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Summary Introduction High Intensity training (HIT) is a time‐effective alternative to traditional exercise programs in adults with obesity, but the superiority in terms of improving cardiopulmonary fitness and weight loss has not been demonstrated. Objective to determine the effectiveness of HIT on cardiopulmonary fitness and body composition in adults with obesity compared to traditional (high volume continuous) exercise. Methods A systematic search of the main health science databases was conducted for randomized controlled trials comparing HIT with traditional forms of exercise in people with obesity. Eighteen studies were included in the meta‐analysis. The (unstandardized) mean difference of each outcome parameters was calculated and pooled with the random effects model. Results HIT resulted in greater improvement of cardiopulmonary fitness (VO2max) (MD 1.83, 95% CI 0.70, 2.96, p

Background: Inhaled corticosteroids (ICSs) and long-acting β2-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) Setting: 2 university medical centers in The Netherlands. Patients: 114 steroid-naive current or former smokers with moderate to severe COPD. Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 μg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 μg twice daily, and salmeterol, 50 μg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3+ cells (-55% [95% CI, -74% to -22%]; P - 0.004), CD4- cells (-78% [CI, -88% to 60%]; P < 0.001), CD8+ cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV1 decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3+ cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV1 level. Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. Primary Funding Source: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center.

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 George9s Respiratory Questionnaire), with ORs between 3.61 and 2.22 (p 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.

Epidemiological studies showed that farmer’s children have a lower incidence of childhood asthma, which was partly attributed to a higher microbial exposure. Recently, distorted airway epithelium is considered an active player in pathogenesis of asthma. Interestingly, Toll-like receptor (TLR) ligation in the gut was found to enhance the gut epithelial barrier function. We hypothesize that exposure of the airways to microbial-rich farm dust may have barrier-enhancing effects on the airway epithelium and thereby may contribute to the protection against asthma in farmer’s children. In this study, the effect of farm dust extracts (FDE) collected from traditional German farms was investigated on barrier function and -repair in primary bronchial epithelial cells (PBECs). The expression of tight (TJs) and adherens junctions (AJs)-important to maintain the barrier function- and the involvement of TLR-induced MyD88 signalling were investigated. FDE exposure induced a dose-dependent two-fold increase in resistance measured by ECIS and up to 70% reduction in permeability in undifferentiated PBECs. Furthermore, restoration of barrier function of fully differentiated PBECs after cigarette smoke exposure was accelerated in the presence of FDE. The increase in barrier function was accompanied by an 1.5 to 2-fold enhanced mRNA expression of TJs occludin-1, claudin-1 and −4 and AJ E-cadherin. In search for the underlying mechanisms, we found that the increased barrier resistance could be significantly attenuated by blocking MyD88 signalling. These data altogether suggest that FDE exposure strengthen the epithelial barrier function partly via MyD88 signalling and, thereby, possibly reduce the risk of development of asthma and allergies.

OBJECTIVE : To determine if long-term treatment with inhaled steroids (ICS), both with and without long-acting β2-agonists (LABA) reduces inflammation and improves pulmonary function in COPD. DESIGN : Randomized placebo-controlled trial in two Dutch centres (http://clinicaltrials.gov/ct2/show/NCT00158847). METHODS : 114 steroid-naïve patients with moderate to severe COPD (smokers or ex-smokers) were treated double-blind with: (n = 26) fluticasone propionate 500 µg twice daily (bid) for 6 (n = 31) or 30 months, or with fluticasone 500 µg bid and salmeterol 50 µg bid (n = 28) for 30 months, or with placebo bid (n = 29). Primary outcomes were the cell counts of bronchial biopsies and sputum. Airway hyper-responsiveness was measured before randomisation and at 6 and 30 months; clinical outcomes were determined every 3 months. RESULTS : A total of 101 patients were > 70% adherent to therapy. After 6 months of fluticasone use the lymphocyte (CD3+, CD4+, and CD8+) and mast cell count in the airway wall decreased (only p

Background Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia. These features are partially attributed to activation of the epidermal growth factor receptor (EGFR). Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists. We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation. Methods 114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV1 63 ± 9% predicted. Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue+) area (%), proliferating (Ki-67+) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies. Results Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression. Epithelial features were not different between short-term quitters ( Conclusion Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years). Trial registration NCT00158847

