Volume 169 Issue 9

Outdoor air pollution and children's respiratory symptoms in the steel cities of New South Wales Peter R Lewis, Michael J Hensley, John Wlodarczyk, Ruth C Toneguzzi, Victoria J Westley-Wise, Trevor Dunn and Dennis Calvert MJA 1998; 169: 459-463 For editorial comment, see Abramson & Beer Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Public and environmental health - ©MJA1998 Abstract Objective: To investigate the relationship between outdoor air pollution and the respiratory health of children aged 8 to 10 years. Design: A cross-sectional survey (between October 1993 and December 1993) of children's health and home environment. Summary measures of particulate pollution (levels of particles with an aerodynamic diameter less than 10 µm [PM10] each 6th day) and SO2 (daily mean and maximum hourly values) were estimated for each area (using air quality monitoring station data from July 1993 to June 1994). Setting and survey participants: Parents of 3023 primary school children (Years 3, 4 and 5) from industrial and non-industrial areas with air quality monitoring stations in the Hunter and Illawarra regions of New South Wales. Main outcome measures: Reported occurrence of four or more chest colds, four or more attacks of wheezing, and night-time cough without a cold for more than two weeks, all within the previous 12 months. Results: 77% response rate, ranging by area from 66% to 88%. The average annual outdoor air pollution for the nine areas was 18.6-43.7 µg/m3 for PM10 and 0.16-0.90 parts per hundred million for SO2. The proportion of children reported to have the main outcome symptoms were: chest colds, 3.0%-9.7%; night cough, 12.3%-30.5%; and wheeze, 3.4%-11.3%. There was no significant association with SO2, but a significant increase in the odds of symptoms per 10 µg/m3 increase in PM10 on chest colds (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.12-1.82) and night-time cough (OR, 1.34; 95% CI, 1.19-1.53), but not wheeze. Passive smoking was significantly associated with chest colds but not with the other symptoms. Maternal allergy was associated with all three respiratory symptoms, most strongly with wheeze. Conclusion: These results provide evidence of health effects at lower than expected levels of outdoor air pollution in the Australian setting. They also suggest differences in contributions of environmental and hereditary factors to cough and chest colds compared with wheeze. Introduction The effect of outdoor air pollution on the respiratory system has been investigated and reviewed often.1,2 Various health outcomes have been studied; for example, the relationship between exposure to elevated sulfur dioxide, total suspended particulates (TSP) and respiratory symptoms;3 the association between increased air pollution and hospital admissions for asthma;4,5 and studies of air pollution and mortality.6,7 These studies consistently report associations between air pollution and health outcomes, and illustrate the coherence of effects8 across the range of outcomes. There have been few studies of the relationship between air quality and health in Australia. Studies of asthma in school children living near power stations in the Hunter region of New South Wales had very low levels of exposure and lacked the power to detect small associations.9,10 Other studies in south-eastern Australia confirmed the high prevalence of asthma in Australia but had no exposure measures.11-13 The lower Hunter and Illawarra regions of New South Wales are on the coast, about 150 km north and 80 km south of Sydney, respectively. The main cities are Newcastle, in the Hunter region, and Wollongong, in the Illawarra region. The estimated resident populations in 1993 for Newcastle and Wollongong were 451 100 and 248 700, respectively.14 Both regions have fully integrated steelworks, combining coke ovens, blast furnaces, steel-making vessels and rolling mills, and the main pollutants are coke oven gases, blast furnace gases and particulates. In addition, lead smelting occurs in the Hunter region, and copper smelting in the Illawarra region. The Hunter Illawarra Study of Airways and Air Pollution (HISAAP) arose out of longstanding community concerns about the health effects of air pollution near heavy industry in Newcastle and Wollongong. The generalisability of overseas studies to Australia was not known, because of differences in climate, geography, population and pollution sources. Public health workers need local data to initiate action on air quality at the community level and to formulate air quality guidelines. This study, the first part of HISAAP, investigated the association between outdoor air quality, as particulates and sulfur dioxide, and respiratory symptoms among primary school children. Methods The study was a cross-sectional survey to measure the prevalence of respiratory and atopic symptoms among primary school children and relate these to measures of ambient air quality. Study areas