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Eur Respir J 1997; 10:1064-1071 Pdntod in UK - all dghts reserved EUR RESP]~R J 97 (O~UNKSGAARD ZNT PUBL LTD ANDE DE Copyright @ER$ Journals Lid 1997 European Respiratory Journal ISSN 0903 - 1936 Air pollution and daily admissions for chronic obstructive pulmonary disease in 6 European results from the APHEA project cities: H.R. Anderson*, C. Spix**, S. Medina***, J.P. Schouten÷, J. Castellsague**, G. Rossi***, D. Zmirou$, G. Touloumi*$, B. Wojtyniak*¢$, A. Ponka#, L. Bacharova##, J. Schwartz#*~, K. Katsouyanni$¢ Air pollution and daily admissions for chronic obstructive pulmonary disease in 6 European cities: results from the APHEA project. H.R. Anderson, C. Spix, S. Medina, J.P. Schouten, J. Castellsague, G. Rossi, D. Zmirou, G. Touloumi, B. Wojtyniak, A. Ponka, L Bacharova, J. Schwartz, K. Katsouyanni. ©ERS Journals Ltd 1997. ABSTRACT: We investigated the short-term effects of air pollution on hospital admissions for chronic obstructive pulmonary disease (COPD) in Europe. A~ part of a European project (Air Pollution and Health, a European Approach (APHEA)), we analysed data from the cities of Amsterdam, Barcelona, London, Milan, Paris and Rotterdam, using a standardized approach to data eligibifity and statistical analysis. Relative risks for daily COPD admissions were obtained using Poisson regression, controlling for: seasonal and other cycles; influenza epidemics; day of the week; temperature; humidity and autocorrelation. Summary effects for each pollutant were estimated as the mean of each city's regression coefficients weighted by the inverse of the variance, allowing for additional between-cities vari- For all ages, the relative risks (95 % confidence limits (95 % CL)) for a 50 pg.m-~ inerease in daily mean level of pollutant (lagged 1-3 days) were (95% CL): sul- phur dioxide 1.02 (0.98, 1.06); black smoke 1.04 (1.01, 1.06); total suspended par- ticulates 1.02 (1.00, 1.05), nitrogen dioxide 1.02 (1.00, 1.05) and ozone (8 h) 1.04 (1.0Z, 1.07). The results confh'm that air pollution is associated with daily admissions for chronic obstructive pulmonary disease in European cities with widely varying cli- mates. The results for particles and ozone are broadly consistent with those from North America, though the coefficients for partieles are substantially smaller. Overall, the evidence points to a causal relationship but the mechanisms of action, exposure response relationships and pollutant interactions remain unclear. Eur Respir J 1997; 10: 1064-1071. *Dept of Public Health Sciences, St. Geor- ge's Hospital Medical School, London, UK. **GSF - National Research Centre for Environment and Health, Institute for Epidemiology, Neuherberg, Germany. ***Observatoire R6gional de la Sant~, Paris, France. +Dept of Epidemiology and Statistics, University of Gxoningen, The Netherlands. ~Institute Municipal D'In- vestigacio Medica, Barcelona, Spain. +~-qnstitute of Clinical Physiology, National Research Council, Pisa, Italy. *Facult~ de Mt~dicine, Universit~ de Grenoble, France. ttDept of Hygiene and Epidemiology, Uni- versity of Athens Medical School, Greece. tttNational Institute of Hygiene, Warsaw, Poland. #Heisinki City Centre of the En- vironment, Finland. ~National Centre for Health Promotion, Bratlslava, Slovakia. ~Harvard School of Pubfic Health, Boston, USA. Correspondence: H.R. Anderson, Dept of Public Health Sciences, St George's Hospi- tal Medical School, Cranmer Terrace. London SWI7 ORE, UK Keywords: Air pollution, chronic obsffuc- tive pulmonary disease, hospital admis- sions, meta-analysis Received: August 12 1996 Accepted after revision January 22 1997 This work was supported by the European Community Environment 91-94 programme (Contract EV5V CT 920202; DG XII). There is considerable evidence that severe air pollu- tion episodes may be associated with an increase in mor- bidity and mortality [1, 2]. Recent studies have found that daily morbidity and mortality may also be associated with levels of air pollution which are well below those observed in episodes and are within current air quality standards [3]. A vulnerable group is likely to be older people with pre-existing cardiorespiratory disease, inclu- ding chronic obstructive pulmonary disease (COPD) [1, 3, 4]. This condition is characterized by chronic and usually progressive impairment of airflow due to obstruc- tion, damage and disorganization of the airways, as well as to loss of alveolar tissue. Advanced stages of the dis- ease are associated with poor respiratory reserve, and affected individuals are likely to be especially vulnera- ble to additional stress on the respiratory system, such as might be caused by the toxic effects of inh.aled pol- lutants. Evidence from panels of patients with COPD suggests that they experience small reductions in lung function in association with increased pollution levels in the ambient range [5, 6]. Hospital admissions for COPD might, therefore, be a sensitive indicator of the adverse effects of outdoor air pollution. Studies from Birmingham (AL, USA) [7], Detroit (MI, USA) [8], Minneapolis-St Paul (MN, USA) [9], Ontario (Canada) [10] and Spokane (WA, USA) [11] have reported asso- ciations between daily admissions for COPD and par- ticulate and ozone pollution. In the Air Pollution and Health, a European Appro- ach (APHEA) collaboration, a standardized prospective approach was used to examine the short-term effects of air pollution on mortality and morbidity in a wide range THIS ARTICLE IS FOR INDIVIDUAL USE ONLY AND NAY NOT DE FURTHER REPRODUCED OR STORED ELECTRONICALLY HITHOUT HRITTEN PERHISSION FROH THE COPYRIGHT HOLDER. * UNAUTHOR'rZED REPRODU(3TION MAY RE.~ULT .'. IN FZNANC]'AL AND OTHER PENALTIES.