Foram estudados 114 doentes (99 homens) com DPOC, com uma idade média de 62 anos, carga tabágica de 42 UMA e duração de exposição de 44 anos, todos fumadores ou ex-fumadores (42 doentes, critério de ex-fumador> 1 mês de cessação, mediana de 3,5 anos). No grupo dos fumadores 56% apresentavam queixas compatíveis com bronquite crónica (não é referida a dispneia), enquanto só 31% as referiam no grupo dos ex-fumadores. Foram incluídos doentes com FEV1> 1,3 L e> 20% de referência. Assim todos os doentes estavam nos estádios II e III GOLD, os fumadores com FEV1 pós-BD de 63,3%, reversibilidade de 6,9% e KCO de 73% e os ex-fumadores com FEV1 pós-BD de 62,5%, reversibilidade 6,8% e KCO de 80%. Os doentes incluídos não podiam ter feito um curso de corticóides orais nos 3 meses anteriores ou tratamento regular de corticóides inalados ou orais nos 6 meses anteriores. O estudo da inflamação consistiu na colheita de 4 fragmentos de biópsia brônquica das carinas dos segmentos dos lobos inferiores (em cada doente só retiradas do mesmo lado, alternando o direito e esquerdo por doente). Nos fragmentos estudados foram analisadas a presença de plasmócitos, eosinófilos, mastócitos, macrófagos e linfócitos CD4 e CD8 (CD3 - total). Dos resultados salienta-se: - Fumadores vs ex-fumadores: Os ex-fumadores tinham mais plasmócitos, CD3 e CD4 do que os fumadores. Não existiram diferenças nas outras células inflamatórias. Após ajustamento para género, idade e obstrução (FEV1/IVC) os resultados mantiveram-se. - Duração da cessação tabágica: Foram encontradas diferenças significativas para CD4, CD8 e relação CD8/CD3 entre fumadores e ex-fumadores (de curta e longa duração). Os ex-fumadores de curta duração tinham CD4 e CD8 mais elevados que os fumadores. Em contraste, os ex-fumadores de longa duração tinham menos CD8 que os de curta duração, menor CD8/CD3 que ex-fumadores de curta duração e fumadores e níveis mais altos de plasmócitos que os fumadores. - Correlação entre duração de exposição e inflamação A duração da cessação tabágica estava associada a valores mais altos de CD3, CD4, plasmócitos, e uma tendência para mais alto CD4/CD8. Excluindo os fumadores, a maior duração de cessação tabágica estava associada a CD8/CD3 mais baixo e tendência para plasmócitos mais altos. O valor de UMA estava inversamente correlacionado com os níveis de plasmócitos. Na discussão, os autores salientam que este será o 1º estudo a avaliar e comparar a inflamação brônquica em fumadores versus ex-fumadores, e se o tipo da inflamação terá relação com o tempo de cessação tabágica. Fica demonstrada a persistência de inflamação, num grupo de doentes com DPOC ex-fumadores, aproximando-se o perfil inflamatório, após a cessação tabágica superior a 3,5 anos, da reversão do estado de imunossupressão, isto é, com aumento de CD4 e CD8 inicialmente e posteriormente descida de CD8 e aumento dos plasmócitos. Esta inflamação persistente na DPOC após a cessação tabágica sugere a presença de estímulos persistentes que actuam independentemente do fumo do tabaco. Várias explicações têm sido referidas na literatura como, a colonização crónica por vírus ou bactérias, alteração do balanço de mecanismos endógenos pró-inflamatórios e anti-inflamatórios auto-perpetuantes desencadeados pelo tabaco, fenómenos do tipo auto-imune ou ainda a persistência de apoptose das células epiteliais que pode ser o estímulo indutor de persistência da inflamação.

BACKGROUND: Exacerbations of asthma are often associated with rhinovirus (RV)-induced common colds. During experimental RV-infection in healthy subjects, increased levels of the pro-inflammatory mediator IL-1beta and the anti-inflammatory IL-1 receptor antagonist (IL-1ra) have been found in nasal lavage. OBJECTIVE: We postulated that the balance between nasal pro- and anti-inflammatory mediator expression is disturbed in asthma, resulting in more extensive inflammation following RV-exposure in asthma. METHODS: We determined IL-1ra, IL-1beta, and IL-8 in nasal lavages (days -2, 3, and 6) of non-asthmatics and asthmatics (with and without pre-treatment with the inhaled steroid budesonide) before and after experimental RV16-infection (days 0 and 1). RESULTS: Following RV16-infection, a significant increase in IL-8 was observed in the placebo- and budesonide-treated asthmatics (P=0.033 and 0.037, respectively), whereas IL-1beta only increased in the two asthma groups combined (P=0.035). A small, but significant, increase in IL-1ra was only observed in the budesonide-treated asthmatics (P=0.047). At baseline, IL-1ra levels were significantly higher in the non-asthmatics than in the placebo-treated asthmatics (P=0.017). CONCLUSION: These results demonstrate differences between non-asthmatic and asthmatic subjects in the basal levels of nasal cytokines and their inhibitors, and in the effect of experimental RV-infection on these levels. The results indicate that RV may enhance inflammation more markedly in asthmatics, and suggest that this may in part be explained by lower IL-1ra levels. In addition, the observation that budesonide-treatment may result in higher nasal IL-1ra levels supports the hypothesis that steroids act in part by increasing the endogenous anti-inflammatory screen

