Roelinde Middelveld

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach. This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements. Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids. Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of “omic” datasets that are at the core of this systems medicine approach. Severe asthma results in more airway inflammation, worse symptoms and lower lung function, despite increased therapy http://ow.ly/QznR3

Increased Prevalence of Symptoms of Rhinitis but Not of Asthma between 1990 and 2008 in Swedish Adults: Comparisons of the ECRHS and GA2LEN Surveys

Background The increase in asthma prevalence until 1990 has been well described. Thereafter, time trends are poorly known, due to the low number of high quality studies. The preferred method for studying time trends in prevalence is repeated surveys of similar populations. This study aimed to compare the prevalence of asthma symptoms and their major determinants, rhinitis and smoking, in Swedish young adults in 1990 and 2008. Methods In 1990 the European Community Respiratory Health Survey (ECRHS) studied respiratory symptoms, asthma, rhinitis and smoking in a population-based sample (86% participation) in Sweden. In 2008 the same symptom questions were included in the Global Allergy and Asthma European Network (GA2LEN) survey (60% participation). Smoking questions were however differently worded. The regions (Gothenburg, Uppsala, Umeå) and age interval (20–44 years) surveyed both in 1990 (n = 8,982) and 2008 (n = 9,156) were analysed. Results The prevalence of any wheeze last 12 months decreased from 20% to 16% (p<0.001), and the prevalence of “asthma-related symptoms” was unchanged at 7%. However, either having asthma attacks or using asthma medications increased from 6% to 8% (p<0.001), and their major risk factor, rhinitis, increased from 22% to 31%. Past and present smoking decreased. Conclusion From 1990 to 2008 the prevalence of obstructive airway symptoms common in asthma did not increase in Swedish young adults. This supports the few available international findings suggesting the previous upward trend in asthma has recently reached a plateau. The fact that wheeze did not increase despite the significant increment in rhinitis, may at least in part be due to the decrease in smoking.

Limitation of infarct size and attenuation of myeloperoxidase activity by an endothelin A receptor antagonist following ischaemia and reperfusion

Abstract It has previously been shown that endothelin (ET) receptor antagonists limit myocardial ischaemia/reperfusion (I/R) injury. The mechanism behind this effect is still unclear. The aim of this study was to elucidate the possible relationship between cardioprotection by an ETA receptor antagonist and inhibition of neutrophil accumulation or activation in the myocardium determined as myeloperoxidase (MPO) activity during I/R. Anaesthetised pigs were subjected to 45 min ischaemia by ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Infiltration of MPO-containing cells, presumably neutrophils, into the ischaemic area was confirmed with an immunohistochemical technique using antibodies against porcine MPO. Vehicle (n = 7) or the selective ETA receptor antagonist LU 135252 (LU; n = 7) were given into the LAD during the last 10 min of ischaemia and the first 5 min of reperfusion. There were no significant differences in LAD flow, mean arterial pressure, heart rate, or rate pressure product between the groups during I/R. The area at risk was similar in the two groups. LU reduced the final infarct size to 40 ± 6 % of the area at risk compared to 80 ± 6 % in the vehicle group (P < 0.001). Endothelin-like immunoreactivity increased 2-fold in the ischaemic area in the vehicle group (P < 0.01), but not in the group given LU. MPO activity was higher (2.5x) in the ischaemic than in the non-ischaemic myocardium of the vehicle group. The MPO activity in the ischaemic myocardium was significantly lower in the group given LU (7.0 ± 1.2 units g−1) than in the vehicle group (14.2 ± 1.9 units g−1; P < 0.01). There was a significant correlation between the infarct size and MPO activity (P < 0.01, r = 0.68). In conclusion, local administration of the selective ETA receptor antagonist LU during the last period of ischaemia and early reperfusion reduces the extent of myocardial necrosis and MPO activity. This suggests that LU may exert its cardioprotective effect by inhibiting neutrophil-mediated injury.

Chronic rhinosinusitis in asthma is a negative predictor of quality of life: results from the Swedish GA(2)LEN survey.

Asthma and chronic rhinosinusitis (CRS) both impair quality of life, but the quality‐of‐life impact of comorbid asthma and CRS is poorly known. The aim of this study was to evaluate the impact of CRS and other relevant factors on quality of life in asthmatic subjects.

Asthma symptoms and nasal congestion as independent risk factors for insomnia in a general population : Results from the GA 2 LEN survey

Asthma and rhinitis have been related to insomnia. The aim of this study was to further analyse the association between asthma, nasal symptoms and insomnia and to identify risk factors for sleep disturbance among patients with asthma, in a large population‐based set of material.

