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Tuberculosis in the Era of Globalization

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Khalid Ahmed Al-Anazi Asma Marzouq Al-Jasser

Table of Contents
1. 2. 3. 4. 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 4.12 4.13 4.14 Introduction Tuberculosis Historic Landmarks Health Aspects of Globalization Tuberculosis in Patients with Known Risk Factors: Human immunodeficiency virus and TB Diabetes Mellitus and TB Solid tumors and TB Hematologic malignancy and TB Hematopoietic stem cell transplantation and TB Solid organ transplantation and TB End stage renal disease and TB Chronic liver disease and TB TB in collagen vascular and autoimmune disorders TB and alcoholism TB and illicit drug use TB and tobacco TB and malnutrition TB and pregnancy 4.15 4.16 4.17 4.18 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. TB and climate TB and travel TB in prison inmates TB in elderly individuals Role of Genetics in TB TB in Healthy Individuals Latent Tuberculosis Active Tuberculosis Disseminated Tuberculosis Immunological and Genetic Tests for TB New Tests for TB Cost Effectiveness of TB Screening Tests Management of TB Infections Corticosteroid Therapy in Tuberculosis Non-compliance and Tolerance Role of Surgery in TB Chemoprophylaxis in Immunocompromised Patients Tuberculosis Vaccines Conclusions and Future Directions References

Tuberculosis in the Era of Globalization


Khalid Ahmed Al-Anazi1* and Asma Marzouq Al-Jasser2
Department of Adult Hematology and Hematopoietic, Stem Cell Transplant, Oncology Centre, King Fahad Specialist Hospital, KSA
1 2

Central Laboratory, Ministry of Health, KSA

*Corresponding author: Khalid Ahmed Al-Anazi, Department of Adult Hematology and Hematopoietic Stem Cell Transplant, Oncology Centre, King Fahad Specialist Hospital, P.O. Box: 15215, Dammam 31444, Saudi Arabia, Tel: 966 03 8431111; Fax: 966 03 8427420; E-mail: kaa_alanazi@yahoo.com

Abbreviations:

TB: Tuberculosis; M. tuberculosis: Mycobacterium tuberculosis; MDR: Multidrug Resistance; DR-TB: Drug Resistant Tuberculosis; XDR: Extensively Drug Resistant; HIV: Human Immunodeficiency Virus; AIDS: Acquired Immune Deficiency Syndrome; DOTS: Directly Observed Therapy, Short Course; WHO: World Health Organization; FDA: Food And Drug Administration; CDC: Centers for Disease Control and Prevention; DM: Diabetes Mellitus; ART: Antiretroviral Therapy; IRIS: Immune Reconstitution Inflammatory Syndrome; NTB: Nontuberculous Tuberculosis; AFB: Acid Fast Bacillus; HSCT: Hematopoietic Stem Cell Transplantation; SOT: Solid Organ Transplantation; ARDS: Adult Respiratory Distress Syndrome; BAL: Bronchoalveolar Lavage; FUO: Fever of Unknown Origin; PCR: Polymerase Chain Reaction; ESRD: End Stage Renal Disease; TNF: Tumor Necrosis Factor; RA: Rheumatoid Arthritis; SLE: Systemic Lupus Erythromatosis; HLA: Human Leukocyte Antigen; IGRA: Interferon-Gamma Release Assay; INF-: Interferon Gamma; IL: Interleukin; BCG: Bacillus CalmetteGurin; PPD: Purified Protein Derivative; TST: Tuberculin Skin Test; NAA: Nucleic Acid Amplification; NAAT: Nucleic Acid Amplification Test; RFLP: Restriction Fragment Length Polymorphism; CXR: Chest X Ray; CAT scan: Computerized Axial Tomography; INH: Isoniazid; POC: Point-of-Care

Introduction
Tuberculosis (TB) is caused by members of the Mycobacterium tuberculosis (M. tuberculosis) complex, which include: M. tuberculosis, M. bovis, M. bovis BCG, M. africanum, M. microti, M. canetti, M. pinipedii, M. caprae and M. mungi [1]. Other Tuberculosise that may infect humans include: M. leprae, M. avium, M. intracellulare and M. scrofulaceum. M. tuberculosis is an aerobic, non-spore-forming, non-motile bacillus. It belongs to the family Tuberculosisceae [2]. M. tuberculosis is pathogenic for humans while M. bovis is usually pathogenic for animals. Once infected, active disease develops in about 10% of cases, usually within 1 - 2 years after exposure. The remaining individuals enter into a state of latency which can reactivate at a later stage particularly if the individual becomes immunocompromised [3]. Active TB is predominantly pulmonary in nature and develops in 59% of cases, while extrapulmonary TB occurs in the rest. Latent TB infection has no clinical manifestations and is not contagious, but can reactivate at a later stage, particularly if the immunity of the host decreases significantly [3,4]. Immunocompromised patients and those receiving treatment with immunosuppressive agents or monoclonal antibodies should be evaluated and treated for latent TB infection at the time of diagnosis or just before starting immunosuppressive therapy [5].

Tuberculosis Historic Landmarks


In the ancient times, TB had different names: consumption, Kings Evil, lupus vulgaris and phthisis [6]. Paleopathological investigation of human remains from Egypt, Sudan, Hungary, Latvia, Siberia and South Germany and archeological studies from the ancient empires of Egypt, Rome and Greece showed evidence of disease consistent with TB infection [6-8]. The main landmarks in the history of TB are listed in the box below. In 1882, Robert Koch discovered that TB is caused by an infectious agent, the tubercle bacillus [6]. In 1991, directly observed treatment, short-course (DOTS) was standardized by the world health organization (WHO) in order to prevent the evolution of drug resistance [9-11]. In 1993, the WHO declared TB as a global health emergency [8]. In 1997, drug-resistant TB (DR-TB) was present in all 35 countries surveyed by the WHO [9]. In 2000, another survey performed by the WHO showed presence of DR-TB in all 100 countries surveyed [9]. In 2006, the WHO launched the new Global Plan to Stop TB, 2006-2015 [12].
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Health Aspects of Globalization


Globalization is an extremely complex phenomenon or a comprehensive process that is affected by a multitude of factors and events that are rapidly reshaping our world. It is not merely an economic process, but rather an interactive co-evolution of multiple technological, cultural, economic, social and environmental factors. So, the globalization process has the following global components: governance structures, markets, communication and diffusion of information, mobility, cross-cultural interaction and environmental changes. Globalization is causing profound and complex changes in societies, on one hand bringing opportunities but on the other hand adding new risks [13]. The fall of Berlin wall in 1989 marked a new global era of unparalleled human movement and interaction that created

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economic opportunities and growth but also exposed people to health hazards. The rapid spread of human immunodeficiency virus infection (HIV) in Russia and the global spread of multidrug-resistant (MDR) TB are few examples of the adverse effects of globalization on the health sector. No nation is immune to the threat of infection outbreaks. On the other hand, there are enormous efforts to prevent and control the spread of emerging and reemerging infectious diseases combined with global proliferation of technology and information to strengthen public health services at global level [14]. A pathogen may emerge as an important public health problem because of: changes in itself or its transmission pathways or changes in host susceptibility to infection. Factors that influence host susceptibility within the population as a whole include: increases in the numbers of immunocompromised patients; increased use of immunosuppressive agents particularly in cancer patients and solid organ transplant recipients; aging of the population and malnutrition. Advances in medical care and therapeutics have resulted in increased number and survival of immunocompromised hosts, e.g. patients with cancer and recipients of solid organ transplantation (SOT), and individuals having serious underlying chronic medical conditions who are at risk of infection with certain microorganisms [15]. In many developed countries, the emergence of MDR-TB is somehow related to the massive influx of immigrants from poor countries that are endemic for TB. The situation may worsen in the future as the economic gap between the industrialized world and developing countries is likely to become deeper and as larger numbers of people are likely to be displaced from their homeland due to poverty, famine and wars. Therefore, new approaches to infectious disease control should take the following into consideration: global thinking and planning, long-term collaboration between public and private sectors, governmental and nongovernmental organizations, regional and multinational health organization; having more flexible and well supported global fund to fight acquired immune deficiency syndrome (AIDS), TB and malaria and finally dissemination of knowledge and easy access to medical technology, drug therapy and motivation of local research in developing, resource-poor countries [14]. Recently, the global rates of TB are rising, especially in Africa, Asia and Latin America, where co-infection with HIV is common. Approximately 8 million new cases of TB are reported annually, with 95% of them occurring in developing countries and most of the new cases of TB arise as reactivations of old tuberculous infections. Out of the 8 million new cases of TB reported annually, 5 million receive some treatment and only 0.5 million cases receive short course of DOTS [16]. In sub-Saharan Africa, the pandemics of TB, HIV and diabetes mellitus (DM) coexist. The 3 diseases adversely affect each other and they largely contribute to the relatively high mortality rates in that part of the world. Poor control of infections that predispose to certain cancers e.g. cervical, gastric and liver carcinomas add more to the existing health hazards [17,18]. DM poses a major threat to TB control programs. The high prevalences of obesity, DM and HIV in sub-Saharan Africa have adverse effects not only on the prevalence of TB but also on its management [18]. The WHO declared TB a global health emergency in 1993. One-third of the world population is currently infected with the latent form of TB and 5-10% of these latent forms may become active at any time. Approximately, 95% of TB cases and 98% of TB deaths occur in poor countries [8]. Resistance to anti-TB drugs may be due to: (1) failure to complete a full course of TB therapy particularly in homeless individuals, drug addicts and alcoholics or interruptions of treatment in order to avoid toxicity or side effects, (2) weak health-care infrastructure: drugs unavailable, drugs out of stock, drugs expensive and unaffordable or old and poor quality medications, (3) lack of diagnostics for drug susceptibility testing and (4) no new anti-TB drug available since 1960s [8]. Drug resistance may be overcome by improving access to current medications and modern diagnostic techniques. Drug-resistant TB was present in all 35 countries surveyed by the WHO in the year 1997. Another survey, performed by the WHO 3 years later, showed presence of DR-TB in all 100 countries surveyed. Given the increasing trend toward globalization, transnational migration and tourism, all countries are potential targets for outbreaks of MDR-TB [9]. DOTS is the most effective strategy available for TB control. The DOTS protocol requires the following 5 components: (1) government commitment, (2) case detection by sputum smear microscopy, (3) standardization of treatment for 6 to 8 months with DOT for at least 2 months, (4) constant supply of all anti-TB drugs, and (5) standardized recording and reporting system [10,11].

