Tuberculosis

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in the Era of Globalization

Khalid Ahmed Al-Anazi

Asma Marzouq Al-Jasser
Tuberculosis in the Era of Globalization

Authors: Khalid Ahmed Al-Anazi

Asma Marzouq Al-Jasser

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 Table of Contents
1. Introduction 4.15 TB and climate
2. Tuberculosis Historic Landmarks 4.16 TB and travel
3. Health Aspects of Globalization 4.17 TB in prison inmates
Tuberculosis in Patients with Known 4.18 TB in elderly individuals
4.
Risk Factors: 5. Role of Genetics in TB
4.1 Human immunodeficiency virus and TB 6. TB in Healthy Individuals
4.2 Diabetes Mellitus and TB 7. Latent Tuberculosis
4.3 Solid tumors and TB 8. Active Tuberculosis
4.4 Hematologic malignancy and TB 9. Disseminated Tuberculosis
Hematopoietic stem cell 10. Immunological and Genetic Tests for TB
4.5
transplantation and TB 11. New Tests for TB
4.6 Solid organ transplantation and TB 12. Cost Effectiveness of TB Screening Tests
4.7 End stage renal disease and TB 13. Management of TB Infections
4.8 Chronic liver disease and TB 14. Corticosteroid Therapy in Tuberculosis
TB in collagen vascular and 15. Non-compliance and Tolerance
4.9
autoimmune disorders 16. Role of Surgery in TB
4.10 TB and alcoholism Chemoprophylaxis in
4.11 TB and illicit drug use 17.
Immunocompromised Patients
4.12 TB and tobacco 18. Tuberculosis Vaccines
4.13 TB and malnutrition 19. Conclusions and Future Directions
4.14 TB and pregnancy 20. References
 Tuberculosis in the Era of
Globalization
Khalid Ahmed Al-Anazi1* and Asma Marzouq Al-Jasser2
1
Department of Adult Hematology and Hematopoietic, Stem Cell
Transplant, Oncology Centre, King Fahad Specialist Hospital, KSA
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-γ: Interferon
Gamma; IL: Interleukin; BCG: Bacillus Calmette–Guérin; 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, King’s 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].

Health Aspects of Globalization

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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 004
new risks [13]. The fall of Berlin wall in 1989 marked a new global era of unparalleled human movement and interaction that created
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]. Sub-
Saharan 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 case-
finding rates [26]. Fever, anorexia, cough, fatigue and weight loss are the commonest clinical manifestations. Radiologically, pulmonary
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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 005
inflammatory syndrome (IRIS), the pathogenesis and management of which are poorly understood [23,24,28]. The optimal duration of
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

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
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[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: 006
significant pulmonary infiltration, tendency to dissemination and frequent development of extrapulmonary disease. However, a high
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 [4,54,67-
69,75,76,78]. 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-γ (IFN-γ) 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
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[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 007
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
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].
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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 008
and pyrizinamide. The scenario becomes more complicated in HIV positive pregnant women [2].
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 [142-
144]. 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].
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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 009
occasionally commenced before a positive diagnosis is obtained [138].
 Additionally, anti-TB chemotherapy is usually poorly tolerated by elderly patients and they are more likely to suffer side effects of anti-
TB 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 person’s 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-γ 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 Calmette–Guérin (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].
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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].
0010
Conventional diagnosis of pulmonary TB continues to rely on: clinical features, smear microscopy, cultivation of M. tuberculosis
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) genetic-
base 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 [173-
177,179]. 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-γ 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].
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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].
011
IGRAs are blood tests that indicate the immune response to the few bacilli responsible for latent TB infection. Their sensitivity may be
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 two-
step 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-α 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 permanent-
resident 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
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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 012
all TB control efforts [198].
 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 world’s 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
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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 013
and are good candidates to improve the effect of BCG. Progress to date with live-attenuated M. tuberculosis vaccines indicates that it
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-γ 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.

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