reduced risk of active TB and 68% reduction in mortality compared to the 6-month course [103]. The REMEMBER (reducing early mortality and early morbidity by empirical tuberculosis treatment regimens) study aimed to assess whether empirical TB treatment will reduce early mortality compared with IPT in patients with advanced HIV disease initiating antiretroviral therapy. Overall, empirical TB therapy did not reduce early mortality compared to IPT. However, the low mortality rate in the study underscores the need for TB screening and IPT in

Insights into Recurrent Tuberculosis: Relapse Versus Reinfection and Related Risk Factors

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27

In their review of four studies, Bruin et al. reported the effect of sPT for the prevention of recurrent TB in HIV-infected individuals and the context in which the preventative approach may be applied. All four studies reported that sPT decreased incidence of recurrent TB in comparison to nontreatment groups. Relative reductions varied from 55.0 to 82.1%. However, only one of the four studies reported a significant effect on overall survival [100]. Perriens et al. described the use of isoniazid (INH) and rifampicin (RIF) twice weekly for an additional 6 months in comparison to a placebo. Patients receiving sPT were reported to be significantly less likely to develop recurrent TB compared to the placebo group (relative risk 0.21, p < 0.01) [105]. Haller et al. assessed the effectiveness of INH and sulphadoxine-pyrimethamine as sPT. The relative rate for the incidence of recurrent TB in patients receiving additional treatment (n = 134) and those not (n = 129) was 0.30 (95% confidence interval: 0.09–0.94) [106]. Fitzgerald et al. assessed the use of INH for an additional year following the completion of initial treatment compared to a placebo group. The intervention significantly reduced the incidence of recurrent TB from 7.8 per 100 person-years to 1.4 per 100 person-years (relative risk 0.18, confidence interval: 0.04–0.83) [107]. Churchyard et al. assessed the effect of INH in combination with cotrimoxazole versus cotrimoxazole only or no intervention in HIV-infected gold miners in South Africa. The rate ration for the development of recurrent TB in comparing the groups with INH and the group without INH was 0.45 (95% confidence interval: 0.26–0.78) [108]. As with pPT, the ideal duration and drug choice remain unclear. In all four studies, the duration of treatment varied from 6 to 24 months. The duration of effectiveness of sPT could not be assessed due to the short follow-up periods of the studies. None of the studies included made a distinction between relapse and reinfection as the mechanism of recurrent TB. Furthermore, Haller et al. and Fitzgerald et al. diagnosed recurrent TB by clinical assessment only,

Recurrent TB poses a major threat to TB control programs, especially given the persistent vulnerability of HIV-infected patients to tuberculosis, and the higher propensity of recurrent disease being due to resistant MTB strains. In the absence of large-scale population-based surveillance reports, the overall rate of recurrent TB following completion of treatment is significantly underestimated. Current estimates are based on a combination of randomized controlled trials and observational studies, with reliability estimates of the former limited by study follow-up time, and the latter prominently demonstrating higher rates of recurrence. Under clinical trial conditions, adherence rates are better; treatment facilities are more accessible and incorporate adequate follow-up after treatment, leading to improved treatment

which could indicate overestimation of recurrent TB [106, 107].

11. Conclusion and future perspectives

patients with HIV [104].

In the context of recurrence due to relapse or reinfection disease, a different treatment approach is required. In the case of reinfection, this can be considered as a new primary infection, and thus, standard regimens may be effective. In contrast, relapse is associated with an increased risk of drug resistance due to the persistence of the original infecting strain under suboptimal treatment. Collectively, all the factors mentioned here underscore the significance an individualized treatment approach guided by DST [92, 93].

#### 10. Preventative therapy for recurrent TB

Active TB disease has been shown to be preventable by the use of primary preventative therapy (pPT), which aims to prevent the first episode of TB in individuals in whom active TB has been excluded. The average preventative effect of pPT in HIV-uninfected individuals is a 60% reduction in the incidence of recurrent TB, while in HIV-infected individuals, the average effect is a 30% reduction in recurrent TB [98, 99]. A potential approach to prevent recurrent TB is secondary preventative therapy (sPT), by continuing the use of anti-TB therapy following completion of treatment for TB. sPT aims to reduce the incidence of recurrent TB in TB patients who have completed treatment for their most recent episode of TB [100]. The World Health Organization (WHO) recommends the use of isoniazid preventative therapy (IPT) in patients with HIV infection.

The TEMPRANO (trial of early antiretrovirals and isoniazid preventative therapy in Africa) study demonstrated that the use of 6 months of IPT combined with early antiretroviral therapy reduced the risk of severe HIV-related comorbidities by 44% and all-cause mortality by 33% [101]. Kabali et al. reported reduced mortality in tuberculin skin test (TST)-positive patients with CD4+ T-cell counts >200 cells/mm3 in a Tanzanian cohort [102]. Charalambous et al. demonstrated a 49% reduction in mortality that remained significant even in patients who had a past history of TB. However, in high-burden countries and in TST-positive patients, a 36-month course of IPT has been recommended. The 36-month IPT course demonstrated a 74% reduced risk of active TB and 68% reduction in mortality compared to the 6-month course [103]. The REMEMBER (reducing early mortality and early morbidity by empirical tuberculosis treatment regimens) study aimed to assess whether empirical TB treatment will reduce early mortality compared with IPT in patients with advanced HIV disease initiating antiretroviral therapy. Overall, empirical TB therapy did not reduce early mortality compared to IPT. However, the low mortality rate in the study underscores the need for TB screening and IPT in patients with HIV [104].

In their review of four studies, Bruin et al. reported the effect of sPT for the prevention of recurrent TB in HIV-infected individuals and the context in which the preventative approach may be applied. All four studies reported that sPT decreased incidence of recurrent TB in comparison to nontreatment groups. Relative reductions varied from 55.0 to 82.1%. However, only one of the four studies reported a significant effect on overall survival [100]. Perriens et al. described the use of isoniazid (INH) and rifampicin (RIF) twice weekly for an additional 6 months in comparison to a placebo. Patients receiving sPT were reported to be significantly less likely to develop recurrent TB compared to the placebo group (relative risk 0.21, p < 0.01) [105]. Haller et al. assessed the effectiveness of INH and sulphadoxine-pyrimethamine as sPT. The relative rate for the incidence of recurrent TB in patients receiving additional treatment (n = 134) and those not (n = 129) was 0.30 (95% confidence interval: 0.09–0.94) [106]. Fitzgerald et al. assessed the use of INH for an additional year following the completion of initial treatment compared to a placebo group. The intervention significantly reduced the incidence of recurrent TB from 7.8 per 100 person-years to 1.4 per 100 person-years (relative risk 0.18, confidence interval: 0.04–0.83) [107]. Churchyard et al. assessed the effect of INH in combination with cotrimoxazole versus cotrimoxazole only or no intervention in HIV-infected gold miners in South Africa. The rate ration for the development of recurrent TB in comparing the groups with INH and the group without INH was 0.45 (95% confidence interval: 0.26–0.78) [108]. As with pPT, the ideal duration and drug choice remain unclear. In all four studies, the duration of treatment varied from 6 to 24 months. The duration of effectiveness of sPT could not be assessed due to the short follow-up periods of the studies. None of the studies included made a distinction between relapse and reinfection as the mechanism of recurrent TB. Furthermore, Haller et al. and Fitzgerald et al. diagnosed recurrent TB by clinical assessment only, which could indicate overestimation of recurrent TB [106, 107].

#### 11. Conclusion and future perspectives

It is well recognized by many that a stratified medicine approach would be a desirable approach for the retreatment of TB. However, the challenge associated with a stratified medicine approach is in identifying groups that are eligible for a longer treatment regimen [94, 95]. There are many identifiable risk factors associated with recurrence, such as a baseline cavitation and month-two smear status that may indicate the need for increasing treatment duration. However, the recent REMoxTB and RIFQUIN studies, which evaluated new regimens aimed at shortening treatment duration for drug-susceptible TB, reported a relapse risk of 2.8 and 3.2%, respectively, with an 18 month follow-up period [96]. Among the factors attributed to poor success of the new regimens in the REMoxTB study, it was suggested that baseline cavitation modified the differences between the results. In contrast, 91% (n = 386) of the patients on the standard 6-month regimen with baseline cavitation had a favorable outcome at the end of the follow-up period [71]. A systematic review by Menzies et al. related to treatment outcomes of rifampicin-containing regimens of various durations showed only a modest benefit in regimens given for nine or more months in comparison to the standard six-month treatment. Thus, the benefit of a stratified

In the context of recurrence due to relapse or reinfection disease, a different treatment approach is required. In the case of reinfection, this can be considered as a new primary infection, and thus, standard regimens may be effective. In contrast, relapse is associated with an increased risk of drug resistance due to the persistence of the original infecting strain under suboptimal treatment. Collectively, all the factors mentioned here underscore the significance an individualized treat-

Active TB disease has been shown to be preventable by the use of primary preventative therapy (pPT), which aims to prevent the first episode of TB in individuals in whom active TB has been excluded. The average preventative effect of pPT in HIV-uninfected individuals is a 60% reduction in the incidence of recurrent TB, while in HIV-infected individuals, the average effect is a 30% reduction in recurrent TB [98, 99]. A potential approach to prevent recurrent TB is secondary preventative therapy (sPT), by continuing the use of anti-TB therapy following completion of treatment for TB. sPT aims to reduce the incidence of recurrent TB in TB patients who have completed treatment for their most recent episode of TB [100]. The World Health Organization (WHO) recommends the use of isoniazid preventative therapy (IPT) in patients

The TEMPRANO (trial of early antiretrovirals and isoniazid preventative therapy in Africa) study demonstrated that the use of 6 months of IPT combined with early antiretroviral therapy reduced the risk of severe HIV-related comorbidities by 44% and all-cause mortality by 33% [101]. Kabali et al. reported reduced mortality in tuberculin skin test (TST)-positive patients with CD4+ T-cell counts >200 cells/mm3 in a Tanzanian cohort [102]. Charalambous et al. demonstrated a 49% reduction in mortality that remained significant even in patients who had a past history of TB. However, in high-burden countries and in TST-positive patients, a 36-month course of IPT has been recommended. The 36-month IPT course demonstrated a 74%

treatment approach remains debatable [97].