We investigated correlations between ozone-induced increases in inflammatory markers in induced sputum and in bronchial lavage fluid. Sixteen volunteers with intermittent asthma participated in a placebo-controlled parallel study with two exposures. Six days before and 16 h after the first exposure to ozone (0.4 ppm during 2 h) sputum was induced with hypertonic saline. This resulted in a significant increase in the sputum levels of eosinophil cationic protein (ECP; 1.8-fold; p = .03), neutrophil elastase (5.0-fold; p = .005) and the total cell number (1.6-fold; p = .02). After 4 weeks, a second exposure was randomized for air or ozone. Six days before and 16 h after the second exposure a bronchial lavage was performed. ECP values in sputum and in bronchial lavage fluid obtained after ozone correlated significantly (Rs = .79; p = .04), as did interleukin-8 (IL-8) values (Rs = .86; p = .01), and the percentage eosinophils (Rs = .89; p = .007). Moreover, the ozone-induced changes in percentage eosinophils observed in sputum and lavage fluid were highly correlated (Rs = .93; p = .003). In conclusion, changes in eosinophils, IL-8, and ECP markers induced by ozone and measured in sputum reflect the inflammatory responses in the lower airways of asthmatics, and may provide a noninvasive tool in epidemiologic studies on air pollution and asthma. (C) 1999 Elsevier Science Inc.

Exacerbations of asthma have been associated with exposure to ozone or particles with a 50% cut-off aerodynamic diameter of 10 microm (PM10). We postulated in this study that the association of summertime air pollution (i.e. ozone and PM10) with acute respiratory symptoms, medication use and peak expiratory flow differs among patients grouped according to asthma severity. During the summer of 1995, effects of ambient air pollution on these parameters were studied in a panel of 60 nonsmoking patients with intermittent to severe persistent asthma. These patients were recruited from our Pulmonary Out-patient Clinic. Subgroup analysis was performed on the degree of hyperresponsiveness and lung steroid use before the start of the study, as indictors for the severity of asthma. Associations of the parameters studied with ozone, PM10, nitrogen dioxide (NO2), sulphur dioxide (SO2) and black smoke were evaluated using time series analysis. Several episodes with increased summertime air pollution occurred during the 96 day study period. Eight hour average ozone concentrations exceeded the World Health Organization (WHO) Air Quality Guidelines (120 microg x m(-3)) on 16 occasions. Daily mean levels of PM10 were moderately elevated (range 16-98 microg x m(-3)). Levels of the other measured pollutants were low. There was a consistent, positive association of the prevalence of shortness of breath (maximal relative risk (RRmax) 1.18) with ozone, PM10, black smoke and NO2. In addition, bronchodilator use was associated with both ozone and PM10 levels (RRmax 1.16). Stratification by airway hyperresponsiveness and steroid use did not affect the magnitude of the observed associations. No associations with peak expiratory flow measurements were found. We conclude that the severity of asthma is not an indicator for the sensitivity to air pollution

Sputum induced by inhalation of nebulized hypertonic saline is increasingly used to monitor airways inflammation in asthma. The aim of this study was to assess the repeatability of measuring cellular and soluble markers of inflammation in whole sputum samples as obtained by sputum induction in patients both with mild and moderate-to-severe asthma. Twelve patients with mild, atopic asthma without inhaled steroid treatment and nine patients with moderate-to-severe, atopic asthma treated with inhaled steroids were studied on two separate days at least 2 days apart. Whole sputum samples, induced by inhalation of hypertonic (4.5%) saline, were homogenized, and analysed for differential cell counts and for concentrations of albumin, fibrinogen, interleukin-8 (IL-8), and eosinophil cationic protein (ECP). Repeatability was expressed as intraclass correlation coefficient (Ri), and as coefficient of repeatability (CR) in percentage cells or in doubling concentration. Samples from two patients with mild asthma contained more than 80% squamous cells and were excluded from analysis. The repeatability for cell differential counts in both groups combined was: for neutrophils, Ri = 0.57 and CR = 31.0; for eosinophils, Ri = 0.85 and CR = 12.4; and for lymphocytes, Ri = 0.76 and CR = 6.9. The repeatability of the fluid phase measurements was: for albumin, Ri = 0.71 and CR = 3.2; for fibrinogen, Ri = 0.88 and CR = 2.8; for IL-8, Ri = 0.66 and CR = 2.2; and for ECP, Ri = 0.82 and CR = 1.1. We conclude that the repeatability of cellular and soluble markers of inflammation in induced sputum from patients with mild and moderate-to-severe asthma is satisfactory. Hence, induced sputum, processed by using the whole expectorated sample, seems to be a valuable method to monitor airway inflammation in asthma