Tuberculosis in Patients with Known Risk Factors


Human immunodeficiency virus and TB
The convergence of HIV and TB pandemics in developing countries has been a disaster practically unequalled in medical history [19,20]. MDR-TB is common in HIV infected patients and nosocomial transmission of MDR-TB strains is well documented [21,22]. SubSaharan Africa bears the brunt of 8 million new cases of active TB reported annually worldwide [19,23]. Thirteen of the 15 countries with the highest incidence rates of TB per capita lie in sub-Saharan Africa. TB is the leading cause of death among HIV-infected individuals. Alarmingly, fewer than half of TB cases in HIV-infected patients are diagnosed before death [19]. Challenges and difficulties in diagnosis and treatment of TB in HIV patients include: (1) patients co-infected with HIV and M. tuberculosis have a greatly increased risk of developing active disease, (2) limited health-care provision in many resource-poor countries, (3) lack of sensitive, specific and rapid point-of-care diagnostic tests, (4) presence of large numbers of smear-negative TB cases and lack of pulmonary cavitations, (5) increased prevalence of extrapulmonary forms of TB, (6) many opportunistic infections in HIV patients resemble TB clinically, and (7) high incidence of drug adverse effects, drug interactions and drug resistance [19,24]. One of the most common opportunistic infections in HIV infected patients is TB with pulmonary infections occurring in 9% of HIV infected patients [20,24-26]. The manifestations of TB in HIV infected patients vary according to the degree of immunosuppression. Pulmonary TB occurs in 80% of patients and extrapulmonary infections occur in 38% of patients. Commonest forms of extrapulmonary involvement are lymphadenopathy and pleural effusions [20]. Lack of symptoms suggestive of pulmonary TB may contribute to low casefinding rates [26]. Fever, anorexia, cough, fatigue and weight loss are the commonest clinical manifestations. Radiologically, pulmonary infiltrates occur in 35% of cases, pulmonary cavitations in 25% of cases and upper lobe involvement occurs in 67% of cases. Typical clinical and radiological features occur in patients with relatively intact immune system while atypical clinical and radiological manifestations develop in severely immunosuppressed individuals. Patients with low CD4 cell counts have absence of pulmonary cavitations and prominent extrapulmonary disease [20]. The most successful approach is to start anti-TB drugs first, manage the common side-effects then introduce antiretroviral therapy (ART) in 2 to 3 weeks [24,27]. Combined ART and anti-TB therapy increases the chances of development of the immune reconstitution inflammatory syndrome (IRIS), the pathogenesis and management of which are poorly understood [23,24,28]. The optimal duration of

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anti-TB therapy in HIV patients is still controversial. Extending the 6 months standard therapy for up to 8-9 months is necessary to avoid relapse of TB which is associated with shorter duration of treatment [27,29]. All HIV-infected patients should receive TB therapy with DOT [25,26]. ART dramatically reduces TB risk by about 80%. High TB incidence rates have been noted in the first 3 months of ART in developing countries [23]. Drug resistance and drug interactions are common problems [25,28,29]. HIV-1 co-infection modifies natural history and clinical presentation and adversely affects the outcome of TB. Early disease is characterized by very few or no symptoms while severe disseminated TB disease is well recognized finding in HIV patients [24].

Diabetes Mellitus and TB


The current pandemic of type 2 DM, which accounts for 90-95% of all cases of DM, is accelerating in the world. DM affected 5.1% of people belonging to the age group 20-79 years and also affected 230 million people worldwide in the early part of the 21st century and this number is anticipated to reach 366 million by the year 2030. About 80% of cases of DM live in low and middle income countries such as India and China [30-32]. However, the highest prevalence of DM has been reported in Saudi Arabia. The prevalence of DM in USA, Switzerland and Austria is more than 10% of the adult population, while in Norway, China and Iceland, the prevalence of DM is still relatively low. Predictions of epidemiologists for the first third of the 21st century claim that up to 2.5 times increase in the prevalence of DM in Middle East, Sub Saharan Africa, India, other parts of Asia and in Latin America [33]. DM causes significant morbidity and mortality. The WHO estimates that 1 million deaths were caused by DM in the year 2001. Almost 2 thirds of these deaths occurred in developing countries. The risk factors for type 2 DM include: obesity, physical inactivity, pregnancy, improper diet and socioeconomic characteristics [32,33]. The association between DM and TB was documented by Avicenna who lived from 980 to 1027 [30]. Since the early part of the 20th century, clinicians observed an association between DM and TB and it was said that a patient with DM who did not die in a diabetic coma was likely to die from TB particularly if the patient was poor [30,31]. Currently, 8 to the 10 countries with the highest incidence of DM worldwide are also classified as high-burden countries for TB by the WHO. Hence, the consequences of these converging epidemics are likely to be substantial. Experts have raised concerns about the merging of epidemics of DM and TB particularly in low to middle income, heavily populated, countries such as India and China that are experiencing the fastest increase in the prevalence of DM and the highest burden of TB worldwide [30,31]. Patients with TB who have DM: have higher bacillary load in sputum and delayed Mycobacterium clearance i.e 5-day delay in tuberculosisl clearance within the first 60 days of anti-TB therapy hence they are more seriously ill and at higher risk of death; have higher rate of MDR-TB, hence risk of spread is higher and have active, culture-confirmed and pulmonary TB rather than extrapulmonary infections [30,31,34-36]. Patients with DM have 1.5 to 6.8 fold increased risk of developing TB and the risk of TB is higher in diabetic patients who are on insulin [37,38].

