined by flow cytometry, the proportion of CD4+ T cells and CD4+CD25highCD127low Treg cells as well as the expression of FoxP3, GITR, CTLA-4, and FAS by CD4+CD25highCD127low Treg cells. Moreover, FOXP3 mRNA expression was measured by quantitative real time polymerase chain reaction (real-time RT-PCR). RESULTS: The absolute number of CD4+CD25highCD127low Treg cells and the percentages of CD4+CD25highCD127low Treg cells expressing one of the four selected markers were significantly lower in allergic asthma subjects compared with controls. We observed no significant decreased absolute CD4+ T cell count in the examined groups compared to the control group. Except for GITR, circulatory CD4+CD25highCD127low Treg cells of severe allergic asthma (SA) subjects showed significantly lower expressions of FoxP3, CTLA-4, and CD95 than did those isolated from mild to moderate asthma (MA) patients. There was no statistically significant difference in the level of mRNA FoxP3 expression in CD4+CD25+ Treg cells between allergic asthma subjects and healthy controls groups, and within the examined groups (p>0.05). CONCLUSIONS: These findings suggest that allergic asthma and the use of glucocorticosteroids are associated with decreased absolute number of circulatory CD4+CD25highCD127low Treg cells and the decreased frequencies of CD4+CD25highCD127low Treg cells expressing one of the four selected markers.

Low frequency of CD8+CD25+FOXP3(BRIGHT) T cells and FOXP3 mRNA expression in the peripheral blood of allergic asthma patients.

The aim of this study is to determine whether frequencies of CD8+CD25+ T cells and FoxP3 messenger RNA (mRNA) expression levels in CD8+ T cells isolated from peripheral blood are related to allergic asthma and disease severity. We enrolled 50 patients with allergic asthma (AA) and 25 healthy control subjects (NC) in our study. The frequencies of CD8+CD25+FoxP3 -/+ T cells were assessed with flow cytometry, and mRNA FoxP3 level in CD8+ T cells was determined with real time polymerase chain reaction (RT-PCR). Asthma patients had fewer CD8+CD25+FoxP3bright T cells [SA (median = 3.4%, IQR = 3.1) vs MA (median = 7.5%, IQR = 4.7)] than controls NC [median = 12.1 %, IQR = 8, P < 0.0001] but more CD8+CD25+FoxP3- T cells [SA (median = 96 %, IQR = 3.1) vs MA (median = 92.5%, IQR = 4.7)] than controls NC [median = 87.9%, IQR = 9.2, P < 0.0001]. FoxP3 mRNA level was significantly decreased in CD8+ T cells of severe asthma patients (median = 0.82, IQR = 0.54) than that of patients with mild to moderate asthma and controls [(median = 2.29, IQR = 4.40) vs (median = 2.11, IQR = 3.2)]. The percentage of FoxP3+ T cells was correlated positively with the percentage of forced expiratory volume in 1 second (FEV1) (r = 0.71, p< 0.01) in patients with severe asthma. The proportion of CD8+CD25+FoxP3bright T cells and the level of FOXP3 gene expression in CD8+ T cells are relevant to allergic asthma and disease severity. The manipulation of FoxP3+CD25+CD8+ T cells may prevent chronic allergic inflammation and improve lung function during an acute allergic asthma exacerbation.

Effects of celecoxib on major prostaglandins in asthma.

BACKGROUND: Prostaglandin (PG) D(2) is a pro-inflammatory and bronchoconstrictive mediator released from mast cells, and is currently evaluated as a new target for treatment of asthma and rhinitis. It is not known which cyclooxygenase (COX) isoenzyme catalyses its biosynthesis in subjects with asthma. OBJECTIVES: Primarily, to assess whether treatment with the COX-2 selective inhibitor celecoxib inhibited biosynthesis of PGD(2) , monitored as urinary excretion of its major tetranor metabolite (PGDM). Secondarily, to determine the effects of the treatment on biosynthesis of PGE(2) , thromboxane A(2) and PGI(2) , also measured as major urinary metabolites. METHODS: Eighteen subjects with asthma participated in a cross-over study where celecoxib 200mg or placebo were given b.i.d. on 3 consecutive days following 2 untreated baseline days. Six healthy controls received active treatment with the same protocol. Urinary excretion of the eicosanoid metabolites was determined by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Lung function was followed as FEV(1) and airway inflammation as fraction of exhaled nitric oxide (F(E) NO). RESULTS: Celecoxib treatment inhibited urinary excretion of PGEM by 50% or more in subjects with asthma and healthy controls, whereas there was no significant change in the excretion of PGDM. In comparison with the healthy controls, the subjects with asthma had higher baseline levels of urinary PGDM but not of PGEM. The 3-day treatment did not cause significant changes in FEV(1) or F(E) NO. CONCLUSION AND CLINICAL RELEVANCE: Biosynthesis of PGD(2) was increased in subjects with asthma and its formation is catalysed predominantly by COX-1. By contrast, COX-2 contributes substantially to the biosynthesis of PGE(2) . The asymmetric impact of celecoxib on prostanoid formation raises the possibility of long-term adverse consequences of COX-2 inhibition on airway homeostasis by the decreased formation of bronchodilator PGs and maintained production of increased levels of bronchoconstrictor PGs in asthmatics.