To make best use of resources, study areas were selected on the basis of existing or proposed air quality monitoring stations. In the lower Hunter region, the study areas close to industrial sources of air pollution were North Lake Macquarie, Mayfield and Stockton, and distant areas were Beresfield and Wallsend (Figure 1a). In the Illawarra region, we estimated that there would be an increasing gradient of exposure to air pollution, from Wollongong, to Albion Park, Kembla Grange and Port Kembla (Figure 1b). Wallsend, Beresfield, Wollongong and Albion Park were expected to have background levels of air pollution. We were able to compare these multiple control areas with those areas close to point sources of air pollution. Sampling strategy All primary schools within a three-kilometre radius of the air quality monitoring sites were approached to be involved in the study. The sampling frame included all children in Years 3 and 4, aged 8 to 10 years, whose parents or guardians approved their child's participation. In areas that had small numbers of children, children in Year 5 were included. We aimed to enrol about 300 children in each of the nine areas. Questionnaire Our questionnaire incorporated features used by previous investigators in the Hunter region and NSW,9,11,12 the International Study of Asthma and Allergies in Childhood,15 the American Thoracic Society questionnaire16 and the Six Cities study.17 It addressed demographic data and parental education; child's health (cough, chest colds, wheeze) and atopic symptoms (hayfever, eczema); child's use of respiratory medications; family's symptoms; and home environmental factors (indoor smoking, heating, cooking, carpets, cats). The questionnaire was piloted in both regions.18The primary health outcomes were night-time cough, chest colds and frequent wheeze. They were the responses to the following questions: In the last 12 months has your child had a dry cough at night, apart from a cough with a cold or chest infection? If yes, has this cough lasted for more than 2 weeks? In the last 12 months how many chest colds did your child have? . . . 4 or more chest colds. How many attacks of wheezing has your child had in the last 12 months? . . . 4 or more attacks. Exposure to indoor tobacco smoke was assessed by asking whether the respondent, other adult or any other person smoked cigarettes inside the home. The survey was conducted from October 1993 to December 1993. Children received consent forms and questionnaires at school. Parents completed the questionnaires, and children returned them to their teachers. If a questionnaire was not returned after two weeks, a copy was posted to the parents for completion and return by reply-paid post. Exposure measurement The lower Hunter and Illawarra Air Pollution Monitoring Networks19 consist of sites operated by the Environment Protection Authority (EPA) and industry self-monitoring sites audited by the EPA. Particulate and sulfur dioxide measures were collected for all study areas, from January 1993 to December 1994. As air pollution data were incomplete for some sites in 1993, the goal was to have representative data for 12 consecutive months close to the reference period of the questionnaire (the 1993 calendar year). The most complete data were found to be from July 1993 to June 1994. Sensitivity analyses using data from adjacent 12-month periods showed very little effect on the results. Particulate pollution as PM10 (particles with an aerodynamic diameter less than 10 µm) was measured for 24 hours every sixth day using high volume air samplers with a size-selective inlet, and these measures were averaged over the 12 months. North Lake Macquarie, Mayfield and Stockton measured only TSP, so local data in which both TSP and PM10 were measured for shorter periods20,21 were used to derive a conversion factor to PM10. In North Lake Macquarie, PM10 was estimated to be 60% of TSP, close to the value used by others.22 In Mayfield and Stockton, PM10 was estimated to be 45% of TSP. Sulfur dioxide measurements were obtained hourly using pulsed fluorescent spectrophotometry. Twelve-month averages of the daily maximum values and of the daily mean values were calculated. There were no major trends in air pollution during this time. Seasonal changes did not affect the relative ranking of the areas in terms of air pollution. Analysis We used SAS software for the analysis.23 Descriptive statistics were produced for participation rates, health measures and environmental measures for each of the nine study areas. Logistic regression analysis using generalised estimating equations (GEEs) was used to model the reported symptom (outcome variable) on the following explanatory variables: PM10 and sulfur dioxide measures, unflued gas heating, adults smoking inside the home, indoor cats, age, sex, and maternal allergy.24 The level of clustering for this analysis was the school (ie, clusters of children within schools), with 35 schools in