Solid tumors and TB


The global burden of cancer is increasing in economically developing countries as a result of aging, growth of the world population in addition to the increase in the adoption of cancer-associated lifestyle choices including smoking, physical inactivity and consumption of westernized calorie-dense food. However, the incidence and mortality rates for most cancers such as lung, breast, colorectal and prostate carcinomas are decreasing in the USA and many western countries [39-42]. Cancer is now the third leading cause of death worldwide with 12.7 million cancer cases and 7.6 million cancer deaths estimated to have occurred in 2008. By 2030, the projected number of deaths from all types of cancer is expected to reach 11.5 million, nearly double the 6 million new causes reported in the year 1990 [40-42]. Additional factors such as reproductive behavior and inability to control infectious causes of cancer, e.g. carcinomas of cervix, liver and stomach, in low resource countries prevent decline of cancer incidence in the third world countries particularly in Africa and Asia where pressing public health problems such as AIDS, malaria and TB are given priority [39,41,43]. Poverty, poor socioeconomic conditions, late diagnosis, inadequate national and regional based cancer registries add more to the burden of cancer and other global health problems in developing countries [39-44]. Cancer patients are at increased risk of tuberculosisl infections due to their immunocompromised state, because of the underlying malignancy and its treatment. Pulmonary involvement is common and infection may be due to M. tuberculosis or nontuberculous Tuberculosis (NTM) as both have similar clinical and radiological manifestations [45]. In these patients, TB may manifest as pneumonia or lung cavitation. In cancer patients, TB occurs 9-22 times more frequently than in the general population [46,47]. Recent high dose corticosteroid therapy is a significant predictor of mortality in cancer patients. Although active TB infection is rare in the western world, it is most frequently encountered in immigrants [48]. In patients with cancer developing TB after starting cytotoxic chemotherapy to treat their primary malignancies, reactivation of latent TB infection is the most likely scenario and TB infections tend to be more severe and disseminated in these patients. Anti-TB therapy is successful in about 75% of such patients [49,50]. Identification of latent TB and provision of prophylactic treatment during the initial months of chemotherapy may prevent the development of active TB infection. Routine screening of patients for latent TB infection and exclusion of active disease prior to the initiation of cancer chemotherapy may be indicated in endemic areas [51,52]. Despite the recent improvements in clinical and laboratory methods, the diagnosis of tuberculosisl infections may still take weeks [45]. Therefore, cancer patients having tuberculosisl infections should have prompt diagnosis and rapid initiation of efficient therapy as prompt response to conventional anti-TB chemotherapy is usually encountered, despite their immunosuppressed condition. In case of further suppression of the immune status, chemoprophylaxis for tuberculin positive patients should help to reduce the number of such reactivations [4,45,49].

Hematologic malignancy and TB


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The prevalence of TB in patients with hematologic malignancy ranges from less than 1% to more than 10% [53,54]. Clinically evident TB can antedate malignancy, both may evolve simultaneously or TB may develop after starting specific therapy for the hematologic malignancy. The average time interval between the completion of cytotoxic chemotherapy and the development of TB is 3 to 20 months [4,46,54]. There is a strong association between TB and hematologic malignancy, with acute leukemia being the most frequently encountered hematologic malignancy in patients with TB [46,54,55]. The risk factors for the development of TB in patients with malignant hematological disorders include: reduced immunity due to the primary hematological disorder, age more than 50 years, corticosteroid therapy, cytotoxic chemotherapy and administration of radiotherapy [4,53,54]. In patients with malignant hematological disorders having TB infection, clinical and radiological evidence of pulmonary involvement may be encountered in 70-90% of cases [53,56]. Characteristic features of TB infection in such patients include: significant pulmonary infiltration, tendency to dissemination and frequent development of extrapulmonary disease. However, a high

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index of suspicion should be maintained in patients with acute leukemia living in areas that are endemic for TB. Anti-TB treatment is usually successful despite the immunocompromised state of patients with leukemia [4,47,53-55]. Reactivation of TB should be considered in patients with hematologic malignancy treated with: tyrosine kinase inhibitors or monoclonal antibodies presenting with: unexplained fever and other symptoms [57,58]. In patients with hematological disorders, a major precipitating factor for disseminated TB is severe immunosuppression and the presence of other co-morbid conditions e.g. DM. As disseminated TB is cryptic and progresses rapidly, early diagnosis of TB is crucial [59]. Miliary TB (disseminated TB with miliary shadows) and pleural effusions have been reported to develop in 10.1 to 15% of patients with hematologic malignancy having TB infection [56,60]. The diagnosis of TB in these patients can be confirmed by microbiological studies in only 27.8 to 55.6% of cases. Anti-TB treatment has prompt and significant effects on the elimination of fever and on the cessation of bacterial isolation and is usually successful in 90 to 95% of cases [4,60]. Lethal outcome may be encountered in 5-10% of cases, but in patients with late diagnosis and disseminated forms of TB, mortality rate may reach 62.5% [4,53-55,60-62]. In patients with lymphoproliferative disorders, the prevalence of TB is about 23 times higher than in the general population and pulmonary TB has been reported to develop in about 34% of patients living in endemic areas [62,63]. In patients with lymphoma having TB, acid fast bacilli (AFB) may not be histologically documented although cultures may be positive but material may not reveal the typical epithelioid cell granulomas with caseation necrosis and mortality in such patients is negligible provided treatment is administered early [62].

Hematopoietic stem cell transplantation and TB


M. tuberculosis infections are 10 to 40 times commoner in recipients of HSCT than in the general population [64-66]. The incidence of M. tuberculosis infections in recipients of allogeneic HSCT ranges between 0.49% and 9.7% and varies considerably according to: the type of HSCT and the geographical location [4,54,67-74]. The risk factors for M. tuberculosis infections in recipients of allogeneic HSCT are: the primary hematological disorder; total body irradiation, cyclophosphamide and busulphan use in the conditioning therapy; acute or chronic extensive graft versus host disease; corticosteroid therapy; T-cell depletion in allografts; mismatched allografts or matched unrelated donor grafts and previous history of TB infection [4,54,65,67-69,71,72]. Usually, M. tuberculosis infections develop approximately 45 to 365 days post-allografts [4,54,64,65,67,68,71-73]. Occasionally, the course may be rapidly progressive and the following complications may be encountered: disseminated infection, severe hyperpyrexia, adult respiratory distress syndrome (ARDS), hypotension, hypoxia, sepsis, multiorgan failure and death. Lung involvement by M. tuberculosis infections in allograft recipients varies from 50% to 100% [4,54,57,64,65,67,71]. One third or more of M. tuberculosis infections in HSCT recipients are disseminated at presentation with predominant extrapulmonary involvement and about one quarter of them result from reactivation of latent tuberculous infections [4,54,66,70,72-75]. The diagnosis of M. tuberculosis infections in HSCT recipients should be made on: clinical grounds; sputum microscopy and cultures; culture of pleural and pericardial fluid; bronchoalveolar lavage (BAL) samples; bone marrow cultures, serology and molecular testing and finally tissues obtained by biopsy of lung, lymph nodes, liver or bone marrow samples [4,54,70,71,76,77]. Unfortunately, a definitive diagnosis of M. tuberculosis infections in HSCT recipients is usually difficult to be established because: immunological defects may lead to mild and non-specific clinical features and because histology does not usually show the typical granuloma formation [75]. M. tuberculosis infections in HSCT recipients usually respond well to anti-TB treatment, particularly if the diagnosis is made early [4,54,65]. A high index of suspicion should be maintained in recipients of HSCT, living in endemic areas, presenting with: unexplained pyrexia, cough, pleuritic chest pain, diffuse reticulonodular shadows on chest X ray (CXR) and rapidly progressive illness or disseminated infection [4,54,6769,75,76,78]. High mortality rates are encountered in patients with miliary or disseminated TB infections [4]. Isoniazid (INH) prophylaxis has been successfully used to prevent reactivation of old TB infections in recipients of HSCT [4]. However, routine prophylaxis against TB infections for patients with skin test reactivity and a normal CXR should be balanced against the possibility of hepatotoxicity in recipients of HSCT [67]. Therefore, INH prophylaxis should not be given routinely, but close follow up and monitoring for reactivation of latent infections is recommended [68]. However, in countries where TB is prevalent, pre and post-HSCT follow up for TB should be taken into consideration and the use of INH prophylaxis should be seriously considered [64].

Solid organ transplantation and TB


The prevalence of active TB among SOT recipients is 20-74 times higher than in the general population and it varies according to the geographic location. The prevalence in developed countries ranges from 0.35 to 6.4% but may reach as high as 10-15% in regions that are endemic for TB infection [79-81]. The diagnosis of TB in SOT recipients presents challenges that may lead to treatment delay. These challenges include: atypical clinical presentation; increased likelihood of negative tuberculin skin test and negative sputum smear despite active infection [79,80,82,83]. Treatment of TB in recipients of SOT has its own challenges that include: pharmacokinetic interactions between immunosuppressive agents and anti-TB medications; allograft-related drug toxicities and inadequate immune responses to M. tuberculosis due to exogenous immunosuppression [79,80,82]. TB may directly contribute to graft dysfunction and it carries a high mortality rate that may reach 30% [80-82,84]. TB is a serious opportunistic infection that may affect SOT recipients. The most common form of acquisition of TB after SOT is reactivation of latent infections in patients with previous exposure to TB [80-82]. The clinical presentation of TB in SOT patients is frequently atypical and diverse and may include fever of unknown origin (FUO) and weight loss in addition to allograft dysfunction and hemophagocytic syndrome. Co-infection with other pathogens is not uncommon [80,83]. New techniques such as polymerase chain reactions (PCR) and quantification of interferon- (IFN-) have been developed to achieve more rapid and more accurate diagnoses [80]. Prophylaxis against latent TB infection is the main approach to treatment, but has its own challenges such as difficulty in identifying patients at risk and toxicity of drugs used in prophylaxis [80,81]. However, INH prophylaxis in SOT patient has been found to reduce the incidence of TB reactivation. It is generally safe and effective in high risk transplant candidates [85]. In recipients of SOT, the highest incidence of TB infection was encountered among lung transplant recipients [84]. In SOT patients; 95% of TB infections occur in the first year after transplant and 76% of TB infections involve the lung. Extrapulmonary and disseminated TB may be observed in 33% of TB cases [83,84].

