ABSTRACT

INTRODUCTION

Tuberculosis is the second leading cause of infectious-disease death worldwide, after AIDS. Most tuberculosis patients in Cuba have pulmonary TB and recovery rates are high. When TB chemotherapy fails, the most common adverse outcome is death.

OBJECTIVE

Determine survival patterns in a cohort of pulmonary TB patients in Cuba.

METHODS

A retrospective cohort study was conducted of pulmonary TB patients who were notified and treated in Cuba in 2009 and 2010. Time elapsed between diagnosis and death was examined. Patient survival was analyzed with the Kaplan–Meier method and comparisons were made with the log-rank estimator; an adjusted Cox model was used to analyze risk of death.

RESULTS

The study included 1339 patients, of whom 71.7% were aged 25–64 years and 77.4% were men. Infectious pulmonary tuberculosis was the most common form (75.6%). Only a small number of patients (5.7%) presented TB/HIV coinfection. Ninety-four deaths were reported, 55% during the first 60 days of treatment. Lower survival rates were observed among men (HR 1.87, 95% CI 1.02–3.45), patients coinfected with HIV/AIDS (HR 6.25, 95% CI 3.46–11.31), and patients aged ≥48 years (HR 3.93, 95% CI 2.41–6.40).

CONCLUSION

The preponderance of deaths early in TB treatment course may be related to diagnostic and/or treatment delays. Older age at diagnosis, male sex and TB/HIV coinfection increase risk of death.

Pulmonary tuberculosis; HIV/AIDS; mortality; survival; case fatality; Cuba

INTRODUCTION

Tuberculosis (TB) is one of the main causes of morbidity and mortality in many countries and is considered a priority global health problem. Although it is a curable disease, every year some nine million people develop active disease and two million die from it.[¹1. World Health Organization. The global plan to stop TB 2011-2015: transforming the fight towards elimination of tuberculosis. Geneva: World Health Organization; 2010 Feb. 96 p.,²2. World Health Organization. Global tuberculosis report 2012. Geneva: World Health Organization; 2012. 89 p.] WHO has coordinated multiple efforts towards global TB control. A goal of the Global Plan to Stop TB is to reduce TB deaths by half from 1990 to 2015.[¹1. World Health Organization. The global plan to stop TB 2011-2015: transforming the fight towards elimination of tuberculosis. Geneva: World Health Organization; 2010 Feb. 96 p.]

Monitoring TB chemotherapy outcomes is essential for TB elimination.[³3. World Health Organization. Priorities in operational research to improve tuberculosis care and control. Geneva: World Health Organization; 2011 Aug 29. 133 p.,⁴4. World Health Organization. Global tuberculosis control: WHO report 2011. Geneva: World Health Organization; 2011. 246 p.] Even under treatment, >10% of patients can die when adherence is low or when rates of HIV infection and multidrug-resistant TB (MDR-TB) are high.[⁵5. González Ochoa E, Armas Pérez L. Tuberculosis. Procedimientos para la vigilancia y el control: experiencia cubana. Havana: UNDP; 2010. Spanish.,⁶6. World Health Organization. Global tuberculosis control: epidemiology, strategy, financing: WHO report 2009. Geneva: World Health Organization; 2009.] Studies of adverse outcomes of TB chemotherapy have associated them with advanced age, alcoholism, HIV infection (more common among men), previous treatment with TB drugs and the rising rate of extrapulmonary forms of TB.[⁷7. Kruijshaar ME, Abubakar I. Increase in extra-pulmonary tuberculosis in England and Wales 1999-2006. Thorax. 2009 Dec;64(12):1090-5.,⁸8. Chiang CY, Lee JJ, Yu MC, Enarson DA, Lin TP, Luh KT. Tuberculosis outcomes in Taipei: factors associated with treatment interruption for 2 months and death. Int J Tuberc Lung Dis. 2009 Jan;13(1):105-11.]