the study. Although schools were also clustered within study areas, area was not chosen as the clustering level because of the allocation of exposure measure by area. Ethical approval The study received ethical approval from the NSW Education Department, the Regional Catholic Education Office, and the Ethics Committees of the Hunter Area Health Service, the University of Newcastle, the Illawarra Area Health Service, and the University of Wollongong. Results Subjects Questionnaires were given to 3023 primary school children -- 1554 children (from 18 schools) in the Hunter region, and 1469 (from 17 schools) in the Illawarra region. In the Hunter region, 1284 (82%) questionnaires were returned, and in the Illawarra region 1056 (72%) were returned. There were no significant differences in age and sex profiles across the study areas (Table 1). Respiratory symptoms About a quarter of the children were reported to have had at least one of the primary respiratory symptoms in the preceding 12 months (Table 2). While some areas with high proportions of children with symptoms were close to industry (Mayfield and Stockton with children having chest colds), this was not a consistent pattern (Beresfield and children with night cough). The proportion of children who had ever been diagnosed with asthma ranged from 17.4% to 38.4%. Home environment and outdoor air pollution Depending on the study area, a third to half of the children lived in homes where one or more adults smoked cigarettes in the home (Table 3). The proportion of children in homes with gas heating that did not have a flue to the outside varied greatly between the areas. The levels of particulate pollution in Mayfield and Stockton approached the US EPA standard for PM10 of 50 µg/m3 (annual mean) (Table 3) and the Australian standard, at that time set for TSP at 90 µg/m3 (annual mean). The annual mean sulfur dioxide levels (daily means) were below the Australian standard of 2 parts per hundred million (annual mean).19 Within study areas, particulate levels were not necessarily high in high sulfur dioxide areas, and vice-versa. Scatter plots of primary health outcomes by air quality measures suggested some positive associations between PM10 and both night cough and chest colds (Figure 2). Generalised estimating equation analysis For each 10 µg/m3 increase in annual mean PM10, children were 43% more likely to be reported as having four or more chest colds (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.12-1.82). The approximate difference in particulate pollution between the area with the highest PM10 level and the area with the lowest was 25 µg/m3, and children were 144% more likely to be reported to have frequent chest colds per 25 µg/m3 increase in annual mean PM10 (OR, 2.44; 95% CI, 1.33-4.49). There was a consistent significant association between particulate pollution and symptoms of night cough and chest colds (Table 4). No association was found between sulfur dioxide and the three respiratory symptoms. An adult smoking in the home was associated with chest colds, and unflued gas heating was associated with frequent wheeze. Boys were more likely to experience frequent wheeze, and there was a significant association between increasing age and likelihood of frequent wheeze. Maternal allergy was consistently associated with an increased risk for all health outcomes, but strongest for wheeze. To estimate the possible impact of the two areas with the largest particulate pollution (Mayfield and Stockton, in the Hunter region), the GEE analysis was repeated excluding those areas. There was little change in the coefficients for most variables, including maternal allergy, for each outcome. However, the odds ratio for chest colds per 10 µg/m3 increase in annual mean PM10 increased substantially -- with Mayfield and Stockton excluded, the odds ratio was 2.05 (95% CI, 1.46-2.87), compared with 1.43 for the full dataset. Discussion This cross-sectional study of primary school children has shown an important association between relatively low levels of particulate air pollution and respiratory symptoms. The importance is reflected in the finding that the odds ratios for particulates were of the same order as for exposure to indoor tobacco smoke. We found an association with maternal allergy across all three symptom outcomes, but strongest for wheeze. The prevalence estimates of respiratory symptoms are similar to those found in other Australian and New Zealand studies.11-13,25 The association between air pollution and respiratory symptoms in children is also consistent with similar cross-sectional studies from other countries. An Italian study found that children living in polluted areas experienced more cough, rhinitis, pneumonia and early respiratory infections than control subjects,26 but that study did not measure actual air pollution exposure. A British study found that children were more likely to miss school because of respiratory symptoms of cough and