26 Tuberculosis

ment approach guided by DST [92, 93].

with HIV infection.

10. Preventative therapy for recurrent TB

Recurrent TB poses a major threat to TB control programs, especially given the persistent vulnerability of HIV-infected patients to tuberculosis, and the higher propensity of recurrent disease being due to resistant MTB strains. In the absence of large-scale population-based surveillance reports, the overall rate of recurrent TB following completion of treatment is significantly underestimated. Current estimates are based on a combination of randomized controlled trials and observational studies, with reliability estimates of the former limited by study follow-up time, and the latter prominently demonstrating higher rates of recurrence. Under clinical trial conditions, adherence rates are better; treatment facilities are more accessible and incorporate adequate follow-up after treatment, leading to improved treatment outcomes and lower rates of recurrence. In contrast, observational studies reflect the operating environment of most high-burden TB facilities.

[3] Trinh QM, Nguyen HL, Nguyen VN, et al. Tuberculosis and HIV co-infection-focus on the Asia-Pacific region. International Journal of Infectious Diseases. 2015;32:170-178.

Insights into Recurrent Tuberculosis: Relapse Versus Reinfection and Related Risk Factors

http://dx.doi.org/10.5772/intechopen.73601

29

[4] Mathema B, Kurepina NE, Bifani PJ, et al. Molecular epidemiology of tuberculosis: Current insights. Clinical Microbiology Reviews. 2006;19(4):658-685. DOI: 10.1128/CMR.00061-05

[5] Panjabi R, Comstock GW, Recurrent GJE. Tuberculosis and its risk factors: Adequately treated patients are still at high risk. The International Journal of Tuberculosis and Lung

[6] Lambert ML, Hasker E, Van Deun A, et al. Recurrence in tuberculosis: Relapse or reinfec-

[7] Chaisson RE, Churchyard GJ. Recurrent tuberculosis: Relapse, reinfection, and HIV. The

[8] Guerra-Assunção JA, Houben RMGJ, Crampin AC, et al. Recurrence due to relapse or reinfection with Mycobacterium tuberculosis: A whole-genome sequencing approach in a large, population-based cohort with a high HIV infection prevalence and active follow-

[9] Glynn JR, Murray J, Bester A, et al. High rates of recurrence in HIV-infected and HIVuninfected patients with tuberculosis. The Journal of Infectious Diseases. 2010;201(5):

[10] Charalambous S, Grant AD, Moloi V, et al. Contribution of reinfection to recurrent tuberculosis in South African gold miners. The International Journal of Tuberculosis

[11] Narayanan S, Swaminathan S, Supply P, et al. Impact of HIV infection on the recurrence of tuberculosis in South India. The Journal of Infectious Diseases. 2010;201:691-703 [12] Sun Y, Harley D, Vally H, et al. Impact of multidrug resistance on tuberculosis recur-

[13] Luzze H, Johnson DF, Dickman K, et al. Relapse more common than reinfection in recurrent tuberculosis 1–2 years post treatment in urban Uganda. The International

[14] Vree M, Huong NT, Duong BD, et al. Survival and relapse rate of tuberculosis patients who successfully completed treatment in Vietnam. The International Journal of Tuber-

[15] Datiko DG, Lindtjørn B, et al. Tuberculosis recurrence in smear-positive patients cured under DOTS in Southern Ethiopia: Retrospective cohort study. BMC Public Health. 2009;

[16] Moosazadeh M, Bahrampour A, Nasehi M, et al. The incidence of recurrence of tuberculosis and its related factors in smear-positive pulmonary tuberculosis patients in Iran: A

DOI: 10.1016/j.ijid.2014.11.023

Disease. 2007;11(8):828-837

and Lung Disease. 2008;12:942-948

704-711

9(348)

tion? The Lancet Infectious Diseases. 2003;3:282-287

Journal of Infectious Diseases. 2010;201(5):653-655

up. The Journal of Infectious Diseases. 2015;211(7):1154-1163

rence and long-term outcome in China. PLoS. 2017;12(1):e0168865

Journal of Tuberculosis and Lung Disease. 2013;17(3):361-367

retrospective cohort study. Lung India. 2015;32(6):557-560

culosis and Lung Disease. 2007;11(4):392-397

Distinguishing between relapse and reinfection is of paramount importance in addressing the burden of recurrent TB disease. High rates of relapse demand renewed interventions to improve individual patient care while high rates of reinfection demand improved infection and epidemic control measures. Urgent attention is required to address challenges of adherence, such as social and health care worker support systems and step-down management facilities. With the heightened risk or recurrent TB in HIV, TB screening should be conducted at all ART follow-up visits, and TB preventative therapy should be implemented in all HIVpositive patients completing TB treatment. Enhanced infection control strategies should be implemented in clinical and community settings to reduce ongoing transmission of TB. There has been considerable disparity in the studies reporting on the role of relapse versus reinfection. Further large-scale studies are required to address the role of relapse and reinfection as well as the role of mixed infections in recurrent TB.

This review highlights well-established principles in TB control. TB recurrence rates are grossly underestimated and are highest in those with extensive pulmonary disease and cavitary disease and in those with comorbidities such as HIV infection and diabetes. Active case findings among these patients within 12 months of completing treatment would enable early detection of TB recurrence. Enhanced treatment options, such as intensified initial treatment, extension of treatment, and secondary preventative therapy for patients presenting with multiple risk factors will prevent recurrent TB infection. Understanding the immunological correlates that offer protection against recurrent TB will also play a role in host-directed therapy and reducing recurrent TB.

#### Author details

Kogieleum Naidoo1,2\* and Navisha Dookie1

\*Address all correspondence to<EMAIL_ADDRESS>
1 Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa

2 South African Medical Research Council (SAMRC) – CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Durban, South Africa

#### References

[3] Trinh QM, Nguyen HL, Nguyen VN, et al. Tuberculosis and HIV co-infection-focus on the Asia-Pacific region. International Journal of Infectious Diseases. 2015;32:170-178. DOI: 10.1016/j.ijid.2014.11.023

outcomes and lower rates of recurrence. In contrast, observational studies reflect the operating

Distinguishing between relapse and reinfection is of paramount importance in addressing the burden of recurrent TB disease. High rates of relapse demand renewed interventions to improve individual patient care while high rates of reinfection demand improved infection and epidemic control measures. Urgent attention is required to address challenges of adherence, such as social and health care worker support systems and step-down management facilities. With the heightened risk or recurrent TB in HIV, TB screening should be conducted at all ART follow-up visits, and TB preventative therapy should be implemented in all HIVpositive patients completing TB treatment. Enhanced infection control strategies should be implemented in clinical and community settings to reduce ongoing transmission of TB. There has been considerable disparity in the studies reporting on the role of relapse versus reinfection. Further large-scale studies are required to address the role of relapse and reinfection as

This review highlights well-established principles in TB control. TB recurrence rates are grossly underestimated and are highest in those with extensive pulmonary disease and cavitary disease and in those with comorbidities such as HIV infection and diabetes. Active case findings among these patients within 12 months of completing treatment would enable early detection of TB recurrence. Enhanced treatment options, such as intensified initial treatment, extension of treatment, and secondary preventative therapy for patients presenting with multiple risk factors will prevent recurrent TB infection. Understanding the immunological correlates that offer protection against recurrent TB will also play a role in host-directed therapy and

1 Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of

2 South African Medical Research Council (SAMRC) – CAPRISA HIV-TB Pathogenesis and

[1] World Health Organization. Global Tuberculosis Report. 2017 [cited Nov 30, 2017]. Avail-

[2] Kwan CK, Ernst JD. HIV and tuberculosis: A deadly human syndemic. Clinical Microbi-

able from: http://www.who.int/tb/publications/global\_report/en/

ology Reviews. 2011;24(2):351-376. DOI: 10.1128/CMR.00042-10

environment of most high-burden TB facilities.

28 Tuberculosis

well as the role of mixed infections in recurrent TB.

Kogieleum Naidoo1,2\* and Navisha Dookie1

Treatment Research Unit, Durban, South Africa

KwaZulu-Natal, Durban, South Africa

\*Address all correspondence to<EMAIL_ADDRESS>
reducing recurrent TB.