Cuba has 11.2 million inhabitants and a population density of 102/km².[⁹9. National Health Stat istics and Medical Records Division (CU). Anuario Estadístico de Salud 2013. Havana: Ministry of Public Health (CU); 2014 May [cited 2014 May 27]. 205 p. Available from: http://files.sld.cu/dne/files/2014/05/anuario-2013-esp-e.pdf. Spanish.
http://files.sld.cu/dne/files/2014/05/an... ] The first National Tuberculosis Control Program (PNCT) was established in 1963, and since, TB has been a notifiable disease.[¹⁰10. Programa Nacional de Control de la Tuberculosis. Manual de normas y procedimientos. Havana: Editorial Ciencias Médicas; 1999. Spanish.] Cuba was an early adopter of the global Directly Observed Treatment Short Course (DOTS) strategy, implementing in 1971 a strategy based on intensive contact tracing and strictly controlled ambulatory treatment, and using standard treatment protocols and case definitions based on WHO recommendations.[⁵5. González Ochoa E, Armas Pérez L. Tuberculosis. Procedimientos para la vigilancia y el control: experiencia cubana. Havana: UNDP; 2010. Spanish.,¹¹11. González E, Armas L, Llanes MJ. Progress towards tuberculosis elimination in Cuba. Int J Tuberc Lung Dis. 2007 Apr;11(4):405-11.,¹²12. World Health Organization. Treatment of tuberculosis: guidelines. 4th ed. Geneva: World Health; 2010. 147 p. English, Russian.] Cuba has low TB incidence for a middle-income country,[¹³13. Jordán Severo T, Oramas González R, Díaz Castrillo AO, González Ochoa E, Armas Pérez L. Evaluación de la detección de casos de tuberculosis mediante un indicador sintético en dos municipios de Ciudad de La Habana. Rev Cubana de Hig Epidemiol [Internet]. 2008 Sep-Dec [cited 2014 May 27];46(3). Available from: http://scielo.sld.cu/scielo.php?script=sci_arttext&pid=S1561-30032008000300004&nrm=iso. Spanish.
http://scielo.sld.cu/scielo.php?script=s... ] an indicator of PNCT’s impact, and is on WHO’s list of countries making progress towards TB elimination.[¹⁴14. World Health Organization. Framework for tuberculosis elimination in low-incidence countries. Geneva: World Health Organization; 2014.]

Cuba has one of the lowest TB incidence rates in Latin America,[¹⁵15. Pan American Health Organization. Plan Regional de Tuberculosis 2006-2015. Washington, D.C.: Pan American health Organization; 2006. Spanish.] at 6.1/100,000 population in 2012.[¹⁶16. National Health Statistics and Medical Records Division (CU). Anuario Estadístico de Salud 2012. Havana: Ministry of Public Health (CU); 2013 Apr [cited 2013 Jun 4]. 205 p. Available from: http://files.sld.cu/dne/files/2013/04/anuario_2012.pdf. Spanish.
http://files.sld.cu/dne/files/2013/04/an... ] Two studies from 2009–2010 in western[¹⁷17. León Venero MA. Desenlaces de la quimioterapia antituberculosa: un estudio en el occidente de Cuba, 2009-2010 [thesis]. [Havana]: Pedro Kourí Tropical Medicine Institute (CU); 2012. Spanish.] and central[¹⁸18. Calzado Benítez A. Factores asociados al desenlace desfavorable de la quimioterapia antituberculosa, región central de Cuba, 2009-2010 [thesis]. [Havana]: Pedro Kourí Tropical Medicine Institute (CU); 2012. Spanish.] Cuba found pulmonary TB the most common form and death the most important adverse outcome of TB chemotherapy. In 2014, the TB mortality rate was 0.2/100,000 population.[¹⁹19. National Health Statistics and Medical Records Division (CU). Anuario Estadístico de Salud 2014. Havana: Ministry of Public Health (CU); 2015 Apr [cited 2016 Feb 15]. 205 p. Available from: http://istmat.info/files/uploads/46577/2014.pdf. Spanish.
http://istmat.info/files/uploads/46577/2... ] There are no available publications with in-depth evaluations of the determinants of TB case fatality in Cuba.