End stage renal disease and TB


M. tuberculosis infections are common in patients with end stage renal disease (ESRD) due to impairment of cellular immunity in advanced renal failure. In patients with ESRD, the incidence of TB is 4.5 to 25 times higher than in the general population. High index of

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suspicion is required particularly in case of extrapulmonary TB where tissue biopsy may be needed to establish the diagnosis. Disseminated TB infections are associated with significant mortality in such patients [86-89]. The risk factors for M. tuberculosis infection in patients with ESRD include: old age, male gender, silicosis and chronic obstructive pulmonary disease. However, low M. tuberculosis infection rates are encountered in patients with hyperlipidemia and hypertension [86]. The genitourinary tract is the third most commonly affected site in extrapulmonary TB [90].

Chronic liver disease and TB


Hepatic involvement is common in disseminated forms of TB, but it rarely causes marked impairment of hepatic function. Patients with pre-existing chronic liver disease may develop M. tuberculosis infection. Most patients with pre-existing liver disease tolerate standard anti-TB chemotherapy with careful monitoring for hepatotoxicity. However, hepatotoxicity may evolve as an adverse reaction to anti-TB therapy and this may mimic acute viral hepatitis in presentation [91]. The combination of ethambutol, pyrizinamide, INH and rifampicin can lead to severe hepatotoxicity. Predisposing factors for hepatotoxicity during anti-TB therapy include: alcohol intake, old age, pregnancy, chronic hepatitis B infection, paracetamol and enzyme inducers [92]. In the presence of severe liver disease, it is recommended to prescribe few hepatotoxic drugs and to extend the duration of therapy [91].

B in collagen vascular and autoimmune disorders


The risk of TB in patients with rheumatoid arthritis (RA) is 4 times that in the general population [93]. Therapy with anti-tumor necrosis factors (TNFs), such as infliximab, adalimumab and etanercept, increases the risk of pulmonary and extrapulmonary TB. The latter is more frequently encountered than the former. Reactivation of latent TB is the most likely scenario [94-100]. INH prophylaxis for 9 months should be offered to patients with RA having latent TB infection and being treated with anti-TNFs. Screening for latent TB is essential prior to therapy with these agents [97]. TB infections usually develop around the 6th dose of anti-TNFs i.e during the first 6 months of infliximab therapy in patients with refractory RA. At times emergence of TB follows a biphasic pattern [95,101,102]. Patients with collagen vascular disorders such as RA and systemic lupus erythromatosis (SLE) treated with immunosuppressive therapy eg prednisolone at dose of 15 to 20 mg / day are at increased risk of developing active TB infection [103]. In patients with SLE, there is an increase in the incidence of M. tuberculosis infections that account for increase mortality. The diagnosis of TB may be difficult and may be established late as TB infection may mimic SLE at clinical presentation [104,105]. TB infections in SLE patients are usually advanced in nature i.e they are either advanced extrapulmonary or far advanced pulmonary or miliary in nature [105]. The mean daily dose and the cumulative dose of prednisone are related to severity of TB infection. TB infections are predisposed to by primary disease e.g. SLE or its treatment ie prednisone and anti-TNFs [106]. SLE patients may also have genetic predisposition to TB infections [107].

TB and alcoholism
Alcoholism decreases host resistance to infection due to: malnutrition; impaired bronchial clearance and defective neutrophilic chemotaxis [108,109]. Analysis of drinking habits and incidence of pulmonary TB have shown a relatively high percentage (47%) among patients with pulmonary TB taking alcohol beverages compared to 15% among age and sex matched controls. The incidence of pulmonary TB is higher amongst frequent and regular alcohol drinkers. Alcoholics often exhibit far or moderately advanced pulmonary TB [108]. Failure of TB treatment due to erratic intake of anti-TB chemotherapy is often encountered in alcoholics [110]. Management of TB in alcoholics is a real challenge and in the past, it was requiring detention in order to guarantee intake of the prescribed therapy. However, detention has recently been replaced by DOT [110,111].

TB and illicit drug use


Illicit drug use and injection drug use are important factors in the epidemiology of TB in developed as well as developing countries. Successful identification and treatment of TB among illicit drug users remain important components of a comprehensive TB control strategy although this group of individuals presents a unique set of challenges for TB diagnosis and control. Special attention should be given to co-infection with viral hepatitis, co-infection with HIV and rifampicin-methadone drug interactions [112].

TB and tobacco
Tobacco smoking has increased substantially over the past 3 decades especially in developing countries [113]. The association between cigarette smoking and TB was noted as early as 1918 [114]. Recently with growing smoking epidemic, the association between tobacco smoking and TB became clear and strong [113-115]. A preliminary analysis of the WHO suggests that a significant proportion, more than 20%, of the global TB burden may be attributable to smoking [115]. Therefore, it is recommended that cessation of smoking, using both cognitive and pharmacologic methods, should be included as a standard practice in DOTs and other TB control programs [115]. Both epidemics, TB and smoking, will benefit from the combined non-communicable and communicable disease control efforts [113-115].

TB and malnutrition
Malnutrition has a profound effect on cell mediated immunity which is the principle host defense against TB [116,117]. Despite counter arguments, the association between TB and body wasting has long been recognized. Recent studies have confirmed that malnutrition is a risk factor for the evolution of TB. On the other hand, TB itself causes malnutrition [116,118]. In malnourished individuals, there is increased likelihood of progression of primary or latent TB infection to active disease. There are 3 streams of evidence relating the risk of TB to malnutrition: observations in humans, experimental work in animal models and references from related work in microbiology and immunology [116].

TB and pregnancy
TB is a significant contributor to maternal mortality and is among 3 leading causes of death among women aged 15-45 years in high burden areas. The incidence of TB in pregnancy is expected to be as high as that in the general population. Diagnosis of TB in pregnancy may be challenging as the normal weight gain in pregnancy may mask the weight loss caused by TB [2]. TB in pregnancy has the following complications: spontaneous abortion, low birth weight, preterm labor and increased neonatal mortality. Congenital TB, though rare, is associated with high perinatal mortality. M. tuberculosis infections in pregnancy can be treated with: isoniazid, rifampicin, ethambutol and pyrizinamide. The scenario becomes more complicated in HIV positive pregnant women [2].

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TB and climate
There is considerable variation in the incidence of TB with respect to climate. However, seasonal fluctuation of TB varies from one geographic location or country to another, but the variation becomes more obvious in countries or geographic locations where the climate shows wide fluctuation throughout the year [119,120]. Historically, the ancient Greek physician, Hyppocrates, clearly described the impact of climate on TB and the seasonality of TB. Recently, an analysis of 57,313 cases of TB in England and Wales over a 10-year period (1983-1992) revealed a peak of TB in summer in contrast to other respiratory disorders that peak in winter [121]. The unusual seasonality of TB can be explained by the low post-winter trough levels of vitamin D which may result in impaired cellular immunity and decreased macrophage function that ultimately result in the reactivation of dormant tuberculosis [122]. The possible implication of vitamin D deficiency and reduced exposure to ultraviolet light in the reactivation of TB has been suggested by another Australian study [123]. In other geographic locations, TB notifications generally show a peak in spring and summer and a trough in autumn. The possible explanations are: (1) winter overcrowding may result in an increase in TB transmission, (2) immunity to tuberculosisl infections is impaired at the end of winter and (3) vitamin D deficiency decreases cellular immunity further [124,125].

TB and travel
The ease of access to air travel and its increased popularity over the last 40 years have led to a significant incidence of imported infectious diseases and potential infectious hazards. However, TB has been shown to have relatively low infectivity on commercial air lights [126].