The Innovative Medicines Initiative (IMI): a new opportunity for scientific collaboration between academia and industry at the European level

The introduction of truly new drug treatments is dwindling to a troublesome extent in all fields of medicine, at the same time as the costs for drug development are skyrocketing. New strategies are urgently required as old schemes for drug development are failing. The largest European public–private partnership in biomedical research, the Innovative Medicines Initiative (IMI), is therefore launched. IMI is a unique pan-European research and development (R&D) initiative with the strategic focus of strengthening the competitiveness of European Union (EU)-based biopharmaceutical industry by, amongst other activities, supporting research that aims at a faster discovery and development of safer and more effective medicines for patients. The founding organisations of this new legal entity are the European Federation of Pharmaceutical Industries and Associations (EFPIA) 1 and the European Commission (EC). The partnership is a \#8364;2 billion joint venture, which will be set up to run over the next 10 yrs. The funding system is balanced 1:1; the EC will contribute funding and the industry will contribute in kind, for instance by providing access to specialised expertise and platform approaches. Public consortia made up of universities, hospitals, regulatory authorities, small- and medium-sized biopharmaceutical and healthcare companies (or SMEs) and patient organisations will, on a competitive basis, be able to apply for funding; if this is approved, it will be matched by equal in-kind resources from the EFPIA members. The overarching objectives of IMI have been outlined in a Strategic Research Agenda (SRA) of IMI 2, which was developed over the past 3 yrs by the Research Directorate of the EC and EFPIA via numerous consultations that included stakeholders, such as academic scientists, regulatory authorities and patient groups. The legal act on IMI was adopted by the Council in December 2007 and was published in the Official Journal of the European Union in February 2008 …

Synergistic septicemic action of the gram-positive bacterial cell wall components peptidoglycan and lipoteichoic acid in the pig in vivo.

ABSTRACT Despite the fact that Gram‐positive infections constitute around 50% of all cases leading to septic shock, little is yet known about the mechanisms involved. This study was carried out to find out more about the effects of cell wall components peptidoglycan (PepG) and lipoteichoic acid (LTA) of the Grampositive bacterium Streptococcus pyogenes in the pig. Specific pathogen‐free pigs (20 kg bodyweight) were pretreated with metyrapone (a cortisol‐synthesis inhibitor) and then were given 2‐h infusions of 160 &mgr;g/kg of PepG (n = 5), 160 &mgr;g/kg LTA (n=5), or a combination of both (LTA + PepG, 160 &mgr;g/kg each, n = 5). Four hours after start of the infusions, the PepG, LTA, and LTA + PepG groups showed decreases in mean arterial pressure (change of ‐11%, ‐25%, and ‐47% from baseline, respectively), dynamic lung compliance (‐18%, ‐24%, and ‐38%), arterial oxygen tension (‐10%, ‐16%, and ‐37%), changes in blood leukocyte numbers (+11%, ‐27%, and ‐67%), and increases in pulmonary vascular resistance index (+7%, +106%, and +307% from baseline) and metabolic acidosis (base excess values decreased with 1.8, 2.3 and 8.1 units). The differences between the PepG and LTA + PepG groups were statistically significant (P < 0.05, Kruskal‐Wallis tests), but not between LTA and LTA + PepG groups. However, no changes in systemic nitric oxide (NO) production could be detected, which is much in contrast to studies on lower order animals. Moreover, comparison of the results obtained using this model with those obtained in a model of endotoxin‐induced septic shock showed distinct difference in the mechanisms by which Gram‐positive and Gram‐negative bacterial components exert their actions. For example, a marked fall in systemic blood pressure and dynamic lung compliance is seen in both models, but in the present Gram‐positive sepsis model, much less interleukin‐8 and tumor necrosis factor‐&agr; are produced. In conclusion, this study showed that PepG and LTA act synergistically to cause respiratory failure and septic shock in the pig. The infusion of the combination of PepG and LTA in the pig could serve as a new, well‐controlled model for studies of Gram‐positive sepsis.

