Smoking and Tuberculosis among the Elderly in Hong Kong

Transcription

1 Smoking and Tuberculosis among the Elderly in Hong Kong Chi C. Leung, Teresa Li, Tai H. Lam, Wing W. Yew, Wing S. Law, Cheuk M. Tam, Wai M. Chan, Chi K. Chan, Kin S. Ho, and Kwok C. Chang TB and Chest Service; Elderly Health Service, Department of Health; Department of Community Medicine, The University of Hong Kong; and the TB and Chest Unit, Grantham Hospital, Hong Kong, China A cohort of 42,655 clients that were first registered with the Elderly Health Service in 2000 were followed prospectively through the tuberculosis (TB) notification registry until the end of A total of 286 active TB cases (186 culture confirmed) were identified. The annual TB notification rates were 735, 427, and 174 per 100,000 among current smokers, ex-smokers, and never-smokers, respectively (p 0.001). The trend in TB risk persisted after the control of background characteristics using Cox proportional hazards analysis (adjusted hazard ratios [HRs]: 2.63, 1.41, and 1, p 0.001). In comparison with never-smokers, current smokers had an excess risk of pulmonary TB (adjusted HR, 2.87; 95% confidence interval [CI], ; p 0.001), but not extrapulmonary TB (adjusted HR, 1.04; 95% CI, ; p 0.95). Among the current smokers, those who developed TB smoked more cigarettes per day than those who did not (13.43, SD 8.76 vs , SD 7.87, p 0.01). A statistically significant dose response relationship was observed with respect to active TB and culture-confirmed TB (both p 0.05). Smoking accounted for 32.8% (95% CI, %), 8.6% (95% CI, %), and 18.7% (95% CI, %) of the TB risk among males, females, and the entire cohort, respectively. Approximately 44.9% (95% CI, %) of the sex difference was attributable to smoking. Keywords: Chinese; elderly; notification; smoking; tuberculosis Although several studies have shown a relationship between smoking and tuberculosis (TB), many of them were based on infection (1 3) or mortality rate (4 7). Because of the diagnostic uncertainty related to latent TB infection and the rapidly reduced TB mortality after the introduction of effective treatment, it is not clear whether the association is causal. Although a few studies examined the relationship between smoking and the development of TB (8 13), they had various limitations such as the case-control or cross-sectional design, small sample size, and inadequacy in controlling confounders. A large longitudinal study that adequately controls for the main confounders and other background socioeconomic variables is required to clarify the ongoing controversy. In Hong Kong, smoking and TB are both common conditions. The prevalence of smoking is much higher in males than females (14). Over 20% of adult males are daily smokers (14). The annual TB notification rate is approximately 100 per 100,000 and is substantially higher in males and those aged over 65 years (15). The Elderly Health Service provides a health maintenance program through 18 elderly health centers situated in different parts of Hong Kong. Publicity and recruitment are directed at the elderly living in the community. Institutionalized people are (Received in original form April 18, 2004; accepted in final form July 27, 2004) Correspondence and requests for reprints should be sent to Chi Chiu Leung, M.B., F.C.C.P., Wanchai Chest Clinic, 99 Kennedy Road, Wanchai, Hong Kong, China. cc_leung@dh.gov.hk Am J Respir Crit Care Med Vol 170. pp , 2004 Originally Published in Press as DOI: /rccm OC on July 28, 2004 Internet address: not targeted. Enrollment is entirely voluntary with a small fee equivalent to U.S. $14, but the fee is waived for those on public financial assistance. For each client on first enrollment, a trained nurse administers a standardized questionnaire, which collects information on the Hong Kong identity card number, smoking history, sociodemographic situation, and health status. The key variables are entered into a structured database and are regularly checked for completeness. After the baseline health assessment, health education and individual counseling are given. Subsequently, clients