Brazilian Journal of Pulmonology

ISSN (on-line): 1806-3756 | ISSN (printed): 1806-3713


Publication continuous and bimonthly

SCImago Journal & Country Rank
Advanced Search


Current Issue: 2019 - Volume 45 - Number 2 (March/April)


Smoking and pulmonary tuberculosis treatment failure: a case-control study

Tabaquismo y fracaso del tratamiento de la tuberculosis pulmonar. Un estudio de casos y controles


Juan Pablo Aguilar1; a; María B Arriaga2; 3; b; Monica Ninet Rodas1; 4; c; Eduardo Martins Netto1; 3; 5; d


1. Programa de Pós-Graduação em Medicina e Saúde. Universidade Federal da Bahia - UFBA - Salvador (BA) Brasil.
2. Programa de Pós-Graduação em Patologia Humana e Patologia Experimental. Fundação Oswaldo Cruz - Fiocruz-BA - Salvador (BA) Brasil.
3. Fundação José Silveira, Salvador (BA) Brasil.
4. Coordinación de Trabajos de Graduación, Facultad de Medicina, Universidad de
San Carlos - USAC - Ciudad de Guatemala, Guatemala.
5. Laboratório de Pesquisa em Infectologia - LAPI - Universidade Federal da Bahia - UFBA - Salvador (BA) Brasil.
Submitted: 17 November 2018.
Accepted: 5 January 2019.
Study carried out under the auspices of the Programa de Pós-Graduação em Medicina e Saúde. Universidade Federal da Bahía - UFBA - Salvador (BA) Brasil.

Correspondence to:
Juan Pablo Ticona. Rua Doutor Augusto Viana, S/N, Canela, CEP 40110-060, Salvador, BA, Brasil.
Tel.: 55 71 98431-8399. E-mail:
Financial support: Juan Pablo Aguilar is the recipient of a grant from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education). Maria Arriaga is the recipient of a grant from the Fundação de Amparo à Pesquisa da Bahia (FAPESB, Foundation for the Support of Research in the State of Bahia).



Objective: To determine the association between smoking and pulmonary tuberculosis treatment failure. Methods: This was a case-control study conducted at the Brazilian Institute for Tuberculosis Research in the city of Salvador, Brazil, between 2007 and 2015. We evaluated 284 patients treated for pulmonary tuberculosis, comparing 50 cases of treatment failure with 234 control cases in which the final outcome was cure. Results: Treatment failure was attributed to smoking and age rather than to gender, income, level of education, alcohol consumption, or marital status. Therefore, even after adjustment for age, the risk of treatment failure was 2.1 times (95% CI: 1.1-4.1) higher among the patients with a history of smoking. In addition, being over 50 years of age was found to increase the likelihood of treatment failure by 2.8 times (95% CI: 1.4-6.0). Conclusions: Smoking and aging are both associated with pulmonary tuberculosis treatment failure. Therefore, as part of a tuberculosis control program, health personnel should be prepared to offer strategies to promote smoking cessation and should be more careful with older patients.



Objetivo: Determinar la asociación entre el tabaquismo y el fracaso del tratamiento de la tuberculosis pulmonar. Metodología: Este es un estudio caso - control, realizado en el Instituto Brasilero para la Investigación de la Tuberculosis en Salvador, Brasil entre 2007 y 2015. Se compararon 50 casos de fracaso en el tratamiento con 234 controles de pacientes con diagnóstico de tuberculosis pulmonar y con resultado final de cura. Resultados: Se atribuyó el fracaso del tratamiento al tabaquismo y a la edad, y no al sexo, salario, escolaridad, consumo de alcohol o estado civil. Así, aun después del ajuste por edad, los pacientes con antecedentes de tabaquismo tienen 2,1 (IC95% 1,1-4,1) veces más chance de fracaso en el tratamiento de la tuberculosis. Además, tener una edad mayor de 50 años mostró que la posibilidad de fracaso aumenta 2,8 (IC95% 1,4-6,0) veces más. Conclusiones: El tabaquismo está relacionado con el fracaso del tratamiento de la tuberculosis pulmonar, así como también el envejecimiento. Por tal motivo, como parte del control de la tuberculosis, el personal de salud debe estar preparado para ofrecer estrategias que promuevan la cesación tabáquica y tener un mayor cuidado con pacientes de grupos etarios superiores.



