3. Pathobiology of LTBI

an increase in the number of new TB cases from 9.2 million in 2014 [1]. Sixty percent of the new TB cases are reported from India, Indonesia, China, Nigeria, Pakistan and South Africa [1]. It has been difficult to rein in the TB epidemic, and there are many reasons for it. One of the main reasons for spread of TB in low TB/HIV burden countries is the reactivation of latent tuberculosis. In high TB/HIV burden countries, the main factors are lack of accessible health facilities where timely and effective treatment of TB can be given and the burgeoning numbers of drugresistant TB cases. Another significant factor in the failure of TB control programmes in the developing countries has been the ongoing HIV epidemic. HIV-infected patients are at increased risk of new TB infection as well as reactivation of latent TB infection (LTBI). Prevention of reactivation TB in those with LTBI is now considered as one of the key strategies of TB prevention and is one of the pillars for the WHO "End TB Strategy" [1]. The WHO aims to implement LTBI detection and treatment in the 30 high-TB burden countries first. In these countries, it has set out an ambitious target of bringing 90% of children under 5 years who are TB contacts and PLHA under the chemoprophylaxis programme by 2025 [1]. Biostatistical modeling shows that if 8% of persons with latent tuberculosis could be permanently protected each year, the global incidence in 2050 would be 14 times lower than incidence in 2013, with no

Latent tuberculosis infection (LTBI) is a state of persistent immune response to Mycobacterium tuberculosis (Mtb) antigens without evidence of clinically manifested active TB [3]. In simpler terms, LTBI is infection with viable bacilli of Mtb complex but without symptoms of the disease. LTBI has great public health significance because a significant proportion of these people can develop active TB and contribute to spread and persistence of TB in the population. About 2–3 billion people, that is, one-third of the world's population, has TB infection but no TB disease. Among the people with LTBI, the lifetime risk of developing TB disease is 5–15% [4–6]. In HIV-infected, the annual risk of developing reactivation TB is 5–15% [7]. The risk is similar in people on anti-TNF-α therapy, patients on dialysis and those undergoing solid organ or hematological transplant [3]. Another similar high-risk group is that of children under

Operational constraints and unfounded fears of increased incidence of drug-resistant TB have been the two main reasons for the poor implementation of LTBI programme in high-TB burden countries. Only 87,236 children under 5 years age who were household contacts of TB cases were initiated on TB chemoprophylaxis in 2015 [1]. The best chemoprophylaxis coverage was from the Americas (67%, range 63–71%) and European Region (42%, range 40–44%). In high TB or HIV/TB burden countries, the figures ranged from 2.6% in Cameroon to 41% in Malawi. These numbers belie the actual magnitude of the problem. The total number of children on TB chemoprophylaxis (87236) is only 7.1% (range 6.9–7.4%) of the 1.2 million children who are eligible for treatment. PLHA have a higher coverage with TB chemoprophylaxis, especially in the African region. In 2015, TB chemoprophylaxis was being offered to PLHA enrolling for HIV care in 57 countries. These countries represent 61% of the global TB burden. These data

5 years of age who are household contacts of pulmonary TB cases [3].

other intervention needed [2].

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2. LTBI

Ninety percent of people infected with Mtb are able to successfully contain the microbe and ward of clinical disease. It should be realized that Mtb infection cannot be eradicated but only contained even in healthy immune-competent people and a key pathological mechanism in this is formation of tubercular granuloma.

Mtb infection occurs via the respiratory tract and on entry, mycobacteria encounter alveolar macrophages in the airways and immediately infect them. Macrophages can provide an intracellular sanctuary for mycobacteria, and Mtb has evolved numerous mechanisms to survive within macrophages. A characteristic set of pro-inflammatory cytokines and chemotactic factors for macrophages are released and cause granuloma formation. The granuloma is composed of various cells including macrophages, lymphocytes, dendritic cells, neutrophils, and sometimes fibroblasts, often with a necrotic centre. This structure serves to contain the bacilli and acts as an immune microenvironment that limits M tuberculosis replication. However, formation of a granuloma is not enough to control infection, as it has been seen that persons with active TB can have multiple granulomas in the lungs and possibly other tissues. Instead, granulomata must have optimal immunologic function to contain or eliminate the bacilli [9]. When they fail to do so, they release anti-inflammatory cytokines which aim to prevent tissue destruction but at the same time trigger fibrosis.