Reduction of asthma burden is possible through National Asthma Plans.

Despite increase in understanding of asthma patomechanisms the practical actions to lessen asthma burden in the communities are far behind of scientific knowledge. There are still reports of uderdiagnosis and poor treatment leading to repeated severe exacerbations, often demanding emergency care and hospitalisation, which cause most of the economic burden both for families and society. From the public health perspective, the key issue is to implement the best standards of care in every-day practice. The problems are different in high income compared to low- and middle-income countries, and the solutions have to be tailored to each country needs and resources. We present here examples from Finland, Poland and Brazil, to show that asthma burden can be reduced using varied strategies in quite different societal, economical and health care environments. The experience from those interventions confirms that regardless of the health care system and its coverage, a major change for the better can be achieved by local efforts, systematic planning and networking to implement the best asthma practice.

Lipoxin A4 generation is decreased in aspirin-sensitive patients in lysine-aspirin nasal challenge in vivo model.

BACKGROUND: Lipoxins represent a group of lipoxygenase derived eicosanoids which, in contrast to leukotrienes, are potent anti-inflammatory mediators. The aim of our study was to determine lipoxin A(4) (LXA(4)) and leukotriene C(4) (LTC(4)) levels in nasal lavages after intranasal challenge with aspirin in aspirin intolerant (AIA) in comparison to aspirin tolerant (ATA) asthmatics and after allergen challenge in patients suffering from allergic rhinitis. METHODS: Twelve AIA, 8 ATA and 20 allergic patients were challenged with placebo, 16 mg of lysine-aspirin (Lys-ASA) or allergen (grasses). Nasal lavages were collected and eicosanoids' levels were determined using ELISA. RESULTS: Clinically positive Lys-ASA challenge in AIA resulted in influx of leukocytes (eosinophils and basophils) to nasal secretions and increase of LTC(4) to 106.82 pg/ml (P < 0.05 vs baseline (26.58 pg/ml)) on first hour after the challenge. We did not observe any differences in LTC(4) level before and after ASA challenge in ATA. In AIA group the mean level of LXA(4) was 43 +/- 21.5 pg/ml after placebo and decreased in 2 h after Lys-ASA challenge (29 +/- 17 pg/ml, P = 0.015). We found an increase in LXA(4) in ATA after ASA provocation as compared to placebo (33 +/- 16 pg/ml vs 52 +/- 31 pg/ml, P = 0.046). In atopic patients baseline level of LXA(4) was 33.49 +/- 16.95 pg/ml with no difference after the clinically positive allergen challenge (36.22 +/- 13.26 pg/ml, P = 0.23). CONCLUSIONS: Results of our study confirm that AIA have diminished LXs' biosynthesis capacities in vivo after ASA challenge. Taking into consideration anti-inflammatory properties of lipoxins this phenomenon may be partially responsible for the development of chronic inflammation in AIA patients.

Intravenous iron sucrose changes the intraperitoneal homeostasis.

BACKGROUND/AIMS: Intravenous iron infusion is the accepted way of supplementation of that compound in uremic patients. The aim of the study was to evaluate whether this treatment affects intraperitoneal homeostasis in patients on peritoneal dialysis. METHODS: Blood and peritoneal dialysate samples were collected from 10 patients treated with continuous ambulatory peritoneal dialysis who were given 100 mg iron sucrose (IS) intravenously. Systemic and peritoneal permeability as well as transperitoneal transport were studied. The effect of spent dialysate was tested in vitro on human peritoneal mesothelial cells (MCs). RESULTS: Dialysate total iron was increased (+19%, p < 0.01) during intravenous infusion of IS. Immediately after infusion the concentration of 8-OHdG was increased in plasma (+10%, p < 0.01) and in dialysate (+5%, p < 0.05). IS infusion caused a transient decrease in peritoneal permeability to protein (-42%, p < 0.05) and glucose (-30%, p < 0.01) and a reduction in dialysate cell count (-58%, p < 0.05). During the exchange dialysate hyaluronan was increased by 27% (p < 0.01). Spent dialysate, tested ex vivo on cultured MC, induced oxidative stress (+39%, p < 0.01), slowed their proliferation (-20%, p < 0.01), and stimulated MCP-1 synthesis (+46%, p < 0.01). Iron content in MCs exposed to dialysate obtained after IS infusion was increased by 32% (p < 0.01). CONCLUSION: Intravenous infusion of IS causes oxidative stress and inflammation within peritoneal MCs which may impair viability of the peritoneum.