HISTAMINE AND 5. Kesten S, Maleki-Yazdi MR, Sanders BR, et aL Respiratory rate during acute asthma. Chest 1990; 97: 58-62. 6. Chadha TS, Schneider AW, Birch S, Jenoud G, Sackner MA. Breathing pattern during induced bronehocon- strietion. J Appl Physiol: Respirat Environ Exercise Physiol 1984; 56: 1053-1059. 7. Kelsen SG, Prestel TF, Cherniaek NS, Chester EH, Deal EC Jr. Comparison of the respiratory responses to exter- nal resistive loading and bronchoconstdetion. J Clin Invest 1981; 67: 1761-1768. 8. Savoy J, Louis M, Kryger MH, Forster A. Respiratory response to histamine- and methacholine-induced bron- ehospasm in nonsmokers and asymptomatic smokers. Eur Respir J 1988; 1: 209-216. 9. Oliven A, Cherniack NS, Deal EC, Kelsen SG. The effects of acute bronehoconstrietion on respiratory activity in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985; 131: 236-241. 10. Woolcock AJ. Asthma: What are the important experi- ments? Am Rev Respir Dis 1988; 138: 730-744. 11. Lougheed MD, Lain M, Forkert L, Webb A, O'Donnell DE. Breathlessness during acute bronehoconstricfion in asthma: pathophysiologie mechanisms. Am Rev Respir Dis 1993; 148: 1452-1459. 12. Savoy J, Fleetham JA, Arnup M-E, Anthonisen NR Airway anesthesia and respiratory response to metha- choline-induced bronchoconstriction. Respir Physiol 1981; 43: 59-68. 13. Stromberg NOT Gustafsson PM. Ventilatory pattern during bronchial histamine challenge in asthmatics. Eur Respir J 1993; 6:1126-1131. 14. Fanelli A, Duranti R, Gorini M, Spinelli A, Gigliotti F, Scano G. Histamine-induced changes in breathing pat- tern may precede bronchoeonstfiction in selected pat- ients with bronchial asthma. Thorax 1994; 49: 639-643. 15. Millman RP, Silage DA, Peterson DD, Pack AI. Effect of aerosolized histamine on occlusion pressure and ven- tilation in humans. J Appl Physiol: Respirat Environ Exercise Physiol 1982; 53: 690-697. 16. Savoy J, Allgower E, Courteheuse C, Junod AF. Ventila- tory response to bronchospasm induced by methacho- line and histamine in man. Respir Physiol 1984; 56: 195-203. 17. Armstrong DJ, Luck JC. A comparative study of irri- tant and type J receptors in the cat. Respir Physiol 1974; 21: 47-60. 18. Coleridge HM, Coleridge JCG. Reflexes evoked from tracheobronchial tree and lungs. In: Cherniack NS, Widdicombe JG, eds. Handbook of Physiolggy. The Respiratory System. Control of Breathing. Vol. II. Bethe- sda, MD, American Physiological Society, 1986; pp. 395-429. BREATHING PATTERN 1063 19. Davies A, Roumy M. A role of pulmonary rapidly- adapting receptors in control of breathing. Aust J Exp Biol Med Sci 1986; 64: 67-78. 20. Meessen NEL, van der Grinten CPM, Folgedng HTM, Luijendijk SCM. Histamine-induced end-tidal inspira- tory activity and lung receptors in cats. Eur Respir J 1995; 8: 2094-2103. 21. Meessen NEL, van der Grinten CPM, Folgering HTM, Luijendijk SCM. Tonic activity in inspiratoty muscles during continuous negative airway pressure. Respir Phy- siol 1993; 92: 151-166. 22. White MV, Kaliner MA. Regulation by histamine. In: Crystal RG, West JB, Barnes PJ, Cherniack NS, Weibel ER, eds. The Lung: Scientific Foundations. New York, Raven Press, 1991; pp. 927-939. 23. Dixon M, Jackson DM, Richards IM. The effects of H 1 and H2 receptor agonists and antagonists on total lung resistance, dynamic lung compliance and irritant recep- tor discharge in the anaesthetized dog. Br J Pharmacol 1979; 66: 203-209. 24. Vidruk EH, Hahn HL, Nadel JA, Sampson SR. Mecha- nisms by which histamine stimulates rapidly-adapting receptors in dog lungs. J Appl Physiol: Respirat Environ Exercise Physiol 1977; 43: 397-402. 25. Sellick H, Widdicombe JG. Stimulation of lung irritant receptors by cigarette smoke, carbon dust, and hista- mine aerosol. J Appl Physiol: Respirat Environ Exercise Physiol 1971; 31: 15-19. 26. Meessen N'EL, van der Gdnten CPM, Lnijendijk SCM, Folgedng HTM. Histamine-induced bronchoconstric- tion and end-tidal inspiratory activity in man. Thorax 1996; 51: 1192-1198. 27. Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7: 235-243. 28. Quanjer Phil (ed). Standardized lung function testing. Report Working Party "Standardization of Lung Func- tion Tests". Bull Eur Physiopathol Respir 1983; 19 (Suppl.): 1-95. 29. Hargreave FE, Ryan G, Thomson NC, et al. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clin Immunol 1981; 68: 347-355. 