may also attend the health centers for curative care and health education at any time. Patients with symptoms suspicious of TB are referred to the 18 chest clinics under a centralized TB and Chest Service of the Department of Health. In Hong Kong, medical practitioners are statutorily required to notify TB to the Department of Health. The notification database is held by the TB and Chest Service and has been computerized with the identity card number as the unique identifier. The high incidence of TB and the availability of appropriate service infrastructure provided a unique opportunity to examine prospectively the relationship between smoking and TB in Hong Kong. METHODS A cohort of clients who first enrolled at the 18 elderly health centers from January 1, 2000, to December 31, 2000, was retrospectively assembled. Information on the date of enrollment, name, sex, age, identity card number, smoking status, alcohol use, language spoken, education level, marital status, housing situation, working status, public financial assistance status, monthly expenditure, self-rated health status, hospital admissions during the past 12 months, and co-existing medical conditions was retrieved from the baseline health-assessment database of the Elderly Health Service. The data were entered into a Microsoft Excel spreadsheet. A never-smoker was defined as one who had never smoked as many as one cigarette a day or equivalent for the duration of 1 year. An ever-smoker was defined as one who had smoked at least one cigarette a day for at least 1 year. An ex-smoker was defined as an ever-smoker who had stopped smoking for at least 1 year. A current smoker was defined as an ever-smoker who was still smoking during the past year. A regular drinker and a social drinker were defined as one who drank on 4 or more days per week and on 3 or less days per week, respectively. An ex-drinker referred to a regular or social drinker who had stopped drinking. A never drinker was defined as one who had never been a regular or social drinker. The baseline database was exported into Epi-info (version 6) (CDC, Atlanta, GA) format and was cross-matched prospectively with the death registry and the TB notification registry from the time of enrollment to December 31, The vital status and the date of death were ascertained from the death registry. The duration of follow-up was defined as the period from enrollment to the date of notification of TB, death, or December 31, 2002, whichever was earlier. Information on date of TB notification, bacteriologic status, form of TB, and previous TB history was retrieved from the notification registry. The diagnosis and clinical information of all identified TB cases were verified by reviewing the medical records retrieved from the chest clinics and other relevant sources, as well as the public health records of the TB and Chest Service. An active case of TB was defined as disease proven by isolation of Mycobacterium tuberculosis, or in the absence of bacterio-

2 1028 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL logical confirmation, disease diagnosed on clinical, radiologic, and/or histologic grounds together with an appropriate response to anti-tb treatment. Univariate analysis was first performed to analyze the effect of baseline smoking status on active TB, culture-confirmed TB, and other TB-related outcomes, as well as the relationships between smoking and other potentially confounding variables. Chi-square and Fisher exact tests were used as appropriate for categoric variables, and analysis of variance was used for numerical variables. Cox proportional hazards analysis (SPSS version 10) was then used to control for all the confounding baseline variables by the enter method. A two-tailed p value of less than 0.05 was taken as statistically significant. The risk of TB attributable to smoking within the cohort was derived by applying the adjusted hazard ratios (HR) to a modified version of the Levin formula (16): Population attributable risk (observed rate unexposed rate)/observed rate 1 (unexposed rate/observed rate) 1 [(N 1 N 2 N 3 ) 1/(N 1 HR 