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Cigarette smoking as a risk factor for tuberculosis in young adults: A casecontrol study
Tubercle and Lung Disease (1996)77, 112-116 © 1996PearsonProfessionalLtd
Cigarette smoking as a risk factor for tuberculosis in young adults: a casecontrol study J. Alcaide*, M. N. Altet*, P. Plans*, I. Parr6n*, L1. Folguera*, E. Salt6*, A. Domfnguez*, H. Pardell*, L1. Salleras* *Direcci6 General de Salut P~blica, Departament de Sanitat l Seguretat Social, Generalitat de Catalunya; tCentre de Prevenci6 l Control de la Tuberculosi 'Dr. Ll. Sayd' ; ¢Folgueralab, S. A., Barcelona, Spain. S U M M A R Y. Setting: The association between smoking and pulmonary tuberculosis has not often been studied. Objective: To assess the influence of cigarette smoking on the development of active pulmonary tuberculosis in young people who were close contacts of new cases of smear-positive pulmonary tuberculosis. Design: A case-control study in which 46 'cases' (patients with active pulmonary tuberculosis: isolation of Mycobacterium tuberculosis or clinical and/or radiographic evidence of current pulmonary tuberculosis, with a positive tuberculin skin test) and 46 'controls' (persons with positive tuberculin reaction, negative bacteriological test and without clinical and/or radiological evidence of pulmonary tuberculosis) were included. Smoking habits were investigated by questionnaire. Univariate and multivariate analysis was performed, and odds ratio (OR) was adjusted for age, gender and socio-economic status. Results: Statistically significant differences were found in active smokers (occasional and daily smokers) (OR: 3.65; 95% CI, 1.46 and 9.21; P < 0.01), daily smokers (OR: 3.53; 95% CI, 1.34 and 9.26; P < 0.05), and individuals who were both passive and active smokers (OR: 5.10; 95% CI, 1.97 and 13.22; P < 0.01) and passive and daily smokers (OR: 5.59; 95% CI, 2.07 and 15.10; P < 0.001). There was a dose-response relationship between the n u m b e r of cigarettes smoked daily and the risk of active pulmonary tuberculosis. Conclusions: The data studied show that cigarette smoking is a risk factor for pulmonary tuberculosis in young people, with a dose-response relationship with the number of cigarettes consumed daily. R E S U M E. Cadre: L'assoeiation entre le tabagisme et la tuberculose pulmonaire n'a pas souvent 6t6 6tudide. Objet: Evaluer l'influence du tabagisme sur la progression d'une tuberculose pulmonaire active chez des sujets jeunes, contacts de nouveaux cas de tuberculose pulmonaire frottis positif. Schdma: Celui-ci eomprend l'6tude de eas et de leurs t6moins portant sur 46 cas (malades atteints d'une tuberculose pulmonaire active: Mycobacterium tuberculosis isol6 ou preuve clinique et/ou radiographique d'une tuberculose pulmonaire commune avec un test tuberculinique positif) et 46 t6moins (individus ayant une r6action tuberculinique positive, une culture n6gative et sans preuve clinique et/ou radiologique de tuberculose). Les habitudes de tabagisme 6talent 6tudi6es par questionnaire. Des analyses univari6es et multivari6es ont 6t6 effectu6es. L'odds ratio (OR) a dt6 ajust6 pour les facteurs ~ge, sexe et niveau socio-dconomique. Resultats: Des diff6rences statistiquement significatives out 6t6 trouvdes chez les fumeurs actifs (fumeurs occasionnels ou quotidiens) (OR 3,65; 95% IC 1,46 et 9,21; P < 0,01), les fumeurs quotidiens (OR 3,53; 95% IC 1,34 et 9,26; P < 0,05) et les individus qui 6talent ~ la lois des fumeurs passifs et actifs (OR 5,10; 95% IC 1,97 et 13,22; P < 0,01) et les fumeurs passifs et quotidiens (OR 5,59; 95% IC 2,07 et 15,10; P < 0,001). Il existait une relation dose-rdponse entre le nombre de cigarettes consomm6es chaque jour et le risque de tuberculose pulmonaire active. Conclusion: Les donn6es 6tudi6es montre que le tabagisme est un facteur de risque pour la tubereulose pulmonaire chez les jeunes gens, avee une relation dose-r~ponse assoei6e au nombre de cigarettes consomm6es chaque jour.
Correspondenceto: Dr J. Alcaide,Programade Prevenci6i Controlde la TubercuIosi,Direcci6Generalde Salut Pfblica, Departamentde Sanitat i SegttretatSocial,Travesserade les Corts 131-159,E-08028 Barcelona,Spain.Tel: +34-3-3391111;Fax: +34-3-4111114. Paper received15 February 1995. Final version accepted30 October 1995. 112
Smoking as a risk factor for TB 113
R E S U M E N . Marco de referencia: La asociaci6n entre tabaquismo y tuberculosis pulmonar no ha sido estudiada frecuentemente. Objetivo: Evaluar la influencia del tabaquismo en el desarrollo de la tuberculosis pulmonar activa en j6venes que han estado en estrecho contacto con pacientes que presentan tuberculosis pulmonar con baciloscopia positiva. M(todo: Un estudio de casos-control en el cual se incluyeron 46 'casos' (pacientes con tuberculosis pulmonar activa: identificaci6n de Mycobacterium tuberculosis o evidencia clinica y/o radioldgica de tuberculosis pulmonar con un test de tuberculina positivo) y 46 'controles' (personas con una reacci6n de tuberculina positiva, estudios bacteriol6gicos negativos y sin evidencia clinica y/o radioldgica de tuberculosis pulmonar). Las caracteristicas del tabaquismo fueron estudiadas mediante un cuestionario. Se efectu6 un amilisis mono y multiparam6trico. El 'Odds Ratio' (OR) fue ajustado segfn la edad, el sexo y el nivel socio-econ6mico. Resultados: Se observaron diferencias estadisticamente significativas entre los fumadores activos (fumadores ocasionales y cotidianos) (OR: 3,65; 95% IC, 1,46 y 9,21; P < 0,01), los fumadores cotidianos (OR: 3,53; 95% IC, 1,34 y 9,26; P < 0,05) y los individuos que eran tanto fumadores activos como pasivos (OR: 5,1; 95% IC, 1,97 y 13,22; P < 0,01) asi como con los fumadores pasivos y cotidianos (OR: 5,59; 95% IC, 2,07 y 15,1; P < 0,001). Se observ6 una relaci6n dosis-respuesta entre el nfimero de cigarrillos que la persona fumaba diariamente y el riesgo de tuberculosis pulmonar activa. Conclusiones: Los datos analizados demuestran que el tabaquismo constituye un factor de riesgo de tuberculosis pulmonar en los j6venes, con una relaci6n dosis-respuesta asociada al nfmero de cigarrillos fumados diariamente.
