[Show abstract][Hide abstract] ABSTRACT: RationaleThere is conflicting evidence on whether patients with asthma experience an accelerated decline in lung function with age. We examined the association between post-bronchodilator lung function, asthma, chronic rhinosinusitis (CRS), and atopy with age using a large European cohortMethods
In 17 centres in 11 European countries, case-control studies were nested within representative cross-sectional surveys of adults aged under 75 years. Representative samples of participants with asthma, CRS or both and controls were assessed for post-bronchodilator ventilatory function, smoking history, atopy and treatment. Multiple regression was used to assess the interactive effects of age and diagnostic group on decline in post-bronchodilator ventilatory function.ResultsA total of 3,337 participants provided adequate data (778 with asthma, 399 with CRS, 244 with both asthma and CRS and 1916 controls who had neither asthma nor CRS). Participants with asthma had lower FEV1/FVC (-4.09% (95% CI: -5.02, -3.15, p <0.001) and a steeper slope of FEV1/FVC against age (-0.14%/annum (95%CI: -0.19, -0.08)) equivalent to smoking 1-2 packs of cigarettes/day. Those with atopy had a slope equivalent to controls.Conclusions
People with asthma have a steeper decline in post-bronchodilator lung function with age, but neither CRS nor atopy alone were associated with such decline.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Transforming growth factor-beta 1 (TGF-β1) has been reported being involved in the remodeling and immunosuppression processes of inflammatory airway diseases; understanding the regulation of TGF-β1 is therefore a key to unravel the pathomechanisms of these diseases. This review briefly summarizes the current knowledge on the influencing factors for driving TGF-β1 and its regulatory pathways in inflammatory airway diseases and discusses possible therapeutic approaches to TGF-β1 control. The factors include smoking and oxidative stress, prostaglandins (PGs), leukotrienes (LTs), bradykinin (BK), and microRNAs (miRs). Based on the summary, new innovative treatment strategies may be developed for inflammatory airway diseases with an impaired expression of TGF-β1.
[Show abstract][Hide abstract] ABSTRACT: Background
Geographical variation in the prevalence of sensitization to aeroallergens may reflect differences in exposure to risk factors such as having older siblings, being raised on a farm or other unidentified exposures.Objective
We wanted to measure geographical variation in skin prick test positivity and assess whether it was explained by differences in family size and/or farm exposure. We also compared prevalence in younger and older subjects.Methods
Within the Global Allergy and Asthma European Network (GA2LEN) survey, we measured the prevalence of skin prick positivity to a panel of allergens, and geometric mean serum total immunoglobulin E (IgE), in 3451 participants aged 18–75 years in 13 areas of Europe. Estimated prevalence was standardized to account for study design. We compared prevalence estimates in younger and older subjects and further adjusted for age, gender, smoking history, farm exposure, number of older siblings and body mass index (BMI).ResultsSkin prick test positivity to any one of the measured allergens varied within Europe from 31.4% to 52.9%. Prevalence of sensitization to single allergens also varied. Variation in serum total IgE was less marked. Younger participants had higher skin prick sensitivity prevalence, but not total IgE, than older participants. Geographical variation remained even after adjustment for confounders.Conclusion
Geographical variation in the prevalence of skin prick test positivity in Europe is unlikely to be explained by geographical variation in gender, age, smoking history, farm exposure, family size and BMI. Higher prevalence in younger, compared to older, adults may reflect cohort-associated increases in sensitization or the influence of ageing on immune or tissue responses.