TB in prison inmates
Worldwide, approximately 8 to 10 million people are incarcerated [127,128]. Prisons constitute an ideal environment for the transmission of TB and prison inmates are important but neglected reservoirs of TB transmission in both developing and industrialized countries [128-130]. Compared to the general population, prevalence rates of active and latent TB infections are much higher in prison inmates than in the general population. Studies have shown that the prevalence of TB in prisoners is 6 to 83.6 times higher than that in the general population [127,130-132]. The risk factors for TB infection in prison inmates are related both to the institution and the individual and they include: (1) overcrowding and poor ventilation, (2) poor socioeconomic and living conditions, (3) poor nutrition, (4) limited access to health services, inadequate treatment of infectious diseases and poor implementation of TB infection control measures, (5) alcohol and drug use, (6) HIV infection, (7) cigarette smoking and (8) presence of other comorbid medical conditions such as DM [127-129,133]. Prison inmates are also at risk of rapid progression of latent TB infection to TB disease. Screening studies of prison inmates have shown that 5% of screened prisoners have pulmonary TB. Other studies have shown that TB infection is a leading cause of death in prison inmates living in developing countries [129,134]. Therefore, prison authorities should have a strong cooperation with national TB control programs to implement appropriate interventions that include: (1) active screening of prisoners for pulmonary TB by performing periodic diagnostic investigations such as active search for cases, sputum-smear microscopy, CXR and TST, (2) examination of contacts whenever an infectious case is identified, (3) reduction of transmission of TB and prevention of emergence of MDR species, (4) DOTs of cases of active TB infection, (5) INH prophylaxis for HIV positive prison inmates and guards and (6) health education of prisoners and prison staff about TB [130-132,134,135]. Without the control of TB in prisons and confinement institutions, the control of the disease outside them will be practically impossible. Therefore, prison authorities must also improve their laboratory facilities and diagnostic tools in order to perform effective TB screening [127,131].

TB in elderly individuals
TB is emerging as a significant health problem in elderly individuals mainly due to the increase in the incidence of TB reactivation at old age [136-138]. In 2009, WHO reported that the elderly population accounted for 244,062 new smear-positive case notifications worldwide, with the majority of cases reported from developing countries [139]. Increased susceptibility to TB disease in the elderly has been linked to: waning of immune function, comorbid medical conditions, impaired mechanical lung function and institutionalization [139,140]. Compared to younger patients, elderly individuals are 6 times more likely to die from TB and more than 20 times more likely to have the diagnosis of TB made at autopsy rather than during life [137,141]. In Africa, TB remains mostly a disease of the young, whereas in the Indian subcontinent, the United Kingdom, Europe and North America, TB is increasingly common in the elderly population [141,142]. The clinical manifestations of TB in the elderly are often non-specific or atypical and may be altered by other comorbid illnesses [137,142]. Compared to younger patients, dyspnea is more frequent whereas fever, night sweats, weight loss and hemoptesis are experienced less often in the elderly [137,142]. The diagnosis of TB in the elderly is often delayed and more advanced disease may be encountered at presentation [137,142]. The radiological features are more often in the form of lower lung infiltrates and less often with lung cavitations, nodules and masses. The radiological appearances of pulmonary TB in the elderly include: (1) atypical form with lower zone opacities, basal thickening, pleural effusions and few apical or lower zone cavitations, (2) classical, post-primary or reactivated, form with apical interstitial fibrosis, pleural thickening, cavitations and opacities and (3) disseminated and miliary form with miliary lung nodules [142144]. Although the characteristic presentation of chronic cough, malaise and weight loss with cavitary changes in the upper lobes still predominates, there has been an increased incidence of cryptic miliary disease in which the onset is insidious and the CXR is often normal [138]. Studies have shown that institutionalized elderly individuals are at high risk of reactivation of latent TB and acquisition of new TB infection and that miliary and extra-pulmonary forms of TB are common in elderly patients [145,146]. Maintenance of a high index of suspicion for TB in this vulnerable population is undoubtedly justified, particularly when they present with non-specific and vague symptoms, non-resolving pulmonary infiltrates on CXR and laboratory abnormalities that remain unexplained [137,140,142]. The difficulty in diagnosing TB at old age leads to increased mortality [145,146]. Studies have shown that mortality rates due to TB are higher in elderly individuals compared to younger patients and that, at times, active TB in the elderly can only be diagnosed at autopsy due to the subtle clinical manifestations of TB in the elderly [136,140,142]. TST is frequently negative in elderly subjects even in the presence of active disease. So, the diagnosis of TB is often made on suspicion and anti-TB treatment is occasionally commenced before a positive diagnosis is obtained [138].

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Additionally, anti-TB chemotherapy is usually poorly tolerated by elderly patients and they are more likely to suffer side effects of antiTB treatment compared to younger patients. However, drug resistance in rather uncommon in elderly patients [138]. The recommended treatment of TB in elderly individuals is as follows: (1) INH, rifampicin and pyrazinamide should be given for the first 2 months and (2) INH and rifampicin should be given for a total duration of 6 months except in TB meningitis, where the total duration of therapy should be 12 months [138]. Reactivation of TB can be prevented by: protein-rich diet and adequate vitamin D supplements, hygienic mode of life, adequate living conditions and control of non-tuberculous diseases in the elderly [145].

Role of Genetics in TB
Numerous epidemiological observations and several candidate gene studies have provided evidence for the role of human genes in the susceptibility to TB infection [147-149]. A complex interaction of environmental and genetic factors causes the evolution of clinical TB in the majority of patients [149]. Human pulmonary TB has a strong genetic basis, and the genetic component involves at least one major locus with a dominant susceptibility allele [150]. Both linkage and association studies have identified human genetic variants associated with susceptibility to pulmonary TB, but few genetic studies have evaluated extrapulmonary disease. Because extrapulmonary and pulmonary forms of TB are likely to have different underlying pathophysiology and genetic predisposition, identification of genetic mutations associated with extrapulmonary disease is important [151]. Future multidisciplinary studies should carefully consider phenotype definition and genetic epidemiological principles when designing, analyzing, and interpreting study findings. Ideally, culture confirmation for pulmonary TB should be conducted where feasible, thorough epidemiological data should be collected in individuals without TB to better understand latent TB infection as well as risk of progression to active TB, and population genetic factors should be carefully characterized [148]. Several studies have shown that a persons resistance level to M. tuberculosis infection correlates with the region of his or her ancestry and that the ancestors of more-susceptible persons tend to come from areas once free of TB. Similarly, the incidence of clinical TB has been found to be particularly high during outbreaks in populations, such as that of native Americans, with no ancestral experience of the infection. Twin studies have also demonstrated the importance of host genes, by showing higher concordance rates for clinical tuberculosis among monozygotic than among dizygotic pairs. The major-gene control supports the hypothesis of a continuous spectrum in the genetic control of clinical tuberculosis, since it bridges the gap between simple Mendelian susceptibility and complex polygenic predisposition to clinical TB. The identification of host genes with their functional alleles controlling the response to tuberculosisl infection should be incorporated into new prevention and treatment strategies for TB [147]. A long-standing challenge to human genetics research is the contribution of genetics of host resistance to human TB infection. Several studies have demonstrated the association between various human leukocyte antigens (HLA) and susceptibility to TB in different ethnic populations. Many more TB susceptibility genes are likely to be identified in the future [149].

TB in Healthy Individuals
TB is commonly encountered in immunocompromised individuals, patients with certain underlying medical illnesses and individuals with specific risk factors for development of TB. However, it is occasionally encountered in apparently healthy immunocompetent individuals. Not only pulmonary but also extrapulmonary and even disseminated forms of TB have been reported in immunocompetent hosts. Healthy subjects have been reported to have TB causing: pneumonia with cavitations, pancreatitis with pancreatic masses, breast nodules, splenomegaly and lymphadenopathy [152-161]. TB may occasionally present as FUO in immunocompetent individuals [160].

Latent Tuberculosis
Given the infectious nature of pulmonary TB, fast and accurate diagnosis by targeted testing and treatment of individuals with latent TB infection who are at increased risk of progression to active disease are the key elements to TB control [162,163]. Until recently, the diagnosis of latent TB infection depends solely on the century old tuberculin skin test (TST) which has its own limitations [164,165]. The most significant advance in tuberculosisl genomics and human cellular immunology in recent times has been the development of the 2 interferon-gamma release assays (IGRAs) [164,165]. These blood tests have emerged as alternatives to TST [166]. IGRA assays detect latent TB infection by measuring IFN- released from T-cells after stimulation with specific TB antigens [163,164,166]. IGRAs were designed to detect M. tuberculosis infection, not active TB, consequently a negative IGRA cannot be used alone to exclude the diagnosis of active TB. Also, these assays should not be considered as replacements for sputum smear microscopy [166]. IGRAs have higher specificity than TST, better correlation with surrogate markers of exposure to M. tuberculosis in low-incidence settings and no cross-reactivity due to bacillus CalmetteGurin (BCG) vaccination than the TST. IGRAs also appear to be at least as sensitive as the purified protein derivative (PPD)-based TST for active TB. They can be useful in low-endemic, high income settings where cross reactivity due to BCG may adversely impact the utility of TST [167]. Incorporation of T-SPOT.TB and QuantiFERON-TB Gold tests into programs for targeted testing of latent TB infection will reduce false-positive and false-negative results inherent to TB testing, equipping clinicians with more accurate tools for TB control and elimination in the 21st century [163]. The updated centers for disease control and prevention (CDC) guidelines for the use of IGRAs in the diagnosis TB include: (1) TST and IGRAs should be used as aids in diagnosing infection with M. tuberculosis, (2) TST and IGRAs should not generally be used for testing individuals who have a low risk for infection and progression to active TB if infected, (3) IGRAs should be performed and interpreted according to protocols using food and drug administration (FDA)-approved test formats, (4) Arrangements for IGRA testing should be made prior to blood collection, (5) Prior to implementation of IGRAs, each institution and TB-control program should evaluate the availability and cost-effectiveness of IGRAs for their own setting, (6) IGRAs are preferred to TST in recipients of BCG vaccination and in individuals who are not expected to return to have their TST read [164].