13 N 2 HR 23 N 3 1)], where N 1,N 2,N 3 were the number of current smokers, ex-smokers, and never-smokers, respectively, and HR 13 and HR 23 were the adjusted HRs of current smokers versus never-smokers and ex-smokers versus neversmokers, respectively. Never-smokers were used as the reference group withahrof1. RESULTS A total of 42,659 clients aged 65 years or more were recruited into the health maintenance program of the Elderly Health Service in Smoking history was absent in four, and they were therefore excluded, leaving 42,655 subjects in the cohort. The background characteristics of the cohort are shown in Table 1. The data were over 99.9% complete for the variables listed. There were 2,830 current smokers (19.1%), 6,377 ex-smokers (43.0%), and 5,634 never-smokers (38.0%) among the males, and the corresponding figures for females were 1,036 (3.7%), 2,244 (8.1%), and 24,534 (88.2%). The mean age at enrollment was (mean SD) years, and ex-smokers were slightly older than the other two groups. Almost all ( 98%) of the three groups were ethnically Chinese speaking Cantonese. Significant differences were found among the three groups with respect to sex, language, marital status, housing situation, education level, working status, public assistance, monthly expenditure, participation in social activities in elderly/social centers, alcohol use, self-rated health, admission within past 1 year, and diabetes mellitus, chronic obstructive pulmonary disease, hypertension, heart disease, and cerebrovascular disease (all p 0.05). A total of 1,357 deaths were identified from the death registries. The mean duration of follow-up from the day of enrollment to death or December 31, 2002, was (mean SD) days overall and , , and for current smokers, ex-smokers, and never-smokers, respectively (F 58.8, p 0.001). A total of 299 new TB notifications were identified from the TB notification registry during the period of follow-up, excluding all prevalent cases (26 males and 17 females) known to be suffering from TB at time of enrollment. Thirteen cases (two cases of carcinoma of lung, eight cases of nontuberculous mycobacterial infection, three cases of old lung scars) were found to have incorrect diagnosis after reviewing the records, leaving for analysis 286 cases of active TB, 186 (65.0%) of which were culture confirmed. A higher proportion of culture-confirmed TB cases was found among ever-smokers (current and ex-smokers) than never-smokers (70.1% vs. 58.9%, p 0.05). Of the 286 active TB cases, 252 (88.1%) and 42 (14.7%) involved the lung (pulmonary) and sites other than the lung (extrapulmonary), respectively, including eight cases with both pulmonary and extrapulmonary involvement. Pulmonary involvement was more prevalent among ever-smokers than never-smokers (92.4% vs. 82.9%, p 0.01), and the reverse was true for extrapulmonary involvement (9.6% vs. 20.9%, p 0.01). Of 232 patients consenting to voluntary human immunodeficiency virus testing, only 1 patient (0.43%) was found to be human immunodeficiency virus infected. Significantly more current smokers developed TB and subsequently died (from any causes) within the follow-up period than ex-smokers and never-smokers (p 0.001), although only 9 of the 37 deaths (24.3%) could be attributed directly to TB. The univariate odds ratios for the TB-related outcomes are as shown in Table 2. Table 3 summarizes the results for active TB and culture-confirmed TB after stratification by alcohol use among the males. The mean time interval from enrollment to notification of TB was (mean SD) days overall and , , and days for current smokers, ex-smokers, and never-smokers, respectively (F 1.80, p 0.17). The annual active TB rates were 274 per 100,000 overall and 735, 427, and 174 per 100,000 for the three groups, respectively (p 0.001). The corresponding rates for males were 486 (overall), 876, 506, and 275 per 100,000, whereas those for females were 163 (overall), 357, 202, and 151 per 100,000 (both p 0.001). Figure 1 shows the cumulative hazards for active TB with respect to baseline smoking status after adjustment for potentially confounding