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    transported through the lymphatics to establish secondary sites (lymphohematogenous spread).

    The development of an immune response, heralded by a delayed-type hypersensitivity reaction

    over the next 4 weeks, leads to granuloma formation, with a subsequent decrease in the number

    of bacilli. Some of them remain viable, or dormant, for many years. This stage is called latent TB

    infection (LTBI), which is generally an asymptomatic, radiologically undetected process in

    humans. Sometimes, a primary complex (Ghon complex) can be seen radiographically, mostly in

    the lower and middle lobes, and comprises the primary lesion, hilar lymphadenopathy, with or

    without a lymphangitic track. Later, the primary lesion tends to become calcified and can be

    identified on chest radiographs for decades. Most commonly, a positive tuberculin test result

    remains the only proof of LTBI, and therefore does not signify active disease.

    Under certain conditions of immature or disregulated immunity, alveolar macrophagesand the subsequent biologic cascade could fail in limiting the mycobacterial proliferation,

    leading to primary progressive tuberculosis; this is seen mostly in children younger than 5 years

    or in HIV-positive or profoundly immunosuppressed individuals. Factors known to influence this

    unfavorable course are patient's age, nutritional status, host immunity, and bacterial infective

    load.

    Once infected withM. tuberculosis, 3% to 5% of immunocompetent persons develop

    active disease (i.e., secondary progressive tuberculosis) within 2 years and an additional 3% to

    5% later on during their lifetime. Overall, there is a lifetime risk of re-activation of 10%, with

    one half occurring during the first 2 years after infectionhence, the necessity to treat all

    tuberculin skin test converters. The lifetime re-activation rate is approximately 20% for most

    persons with purified protein derivative (PPD) induration of more than 10 mm and either HIV

    infection or evidence of old, healed tuberculosis; it is between 10% and 20% for recent PPD skin

    test converters, adults younger than 35 years with an induration of more than 15 mm or on

    therapy with infliximab (a tumor necrosis factor [TNF-] receptor blocker), and children

    younger than 5 years and a skin induration of more than 10 mm.

    Studies performed in New York City and San Francisco using DNA fingerprinting have

    indicated that recent transmission (exogenous reinfection), especially among HIV patients, could

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    account for up to 40% of new TB cases. This is significantly different from older studies, which

    have shown that approximately 90% of new TB cases are the result of endogenous re-activation.

    After inhalation, the pathogenic bacilli start to replicate slowly and continuously and lead

    to the development of a cellular immunity in about 4 to 6 weeks. T lymphocytes and local

    (pulmonary and lymphatic node) macrophages represent key players in limiting further spread of

    bacilli in the host. This can be seen at the pathologic level, where the bacilli are in the center of

    necrotizing (caseating) and non-necrotizing (noncaseating) granulomas, surrounded by

    lymphocytes and macrophages. The infected macrophages release interleukins 12 and 18 (IL-12

    and IL-18), which stimulate CD4-positive T lymphocytes to secrete IFN-(interferon gamma),

    which in turn activate the macrophage phagocytosis ofM. tuberculosis and the release of TNF-.

    TNF-has an important role in granuloma formation and the control of infection.

    Genetic defects are illustrated by different polymorphisms of theNRAMP-1gene (natural

    resistance-associated macrophage protein-1); vitamin D receptors, and interleukin-1 have also

    been shown to be involved in TB pathogenesis. It can be difficult to differentiate between genetic

    predisposition and overwhelming bacteriologic load, as often seen in countries with a high

    prevalence of TB.

    HIV coinfection is the greatest risk factor for progression to active disease in adults. Therelation between HIV and TB has augmented the deadly potential of each disease. Other risk

    factors include diabetes mellitus, renal failure, coexistent malignancies, malnutrition, silicosis,

    immunosuppressive therapies (including steroids and anti-TNF drugs), and TNF-receptor, IFN-

    receptor, or IL-12 1receptor defects (Ioachimescu and Tomford, 2010).

    2.2 Risk Factors

    Tuberculosis is associated with a wide range of comorbidities. Globally, about 15% of

    people with this disease are infected with HIV (WHO, 2009). About 50% of patients with

    tuberculosis in high-burden countries are undernourished; in adults, about 50% are smokers,

    about 20% misuse alcohol, and about 15% have diabetes, with much higher numbers in some

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    countries than in others. Services for these diseases are often underdeveloped in low-income and

    middle-income countries and, as a result, they are often not diagnosed (Harries et al, 2009).