30. Sterk PJ, Fabbri LM, Quanjer Phil, et al. Airway res- ponsiveness: standardized challenge testing with phar- macological, physical and sensitizing stimuli in adults. Eur Respir J 1993; 6: $53-$83. 31. Quanjer Phil, Tammelin GJ, Cotes JE, Pedersen OF, Peslin R, Yernault J-C. 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AIR POLLUTION AND of European cities [12]. In six cities (Amsterdam, Barce- lona, London, Milan, Paris and Rotterdam) data on ad- missions for COPD were analysed. In this paper, we present the results of an analysis, in which the indivi- dual city results have been combined using meta-analy- tical techniques to provide summary estimates of the relative risks of daily admissions for COPD associated with ambient levels of sulphur dioxide (SO2), nitrogen dioxide (NO2) ozone (03) and particles (black smoke (BS) or total suspended particulates (TSP)). Papers con- cemed with all emergency respiratory admissions (Inter- national Classification of Diseases 9th Revision (ICD9) 460-519) and asthma (ICD9 493) will be published sep- arately. Methods Details of each city's methods have been reported previously [13-17]. From routine sources, daily counts of emergency hospital admissions for ICD9 490 (un- specified bronchitis), 491 (chronic bronchitis), 492 (em- physema) and 496 (chronic airways obstruction) were obtained. For the purpose of this analysis, these four codes comprise COPD. In Barcelona, data collection was part of a special project. The admissions covered all hospitals in each city which admit medical emer- gencies, except for Barcelona, where six participating hospitals, which cover 90% of emergencies, provided data on emergency COPD admissions. In Milan and Pads, emergency admissions could not be separat~ from total admissions, but based on an analysis of London data, which found that 95% of COPD admissions in that city were "immediate", it is likely that the large major- ity of COPD admissions in Paris and Milan were also "immediate" i.e. unplanned emergency admissions. The proportion of all medical admissions with diagnostic co- ding was over 90% in all cities except London, where it rose from 73 to 95% during the period of study. These systems record the diagnosis of the condition responsi- ble for admission at the time of discharge. The effects of pollutants that were already available from routine monitoring systems measuring background concentrations were studied. The criteria for inclusion of monitors and for dealing with missing values were decided in advance by the APHEA group [12]. SO2 and NO2 were analysed as 24 h and maximum 1 h means for each day. Indicators of particles used in this analy- sis were TSP and BS analysed as 24 h values. Ozone was analysed as an 8 h mean (09:00 to 17:00 h) and as the daily maximum 1 h mean. Temperature and humid- ity were analysed as mean 24 h values. The APHEA group agreed the analytical approach in advance to ensure the maximum degree of comparabil- ity. This was Poisson time series regression controlling for trend, seasonal and other cycles down to 2 months (6 weeks in the case of London) [15], day of the week, holidays, influenza epidemics, temperature, humidity and autocorrelation [18, 19]. Within the constraints of the agreed approach, each centre analysed their data individually rather than on a pooled basis. This deci- sion was made because factors, such as access patterns, pollution mixtures, climate and seasonal influences dif- fered between cities, and might need to be taken into DAILY COPD ADMISSIONS 1065 account on a city by city basis. Similarly, each centre determined for each pollutant the best 1 day lag (up to 3 days) and cumulative lag (the mean over several pre- vious days) for each pollutant. For ozone, up to 5 days were allowed. For eentres with higher levels of pollu- tion (days above 200 lag-m-3), the exposure response was sometimes logarithmic, flattening out at higher lev- els. To simplify the meta-analysis, each centre fitted a linear relationship between the pollutant and COPD ad- missions for days below 200 lag-m-3. In addition to all year models, coefficients were estimated for the cool (October to March) and warm (April to September) sea- sons separately. The summary effect of each air pollution indicator on COPD admissions was estimated by calculating the wei- ghted mean of each city's