INTRODUCTION Tuberculosis is the world's main cause of infectious disease-related mortality, j The incidence of new cases of tuberculosis has increased in the majority of countries, due primarily to its association with the human immunodeficiency virus (HIV) epidemic, ~,2 but also to other conditions, such as migration, homelessness, poverty, addictions or inadequacy of health care resources. ~,3 There are a number of factors, environmental as well as constitutional, that alter individual response to tuberculous infection and favour the development of the disease. Although active smoking is one of the cited factors, ~ the association between smoking and pulmonary tuberculosis has been assessed in very few s t u d i e s Y A case-control survey was carried out to assess the association between tuberculosis and smoking in young people living with new cases of smear-positive pulmonary tuberculosis.
S U B J E C T S A N D METHODS Subjects included in this study ranged from 15 to 24 years of age and were randomly selected from close contacts of new cases of smear-positive pulmonary tuberculosis (index cases) diagnosed at the 'Centre de Prevenci6 i Control de la Tuberculosi' in Barcelona during 1992. A 'case' was a patient in whom Mycobacterium tuberculosis complex was isolated from bronchopulmonary specimens (sputum, bronchial washings or bronchoalveolar lavage). In the absence of a positive culture, a case was defined as a patient with clinical, radiological and epidemiological evidence of current pulmonary tuberculosis, and a positive tuberculin skin test reaction) A 'control' was a person with a positive reaction to tuberculin skin test, negative bacteriological test and no clinical or ra-
diographic evidence of current or previous pulmonary tuberculosis, exposed to index cases. 8 A period of less than one month between diagnosis of the index case and assessment of contacts was required. Exclusion criteria included tuberculin-negative persons, positive tuberculin reaction previously known, previous bacille Calmette Gu6rin (BCG) vaccination, previous chemoprophylaxis or antituberculosis medication, and immunocomproraised patients or patients with other associated conditions identified as risk factors for tuberculosis. All those participating in the study gave written informed consent and were subjected to identical diagnostic procedures, including tuberculin skin test screening following the World Health Organization (WHO)'s standard technique (two tuberculin units of PPD-RT 23 stabilized with Tween 80), chest X-ray, and sputum smear for acid-fast bacilli. A reaction of 5 m m or more was considered positive, in the absence of BCG vaccination; as has been demonstrated, in Catalonia, Spain, infection with environmental mycobacteria rather than M. tuberculosis is very low and does not interfere with the interpretation of the tuberculin skin test. 9,1° To obtain information on smoking habits, a special questionnaire based on the Antitobacco Action Plan 11 was administered. The interview was performed by a specially trained nurse who later repeated the interview to confirm the participants' responses. Smoking habit was classified using the definitions proposed by WHO. H Daily smoker (any person who smoked a tobacco product every day at the time of the survey), Occasional smoker (any person who smoked a tobacco product less than once a day). Both daily and occasional smokers were classified as Active smokers. Non-smoker: any person who did not smoke at all at the time of the study; however, to avoid any influence on the risk of progressing to active tuberculosis after infection we considered as a non-smoker any person that had not
114
Tubercle and Lung Disease
smoked in the 6 months before the index case was diagnosed. Passive smoker: a non-smoker exposed to the combustion products of tobacco smoked b y others. In addition, two conditions were taken into account: Active - daily or occasional - and Passive smoker (any person who smoked a tobacco product and who was also exposed to the combustion products of tobacco smoked by others at home and/or at work); Active (daily) and Passive smoker (any person who smoked a tobacco product every day and was also exposed to the combustion products of tobacco smoked by others at home and/ or at work). Occupation and socio-economic status were codified according to the National Occupational Classification, 12 in which groups I - I I I correspond to the most highly qualified occupations (professionals, directors, btlsinessmen, technicians, salesmen, etc.), groups I V - V to those in the hotel trade, housekeeping, agriculture, etc., and group VI to those who were not classified under any occupation, such as students, unemployed, retired, pensioner, etc. Urinary concentration of cotinine was determined by specific radioimmunoassay using the first urine sample of the morning, as an excellent correlation has been proved between this method and the assay of cotinine in 24-h urine specimens, 13 enabling distinction between non-smokers, active smokers and passive smokers. 84 Statistical analysis
The sample size was calculated given a prevalence of smoking in the population (Po) of 0.38, hypothetical relative risk (RR) of 4, alpha error of 0.05 and beta error of 0.10. Smoking was the study variable in relation to the risk of developing tuberculosis in infected persons. Age and gender were controlled variables; social class was investigated by relationship with tuberculosis and smoking. Smoking habits were classified as indicated above; the crude Odds ratio (OR) and the )~2 test were estimated by the Mantel-Haenszel method and the 95% Confidence Interval (CI) by Cornfield's method; Is the OR of each smoking habit was first adjusted for the joint effects of age, gender and socio-economic status by multiple logistic regression analysis. A multiple logistic regression model was then obtained, including in the analysis active and passive smoking, social class IV-V, Table 2.