    Meeting the medical-care needs of patients with tuberculosis therefore requires access to basic

    primary health-care services, beyond good tuberculosis care. Within national health plans, NTPs

    should strengthen collaboration with other public health programs to contribute to the

    prevention, treatment, and management of these conditions. Frameworks for such work are

    already well established for HIV, and are being developed for smoking-related diseases (WHO,

    2008). Finally, the challenge of inadequate information about tuberculosis morbidity and

    mortality needs to be addressed in the context of broad efforts to tackle general deficiencies in

    health-information systems. Experience in China has shown how improvements in the general

    disease-notification system, combined with increased public health funding and regulatory

    interventions, improved both the quality of tuberculosis statistics and program performance

    (Wang, 2007).

    The positive effects of improved living conditions and nutritional status in industrialized

    countries over the past century, the negative effects of the economic downturn in countries of

    eastern Europe and the former Soviet Union in the 1990s (Shilova and Die, 2001) and the clear

    association between broad development indicators and tuberculosis incidence trends in the past

    century and in recent years (Oxlade et al, 2009) are examples of how socioeconomic factors can

    affect tuberculosis epidemics. Most of the proximate risk factors for tuberculosis are associated

    with social conditions. People from low socioeconomic status groups typically have more

    frequent contact with people with active disease, a higher likelihood of crowded living and

    working conditions, greater food insecurity, lower levels of health awareness or less power to act

    on existing knowledge concerning healthy\behaviour, and less access to quality health care than

    do those from high socioeconomic groups (Lonroth et al, 2009). Malnutrition, crowding, and

    exposure to indoor air pollution are direct markers of poverty. The prevalence of smoking is

    consistently highest in low socioeconomic groups in all regions worldwide. For HIV, alcohol

    misuse, and diabetes, the trend is not straightforward, but in middle-income and high-income

    countries these factors are more prevalent in low socioeconomic groups (Blas and Sivasankara,

    2010).

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    Improved wealth, education, and social protection would greatly benefit tuberculosis

    control. However, some aspects of economic development might have a negative effect. Rapid

    industrialization, urbanization, and migrationdominant occurrences in most developing

    countriescan create ideal conditions for tuberculosis epidemics to flourish, unless

    accompanied by good urban planning, social reforms, environmental protection, and a strong and

    well coordinated health system. The incidence in urban areas is generally higher than in rural

    areas, possibly because of a combination of high population density and lifestyle changes

    associated with urban living. Exposure to some tuberculosis risk factors such as smoking,

    alcohol misuse, and unhealthy diet can increase when absolute poverty falls at the same time as

    rapid sociocultural transition leads to changed patterns in health behavior (Kjellstrom, 2007).

    2.2.1 Silicosis

    People with silicosis have an approximately 30-fold greater risk for developing TB. Silica

    particles irritate the respiratory system, causing immunogenic responses such as phagocytosis,

    which results in high lymphatic vessel deposits. It is probably this interference and blockage

    of macrophage function that increases the risk of tuberculosis. Persons with chronic renal failure

    and also on hemodialysis have an increased risk (Segall and Covick, 2010). Given that silicosis

    greatly increases the risk of tuberculosis, more research about the effect of various indoor or

    outdoor air pollutants on the disease would be necessary. Some possible indoor sources of silica

    include paint, concrete, and Portland cement. Crystalline silica is found in concrete, masonry,

    sandstone, rock, paint, and other abrasives. The cutting, breaking, crushing, drilling, grinding, or

    abrasive blasting of these materials may produce fine silica dust. It can also be in soil, mortar,

    plaster, and shingles. Some drugs, including rheumatoid arthritis drugs that work by

    blocking tumor necrosis factor-alpha (an inflammation-causingcytokine), raise the risk of

    activating a latent infection due to the importance of this cytokine in the immune defense against

    TB (Mutlu et al, 2006).

    2.2.2 HIV

    HIV is a major risk factor for tuberculosis. The risk of developing TB is estimated to be

    between 20-37 times greater in people living with HIV than among those without HIV infection.

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    TB is a leading cause of morbidity and mortality among people living with HIV. In 2009, there

    were 9.4 million new cases of TB, of which 1.2 (13%) million were among people living with

    HIV. Of the 1.7 million people who died of TB, 400,000 (24%) were living with HIV (Reuben,

    2010).