Keywords: Tobacco use disorder; Tuberculosis; Treatment failure.


Palavras-chave: Tabaquismo; Tuberculosis; Insuficiencia del tratamiento.




Smoking and tuberculosis are public health problems worldwide.(1-3) Tuberculosis is considered one of fastest growing infectious diseases. According to data from the World Health Organization (WHO), there were 6.3 million reported new cases of tuberculosis, as well as 1.3 million reported deaths from the disease, in 2016. (3) Smoking is directly responsible for 6 million deaths worldwide each year(1) and is a risk factor for diseases with high mortality, such as pulmonary tuberculosis.(1,4) When both diseases act together, they increase their impact, and the product of this interaction can be considered a synergistic epidemic, or syndemic.(5)

Within the syndemic framework, it is estimated that smoking is responsible for 20%(6) of the burden of tuberculosis and that smoking will be responsible for a total of 18 million new cases and 40 million deaths in the 2010-2050 period.(7,8) Smoking is also associated with severe forms of tuberculosis in terms of sequelae and with poor tuberculosis treatment outcomes, such as recurrence and death.(6,9) That is due to the fact that the components of tobacco smoke cause numerous pathophysiological changes in the respiratory system, promoting local inflammatory and immunological changes, thus inhibiting cell growth and the action of some chemical mediators of innate immunity.(10,11) In addition, adherence to tuberculosis treatment has been found to be poor among patients who smoke during treatment, especially those who are male.(12,13)

Poor tuberculosis treatment outcomes include treatment failure, defined by the WHO as ". . . sputum smear or culture . . . positive at month 5 or later during treatment."(14) Treatment failure lengthens the period during which patients are infectious, and such patients may harbor resistant bacilli.(15,16) Although there have been few studies focusing on this type of poor outcome, it has been proposed that smoking doubles the risk of pulmonary tuberculosis treatment failure.(17,18) However, it remains unclear which variables can change the outcome of tuberculosis treatment; alcohol consumption, poverty, and gender should be considered potential confounders.(18,19) Therefore, the objective of this study was to determine the risk of pulmonary tuberculosis treatment failure in smokers and to analyze the potential confounders described in the literature.


This was an unmatched case-control study including patients who received pulmonary tuberculosis treatment between 2007 and 2015 at the José Silveira Foundation Instituto Brasileiro para Investigação da Tuberculose (IBIT, Brazilian Institute for Tuberculosis Research), a referral center for tuberculosis control and treatment in the city of Salvador, Brazil.

We included patients over 15 years of age who were diagnosed with pulmonary tuberculosis on the basis of a positive sputum smear or culture and who received treatment for drug-susceptible tuberculosis for 6 months, additional sputum smears being performed at months 2, 4, and 6 of treatment. We excluded patients with diabetes mellitus, HIV/AIDS, or comorbidities associated with drug abuse during treatment, as well as patients who dropped out of treatment or who did not comply with their follow-up visits.

Definitions of cases and controls

Cases were defined as pulmonary tuberculosis patients who experienced treatment failure. Treatment failure was defined by the criteria of the Brazilian National Guidelines for the Control of Tuberculosis(20): remaining smear positive at the end of treatment; initiating treatment with a strongly positive (++ or +++) result and continuing to have this result up until month 4 of treatment; or having an initial positive result followed by negative results, then having new positive results for 2 consecutive months after month 4 of treatment. Controls were defined as pulmonary tuberculosis patients who, at the end of treatment, were classified as cured.

All cases in the IBIT database (MV System) that met the inclusion criteria were selected. Controls were selected by using the Predictive Analytics Software package, version 18.0 (SPSS Inc., Chicago, IL, USA) as a random number generator from the IBIT database. We considered a case/control ratio of 1:4. Sociodemographic and microbiological data were extracted from the medical records of each selected patient. Laboratory test results were obtained from the IBIT database.