age and gender. The etiologic fraction was calculated using the equation proposed by Schlesselman. is
RESULTS
A total of 46 cases and 46 controls (48 men and 44 women aged between 15 and 24 years) were included in the study (Table 1). More than 50% of each group were students. The mean age was 20.1 years among cases and 19.6 years among controls. Differences of these variables between cases and controls are not statistically significant, including social class IV-V, probably due to the small number of individuals in this group. Seventy-two percent of cases and 41% of controls were considered active smokers, whereas 76% of cases and 54% of controls were considered passive smokers. Cigarette smoking favoured the development of pulmonary tuberculosis in young infected adults who were in close contact with recently diagnosed cases of bacillary pulmonary tuberculosis. The crude OR (Table 2) was 3.6 (95% CI: 1.4-9.5) in active (daily plus occasional) smokers (P < 0.01), and has the highest value when the smoker is both active (daily) and passive (OR: 5.7; 95% CI:2 - 17.5; P < 0.001). The adjusted OR for age, gender and socio-economic status had statistically significant differences in active smokers (daily and occasional) (P < 0.01), and in daily smokers (P < 0.05). The crude OR of passive smokers (OR: 2.7; 95% CI:1.017.2) had statistically significant differences (P < 0.05), but become non-significant when adjusted (OR: 2.5;
Table 1. Comparison of demographic variables in a case-control study of smoking as a risk factor of pulmonary tuberculosis in young adults (15-24 yrs) Data
Cases n (%)
Controls n (%)
Total Gender: Men Women Social class: I-III IV-V VI Mean age (SD)
46 (100)
46 (100)
25 (54) 21 (46)
23 (50) 23 (50)
1.2 (0.5-2.9) 0.8 (0.3-2.1)
13 (28) 9 (20) 24 (52) 20.1 (3.4)
13 (88) 3 (7) 30 (65) 19.6 (3.1)
1.0 (-) 3.0 (0.8-17.7) 0.6 (0.2-1.5)
Cigarette smoking and risk of active pulmonary tuberculosis in young adults (15-24 yrs)
Smoking habit Active (daily and occasional) Active (daily) Passive Active and passive (daily and occasional) Active and passive (daily)
Cases n = 46 n (%)
Controls n = 46 n (%)
Crude odds ratio (95% CI)
Adjusted odds ratio* (95% CI)
33 (72)
19 (41)
3.6 (1.4-9.5)*
3.6 (1.5-2.2)*
28 (61)
17 (37)
3.4 (1.3-9.3) *
3.5 (1.3-9.3)*
35 (76) 26 (56)
25 (54) 9 (20)
2.7 (1.0-7.2)* 5.3 (1.9-15.2) ~
2.5 (1.0-6.2) 5.1 (2.0-13.2)-
23 (50)
8 (17)
5.7 (1.9-17.5) 8
5.6 (2.1-15.1) 8
*Adjusted for age, gender and socio-economic status by multiple logistic regression analysis *P < 0.05; *P < 0.01; 8p < 0.001.
Odds ratio (95% CI)
Smoking as a risk factor for TB Table 3. analyzed
Multiple logistic regression model for the variables
Variable
Odds Ratio (95% CI)
P value
Active smoking Passive smoking Social class IV-V Age Gender
3.8 2.5 3.1 0.9 0.9
< 0.01 N.S. N.S. N.S. N.S.
(1.5-9.8) (0.9-6.4) (0.6-15.4) (0.8-1.i) (0.4-2.4)
Table 4. Cigarette smoking and risk of active pulmonary tuberculosis in young adults according to cigarette consumption Cigarettes per day
Cases n = 46 n (%)
Controls n = 46 n (%)
Crude odds ratio (95% CI)
Adjusted odds ratio (95% CI)
0 1-20 > 20
13 (28) 21 (46) 12 (26)
27 (59) 15 (33) 4 (9)
1.0" 2.9 (1.0-8.3)* 6.2 (1.4-28.6)*
1.0" 3.0 (1.3-7.9)* 13.0 (2.3-73.8) *
• Reference group.; *P < 0.05; *P < 0.001.
Table 5. Mean (SD) urinary concentration of cotinine (ng/ml) in the study population according to cigarette consumption Cases Cigarettes per day
n
Controls ng/ml (SD)
1
None None, but passive smoker l to 20 > 20
9 21 12
Total
43
22
n
ng/ml (SD)
11
10.3 (6.3)
166 (95.4) 2263 (1903.4) 3233 (1773.5)
16 15 4
42.9 (50.5) 1814.8 (1170.9) 2965.0 (1906.2)
2076.0 q1981.1)
46
990.7 (1534.9)
95% CI: 1 -6.2). The association between smoking and the risk of becoming diseased when infected by M. tuberculosis increased when the person was both an active and passive smoker. The multiple logistic regression model (Table 3) showed that only active smoking was independently associated with pulmonary tuberculosis; the adjusted OR was 3.8 (95% CI: 1.5-9.8) for active smoking. There was a dose-response relationship between the number of cigarettes that the person smoked daily and the risk of active pulmonary tuberculosis (Table 4). The Etiological Fraction estimated in smokers was 0.48 (95% CI: 0.13-0.69). Urinary concentration of cotinine (ng/ml) was analyzed in 89 individuals; Table 5 shows the mean urinary concentration in relation to the number of cigarettes smoked daily.
DISCUSSION This study shows that cigarette smoking was associated with the development of active pulmonary tuberculosis in young adults in close contact with a person in whom the diagnosis of smear-positive pulmonary tuberculosis had recently been established. The strength of the association was even greater when the person was not only an active or daily smoker, but a passive smoker as well.