Phenotypic predictors of response to oral glucocorticosteroids in severe asthma

BACKGROUND Systemic glucocorticosteroids are side-effect prone but often necessary for the treatment of severe asthma (SA). Our goal was to assess the usefulness of medical history, physiological variables and biomarkers as predictors of response to oral steroids. METHODS After 4 weeks of treatment optimization, 84 patients with SA and 62 with mild-to-moderate asthma (MA) underwent a 2 week double-blind placebo-controlled oral prednisolone intervention (0.5 mg/kg BW daily) (NCT00555607). RESULTS Responders had a lower FEV1% (73.7 vs. 88.0), lower FEV1/FVC ratio (0.65 vs. 0.73), lower quality of life (SGRQ score 39.1 vs. 31.4), lower total sputum cell number (1.0 vs. 4.5×10(6)) and higher number of sputum eosinophils (16.8% vs. 6.3%) (p<0.05). For all asthmatics, the degree of improvement in FEV1 correlated with sputum eosinophils, level of asthma control, FeNO, quality of life, age of asthma onset and blood eosinophils. In SA, sputum eosinophils≥3% (OR 9.91), FEV1≤60% (OR 3.7), and SGRQ>42.2 (OR 3.25) were associated with a good response to oral prednisolone. The highest sensitivity and specificity to predict more than 12% increase in FEV1 in SA after oral prednisolone was found for sputum eosinophils≥3% and FeNO>45 ppb. CONCLUSIONS Sputum eosinophils and FeNO were the best predictors of favorable response to oral prednisolone in severe asthmatics. A guided approach to glucocorticosteroid treatment should be recommended as it favors better control of the disease and presumably a lower rate of adverse events. The study has been registered at the site: clinicaltrials.gov with number: NCT00555607.

Higher Risk of Wheeze in Female than Male Smokers. Results from the Swedish GA2LEN Study

Background Women who smoke have higher risk of lung function impairment, COPD and lung cancer than smoking men. An influence of sex hormones has been demonstrated, but the mechanisms are unclear and the associations often subject to confounding. This was a study of wheeze in relation to smoking and sex with adjustment for important confounders. Methods In 2008 the Global Allergy and Asthma European Network (GA2LEN) questionnaire was mailed to 45.000 Swedes (age 16–75 years), and 26.851 (60%) participated. “Any wheeze”: any wheeze during the last 12 months. “Asthmatic wheeze”: wheeze with breathlessness apart from colds. Results Any wheeze and asthmatic wheeze was reported by 17.3% and 7.1% of women, vs. 15.8% and 6.1% of men (both p<0.001). Although smoking prevalence was similar in both sexes, men had greater cumulative exposure, 16.2 pack-years vs. 12.8 in women (p<0.001). Most other exposures and characteristics associated with wheeze were significantly overrepresented in men. Adjusted for these potential confounders and pack-years, current smoking was a stronger risk factor for any wheeze in women aged <53 years, adjusted odds ratio (aOR) 1.85 (1.56–2.19) vs. 1.60 (1.30–1.96) in men. Cumulative smoke exposure and current smoking each interacted significantly with female sex, aOR 1.02 per pack-year (p<0.01) and aOR 1.28 (p = 0.04) respectively. Female compared to male current smokers also had greater risk of asthmatic wheeze, aOR 1.53 vs. 1.03, interaction aOR 1.52 (p = 0.02). These interactions were not seen in age ≥53 years. Discussion In addition to the increased risk of COPD and lung cancer female, compared to male, smokers are at greater risk of significant wheezing symptoms in younger age. This became clearer after adjustment for important confounders including cumulative smoke exposure. Estrogen has previously been shown to increase the bioactivation of several compounds in tobacco smoke, which may enhance smoke-induced airway inflammation in fertile women.

Detection of exacerbations in asthma based on electronic diary data: results from the 1-year prospective BIOAIR study

Background Objective measures are required that may be used as a proxy for exacerbations in asthma. The aim was to determine the sensitivity and specificity of electronic diary data to detect severe exacerbations (SEs) of asthma. A secondary aim was to identify phenotypic variables associated with a higher risk of exacerbation. Methods In the BIOAIR study, 169 patients with asthma (93 severe (SA); 76 mild to moderate (MA)) recorded lung function, symptoms and medication use in electronic diaries for 1 year. Data were analysed using receiver-operator characteristics curves and related to physician-diagnosed exacerbations. Medical history and baseline clinical data were used to assess risk of exacerbation. Results Of 122 physician-diagnosed exacerbations, 104 occurred in the SA group (1.1 per patient/year), 18 in the MA group (0.2 per patient/year) and 63 were severe using American Thoracic Society/European Respiratory Society criteria. During exacerbations, peak expiratory flow (PEF) and forced expiratory volume in 1 s significantly decreased, whereas day and night symptoms significantly increased. An algorithm combining a 20% decrease in PEF or a 20% increase in day symptoms on 2 consecutive days was able to detect SEs with 65% sensitivity and 95% specificity. The strongest risk factors for SEs were low Asthma Control Questionnaire score, sputum eosinophils ≥3%, body mass index >25 and low quality of life (St Georges Respiratory Questionnaire), with ORs between 3.61 and 2.22 (p<0.05). Conclusions Regular electronic monitoring of PEF and asthma symptoms provides an acceptable sensitivity and specificity for the detection of SEs and may be suitable for personal internet-based monitoring of asthma control.