wheeze if their school was exposed to a higher coal dust burden (OR, 1.55; 95% CI, 1.17-2.06).27 Our results are directly comparable with those of the Six Cities and 24 Communities studies in North America;17,28,29 effects of particulate pollution on respiratory symptoms and effects of indoor smoking were of the same order in those studies and ours. Two results of particular note are the relationship between frequent wheeze and age, and the effect of removing from the analysis the areas with the highest particulate pollution. The increase in wheeze with age is quite large (OR, 1.38 per year). Stratified analysis revealed similar coefficients for younger and older age groups, suggesting that a sampling bias may explain the strength of the relationship. The substantial increase in the odds ratio of particulate pollution and chest colds after removal of the areas with highest PM10 suggests that the dose-response curve for particulate pollution and chest colds is curvilinear and much steeper at lower pollution levels. Potential limitations of our study include possible reporting bias by residents of industrial areas and the variability in the measurement methods for particulate air pollution. It is not possible to estimate the level of possible reporting bias, but its effect may be reduced by selection bias in that families with children with lung disease may not come to, or may leave, polluted areas. The difference in measurement of particulates was unavoidable. A subsequent diary study obtained comparisons of TSP and PM10 which provided evidence on which to convert the measures for local conditions.20,21 Particularly striking are the results which show differences in the determinants of wheeze compared with coughs and colds. While maternal allergy played a part in all, passive smoking was restricted to colds, and particulates to coughs and colds. This suggests differences in underlying pathology which deserve further exploration. Our data lead us to question the current air quality standards, which are based on the premise that levels at or below recommended ambient levels are not likely to produce a clinically important effect. In particular, recommended levels do not consider increased individual sensitivity caused by a disease such as asthma. While this study cannot infer causation, it adds to other local and overseas work that increasingly indicates the role of air pollution in respiratory health -- alone and synergistically with other aeroallergens.30 This information contributes to the review of Australian air quality guidelines, and to the broader societal debate about lifestyle, transport and energy consumption. Individuals, communities, industry and organisations need to reassess their environmental performance not only for the environment, but also for health. Acknowledgements Our thanks to members of the following organisations which supported the study: Newcastle Environmental Toxicology Research Unit (especially Randall Robertson and Julie Holt), University of Newcastle, Hunter Public Health Unit, Hunter Area Pathology Service, Newcastle City Council, Lake Macquarie Council, Illawarra Public Health Unit, University of Wollongong, NSW Health Department, NSW Environment Protection Authority, Australian Nuclear Science and Technology Organisation, BHP (Newcastle and Port Kembla), Incitec, Pasminco Metals Sulphide, Southern Copper. We are grateful to the schools, parents, and children who participated in this study. HISAAP was partly funded by the NSW Health Department as part of its Health and Air Research Program. Dr P Lewis received an NHMRC Public Health Fellowship for two years. References Committee on the Medical Effects of Air Pollution. Asthma and outdoor air pollution. London: HMSO, 1995. Committee of the Environmental and Occupational Health Assembly of the American Thoracic Society. Health effects of outdoor air pollution. Am J Respir Crit Care Med 1996; 153: 3-50. Lunn FE, Knowelden J, Handyside AJ. Patterns of respiratory illness in Sheffield infant schoolchildren. Br J Prev Soc Med 1967; 21: 7-16. Pope CA III. Respiratory admissions associated with PM10 pollution in Utah, Salt Lake and Cache Valleys. Arch Environ Health 1991; 46: 90-97. Bates DV, Baker-Anderson M, Sizto R. Asthma attack periodicity: a study of hospital emergency visits in Vancouver. Environ Res 1990; 51: 51-70. Anderson HR, Ponce de Leon A, Bland JM, et al. Air pollution and daily mortality in London: 1987-92. BMJ 1996; 312: 665-669. Dockery DW, Pope CA III, Xu X, et al. An association between air pollution and mortality in six US cities. N Engl J Med 1993; 329: 1753-1759. Bates DV. Health indices of the adverse effects of air pollution: the question of coherence. Environ Res 1992; 59: 336-349. Henry RL, Abramson R, Adler JA, et al. Asthma in the vicinity of power stations: I. A prevalence study. Pediatr Pulmonol 1991; 11: 127-133. Henry RL, Bridgman HA, Wlodarczyk J, et al. Asthma in the vicinity of power stations: II. Outdoor air quality and symptoms. Pediatr Pulmonol 1991; 11: 134-140. Bauman A, Mitchell CA, Henry RL, et al. Asthma morbidity in Australia: an epidemiological study. Med J Aust 1992; 156: 827-831. Peat JK, Toelle BG, Gray EJ, et al. Prevalence and severity of childhood asthma and allergic sensitisation in seven climatic regions of New South Wales. Med J Aust 1995; 163: 22-26. Robertson CF, Bishop J, Dalton M, et al. Prevalence of asthma in regional Victorian schoolchildren. Med J Aust 1992; 156: 831-833. Australian Bureau of Statistics. Regional population growth 1991 and 1996. Canberra: ABS, 1997. (Catalogue No. 3218.0.) Asher M, Keil U, Anderson H. International study of asthma and allergies in childhood (ISAAC): rationale and methods. Eur Respir J 1995; 8: 483-491. Ferris BG. Epidemiology standardisation project. Part II. Am Rev Respir Dis 1978; 118: 1-53. Ware JH, Dockery DW, Spiro A III, et al. Passive smoking, gas cooking and respiratory health of children living in six cities. Am Rev Respir Dis 1984; 129: 366-374. Lewis PR, Toneguzzi R, Long K, et al. The Hunter Illawarra study of airways and air pollution: refining the process. NSW Public Health Bulletin 1995; 6: 110-112. State Pollution Control Commission. Quarterly air quality monitoring report No 4, 1990. Sydney: SPCC, 1992. Lewis P, Holt J, Fryer J. Daily particulate monitoring in the Speers Point/Boolaroo area -- Lake Macquarie Research Grant 94-9. Newcastle: University of Newcastle, Newcastle Environmental Toxicology Research Unit, 1997. Environment Section, BHP. Mayfield quality control: measures of particulate pollution. BHP, 1995. Dockery DW, Pope CA III. Acute respiratory effects of particulate air pollution. Annu Rev Public Health 1994; 15: 107-132. SAS for Windows [computer program]. Version 6.03. Cary, North Carolina: SAS Institute, 1988. Karim MR. PC version of GEE1 [computer program]. Baltimore: Department of Biostatistics, The Johns Hopkins University, 1989. Moyes CD, Waldon J, Ramadas D, et al. Respiratory symptoms and environmental factors in schoolchildren in the Bay of Plenty. N Z Med J 1995; 108: 358-361. Corbo GM, Forastiere F, Dell'Orco V, et al. Effects of environment on atopic status and respiratory disorders in children. J Allergy Clin Immunol 1993; 92: 616-623. Brabin B, Smith M, Milligan P, et al. Respiratory morbidity in Merseyside schoolchildren exposed to coal dust and air pollution. Arch Dis Child 1994; 70: 305-312. Cunningham J, O'Connor GT, Dockery DW, Speizer FE. Environmental tobacco smoke, wheezing and asthma in children in 24 communities. Am J Respir Crit Care Med 1996; 153: 218-224. Dockery DW, Speizer FE, Stram DO, et al. Effects of inhalable particles on respiratory health of children. Am Rev Respir Dis 1989; 139: 587-594. Devalia JL, Rusznak C, Herdman MJ, et al. Effect of nitrogen dioxide and sulphur dioxide on airway response of mild asthmatic patients to allergen inhalation. Lancet 1994; 344: 1668-1671. (Received 29 Oct 1997, accepted 21 Jul, 1998) Authors' details Newcastle Environmental Toxicology Research Unit, University of Newcastle, Newcastle, NSW. Peter R Lewis, MPH, FAFPHM, Public Health Research Fellow; Michael J Hensley, MB BS, PhD, Director and Professor of Medicine; John Wlodarczyk, BEc, PhD, Statistician; Ruth C Toneguzzi, RN, DipClinEpi, Clinical Nurse Specialist. Illawarra Public Health Unit, Wollongong, NSW. Victoria Westley-Wise, MPH, FAFPHM, Director; Trevor Dunn, GdDipSc(Nursing), MPH(Occ Health), Project Manager. University of Wollongong, Wollongong, NSW. Dennis Calvert, MD, FRACP, Professor in Medicine and Public Health. Reprints will not be available from the authors. Correspondence: Dr P R Lewis, Newcastle Environmental Toxicology Research Unit, Division of Medicine, John Hunter Hospital, Locked Bag 1, Hunter Regional Mail Centre, NSW 2310. E-mail: plewiATdoh.health.nsw.gov.au - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Peter R Lewis · Michael J Hensley · John Wlodarczyk · Ruth C Toneguzzi · Victoria J Westley-Wise · Trevor Dunn · Dennis Calvert

HIV disease progression in Australia in the time of combination antiretroviral therapies Patricia K Correll, Matthew G Law, Ann M McDonald, David A Cooper and John M Kaldor MJA 1998; 169: 469-472 For editorial comment, see Stewart Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Infectious diseases and parasitology - ©MJA1998 Abstract Objective: To examine the effect of recent developments in antiretroviral therapy on HIV disease progression and survival. Design: Retrospective cohort study. Participants and setting: Two cohorts of people with HIV were defined retrospectively from the records of a large immunology laboratory. The first cohort were subjects whose CD4+ T cell counts had dropped to 200 x 106/L during 1990, and the second were subjects whose CD4+ T cell counts had dropped to 200 x 106/L in 1994. Main outcome measures: HIV disease progression and survival was determined over a minimum three years of follow-up