115
A dose-response relation with the number of cigarettes consumed was also observed. In the group of passive smokers, results were not statistically significant, probably because this study was designed to assess the effect of active smoking and the sample size was too small to analyze passive smoking. Active smoking was the only factor independently associated with the development of pulmonary disease when infected; in this group 48% of cases of pulmonary tuberculosis resulting from recent infection would have been associated with cigarette smoking. According to the present results, the effect of smoking on the risk of pulmonary tuberculosis amongst young adults (both daily and passive smokers) is similar to that experienced by children who are passive smokers, 16 since a five-fold increase as compared with controls has been shown in both groups. HIV and M. tuberculosis coinfection is currently considered the most important epidemiological risk factor for tuberculosis, particularly in the population segment of younger males using injecting drugs. 1'4'17 There are other factors that contribute to activation of latent foci of infection? ,4,18 While young women are those most commonly afflicted in developing countries with high p r e v a l e n c e r a t e s , 19 tuberculosis is mainly seen in adult males and in the elderly in industrialized countries. 4 Although age, gender and socio-economic status have not been associated independently with tuberculosis in this study, multiple logistic regression analysis was used to control the influence of these variables. Factors that tie in with man's habits probably exert an influence of the development of active tuberculosis. Results of studies on the effect that active smoking has on the development of active M. tuberculosis disease are controversialy probably because of the interference of other factors, such as alcohol consumption, age or socioeconomic status. One study of public health workers in Shanghai 2° showed a relative risk of tuberculosis of 2.17 amongst smokers consuming 400 or more cigarettes per year independently of age, gender, contact with a patient with active tuberculosis, and type or place of work; it was found that the effect of age and gender was mainly associated with smoking. In residential homes for the elderly in Liverpool, Nisar and co-workers 2~ have shown that tobacco smoking was associated with an increase in the number of positive reactors to multiplepuncture PPD tuberculin test (Heaf test) and the male sex. However, smoking is a risk factor rarely recorded in the history of patients with tuberculosis, although Crofton et al ~s recognize it as a toxic factor capable of reducing host defence mechanisms. In Barcelona, 22 tobacco smoking was notified in 53.4% of tuberculosis cases, including cases in the paediatric age group. In Gran Canaria (Canary Islands), Caminero and associates 23 reported a figure of 56%. In a study of 3627 necropsiesy active tuberculosis was documented in 3.52% of cases, accompanied by other conditions (cardiovascular disorders, chronic obstructive pulmonary disease, alcohol-induced liver damage) frequently associated with smoking in 70% of these cases.
116 Tubercle and Lung Disease C i g a r e t t e s m o k i n g is a p r i n c i p a l c a u s e o f p r e v e n t a b l e diseases and premature death in industrialized nations, a n d t h e c h i e f c o n t r i b u t o r to c h r o n i c p u l m o n a r y d i s e a s e in adults. 2s-26 A h i g h e r i n c i d e n c e o f r e s p i r a t o r y m o r b i d i t y d u e to t o b a c c o s m o k i n g a m o n g s t s t u d e n t n u r s e s 27 a n d y o u n g adults 28 h a s also b e e n r e p o r t e d . S m o k e r s r o u t i n e l y present respiratory signs and symptoms, especially cough. On the other hand, 90% of patients with contagious tuberculosis had clinical symptoms, with coughing as o n e o f t h e m o s t f r e q u e n t m a n i f e s t a t i o n s a n d o f m a j o r e p i d e m i o l o g i c a l r e l e v a n c e . 18,26 C o u g h in h e a v y s m o k e r s c a n f r e q u e n t l y b e r e s p o n s i b l e for i m p o r t a n t d e l a y s in the diagnosis of tuberculosis. I n s u m m a r y , c i g a r e t t e s m o k i n g is a r i s k f a c t o r i n the development of pulmonary tuberculosis in young people, w i t h a d o s e - r e s p o n s e r e l a t i o n s h i p w i t h the n u m b e r o f c i g a r e t t e s c o n s u m e d daily. T h e r e s u l t s o f this s t u d y h o l d t h a t e f f e c t i v e a n t i - s m o k i n g c a m p a i g n s will h a v e positive repercussions on tuberculosis incidence.
Acknowledgement We thank Marta Pulido, MD, for the English translation and for editing the manuscript.
References 1. Centers for Disease Control and Prevention. Estimates of future global tuberculosis morbidity and mortality. JAMA 1994; 271: 739-740. 2. Such-eP, ten Dam G, Kochi A. Tuberculosis: a global overview of the situation today. Bull World Health Organ 1992; 70: 149-159. 3. Brudney K, Dobkin J. Resurgent tuberculosis in New York City. Human immnnodeficieney virus, homelessness, and the decline of tuberculosis control programs. Am Rev Respir Dis 1991; 144: 745-749. 4. Rieder H L, Cauthen G M, Comstock G W, Snider D E Jr. Epidemiology of tuberculosis in the United States. Epidemiol Rev 1989; 11: 79-98. 5. Lowe C R. An association between smoking and respiratory tuberculosis. BMJ 1956; 2: 1081-1083. 6. Adelstein A M, Rimington J. Smoking and pulmonary tuberculosis: analysis based on a study of volunteers for mass miniature radiography. Tubercle 1967; 48: 219-226. 7. Lewis J G, Chamberlain D A. Alcohol consumption and smoking habits in male patients with pulmonary tuberculosis. Br J Prev Soc Med 1963; 17: 149. 8. Grupo de Trabajo sobre Tuberculosis. Fondo de fuvestigaci6n Sanitaria (FIS) Ministerio de Sanidad y Consumo. Consenso nacional para el control de la Tuberculosis en Espafia. Med Clin (Barc) 1992; 98: 24-31.