variables. Table 4 shows significant trends of adjusted HRs for all TB-related outcomes among current smokers, ex-smokers, and never-smokers, the only exception being extrapulmonary involvement. Among the current smokers, the mean number of cigarettes smoked per day was (SD) overall and and , respectively, for those who developed active TB and those who did not (F 6.52, p 0.01). There was a statistically significant trend in the risk of TB with increasing number of cigarettes smoked for both active TB and cultureconfirmed cases (both p 0.05) (Table 5). Such a dose response relationship persisted even after adjusting for the same confounding variables. On applying the derived HRs to the cohort, 32.8% (95% confidence interval [CI], %), 8.6% (95% CI, %), and 18.7% (95% CI, %) of the active TB cases were attributable to ever-smoking among males, females, and the overall cohort, respectively. By multiplying the annual active TB rates of 486/100,000 for males and 163/100,000 for females in this cohort by one minus the corresponding attributable risk, the baseline rates in the absence of smoking were 327/100,000 and 149/100,000, respectively. The sex difference was reduced from 323/100,000 to 178/100,000. Smoking therefore accounted for 145 of the 323 excess male cases per 100,000 person-years or 44.9% (95% CI, %) of the observed sex difference. DISCUSSION According the 2001 census (17), there were 747,052 persons (including those institutionalized) aged 65 years or older in Hong Kong. This cohort therefore constituted 5.7% of the elderly subjects locally. As the Elderly Health Centers reached their maximum capacity within the first few years of operation, those who enrolled early were likely to represent the more healthconscious sector of the elderly population. The proportion of males was only 34.8%, significantly lower than the corresponding figure of 46.2% in the 2001 census (17). Selection factors, especially those related to the Inverse Care Law (18), might have been at work. Elders with the highest morbidity and most in need of care might be least likely to come forward for the health

3 Leung, Li, Lam, et al.: Smoking and TB in Hong Kong 1029 TABLE 1. BACKGROUND CHARACTERISTICS OF THE COHORT BY BASELINE SMOKING STATUS Current Ex-smoker Never Variable (n 3,866) (n 8,621) (n 30,168) Overall p Value Male sex, % Age, yr Language, % Cantonese Mandarin Other Chinese Other Marital, % Never Married Widow/divorced/other Housing, % Public Privately rented Privately owned Other Education, % Postsecondary Secondary Primary No formal Illiterate Working full/part-time, % On public assistance, % Monthly expenditure HK $2,000, % Participate in social activities in centers Alcohol, % Regular Social Ex-drinker Never Self-rated health, % Better than others Normal Worse than others Admission within 1 year, % Diabetes mellitus, % Chronic obstructive pulmonary disease, % Hypertension, % Heart, % Cerebrovascular disease, % Definition of abbreviation: HK Hong Kong. maintenance program. Despite these, the smoking prevalence and TB incidence in both sexes were fairly representative of the population. In this study, 19.1% of males and 3.7% of females were current smokers, whereas a territory-wide General Household Survey reported 21.8% and 4.9% of current daily smokers among males and females aged 60 years or more, respectively, in 2000 (14). High TB notification rates of 274 (overall), 486 (males), and 163 (females) per 100,000 were reported in this cohort. These were comparable to the reported population agespecific notification rates of 342 (overall), 552 (males), and 145 (females) per 100,000 for those aged 70 to 74 in 2000 (19). As we examined the differences between subgroups in this cohort, there should be good internal validity. Both current smokers and ex-smokers were found to have a higher risk of TB than never-smokers. As smokers were more likely to have smoking-related symptoms, it could be argued that these symptoms might have motivated them to seek healthcare, thereby resulting in incidental diagnosis of TB. However, the association between smoking and TB persisted even when