for each cohort (ie, 1990-1993; 1994-1997). Results: 346 subjects were included in the analysis (193 subjects from 1990 and 153 from 1994). The relative risk of progression to AIDS in the 1994 cohort compared with the 1990 cohort was 0.57 (95% confidence interval, 0.35-0.91; P = 0.018) and the relative risk of death was 0.20 (95% confidence interval, 0.08-0.49; P < 0.001). Conclusions: There were 43% fewer AIDS cases and 80% fewer deaths in the time following the increased availability of combination antiretroviral therapy in Australia. Introduction In recent years there have been major advances in antiretroviral treatments for people with HIV infection. Evidence from clinical trials (DELTA and ACTG 175)1,2 first defined the superiority of combination therapy over monotherapy in delaying progression to AIDS and prolonging survival. Since that time more potent antiretroviral agents have been approved, including lamivudine (widely available in Australia since early 1995) and protease inhibitors (available since late 1995). In clinical trials, these drugs have demonstrated significant ability to reduce disease progression and improve survival when added to existing regimens of antiretroviral treatments.3,4Although there has been anecdotal evidence in Australia suggesting that these treatments have reduced the overall number of AIDS cases and improved survival following AIDS, their effect has not been systematically studied. We therefore decided to compare the rates of progression to AIDS and survival in two cohorts of people between 1990-1993 and 1994-1997, with CD4+ T cell counts of 200 x 106/L (CD4 cell count 200/µL) at entry to the study, as a basis for assessing the impact of new treatments. Methods Subject identification Two cohorts of subjects in this study with CD4 cell counts of 200/µL were defined retrospectively from records of routine CD4 cell counts undertaken at the Centre for Immunology, St Vincent's Hospital, Sydney. St Vincent's Hospital has been responsible for the care of about 25% of people with AIDS in Australia, and its immunology laboratory is used by St Vincent's Hospital inpatient and outpatient services, and by several general practitioner clinics that specialise in managing people with HIV infection. Subjects whose CD4 cell counts fell below 200/µL in 1990 would not have had access to combination therapies, whereas the 1994 cohort was under follow-up when combination therapies with more potent drugs were becoming available in Australia. A CD4 cell count of 200/µL was used as the starting point for follow-up because at this point individuals have not usually developed AIDS-defining illnesses,5 but are considered to be at a point of immune decline where the probability of developing AIDS in the near future has greatly increased.6,7 Subjects included were HIV-positive but without AIDS at entry to the study, with CD4 cell counts declining through 200/µL in the index year (1990 or 1994) or with a single CD4 cell count in the range 180-220/µL. All eligible subjects were included, except subjects from two large clinics which had used the Centre for Immunology laboratory in 1990 but not in 1994. Where available, two or more CD4 cell count results from the period beginning in the middle of the year before the index year and ending at the middle of the following year were recorded so that the rate of CD4 cell change could be estimated. Subjects with multiple CD4 cell counts entered the study on the date of the first test in the index year that was below 200/µL. For subjects with a single CD4 cell count only, entry to the study was on the date of this test, provided the result fell between 180-220/µL. Follow-up Analysis was based on a minimum of three (up to four) years' follow-up of both cohorts through linkage to the National AIDS Registry, which records AIDS diagnoses and deaths following AIDS in Australia. Testing records were linked to Registry data by matching name codes (first two letters of the surname and given name) and dates of birth from the reference laboratory database with the Registry. Because reporting of AIDS diagnoses and deaths to the Registry is subject to delay, subjects from the 1994 cohort who did not appear on the Registry were followed up through their referring doctors. The doctor was also contacted for follow-up information if a name code was not available with the CD4 count records. Information sought included name code, date of birth, whether the subject had progressed to AIDS or died with AIDS, and date of the doctor's most recent contact with the subject. Statistical methods All statistical analyses were performed using SAS.8 Decline of CD4 cells was estimated for subjects with two or more CD4 cell counts by linear regression. Baseline characteristics in the two cohorts were compared by means of Fisher's exact test for categorical variables and the Mann-Whitney rank sum test for continuous variables. We calculated AIDS-free survival and overall survival curves