regression coefficients, the weights being inversely proportional to the local vari- ances. The weights were calculated assuming a fixed effects model when a Chi-squared test failed to detect heterogeneity at the sensitive level of alpha=20%. When the assumption of homogeneity had to be rejected, a random effects model was adopted; this gives weights which are more similar between cities but a larger vari- ance, reflecting greater uncertainty about the summary estimate when local results are heterogeneous [20]. Where heterogeneity was observed, we tried to explain this using weighted linear regressions of local coeffi- cients on non-time-dependent properties of the cities, including indicators of general population health status, climate, quality of outcome data, quality of pollutant data, and pollutant features, such as heterogeneity in overall levels of pollution within and between cities. Results Table 1 summarizes the health and environmental data used in the analysis. The cities varied considerably in size and environmental characteristics. The median sum- mer temperature ranged from 14°C in Amsterdam and Rotterdam to 22°C in Milan, and the median winter tem- perature from 5°C in Amsterdam and Rotterdam to 13°C in Barcelona. The contrast between summer and winter temperatures (expressed as percentage difference) was greatest for Amsterdam (47%), Rotterdam (47%) and Milan (48%), intermediate for London (30%) and Paris (29%), and lowest for Barcelona (16%). For pollution levels, the highest and lowest cities, respectively, were: SO2, Milan and Amsterdam; NO2, London and Paris; BS, Barcelona and Amsterdam; and 03, Amsterdam and Paris. The daily number of COPD admissions varied from 1 (Amsterdam and Rotterdam) to 20 (London). The pro- portion of COPD admissions for patients aged >65 yrs ranged from 48% in Paris to 70% in Barcelona. Figure 1 a--e shows, for the 24 h concentration of each pollutant (8 h for ozone), the relative risks for each city and the summary estimate for an increase of 50 lag-m-3 in each pollutant. Table 2 shows the relative risk esti- mates for single day and cumulative lags, and also in- eludes maximum 1 h values for SO2, NO2 and ozone. The effect of SO2 varied considerably across cities but the summary estimate was significant for the 1 h measure and borderline significant for the daily mean.

1066 Table 1. H.R. ANDERSON ET AL. - Summary data for health and environmental variables for the six European cities Amsterdam Barcelona London Milan Paris Rotterdam Population millions 0.7 1.7 7.2 1.5 6.5 0.6 Period of study 1977-1989 1986-1992 1987-1991 1980-1989 1987-1992 197%1989 COPD admissions# n.day-1 All year l.l 11 20 5 11 1.1 Cool 2.0 13 23 6 13 1. I Warm 1.1 9 18 4 l0 l.l Temperature# °C All year 10 15 12 14 12 10 Cool 5 13 9 7 7 5 Warm 14 18 16 22 17 14 Relative humidity# % All year 83 76 73 64 78 83 Cool 86 75 77 71 83 86 Warm 80 77 68 60 72 80 SO2 24 h# ~g.m-3 All year 21 40 31 53 23 32 Cool 27 46 32 118 31 41 Warm 17 36 30 30 18 26 SO2 1 h# ttg,m"3 All year 50 60 47 82 Cool 59 78 62 97 Warm 41 50 37 70 NO2 24 h# I.tg.m-3 All year 50 53 67 42 52 Cool 51 53 67 43 55 Warm 48 53 67 41 49 NO2 1 h# ~tg.m-3 All year 75 93 98 64 78 Cool 71 88 96 62 78 Warm 75 97 101 67 76 BS 24 h# ttg.m-3 All year 6 41 13 26 22 Cool 8 50 15 32 23 Warm 5 35 11 22 22 TSP 24 h# i~g.m-3 All year 41 155 105 41 Cool 40 144 131 40 Warm 43 162 90 43 Ozone 8 h# I~g-m"3 All year 69 56 28 20 61 Cool 55 36 16 9 44 Warm 82 79 36 36 75 Ozone 1 h# ~tg-m-3 All year 77 64 38 36 71 Cool 64 55 26 20 56 Warm 91 86 48 57 86 COPD: chronic obstructive pulmonary disease; BS: black smoke; The lags were inconsistent, being either same day or day 2. This heterogeneity was largely from Amsterdam and Rotterdam; there were indications that this was asso- ciated with the use of fewer monitoring stations (one compared with three or more in the other cities) and relatively low temperatures. The effect of particles was more consistent, and the summary estimates for BS and TSP were both statisti- cally significant or borderline significant. The lags var- ied from same day to day 2. For increases of 50 ~tg-m-3 in BS and TSP all-age COPD admissions were increa- sed by 3.5% (95% CL 1-6) and 2.2% (95% CL 1-5), respectively. Both 24 h and 1 h NO2 were significantly associated with COPD admissions and the cities tended to be con- sistent, apart from Amsterdam which was a negative outlier causing heterogeneity in the 1 h NO2 effects. This heterogeneity could not be explained using the vad- ables described in the Methods section, as there were few differences between Amsterdam and Rotterdam in these respects. The lags varied from 0 to 2 days. An increase of 50 I~g.m"3 in 24 h NO2 was associated with a 1.9% increase in admissions (95% CL 0-5). The most consistent and significant findings were for ozone, and there was no significant heterogeneity be- tween the cities. The lags varied from 0 to 2 days. A TSP: total suspended particulates. #: median value. 