Definition of exposure

Patients were categorized, by smoking status, as follows: current smokers-those who, at the time of diagnosis and during treatment, reported smoking; former smokers-those who, at the time of diagnosis, reported having stopped smoking and who did not smoke during treatment; and never smokers-those who had not smoked before being diagnosed and still did not smoke when they were classified as cured.

In addition to data on the exposure variable, we collected data on variables that could have an effect on tuberculosis treatment outcomes. We identified the following variables in the literature(18,19): patient income; history of alcohol consumption; gender; age; level of education; and marital status.

Sample size and statistical analysis

Between 2007 and 2015, a total of 2,437 patients were diagnosed with pulmonary tuberculosis and treated at the IBIT. Our initial sample size calculation indicated that 60 cases and 240 controls were required in order to achieve a confidence interval of 95% and a power of 80%. We based our calculation on a previous study, conducted by Tachfouti et al.,(17) in which treatment failure was found to be associated with smoking (OR = 2.25).

Data analysis was performed with the Predictive Analytics Software package, version 18.0 (SPSS Inc.). Categorical variables were described as absolute and relative frequencies; age and income were stratified into categories. The smoking variable was grouped into two categories, current smokers and former smokers being grouped together and compared with never smokers, because the risk of having poor tuberculosis treatment outcomes is similar in current and former smokers.(21) Pearson's chi-square test was used in order to determine the statistical difference among the variables. We calculated ORs as a measure of association between treatment failure and the variables of interest, using a confidence interval of 95%. Values of p < 0.05 were considered statistically significant.

Covariates (gender, age, income, level of education, marital status, and alcohol consumption) were analyzed with the use of the Mantel-Haenszel test to determine whether any of them behaved as an effect-modifying factor in the association between smoking and treatment failure. We employed multivariate binary logistic regression analysis to adjust the effect of this association and the covariates, using a combined backward-forward procedure. The final logistic regression model included variables that changed the OR by at least 10%.

Ethical aspects

This study was approved by the Research Ethics Committee of the Federal University of Bahia Climério de Oliveira Maternity Hospital (CAAE protocol no. 51244415.4.0000.5543). All procedures were conducted in accordance with the principles of the Declaration of Helsinki.


We included 284 patients (50 cases and 234 controls), 180 (63.3%) of whom were male. Of those 284 patients, 97 (34.1%) were current or former smokers. The mean age was 40.5 ± 14.7 years. The number of cases of treatment failure was higher among patients over 50 years of age (OR = 3.4; 95% CI: 1.8-6.4; Table 1 and Figure 1). The risk of treatment failure was 2.5 times higher (95% CI: 1.3-4.6) among the current or former smokers than among the never smokers (52.0% vs. 30.3%). However, gender, alcohol consumption, level of education, income, and marital status had similar distributions between the groups (Table 1).

After being adjusted for age, the OR for pulmonary tuberculosis treatment failure in current or former smokers was 2.1 (95% CI: 1.1-4.1; Table 2).

Stratified analysis showed that being a woman and being a current smoker collectively increase the risk of treatment failure (OR = 6.0; 95% CI: 1.5-23.3 vs. OR = 3.1; 95% CI: 1.3-7.3 for being a man and a current smoker; Table 3). However, the homogeneity tests were not significant, and, during multivariate adjustment, the gender variable was not found to be a determining factor in the model.


In the group of patients who were treated at the IBIT and selected for inclusion during the 8-year study period, we found that being a current or former smoker increased the risk of pulmonary tuberculosis treatment failure. That association persisted even after adjustment for potential confounders. We also found that, among the patients in whom treatment failed, the proportion of smokers was higher in the > 50-year age group. Previous studies have identified an association between treatment failure and smoking. (9,17) However, such studies have grouped treatment failure with other poor outcomes, such as treatment nonadherence and death, rather than measuring it separately.(9) In the Tachfouti et al. study,(17) which was conducted in Morocco, the model was adjusted for age and monthly income, and the risk of treatment failure was found to be higher in patients with a low income and in those who smoked. Of the covariates in our study (age, gender, income, level of education, marital status, and alcohol consumption), age had the greatest effect in the final model. Data stratification by age showed a higher proportion of current smokers over 50 years of age in the case group. This result is similar to that reported in the study conducted in China by Wang et al.,(22) in which the risk of treatment failure was shown to increase with age. However, that could be related to the fact that the prevalence of tuberculosis in the > 50-year age group is high in China and in Brazil.(23)