using Kaplan- Meier methods, and assessed the statistical significance of the difference in survival between the two cohorts by the log rank test. Proportional hazards regression was used to assess the effect of age, CD4 cell count at entry, and decline of CD4 counts on AIDS incidence and survival. In survival analysis, subjects without an AIDS diagnosis or death reported to the National AIDS Registry were assumed to be AIDS-free and alive at the end of follow-up. Secondary analyses were also performed based on confirmed AIDS-free and survival times by censoring at the date of last confirmed contact on the National AIDS Registry or with the referring doctor. Results After excluding 109 subjects in 1990 who had been referred from two clinics which did not use the Centre for Immunology laboratory in 1994, the database search identified 214 eligible subjects from 1990 and 169 from 1994, of whom 193 and 153, respectively, could be traced for follow-up and were included in the analysis (Box 1). As shown in Box 1, 60% of subjects who were followed up during 1990-1993 progressed to AIDS and 38% died, compared with 37% who progressed to AIDS and 13% who died during follow-up between 1994-1997. This corresponds to a 43% decrease in AIDS and an 80% reduction in death. As shown in Box 2, the median age at entry of the 1994 cohort was older than in the 1990 cohort, but sex, CD4 cell count at entry and CD4 cell decline were similar. The median age and sex of excluded subjects who came from the two clinics which did not use the Centre for Immunology laboratory in 1994 (age 37.5 years, 96% male) were similar to those included in the 1990 cohort (age 35 years, 98% male). Box 3 shows that progression to AIDS was slower and survival longer in the 1994 cohort than in the 1990 cohort, and that the improvement in both indices appeared to emerge after about one year of follow-up. Adjustment for age, CD4 count and CD4 slope at entry did not materially affect the differences between the two cohorts in progression time to AIDS and survival (Box 4). There were 52 subjects for whom only one CD4 cell count was recorded and rate of CD4 cell decline could not be estimated. A sensitivity analysis excluding these subjects gave very similar results to those for the full cohort (relative risk of AIDS and death in the 1994 group, 0.51 [P = 0.02] and 0.21 [P < 0.01], respectively). When follow-up was censored at the date of last confirmed contact, there remained a 28% decrease in progression to AIDS (P = 0.04) and a 45% reduction in death (P = 0.021). Discussion In this study, progression to AIDS was nearly halved and deaths fell by 80% among people with HIV infection whose CD4 cell count fell below 200/µL in 1994 compared with the corresponding 1990 cohort. The difference between the two groups emerged after about one year of follow-up, which in the 1994 cohort corresponded roughly to the introduction of lamivudine in early 1995, followed by protease inhibitors later in the same year. Although other differences between the cohorts cannot be entirely ruled out, the most likely explanation for the improved outcomes is advances in treatment strategies for people with HIV, including combination antiretroviral therapies. The benefit of combination therapy and new antiretroviral agents has been demonstrated so far largely through randomised controlled trials.9 Only recently has information started to emerge of the effectiveness of new therapies in a community-wide setting. The results of this study concur with recent cohort studies overseas, where substantial decreases in AIDS and deaths have been identified in patients followed up after the introduction of combination therapies compared with those under follow-up in earlier times.10,11 Although information on antiretroviral treatment was unavailable for the individuals in our cohorts, recent evidence suggests a dramatic change in the use of antiretroviral therapies in Australia over the time in which the two cohorts reported in our study were followed up. HIV-infected participants in the Sydney Men and Sexual Health Study (a prospective study of homosexually active men in Sydney) increased their uptake of combination antiretroviral therapy from about 2% in 1993 to more than 70% in 1997.12 Our study relied on the National AIDS Registry, which is subject to both reporting delay and underreporting. It is believed that about 70% of HIV diagnoses are reported to the Registry within six months (the minimum reporting time available in this study) and that nearly 100% are reported within three years.13 It is possible that incomplete reporting of AIDS and AIDS-related deaths to the National AIDS Registry may have resulted in underestimates of AIDS incidence or mortality in the later cohort. Results were similar, however, when analyses were censored at the date of last contact, suggesting that underreporting to the Registry was not in fact an important source of bias. One other potential source of bias