Author details

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[85] Dheeda K, Schwander SK, Zhu B, et al. The immunology of tuberculosis: From bench to

[86] Cardona PJ. Reactivation or reinfection in adult tuberculosis: Is that the question? Inter-

[87] Thobakgale C, Naidoo K, McKinnon LR, et al. Interleukin 1-beta (IL-1β) production by innate cells following TLR stimulation correlates with TB recurrence in ART-treated HIVinfected patients. Journal of Acquired Immune Deficiency Syndromes. 2017;74(2):213-220

[88] Sivro A, McKinnon LR, Yende-Zuma N, et al. Plasma cytokine predictors of tuberculosis recurrence in antiretroviral-treated HIV-infected individuals from Durban, South Africa.

[89] Mistry R, Cliff JM, Clayton CL, et al. Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis. The Journal of Infectious Diseases. 2007;195:

[90] Cliff JM, Cho J, Lee J, et al. Excessive cytolytic responses predict tuberculosis relapse after apparently successful treatment. The Journal of Infectious Diseases. 2016;213:485-495 [91] Thompson EG, Du Y, Malherbe ST, et al. Host blood RNA signatures predict the out-

[92] De Steenwinkel JEM, Knegt GJ, Ten Kate MT, et al. Relapse of tuberculosis versus primary tuberculosis; course, pathogenesis and therapy in mice. Tuberculosis. 2013;93:

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[96] Jindani A, Harrison TS, Nunn AJ, et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. The New England Journal of Medicine. 2014;371:1599-1608 [97] Menzies D, Benedetti A, Paydar A, et al. Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: A systematic review and meta-analysis. PLoS Med-

[98] Smieja MJ, Marchetti CA, Cook DJ, et al. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database of Systematic Reviews. 2000;(2):CD001363

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[75] Kim L, Moonan PK, Heilig CM, et al. Factors associated with recurrent tuberculosis more than 12 months after treatment completion. The International Journal of Tubercu-

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34 Tuberculosis

[99] Akolo C, Adetifa I, Shepperd S, et al. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database of Systematic Reviews. 2010;CD000171

**Chapter 2**

**Provisional chapter**

**Tuberculosis: A Risk Factor Approach**

**Tuberculosis: A Risk Factor Approach**

DOI: 10.5772/intechopen.73538

One in three people in the world is infected with *Mycobacterium tuberculosis*, and 10% of infected individuals will develop the disease at any time in their lifetime. Today, despite the advances in diagnosis and treatment, tuberculosis (TB) remains as one of the biggest challenges in global public health, and low and middle-income countries are the most affected. The risk for developing the disease depends on endogenous, exogenous, and environmental factors. Among the most relevant conditions that could precipitate TB development are those that affect the host-immune response. HIV infection increase about 20 times the risk of TB, and other more common conditions, such as diabetes mellitus, malnutrition, and smoking, also contribute in a big way to the TB pandemic. Global TB control programs in order to achieve the disease control objectives must integrate strategies that have a direct impact on risk factors, not only at an individual level but also on a public health policy level. Here, we review some of the most important risk factors

for the development of TB, as one of the most relevant ways for TB control.

Tuberculosis (TB) is a bacterial infectious disease caused by *Mycobacterium tuberculosis* complex organisms, it is an airborne-transmitted condition pathologically characterized by a necrotizing granulomatous response (**Figure 1**) that involves the lungs in 80% of cases, however any organ can be affected [1]. This disease probably emerged about 70,000 years ago, along with the modern-human being's migration from Africa [2]. An estimated of 1 billion people have died of TB in the last two centuries, and now represents one of the biggest public health

**Keywords:** tuberculosis, risk factor, epidemiology, prevention, control

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Leonardo F. Jurado and Diana M. Palacios

Leonardo F. Jurado and Diana M. Palacios

http://dx.doi.org/10.5772/intechopen.73538

**Abstract**

**1. Introduction**

problems worldwide [3].

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **Tuberculosis: A Risk Factor Approach Tuberculosis: A Risk Factor Approach**

Leonardo F. Jurado and Diana M. Palacios Leonardo F. Jurado and Diana M. Palacios

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73538

#### **Abstract**

[99] Akolo C, Adetifa I, Shepperd S, et al. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database of Systematic Reviews. 2010;CD000171

[100] Bruins WS, van Leth F. Effect of secondary preventive therapy on recurrence of tuberculosis in HIV-infected individuals: A systematic review. Infectious Diseases. 2017;49(3):

[101] The Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. Agence National de Recherche sur le Sida et les h'epatites virales 12136 Study Group. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. The New England

[102] Kabali C, von Reyn CF, Brooks DR, et al. Completion of isoniazid preventive therapy and survival in HIV-infected, TST positive adults in Tanzania. The International Journal

[103] Charalambous S, Grant AD, Innes C, et al. Association of isoniazid preventive therapy with lower early mortality in individuals on antiretroviral therapy in a workplace

[104] Hosseinipour MC, Bisson GP, Miyahara S, et al. Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): A multicountry open-label randomised controlled trial. Lancet. 2016;

[105] Perriens JH, St Louis ME, Mukadi YB, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. The New

[106] Haller L, Sossouhounto R, Coulibaly IM, et al. Isoniazid plus sulphadoxine-pyrimethamine can reduce morbidity of HIV-positive patients treated for tuberculosis in Africa: A con-

[107] Fitzgerald DW, Desvarieux M, Severe P, et al. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: A randomized trial.

[108] Churchyard GJ, Fielding K, Charalambous S, et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: Time to change policy?

programme. Acquired Immune Deficiency Syndrome. 2010;24(5):S5-S13

161-169

36 Tuberculosis

Journal of Medicine. 2015;373:808-822

387(10024):1198-1209

Lancet. 2000;356:1470-1474

of Tuberculosis and Lung Disease. 2011;15:1515-1521

England Journal of Medicine. 1995;332:779-784

trolled clinical trial. Chemotherapy. 1999;45:452-465

Acquired Immune Deficiency Syndrome. 2003;17:2063-2070

One in three people in the world is infected with *Mycobacterium tuberculosis*, and 10% of infected individuals will develop the disease at any time in their lifetime. Today, despite the advances in diagnosis and treatment, tuberculosis (TB) remains as one of the biggest challenges in global public health, and low and middle-income countries are the most affected. The risk for developing the disease depends on endogenous, exogenous, and environmental factors. Among the most relevant conditions that could precipitate TB development are those that affect the host-immune response. HIV infection increase about 20 times the risk of TB, and other more common conditions, such as diabetes mellitus, malnutrition, and smoking, also contribute in a big way to the TB pandemic. Global TB control programs in order to achieve the disease control objectives must integrate strategies that have a direct impact on risk factors, not only at an individual level but also on a public health policy level. Here, we review some of the most important risk factors for the development of TB, as one of the most relevant ways for TB control.

DOI: 10.5772/intechopen.73538

**Keywords:** tuberculosis, risk factor, epidemiology, prevention, control

#### **1. Introduction**

Tuberculosis (TB) is a bacterial infectious disease caused by *Mycobacterium tuberculosis* complex organisms, it is an airborne-transmitted condition pathologically characterized by a necrotizing granulomatous response (**Figure 1**) that involves the lungs in 80% of cases, however any organ can be affected [1]. This disease probably emerged about 70,000 years ago, along with the modern-human being's migration from Africa [2]. An estimated of 1 billion people have died of TB in the last two centuries, and now represents one of the biggest public health problems worldwide [3].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**2. Human immunodeficiency virus and TB coinfection**

tion and its associated morbidity and mortality outcomes [10, 15].

infectious-related mortality [10].

cell levels [10].

areas where HIV and poverty coexist [10].

less frequent, with sputum smears likely negative [24].

HIV coinfection is the most important immunosuppressive condition for developing active TB [10]. HIV infection substantially increases the possibility of TB reactivation from latent infection [11], and in the same way contributes to rapid TB progression after infection with *M. tuberculosis* [12, 13]. According to WHO estimations, people living with HIV (PLWHIV) latently TB-infected, have a 26-fold-higher risk of disease progression than those with no HIV [14]. Thus, HIV and TB coinfection configure a lethal synergy, where HIV markedly increases susceptibility for TB and exacerbates the severity of the disease, while TB accelerates HIV replica-

Tuberculosis: A Risk Factor Approach http://dx.doi.org/10.5772/intechopen.73538 39

In 2012, 34.5 million people were living with HIV worldwide [16]. This epidemic affects every country in the world, but the disease burden is highest in developing countries, among which the sub-Saharan Africa region is the most affected, where 69% of worldwide infected people live [16]. Due to the advances on therapy and prevention strategies, deaths related to HIV have decreased substantially over the past years, but reductions in TB-related deaths have not kept pace, a sample of this, in 2014 TB overpasses HIV as the leading cause of global

Among 9.6 million new TB cases reported worldwide in 2014, 12% (1.2 million) were also HIV positive, and of the 1.5 million who died from TB, 33% (4,00,000) were HIV coinfected, thus TB constitutes main mortality cause in PLWHIV [14]. Evidently, the TB incidence and TB-related mortality are strengthened by HIV burden and represent a real public health challenge in