Structural or functional disruption of the granuloma is likely to lead to reactivation of latent M. tuberculosis infection, dissemination, and active disease [9]. Research in HIV-TB has given insight into some of the mechanisms involved in reactivation of TB [10]. The cause of disruption can be understood as general and overlapping processes, including increase in the HIV viral load within involved tissue, a reduced number of CD4 T cells, a defective macrophage function, and perturbation of Mtb-specific T-cell function [9]. They can all lead to detrimental changes within granulomas.

Depletion of CD4 cell population leads to an inability to mount an effective cell-mediated immune response against Mtb. Studies on macaques infected with simian immunodeficiency virus (SIV) have shown that reactivation of LTBI is directly associated with depletion of CD4+ T cells [10–12]. Critical decline in the number of CD4+ T cells is associated with a decrease in the number of memory CD4+ T cells (CD27+ CDRO45+) that can recognize Mtb antigens, decrease in polyfunctional antigen-specific CD4+ T cells and a relative increase in interferon gamma + CD 8+ T cells [10–12]. Other mechanisms include suppression of cell-mediated responses of regulatory T cells (Tregs) and impairment of TNF-α- mediated apoptosis of Mtb-infected cells [13].

There are two important causes of false-positive results: nontuberculous mycobacterial (NTM) infection and prior BCG vaccination [15]. NTMs are not a clinically important cause of falsepositive TST results, except in populations with a high prevalence of NTM sensitization and a very low prevalence of TB infection [15]. The impact of BCG on TST specificity depends on when BCG is given and on how many doses are administered. If BCG is administered at birth or infancy and not repeated, then its impact on TST specificity is minimal and can be ignored while interpreting the results [15]. In contrast, if BCG is given after infancy (e.g., school entry) and/or given multiple times (i.e., booster shots), then TST specificity is compromised [15].

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Tuberculin skin tests are subject to variability when repeated tuberculin tests are given. Chance variation should result in differences of less than 6 mm (representing two standard deviations) in 95% of subjects. This supports the adoption of 6 mm as a criterion to distinguish increases in reaction size due to random variation alone from true biologic phenomena, which could be either conversion or boosting [16]. Boosting is best distinguished from conversion on clinical grounds. One can attribute an increase in reaction size to boosting when the increase in reaction is seen after an interval of 1–5 weeks during which there has been no possibility of exposure, such as pre-employment testing of a health care worker [16]. Conversion can be confidently stated to have occurred when a previously tuberculin-negative individual becomes tuberculin test positive after receiving BCG vaccination, or following significant exposure such as during an outbreak or as a result of close contact with a highly contagious index case [17, 18]. Among subjects vaccinated in infancy, and tested after an interval of 5 years or more, prevalence of initial tuberculin reactions is the same in vaccinated and unvaccinated reference populations but prevalence of boosting was 7% higher in vaccinated than unvaccinated [19].

The other method of detecting LTBI is based on IFNγ release assays (IGRA). These tests detect a set of Mtb genes that are present in Mtb complex but not present in BCG immunized or in a setting of NTM infection. In this test, the sera of patients is incubated with Mtb specific T lymphocytes. The T cells respond to Mtb-specific gene products by secretion of proinflammatory cytokines that are detected. Two IGRAs are commercially available today. QuantiFERON-Gold In Tube test (QFT; Germany) uses whole blood and is ELISA based. The T-SPOT.TB test (Oxford Immunotec, Abingdon, UK) uses peripheral blood mononucleated cell (PBMC) and ELISPOT technique. Both IGRAs incorporate the region of difference 1 (RD1) encoded 6 kDa early secretory antigenic target (ESAT-6) and 10 kDa culture filtrate protein (CFP10) antigens, whereas an additional single peptide from TB7.7, encoded in RD11, is added to the QFT [20]. The selections of antigens for these tests are critical. Natural immunity to M. tuberculosis is highly individual, multi-epitopic and multiantigenic, and more than 80 antigens are necessary to capture 80% of the MTB-specific T-cell response [21]. The currently used antigens ESAT-6, CFP10 and TB7.7 were selected for their high immunogenicity and specificity for M. tuberculosis infection, not for their predictive potential. ESAT-6 is considered among the most immunogenic proteins, but it has a drawback when used to detect LTBI. It is secreted through the entire spectrum of latency and also in active stages of the infection.

Therefore, disease stage-specific diagnosis is impossible using ESAT-6 [22].

Various studies have evaluated the utility of IGRAs and TST. A study from Turkey published in 2007 seems relevant to countries like India as Turkey is also a country with high prevalence of TB