[Show abstract][Hide abstract] ABSTRACT: Background Cross-sectional and longitudinal reports show that obese adults have more asthma than non-obese adults. A proposed mechanism is via effects of adipokines (leptin and adiponectin) on the immune system. Objective We wished to measure the associations of asthma and other atopic diseases with serum adipokine levels and to find whether the associations with asthma were strong enough to rule out the possibility that they are secondary to the association of fatness measures with asthma. Methods The Global Asthma and Allergy Network of Excellence (GA 2 LEN) clinical follow-up survey is a clinical survey, embedded in a larger multi-centre cross-sectional postal survey, involving, with a case/control design, enrichment of the sample with subjects with asthma and chronic rhinosinusitis (CRS). We recorded serum leptin or adiponectin in 845 men and 1110 women in 15 centres and also anthropometric measures of fatness includ-ing body mass index and waist/hip ratio, current asthma, and specific skin prick and IgE sensitisation. We used inverse sampling-probability-weighted rank and regression statis-tics to measure population associations of disease outcomes with adipokines in males and females, adjusting for confounders (area, age, smoking history, and number of elder sib-lings) and also mutually adjusting associations with adipokines and fatness measures. Results One thousand nine hundred and fifty-five subjects aged 16–77 years had infor-mation on leptin or adiponectin levels. Leptin and leptin/adiponectin ratio were positively associated with the level of asthma, especially in females (Somers' D of leptin by asthma score, 0.20; 95% CI, 0.08–0.30; P = 0.00079). These associations were attenuated after adjusting for confounders and became non-significant after additionally adjusting for fatness measures and multiple comparisons. Conclusions and Clinical Relevance Asthma levels are positively associated with serum leptin. However, we cannot rule out the possibility that this association is secondary to associations of both with fatness measures.
[Show abstract][Hide abstract] ABSTRACT: Nasal polyposis is a severe, chronic inflammatory condition of the paranasal sinuses and is frequently associated with asthma and aspirin sensitivity. Mesenchymal stem cells exhibit a potent immunosuppressive effect in several inflammatory conditions, and their role in nasal polyposis remains little explored. Hence, we investigated whether bone marrow-derived mesenchymal stem cells could modulate cell phenotype in the nasal polyp milieu. After coculture with mesenchymal stem cells, the frequency of these inflammatory cells was found to decrease. Furthermore, mesenchymal stem cells promoted strong inhibition of CD4+ and CD8+ T cell proliferation, increased the frequency of CD4+CD25+Foxp3 T cells, and changed the global cytokine profile from an inflammatory to an anti-inflammatory response. We believe that mesenchymal stem cells may be a very useful adjunct for investigation of the inflammatory process in nasal polyposis, contributing to better understanding of the inflammatory course of this condition.
Mediators of Inflammation 01/2014; 2014:583409. · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Patients with chronic rhinosinusitis with/without nasal polyps (CRSwNP/CRSsNP) benefit from endoscopic sinus surgery (ESS), with an estimated success rate of 80%. At present, the influence on clinical outcome after ESS of eosinophils, eosinophilic mucin (EM), and fungal hyphae (FH) in secretions remains unclear. By delineating CRS groups and subgroups based on the finding of eosinophils, EM, and FH, differences in recurrence after ESS were investigated. Methods: A prospective monocenter study including 221 CRS patients who were unresponsive to medical treatment and underwent ESS was performed. All tissue and sinonasal secretions were microscopically examined for the presence of eosinophils, EM, and FH. Patients were followed for 3 years after surgery. Recurrence was defined according to the European position paper on rhinosinusitis and nasal polyps. Results: In total, 96 CRSwNP and 125 CRSsNP patients were included. Tissue eosinophils were found in 78% of CRSwNP patients compared with 42% in CRSsNP patients. EM was observed in 52% of the CRSwNP group versus 20% of the CRSsNP group. Furthermore, secretion analysis revealed FH in 7% of CRS. Recurrence in the total group was 22% over 3 years. CRSwNP patients with tissue eosinophilic involvement showed a recurrence rate of 48%, and those with additional EM showed recurrence in 56%. Conclusion: The presence of eosinophils in tissue or airway secretions greatly increases the risk of recurrent disease in CRSwNP patients. The finding of tissue eosinophilia and EM provides valuable information regarding the increased likelihood of CRS recurrence after ESS, whereas the finding of FH does not.
American journal of rhinology & allergy 01/2014; 28(3). · 1.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In chronic rhinosinusitis (CRS) different phenotypes have been reported based on cytokine profile and inflammatory cell patterns. The aim of this study was to characterize the intracytoplasmatic cytokines ofTcells infiltrating theinflamed sinonasal mucosa.