50 gg.m-3 increase in 8 h ozone was associated with a 4.3% (95% CL 2-7) increase in admissions. With one exception, all the cities had a zero or 1 day lag. The ex- ception was Rotterdam (also the smallest city), which had a lag of 2 days. In general, the use of cumulative lags did not give stronger effects than single day lags. Table 3 shows the effects of pollutants in the warm and cool seasons separately. In the warm season, sig- nificant or borderline significant effects were observed for SO2, NO2 and ozone, but not for BS or TSP. In the cool season, marginally significant effects (10% level) were obtained for BS and ozone. The difference in pol- lution effect between warm and cool seasoas was sig- nificant only for 8 h ozone, with a much stronger effect in the warm season. Too few cities provided analyses of the >_65 age group to justify mete-analysis of this age group. However, because most other reports of the effects of air pollu- tion on COPD admissions have been confined to this age group, the results will be mentioned here. London, Milan and Pads analysed the effects of 24 h SO2 on this age group; all the relative risks were positive and of similar size: 1.043 (Ns), 1.069 (p<0.05) and 1.048 (p<0.1), respectively. All three individual effects were higher than the all-ages summary estimate of 1.022.

AIR POLLUTION AND DAILY COPD ADMISSIONS 1067 a) RR for 50 ~g.m-3 increase 0.84 0,92 1.=..___~00 1.09 1.19 1..~,~30 Lag London, Amsterdam. Rotterdam. Paris. Milan. Barcelona. Meta (R). c) Amsterdam- Rotterdam- Milan- Barcelona- Meta (F)- -3.5 -1.75 0.00 1.75 3.5 5.21 J~-coefficient ~g.m-3 (xl,000) RR for 50 p.g.m-3 increase 0.64 0.801~00 1.25 1 ..~~,57 Lag '----~'-" -' 0 ~ 0 E~ 2 -9.0 0.0 4.5 [~-coefficient I.U:j.m-3 (×1,000) London- Amsterdam- Rotterdam- Paris- Barcelona- Meta (F)- b) London- Amsterdam- Rotterdam- Paris- Barcelona- Meta (F)- d) RR for 50 ~g.m-3 increase 0.64 0.80 1~00 1 25 1.5~ 2 0 2 0 0 -9.o 0.0 41s 9.0 [~-coefficient l~g.m-3 (xl,000) RR for 50 l~g.m"3 increase 0.74 0.86 1.=.~.~__~~00 1.16 1..~.~,~~ London. Amsterdam. Rotterdam~ Paris. Barcelona. Meta (F)' 9.0 -6.0 -3'.0 RR for 50 l~g.m-3 increase 1.00 1.19 1.~42 La9 ~ 1 EP----,0 ~ 2 ~ 0 ~ 1 p-coefficient i~g.m"3 (xl,000) 6.0 -8.5 0.0 3.5 7.0 I~-coefficient iJ, g.m"3 (xl,000) Fig. 1. - Relative risks (RR) and (95% confidence limits) for daffy admissions for COPD, for each city, associated with a 50 pg-m"3 increase in pollutant. Summary estimate from meta-analysis shown as Meta (F) = fixed effects model or Meta (R) = random effects model. Abscissa show beta-coefficient for log of admissions. The circled area is proportional to the weight attributed to each city in the meta-analysis, a) 24 h sulphur dioxide; b) 24 h black smoke; c) total suspended particulates; d) 24 h nitrogen dioxide; e) 8 h ozone. Lag: effects may be on the same day or lagged up to 3 days (ozone 5 days). O

1068. H.R. ANDERSON ET Table 2. - Summary effects of pollutants on daily emergency hospital admissions for chronic obstructive eases (expressed as relative dsk (RR) per 50 pg.m"3 increase in pollutant) lung dis- Pollu~at Cities Lag RR# 95% CL SO2 24 h A,B,L,M,P,R One day 1.022 0.981, 1.055 Cumulative 1.021(*) 0.998, 1.045 SO2 1 h A,B,P,R One day • 1.011 0.994, 1.029 Cumulative 1.015" 1.003, 1.027 BS 24 h A,B,L,P,R One day 1.035" 1.010, 1.060 Cumulative 1.038" 1.008, 1.070 TSP 24 h A,B,M,R One day 1.022(*) 0.998, 1.047 Cumulative 1.033 0.994, 1.074 NO2 24 h A,B,L,P,R One day 1.019" 1.002, 1.047 Cumulative 1.026" 1.004, 1.036 NO~ 1 h A,B,L,P,R One day 1.013" 1.003, 1.022 Cumulative 1.014 0.976, 1.054 Ozone 8 h A,B,L,P,R One day 1.043" 1.022, 1.065 Cumulative 1.056" 1.027, 1.086 Ozone 1 h A,B,L,P,R One day 1.029" 1.011, 1.047 Cumulative 