is that changes in the natural history of the HIV epidemic may have resulted in a lower proportion of rapid progressors in more recent years, so that patients with CD4 counts of 200/µL in 1990 progressed more rapidly than those in 1994.14 In our analysis, there was little difference between the cohorts in CD4 cell decline (Box 2), and survival analysis adjusted for this gave very similar results. Furthermore, a sensitivity analysis excluding those subjects with only a single CD4 cell count also did not significantly affect the results. This analysis was based on CD4 cell counts collected over two years (mid year before the index year to mid year after), and is robust enough to suggest that both cohorts were subject to similar rates of progression. As the subjects were identified at two different times, it is possible that there were unidentifiable differences between the cohorts that may have influenced the outcomes in this study. However, the possibility of bias was substantially reduced by identifying all subjects from the same laboratory. This study contributes evidence to suggest that the rate of progression of HIV disease has decreased in Australia at the same time as new, more potent combination antiretroviral treatments have become available. It would be useful to study similar cohorts in the future to monitor the evolving pattern of the epidemic at a population level. Acknowledgements The National Centre in HIV Epidemiology and Clinical Research is funded by the Commonwealth Department of Health and Family Services through the Australian National Council on AIDS and Related Diseases. The help of the following medical practitioners in study follow-up is gratefully acknowledged: B Anderson, P Brooke, K Brown, A Carr, B Donovan, N Doong, C Duncombe, W Genn, J Kidd, A Mackie, M McMurchie, A McNulty, R Penny, A Pethebridge, M Robertson. We also thank John Zaunders at the St Vincent's Hospital Centre for Immunology for assistance in identifying the study sample. References Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283-291. Hammer SM, Katzenstein DA, Hughes MD, et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4+ cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996; 335: 1081-1090. CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus loviride-zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997; 349: 1413-1421. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4+ cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337: 725-733. Centers for Disease Control. Conditions included in the 1993 AIDS surveillance case definition. MMWR Morb Mortal Wkly Rep 1992; 41: RR-17. Hoover DR, Rinaldo C, Yanhua H, et al. Long-term survival without clinical AIDS after CD4+ cell counts fall below 200 x 106/L. AIDS 1995; 9: 145-151. Tindall B, Swanson CE, Cooper DA. Development of AIDS in a cohort of HIV-seropositive homosexual men in Australia. Med J Aust 1990; 153: 260-265. SAS statistical software version 6.12. Carey, NC: SAS Institute Incorporated, 1994. HIV/AIDS Clinical Trials and Treatments Advisory Committee of the Australian National Council on AIDS and Related Diseases. Antiretroviral therapy for HIV infection: principles of use. Standard of care guidelines; October 1997. Sydney: HIV/AIDS Clinical Trials and Treatments Advisory Committee, 1997. Egger M, Hirschel B, Francioli P, et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. BMJ 1997; 315: 1194-1199. Palella F, Delaney K, Moorman A, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New Engl J Med 1998, 338: 853-860. National Centre in HIV Epidemiology and Clinical Research. HIV/AIDS and related diseases in Australia: Annual Surveillance Report 1998. Sydney: National Centre in HIV Epidemiology and Clinical Research, 1998. National Centre in HIV Epidemiology and Clinical Research. An epidemiological assessment of the HIV epidemic in Australia. Evaluation of the National HIV/AIDS Strategy 1993-1994 to 1995-1996. Canberra: Commonwealth Department of Health and Family Services, 1996. Ioannidis JPA, Cappelleri JC, Schmid CH, Lau J. Impact of epidemic and individual heterogeneity on the population distribution of disease progression rates. Am J Epidemiol 1996; 144: 1074-1085. (Received 13 Jan, accepted 30 Apr, 1998) Authors' details National Centre in HIV Epidemiology and Clinical Research, Sydney, NSW. Patricia K Correll, BN, MPH, Research Assistant; Matthew G Law, MA, MSc, Statistician; Ann M McDonald, BSc, MPH, Senior Research Assistant; David A Cooper, DSc, MD, FRACP, Director; John M Kaldor, PhD, Deputy Director. Reprints will not be available from the authors. Correspondence: Patricia Correll, National Centre in HIV Epidemiology and Clinical Research, Level 2, 376 Victoria Street, Sydney, NSW 2010. Email: pcorrellATnchecr.unsw.edu.au - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. 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Patricia K Correll · Matthew G Law · Ann M McDonald · David A Cooper · John M Kaldor