PLoS ONE 01/2014; 9(6):e97581. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Surgery for chronic rhinosinusitis with nasal polyps (CRSwNPs) often fails because of recurrence of disease. So far, we do not know if specific cytokine profiles are linked to recurrence after functional endoscopic sinus surgery (FESS) or can predict recurrence. In this study we investigate the cytokine profile in CRSwNPs that underwent FESS for the first time and recurrent CRSwNPs. Methods: Tissue samples (n = 21) of CRSwNP patients with no recurrence after the first surgery were randomly selected out of 131 primary FESS surgeries and compared with tissue samples (n = 15) from patients who had a first and second surgery because of recurrence. Interleukin (IL)-1beta, IgE, specific IgE, IL-5, interferon (IFN) gamma, IL-6, IL-17, transforming growth factor (TGF) beta1, and myeloperoxidase were measured on tissue homogenates. Results: Levels of IgE, specific IgE to Staphylococcus aureus enterotoxin, eosinophilic cationic protein (ECP), and IL-5 were significantly increased in recurrent versus nonrecurrent CRSwNPs at the moment of the first surgery, whereas IL-17, IL-6, TGF-beta1,and IL-1beta did not show any significant difference. IFN-gamma protein levels were significantly higher in nonrecurrent CRSwNPs. The odds ratio for recurrence of CRSwNPs was reduced to 0.029, if IFN-gamma was present in tissue homogenates. Asthma and aspirin intolerance were significantly more frequent in the recurrent CRSwNPs compared with nonrecurrent CRSwNPs. Discussion: Nonrecurrent and recurrent CRSwNPs needing revision surgery have different types of inflammatory patterns. Nonrecurrent CRSwNPs exhibits a mixed pattern of T helper (Th) cytokines with significant higher levels of IFN-gamma and lower concentrations of IgE, ECP, and IL-5 as compared with recurrent CRSwNPs that had a predominant Th2 type of inflammation.
American journal of rhinology & allergy 01/2014; 28(3). · 1.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized as a Th2-driven disease.
Activated dendritic cells (DCs) are the main T-cell activators; their role in the chronic inflammatory process of nasal polyposis is still unclear.
The regulation of DC subsets was analyzed in nasal polyp tissue from CRSwNP patients and compared to inferior turbinate tissue from healthy subjects. Tissue localization and expression of both plasmacytoid and myeloid DCs were assayed by means of immunohistochemistry and flow cytometry. Plasmacytoid DCs were also assayed by PCR, and tissue homogenates were assayed for various inflammatory markers.
The number of plasmacytoid (pDCs) and myeloid (mDCs) dendritic cells was significantly increased in nasal polyp tissue when compared to non-inflamed nasal mucosa. The number of pDCs, but not mDCs, was down-regulated in more severe cases (nasal polyps with asthma) and varied with the cytokine milieu. The amount of pDCs was significantly decreased in IL5 + IFNγ- nasal polyp tissue compared to tissues with high IFNγ levels (IL5 + IFNγ+). Furthermore, levels of indoleamine 2,3-dioxygenase were increased in nasal polyp compared to inferior turbinate tissue and correlated negatively with the number of pDCs.
There is an altered balance of pDC and mDC numbers in nasal polyp tissue. pDCs seem to be more susceptible to an inflammatory cytokine milieu and may play a crucial role in disease severity.
[Show abstract][Hide abstract] ABSTRACT: Topical glucocorticosteroids are the first line therapy for airway inflammation. Modern compounds with higher efficacy have been developed, but head-to-head comparison studies are sparse.
To compare the activity of two intranasal glucocorticoids, fluticasone furoate (FF) and mometasone furoate (MF) with respect to the inhibition of T helper (Th)1, Th2 and Th17 cytokine release in airway mucosa.
We used an ex-vivo human nasal mucosal tissue model and employed pre- and post- Staphylococcus aureus enterotoxin B (SEB)-challenge incubations with various time intervals and drug concentrations to mimic typical clinical situations of preventive or therapeutic use.