1.049" 1.024, 1.075 #: the original Poisson regression coefficient may be calculated by dividing the natural logarithm of the RR by 50. A: Amsterdam; B: Barcelona; L: London; M: Milan; P: Paris; R: Rotterdam; one day lag: effects may be on the same day or lagged up to 3 days (ozone 5 days); Cumulative: effects of mean of same day and up to 3 previous days (ozone up to 5 previous days); 95% CL: 95% confidence limits; BS: black smoke; TSP: total suspended particulates. *: 13<0.05; (*): p---0.05-0.1. Table 3. - Summary effects of air pollutants on COPD admissions by "cool" and "warm" season; single day lags only (expressed as relative risk (RR) per 50 i~g.m-a increase in pollutant) Pollutant Cities Season RR~ 95% CL SO2 24 h A,B,L,M,P,R Cool 1.02 0.98, 1.05 Warm 1.05" 1.01, 1.I0 SO2 1 h A,B,P,R Cool 1.01 0.99, 1.03 Warm 1.02" 1.00, 1.04 BS 24 h A,B,L,P,R Cool 1.03(*) 1.00, 1.06 Warm 1.05 0.98, 1.12 TSP 24 h A,B,M,R Cool 1.04 0.99, 1.09 Warm 1.01 0.98, 1.05 NO2 24 h A,B,L,P,R Cool 1.01 0.99, 1.03 Warm 1.03(*) 1.00, 1.06 NO2 I h A,B,L,P,R Cool 1.02 0.99, 1.05 Warm 1.02" 1.00, 1.05 Ozone 8 h A,B,L,P,R Cool 1.03(*) 1.00, 1.07 Warm 1.04" 1.02, 1.07 Ozone 1 h A,B,L,P,R Cool 1.01 0.98, 1.05 Warm 1.03" 1.01, 1.05 For definitions see legends to tables 1 and 2. *: p<0.05; (*): p=0.05--0.1. The summary estimate of 1.053 for SO2 for the >65 age group was significant (p<0.05). London and Paris show- ed similar effects of BS on COPD in the _>65 age group (1.039 and 1.032, respectively). These effects were not significant and the summary estimate of 1.034, while not significant, was almost identical to the all-ages sum- mary estimate of 1.035. Discussion In a prospective standardized study of six European cities, the effect of various air pollutants on daily admis- sions for COPD were analysed using a Poisson regres- sion technique. Using meta-analytical statistical techni- ques to combine the individual city effects, it was found that relative risks were significantly increased for a num- ber of pollutants. The most consistent effects were for ozone in the warm season, but significant effects were also observed for SO2, NO2 and measures of particles (TSP and BS). The concentrations of pollutants were generally well within World Health Organization (WHO) Guidelines for health protection in Europe [21]. This study differs from previous meta-analyses [3, 11] in that the meta-analysis was a prospective part of the APHEA project and analysed a wider range of poilu- tants. The parametric Poisson regression approach cho- sen has some potential deficiencies'. Complex seasonal patterns might not be appropriately modelled by harmo- nic waves, while other estimates potentially depend on the assumed shape of the exposure response curve [19, 22, 23]. However, investigations into the sensitivity of this approach using different models and comparisons with more sophisticated nonparametric techniques sug- gest that the approach used in the present study is quite robust [8, 9, 24]. Control for meteorological variables is always a critical issue in temporal air pollution studies. A recent study, which compared the synoptic approach, favoured by some biometeorologists, with controlling for weather variables using the same methods as the APHEA collaboration found that similar results were obtained [25]. The interpretation of the present data should take into account that each centre selected the lag which gave the greatest effect, rather than a priori. This policy was agreed because at the outset of the study there was insufficient epidemiological or biological in- formation upon which to base an a priori hypothesis as to lag, and there was the strong possibility that diffe- rent environments and health care systems might be associated with different lags. The final meta-analysis of the results has to be judged differently from retrospective meta-analyses published previously, as it was planned from the start, and care