only culture-confirmed cases were considered. Indeed, the adjusted HRs were substantially higher. It might also be argued that symptomatic patients were more likely to join the elderly health program and that this might have caused a spurious association between smoking and TB. However, the association persisted even if cases notified less than 3 months after enrollment were excluded. Although a moderate degree of association between smoking and TB has been reported by various studies, controversy remains as to whether this reflects just the conglomerate effects of various background variables associated with both conditions. In this study, there were substantial differences in the background variables across the three smoking categories. Alcohol use is a well-known confounder (20, 21). However, as shown in Table 3, a statistically significant increase in TB risk persisted even after stratification by alcohol use. The odds ratios were relatively consistent, even though some of the p values failed to reach statistical significance, especially among those categories with fewer patients. The result of voluntary human immunodeficiency virus testing was comparable to the figure of 0.37% reported by unlinked anonymous urinary testing for TB patients of all age in 2001 (22). With such low prevalence, human immunodeficiency virus infection was not likely to be an important confounding factor. After controlling for all of the studied variables, the increased risk among current smokers and ex-smokers

4 1030 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 2. UNIVARIATE ANALYSIS OF TB-RELATED OUTCOMES BY SMOKING STATUS Ex-smokers Current Smokers Outcomes Sex OR 95% CI p Value OR 95% CI p Value Active TB Male Female Culture-confirmed TB Male Female TB 3 mo after enrollment* Male Female Culture-confirmed TB 3 mo* Male Female New TB Male Female Retreatment TB Male Female NA NA Pulmonary TB Male Female Extrapulmonary TB Male Female Extrapulmonary TB only Male Female TB followed by death Male Female NA NA 1.00 Definition of abbreviations: CI confidence interval; NA not applicable; OR odds ratio; TB tuberculosis. * Notified over 3 months after enrollment. Without past history of anti-tb treatment. With or without pulmonary involvement. Developed TB and died from any cause within the period of follow-up. Two-sided Fisher s exact test. persisted for all TB-related outcomes with the only exception of extrapulmonary involvement (Table 4). Although substantial mortality was seen among this study cohort, only a minority of the deaths were associated with TB before or at time of death (Table 2). With the availability of effective chemotherapy, it is much less likely for TB to result in death. Indeed, in this study, only a very small proportion of deaths was directly attributable to TB. Such a low proportion may seriously limit the role of mortality studies in quantifying the risk within this locality. In a previous mortality study by Lam and colleagues in Hong Kong (5), the adjusted risk ratios for respiratory TB deaths (ever-smokers versus never-smokers) were only 1.63 (95% CI, ) for men aged 70 years or more and 1.03 (95% CI, ) for women aged 70 years or more, which were substantially lower than those reported in this study. Undernotification is always a concern for all notifiable diseases (23). In a local audit of TB notifications by reviewing discharge code and microbiological or hospital reports, the undernotification rates were found to be 3.0%, 27.6%, and 31.4% for TABLE 3. STRATIFIED ANALYSIS OF ACTIVE TUBERCULOSIS AND CULTURE-CONFIRMED TUBERCULOSIS BY SMOKING STATUS AFTER STRATIFICATION BY ALCOHOL USE AMONG THE MALES Outcomes TB Cases Ex-smokers Current Smokers Alcohol Use (% ) OR 95% CI p Value OR 95% CI p Value Active TB Regular 13 (1.0) Social 34 (1.0) Ex-drinker 42 (1.5) Never 86 (1.2) Combined* 175 (1.2) Culture-confirmed TB Regular 10 (0.7) Social 23 (0.6) Ex-drinker 29 (1.1) Never 59 (0.8) Combined* 121 (0.8) For definition of abbreviations, see Table 2. * Mantel-Haenszel stratified analysis. Percentage within the alcohol use category. Two-sided Fisher s exact test.