The purpose of this study was to assess survival patterns and predictors of death in Cuban patients with pulmonary TB.

METHODS

Population and study design

This was a retrospective cohort study in Cuba with all notified cases of pulmonary TB in which patients started chemotherapy between January 1, 2009 and December 31, 2010. The censoring date was September 17, 2011. We studied factors to which patients were exposed before starting chemotherapy, to assess possible associations with case fatality.

Data collection

We reviewed the database and notifiable disease records of the National Medical Records and Health Statistics Bureau of the Ministry of Public Health (MINSAP). The database contains information from death certificates (primary data), which are filled out by physicians. Epidemiologic histories of notified TB cases were also reviewed, as were patient treatment records.

Data on drug culture and sensitivity test results were obtained from the National Reference and Research Laboratory on Tuberculosis and Mycobacteria of the Pedro Kouri Tropical Medicine Institute (IPK).

Definitions

Patient age (at diagnosis) was analyzed as a quantitative variable and dichotomized based on the median.

Patients were classified as follows:

• New case: patient who had never received TB drugs or was treated for less than 30 days and was not previously reported as a TB case[¹⁰10. Programa Nacional de Control de la Tuberculosis. Manual de normas y procedimientos. Havana: Editorial Ciencias Médicas; 1999. Spanish.]

• Retreated: patient retreated after chemotherapy failure, treatment interruption, or recurrence (patient diagnosed bacteriologically with TB after being declared cured or receiving complete cycle of chemotherapy)[¹⁰10. Programa Nacional de Control de la Tuberculosis. Manual de normas y procedimientos. Havana: Editorial Ciencias Médicas; 1999. Spanish.]

• Deceased: patient who died (for any reason) during chemotherapy or who completed treatment and died during study period.[¹⁰10. Programa Nacional de Control de la Tuberculosis. Manual de normas y procedimientos. Havana: Editorial Ciencias Médicas; 1999. Spanish.] In both cases, TB appears on death certificate as a cause of death.

Patients whose sputum smear microscopy revealed acid-fast bacilli (AFB) were classified as having AFB+ pulmonary TB; if bacteriological sputum examination was negative, they were deemed to have AFB– pulmonary TB.[¹⁰10. Programa Nacional de Control de la Tuberculosis. Manual de normas y procedimientos. Havana: Editorial Ciencias Médicas; 1999. Spanish.]

Patients who were incarcerated during the study or who reported having been so at any point in their lives were defined as having a history of incarceration.

TB diagnosis was made following PNCT protocols in various health settings: family doctor-and-nurse offices, polyclinics (community-based multispecialty clinics at the primary level, to which family doctor-and-nurse offices report) or hospitals. Prisoners with TB were diagnosed in penitentiary infirmaries.[¹⁰10. Programa Nacional de Control de la Tuberculosis. Manual de normas y procedimientos. Havana: Editorial Ciencias Médicas; 1999. Spanish.]

Drug sensitivity tests on isolated strains of all TB cases identified two groups for comparison: resistant and sensitive. A case was considered resistant when the patient had a strain resistant to at least one TB drug.[¹⁰10. Programa Nacional de Control de la Tuberculosis. Manual de normas y procedimientos. Havana: Editorial Ciencias Médicas; 1999. Spanish.]

Analysis

A descriptive analysis was conducted using the chi-square and Fisher exact tests to compare categorical variables, with a statistical significance level of 0.05.

For survival analysis, censoring was established by analyzing the number of days from start of chemotherapy to the censoring date or exit date when the patient was released from the cohort (cured; or treatment completed, failed, or abandoned). The Kaplan-Meier method was used to estimate survival. The log-rank test was used to compare survival curves of the different categories of a single variable. The Cox univariate model was also used and a multivariate model was adjusted to calculate risk of death, and the Wald test was applied; the best model was selected and risks considered significant (by hazard ratio, HR) were reported, with 95% confidence intervals.

The assumption of risk proportionality was verified graphically and by goodness of fit with the Grambsch and Therneau test based on analysis of residuals.[²⁰20. Grambsch P, Therneau T. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81(3):515-26.] The programs SPSS Statistics 19 and R 3.3.0 were used.