9. Comit6 de Expertos en Tuberculosis. Informe. La Tuberculosis en Catalufia. Generalitat de Catalufia. Departamento de Sanidad y Seguridad Social. Barcelona 1983. pp 61-65. 10. Comit6 d'experts en tuberculosi a Catalunya. Gufa per a la prevenci6 i el control de la tuberculosi. Quaderns de Salut Pt~blica. Generalitat de Catalunya. Departament de Sanitat i Seguretet Social, Barcelona 1992. 11. WHO's Regional Committee for Europe. Europe against the cancer programme: the evaluation and monitoring of public action on tobacco. Smoke-fi'ee Europe 3. WHO Regional Office for Europe, Copenhagen, 1987. 12. Clasificaci6n nacional de ocupaciones. Instituto Nacional de Estadfstica, Madrid, 1987. 13. Roussel G, Le Quang N T, Migurres M L et al. Interprdtation des valeurs de la cotinurie chez les fumeurs et les non-fumeurs. Rev Mal Resp 1991; 8: 225-232. 14. Wall M A, Johnson J, Jacob P, Benowith N L. Cotinine in the serum, saliva and urine of nonsmokers, passive smokers and active smokers. Am J Public Health 1988; 78: 699-701. 15. Schlesselmann J J. Case-control studies. Design, conduct, analysis. New York: Oxford University Press, 1982: pp 220-222. 16. Altet N, Alcaide J, Lozano P, Plans P, Parr6n I, Salleras L1. Smoking as risk factor of tuberculosis in children and youth [abstract]. Tubercle Lung Dis 1994; 75 (Suppl 1): 68-69. 17. Barnes P F, Bloch A B, Davidson P T, Snider D E Jr. Tuber~:ulosis in patients with human immunodeficiency virus infection. N Engl J Med 1991; 324: 1644-1650. 18. Crofton J, Home N, Miller F. Clinical tuberculosis. Hong Kong: The MacMillan Press LTD, published in association with TALC and IUATLD, 1992. 19. Murray C J. Social, economic and operational research on tuberculosis: recent studies and some priority questions. Bull Int Union Tuberc Lung Dis 1991; 66(4): 149-156. 20. Yu G P, Hsieh C C, Peng J. Risk factors associated with the prevalence of pulmonary tuberculosis among sanitary workers in Shanghai. Tubercle 1988; 69:105-112. 21. Nisar M, Williams C S D, Ashby D, Davies P D O. Tuberculin testing in residential homes for the elderly. Thorax 1993; 48: 1257-1260. 22. Cayhl J A, Gald6s-Tangtiis H, Jansgt J M, Garc/a P, Diez E, Plasencia A. La tuberculosi a Barcelona. Informe 1992. Area de Salut Publica. Ajuntament de Barcelona, Barcelona, 1993. 23. Caminero J A, Dfaz F, Rodrfguez de Castro F et al. Epidemiologfa de la enfermedad tuberculosa en la isla de Gran Canaria. Med Clin (Barc) 1991; 97: 8-13. 24. Mallofr6 C, Bomb/J A, Palacfn A, Cardesa A. Tuberculosis en Espafia. Estudio necr6psico. Med Clin (Barc) 1988; 90: 735-738. 25. Reducing the health consequences of smoking: 25 years of progress. A report of the Surgeon General, 1989. US Department of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health, DHSS Publication No (CDC) 89-8411, 1989. 26. Crofton J, Bjartveit K. Smoking as a risk factor for chronic airways disease. Bull fut Union Tuberc Lung Dis/Chest 1989; 64(4): 307S-312S. 27. Schwartz J, Zeger A. Passive smoking, air pollution, and acute respiratory symptoms in a diary study of student nurses. Am Rev Respir Dis 1990; 141: 62-67. 28. Godden D J, Ross S, Abdalla M et al. Outcome of wheeze in childhood. Symptoms and pulmonary function 25 years later. Am J Respir Crit Care Med 1994; 149: 106-112.
Cigarette smoking as a risk factor for tuberculosis in young adults: a casecontrol study J. Alcaide*, M. N. Altet*, P. Plans*, I. Parr6n*, L1. Folguera*, E. Salt6*, A. Domfnguez*, H. Pardell*, L1. Salleras* *Direcci6 General de Salut P~blica, Departament de Sanitat l Seguretat Social, Generalitat de Catalunya; tCentre de Prevenci6 l Control de la Tuberculosi 'Dr. Ll. Sayd' ; ¢Folgueralab, S. A., Barcelona, Spain. S U M M A R Y. Setting: The association between smoking and pulmonary tuberculosis has not often been studied. Objective: To assess the influence of cigarette smoking on the development of active pulmonary tuberculosis in young people who were close contacts of new cases of smear-positive pulmonary tuberculosis. Design: A case-control study in which 46 'cases' (patients with active pulmonary tuberculosis: isolation of Mycobacterium tuberculosis or clinical and/or radiographic evidence of current pulmonary tuberculosis, with a positive tuberculin skin test) and 46 'controls' (persons with positive tuberculin reaction, negative bacteriological test and without clinical and/or radiological evidence of pulmonary tuberculosis) were included. Smoking habits were investigated by questionnaire. Univariate and multivariate analysis was performed, and odds ratio (OR) was adjusted for age, gender and socio-economic status. Results: Statistically significant differences were found in active smokers (occasional and daily smokers) (OR: 3.65; 95% CI, 1.46 and 9.21; P < 0.01), daily smokers (OR: 3.53; 95% CI, 1.34 and 9.26; P < 0.05), and individuals who were both passive and active smokers (OR: 5.10; 95% CI, 1.97 and 13.22; P < 0.01) and passive and daily smokers (OR: 5.59; 95% CI, 2.07 and 15.10; P < 0.001). There was a dose-response relationship between the n u m b e r of cigarettes smoked daily and the risk of active pulmonary tuberculosis. Conclusions: The data studied show that cigarette smoking is a risk factor for pulmonary tuberculosis in young people, with a dose-response relationship with the number of cigarettes consumed daily. R E S U M E. Cadre: L'assoeiation entre le tabagisme et la tuberculose pulmonaire n'a pas souvent 6t6 6tudide. Objet: Evaluer l'influence du tabagisme sur la progression d'une tuberculose pulmonaire active chez des sujets jeunes, contacts de nouveaux cas de tuberculose pulmonaire frottis positif. Schdma: Celui-ci eomprend l'6tude de eas et de leurs t6moins portant sur 46 cas (malades atteints d'une tuberculose pulmonaire active: Mycobacterium tuberculosis isol6 ou preuve clinique et/ou radiographique d'une tuberculose pulmonaire commune avec un test tuberculinique positif) et 46 t6moins (individus ayant une r6action tuberculinique positive, une culture n6gative et sans preuve clinique et/ou radiologique de tuberculose). Les habitudes de tabagisme 6talent 6tudi6es par questionnaire. Des analyses univari6es et multivari6es ont 6t6 effectu6es. L'odds ratio (OR) a dt6 ajust6 pour les facteurs ~ge, sexe et niveau socio-dconomique. Resultats: Des diff6rences statistiquement significatives out 6t6 trouvdes chez les fumeurs actifs (fumeurs occasionnels ou quotidiens) (OR 3,65; 95% IC 1,46 et 9,21; P < 0,01), les fumeurs quotidiens (OR 3,53; 95% IC 1,34 et 9,26; P < 0,05) et les individus qui 6talent ~ la lois des fumeurs passifs et actifs (OR 5,10; 95% IC 1,97 et 13,22; P < 0,01) et les fumeurs passifs et quotidiens (OR 5,59; 95% IC 2,07 et 15,10; P < 0,001). Il existait une relation dose-rdponse entre le nombre de cigarettes consomm6es chaque jour et le risque de tuberculose pulmonaire active. Conclusion: Les donn6es 6tudi6es montre que le tabagisme est un facteur de risque pour la tubereulose pulmonaire chez les jeunes gens, avee une relation dose-r~ponse assoei6e au nombre de cigarettes consomm6es chaque jour.