It is estimated that 20% of the incidence of pulmonary tuberculosis can be attributed to smoking.(6) In the patient cohort from which the cases of this study were extracted, the overall prevalence of smoking at the time of diagnosis of pulmonary tuberculosis was 15.8%. That is higher than the prevalence of smoking in Brazil and in the city of Salvador, which was 12.0% and 5.1%, respectively, in 2016.(24) Other authors have also found a high prevalence of smoking among tuberculosis patients.(25,26)

There have been few studies addressing the associations of gender and smoking with poor pulmonary tuberculosis treatment outcomes, because the trend is to use age-matched controls or to select only men. (27-30) There is a disconnect between studies showing that gender is not associated with poor tuberculosis treatment outcomes(31,32) and those showing that being male is the strongest predictor of a poor outcome.(33,34) In our stratified analysis, female smokers were at greater risk of treatment failure than were male smokers, although the difference was not statistically significant, perhaps because of the small number of women in our sample. One likely explanation is related to the context or the socioeconomic profile of women, in terms of variables such as malnutrition, access to health care services, and stigma.(35,36) In addition, there is a trend toward gender equality in smoking prevalence rates with the passing of the epidemic.(37-39) We believe that this association should be further explored in future studies and that reporting of poor tuberculosis treatment outcomes by gender should be encouraged.

Although our study covered a relatively long period of time (8 years), its major limitation is that the number of available cases was small and, consequently, the sample size was smaller than the required sample size calculated, because treatment failure is an uncommon event, as was observed in a cohort in the state of Pernambuco, Brazil, in which the reported treatment failure rate was 2.1%.(40) However, the final number of patients included was large enough to demonstrate the association and achieve the major objective. Another important limitation is that inherent to retrospective studies, which is the use of clinical records to try to obtain data, because complete data were not available for all patients. Nevertheless, it was possible to adjust the model for the main variables described in the literature as potential confounders,(6,19) and we managed to use other data sources in addition to clinical records.

Smoking is a modifiable risk factor that has a major impact on pulmonary tuberculosis. To meet the objective of reducing the prevalence of smokers in the general population, in order to reduce the risk of pulmonary tuberculosis and poor treatment outcomes such as treatment failure, it is necessary to devise tuberculosis control strategies that include anti-smoking interventions, such as offering smoking cessation treatment at the time of diagnosis, as a means of achieving success in the treatment of tuberculosis.