It is clear that antiretroviral therapy (ART) reduces rapidly and substantially TB incidence in PLWHIV, and this is true both in high and low endemic TB areas [17–19]. Nevertheless, even in people under ART, the risk of TB remains high compared with the general population. For HIV-negative people with latent TB infection (LTBI), the lifetime risk of developing TB rounds 5–10% [20, 21], but in the case of PLWHIV the annual risk of reactivation is 3–16% [22], with the higher risk of TB disease almost immediately after HIV infection, even with normal CD4

The immunologic control of TB is an intricate phenomenon that involves multiple pathways, cellular lines, and host-pathogen interactions [6]. In PLWHIV, macrophages present a phenotype with altered activity of molecules like iNOS and TNFα, which is reflected as incapacity for *M. tuberculosis* killing [23]. The histopathologic features in PLWHIV who develop TB, correlate and depend on the level of immunosuppression, individuals with apparently normal immune response present typical granulomas (**Figure 1**), these well-structured aggregates may break down, giving way to cavitary disease and bacilli expectoration, but as the immunodeficiency advance, granulomas are poorly formed or even absent, so the cavitary form is

In like manner that HIV infection increases the TB risk and its related complications, TB also affects HIV infection outcomes. In a study conducted by Lawn et al. [25], HIV patients on

**Figure 1.** This illustration represents a tuberculous granuloma at its most basic way. It is a compact, dynamic and organized aggregate of epithelioid macrophages, and these cells usually fuse into multinucleated giant cells or differentiate into foam cells characterized by lipid accumulation. *M. tuberculosis* is usually present in the central necrotic area in which dead and dying cells are present. Many other cell types are also infiltrating the granuloma (neutrophils, dendritic cells, B and T lymphocytes, natural killer cells and fibroblasts) (original illustration by Jurado LF).

One third of world population is latently infected with *M. tuberculosis*, but only 10% of infected people will develop active disease during their live, half during the first 2 years after infection, and the remainder at any moment of their lifetime [4]. In most infected individuals, the progression is contained by the immune system. In 2013, an estimated 9 million new TB cases were reported globally, equivalent to 126 cases per 100,000 population, with more than 60% of the ill people living in 22 countries (considered as high-burden countries). However, according to WHO estimations during the same year around 3.3 million cases were missed (not reported or undiagnosed), accounting for a detection rate of only around 64%. The global HIV-coinfection proportion was 13% (1.1 million people), and HIV-associated TB deaths accounted for 25% of the total number of TB deaths [5].

The pathogenic mechanisms that determine active-TB progression are a multiple-stage game before and after the infection event, where the host-immune response integrity is one of the most relevant performers [6]. The infected individual may either rapidly progress to disease (primary progressive disease), may develop a particular status called latent TB infection, or may be able to kill the organism [7]. The occurrence of one of these scenarios depends on the determinants of host-immune response and the infection-stage in each individual. Most of the immune determinants that drive this pandemic constitute risk factors, which could be modified in order to impact positively on global TB control.

Among the relevant risk factors for TB, HIV infection is the most important, however, at the population level, diabetes mellitus (DM), malnutrition, tobacco smoking, and even immunosuppressive drugs, which are present in a larger section of the population than HIV infection, can represent a bigger impact on TB epidemiology [8, 9]. This chapter aims to summarize some of the most relevant risk factors for TB, focusing on general interventions for disease control.

### **2. Human immunodeficiency virus and TB coinfection**

One third of world population is latently infected with *M. tuberculosis*, but only 10% of infected people will develop active disease during their live, half during the first 2 years after infection, and the remainder at any moment of their lifetime [4]. In most infected individuals, the progression is contained by the immune system. In 2013, an estimated 9 million new TB cases were reported globally, equivalent to 126 cases per 100,000 population, with more than 60% of the ill people living in 22 countries (considered as high-burden countries). However, according to WHO estimations during the same year around 3.3 million cases were missed (not reported or undiagnosed), accounting for a detection rate of only around 64%. The global HIV-coinfection proportion was 13% (1.1 million people), and HIV-associated TB deaths

dendritic cells, B and T lymphocytes, natural killer cells and fibroblasts) (original illustration by Jurado LF).

**Figure 1.** This illustration represents a tuberculous granuloma at its most basic way. It is a compact, dynamic and organized aggregate of epithelioid macrophages, and these cells usually fuse into multinucleated giant cells or differentiate into foam cells characterized by lipid accumulation. *M. tuberculosis* is usually present in the central necrotic area in which dead and dying cells are present. Many other cell types are also infiltrating the granuloma (neutrophils,

The pathogenic mechanisms that determine active-TB progression are a multiple-stage game before and after the infection event, where the host-immune response integrity is one of the most relevant performers [6]. The infected individual may either rapidly progress to disease (primary progressive disease), may develop a particular status called latent TB infection, or may be able to kill the organism [7]. The occurrence of one of these scenarios depends on the determinants of host-immune response and the infection-stage in each individual. Most of the immune determinants that drive this pandemic constitute risk factors, which could be modi-

Among the relevant risk factors for TB, HIV infection is the most important, however, at the population level, diabetes mellitus (DM), malnutrition, tobacco smoking, and even immunosuppressive drugs, which are present in a larger section of the population than HIV infection, can represent a bigger impact on TB epidemiology [8, 9]. This chapter aims to summarize some of the most relevant risk factors for TB, focusing on general interventions for disease

accounted for 25% of the total number of TB deaths [5].

fied in order to impact positively on global TB control.

control.

38 Tuberculosis

HIV coinfection is the most important immunosuppressive condition for developing active TB [10]. HIV infection substantially increases the possibility of TB reactivation from latent infection [11], and in the same way contributes to rapid TB progression after infection with *M. tuberculosis* [12, 13]. According to WHO estimations, people living with HIV (PLWHIV) latently TB-infected, have a 26-fold-higher risk of disease progression than those with no HIV [14]. Thus, HIV and TB coinfection configure a lethal synergy, where HIV markedly increases susceptibility for TB and exacerbates the severity of the disease, while TB accelerates HIV replication and its associated morbidity and mortality outcomes [10, 15].

In 2012, 34.5 million people were living with HIV worldwide [16]. This epidemic affects every country in the world, but the disease burden is highest in developing countries, among which the sub-Saharan Africa region is the most affected, where 69% of worldwide infected people live [16]. Due to the advances on therapy and prevention strategies, deaths related to HIV have decreased substantially over the past years, but reductions in TB-related deaths have not kept pace, a sample of this, in 2014 TB overpasses HIV as the leading cause of global infectious-related mortality [10].

Among 9.6 million new TB cases reported worldwide in 2014, 12% (1.2 million) were also HIV positive, and of the 1.5 million who died from TB, 33% (4,00,000) were HIV coinfected, thus TB constitutes main mortality cause in PLWHIV [14]. Evidently, the TB incidence and TB-related mortality are strengthened by HIV burden and represent a real public health challenge in areas where HIV and poverty coexist [10].

It is clear that antiretroviral therapy (ART) reduces rapidly and substantially TB incidence in PLWHIV, and this is true both in high and low endemic TB areas [17–19]. Nevertheless, even in people under ART, the risk of TB remains high compared with the general population. For HIV-negative people with latent TB infection (LTBI), the lifetime risk of developing TB rounds 5–10% [20, 21], but in the case of PLWHIV the annual risk of reactivation is 3–16% [22], with the higher risk of TB disease almost immediately after HIV infection, even with normal CD4 cell levels [10].

The immunologic control of TB is an intricate phenomenon that involves multiple pathways, cellular lines, and host-pathogen interactions [6]. In PLWHIV, macrophages present a phenotype with altered activity of molecules like iNOS and TNFα, which is reflected as incapacity for *M. tuberculosis* killing [23]. The histopathologic features in PLWHIV who develop TB, correlate and depend on the level of immunosuppression, individuals with apparently normal immune response present typical granulomas (**Figure 1**), these well-structured aggregates may break down, giving way to cavitary disease and bacilli expectoration, but as the immunodeficiency advance, granulomas are poorly formed or even absent, so the cavitary form is less frequent, with sputum smears likely negative [24].

In like manner that HIV infection increases the TB risk and its related complications, TB also affects HIV infection outcomes. In a study conducted by Lawn et al. [25], HIV patients on ART who develop TB, presented more alterations on CD4 counts than individuals who never developed TB. Studies have shown that TB associates with rapid progression to AIDS and higher death risk [26, 27] and TB also appears to induce viral replication and viral diversity via up regulating the host-immune response [15, 28].