Ethics

The study was approved by IPK’s Scientific Council and Ethics Committee and by PNCT and MINSAP coordinators, in compliance with ethical requirements for studies using administrative data. Data management procedures ensured patient confidentiality.

RESULTS

From January 2009 to December 2010 in Cuba, 1339 cases of pulmonary TB (87.6% of all notified TB cases) were notified and chemotherapy was initiated. Of these, 77.4% were men; mean age was 48 years (SD 18; median 47, interquartile range 36–62). Most (92.1%, 1233) were new cases and 72.6% (972) were AFB+; 5.7% (76) were seropositive for HIV; and 4.2% (56) had diabetes. History of alcoholism was reported in 16.6% (222) cases. History of incarceration was reported in 18.1% (243). Of 257 sputum sensitivity tests performed, 7.4% (19) found resistance to at least one TB drug (Table 1).

Case fatality was 7% (94/1339), significantly higher among men, patients aged ≥48 years at time of diagnosis, those coinfected with HIV and those without history of incarceration (Table 1).

Average length of observation of pulmonary TB patients was 208 days (SD 58). Maximum length of observation was 487 days. Average length of observation in the 94 cases of death within the study period was 97 days (SD 110, median 56, interquartile range 22–131); 55.3% of deaths occurred during the first 60 days of treatment (Table 2). Case fatality in the first 60 days of chemotherapy was 3.9% (95% CI 2.8–4.9); case fatality later in the observation period was 3.3% (95% CI 2.3–4.3, p = 0.45).

Survival analysis covered the observation period of the 94 pulmonary TB patients who died and 1245 patients with censored data. Table 3 presents Cox univariate analysis for mortality prediction. We found significant differences in survival by sex, age, TB/HIV coinfection, and presence/absence of a history of incarceration (Figure 1). Case category (new vs. retreated), history of alcoholism, place of diagnosis and resistance to ≥1 TB drug had no significant influence on survival rates.

In multivariate analysis, risk of dying for men with pulmonary TB was almost twice as high as for women (HR 1.87, 95% CI 1.02–3.45). Age ≥48 years at diagnosis almost quadrupled risk of death (HR 3.93, 95% CI 2.41–6.40). Risk of death in patients with TB/HIV coinfection was six times that of patients without HIV (HR 6.25, 95% CI 3.46–11.31). The remaining variables were excluded from the model as they were not significant.

DISCUSSION

Countrywide application of standardized techniques of TB diagnosis, record-keeping and case notification (as well as death certification) ensures data validity and reliability. This study was the first to introduce survival analysis in a population-based study of pulmonary TB in Cuba.

The finding that pulmonary TB affected mostly adult men in their economically active years is consistent with global patterns.[⁶6. World Health Organization. Global tuberculosis control: epidemiology, strategy, financing: WHO report 2009. Geneva: World Health Organization; 2009.,⁸8. Chiang CY, Lee JJ, Yu MC, Enarson DA, Lin TP, Luh KT. Tuberculosis outcomes in Taipei: factors associated with treatment interruption for 2 months and death. Int J Tuberc Lung Dis. 2009 Jan;13(1):105-11.] According to WHO, TB is more common among men and affects mainly working-age adults (approximately two thirds of people with TB are aged 15–59 years).[²2. World Health Organization. Global tuberculosis report 2012. Geneva: World Health Organization; 2012. 89 p.,⁴4. World Health Organization. Global tuberculosis control: WHO report 2011. Geneva: World Health Organization; 2011. 246 p.] Poorer survival observed in patients aged ≥48 years is also in line with global patterns.[²¹21. Waitt CJ, Squire SB. A systematic review of risk factors for death in adults during and after tuberculosis treatment. Int J Tuberc Lung Dis. 2011 Jul;15(7):871-85.,²²22. Millet JP, Orcau A, Rius C, Casals M, de Olalla PG, Moreno A, et al. Predictors of death among patients who completed tuberculosis treatment: a population-based cohort study. PLoS One. 2011;6(9):e25315.] Studies in Mexico and Taiwan also reported lower survival in older groups: aged >45 years in Chiapas, Mexico[²³23. Nájera-Ortiz JC, Sánchez-Pérez HJ, Ochoa-Díaz-López H, Leal-Fernández G, Navarro-Giné A. The Poor Survival among Pulmonary Tuberculosis Patients in Chiapas, Mexico: The Case of Los Altos Region. Tuberc Res Treat. 2012;2012:708423.] and aged >65 years in Taipei, Taiwan. [⁸8. Chiang CY, Lee JJ, Yu MC, Enarson DA, Lin TP, Luh KT. Tuberculosis outcomes in Taipei: factors associated with treatment interruption for 2 months and death. Int J Tuberc Lung Dis. 2009 Jan;13(1):105-11.]