5 Leung, Li, Lam, et al.: Smoking and TB in Hong Kong 1031 Figure 1. Cumulative hazards for active tuberculosis (TB) with respect to baseline smoking status after adjustment for potentially confounding variables by Cox proportional hazards analysis. Wald statistic 31.58, p chest clinics, chest hospitals, and general hospitals, respectively, in 1995 (24). In response to these findings, major improvements had been made, including specially assigned infection control nurses in hospitals, reminders for notification, cross-matching of positive TB cultures with the notification registry, as well as counterchecking of TB treatment cases in chest clinics, and TBrelated deaths in the death registries. Notifications from sources other than chest clinics increased drastically from 1,918 cases in 1995 to 3,354 cases in 1998, whereas those from chest clinics stayed at slightly over 4,000 cases per year (25). The overall notification rate also increased from 101 per 100,000 in 1995 to 116 per 100,000 in 1998 (25). These likely reflected the consequential improvement in the notification, as demonstrated in a previous study in two London hospitals (26, 27). As this cohort was already under the care of a service in the Department of Health and had ready access to the chest clinics in the same department for free TB treatment, it would be reasonable to expect a fairly complete notification. In this study, data on changes in smoking habit within the period of follow-up were not available. However, a relatively large cohort has been assembled to minimize the period of follow-up required to detect a significant difference in TB rates. Even if information on such changes was systematically collected, it would be exceedingly difficult to delineate whether they represented cause or effect. A relatively long cessation period of up to 1 year was employed to distinguish between current smokers and ex-smokers, and this should have minimized the short-term fluctuations associated with abortive smoking cessation attempts. It was only possible to study the dose response relationship among current smokers, as details of the smoking patterns among the ex-smokers were not available in sufficient details. It was also not possible to study the effect of duration of smoking, as this was not included as a data field in the computerized database. Furthermore, such information was missing in a substantial proportion of the hard copies of the questionnaires. However, it should be noted that cumulative doses of cigarettes smoked in terms of pack-years may not necessarily reflect the current risk, as ex-smokers were found to have lower risk than current smokers. Smoking habits may change substantially with time. Accurate data on cumulative doses of cigarettes are relatively difficult to obtain. The number of cigarettes smoked currently is probably least subject to recall bias among the elderly, some of whom may have impaired memory. The association of smoking with the pulmonary, but not the extrapulmonary, form of TB is an interesting finding, which was also reported in a case-control study involving 851 TB patients (28). It might be postulated that smoking is associated with increased exposure to TB, not increased susceptibility. However, this cohort involves an ambulatory group of the elderly within the general community, and the majority of TB cases in Hong Kong appear to arise from reactivation (29). An alternative explanation is the site-specific effect of an airborne insult. Tobacco smoke has been reported to have various effects on the lung in both animal and human studies (30 32). More specifically, smoking has been associated with changes in pulmonary macrophages (33) and lymphocytes (34), which play a major role in cellular immunity. Among smokers, TB appears to cause more aggressive lung lesions, especially in the upper zones of the lung (28). Although these observations lend support to the airborne insult hypothesis, the exact underlying mechanism has yet to be elucidated. TABLE 4. ADJUSTED HAZARD RATIOS OF TUBERCULOSIS-RELATED OUTCOMES BY SMOKING STATUS IN COX PROPORTIONAL HAZARDS ANALYSIS Ex-smokers Current Smokers p Value Outcome HR* 95% CI HR* 95% CI p Value for Trend Active TB Culture-confirmed TB TB 3 mo Culture-confirmed TB 3 mo New TB Retreatment TB cases Pulmonary TB Extrapulmonary TB Extrapulmonary TB only Definition of abbreviations: CI confidence interval; HR hazard ratio; TB tuberculosis. * Adjusted hazard ratio, adjusted for sex, age, alcohol use, language, marital status, education, housing, working status, public financial assistance status, monthly expenditure, participation in social activities, self-rated health status, hospital admission within 12 months, diabetes mellitus, chronic obstructive pulmonary disease, hypertension, heart disease, and cerebrovascular disease, with categories as listed in Table 1.