    2.2.3 Nutrition

    There is strong evidence that primary malnutrition raises the incidence and exacerbates

    clinical manifestations of tuberculosis. In a World War II study, Leyton studied hard-working

    prisoners of war in a German camp. Soviet prisoners had a daily caloric intake of about 1350

    kcal, whereas UK prisoners received additional Red-Cross food supplies, which doubled their

    daily caloric intake. The rate of radiologically and microscopically confirmed pulmonary\

    tuberculosis was 158-fold higher in the Soviet prisoners than in the UK prisoners (190 vs

    12%). Leyton concluded that the lack of food, not poor natural immunity, was the main cause of

    this difference in rate.

    Low body weight is associated with risk of tuberculosis. A body mass index (BMI) below

    18.5 increases the risk by 2 to 3 times. An increase in body weight lowers the risk (Leung, 2007).

    People with diabetes mellitus are at increased risk of contracting tuberculosis (Restrepo, 2007),

    and they have a poorer response to treatment, possibly due to poorer drug absorption (Nijland,

    2006). Other clinical conditions that have been associated with active TB

    include gastrectomy with attendant weight loss and malabsorption, jejunoileal bypass, renal and

    cardiac transplantation, carcinoma of the head or neck, and other neoplasms (e.g., lung cancer,

    lymphoma, and leukemia).

    Diet may also modulate risk. For example, among immigrants in London from the Indian

    subcontinent, vegetarian Hindu Asians were found to have an 8.5 fold increased risk of

    tuberculosis, compared to Muslims who ate meat and fish daily. Although a causal link is not

    proved by this data, this increased risk could be caused by micronutrient deficiencies: possibly

    iron, vitamin B12 or vitamin D. Further studies have provided more evidence of a link between

    vitamin D deficiency and an increased risk of contracting tuberculosis (Nnoaham and Clarke,

    2008). Globally, the severe malnutrition common in parts of the developing world causes a large

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    increase in the risk of developing active tuberculosis, due to its damaging effects on the immune

    system (Lnnroth and Raviglione, 2008). Along with overcrowding, poor nutrition may

    contribute to the strong link observed between tuberculosis and poverty (Davies, 2003).

    Experimental data have since corroborated this observation. Mice with protein caloriemalnutrition infected intravenously with Mycobacterium tuberculosis expressed less interferon-

    gamma, tumour necrosis factor, and inducible nitric oxide in their lungs than did control mice.

    Malnourished mice also had decreased granulomatous reaction,higher lung bacillary load, and a

    more fatal tuberculosis course than did well nourished mice, which could be reversed by

    restoring a diet with normal protein content. In other studies, protein malnutrition has impaired

    T-cell function, particularly the production of T-helper-1 cytokines and macrophage

    antimycobacterial effector functions. The relation between malnutrition and tuberculosis should

    be highlighted in the context of the highly prevalent southern African HIV-1 and tuberculosis co-

    infection. HIV-1 infection devastates CD4 lymphocyte numbers but has similar immunological

    consequences to malnutrition, by suppressing T-helper-1 and macrophage functions, which may

    have an additive effect in raising tuberculosis incidence, morbidity, and mortality. Malnutrition

    will also increase the incidence of tuberculosis in HIV-1-negative individuals. Finally, HIV-1

    infection and tuberculosis impair the nutritional state, which can lead to slim disease and

    consumption, respectively. Thus, a merciless vicious circle exists between these two major

    infections and nutritional deficiency. Therefore, an effective approach to control HIV-1 and

    tuberculosis infection in sub-Saharan Africa, and particularly southern Africa, needs to include

    food security. World leaders at the G8 summit in July, 2000, decided to tackle the three priority

    diseases of povertyHIV-1 infection, tuberculosis, and malariaand to reduce prevalence of

    and death from tuberculosis by 50% by 2010. The way to achieve this ambitious task is paved by

    medical difficulties and by societal issues, including provision.

    2.2.4 Crowding

    Prisoners are particularly vulnerable to infectious diseases such as HIV/AIDS and TB.

    Imprisonment facilities provide conditions that allow TB to spread rapidly due to overcrowding,

    poor nutrition, and a lack of health services. TB outbreaks have been reported in prisons and jails

    throughout the world, and is particularly concerning in the United States, which incarcerates a

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    larger proportion of its population than any other nation. The prevalence of TB in prisons is

    much higher than among the general populationin some countries as much as 40 times higher

    (Larouz, 2008).

    2.2.5 Diabetes Mellitus

    There is also a very high 3 fold increased risk of infection with TB for patients who

    have diabetes mellitus. Higher associations have been found between diabetes mellitus and TB in

    study populations from Central America, Europe, and Asia. Developing countries with

    exponential economic growth such as India and China that account for 40% of incident TB cases

    in 2010 and are estimated to have a 69% increase in people with diabetes mellitus are of concern

    for the joint burden of disease between diabetes mellitus and tuberculosis. The correlation

    between diabetes mellitus and TB concerns public health as it merges communicable and non-

    communicable diseases (Harries et al, 2010).