Poorer survival in men than in women is consistent with studies in Brazil,[²⁴24. Duarte EC, Bierrenbach AL, Barbosa da Silva J Jr, Tauil PL, de Fatima Duarte E. Factors associated with deaths among pulmonary tuberculosis patients: a case-control study with secondary data. J Epidemiol Community Health. 2009 Mar;63(3):233-8.] India [²⁵25. Mukherjee A, Saha I, Sarkar A, Chowdhury R. Gender differences in notification rates, clinical forms and treatment outcome of tuberculosis patients under the RNTCP. Lung India. 2012 Apr;29(2):120-2.] Israel,[²⁶26. Shuldiner J, Leventhal A, Chemtob D, Mor Z. Mortality of tuberculosis patients during treatment in Israel, 2000-2010. Int J Tuberc Lung Dis. 2014 Jul;18(7):818-23.] and in WHO’s global TB reporting.[²2. World Health Organization. Global tuberculosis report 2012. Geneva: World Health Organization; 2012. 89 p.] In Cuba, crude all-cause mortality is also higher for men (8.6/1000 vs. 7.3/1000 for women in 2012).[¹⁶16. National Health Statistics and Medical Records Division (CU). Anuario Estadístico de Salud 2012. Havana: Ministry of Public Health (CU); 2013 Apr [cited 2013 Jun 4]. 205 p. Available from: http://files.sld.cu/dne/files/2013/04/anuario_2012.pdf. Spanish.
http://files.sld.cu/dne/files/2013/04/an... ] A 2010 study on social determinants of mortality in Cuba found that men were more exposed to risk factors (such as smoking and occupational hazards) and hypothesized that the so-called “masculine role” encourages risk-taking behavior.[²⁷27. Corral Martín A, Castañeda Abascal IE, Barzaga Torres M, Santana Espinosa MC. Determinantes sociales en la diferencial de mortalidad entre mujeres y hombres en Cuba. Rev Cubana Salud Pública. 2010 Jan-Mar;36(1):66-77. Spanish.] Other authors have found no differences in men’s and women’s TB mortality and survival: Pardeshino in India in 2009[²⁸28. Pardeshi G. Survival analysis and risk factors for death in tuberculosis patients on directly observed treatment-short course. Indian J Med Sci. 2009 May;63(5):180-6.] and Kim in Korea.[²⁹29. Kim CW, Kim SH, Lee SN, Lee SJ, Lee MK, Lee JH, et al. Risk factors related with mortality in patient with pulmonary tuberculosis. Tuberc Respir Dis (Seoul). 2012 Jul;73(1):38-47.] Neither study, however, was population based; the Indian study was conducted in a TB treatment center in the district of Yavatmal[²⁸28. Pardeshi G. Survival analysis and risk factors for death in tuberculosis patients on directly observed treatment-short course. Indian J Med Sci. 2009 May;63(5):180-6.] and the Korean study was of 960 patients at Yonsei University Hospital.[²⁹29. Kim CW, Kim SH, Lee SN, Lee SJ, Lee MK, Lee JH, et al. Risk factors related with mortality in patient with pulmonary tuberculosis. Tuberc Respir Dis (Seoul). 2012 Jul;73(1):38-47.]