6 1032 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 5. THE DISTRIBUTION OF ACTIVE TUBERCULOSIS AND CULTURE-CONFIRMED TB AMONG CURRENT SMOKERS BY NUMBER OF CIGARETTES PER DAY Number of Cigarettes Number Active TB Cultureconfirmed TB per Day in Cohort n (% ) HR* n (% ) HR* (0.8) (0.3) (1.2) (1.0) (1.9) (1.3) (2.6) (1.6) 5.32 p Definition of abbreviations: HR hazard ratio; TB tuberculosis. * Adjusted hazard ratio, adjusted for sex, age, alcohol use, language, marital status, education, housing, working status, public financial assistance status, monthly expenditure, participation in social activities, self-rated health status, hospital admission within 12 months, diabetes mellitus, chronic obstructive pulmonary disease, hypertension, heart disease, and cerebrovascular disease, with categories as listed in Table 1. Probability for chi square for trend across categories of numbers of cigarettes smoked per day. A clear relationship between smoking and TB has been demonstrated among a cohort of the elderly within the general community in this longitudinal study. A consistent trend of risk was found among never-smokers, ex-smokers, and current smokers. A clear dose response relationship has been shown between the number of cigarettes currently smoked and the subsequent risk of TB. The findings are also in line with studies published elsewhere (35). With the strength of evidence available, it can be concluded that the relationship between smoking and TB is likely to be causal. Smoking accounted for as much as 44.9% of the sex-related difference in TB rates in this cohort. A major contribution from smoking has also been reported in a cross-sectional study in Shanghai, China (11). The increasing prevalence of smoking among the female population in the Asia-Pacific region is most alarming (36), as this may further increase the very high TB prevalence and aggravate the social inequality in many countries of the region. In China, the interaction between smoking and the huge pool of infected individuals in an aging population is a serious concern. Directly observed therapy is relatively powerless in tackling the continuing endogenous reactivation, despite its effectiveness in reducing the risk of ongoing transmission. If we take into account the time, costs, and complications involved in directly observed therapy and treatment of latent TB infection and if smoking is indeed a causal factor for TB, tobacco control should be included as an important and urgent armament in the battle against TB. Apart from the primary preventive measures directed at the younger generation, smokers, including elderly smokers, should be strongly advised to quit. As shown in this study, cessation of smoking can reduce their risk of developing TB almost by half, in addition to many other benefits. Conflict of Interest Statement : C.C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.H.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; W.W.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; W.S.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.M.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; W.M.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.K.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.S.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.C.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. References 1. Plant AJ, Watkins RE, Gushulak B, O Rourke T, Jones W, Streeton J, Sang D. Predictors of tuberculin reactivity among prospective Vietnamese migrants: the effect of smoking. Epidemiol Infect 2002;128: Solsona J, Cayla JA, Nadal J, Bedia M, Mata C, Brau J, Maldonado J, Mila C, Alcaide J, Altet N, et al. Screening for tuberculosis upon admission to shelters and free-meal services. Eur J Epidemiol 2001;17: Anderson RH, Sy FS, Thompson S, Addy C. Cigarette smoking and tuberculin skin test conversion among incarcerated adults. Am J Prev Med 1997;13: Liu BQ, Peto R, Chen ZM, Boreham J, Wu YP, Li JY, Campbell TC, Chen JS. Emerging tobacco hazards in China: 1: retrospective proportional mortality study of one million deaths. BMJ 1998;317: Lam TH, Ho SY, Hedley AJ, Mak KH, Peto R. Mortality and smoking in Hong Kong: case-control study of all adult deaths in BMJ 2001;323: Doll R, Peto R, Wheatley K, Gray R, Sutherland I. Mortality in relation to smoking: 40 years observations on male British doctors. BMJ 