Correspondenceto: Dr J. Alcaide,Programade Prevenci6i Controlde la TubercuIosi,Direcci6Generalde Salut Pfblica, Departamentde Sanitat i SegttretatSocial,Travesserade les Corts 131-159,E-08028 Barcelona,Spain.Tel: +34-3-3391111;Fax: +34-3-4111114. Paper received15 February 1995. Final version accepted30 October 1995. 112
Smoking as a risk factor for TB 113
R E S U M E N . Marco de referencia: La asociaci6n entre tabaquismo y tuberculosis pulmonar no ha sido estudiada frecuentemente. Objetivo: Evaluar la influencia del tabaquismo en el desarrollo de la tuberculosis pulmonar activa en j6venes que han estado en estrecho contacto con pacientes que presentan tuberculosis pulmonar con baciloscopia positiva. M(todo: Un estudio de casos-control en el cual se incluyeron 46 'casos' (pacientes con tuberculosis pulmonar activa: identificaci6n de Mycobacterium tuberculosis o evidencia clinica y/o radioldgica de tuberculosis pulmonar con un test de tuberculina positivo) y 46 'controles' (personas con una reacci6n de tuberculina positiva, estudios bacteriol6gicos negativos y sin evidencia clinica y/o radioldgica de tuberculosis pulmonar). Las caracteristicas del tabaquismo fueron estudiadas mediante un cuestionario. Se efectu6 un amilisis mono y multiparam6trico. El 'Odds Ratio' (OR) fue ajustado segfn la edad, el sexo y el nivel socio-econ6mico. Resultados: Se observaron diferencias estadisticamente significativas entre los fumadores activos (fumadores ocasionales y cotidianos) (OR: 3,65; 95% IC, 1,46 y 9,21; P < 0,01), los fumadores cotidianos (OR: 3,53; 95% IC, 1,34 y 9,26; P < 0,05) y los individuos que eran tanto fumadores activos como pasivos (OR: 5,1; 95% IC, 1,97 y 13,22; P < 0,01) asi como con los fumadores pasivos y cotidianos (OR: 5,59; 95% IC, 2,07 y 15,1; P < 0,001). Se observ6 una relaci6n dosis-respuesta entre el nfimero de cigarrillos que la persona fumaba diariamente y el riesgo de tuberculosis pulmonar activa. Conclusiones: Los datos analizados demuestran que el tabaquismo constituye un factor de riesgo de tuberculosis pulmonar en los j6venes, con una relaci6n dosis-respuesta asociada al nfmero de cigarrillos fumados diariamente.
INTRODUCTION Tuberculosis is the world's main cause of infectious disease-related mortality, j The incidence of new cases of tuberculosis has increased in the majority of countries, due primarily to its association with the human immunodeficiency virus (HIV) epidemic, ~,2 but also to other conditions, such as migration, homelessness, poverty, addictions or inadequacy of health care resources. ~,3 There are a number of factors, environmental as well as constitutional, that alter individual response to tuberculous infection and favour the development of the disease. Although active smoking is one of the cited factors, ~ the association between smoking and pulmonary tuberculosis has been assessed in very few s t u d i e s Y A case-control survey was carried out to assess the association between tuberculosis and smoking in young people living with new cases of smear-positive pulmonary tuberculosis.
S U B J E C T S A N D METHODS Subjects included in this study ranged from 15 to 24 years of age and were randomly selected from close contacts of new cases of smear-positive pulmonary tuberculosis (index cases) diagnosed at the 'Centre de Prevenci6 i Control de la Tuberculosi' in Barcelona during 1992. A 'case' was a patient in whom Mycobacterium tuberculosis complex was isolated from bronchopulmonary specimens (sputum, bronchial washings or bronchoalveolar lavage). In the absence of a positive culture, a case was defined as a patient with clinical, radiological and epidemiological evidence of current pulmonary tuberculosis, and a positive tuberculin skin test reaction) A 'control' was a person with a positive reaction to tuberculin skin test, negative bacteriological test and no clinical or ra-
diographic evidence of current or previous pulmonary tuberculosis, exposed to index cases. 8 A period of less than one month between diagnosis of the index case and assessment of contacts was required. Exclusion criteria included tuberculin-negative persons, positive tuberculin reaction previously known, previous bacille Calmette Gu6rin (BCG) vaccination, previous chemoprophylaxis or antituberculosis medication, and immunocomproraised patients or patients with other associated conditions identified as risk factors for tuberculosis. All those participating in the study gave written informed consent and were subjected to identical diagnostic procedures, including tuberculin skin test screening following the World Health Organization (WHO)'s standard technique (two tuberculin units of PPD-RT 23 stabilized with Tween 80), chest X-ray, and sputum smear for acid-fast bacilli. A reaction of 5 m m or more was considered positive, in the absence of BCG vaccination; as has been demonstrated, in Catalonia, Spain, infection with environmental mycobacteria rather than M. tuberculosis is very low and does not interfere with the interpretation of the tuberculin skin test. 9,1° To obtain information on smoking habits, a special questionnaire based on the Antitobacco Action Plan 11 was administered. The interview was performed by a specially trained nurse who later repeated the interview to confirm the participants' responses. Smoking habit was classified using the definitions proposed by WHO. H Daily smoker (any person who smoked a tobacco product every day at the time of the survey), Occasional smoker (any person who smoked a tobacco product less than once a day). Both daily and occasional smokers were classified as Active smokers. Non-smoker: any person who did not smoke at all at the time of the study; however, to avoid any influence on the risk of progressing to active tuberculosis after infection we considered as a non-smoker any person that had not