(relative risk 3.11; 95% IC 2.27 – 4.26) [42], notwithstanding, this epidemiological aspect is the best characterized in the DM-TB association, a wide variation between studies is observed, with risk ratios around 0.99 and 7.83 [39], which evidences the difficulty of studying DM-TB relation, in part due the heterogeneity in the prevalence and other sociodemographic and cultural features of DM and TB in each part of the world. Besides, in the case of DM, the presence of other host characteristics as smoking, malnutrition, micro- and macrovascular

Tuberculosis: A Risk Factor Approach http://dx.doi.org/10.5772/intechopen.73538 41

The relevance of the DM-TB comorbidity is higher in low and middle-income countries, where both diseases are more prevalent. In fact, as reported by the WHO, of the 10 countries with more DM patients worldwide, six are also classified as high burden countries for TB (China, India, Brazil, Bangladesh, Indonesia, and Russia) [44]. During the last years, studies have marked differences in DM's frequency among patients with TB, from 36% in Mexico to

Talking about the impact of DM in TB control, at the population level, the general attributable risk is 10–20%, and also a variation between different populations is observed, even in the same country, for example, in the United Kingdom, the general population risk rounds 10%, but rises 20% for Asian males [49], in countries like Mexico, where DM is endemic the general attributable risk is about 20% [50], and in the EU – Mexico border, 51% of the TB patients who are 35–60 years-old also have DM [45]. And even though the DM confers a notably lower risk compared with HIV, in certain populations where the HIV prevalence is low, the contribution

Recently, an elegant study by Pan et al. [52], using models of dynamic TB transmission, estimated the potential effects of DM on TB epidemiology in 13 high burden countries, found that interrupting the rise in DM incidence, could prevent 6 million cases and 1.1 million deaths due TB in 2 decades. These findings show how beneficial for TB control would be an integral

It is known that DM modifies the clinical presentation, disease-course and TB prognosis, and represents a risk factor for treatment-failure [35]. DM-TB patients (versus TB patients without DM) are more prone to develop sputum smear-positive TB, pulmonary TB (versus extrapulmonary), cavitary (versus noncavitary) at the moment of diagnosis, and in DM-TB patients the sputum smear conversion takes more time [53]. *Mycobacterium tuberculosis* infection induces a strong cell-mediated immune response that triggers a granulomatous response, which, according to recent investigations is a double-edged sword for the host [54], because although this phenomenon initially limits bacilli replication, the growing and rupture of these structures into the airways, facilitates not only the cavitary form of the disease but also, its sputum smear-positive presentation [44]. These findings, allows to postulate that DM-TB

Evidence from observational studies, have shown that DM comorbidity is related to adverse TB outcomes, as delays in sputum conversion, increased risk for treatment failures, relapse, death, and even reinfection [55]. Baker et al. [56] in a meta-analysis of recent DM-TB association studies found that the odds of dying of TB, or any other reason, was 2-fold higher [RR, 1.89; 95% CI, 1.52–2.36], and this risk rise to 4.95, when data was adjusted for age and potential

compromise, can synergize and increase the TB risk [43].

40 and 56% in the Pacific Islands and India, respectively [45–48].

of DM is more important than HIV infection [51].

patients would be more infectious that TB-only patients.

intervention on DM occurrence.

As we previously exposed, PLWHIV have the higher risk of progression from latent to active TB disease, this possibility can be reduced using two fundamental strategies: adequate ART and prophylactic LTBI treatment [19, 29], studies support the use of both strategies even in patients with high CD4 counts [33]. Thus, it is highly recommended to provide ART to all HIV-infected people irrespective of CD4 count [17].

Considering the risk, all PLWHIV should be screened using TST for LTBI at the time of HIV diagnosis [30]. Once a patient has a positive result for LTBI, active disease must be ruled out, and preventive therapy offered. Among the preventive therapy options, two of the most accepted are: daily isoniazid 5 mg/kg (maximum 300 mg) for 9 months plus pyridoxine supplementation or once a week rifapentine plus isoniazid (900/900 mg) for 3 months (12 total doses) [31, 32]. These regimens can be used with nucleoside reverse transcriptase inhibitors and efavirenz [33], rifapentine cannot be administered together with protease inhibitors, but it could be offered with raltegravir [34].

### **3. Diabetes mellitus and TB comorbidity**

The worldwide rising in type II diabetes mellitus prevalence constitutes one of the biggest challenges for TB control [35]; in fact, nowadays there are more individuals living with DM-TB comorbidity that HIV-TB coinfection [36]. This association has been recognized historically [37]; however, it became less evident in the 1950s, in part due to the development of insulin therapy for a DM and antibiotics for TB [35]. Since 1980 as the DM pandemic (prevalence increasing >20% in three decades) was more evident, many papers on the DM-TB association began to reemerge [35].

As a result of a sedentary lifestyle, changes in diet, population aging, and urbanization, the global DM prevalence by 2000 was 171 million people, and is predicted that this number reaches 642 million in 2040, considering that 80% of DM population live in low- and middleincome countries, where the TB situation is worst [38].

Biological evidence supports that DM induces a direct impairment on innate and adaptive immune responses, increasing TB susceptibility [8]. However, the DM case differs from other causes of immunological impairment like HIV infection or malnutrition, because DM response is more dysfunctional rather than dismissing, characterized by excessive and/or delayed responses against *M. tuberculosis* [39]. Investigations in humans and animals have shown altered production of cytokines as INF- and IL-17 that affects the T-cell immune response [40] and reduced chemotaxis of neutrophils [41].

According to multiple studies, at an individual level, people with DM have three times more risk of developing TB, and two-fold increase in adverse TB therapy outcomes [8]. A systematic review of 13 studies reported that DM increases three times the risk of developing TB, (relative risk 3.11; 95% IC 2.27 – 4.26) [42], notwithstanding, this epidemiological aspect is the best characterized in the DM-TB association, a wide variation between studies is observed, with risk ratios around 0.99 and 7.83 [39], which evidences the difficulty of studying DM-TB relation, in part due the heterogeneity in the prevalence and other sociodemographic and cultural features of DM and TB in each part of the world. Besides, in the case of DM, the presence of other host characteristics as smoking, malnutrition, micro- and macrovascular compromise, can synergize and increase the TB risk [43].

ART who develop TB, presented more alterations on CD4 counts than individuals who never developed TB. Studies have shown that TB associates with rapid progression to AIDS and higher death risk [26, 27] and TB also appears to induce viral replication and viral diversity

As we previously exposed, PLWHIV have the higher risk of progression from latent to active TB disease, this possibility can be reduced using two fundamental strategies: adequate ART and prophylactic LTBI treatment [19, 29], studies support the use of both strategies even in patients with high CD4 counts [33]. Thus, it is highly recommended to provide ART to all

Considering the risk, all PLWHIV should be screened using TST for LTBI at the time of HIV diagnosis [30]. Once a patient has a positive result for LTBI, active disease must be ruled out, and preventive therapy offered. Among the preventive therapy options, two of the most accepted are: daily isoniazid 5 mg/kg (maximum 300 mg) for 9 months plus pyridoxine supplementation or once a week rifapentine plus isoniazid (900/900 mg) for 3 months (12 total doses) [31, 32]. These regimens can be used with nucleoside reverse transcriptase inhibitors and efavirenz [33], rifapentine cannot be administered together with protease inhibitors, but

The worldwide rising in type II diabetes mellitus prevalence constitutes one of the biggest challenges for TB control [35]; in fact, nowadays there are more individuals living with DM-TB comorbidity that HIV-TB coinfection [36]. This association has been recognized historically [37]; however, it became less evident in the 1950s, in part due to the development of insulin therapy for a DM and antibiotics for TB [35]. Since 1980 as the DM pandemic (prevalence increasing >20% in three decades) was more evident, many papers on the DM-TB association

As a result of a sedentary lifestyle, changes in diet, population aging, and urbanization, the global DM prevalence by 2000 was 171 million people, and is predicted that this number reaches 642 million in 2040, considering that 80% of DM population live in low- and middle-

Biological evidence supports that DM induces a direct impairment on innate and adaptive immune responses, increasing TB susceptibility [8]. However, the DM case differs from other causes of immunological impairment like HIV infection or malnutrition, because DM response is more dysfunctional rather than dismissing, characterized by excessive and/or delayed responses against *M. tuberculosis* [39]. Investigations in humans and animals have shown altered production of cytokines as INF- and IL-17 that affects the T-cell immune

According to multiple studies, at an individual level, people with DM have three times more risk of developing TB, and two-fold increase in adverse TB therapy outcomes [8]. A systematic review of 13 studies reported that DM increases three times the risk of developing TB,

via up regulating the host-immune response [15, 28].

40 Tuberculosis

HIV-infected people irrespective of CD4 count [17].

**3. Diabetes mellitus and TB comorbidity**

income countries, where the TB situation is worst [38].

response [40] and reduced chemotaxis of neutrophils [41].

it could be offered with raltegravir [34].

began to reemerge [35].

The relevance of the DM-TB comorbidity is higher in low and middle-income countries, where both diseases are more prevalent. In fact, as reported by the WHO, of the 10 countries with more DM patients worldwide, six are also classified as high burden countries for TB (China, India, Brazil, Bangladesh, Indonesia, and Russia) [44]. During the last years, studies have marked differences in DM's frequency among patients with TB, from 36% in Mexico to 40 and 56% in the Pacific Islands and India, respectively [45–48].

Talking about the impact of DM in TB control, at the population level, the general attributable risk is 10–20%, and also a variation between different populations is observed, even in the same country, for example, in the United Kingdom, the general population risk rounds 10%, but rises 20% for Asian males [49], in countries like Mexico, where DM is endemic the general attributable risk is about 20% [50], and in the EU – Mexico border, 51% of the TB patients who are 35–60 years-old also have DM [45]. And even though the DM confers a notably lower risk compared with HIV, in certain populations where the HIV prevalence is low, the contribution of DM is more important than HIV infection [51].

Recently, an elegant study by Pan et al. [52], using models of dynamic TB transmission, estimated the potential effects of DM on TB epidemiology in 13 high burden countries, found that interrupting the rise in DM incidence, could prevent 6 million cases and 1.1 million deaths due TB in 2 decades. These findings show how beneficial for TB control would be an integral intervention on DM occurrence.