AIR POLLUTION AND DAILY COPD ADMISSIONS 1069 Table 4. - Relative risks (RR) for daily hospital admissions for COPD for a 50 pg.m"3 increase in polliJtant (com- parison of APHEA cities with other studies) City [Ref] COPD RR for 50 pg.m"3 Comments admissions# increase in air pollutant n.day"t Particles Ozone Amsterdam, 1.1 The Netherlands Barcelona, Spain 11 London, UK 20 Milan, Italy 4 Paris, France I 1 Rotterdam, l ol The Netherlands APHEA summary estimates estimates Other studies Birmingham, AL, USA [7] 2 Detroit, MI, USA [8] 5 Spokane, WA, USA [11] 1 Ontario, Canada [10] Minneapolis, MN, USA [9] 2 1.064* 1.019 0.93* 1.042$* 1.053" 1.018+ 1.028* 1.047" 1.044** 1.0341 1.062" 0.096* 1.019 1.056+ 1.035' 1.043" 1.022+(*) 1.12s* 1.03t 1.20s* 1.06" 1.175" 1.13** 1.07++* 1.255" 1.03" Emergency admissions, all ages Emergency room admissions, all ages Emergency admissions, all ages Emergency and nonemergency admissions, all ages Emergency and nonemergency admissions, all ages Emergency admissions, all ages Emergency admissions, >_65 yrs Emergency admissions >_65 yrs Emergency admissions _>65 yrs Emergency admissions, all ages Emergency admissions >-65 yrs #: median value; $: black smoke; +: total suspended particulates; $: particulate matter with aerodynamic diameter <I0 ~tm (PMI0); t: 1 h ozone; $$: ozone only measured in 7 warm months of the year; ~: based on SO4/PMI0 = 0.40 [II]. Note that in London, UK, BS/PMI0 = 0.7; this means that to convert the BS coefficients in APHEA to the PMlo equivalent would mean making them smaller (xO.7). APHEA: Air Pollution and Health, a European Approach. For further definitions see legends to tables 1 and 2. *: p<0.05; (*): p>0.05 <0.01. (Adapted from [11]). was taken to ensure standardized procedures where pos- sible. There is no bias in selection of cities for study or subsequent analysis. The estimate of pollutant exposure, being based on one or several city background monitors was necessar- ily imprecise because ambient concentrations probably vary throughout the city due to the varying nature of emission sources, topography, air mixing, dispersal and removal processes. Furthermore, indoor levels, which comprise the main exposure, do not necessarily reflect outdoor levels. For example, ozone levels axe lower in- doors but small particles may penetrate indoors quite easily. Nitrogen dioxide may be higher indoors due to indoor combustion sources. If outdoor levels correlate with indoor levels, then the present estimates will be biased but still represent an association with outdoor air pollution. If, on the other hand, the misclassification is random, the tendency will be for the present effects to be biased towards the null, leading to an underestimate of effects [26]. The diagnosis of COPD is known to be subject to variation both within and between countries [27, 28]. Furthermore, several of the cities in this study included a small proportion of nonemergeney admissions. It is possible, therefore, that the clinical spectrum of COPD admissions differed from city to city. This might lead to some variation in the size of the estimate, depend- ing on how misclassification affected the average sefi- sitivity of the group coded as COPD, but we are unable to estimate whether and to what extent this occurs. Are these effects likely to be causal? Although the associations observed are unlikely to be due to chance, the small size of the relative risks raises the question of whether the results could be explained by unknown confounding factors or inadequate control of known confounders. Being an observational ecological study, such a possibility cannot be disproved; however, the consistency of some of the findings together with reports of significant effects on COPD admissions in North America [7-1 I] suggests that this is less likely. Few previous studies of this type have systematical- ly analysed pollution effects by season. We observed that the size and significance of effects tended to differ between cities, though the winter/summer differences were statistically significant for one pollutant (ozone). Seasonal differences might have several explanations. One is that there is a threshold effect, exceeded main- ly in one season. A second is that the effect depends on complex interactions with the rest of the pollution mix, which also varies seasonally. A third is that some of the associations observed for a particular pollutant are due to confounding by factors, which themselves vary by season. At present, we have insufficient information to explain this variation. The other important issue is that of plausibility. Pati- ents with advanced COPD tend towards a state of res- piratory failure, in which blood levels of oxygen and carbon dioxide become abnormal and which, in