114
Tubercle and Lung Disease
smoked in the 6 months before the index case was diagnosed. Passive smoker: a non-smoker exposed to the combustion products of tobacco smoked b y others. In addition, two conditions were taken into account: Active - daily or occasional - and Passive smoker (any person who smoked a tobacco product and who was also exposed to the combustion products of tobacco smoked by others at home and/or at work); Active (daily) and Passive smoker (any person who smoked a tobacco product every day and was also exposed to the combustion products of tobacco smoked by others at home and/ or at work). Occupation and socio-economic status were codified according to the National Occupational Classification, 12 in which groups I - I I I correspond to the most highly qualified occupations (professionals, directors, btlsinessmen, technicians, salesmen, etc.), groups I V - V to those in the hotel trade, housekeeping, agriculture, etc., and group VI to those who were not classified under any occupation, such as students, unemployed, retired, pensioner, etc. Urinary concentration of cotinine was determined by specific radioimmunoassay using the first urine sample of the morning, as an excellent correlation has been proved between this method and the assay of cotinine in 24-h urine specimens, 13 enabling distinction between non-smokers, active smokers and passive smokers. 84 Statistical analysis
The sample size was calculated given a prevalence of smoking in the population (Po) of 0.38, hypothetical relative risk (RR) of 4, alpha error of 0.05 and beta error of 0.10. Smoking was the study variable in relation to the risk of developing tuberculosis in infected persons. Age and gender were controlled variables; social class was investigated by relationship with tuberculosis and smoking. Smoking habits were classified as indicated above; the crude Odds ratio (OR) and the )~2 test were estimated by the Mantel-Haenszel method and the 95% Confidence Interval (CI) by Cornfield's method; Is the OR of each smoking habit was first adjusted for the joint effects of age, gender and socio-economic status by multiple logistic regression analysis. A multiple logistic regression model was then obtained, including in the analysis active and passive smoking, social class IV-V, Table 2.
age and gender. The etiologic fraction was calculated using the equation proposed by Schlesselman. is
RESULTS
A total of 46 cases and 46 controls (48 men and 44 women aged between 15 and 24 years) were included in the study (Table 1). More than 50% of each group were students. The mean age was 20.1 years among cases and 19.6 years among controls. Differences of these variables between cases and controls are not statistically significant, including social class IV-V, probably due to the small number of individuals in this group. Seventy-two percent of cases and 41% of controls were considered active smokers, whereas 76% of cases and 54% of controls were considered passive smokers. Cigarette smoking favoured the development of pulmonary tuberculosis in young infected adults who were in close contact with recently diagnosed cases of bacillary pulmonary tuberculosis. The crude OR (Table 2) was 3.6 (95% CI: 1.4-9.5) in active (daily plus occasional) smokers (P < 0.01), and has the highest value when the smoker is both active (daily) and passive (OR: 5.7; 95% CI:2 - 17.5; P < 0.001). The adjusted OR for age, gender and socio-economic status had statistically significant differences in active smokers (daily and occasional) (P < 0.01), and in daily smokers (P < 0.05). The crude OR of passive smokers (OR: 2.7; 95% CI:1.017.2) had statistically significant differences (P < 0.05), but become non-significant when adjusted (OR: 2.5;
Table 1. Comparison of demographic variables in a case-control study of smoking as a risk factor of pulmonary tuberculosis in young adults (15-24 yrs) Data
Cases n (%)
Controls n (%)
Total Gender: Men Women Social class: I-III IV-V VI Mean age (SD)
46 (100)
46 (100)
25 (54) 21 (46)
23 (50) 23 (50)
1.2 (0.5-2.9) 0.8 (0.3-2.1)
13 (28) 9 (20) 24 (52) 20.1 (3.4)
13 (88) 3 (7) 30 (65) 19.6 (3.1)
1.0 (-) 3.0 (0.8-17.7) 0.6 (0.2-1.5)
Cigarette smoking and risk of active pulmonary tuberculosis in young adults (15-24 yrs)
Smoking habit Active (daily and occasional) Active (daily) Passive Active and passive (daily and occasional) Active and passive (daily)
Cases n = 46 n (%)
Controls n = 46 n (%)
Crude odds ratio (95% CI)
Adjusted odds ratio* (95% CI)
33 (72)
19 (41)
3.6 (1.4-9.5)*
3.6 (1.5-2.2)*
28 (61)
17 (37)
3.4 (1.3-9.3) *
3.5 (1.3-9.3)*
35 (76) 26 (56)
25 (54) 9 (20)
2.7 (1.0-7.2)* 5.3 (1.9-15.2) ~
2.5 (1.0-6.2) 5.1 (2.0-13.2)-
23 (50)
8 (17)
5.7 (1.9-17.5) 8
5.6 (2.1-15.1) 8
*Adjusted for age, gender and socio-economic status by multiple logistic regression analysis *P < 0.05; *P < 0.01; 8p < 0.001.
Odds ratio (95% CI)
Smoking as a risk factor for TB Table 3. analyzed
Multiple logistic regression model for the variables
Variable
Odds Ratio (95% CI)
P value
Active smoking Passive smoking Social class IV-V Age Gender
3.8 2.5 3.1 0.9 0.9
< 0.01 N.S. N.S. N.S. N.S.
(1.5-9.8) (0.9-6.4) (0.6-15.4) (0.8-1.i) (0.4-2.4)
Table 4. Cigarette smoking and risk of active pulmonary tuberculosis in young adults according to cigarette consumption Cigarettes per day
Cases n = 46 n (%)
Controls n = 46 n (%)
Crude odds ratio (95% CI)
Adjusted odds ratio (95% CI)
0 1-20 > 20
13 (28) 21 (46) 12 (26)
27 (59) 15 (33) 4 (9)
1.0" 2.9 (1.0-8.3)* 6.2 (1.4-28.6)*
1.0" 3.0 (1.3-7.9)* 13.0 (2.3-73.8) *
• Reference group.; *P < 0.05; *P < 0.001.