It is known that DM modifies the clinical presentation, disease-course and TB prognosis, and represents a risk factor for treatment-failure [35]. DM-TB patients (versus TB patients without DM) are more prone to develop sputum smear-positive TB, pulmonary TB (versus extrapulmonary), cavitary (versus noncavitary) at the moment of diagnosis, and in DM-TB patients the sputum smear conversion takes more time [53]. *Mycobacterium tuberculosis* infection induces a strong cell-mediated immune response that triggers a granulomatous response, which, according to recent investigations is a double-edged sword for the host [54], because although this phenomenon initially limits bacilli replication, the growing and rupture of these structures into the airways, facilitates not only the cavitary form of the disease but also, its sputum smear-positive presentation [44]. These findings, allows to postulate that DM-TB patients would be more infectious that TB-only patients.

Evidence from observational studies, have shown that DM comorbidity is related to adverse TB outcomes, as delays in sputum conversion, increased risk for treatment failures, relapse, death, and even reinfection [55]. Baker et al. [56] in a meta-analysis of recent DM-TB association studies found that the odds of dying of TB, or any other reason, was 2-fold higher [RR, 1.89; 95% CI, 1.52–2.36], and this risk rise to 4.95, when data was adjusted for age and potential confounders, the same study also calculated a 4-fold risk of relapse for DM-TB individuals versus TB-only patients.

housing conditions and nutritional interventions on TB epidemiology, therefore a well-planned

Tuberculosis: A Risk Factor Approach http://dx.doi.org/10.5772/intechopen.73538 43

People with immune-mediated inflammatory diseases, such as rheumatoid arthritis, systemic erythematous lupus, ankylosing spondylitis, inflammatory bowel disease, etc., also represent a high-risk group for developing TB, and this risk is even higher when they are treated with

Different cells produce TNF, including macrophages, T cells, fibroblast, and keratinocytes. TNF is a molecule with a wide functional spectrum, plays a key role in immune response to infections, cancer etiology, and the physiopathology of many immune-mediated disorders [67]. It is also known that is important in the immune response against intracellular bacteria, and the physiology and integrity of granulomatous (**Figure 1**) TB-related response during

During the past two decades, TNF antagonists have been successfully used for the treatment of inflammatory diseases, when patients do not respond to conventional therapy [67]. In the United States, using national surveillance data, found that TB incidence in AR patients increased from 6.2 per 100,000 people to 144 per 100,000 in who received infliximab and 35 per 100,000 for etanercept-treated individuals [69]. A Spanish study collected data from 71 information centers, with a total of 1540 patients receiving infliximab, estimated a TB incidence in 1893 per 100,000 people, compared with a previous reports incidence of 21 per 100,000 in the general population and 95 per 100,000 in AR patients without TNF treatment [70]. An important proportion of extrapulmonary TB is observed, and several reports have attributed

Most of the active TB cases in individuals treated with TNF antagonist correspond to reactivation from LTBI, when this occurs, generally happen concomitantly with the initiation of the TNF antagonist, nevertheless, also cases with long treatment periods, have been reported [67]. Therefore, screening for LTBI before any TNF inhibitor treatment initiation is mandatory, here, as in the case of other immunosuppressive conditions, such as HIV infection, both TST and IGRAs assays could be used, nowadays, there is not sufficient evidence to recommend one method over another, and considering this, an expert consensus, suggest using IGRAs or

Once a patient has a positive result for LTBI, active disease must be ruled out, and preventive therapy offered. Among the preventive therapy options, two of the most accepted are: daily isoniazid 5 mg/kg (maximum 300 mg) for 9 months plus pyridoxine supplementation or a combined regimen with isoniazid and rifampicin for 3 months [69]. Multiple recommendations on delay periods between LTBI preventive chemotherapy and TNF antagonist have been proposed, ranging from starting both concurrently, to waiting even a month after finishing LTBI prophylaxis [67, 68], these decisions must always consider the patients clinical

wide intervention would impact positively on TB control.

tumor necrosis factor α (TNF α) – antagonist [66, 67].

differential risk for each TNF antagonist [68].

TST in people without history of BCG vaccination [71].

status.

LTBI, therefore its antagonism associates with TB progression [6].

**5. Anti-TNF treatment and TB**

Considering this, the World Health Organization has argued that DM is a reemerging and an important risk factor for TB, which needs programmatically routed efforts to positively impact on TB control [57].

#### **4. Malnutrition and TB**

For centuries, the association between malnutrition and TB has been recognized. Nutritional supplementation with protein-rich foods for sick people was reported since the ancient Greece [58]. A classic report from Denmark reports high TB rates during the First World War, once food supplies were restored, TB rates were drastically reduced, while persisting high in neighboring countries where shortages persisted [59].

During the pre-chemotherapy era, the only treatment offered to TB patients consisted in a nutritional plan, resting, and sun therapy. The pharmacological advances of the past century, with the development of streptomycin and isoniazid, replaced nutritional therapy as the focus of anti-TB treatment, however, considering the high rates of TB in areas where malnutrition is endemic, in the last decades, an interest in this association has reemerged [60].

According to estimations of the United Nations, by 2015 there were 795 million undernourished, comprising around 13% of the population of low- and middle-income countries, with the highest prevalence in Sub-Saharan Africa and Southern Asia [61]. In the developing countries, protein-calorie malnutrition is the most frequent form of under nutrition; however, specific micronutrient deficiencies are also common [60]. In addition, the advent of climate change, population growth, the HIV pandemic, and economic inequality, have originated a negative impact on food and nutritional insecurity, and malnutrition rates, constituting one of the most challenging public health problems worldwide [43]. The general way to epidemiologically defining malnutrition is the body mass index (BMI), and malnutrition constitutes a well-known risk factor not only for TB development, but also for poor response to antibiotic treatment and TB-related complications [59].

A biologically plausible association between TB and malnutrition clearly exist; animal studies have shown that PCM affects the immune mechanisms for TB control, among the impaired processes are the TNF, iNOS, and interferon γ production; it is also known that this phenomenon can be reversed thought protein supplementation [59, 62]. Active TB and HIV infection induce a 14 and 30% increment in the resting metabolic rate, respectively, which reflects the physiological cost of the immunologic mechanisms that are activated during these diseases [63]. These conditions aggravate even more the patient-immune impairment in the malnutrition setting [64].

Considering this, is essential that all newly diagnosed individuals with TB have a complete nutritional evaluation, and in the cases with a BMI under 18.8 a micro and macronutrients supplementation at least for the first 2 months of treatment, is strongly recommended [65]. Historical evidence supports the beneficial impact of social interventions, such as improving housing conditions and nutritional interventions on TB epidemiology, therefore a well-planned wide intervention would impact positively on TB control.

## **5. Anti-TNF treatment and TB**

confounders, the same study also calculated a 4-fold risk of relapse for DM-TB individuals

Considering this, the World Health Organization has argued that DM is a reemerging and an important risk factor for TB, which needs programmatically routed efforts to positively

For centuries, the association between malnutrition and TB has been recognized. Nutritional supplementation with protein-rich foods for sick people was reported since the ancient Greece [58]. A classic report from Denmark reports high TB rates during the First World War, once food supplies were restored, TB rates were drastically reduced, while persisting high in

During the pre-chemotherapy era, the only treatment offered to TB patients consisted in a nutritional plan, resting, and sun therapy. The pharmacological advances of the past century, with the development of streptomycin and isoniazid, replaced nutritional therapy as the focus of anti-TB treatment, however, considering the high rates of TB in areas where malnutri-

According to estimations of the United Nations, by 2015 there were 795 million undernourished, comprising around 13% of the population of low- and middle-income countries, with the highest prevalence in Sub-Saharan Africa and Southern Asia [61]. In the developing countries, protein-calorie malnutrition is the most frequent form of under nutrition; however, specific micronutrient deficiencies are also common [60]. In addition, the advent of climate change, population growth, the HIV pandemic, and economic inequality, have originated a negative impact on food and nutritional insecurity, and malnutrition rates, constituting one of the most challenging public health problems worldwide [43]. The general way to epidemiologically defining malnutrition is the body mass index (BMI), and malnutrition constitutes a well-known risk factor not only for TB development, but also for poor response to antibiotic

A biologically plausible association between TB and malnutrition clearly exist; animal studies have shown that PCM affects the immune mechanisms for TB control, among the impaired processes are the TNF, iNOS, and interferon γ production; it is also known that this phenomenon can be reversed thought protein supplementation [59, 62]. Active TB and HIV infection induce a 14 and 30% increment in the resting metabolic rate, respectively, which reflects the physiological cost of the immunologic mechanisms that are activated during these diseases [63]. These conditions aggravate even more the patient-immune impairment in the malnutrition setting [64].

Considering this, is essential that all newly diagnosed individuals with TB have a complete nutritional evaluation, and in the cases with a BMI under 18.8 a micro and macronutrients supplementation at least for the first 2 months of treatment, is strongly recommended [65]. Historical evidence supports the beneficial impact of social interventions, such as improving

tion is endemic, in the last decades, an interest in this association has reemerged [60].

versus TB-only patients.

42 Tuberculosis

impact on TB control [57].

**4. Malnutrition and TB**

neighboring countries where shortages persisted [59].

treatment and TB-related complications [59].