Active Tuberculosis
The diagnosis of active TB requires a high level of suspicion because the clinical and the radiological presentations may be quite variable. TB can be one of the easiest diseases to diagnose and also one of the most difficult, particularly in immunocompromised individuals as the likelihood of sputum smear-positivity is low and as the chances of having non-respiratory disease are high [166]. Conventional diagnosis of pulmonary TB continues to rely on: clinical features, smear microscopy, cultivation of M. tuberculosis

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and chest radiography. Sputum smear examination is the mainstay of the diagnosis of pulmonary TB although its sensitivity is modest [166,168]. Despite significant limitations, microscopy remains the cornerstone of the global TB control strategy. The major problems facing TB control programs are: (1) staining does not differentiate TB from other tuberculosisl infections. (2) TB culture takes at least 4-8 weeks [169-171]. New diagnostic tools include: newer versions of nucleic acid amplification (NAA) tests, immune-based assays, skin patch test and rapid culture systems [168]. NAA assays amplify M. tuberculosis-specific nucleic acid sequences with a nucleic acid probe enabling direct detection of M. tuberculosis in clinical specimens. They allow rapid detection of M. tuberculosis that is 80% sensitive and highly specific, particularly for respiratory specimens [166]. Rapid diagnosis of TB by amplification of tuberculosisl DNA in cases of blood diseases is clinically useful [170]. The following molecular techniques have been increasingly used in clinical laboratories: (1) NAA tests such as PCR and transcription mediated amplification to detect tuberculosisl DNA in clinical specimens, (2) nucleic acid probes to identify culture, (3) restriction fragment length polymorphism (RFLP) analysis to compare strains for epidemiologic purposes, and (4) geneticbase susceptibility test methods for rapid detection of drug resistance [171]. The newly developed molecular techniques are expected to complement our armamentarium of diagnostic tools in the detection of TB and they should not be considered as replacement for the conventional methods till the following considerations are met: (1) sensitivity, specificity and reliability of the new techniques are proven to be equal or higher than the old methods, (2) standardization and quality control measures are applied, (3) guidelines are provided by committees of experts on how to appropriately utilize the new molecular methods for the diagnosis of TB, (4) clinical protocols based on new molecular methods are designed to increase the chances of cure by selecting the most appropriate therapy and improving the quality of life of patients having TB and (5) careful consideration of cost effectiveness and economic constraints particularly in low-income countries [171]. For drug resistance, new diagnostic tools include: line-probe assays, bacteriophage-based assays, molecular beacons and microscopic observation drug susceptibility assay [168]. Recent advances in molecular biology and molecular epidemiology in addition to better understanding of the molecular basis of drug resistance in TB have provided new tools for rapid diagnosis. The high cost of most of these techniques and their requirement for sophisticated equipment and skilled personnel have precluded their implementation on a routine basis, especially in low-income countries. The search for the following nonconventional diagnostic approaches continues: biochemical markers, detection of immunological response and early detection of M. tuberculosis by methods other than colony counting [172].

Disseminated Tuberculosis
The risk factors for disseminated TB infection include: old age, female sex, immunosuppression, diabetes mellitus and weight loss [59,173]. The clinical manifestations of disseminated TB infection include: fever or FUO, anorexia, malaise, weight loss, cough, night sweats, headache, neck stiffness, choroid tubercles, altered mental status, abdominal pain and hepatosplenomegaly [173-175]. The laboratory findings include: chronic anemia, pancytopenia, hemophagocytosis, hypoxemia, hyponatremia and elevated hepatic transaminases [173177,179]. Bone marrow examination usually shows: decreased iron stores, absence of giant cells in granulomas and positive AFB cultures [174,175,178,179]. Hematological abnormalities are common and carry poor prognosis in disseminated TB infection [176,178]. In case of suspected disseminated TB infection, the following investigations should be carried out: (1) CXR and computerized axial tomography (CAT) scan of lungs to check for miliary shadows, (2) blood and bone marrow cultures for M. tuberculosis, (3) sputum cultures for AFB and BAL if feasible and (4) AFB culture of tissue biopsies, such as lung, liver, lymph nodes and bone [175]. Miliary TB accounts for about half of all causes of pulmonary nodules and is predisposed to by: young age, immunocompromised state and several clinical and radiological characteristics [180]. In patients with disseminated TB infection: TST may be positive in one third of cases and tissue biopsies may show granuloma formation [174]. The isolation of M. tuberculosis from a bone marrow specimen is an indication of disseminated infection that carries a high mortality rate [178]. Disseminated TB infection is curable if the diagnosis is made early and if the treatment is initiated promptly, but fatal outcome may be encountered if the diagnosis is delayed or if the treatment is administered late [4,59,173-175].

Immunological and Genetic Tests for TB


The production of interleukin-12 (IL-12), IL-18 and INF- is increased in most TB infections, while IL-12, to a lesser extent IL-18 and possibly IL-23 play an important role in the protection against TB and the plasma level of the IP-10 chemokine may be an indicator of disease severity [181]. CA-125, a glycoprotein with high molecular weight, is usually elevated in certain infections like TB and the assay can be used as a marker of response to treatment and as an indicator of disease activity [182]. MCL1 expression has been found to be upregulated during infection with virulent M. tuberculosis. Polymorphisms in MCL1 may be one of the genetic factors for the risk of clinical TB development. Therefore, the combined effect of several cytokine single-nucleotide polymorphisms may play a crucial role in disease severity [183]. Genetic influences on the course of TB infections during epidemics and in endemic areas have always been suspected, but the precise nature of such genetic control and of the inherited mechanisms of susceptibility has been unknown [184]. Host resistance to TB is a complex multifactorial genetic trait in which many genetic polymorphisms contribute to the phenotype, while their individual contributions are influenced by gene to gene and gene to environment interactions. The sst1 local and the Ipr1 gene participate in the control of intracellular multiplication of virulent M. tuberculosis and have an effect on the mechanisms of cell death of infected macrophages [185]. The resistance of M. tuberculosis strains to anti-TB drugs develops due to mutations in resistance-conferring genes. MDR-TB strains evolve due to sequential accummulation of these mutations. Mutations in the 81-base pair (bp) (hot-spot) region of the rpo B gene occur in 90-95% of rifampicin-resistant strains while mutations in several regions of multiple genes can cause INH resistance [186].

New Tests for TB


Independent reviews by credible agencies such as the FDA or WHO serve as a yardstick for judging new TB technologies. However, not all TB tests are reviewed by the FDA or WHO and most developing countries have weak regulatory systems for diagnostics. Developing countries should create systems for in-country validation for all TB tests, guided by their national TB programs. Expansion of the WHO prequalification diagnostic programs to include TB diagnostic tools will help countries to procure quality-assured TB tests [187]. IGRAs are blood tests that indicate the immune response to the few bacilli responsible for latent TB infection. Their sensitivity may be

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improved by cytokines released by activated macrophages (inducible protein-10). The pattern of the immune response to many or all TB antigens, the immunome, may in future distinguish between active disease and latent TB infection [188]. Both serology (antibody-detection tests) and IGRAs have been found to offer little diagnostic utility for active TB diagnostics and have been discouraged by the WHO. However, IGRAs and TST remain important tools for the diagnosis of latent TB infection. Other novel, simple technologies such as the point-of-care (POC) urine lipoarabinomannan strip test and the visually read loop isothermal amplification PCR nucleic acid amplification technique (NAAT), although of uncertain and restricted clinical utility, highlight the progression toward an inexpensive, instrument-free, laboratory-free POC diagnostic technology for TB in the future [189].