1. Frieden TR. SHATTUCK LECTURE: The Future of Public Health. N Engl J Med. 2015;373(18):1748-54.
2. Eriksen M, Mackay J, Schluger N, Gomeshtapeh FI, Drope J. The Tobacco Atlas. 5th ed. Atlanta: American Cancer Society; 2015.
3. World Health Organization. Global Tuberculosis Report 2015. Geneva: World Health Organization; 2015.
4. World Health Organization. WHO Report on the Global Tobacco Epidemic, 2008: the MPOWER package. Geneva: World Health Organization; 2008.
5. Novotny T, Hendrickson E, Soares ECC, Sereno AB, Kiene SM. HIV/AIDS, tuberculosis, and tobacco in Brazil: a syndemic that calls for integrated interventions. Cad Saude Publica. 2017;33Suppl 3(Suppl 3):e00124215.
6. World Health Organization [homepage on the Internet]. Geneva: WHO; c2018 [cited 2018 Nov 11]. Tuberculosis and Tobacco--a strong association. [Adobe Acrobat document, 2p.]. Available from:
7. Basu S, Stuckler D, Bitton A, Glantz SA. Projected effects of tobacco smoking on worldwide tuberculosis control: mathematical modelling analysis. BMJ. 2011;343:d5506.
8. Brands A, Ottmani SE, Lönnroth K, Blanc LJ, Rahman K, Bettchera DW, et al. Reply to 'Addressing smoking cessation in tuberculosis control.' Bull World Health Organ. 2007;85(8):647-8.
9. Gegia M, Magee MJ, Kempker RR, Kalandadze I, Chakhaia T, Golub JE, et al. Tobacco smoking and tuberculosis treatment outcomes: a prospective cohort study in Georgia. Bull World Health Organ. 2015;93(6):390-9.
10. Shaler CR, Horvath CN, McCormick S, Jeyanathan M, Khera A, Zganiacz A, et al. Continuous and discontinuous cigarette smoke exposure differentially affects protective Th1 immunity against pulmonary tuberculosis. PLoS One. 2013;8(3):e59185.
11. Feng Y, Kong Y, Barnes PF, Huang FF, Klucar P, Wang X, et al. Exposure to cigarette smoke inhibits the pulmonary T-cell response to influenza virus and Mycobacterium tuberculosis. Infect Immun. 2011;79(1):229-37.
12. Lavigne M, Rocher I, Steensma C, Brassard P. The impact of smoking on adherence to treatment for latent tuberculosis infection. BMC Public Health. 2006;6:66.
13. Schneider NK, Novotny TE. Addressing smoking cessation in tuberculosis control. Bull World Health Organ. 2007;85(10):820-1.
14. World Health Organization [homepage on the Internet]. Geneva: WHO; c2018 [cited 2018 Nov 11]. Definitions and Reporting Framework for Tuberculosis- 2013 revision (updated December 2014). [Adobe Acrobat document, 47p.]. Available from:
15. Sawadogo B, Tint KS, Tshimanga M, Kuonza L, Ouedraogo L. Risk factors for tuberculosis treatment failure among pulmonary tuberculosis patients in four health regions of Burkina Faso, 2009: case control study. Pan Afr Med J. 2015;21:152.
16. Mitnick CD, White RA, Lu C, Rodriguez CA, Bayona J, Becerra MC, et al. Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method. Eur Respir J. 2016;48(4):1160-1170.
17. Tachfouti N, Nejjari C, Benjelloun MC, Berraho M, Elfakir S, El Rhazi K, et al. Association between smoking status, other factors and tuberculosis treatment failure in Morocco. Int J Tuberc Lung Dis. 2011;15(6):838-43.
18. World Health Organization. A WHO/The Union Monograph on TB and Tobacco Control: Joining Efforts to Control Two Related Global Epidemics. Geneva, Switzerland: WHO Press; 2007.
19. Slama K, Chiang CY, Enarson DA, Hassmiller K, Fanning A, Gupta P, et al. Tobacco and tuberculosis: a qualitative systematic review and meta-analysis. Int J Tuberc Lung Dis. 2007;11(10):1049-61.
20. Brasil. Ministério da Saúde. Manual de recomendações para o controle da tuberculose no Brasil. Brasília: o Ministério; 2011.
21. Chuang HC, Su CL, Liu HC, Feng PH, Lee KY, Chuang KJ, et al. Cigarette smoke is a risk factor for severity and treatment outcome in patients with culture-positive tuberculosis. Ther Clin Risk Manag. 2015;11:1539-44.