At a fixed concentration of 10-10 M, FF had significantly higher suppressive effects on interferon (IFN)-γ, interleukin (IL)-2 and IL-17 release, but not IL-5 or tumor necrosis factor (TNF)-α, vs. MF. While the maximal suppressive activity was maintained when FF was added before or after tissue stimulation, the cytokine suppression capacity of MF appeared to be compromised when SEB-induced cell activation preceded the addition of the drug. In a pre-challenge incubation setting with removal of excess drug concentrations, MF approached inhibition of IL-5 and TNF-α after 6 and 24 hours while FF maximally blocked the release of these cytokines right after pre-incubation. Furthermore, FF suppressed a wider range of T helper cytokines compared to MF.
The study demonstrates the potential of our human mucosal model and shows marked differences in the ability to suppress the release of various cytokines in pre- and post-challenge settings between FF and MF mimicking typical clinical situations of preventive or therapeutic use.
PLoS ONE 01/2014; 9(4):e93754. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Staphylococcal enterotoxins may influence the pro-inflammatory pattern of chronic sinus diseases via epigenetic events. This work intended to investigate the potential of staphylococcal enterotoxin B (SEB) to induce changes in the DNA methylation pattern. Nasal polyp tissue explants were cultured in the presence and absence of SEB; genomic DNA was then isolated and used for whole genome methylation analysis. Results showed that SEB stimulation altered the methylation pattern of gene regions when compared with non stimulated tissue. Data enrichment analysis highlighted two genes: the IKBKB and STAT-5B, both playing a crucial role in T- cell maturation/activation and immune response.
Allergy Asthma and Clinical Immunology 12/2013; 9(1):48.
[Show abstract][Hide abstract] ABSTRACT: Within a large prospective study the Global Asthma and Allergy European Network (GA(2) LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings.
To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points.
The GA(2) LEN SPT study with 3 068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender and geographical area on SPT results were assessed. For each allergen the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated.
Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size >=3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk for sensitizations being clinically relevant compared to adults. The 80% PPV varied from 3-10 mm depending on the allergen.
These "reading keys" for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Recent studies suggest that Staphylococcus aureus enterotoxin sensitization is a risk factor for asthma. However, there is a paucity of epidemiologic evidence on adult-onset asthma in community-based populations.
We sought to evaluate the epidemiology and the clinical significance of Staphylococcal enterotoxin sensitization in community-based adult populations.
The present analyses were performed using the baseline dataset of Korean adult population surveys, consisting of 1,080 adults (mean age = 60.2 years) recruited from an urban and a rural community. Questionnaires, methacholine challenge tests, and allergen skin tests were performed for defining clinical phenotypes. Sera were analyzed for total IgE and enterotoxin specific IgE using ImmunoCAP.
Staphylococcal enterotoxin sensitization (≥ 0.35 kU/L) had a prevalence of 27.0%. Risk factors were identified as male sex, current smoking, advanced age (≥ 61 years), and inhalant allergen sensitization. Current asthma was mostly adult-onset (≥ 18 years old), and showed independent associations with high enterotoxin specific IgE levels in multivariate logistic regression tests. In multivariate linear regressions, Staphylococcal enterotoxin specific IgE level was identified as the major determinant factor for total IgE level.
Staphylococcal enterotoxin sensitization was independently associated with adult-onset asthma in adult community populations. Strong correlations between the enterotoxin specific IgE and total IgE levels support the clinical significance. The present findings warrant further studies for the precise roles of Staphylococcal enterotoxin sensitization in the asthma pathogenesis. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Allergy diagnosis based on purified allergen molecules provides detailed information regarding the individual sensitization profile of allergic patients, allows monitoring of the development of allergic disease and of the effect of therapies on the immune response to individual allergen molecules. Allergen microarrays contain a large variety of allergen molecules and thus allow the simultaneous detection of allergic patients' antibody reactivity profiles towards each of the allergen molecules with only minute amounts of serum. In this article we summarize recent progress in the field of allergen microarray technology and introduce the MeDALL allergen-chip which has been developed for the specific and sensitive monitoring of IgE and IgG reactivity profiles towards more than 170 allergen molecules in sera collected in European birth cohorts. MeDALL is a European research program in which allergen microarray technology is used for the monitoring of the development of allergic disease in childhood, to draw a geographic map of the recognition of clinically relevant allergens in different populations and to establish reactivity profiles which are associated with and predict certain disease manifestations. We describe technical advances of the MeDALL allergen-chip regarding specificity, sensitivity and its ability to deliver test results which are close to in vivo reactivity. In addition, the usefulness and numerous advantages of allergen-microarrays for allergy research, refined allergy diagnosis, monitoring of disease, of the effects of therapies, for improving the prescription of specific immunotherapy and for prevention are discussed.