Table 5. Mean (SD) urinary concentration of cotinine (ng/ml) in the study population according to cigarette consumption Cases Cigarettes per day
n
Controls ng/ml (SD)
1
None None, but passive smoker l to 20 > 20
9 21 12
Total
43
22
n
ng/ml (SD)
11
10.3 (6.3)
166 (95.4) 2263 (1903.4) 3233 (1773.5)
16 15 4
42.9 (50.5) 1814.8 (1170.9) 2965.0 (1906.2)
2076.0 q1981.1)
46
990.7 (1534.9)
95% CI: 1 -6.2). The association between smoking and the risk of becoming diseased when infected by M. tuberculosis increased when the person was both an active and passive smoker. The multiple logistic regression model (Table 3) showed that only active smoking was independently associated with pulmonary tuberculosis; the adjusted OR was 3.8 (95% CI: 1.5-9.8) for active smoking. There was a dose-response relationship between the number of cigarettes that the person smoked daily and the risk of active pulmonary tuberculosis (Table 4). The Etiological Fraction estimated in smokers was 0.48 (95% CI: 0.13-0.69). Urinary concentration of cotinine (ng/ml) was analyzed in 89 individuals; Table 5 shows the mean urinary concentration in relation to the number of cigarettes smoked daily.
DISCUSSION This study shows that cigarette smoking was associated with the development of active pulmonary tuberculosis in young adults in close contact with a person in whom the diagnosis of smear-positive pulmonary tuberculosis had recently been established. The strength of the association was even greater when the person was not only an active or daily smoker, but a passive smoker as well.
115
A dose-response relation with the number of cigarettes consumed was also observed. In the group of passive smokers, results were not statistically significant, probably because this study was designed to assess the effect of active smoking and the sample size was too small to analyze passive smoking. Active smoking was the only factor independently associated with the development of pulmonary disease when infected; in this group 48% of cases of pulmonary tuberculosis resulting from recent infection would have been associated with cigarette smoking. According to the present results, the effect of smoking on the risk of pulmonary tuberculosis amongst young adults (both daily and passive smokers) is similar to that experienced by children who are passive smokers, 16 since a five-fold increase as compared with controls has been shown in both groups. HIV and M. tuberculosis coinfection is currently considered the most important epidemiological risk factor for tuberculosis, particularly in the population segment of younger males using injecting drugs. 1'4'17 There are other factors that contribute to activation of latent foci of infection? ,4,18 While young women are those most commonly afflicted in developing countries with high p r e v a l e n c e r a t e s , 19 tuberculosis is mainly seen in adult males and in the elderly in industrialized countries. 4 Although age, gender and socio-economic status have not been associated independently with tuberculosis in this study, multiple logistic regression analysis was used to control the influence of these variables. Factors that tie in with man's habits probably exert an influence of the development of active tuberculosis. Results of studies on the effect that active smoking has on the development of active M. tuberculosis disease are controversialy probably because of the interference of other factors, such as alcohol consumption, age or socioeconomic status. One study of public health workers in Shanghai 2° showed a relative risk of tuberculosis of 2.17 amongst smokers consuming 400 or more cigarettes per year independently of age, gender, contact with a patient with active tuberculosis, and type or place of work; it was found that the effect of age and gender was mainly associated with smoking. In residential homes for the elderly in Liverpool, Nisar and co-workers 2~ have shown that tobacco smoking was associated with an increase in the number of positive reactors to multiplepuncture PPD tuberculin test (Heaf test) and the male sex. However, smoking is a risk factor rarely recorded in the history of patients with tuberculosis, although Crofton et al ~s recognize it as a toxic factor capable of reducing host defence mechanisms. In Barcelona, 22 tobacco smoking was notified in 53.4% of tuberculosis cases, including cases in the paediatric age group. In Gran Canaria (Canary Islands), Caminero and associates 23 reported a figure of 56%. In a study of 3627 necropsiesy active tuberculosis was documented in 3.52% of cases, accompanied by other conditions (cardiovascular disorders, chronic obstructive pulmonary disease, alcohol-induced liver damage) frequently associated with smoking in 70% of these cases.
116 Tubercle and Lung Disease C i g a r e t t e s m o k i n g is a p r i n c i p a l c a u s e o f p r e v e n t a b l e diseases and premature death in industrialized nations, a n d t h e c h i e f c o n t r i b u t o r to c h r o n i c p u l m o n a r y d i s e a s e in adults. 2s-26 A h i g h e r i n c i d e n c e o f r e s p i r a t o r y m o r b i d i t y d u e to t o b a c c o s m o k i n g a m o n g s t s t u d e n t n u r s e s 27 a n d y o u n g adults 28 h a s also b e e n r e p o r t e d . S m o k e r s r o u t i n e l y present respiratory signs and symptoms, especially cough. On the other hand, 90% of patients with contagious tuberculosis had clinical symptoms, with coughing as o n e o f t h e m o s t f r e q u e n t m a n i f e s t a t i o n s a n d o f m a j o r e p i d e m i o l o g i c a l r e l e v a n c e . 18,26 C o u g h in h e a v y s m o k e r s c a n f r e q u e n t l y b e r e s p o n s i b l e for i m p o r t a n t d e l a y s in the diagnosis of tuberculosis. I n s u m m a r y , c i g a r e t t e s m o k i n g is a r i s k f a c t o r i n the development of pulmonary tuberculosis in young people, w i t h a d o s e - r e s p o n s e r e l a t i o n s h i p w i t h the n u m b e r o f c i g a r e t t e s c o n s u m e d daily. T h e r e s u l t s o f this s t u d y h o l d t h a t e f f e c t i v e a n t i - s m o k i n g c a m p a i g n s will h a v e positive repercussions on tuberculosis incidence.
Acknowledgement We thank Marta Pulido, MD, for the English translation and for editing the manuscript.
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