People with immune-mediated inflammatory diseases, such as rheumatoid arthritis, systemic erythematous lupus, ankylosing spondylitis, inflammatory bowel disease, etc., also represent a high-risk group for developing TB, and this risk is even higher when they are treated with tumor necrosis factor α (TNF α) – antagonist [66, 67].

Different cells produce TNF, including macrophages, T cells, fibroblast, and keratinocytes. TNF is a molecule with a wide functional spectrum, plays a key role in immune response to infections, cancer etiology, and the physiopathology of many immune-mediated disorders [67]. It is also known that is important in the immune response against intracellular bacteria, and the physiology and integrity of granulomatous (**Figure 1**) TB-related response during LTBI, therefore its antagonism associates with TB progression [6].

During the past two decades, TNF antagonists have been successfully used for the treatment of inflammatory diseases, when patients do not respond to conventional therapy [67]. In the United States, using national surveillance data, found that TB incidence in AR patients increased from 6.2 per 100,000 people to 144 per 100,000 in who received infliximab and 35 per 100,000 for etanercept-treated individuals [69]. A Spanish study collected data from 71 information centers, with a total of 1540 patients receiving infliximab, estimated a TB incidence in 1893 per 100,000 people, compared with a previous reports incidence of 21 per 100,000 in the general population and 95 per 100,000 in AR patients without TNF treatment [70]. An important proportion of extrapulmonary TB is observed, and several reports have attributed differential risk for each TNF antagonist [68].

Most of the active TB cases in individuals treated with TNF antagonist correspond to reactivation from LTBI, when this occurs, generally happen concomitantly with the initiation of the TNF antagonist, nevertheless, also cases with long treatment periods, have been reported [67]. Therefore, screening for LTBI before any TNF inhibitor treatment initiation is mandatory, here, as in the case of other immunosuppressive conditions, such as HIV infection, both TST and IGRAs assays could be used, nowadays, there is not sufficient evidence to recommend one method over another, and considering this, an expert consensus, suggest using IGRAs or TST in people without history of BCG vaccination [71].

Once a patient has a positive result for LTBI, active disease must be ruled out, and preventive therapy offered. Among the preventive therapy options, two of the most accepted are: daily isoniazid 5 mg/kg (maximum 300 mg) for 9 months plus pyridoxine supplementation or a combined regimen with isoniazid and rifampicin for 3 months [69]. Multiple recommendations on delay periods between LTBI preventive chemotherapy and TNF antagonist have been proposed, ranging from starting both concurrently, to waiting even a month after finishing LTBI prophylaxis [67, 68], these decisions must always consider the patients clinical status.

In the cases when active TB is diagnosed during TNF antagonist treatment, there is no evidence that the length of anti-TB therapy needs to be prolonged, and evidence regarding the time for restarting TNF antagonist therapy is limited [72]; however, some international guidelines recommends starting TNF inhibitor at least when initial anti-TB phase is completed, while others recommend waiting until completing all TB treatment [68].

Recent findings have exposed two major principles: there is a main locus that controls most of the TB-resistance phenotypes, and there is evidence that severe forms of childhood TB are directly related with single-gene inborn errors (Mendelian Inheritance), meanwhile genetic association studies of adulthood-TB has shown limited success and reproducibility [81]. Clinical and epidemiological studies conducted since the past century has provided evidence that each step during infection and disease is strongly influenced by host genetic

Tuberculosis: A Risk Factor Approach http://dx.doi.org/10.5772/intechopen.73538 45

Familial studies aimed to investigate the human susceptibility to *M. tuberculosis* infection, have used TST and IGRAs responses as quantitative traits of resistance. Its results suggest that the initial infection-related events mostly depend on the IFNγ and TNF1 and its related cellular functions [83]. In regard to severe primary TB forms, during the last two decades, germ line mutations in seven autosomal and in two X-linked genes have been discovered in particular patients, further analysis have shown that these mutations result in an impairment

Many questions of this field remain unanswered, the identification of the genetic variants underling the stages and forms of TB is critical for understanding TB pathogenesis. These findings could represent a formidable opportunity in the definition of prevention strategies, optimization of vaccines, the development of novel treatments and therefore TB control.

After this short review, it makes evident that a risk factor approach for TB control would have a huge impact on disease burden worldwide. Identification of LTBI along with prophylactic therapy and active disease surveillance constitute the most important tools for reducing the risk of TB and achieve favorable outcomes, especially in the high-risk groups previously

Over the last decades, the understanding of TB epidemiology behavior in the country, and at global level, has changed from an "exposure to bacteria" vision to a phenomenon where the host susceptibility plays a crucial role. Even although, HIV coinfection is the most potent risk factor, globally the most frequent conditions impacting on people immune function include malnutrition, Diabetes, smoking, and immunosuppressive drugs, and while at the individual level, these factors cause an apparently mild immunological impairment, its cumulative importance in a community needs much more attention. So, it is imperative for clinicians, researchers and policy makers, a better consideration, and understanding of these conditions as drivers of TB epidemiology, developing in this way more integrative strategies that could

factors [82].

of IFNγ- and IL12-related immunity [80, 84, 85].

**8.

The authors have no conflict of interest to declare.

**Conflict of interest**

described.

### **6. Smoking, alcoholism and TB**

Globally, there are more than 1.5 billion smokers, the majority live in low- and middle-income countries, where, in addition, the per capita tobacco consumption is increasing continuously [73]. The prolonged exposure to tobacco smoke may directly affect the respiratory and systemic immune function, which can impair alveolar macrophage function by decreasing its TNF production [74]. Therefore, it is considered that smoking has an impact upon the susceptibility to TB development.

There is growing evidence that correlates smoking with TB disease; a cross-sectional study in Shanghai compared heavy smokers with nonsmokers and found that the odds of smokers were 2.2 times higher than nonsmokers [75]. The risk also seemed to be influenced by the amount smoked, and a study from the United States found that the greatest risk was for people who smoked for more than 30 years [76].

 Considering this situation, smoking cessation as a public health strategy is a global priority.

Alcohol is one of the most abused substances in the world. By 2005 among people aged 15 years and older, the annual *per capita* consumption was 6 l [78] with the highest rates in high-income countries. Alcohol abuse is an important cause of immunological impairment, often associated with smoking and malnutrition, increasing its impact on public health [8].

There is considerable evidence to support the association between alcohol abuse and TB, even if it is independent of smoking [79]. Studies have shown that excessive alcohol consumption increases the risk of active TB development and other respiratory infections, a meta-analysis estimated a combined risk of 2.9 for active TB developing [25]. Studies have also shown higher rates of MDR-TB, TB relapse, and treatment failure in alcohol abusers [8].

#### **7. Genetic susceptibility**

Historically, infectious disease research has considered TB as a purely infectious condition. During the last decades, increasing evidence suggest that TB reflects the human genetic vulnerability [80]. Nevertheless, the precise significance and behavior of the genetic factors involved remains widely unknown, in part due to the complex game of infection, latency, and disease, which characterizes TB.

Recent findings have exposed two major principles: there is a main locus that controls most of the TB-resistance phenotypes, and there is evidence that severe forms of childhood TB are directly related with single-gene inborn errors (Mendelian Inheritance), meanwhile genetic association studies of adulthood-TB has shown limited success and reproducibility [81]. Clinical and epidemiological studies conducted since the past century has provided evidence that each step during infection and disease is strongly influenced by host genetic factors [82].

Familial studies aimed to investigate the human susceptibility to *M. tuberculosis* infection, have used TST and IGRAs responses as quantitative traits of resistance. Its results suggest that the initial infection-related events mostly depend on the IFNγ and TNF1 and its related cellular functions [83]. In regard to severe primary TB forms, during the last two decades, germ line mutations in seven autosomal and in two X-linked genes have been discovered in particular patients, further analysis have shown that these mutations result in an impairment of IFNγ- and IL12-related immunity [80, 84, 85].

Many questions of this field remain unanswered, the identification of the genetic variants underling the stages and forms of TB is critical for understanding TB pathogenesis. These findings could represent a formidable opportunity in the definition of prevention strategies, optimization of vaccines, the development of novel treatments and therefore TB control.

#### **8. Final considerations**

In the cases when active TB is diagnosed during TNF antagonist treatment, there is no evidence that the length of anti-TB therapy needs to be prolonged, and evidence regarding the time for restarting TNF antagonist therapy is limited [72]; however, some international guidelines recommends starting TNF inhibitor at least when initial anti-TB phase is completed,

Globally, there are more than 1.5 billion smokers, the majority live in low- and middle-income countries, where, in addition, the per capita tobacco consumption is increasing continuously [73]. The prolonged exposure to tobacco smoke may directly affect the respiratory and systemic immune function, which can impair alveolar macrophage function by decreasing its TNF production [74]. Therefore, it is considered that smoking has an impact upon the suscep-

There is growing evidence that correlates smoking with TB disease; a cross-sectional study in Shanghai compared heavy smokers with nonsmokers and found that the odds of smokers were 2.2 times higher than nonsmokers [75]. The risk also seemed to be influenced by the amount smoked, and a study from the United States found that the greatest risk was for

At a population level, exposure to tobacco smoke has a relevant impact on TB epidemiology; a Chinese modeling-study suggested that a complete cessation of smoking in that country would reduce the estimated TB incidence between 14 and 52% [77]. Considering this situa-

Alcohol is one of the most abused substances in the world. By 2005 among people aged 15 years and older, the annual *per capita* consumption was 6 l [78] with the highest rates in high-income countries. Alcohol abuse is an important cause of immunological impairment, often associated with smoking and malnutrition, increasing its impact on public health [8].

There is considerable evidence to support the association between alcohol abuse and TB, even if it is independent of smoking [79]. Studies have shown that excessive alcohol consumption increases the risk of active TB development and other respiratory infections, a meta-analysis estimated a combined risk of 2.9 for active TB developing [25]. Studies have also shown

Historically, infectious disease research has considered TB as a purely infectious condition. During the last decades, increasing evidence suggest that TB reflects the human genetic vulnerability [80]. Nevertheless, the precise significance and behavior of the genetic factors involved remains widely unknown, in part due to the complex game of infection, latency, and

higher rates of MDR-TB, TB relapse, and treatment failure in alcohol abusers [8].

while others recommend waiting until completing all TB treatment [68].

**6. Smoking, alcoholism and TB**

people who smoked for more than 30 years [76].

tion, smoking cessation as a public health strategy is a global priority.

tibility to TB development.

44 Tuberculosis

**7. Genetic susceptibility**

disease, which characterizes TB.

After this short review, it makes evident that a risk factor approach for TB control would have a huge impact on disease burden worldwide. Identification of LTBI along with prophylactic therapy and active disease surveillance constitute the most important tools for reducing the risk of TB and achieve favorable outcomes, especially in the high-risk groups previously described.

Over the last decades, the understanding of TB epidemiology behavior in the country, and at global level, has changed from an "exposure to bacteria" vision to a phenomenon where the host susceptibility plays a crucial role. Even although, HIV coinfection is the most potent risk factor, globally the most frequent conditions impacting on people immune function include malnutrition, Diabetes, smoking, and immunosuppressive drugs, and while at the individual level, these factors cause an apparently mild immunological impairment, its cumulative importance in a community needs much more attention. So, it is imperative for clinicians, researchers and policy makers, a better consideration, and understanding of these conditions as drivers of TB epidemiology, developing in this way more integrative strategies that could have a bigger impact on TB control.

#### **Conflict of interest**

The authors have no conflict of interest to declare.

### **Author details**

Leonardo F. Jurado1,3\* and Diana M. Palacios1,2,3

\*Address all correspondence to<EMAIL_ADDRESS>
1 Pathology and Laboratories Department, Fundación Santa Fe de Bogotá University Hospital, Bogotá D.C., Colombia

2 School of Medicine, Los Andes University, Bogotá D.C., Colombia

3 Pathology Department, School of Medicine, National University of Colombia, Bogotá D.C., Colombia

[10] Tornheim JA, Dooley KE. Tuberculosis associated with HIV infection. Microbiology Spectrum. 2017;**5**:TNMI7-0028-2016. DOI: 10.1128/microbiolspec.TNMI7-0028-2016

Tuberculosis: A Risk Factor Approach http://dx.doi.org/10.5772/intechopen.73538 47

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**Author details**

46 Tuberculosis

Colombia

**References**

Leonardo F. Jurado1,3\* and Diana M. Palacios1,2,3

Hospital, Bogotá D.C., Colombia

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\*Address all correspondence to<EMAIL_ADDRESS>
2 School of Medicine, Los Andes University, Bogotá D.C., Colombia

1 Pathology and Laboratories Department, Fundación Santa Fe de Bogotá University

3 Pathology Department, School of Medicine, National University of Colombia, Bogotá D.C.,

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**Chapter 3**

**Provisional chapter**

**Determinants of Survival of Patients with Tuberculosis**

**Determinants of Survival of Patients with Tuberculosis**

Tuberculosis (TB), a major disease of public health importance, continues to cause significant morbidity and mortality to populations around the world. In 2016, it accounted for 1.7 million deaths worldwide. While the mortality rate among patients undergoing TB treatment has been declining over the years, TB death rates remains high in developing countries. This chapter discusses the epidemiology of TB mortality, the pathogenesis of TB highlighting susceptibility to mortality, and the interaction of factors which determine an individual's risk to death on account of TB. Furthermore, the chapter proposes the need for a strategic research agenda on reduction of TB burden, focusing on the factors that enable or impede political will towards translating knowledge into effective action.

**Keywords:** tuberculosis, survival, determinants, patients, developing, countries

Tuberculosis (TB) remains a disease of public health importance affecting vulnerable populations. TB is the leading cause of death from a single infectious agent worldwide. The burden of the disease is enormous with an estimated 10.4 million new cases and 1.7 million TB deaths reported in 2016. Furthermore, more than one-fifths of reported deaths occurred among those who were HIV-infected [1]. While TB-mortality rate among HIV-negative people was 17 per 100,000 population, it was 5 per 100,000 among people living with HIV. In addition, 12% of incident cases of TB occurred among HIV-positive people while one in ten of new TB cases occurred among children in the same year [1]. According to WHO, the 30 countries most affected by TB include Angola, Bangladesh, Brazil, Cambodia, China, Congo, Central African Republic, DPR Korea, DR Congo, Ethiopia, India, Indonesia, Kenya, Lesotho, Liberia,

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.75890

**in Developing Countries**

**in Developing Countries**

Abiola Olaleye and Andy Beke

Abiola Olaleye and Andy Beke

http://dx.doi.org/10.5772/intechopen.75890

**Abstract**

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **Determinants of Survival of Patients with Tuberculosis in Developing Countries Determinants of Survival of Patients with Tuberculosis in Developing Countries**

DOI: 10.5772/intechopen.75890

Abiola Olaleye and Andy Beke Abiola Olaleye and Andy Beke

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75890

#### **Abstract**

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Tuberculosis (TB), a major disease of public health importance, continues to cause significant morbidity and mortality to populations around the world. In 2016, it accounted for 1.7 million deaths worldwide. While the mortality rate among patients undergoing TB treatment has been declining over the years, TB death rates remains high in developing countries. This chapter discusses the epidemiology of TB mortality, the pathogenesis of TB highlighting susceptibility to mortality, and the interaction of factors which determine an individual's risk to death on account of TB. Furthermore, the chapter proposes the need for a strategic research agenda on reduction of TB burden, focusing on the factors that enable or impede political will towards translating knowledge into effective action.

**Keywords:** tuberculosis, survival, determinants, patients, developing, countries

#### **1. Introduction**

Tuberculosis (TB) remains a disease of public health importance affecting vulnerable populations. TB is the leading cause of death from a single infectious agent worldwide. The burden of the disease is enormous with an estimated 10.4 million new cases and 1.7 million TB deaths reported in 2016. Furthermore, more than one-fifths of reported deaths occurred among those who were HIV-infected [1]. While TB-mortality rate among HIV-negative people was 17 per 100,000 population, it was 5 per 100,000 among people living with HIV. In addition, 12% of incident cases of TB occurred among HIV-positive people while one in ten of new TB cases occurred among children in the same year [1]. According to WHO, the 30 countries most affected by TB include Angola, Bangladesh, Brazil, Cambodia, China, Congo, Central African Republic, DPR Korea, DR Congo, Ethiopia, India, Indonesia, Kenya, Lesotho, Liberia,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Mozambique, Myanmar, Namibia, Nigeria, Pakistan, Papua New Guinea, Philippines, Russian Federation, Sierra Leone, South Africa, Thailand, UR Tanzania, Viet Nam, Zambia, and Zimbabwe [1].

**2.1. Global trends in TB mortality**

conditions of the populations.

TB/2013.11. Geneva: WHO; 2013.

from 18.5 per million population in 1995 to 12.2 in 2008 [13].

Tuberculosis, often referred to as "consumption," "phthisis," or the "white plague," accounted for the highest number of deaths in Europe and America during the eighteenth and nineteenth centuries. While 70–90% of urban populations of Europe and North America were infected with TB in the late nineteenth century, four-fifths of people infected with TB died of it [9]. Through the knowledge made available by the work of Villemin, Koch, von Pirquet, TB mortality began to decline in the early and mid-nineteenth century [10–12]. TB Decline in TB mortality in these parts of the world was associated with improvement in socio-economic

Determinants of Survival of Patients with Tuberculosis in Developing Countries

http://dx.doi.org/10.5772/intechopen.75890

55

In the United Kingdom, the rapid decline in TB mortality was cited as one of the most important health gains of the twentieth century [13]. Using all certified causes of death (both underlying cause and elsewhere on certificates), TB-mortality in the Oxford region declined from 39.7 deaths per million population in 1979 to 9.0 in 2008. In England, TB-mortality rates fell

TB mortality has been dropping rapidly since 1900 in developed countries, especially after the development of new anti-tuberculosis drugs. In the United States, 74,842 TB-related deaths were reported in 1933 [14]. This had declined by 22.9% by 1942 and a further decline was reported in the following decade such that only 25,080 TB-related deaths were reported in 1952 [12]. Furthermore, TB-mortality rates were 59.6, 43.1, and 16.1 per 100, 000 population in 1933, 1942, and 1952 respectively in the United States [12]. While 644 TB-deaths were reported in 2006, the estimated number of TB-related deaths was 610 in 2016 [1]. In essence, TB-mortality