    The research shows that patients with DM and TB have more severe clinical

    manifestations, delayed sputum conversion and a higher probability of treatment failure,

    recurrence and relapse. Using molecular tools, we found that subsequent episodes among

    patients with DM are due to bacteria with the same genotype or are caused by reinfection with

    bacteria with a different genotype. It is therefore imperative to implement the collaborative

    framework recommended by WHO and the Union broadly to prevent and control TB among

    patients with DM (WHO, 2011).

    2.2.6 Tobacco

    As a risk factor of TB, tobacco smoking has increased substantially over the past three

    decades, especially in developing countries (Lin et al, 2007). Globally, TB and smoking aresimultaneously increasing, both of which could damage the lungs, and interact at an

    immunologic and cellular level. Studies investigating the association between smoking and TB

    have been published since 1918 (Chiang et al, 2007). Both passive and active exposures to

    tobacco smoke have been shown to be associated with TB infection and the transition from being

    infected to developing TB disease. Moreover, cigarette smoking is also associated with the

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    prognosis of TB. A cohort study conducted in Hong Kong found that significantly more current

    smokers developed TB and subsequently died within the follow-up period than ex-smokers and

    never-smokers. Thomas investigated predictors of recurrence among TB patients in South India

    and showed that a higher relapse rate was independently associated with smoking (OR: 3.1, 95%

    CI: 1.66.0) (Thomas et al, 2005).

    However, the association between smoking and TB, which has been shown to exist in

    different studies with different ethnic background, has not yet received sufficient attention in

    terms of TB care standards and research. Though both smoking and TB are targeted by major

    international prevention and control efforts, there has been little research on the measures and

    effects of smoking cessation among TB patients.

    Tobacco contains more than 4,500 compounds in the particulate and vapor phases whichcomprise five known human carcinogens and many toxic agents. Long-term inhalation of

    tobacco smoke alters a wide range of immunological functions, resulting in significantly

    increased risk of heart disease, lung cancer, microbial infections and delayed recovery from these

    diseases. Though the underlying biological mechanism is unclear, strong associations between

    tobacco smoking and TB have been proved in several areas (Slama et al, 2007). Furthermore, a

    dose-response relationship between cigarette smoking and TB was also demonstrated in the

    present study: with the increase of daily cigarettes consumption and duration of smoking, the risk

    for TB also increased accordingly.

    Why are diabetic females more likely to have TB than diabetic males? There are several

    possibilities. First, male diabetic subjects with TB may be misclassified as non-diabetics more

    frequently than women because of less than recommended chronic health care utilization (Asch

    et al, 2006). Second, diabetic women may be more susceptible to TB than diabetic men.

    Estrogens inhibit cytokines such as gamma interferon and alpha tumour necrosis factor (Salem,

    2004). The potential for an immunosuppressive effect might be enhanced by diabetes. Finally,

    observations could be due to increased environmental exposure to TB among women. Women

    may be more likely to be at home as well as in a caregiving role. This could lead to increased

    exposure to others with TB and pose a particular risk of infection for those with diabetes.

    Whatever the underlying reason, the fact that higher rates of TB were found in both RI and

    OSKP diabetic women aged 50-59, and that there is a reversal in the usual increased male to

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    female ratio of TB in diabetic Mexicans (Perez-Guzman, 2003), supports the validity of this

    observation. Diabetes should be considered a risk factor for TB in diabetic women aged 50-59

    regardless of ethnicity and a possible predictor of TB in younger adult women as well.

    An important finding is that diabetes usually preceded TB. Moreover, some oldersubjects in whom TB preceded diabetes may have been in a pre-diabetic state (or had

    undiagnosed diabetes). These observations provide temporal evidence for a possible cause and

    effect relationship. This is supported by a case control study that showed that T2DM is an

    independent risk factor for TB in Hispanic subjects, and by observations that the precise defects

    in cellular immunity and phagocytosis found with diabetes are those known to predispose to TB.

    For example, a recent study reported a decrease in alveolar macrophage activity in diabetics with

    TB.