Cost Effectiveness of TB Screening Tests


In immunocompromised hosts, all available data should be used to demonstrate or exclude latent TB infection. The risk of developing active TB differs among various immunocompromising conditions. Screening for latent infection with M. tuberculosis in immunocompromised patients is carried out irrespective of the type of immunosuppression because the risk of development of active TB is probably higher than that in immunocompetent individuals. Sensitivity of TST is limited in immunocompromised individuals and specificity is limited because of cross reactivity due to prior infection with environmental tuberculosis or BCG vaccination. IGRAs have a higher specificity in populations with a high prevalence of BCG vaccination compared with TST [190]. Screening for latent TB infection with IGRAs or TST is cost effective only if the risk of the disease is high. In immunocompromised patients, IGRAs may be more sensitive than TST for detection of latent TB infection, but they may result in a considerable proportion of indeterminate results. Therefore, using both tests may maximize the efficacy of screening for latent TB infection in immunocompromised patients as studies have shown that the most cost-effective use of IGRAs is in testing TST-positive persons [191,192]. Although the twostep approach seems to be the most favored strategy for IGRAs use, the use of IGRAs alone is recommended in the following groups of patients: (1) HIV/AIDS patients, (2) prior anti-TNF- therapy, (3) hemodialysis patients, (4) patients receiving immunosuppressive therapies and (5) recipients of SOT [190]. Existing TB screening programs for migrants to low TB incidence countries have used CXRs to detect active TB in permanentresident applicants. The major potential benefit of screening at ports of entry is the detection of individuals with latent TB infection and abnormal CXRs, but this screening program should have the capacity to provide treatment for latent TB infection. The detection and treatment of active TB infection through CXRs is more cost-effective than the detection of latent TB infection using TST, but neither is highly cost-effective. The replacement of CXR screening with sputum cultures would offer a small improvement in cost-effectiveness, but would not detect latent TB infection [193]. The available studies on cost-effectiveness provide strong evidence in support of the use of IGRAs in screening high-risk groups such as healthcare workers, immigrants from high-incidence countries and close contacts. In general, the higher unit cost of the IGRAs compared to TST is compensated for the cost savings through the more targeted performance of CXRs and the offering of chemoprevention. If the increasing evidence that IGRA-positive subjects have a higher probability of progression to active TB infection holds true, the IGRAs-only screening strategy should prove to be the more cost-effective test [194].

Management of TB Infections
The standard short-course therapy for TB recommended by WHO is based on the four-drug regimen that must be strictly followed to prevent acquisition of drug resistance and relies on direct observation of patient compliance to ensure effective treatment. Despite the availability of effective chemotherapy and the moderately protective vaccine, new anti-TB agents are urgently needed to decrease the global incidence of TB. The resumption of TB, mainly caused by the emergence of MDR and extensively drug resistant [XDR] strains have led to an increased need to understand the molecular mechanisms of drug action and drug resistance, which should provide significant insight into the development of newer compounds [195-199]. The global risk factors for MDR-TB include: history of treatment for TB and a known contact with a person having drug resistant TB [199]. During the past decade, MDR-TB has been increasing in incidence worldwide. The global emergence of TB and the rapid emergence of MDR-TB underscore the importance of developing new anti-TB drugs and new protocols for efficacious clinical control of TB patients using ordinary antituberculosisl agents [196]. There is an urgent need for the development of drugs that display lasting antituberculosisl activity in vivo and novel anti-TB compounds to combat MDR-TB. Eradication of slowly metabolizing and dormant populations of M. tuberculosis organisms that cause relapse using new classes of anti-TB drugs is promising. The development time of any anti-TB drug will be long but requires the following: (1) recent data on the entire M. tuberculosis genome and on various tuberculosisl virulence genes, (2) application of findings on tuberculosisl genomes to help in drug development, and (3) development of new vehicles of drug administration systems that enable efficacious drug targets through the chemical genomics approach. Unfortunately, no new drugs except rifabutin and rifapentine have been marketed for TB during the 40 years after the release of rifampicin [196]. Currently, there is a focus on the development of new and faster acting anti-TB compounds such as moxifloxacin, nitroimidazole, oxazolidinones, diarylquinoline and rifamycin derivitives [196,197]. Unfortunately, the development of adjuvant immunotherapy for TB infections is not progressing [196]. New clinical information on the whole genome of MTB has recently been elucidated and increasing knowledge on various tuberculosisl virulence genes will promote progress in identification of genes that code for new drug targets. Using such findings on MTB genome, drug development using qualitative structure-activity relationship may be possible in the near future [197]. The emergence of MDR-TB and more recently of XDR-TB is a real threat to achieve TB control and elimination. The prevalences of MDR-TB and XDR-TB are inversely proportional to the quality of TB control and the proper use of second-line anti-TB drugs. Taking into consideration the current levels of financing and commitment to care, the risk of uncontrollable epidemic of MDR-TB and XDR-TB is also real [198]. The evidence base to guide drug treatment of resistant TB is weak and randomized controlled trials are needed. Priorities for prevention of drug resistant TB include: prompt detection of cases, effective treatment of drug sensitive and drug resistant cases and prevention of TB transmission [199]. MDR cases are treatable and regimens incorporating seond-line anti-TB drugs can improve cure rates [198]. Less toxic and more powerful drugs should be introduced, thus reducing duration of treatment and tolerability which are of utmost importance for XDR-TB cases. Nevertheless, adherence to proper standards of care and control is imperative and a top priority to all TB control efforts [198].
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Immunocompromised patients with TB should be treated for 9 to 12 months with: INH and rifampin supplemented during the initial phase by: ethambutol, streptomycin or pyrazinamide [4,200]. Treatment may need to be prolonged if response is slow and patients should also be followed up carefully after treatment to detect early relapse [200]. INH is still the treatment of choice for most patients with latent TB infection. However, there is still a need for new short-course treatments for latent TB infections that are more efficacious, safe and that patients can receive without intensive laboratory monitoring for toxicity [201].

Corticosteroid Therapy in Tuberculosis


Corticosteroid therapy is indicated in the following: (1)certain forms of extrapulmonary disease such as TB pleurisy or pleural effusions, TB meningitis, TB pericarditis and adrenal TB infection, (2) endobronchial disease, particularly in children and (3) control of fever, hypersensitivity reactions to drugs or infection and severe systemic manifestations due to pulmonary or extrapulmonary infection. Local corticosteroid therapy is indicated for keloid reactions related to BCG [202,203]. The usual dose of prednisone is 40 to 60 mg/ day orally for 4 to 6 weeks depending on the system involved, then the dose has to be tapered gradually [202]. There are anecdotal reports that further immune suppression with corticosteroids may predispose to reactivation of latent TB infections but retrospective studies in patients taking low doses of prednisone have not confirmed this risk. Randomized, placebo-controlled studies are required before corticosteroids have a definitive role in the standard therapy of TB [202,203]. Corticosteroids may interact with other medications such as oral contraceptive pills and rifampin [202].

Non-Compliance and Tolerance


Non-compliance with anti-TB treatment regimens increases morbidity and mortality, perpetuates transmission and generates bacterial resistance. Risk factors for non-compliance include: treatment requiring more than 2 months, low socioeconomic status, age between 21 and 30 years, alcoholism, intravenous drug use and skipping treatment more than twice. Strategies to improve compliance with anti-TB treatment include: early diagnosis, opportune treatment, improved family support and immediate intervention in case of interrupted therapy [54,204]. Tolerance to anti-TB medications emerges after a prolonged period of exposure to these drugs and may be an important determinant of the outcome of TB therapy [54,205].

Role of Surgery in TB
In immunocompromised patients having tuberculomas or localized tuberculous pulmonary cavitations, surgical resection of the involved segment or lobe may be essential to eradicate pulmonary TB, especially if the infection is caused by a MDR organism [206-208]. In patients with MDR-TB, poor prognostic factors for surgical lung resection include: low body mass index, primary resistance, resistance to ofloxacin and cavitary lung lesions beyond the range of resection [209].

Chemoprophylaxis in Immnunocompromised Patients


The tuberculin reaction following the intradermal injection of PPD appears 48 to 72 hours after injection [88]. In people at high risk, ie immunocompromised individuals, TST is considered positive if the area of skin induration is 5 mm or more [51,210]. To improve its predictive value, the diagnostic criteria for classifying a positive reaction have recently been revised. High risk populations should be screened to identify individuals who would most benefit from preventive therapy [211]. Immunosuppressive therapy and leukemia increase the risk of progression to active TB. Signs of active TB include: persistent productive cough, hemoptesis, unexplained fever, night sweats and unexplained weight loss. The three control strategies of TB are: prompt identification and correct management of cases, vaccination and chemoprophylaxis. INH prophylaxis is usually performed with 300 mg/day for 6 to 12 months [51,210-212]. However, for patients with latent TB infection, the new guidelines recommend treatment with INH for 6 to 9 months or with rifampin for 4 months or rifampin and pyrazinamide for 2 months [51]. INH prophylaxis is recommended in the following situations: (1) subjects with more than 5 mm tuberculin reaction, (2) recent contacts with patients having infective TB, (3) CXR indicative of old fibrotic lesions, (4) individuals with more than 10 mm tuberculin induration, and (5) clinical conditions at high risk for TB ie patients with malignancy and those on iatrogenic immunosuppression such as HSCT or SOT recipients [210].