1994;309: Gajalakshmi V, Peto R, Kanaka TS, Jha P. Smoking and mortality from tuberculosis and other diseases in India: retrospective study of adult male deaths and controls. Lancet 2003;362: Kolappan C, Gopi PG. Tobacco smoking and pulmonary tuberculosis. Thorax 2002;57: Alcaide J, Altet MN, Plans P, Parron I, Folguera L, Salto E, Dominguez A, Pardell H, Salleras L. Cigarette smoking as a risk factor for tuberculosis in young adults: a case-control study. Tuber Lung Dis 1996; 77: Altet MN, Alcaide J, Plans P, Taberner JL, Salto E, Folguera LI, Salleras L. Passive smoking and risk of tuberculosis in children immediately following infection: a case-control study. Tuber Lung Dis 1996;77: Yu GP, Hsieh CC, Peng J. Risk factors associated with the prevalence of pulmonary tuberculosis among sanitary workers in Shanghai. Tubercle 1988;69: Hnizdo E, Murray J. Risk of pulmonary tuberculosis relative to silicosis and exposure to silica dust in South African gold miners. Occup Environ Med 1998;55: Buskin SE, Gale JL, Weiss NS, Nolan CM. Tuberculosis risk factors in adults in King County, Washington, 1988 through Am J Public Health 1994;84: Census and Statistics Department of Hong Kong. Pattern of cigarette smoking: thematic household report number 5. Census and Statistics Department of Hong Kong; p Hong Kong Tuberculosis and Chest Service. Annual report of the Tuberculosis and Chest Service (2002). The Department of Health of Hong Kong; Mausner JS, Kramer S. Epidemiology: an introductory text. Philadelphia: WB Saunders; p Census and Social Statistics Department of Hong Kong census: tab on CDROM. Census and Social Statistics Department of Hong Kong; Hart JL. The inverse care law. Lancet, 1971;1:7696, Hong Kong Tuberculosis and Chest Service. Annual report of the Tuberculosis and Chest Service (2000). The Department of Health of Hong Kong; Brown KE, Campbell AH. Tobacco, alcohol and tuberculosis. BrJDis Chest 1961;55: Lewis JG, Chamberlain DA. Alcohol consumption and smoking habits in male patients with pulmonary tuberculosis. Br J Prev Soc Med 1963; 17: Special Preventive Program. HIV surveillance report: 2001 update. Department of Health of Hong Kong; p Jenkinson D. Whooping cough: what proportion of cases is notified in an epidemic? BMJ 1983;287: Health Services Research Group of the Department of Community Medicine. The University of Hong Kong: services for the treatment of patients with tuberculosis in Hong Kong, final report to the project steering group. The University of Hong Kong; Hong Kong Tuberculosis and Chest Service. Annual report of the Tuber-

7 Leung, Li, Lam, et al.: Smoking and TB in Hong Kong 1033 culosis and Chest Service (1999). The Department of Health of Hong Kong; Sheldon CD, King K, Cock H, Wilkinson P, Barnes NC. Notification of tuberculosis: how many cases are never reported? Thorax 1992;47: Brown JS, Wells F, Duckworth G, Paul EA, Barnes NC. Improving notification rates for tuberculosis. BMJ 1995;310: Leung CC, Yew WW, Chan CK, Tam CM, Lam CW, Chang KC, Chau CH, Lau KS, Law WS. Smoking and tuberculosis in Hong Kong. Int J Tuberc Lung Dis 2003;7: Chan-Yeung M, Tam CM, Wong H, Leung CC, Wang J, Yew WW, Lam CW, Kam KM. Molecular and conventional epidemiology of tuberculosis in Hong Kong: a population-based prospective study. J Clin Microbiol 2003;41: Wurzel H, Yeh CC, Gairola C, Chow CK. Oxidative damage and antioxidant status in the lungs and bronchoalveolar lavage fluid of rats exposed chronically to cigarette smoke. J Biochem Toxicol 1995;10: Carnevali S, Petruzzelli S, Longoni B, Vanacore R, Barale R, Cipollini M, Scatena F, Paggiaro P, Celi A, Giuntini C. Cigarette smoke extract induces oxidative stress and apoptosis in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2003;284: Ludwig PW, Schwartz BA, Hoidal JR, Niewoehner DE. Cigarette smoking causes accumulation of polymorphonuclear leukocytes in alveolar septum. Am Rev Respir Dis 1985;13: Hocking WG, Golde DW. The pulmonary-alveolar macrophage (first of two parts). N Engl J Med 1979;301: Daniele RP, Dauber JH, Altose MD, Rowlands DT Jr, Gorenberg DJ. Lymphocyte studies in asymptomatic cigarette smokers: a comparison between lung and peripheral blood. Am Rev Respir Dis 1977;116: Maurya V, Vijayan VK, Shah A. Smoking and tuberculosis: an association overlooked. Int J Tuberc Lung Dis 2002;6: Mackay J, Amos A. Women and tobacco. Respirology 2003;8: