Judith M. Vonk

Short-term effects of particulate air pollution on cardiovascular diseases in eight European cities

Study objective: As part of the APHEA project this study examined the association between airborne particles and hospital admissions for cardiac causes (ICD9 390–429) in eight European cities (Barcelona, Birmingham, London, Milan, the Netherlands, Paris, Rome, and Stockholm). All admissions were studied, as well as admissions stratified by age. The association for ischaemic heart disease (ICD9 410–413) and stroke (ICD9 430–438) was also studied, also stratified by age. Design: Autoregressive Poisson models were used that controlled for long term trend, season, influenza epidemics, and meteorology to assess the short-term effects of particles in each city. The study also examined confounding by other pollutants. City specific results were pooled in a second stage regression to obtain more stable estimates and examine the sources of heterogeneity. Main results: The pooled percentage increases associated with a 10 μg/m3 increase in PM10 and black smoke were respectively 0.5% (95% CI: 0.2 to 0.8) and 1.1% (95% CI: 0.4 to 1.8) for cardiac admissions of all ages, 0.7% (95% CI: 0.4 to 1.0) and 1.3% (95% CI: 0.4 to 2.2) for cardiac admissions over 65 years, and, 0.8% (95% CI: 0.3 to 1.2) and 1.1% (95% CI: 0.7 to 1.5) for ischaemic heart disease over 65 years. The effect of PM10 was little changed by control for ozone or SO2, but was substantially reduced (CO) or eliminated (NO2) by control for other traffic related pollutants. The effect of black smoke remained practically unchanged controlling for CO and only somewhat reduced controlling for NO2. Conclusions: These effects of particulate air pollution on cardiac admissions suggest the primary effect is likely to be mainly attributable to diesel exhaust. Results for ischaemic heart disease below 65 years and for stroke over 65 years were inconclusive.

Estimating the Exposure–Response Relationships between Particulate Matter and Mortality within the APHEA Multicity Project

Several studies have reported significant health effects of air pollution even at low levels of air pollutants, but in most of theses studies linear nonthreshold relations were assumed. We investigated the exposure–response association between ambient particles and mortality in the 22 European cities participating in the APHEA (Air Pollution and Health—A European Approach) project, which is the largest available European database. We estimated the exposure–response curves using regression spline models with two knots and then combined the individual city estimates of the spline to get an overall exposure–response relationship. To further explore the heterogeneity in the observed city-specific exposure–response associations, we investigated several city descriptive variables as potential effect modifiers that could alter the shape of the curve. We conclude that the association between ambient particles and mortality in the cities included in the present analysis, and in the range of the pollutant common in all analyzed cities, could be adequately estimated using the linear model. Our results confirm those previously reported in Europe and the United States. The heterogeneity found in the different city-specific relations reflects real effect modification, which can be explained partly by factors characterizing the air pollution mix, climate, and the health of the population.

Severe exacerbations predict excess lung function decline in asthma

Severe asthma exacerbations are periods of intense airway inflammation that have been hypothesised to contribute to structural changes in the airways. If so, accelerated lung function decline over time should be more prevalent in adult patients with asthma who have frequent exacerbations than those without, but to date this has not been demonstrated. A cohort study was performed in order to investigate the effect of severe exacerbations on the progression of airway obstruction in 93 nonsmoking asthmatics with moderate-to-severe disease prior to treatment with inhaled corticosteroids. Subjects were followed for ≥5 yrs (median follow-up 11 yrs). In total, 56 (60.2%) subjects experienced at least one severe exacerbation (median rate 0.10·yr−1). Oral corticosteroid use and more severe airway obstruction at baseline were associated with a higher exacerbation rate. Independent of these variables, asthma patients with frequent exacerbations had a significantly larger annual decline in forced expiratory volume in one second (FEV1; median difference (95% confidence interval) 16.9 (1.5–32.2) mL·yr−1). Exacerbation rate significantly predicted an excess decline in FEV1, such that one severe exacerbation per year was associated with a 30.2 mL greater annual decline in FEV1. These data support the hypothesis that exacerbations, indicating intermittent periods of worsening airway inflammation, are associated with excess lung function decline in asthma.

Short-term effects of ambient particles on cardiovascular and respiratory mortality

Background: Particulate air pollution is associated with increased mortality. There is a need for European results from multicountry databases concerning cause-specific mortality to obtain more accurate effect estimates. Methods: We report the estimated effects of ambient particle concentrations (black smoke and particulate matter less than 10 μm [PM10]) on cardiovascular and respiratory mortality, from 29 European cities, within the Air Pollution and Health: a European Approach (APHEA2) project. We applied a 2-stage hierarchical modeling approach assessing city-specific effects first and then overall effects. City characteristics were considered as potential effect modifiers. Results: An increase in PM10 by 10 μg/m3 (lag 0 + 1) was associated with increases of 0.76% (95% confidence interval = 0.47 to 1.05%) in cardiovascular deaths and 0.58% (0.21 to 0.95%) in respiratory deaths. The same increase in black smoke was associated with increases of 0.62% (0.35 to 0.90%) and 0.84% (0.11 to 1.57%), respectively. Conclusions: These effect estimates are appropriate for health impact assessment and standard-setting procedures.

Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma

Background Asthma is a genetically complex disease characterized by respiratory symptoms, intermittent airway obstruction and airway hyper‐responsiveness due to airway inflammation and remodelling. The ADAM33 gene is associated with asthma and airway hyper‐responsiveness and is postulated as a gene for airway remodelling.

Short-term effects of air pollution on hospital admissions of respiratory diseases in Europe: A quantitative summary of APHEA study results

The Air Pollution and Health: a European Approach (APHEA) project is a coordinated study of the short-term effects of air pollution on mortality and hospital admissions. Five West European cities (i.e., London, Amsterdam, Rotterdam, Paris, Milano) contributed several years of hospital admissions data for all respiratory causes. In the current study, the authors describe the results obtained from the quantitative pooling (meta-analysis) of local analyses. The diagnostic group was defined by ICD 460-519. The age groups studied were 15-64 y (i.e., adults) and 65+ y (elderly). The air pollutants studied were sulfur dioxide; particles (i.e., Black Smoke or total suspended particles); ozone; and nitrogen dioxide. The pollutants were obtained from existing fixed-site monitors in a standardized manner. We used Poisson models and standardized confounder models to examine the associations between daily hospital admissions and air pollution. We conducted quantitative pooling by calculating the weighted means of local regression coefficients. We used a fixed-effects model when no heterogeneity could be detected; otherwise, we used a random-effects model. When possible, the authors investigated the factors correlated with heterogeneity. The most consistent and strong finding was a significant increase of daily admissions for respiratory diseases (adults and elderly) with elevated levels of ozone. This finding was stronger in the elderly, had a rather immediate effect (same or next day), and was homogeneous over cities. The elderly were affected more during the warm season. The Sulfur dioxide daily mean was available in all cities, and it was not associated consistently with an adverse effect. Effects were present in areas in which more than one station was used in the assessment of daily exposure. Some significant associations were observed, although no conclusion that related to an overall particle effect could be drawn. The effect of Black Smoke was significantly stronger with high nitrogen dioxide levels on the same day, but nitrogen dioxide itself was not associated with admissions. The ozone results were in good agreement with the results of similar U.S. studies. The coherence of the results of this study and other results gained under different conditions strengthens the argument for causality.

Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex

Background: Inhaled corticosteroids (ICS) provide short term benefits in asthma but the long term effects are still unknown. Methods: 281 patients diagnosed with moderate to severe asthma in 1963–75 were re-examined in 1991–9. Information was collected on forced expiratory volume in 1 second (FEV1), bronchial hyperresponsiveness, atopy, smoking, use and dosage of oral and ICS. Patients were included in the analyses if they had at least three FEV1 measurements during two consecutive years after the age of 30 and used ICS during follow up. Results: Analyses were performed on 122 patients. During a median follow up period of 23 years, 71 men and 51 women had on average 37 and 40 individual FEV1 measurements, respectively. Linear mixed effect models showed that men had a mean annual decline in FEV1 of 20.6 ml/year less after ICS initiation than before (p = 0.011), and in women the decline in FEV1 was 3.2 ml/year less (p = 0.73). In individuals with <5 pack years of smoking the decline in FEV1 was 36.8 ml/year less after ICS institution in men (p = 0.0097) and 0.8 ml/year less in women (p = 0.94), the difference between the sexes being significant (p = 0.045). These effects were not observed in those with ⩾5 pack years smoking. A higher daily dose of ICS was associated with a smaller decline in FEV1 in men (p = 0.006), an effect not observed in women. Conclusion: Treatment with ICS in adult patients with moderate to severe asthma was associated with a reduction in the decline in FEV1 over a 23 year follow up period in men who had smoked <5 pack years. This effect was dose dependent and was not present in women or in men with ⩾5 pack years of smoking at follow up. The lack of effect of ICS on the decline in FEV1 in women needs further study.

The association of daily sulfur dioxide air pollution levels with hospital admissions for cardiovascular diseases in Europe (The Aphea-II study)

The objective of this study is to assess the short-term effect of sulfur dioxide (SO(2)) air pollution levels on hospital admissions for cardiovascular diseases. Daily mean hospital admissions for cardiovascular diseases, ischemic heart diseases (IHDs), and stroke in seven European areas (the cities of Birmingham, London, Milan, Paris, Rome, and Stockholm, and in The Netherlands) participating in the multicenter European study of air pollution (Aphea-II), were measured. Time series analysis of daily hospital admission counts was performed using poison autoregressive models. A summary regression coefficient for all cities was provided. Daily numbers of all cardiovascular admissions except stroke, and particularly IHDs, rose significantly with an increase of daily SO(2)levels of the same day and day before. After adjusting for PM(10)(i.e. particles with size <10 microm), the association of SO(2)with IHD admissions remained significant (i.e. an increase of 0.7%; 95% confidence interval=0.1-1.3, per each 10 microg/m(3)increase of SO(2)) among subjects younger than 65 years, but not among subjects older than 65. In the older group the increase was only significant for particles (1.3%; CI 0.7-1.8, per each increase in 10 microg/m(3)of PM(10)). This study provides new evidence for the effects of urban air pollution on cardiac diseases in Europe, and suggests that SO(2)pollution may play an independent role in triggering ischemic cardiac events. From a Public Health perspective these results suggest that reduction in SO(2)levels in European cities could imply a reduction of admissions for IHDs.

Effects of ambient air pollution on upper and lower respiratory symptoms and peak expiratory flow in children

BACKGROUND Previous epidemiological studies have shown acute effects of increased amounts of ambient air pollution on the prevalence of respiratory symptoms in children with respiratory disorders. We investigated whether children with bronchial hyperresponsiveness (BHR) and relatively high serum concentrations of total IgE (>60 kU/L, the median value) are susceptible to air pollution. METHODS We collected data from children during three winters (1992-95) in rural and urban areas of the Netherlands. Lower respiratory symptoms (wheeze, attacks of wheezing, shortness of breath), upper respiratory symptoms (sore throat, runny or blocked nose), and peak expiratory flow were recorded daily for 3 months. The acute effects of airborne particulate matter with a diameter of less than 10 microm, black smoke, sulphur dioxide, and nitrogen dioxide were estimated by logistic regression. FINDINGS 459 (73%) of 632 children had complete data. Of these, 26% had BHR and relatively high (above median) serum total IgE, 36% had no BHR and total IgE of 60 kU/L or less, 15% had BHR and total IgE of 60 kU/L or less, and 23% had a total IgE of more than 60 kU/L but no BHR. In children with BHR and relatively high serum total IgE the prevalence of lower respiratory symptoms increased significantly by between 32% and 139% for each 100 microm/m3 increase in particulate matter, and between 16% and 131% for each 40 microm/m3 increase in black smoke, SO2, or NO2. Decrease in peak expiratory flow of more than 10% in that group was more common with increased airborne particulate matter and black smoke. There were no consistent positive or negative associations between increased air pollution and prevalence of respiratory symptoms or decrease in peak expiratory flow in the other three groups of children. INTERPRETATION Children with BHR and relatively high concentrations of serum total IgE are susceptible to air pollution. Although our odds ratios were rather low (range 1.16-2.39) the overall effect of air pollution on public health is likely to be substantial since these odds ratios refer to large numbers of people.

Effect of Fluticasone With and Without Salmeterol on Pulmonary Outcomes in Chronic Obstructive Pulmonary Disease: A Randomized Trial

BACKGROUND Inhaled corticosteroids (ICSs) and long-acting beta(2)-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 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg 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 FEV(1) 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 FEV(1) 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. .