Tuberculosis Vaccines
The current TB vaccine, M. bovis BCG, is the most widely used vaccine as most of the worlds population is vaccinated with it [213,214]. BCG protects against childhood TB and may reduce the overall risk of TB by 50%, but this immunity wanes with age resulting in no or insufficient protection against pulmonary TB, particularly in adults living in certain geographical locations that are endemic for TB [213-215]. Unfortunately, for more than 80 years, no new TB vaccine has successfully been developed [216].Development of a TB vaccine can be considered a moral obligation as reducing morbidity and mortality in addition to the development and deployment of an effective vaccine will reduce the occurrence of conflicts between the rights and liberties of the infected individual versus those of the society. However, there are many complex ethical issues which arise at all stages of TB vaccine development [217]. After declaration of TB as a global emergency in 1993, current research attempts to develop novel and more effective vaccines [215]. The goal is to obtain a new generation of vaccines effective against new transmissible forms of TB. The new TB vaccine candidates are expected to: boost BCG protection, replace the currently used BCG and make the eradication of TB feasible [216]. Over the last 10 to 15 years, using modern techniques, several research groups working with experimental laboratory models have developed more than 200 new vaccine candidates against TB [213,214,217-219]. Currently, there are at least 9 new vaccines being evaluated in clinical trials [213,214,217]. Clinical evaluation of new vaccines should be designed to cover a heterogeneous population with great variation in immune responses [213]. A truly effective TB vaccine may have to elicit an immune response that is greater than that induced by natural infection. Therefore, clinical vaccine candidates may mimic natural infection as closely as possible without causing disease. Subunit vaccines have potential advantages over live tuberculosisl vaccines in terms of safety and quality control of the manufactured vaccine and are good candidates to improve the effect of BCG. Progress to date with live-attenuated M. tuberculosis vaccines indicates that it
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is possible to design strains that are highly attenuated even in immunodeficient animals [216]. It is mandatory that a major effort be made to understand how different BCG vaccine strains influence immune response and why in some cases, vaccines have failed, so we can rationally develop the next generation of TB vaccines to reduce the prevalence from 10% to less than 2% for developed countries [215]. As the most common route of TB is by inhalation of tubercle bacilli which leads to establishment of primary infection in the lung, immunizing through nasal mucosal surface should therefore have an advantage over the other route, hence such vaccine administration elicits protective immune responses also in the lung which is the site of primary infection. Several new TB vaccine candidates have been evaluated for their protective efficacy in animal models using the mucosal route of immunization. In formulating such vaccines, the adjuvants and delivery systems are crucial [218].

Conclusions and Future Directions


Globalization facilitates free flow of health information, medical technology and access to drugs needed to treat certain illnesses, but on the other side may have a negative impact on the spread and control of specific infectious diseases. Tuberculosis is the most important infectious cause of mortality and morbidity worldwide. The pandemic of TB is coinciding and converging with other health pandemics, such as HIV, DM, cancer and tobacco use, that adversely affect not only the diagnosis but also the management of TB infections in these high risk patients. The classical risk factors for tuberculosis are: HIV infection, DM, solid tumors, hematologic malignancy, SOT, HSCT, collagen vascular and autoimmune disorders, alcoholism, cigarette smoking, illicit and intravenous drug use, travel, pregnancy, ESRD, chronic liver disease, malnutrition, old age and immunosuppressive therapies such as corticosteroids, cytotoxic chemotherapy and radiotherapy. According to recent studies, genetic factors play an important role in the predisposition to TB infection. Reactivation of an old infection is usually associated with immunosuppression due to malignancy and its treatment, serious underlying medical illness, SOT and HSCT. Disseminated infections occur in a considerable proportion of immunocompromised hosts and they cause: fever, weight loss, hepatosplenomegaly, abnormal liver function tests, neurological features, pancytopenia and positive bone marrow cultures. CXR, CAT scan, positron emission tomography, bronchoscopy, axial mediastinoscopy and tissue biopsies increase the diagnostic yield of pulmonary and extrapulmonary forms of TB infections. IFN- release assays and the new molecular diagnostic tests have improved the detection rate of TB. Certain ILs are elevated in patients having TB. However, despite the recent advances in the diagnostic tools, the diagnosis of TB may occasionally be difficult. Treatment may be prolonged in: disseminated infection, severe immunosuppression and slow response to therapy. Bone marrow suppression and disordered hepatic function are serious side effects of therapy. Resistance to anti-TB chemotherapy is a real concern as MDR and XDR strains of M. tuberculosis have recently been reported from almost every single country surveyed by the world health organization. In addition, genetic factors play a role in the development of resistance to anti-tuberculous medications. INH is valuable in latent infections and in chemoprophylaxis of certain high risk groups. Corticosteroids and surgical intervention may occasionally be employed under certain circumstances. Global efforts are urgently needed to control the resurgence of TB as the disease has global dimensions and as drug resistant TB is a serious threat to developed and developing countries in the era of globalization.

References
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Fusegawa H, Miyachi H, Ohshima T, Arimori S, Ando Y (1992) Rapid diagnosis of tuberculosis by amplification of mycobacterial DNA in blood diseases. Rihsho Ketsueki 33: 418-422. 171. Su WJ (2002) Recent advances in the molecular diagnosis of tuberculosis. J Microbiol Immunol Infect 35: 209-214. 172. Palomino JC (2005) Nonconventional and new methods in the diagnosis of tuberculosis: feasibility and applicability in the field. Eur Respir J 26: 339350. 173. Funada H, Machi T, Matsuda T (1991) Disseminated mycobacteriosis in patients with severe hematologic disorders. Kansenshogaku Zasshi 65: 1297-1303. 174. Mert A, Bilir M, Tabak F, Ozaras R, Ozturk R, et al. (2001) Miliary tuberculosis: clinical manifestations, diagnosis and outcome in 38 adults. Respirology 6: 217-224. 175. Neonakis IK, Alexandrakis MG, Gitti Z, Tsirakis G, Krambovitis E, et al. 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180. Jin SM, Lee HJ, Park EA, Lee HY, Lee SM, et al. (2008) Frequency and predictors of miliary tuberculosis in patients with miliary pulmonary nodules in South Korea: a retrospective cohort study. BMC Infect Dis 8: 160. 181. Mitsuyama M, Akagawa K, Kobayashi K, Sugawara I, Kawakami K, et al. (2003) Up-to-date understanding of tuberculosis immunity. Kekkaku 78: 51-55. 182. Wani AM, Akhtar M (2008) CA-125: a marker for diagnosis and follow-up of pleuroperitoneal and lymph node tuberculosis. Ann Saudi Med 28: 142-143. 183. Ansari A, Talat N, Jamil B, Hasan Z, Razzaki T, et al. (2009) Cytokine gene polymorphisms across tuberculosis clinical spectrum in Pakistani patients. PloS ONE 4: 4778. 184. Skamene E (1991) Population and molecular genetics of susceptibility to tuberculosis, Clin Invest Med 14: 160-166. 185. Kramnik I (2008) Genetic dissection of host resistance to Mycobacterium tuberculosis: the sst1 focus and the lprl gene. Current Top Microbiol Immunol 321: 123-148. 186. 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217. Fletcher HA, Hawkridge T, McShane H (2009) A New Vaccine for Tuberculosis: The Challenges of Development and Deployment. J Bioeth Inq 6: 219-228. 218. Kllenius G, Pawlowski A, Brandtzaeg P, Svenson S (2007) Should a new tuberculosis vaccine be administered intranasally? Tuberculosis 87: 257266. 219. Martin C (2005) The dream of a vaccine against tuberculosis; new vaccines improving or replacing BCG? Eur Respir J 26: 162-167.

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TIF Publications cater to the needs of readers of all ages and educational backgrounds, and provide concise up-to-date information on every aspect of thalassaemia - from prevention to clinical management. TIFs publications have been translated into numerous languages in order to cover the needs of the medical, scientific, patients and parents communities and the general community.
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UPCOMING TIF PUBLICATIONS Community Awareness Booklets on -thalassaemia, -thalassaemia & Sickle Cell Disease (Greek) (Eleftheriou A) Sickle Cell Disease: A booklet for parents, patients and the community, 2nd Edition (Inati-Khoriaty A) Guidelines for the Clinical Management of Transfusion Dependent Thalassaemias, 3rd Edition (Cappellini M D, Cohen A, Eleftheriou A, Piga A, Porter J, Taher A)

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