turn, leads to problems in other systems, such as the circu- latory system. They are particularly susceptible to acute chest infections. It is plausible that such patien.ts might be made worse by the toxic inflammatory effect of small increases in atmospheric pollution. Experimental cham- ber studies indicate that both healthy subjects and those with asthma or COPD exhibit considerable individual variability in susceptibility to SO2, ozone and NO2 [29-32]. However, there is little evidence from cham- ber studies that ambient levels of ozone [33, 34] or NO2 [35-39], have clinically significant effects on COPD patients. It is conceivable that the disparity between

1070 H.R. ANDERSON ET AL. ambient and chamber studies may arise because cham- ber studies do not involve very severe patients or bec- ause they are inadequate for simulating the pattern and duration of ambient exposure or the complex mix of pollutants found in the ambient situation. Panel studies do, however, suggest that patients with COPD may ex- perience small short-term effects at ambient levels of particles, NO2 and SO2 [5, 6]. It should be noted that, in the ambient situation, the actual exposure of some individuals may be substantially higher or lower than indicated by a background monitor. Previous North American studies of air pollution and COPD admissions have been concerned mainly with the effects of particles or ozone (table 4). The present find- ings confirm the presence and scale of effect reported for ozone, and suggest that this is a widespread and fair- ly consistent phenomenon on both sides of the Atlantic. The results for particles are less consistent than those for ozone. While the APHEA study found that there are significant effects of particles on admissions for COPD, the coefficients were considerably smaller Shun in the North American studies. Most of the North American studies have been con- fined to the >65 yrs age group, whereas 50-70% of European COPD admissions were in this age group. This could account for some of the transatlantic differ- ences in particle effects but is unlikely to be the main explanation, because in the few European cities where analyses were available for the >65 yrs group the coef- ficients for particles were similar to those for all ages, and the coefficients for SO2, though higher in the >65 yrs group, were not significant. Furthermore, the effects of ozone were similar in both continents. The smaller size of particle effects in Europe may be explained by differences in the chemical nature and size distribution of the particle mixture, as well as by dif- ferences in the composition of the whole pollution mix- ture. There is increasing interest in the role of the fine (<2.5 lain) and ultrafine (<0.1 lam) fractions, of which a substantial part is composed of chemical particles, such as sulphates, nitrates and acid aerosols [40-42]. These are inadequately indicated by BS or TSP. We have established that significant associations be- tween air pollution and daily admissions for chronic obstructive pulmonary disease can be detected, and that among the candidate pollutants, the associations with ozone are the strongest and most consistent. Further research is required to examine interactions between pol- lutants, exposure response relationships and health im- pact. The comparatively smaller effects of particles in Europe compared with North America should be inves- tigated further by using comparable measurements of particles and taking into account differences in the over- all pollution mixture. For the present, our results indi- cate that current levels of air pollution are likely to be harmful to people with" chronic obstructive pulmonary disease and that policies to further reduce air pollution should be continued. Members of the APHEA collaborative group: K. Katsouyanni, G. Touloumi, E. Samoli (Greece, Co-ordinating Centre); D. Zmirou, P. Ritter, T. Barumandzadeh, F. Balducei, G. Laham (Lyon, France); H.E. Wiehmann, C. Spix (Germany); I. Strayer, J. Castellsague, M. Suez, A. Tobias (Spain); J.P. Sehouten, J.M. Vonk, A.C.M. de Graaf (l~he Netherlands); A. Ponka (Finland); H.IL Anderson, A. Ponce de Leon, R. Atkinson, J. Bower, D. Strachan, M. Bland (UK); W. Dab, P. Quenel, S. Medina, A. Le Tertre, B. Thelot, B. Festy, Y. Le Moullec, C. 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