Diabetes mellitus is recognized as a risk factor for active TB,[³⁰30. Jeon CY, Murray MB. Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Med. 2008 Jul 15;5(7):e152.,³¹31. Jeon CY, Murray MB, Baker MA. Managing tuberculosis in patients with diabetes mellitus: why we care and what we know. Expert Rev Anti Infect Ther. 2012 Aug;10(8):863-8.] but we found few cases of diabetes, and no association with case fatality, possibly due to small sample size. Cuba’s absence of economic barriers to primary care and diabetes treatment may also have contributed.[³²32. Bonet Gorbea M, Varona Pérez P. III Encuesta nacional de factores de riesgo y actividades preventivas de enfermedades no trasmisibles. Cuba 2010-2011. Havana: Editorial Ciencias Médicas; 2014. 330 p. Spanish.]

Despite its low prevalence in the study cohort, TB/HIV coinfection was positively associated with case fatality. WHO statistics for 2011 indicated that 13% of TB cases worldwide had TB/HIV and 430,000 died.[²2. World Health Organization. Global tuberculosis report 2012. Geneva: World Health Organization; 2012. 89 p.] HIV has been shown to be an important predictor of mortality for TB patients in countries such as Estonia,[³³33. Kliiman K, Altraja A. Predictors and mortality associated with treatment default in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2010 Apr;14(4):454-63.] Brazil,[³⁴34. Maruza M, Albuquerque MF, Braga MC, Barbosa MT, Byington R, Coimbra I, et al. Survival of HIV-infected patients after starting tuberculosis treatment: a prospective cohort study. Int J Tuberc Lung Dis. 2012 May;16(5):618-24.] Zambia and Malawi.[³⁵35. Ciglenecki I, Glynn JR, Mwinga A, Ngwira B, Zumla A, Fine PE, et al. Population differences in death rates in HIV-positive patients with tuberculosis. Int J Tuberc Lung Dis. 2007 0ct;11(10):1121-8.] In turn, tuberculosis is a predictor of mortality in patients with HIV.[³⁶36. dos Santos RP, Deutschendorf C, Scheid K, Zubaran Goldani L. In-Hospital mortality of disseminated tuberculosis in patients infected with the human immunodeficiency virus. Clin Dev Immunol. 2011;2011.] Maruza reported that HAART improved survival in HIV patients coinfected with TB, and that mortality increased with duration of HAART and compromised immune status.[³⁴34. Maruza M, Albuquerque MF, Braga MC, Barbosa MT, Byington R, Coimbra I, et al. Survival of HIV-infected patients after starting tuberculosis treatment: a prospective cohort study. Int J Tuberc Lung Dis. 2012 May;16(5):618-24.]

AFB+ pulmonary TB, the most common form of TB found in the study, is also the most common in other Cuban studies and globally. [²2. World Health Organization. Global tuberculosis report 2012. Geneva: World Health Organization; 2012. 89 p.] Llanes reported that in Cuba from 1992 to 2002 AFB+ pulmonary TB was the most widespread, with 69.5% of total pulmonary TB.[³⁷37. Llanes Cordero MJ, Armas Pérez L, González Ochoa ER, Lazo álvarez MA, Carreras Corzo L, Mathys F, et al. Tuberculosis pulmonar con baciloscopia negativa, peculiaridades de su frecuencia en Cuba 1992-2002. Rev Cubana Med Trop. 2006 May-Aug;58(2):119-23. Spanish.] In Europe, Jordan and Davies reviewed articles on TB chemotherapy outcomes published in 2009 and reported that 60% of pulmonary TB cases in the region were AFB+. In Southeast Asia, however, it was 37.4%, and in Tanzania, Africa, it was 41%.[³⁸38. Jordan TS, Davies PD. Clinical tuberculosis and treatment outcomes. Int J Tuberc Lung Dis. 2010 Jun;14(6):683-8.] This could be because these areas have high prevalence of TB/HIV coinfection and more cases of AFB- and extrapulmonary TB.[³⁹39. Dierberg KL, Chaisson RE. Human immunodeficiency virus-associated tuberculosis: update on prevention and treatment. Clin Chest Med. 2013 Jun;34(2):217-28.,⁴⁰40. World Health Organization. Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents. Recommendations for HIV-prevalent and resource-constrained setting. Geneva: World Health Organization Press; 2007 Jan [cited 2016 Feb 15]. 36 p. Available from: http://apps.who.int/iris/bitstream/10665/69463/1/WH0_HTM_TB_2007.379_eng.pdf
http://apps.who.int/iris/bitstream/10665... ]