[Show abstract][Hide abstract] ABSTRACT: Cross-sectional and longitudinal reports show that obese adults have more asthma than non-obese adults. A proposed mechanism is via effects of adipokines (leptin and adiponectin) on the immune system.
We wished to measure the associations of asthma and other atopic diseases with serum adipokine levels, and to find whether the associations with asthma were strong enough to rule out the possibility that they are secondary to the association of fatness measures with asthma.
The Global Asthma and Allergy Network of Excellence (GA(2) LEN) clinical follow up survey is a clinical survey, embedded in a larger multi-centre cross-sectional postal survey, involving, with a case/control design, enrichment of the sample with subjects with asthma and chronic rhinosinusitus (CRS). We recorded serum leptin or adiponectin in 845 men and 1110 women in 15 centres, and also anthropometric measures of fatness including body mass index and waist/hip ratio, current asthma, and specific skin prick and IgE sensitisation. We used inverse sampling-probability weighted rank and regression statistics to measure population associations of disease outcomes with adipokines in males and females, adjusting for confounders (area, age, smoking history and number of elder siblings) and also mutually adjusting associations with adipokines and fatness measures.
1955 subjects aged 16 to 77 years had information on leptin or adiponectin levels. Leptin and leptin/adopinectin ratio were positively associated with the level of asthma, especially in females (Somers' D of leptin by asthma score, 0.20; 95% CI, 0.08 to 0.30; P=.00079). These associations were attenuated after adjusting for confounders, and became non-significant after additionally adjusting for fatness measures and multiple comparisons.
Asthma levels are positively associated with serum leptin. However, we cannot rule out the possibility that this association is secondary to associations of both with fatness measures. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Edema represents a key feature of nasal polyp (NP) disease. Members of the vascular endothelial growth factor (VEGF) family may be involved, but the precise role of VEGF-A, VEGF-B, placental growth factor (PlGF), and their receptors VEGFR1 and VEGFR2 in NP edema formation remains elusive.
Exploring the expression of VEGF family members and their receptors and their correlation with clinical, radiological, and edema markers in NP.
The expression of VEGF-A, VEGF-B, PlGF, VEGFR1, and VEGFR2 was measured in NP (n = 23) and control tissue (n = 22) at mRNA and protein level. Edema was evaluated by measuring albumin levels and wet/dry ratios. Computed tomography (CT) scans were scored using the Lund-Mackay scoring system. IL-5 mRNA expression was determined by real-time RT-PCR. Cell suspensions from NP (n = 10) and control tissue (n = 12) were stimulated in vitro with IL-1β or TNFα.
mRNA expression of VEGFR1 and VEGF-B was significantly higher in NP compared with control tissue. Expression levels of VEGF-B and VEGFR1 significantly correlated with NP albumin content (VEGF-B: P = 0.0208; VEGFR1: P = 0.0293), CT scan scores (VEGF-B: P = 0.0075; VEGFR1: P = 0.0068), and IL-5 mRNA (VEGF-B: P = 0.0027; VEGFR1: P = 0.0001). In vitro stimulation of control and NP tissue cell suspensions with IL-1β or TNFα significantly reduced the expression of VEGFR2 in control tissue, without altering VEGFR1 and VEGF-B expression. hVEGF-B induced nitric oxide production in NP macrophages (P < 0.05).
Expression levels of VEGFR1 and VEGF-B correlate with edema and clinical markers of NP disease and therefore represent potential therapeutic targets.