    2.2.7 Other

    Other conditions that increase risk include the sharing of needles among IV drug users,

    recent TB infection or a history of inadequately treated TB, chest X-ray suggestive of previous

    TB, showing fibrotic lesions and nodules, prolonged corticosteroid therapy and other

    immunosuppressive therapy, compromised immune system (3040% of people with AIDS

    worldwide also have TB), hematologic andreticuloendothelial diseases, such

    as leukemia and Hodgkin's disease, end-stage kidney disease, intestinal bypass, chronic

    malabsorption syndromes, vitamin D deficiency, and low body weight (Nnoaham and Clark,

    2008).

    2.3. Manifestation

    The fight against tuberculosis would always remain incomplete without addressing theissues related to the control of HIV/AIDS. This study clearly brings out the important message

    that at least 34% of the HIV patients were found to have tuberculosis co-infection at the time of

    detecting or confirming their HIV disease. Significantly, a lower number of women living with

    HIV were found to attend the hospital, reflecting their current health remedy seeking behavior.

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    Further, they need the support of their family members to travel long distances to attend the

    health institutions providing care and support to people living with HIV.

    While the usual pulmonary tuberculosis was detected only to the extent of 56% of HIV-

    TB study population, disseminated TB and extra-pulmonary TB were witnessed in 14% and 30%of the patients respectively. Increasing frequency of dissemination of tuberculosis was observed

    with extra-pulmonary manifestations in several developing countriesas the hallmark of

    advanced HIV disease. This is the resultant of unrecognized and demonstrableMycobacteremia

    in severely immunosuppressed patients.

    Among all the HIV-TB patients, sputum smear positive detection rate was low (31%

    only). Advanced HIV disease is often associated with sputum smear negative pulmonary

    tubercuosis,

    atypical radiographic pictures and extra-pulmonary spread. Unrecognizedtuberculosis in patients with HIV disease has far-reaching consequences, including delayed

    diagnosis, unacceptable therapeutic delayand even rapid progression to 'untreatable TB.'

    (Rajasekaran et al, 2007).

    Manifestation TB to DM.

    Research found that clinical and radiological manifestations are more severe among

    patients with DM and TB (Tatar et al, 2009). Research also found higher independent risks of

    recurrence and relapse among patients with DM. In contrast to the previous literature (Baker et

    al, 2011), the use of M tuberculosis fingerprinting allowed researcher to document whether

    patients with DM experiencing subsequent episodes had TB caused by the same bacteria as the

    previous episode or reinfection with a different strain. Patients with DM are more likely to have

    infections caused by the same bacteria as the previous episode. However, the occurrence of

    exogenous reinfection in one-fifth of the cases merits further consideration. Exogenous TB

    reinfection in patients with DM might be due to nosocomial TB transmission occurring as a

    result of attending clinics where there is a high prevalence of diagnosed and undiagnosed TB, as

    has been described for HIV-infected patients (Bock et al, 2007).

    DM thus appears to have an aggravating effect on TB. Although the physiopathology of

    the coexistence of these two diseases has yet to be elucidated, changes to the immune system of

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    Vitamin D is a secosteroid that is either synthesised in the skin by the action of sunlight

    or ingested in the diet; dietary intake accounts for a much smaller proportion of total vitamin D,

    because it is scarce in foods (Holick, 2007). Vitamin D is generated by the action of ultraviolet B

    radiation on the precursor, 7-dehydrocholesterol, in the skin, and subsequent hydroxylation in

    other organs. The vitamin has pleiotropic effects on many organs, including the adaptive immune

    system and the innate immune system. Vitamin D deficiency increases the risk of type 1 and type

    2 diabetes mellitus, and supplementation is protective against both types (Holick, 2007).

    Vitamin D is thought to affect pancreatic cell function (insulin synthesis and secretion)

    and immune response; (Chiu et al, 2004) low concentrations of vitamin D are associated with

    insulin resistance and glucose intolerance (Chiu et al, 2004). In chronic disease, vitamin D is

    used to restore health in organ systems, the risk of deficiency is therefore increased. Because

    vitamin D deficiency is associated with active tuberculosis (odds ratio 29, 95% CI 1365)

    (Wilkinson et al, 2000), diabetes-related deficiency might lead to susceptibility to tuberculosis

    infection and vice versa. In vitro, the actions of monocytes and macrophages onMycobacterium

    tuberculosisare heavily dependent on vitamin D concentrations (Holick, 2007). If these

    concentrations become too low, phagocytosis cannot occur. The strong association of vitamin D

    concentrations with tuberculosis and diabetes mellitus means that vitamin D deficiency might

    explain some of the association between these two diseases, thus, population-wide

    supplementation measures to prevent both diseases should be considered.

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    REFERENCES

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