Alcoholism is known to increase susceptibility to M. tuberculosis infection through immune system depression (it also affects TB disease course through pharmacokinetic and other mechanisms). [⁴¹41. Rehm J, Samokhva I ov AV, Neuman MG, Room R, Parry C, Lonnroth K, et al. The association between alcohol use, alcohol use disorders and tuberculosis (TB). A systematic review. BMC Public Health. 2009 Dec;5:9:450.] In the United States, Mitruka studied 24 TB outbreaks occurring between 2002 and 2008 and found that in 19, at least 40% of patients were alcoholic.[⁴²42. Mitruka K, Oeltmann JE, Ijaz K, Haddad MB. Tuberculosis outbreak investigations in the United States, 2002-2008. Emerg Infect Dis. 2011 Mar;17(3):425-31.] Rehm estimated that 10% of TB cases worldwide are attributable to alcohol.[⁴¹41. Rehm J, Samokhva I ov AV, Neuman MG, Room R, Parry C, Lonnroth K, et al. The association between alcohol use, alcohol use disorders and tuberculosis (TB). A systematic review. BMC Public Health. 2009 Dec;5:9:450.] Although 16% of pulmonary TB patients we studied were alcoholic, there was no association with case fatality, in contrast to the findings of Rehm’s systematic review.[⁴¹41. Rehm J, Samokhva I ov AV, Neuman MG, Room R, Parry C, Lonnroth K, et al. The association between alcohol use, alcohol use disorders and tuberculosis (TB). A systematic review. BMC Public Health. 2009 Dec;5:9:450.]

Although we found that numbers of pulmonary TB cases and deaths were both lower in persons with history of incarceration than in the general population, it has been reported internationally that TB prevalence among prisoners can be 50 times higher than in the overall population.[⁴³43. O’Grady J, Maeurer M, Atun R, Abubakar I, Mwaba P, Bates M, et al. Tuberculosis in prisons: anatomy of global neglect. Eur Respir J. 2011 Oct;38(4):752-4. 44. Baussano I, Williams BG, Nunn P, Beggiato M, Fedeli U, Scano F. Tuberculosis incidence in prisons: a systematic review. PLoS Med. 2010 Dec 21;7(12):e1000381. 45. Dara M, Acosta CD. Tuberculosis prevention and control in prisons: do we know enough? Int J Tuberculosis Lung Dis. 2014 Jul;18(7):758-9.–⁴⁶46. Palomino JC, Cardoso Leao S, Ritacco V. Tuberculosis 2007-From basic science to patient care. [place unknown]: TuberculosisTexbook.com; 2007. 687 p.
TuberculosisTexbook.com... ] Vinkeles Melchers reviewed 52 scientific articles on TB control in prisons and found descriptions of shortcomings in TB control program implementation in such facilities.[⁴⁷47. Vinkeles Melchers NVS, van Elsland SL, Lange JM, Borgdorff MW, van den Hombergh J. State of affairs of tuberculosis in prison facilities: a systematic review of screening practices and recommendations for best TB control. PLoS One. 2013;8(1):e53644.] Perhaps Cuba has succeeded in avoiding these problems because it adheres to WHO recommendation for active TB case-finding in vulnerable groups, including prisoners and exprisoners.[¹1. World Health Organization. The global plan to stop TB 2011-2015: transforming the fight towards elimination of tuberculosis. Geneva: World Health Organization; 2010 Feb. 96 p.,³3. World Health Organization. Priorities in operational research to improve tuberculosis care and control. Geneva: World Health Organization; 2011 Aug 29. 133 p.] Gonzalez-Ochoa’s study in Las Tunas Province found that combining passive TB case-finding in health services with active case-finding in vulnerable communities (where exprisoners lived) was five times more effective than passive case-finding alone. He emphasized the importance of such a combined strategy in areas of low TB incidence.[⁴⁸48. González-Ochoa E, Brooks JL, Matthys F, Caliste P, Armas L, Van der Stuyft P. Pulmonary tuberculosis case detection through fortuitous cough screening during home visits. Trop Med Int Health. 2009 Feb;14(2):131-5.]