22. Wang N, Ma Y, Liu YH, DU J, Zhang H, Xie SH, et al. Risk of Treatment Failure in Patients with Drug-susceptible Pulmonary Tuberculosis in China. Biomed Environ Sci. 2016;29(8):612-617.
23. Brasil. Ministério da Saúde. Portal da Saúde [homepage on the Internet] Brasília: o Ministério; c2008 [cited 2018 Nov 11]. Informações de saúde Epidemiológicas e Morbidade. Available from:
24. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Vigitel Brasil 2016: vigilância de fatores de risco e proteção para doenças crônicas por inquérito telefônico. Brasília: Ministério da Saúde; 2017.
25. Wang J, Shen H. Review of cigarette smoking and tuberculosis in China: intervention is needed for smoking cessation among tuberculosis patients. BMC Public Health. 2009;9:292.
26. Jiménez-Fuentes MÁ, Rodrigo T, Altet MN, Jiménez-Ruiz CA, Casals M, Penas A, et al. Factors associated with smoking among tuberculosis patients in Spain. BMC Infect Dis. 2016;16:486.
27. Chang KC, Leung CC, Tam CM. Risk factors for defaulting from anti-tuberculosis treatment under directly observed treatment in Hong Kong. Int J Tuberc Lung Dis. 2004;8(12):1492-8.
28. Salami AK, Oluboyo PO. Management outcome of pulmonary tuberculosis: a nine year review in Ilorin. West Afr J Med. 2003;22(2):114-9.
29. Gajalakshmi V, Peto R, Kanaka TS, Jha P. Smoking and mortality from tuberculosis and other diseases in India: retrospective study of 43000 adult male deaths and 35000 controls. Lancet. 2003;362(9383):507-15.
30. Kolappan C, Gopi PG. Tobacco smoking and pulmonary tuberculosis. Thorax. 2002;57(11):964-6.
31. dos Santos MA, Albuquerque MF, Ximenes RA, Lucena-Silva NL, Braga C, Campelo AR, et al. Risk factors for treatment delay in pulmonary tuberculosis in Recife, Brazil. BMC Public Health. 2005;5:25.
32. Thomas A, Gopi PG, Santha T, Chandrasekaran V, Subramani R, Selvakumar N, et al. Predictors of relapse among pulmonary tuberculosis patients treated in a DOTS programme in South India. Int J Tuberc Lung Dis. 2005;9(5):556-61.
33. Bashour H, Mamaree F. Gender differences and tuberculosis in the Syrian Arab Republic: patients' attitudes, compliance and outcomes. East Mediterr Health J. 2003;9(4):757-68.
34. Tachfouti N, Slama K, Berraho M, Elfakir S, Benjelloun MC, El Rhazi K, et al. Determinants of tuberculosis treatment default in Morocco: results from a national cohort study. Pan Afr Med J. 2013;14:121.
35. World Health Organization [homepage on the Internet]. Geneva: WHO; c2018 [cited 2018 Nov 11]. Tuberculosis in Women. [Adobe Acrobat document, 2p.]. Available from:
36. Hudelson P. Gender differentials in tuberculosis: the role of socio-economic and cultural factors. Tuber Lung Dis. 1996;77(5):391-400.
37. Lombardi EM, Prado GF, Santos Ude P, Fernandes FL. Women and smoking: risks, impacts, and challenges. J Bras Pneumol. 2011;37(1):118-28.
38. Amos A, Greaves L, Nichter M, Bloch M. Women and tobacco: a call for including gender in tobacco control research, policy and practice. Tob Control. 2012;21(2):236-43.
39. Hitchman SC, Fong GT. Gender empowerment and female-to-male smoking prevalence ratios. Bull World Health Organ. 2011;89(3):195-202.
40. de Albuquerque Mde F, Ximenes RA, Lucena-Silva N, de Souza WV, Dantas AT, Dan-tas OM, et al. Factors associated with treatment failure, dropout, and death in a co-hort of tuberculosis patients in Recife, Pernambuco State, Brazil. Cad Saude Publica. 2007;23(7):1573-82.



The Brazilian Journal of Pulmonology is indexed in:

Latindex Lilacs SciELO PubMed ISI Scopus Copernicus pmc


CNPq, Capes, Ministério da Educação, Ministério da Ciência e Tecnologia, Governo Federal, Brasil, País Rico é País sem Pobreza
Secretariat of the Brazilian Journal of Pulmonology
SCS Quadra 01, Bloco K, Salas 203/204 Ed. Denasa. CEP: 70.398-900 - Brasília - DF
Fone/fax: 0800 61 6218/ (55) (61) 3245 1030/ (55) (61) 3245 6218

Copyright 2019 - Brazilian Thoracic Association

Logo GN1