While our study did not find an association between M. tuberculosis drug resistance and case fatality, other studies have done so.[²2. World Health Organization. Global tuberculosis report 2012. Geneva: World Health Organization; 2012. 89 p.] In Estonia, Kliiman reported that patients with MDR pulmonary TB had a greater than eightfold risk of death (HR 8.56; 95% CI:1.81–40.4).[³³33. Kliiman K, Altraja A. Predictors and mortality associated with treatment default in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2010 Apr;14(4):454-63.] In Singapore, Low also reported a significant risk of death for MDR patients.[⁴⁹49. Low S, Ang LW, Cutter J, James L, Chee CB, Wang YT, et al. Mortality among tuberculosis patients on treatment in Singapore. Int J Tuberc Lung Dis. 2009 Mar;13(3):328-34.] It should be borne in mind that MDR TB is relatively infrequent in Cuba, reflecting the high priority given to directly observed treatment.[⁵⁰50. Montoro E, Lemus D, Echemendía M, Díaz R, Mederos L, Martínez MR, et al. Vigilancia de la resistencia a los farmacos antituberculosos en Cuba, 2000-2009. Rev Panam Salud Publica. 2011 Dec;30(6):615-8. Spanish.]

The higher relative frequency of deaths within the first two months of TB chemotherapy may be attributable to delayed diagnosis and treatment. Treatment delay can affect clinical severity[⁵¹51. Virenfeldt J, Rudolf F, Camara C, Furtado A, Gomes V, Aaby P, et al. Treatment delay affects clinical severity of tuberculosis: a longitudinal cohort study. BMJ Open. 2014 Jun 10;4(6):e004818.] and increase risk of death and community transmission.[⁵²52. Sreeramareddy CT, Panduru KV, Menten J, Van den Ende J. Time delays in diagnosis of pulmonary tuberculosis: a systematic review of literature. BMC Infect Dis. 2009 Jun 11;9:91.] Evaluations of case detection procedures in several Cuban municipalities documented delays “attributable to the patient” (delays between respiratory symptom onset and first medical appointment),[⁵³53. Gómez Murcia P, Méndez Martínez J, Armas Pérez L, González Ochoa E. Evaluación de la detección de casos de tuberculosis mediante un indicador sintético (ISILOC). Provincia de Matanzas. Rev Médica Electrón [Internet]. 2009 [cited 2013 Feb 28];31(4). Available from: http://www.revmatanzas.sld.cu/revista%20medica/ano%202009/vol4%202009/tema05.htm. Spanish.
http://www.revmatanzas.sld.cu/revista%20... ,⁵⁴54. Armas Pérez L, Medina Verde N, Peralta Pérez M, González Ochoa E. Un indicador sintético (ISILOC) para valorar la calidad de la detección de casos de tuberculosis. Rev Cubana Med Trop. 2009 Apr;61(1). Spanish.] which affected promptness of diagnosis and treatment. Such findings reinforce the importance of active case-finding in vulnerable groups.

A limiting factor in the study was lack of data on a range of risk factors that might affect survival: nutritional status, presence of other chronic diseases, smoking, HAART adherence, immune status and other factors not available in records consulted. Nevertheless, the population-based nature of the study makes it useful as a basis for future research aimed at reducing mortality and eliminating TB in Cuba.

CONCLUSION

The higher relative frequency of deaths early in TB treatment course may be related to diagnostic and/or treatment delays. Older age at diagnosis, male sex and TB/HIV coinfection increase risk of death.

REFERENCES

Publication Dates

History