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      Management of latent tuberculosis infection: An evidence-based approach

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          Abstract

          Most individuals who get exposed to Mycobacterium tuberculosis (MTB) manage to eliminate or contain the infection using host T-cell immune defenses. However, some MTB bacilli may remain viable (latent) and “reactivate” later to cause active TB disease. This state is called latent TB infection (LTBI). Although LTBI and active TB disease are part of a dynamic spectrum,[1] people with LTBI are asymptomatic and not infectious. For example, nearly 50% of doctors and health care workers in India will test positive on the Mantoux tuberculin skin test, but a majority will not display any TB symptoms, or develop active TB disease.[2] Such individuals, presumably, have LTBI. However, some health care workers may go on to develop symptoms, and if found to have active TB require the standard four-drug short course anti-TB therapy. Identification and treatment (i.e. preventive therapy or prophylaxis) of LTBI can substantially reduce the risk of development of active disease (by as much as 60%), and is an important TB control strategy in low-TB incidence settings where reactivation disease usually accounts for the majority of non-imported TB disease[3] For example, LTBI screening and treatment is a major component of TB control programs in both USA and Canada, and large numbers of individuals are tested for LTBI and treated with isoniazid for 9 months. The goal of testing for LTBI is to identify individuals who are at an increased risk for the development of active TB; these individuals would benefit most from treatment of LTBI. There is no diagnostic gold standard for LTBI and all existing tests are immunological tests that provide indirect evidence of sensitization of the host to TB antigens. There are two available tests for identification of LTBI: Tuberculin skin test (TST) and interferon-gamma release assays (IGRA). TST is usually performed using the Mantoux skin test method, and purified protein derivative (PPD) is the antigen injected intradermally. Skin induration is read after a period of 48-72 h. IGRAs are done in vitro, and instead of PPD, they use highly specific peptides from two main antigens-early secreted antigenic target (ESAT6) and culture filtrate protein (CFP10). Commercial IGRAs include QuantiFERON-TB Gold In Tube (Qiagen, Valencia, CA, USA), and T-SPOT. TB (Oxford Immunotec, UK). Both TST and IGRA depend on cell-mediated immunity (memory T-cell response), and a positive result suggests that the patient has been exposed and sensitized to MTB in the past. A detailed recent review of these tests is available elsewhere.[4] Briefly, published data suggest that both TST and IGRA are acceptable, but somewhat imperfect tests. Both represent indirect markers of MTB exposure and measure a cellular immune response to MTB (read as mm induration with the TST, and amount of interferon-gamma released by T-cells in IGRAs). Neither test can accurately differentiate between LTBI and active TB. Neither test can resolve the various stages within the spectrum of MTB infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients (e.g., people living with HIV/AIDS), and have low predictive value for progression to active TB. In other words, a majority of individuals with positive TST or IGRA results will not progress to active TB disease.[5] Tuberculin skin test surveys in India show a very high annual risk of TB infection.[6] Given the very high TB burden of active TB in India, it is not surprising that nearly 40% of Indians are estimated to be latently infected.[7] Given the large number of latently infected individuals in the country, the Revised National TB Control Program (RNTCP) does not give priority to LTBI detection and treatment in the public sector. This is true for most high TB burden countries around the world. For high-burden countries such as India, what should be the approach toward the management of LTBI? In 2014, World Health Organization (WHO) published its first comprehensive guideline on management of latent TB infection.[8] This guideline offers a clear, evidence-based algorithm [Figure 1].[8] Figure 1 World Health Organization algorithm for latent tuberculosis infection management. Source: Adapted from WHO, Geneva[8] As shown in the algorithm, WHO recommends that only selected risk groups should be evaluated for LTBI.[8] These include people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumor necrosis factor (TNF-alpha) treatment, patients with end-stage renal failure on dialysis, patients preparing for organ or hematologic transplantation, and patients with silicosis. The rationale for giving priority to these subgroups is that they are at a very high risk of progressing from latent infection to active disease, and this progression could be prevented by treating LTBI. If an individual has any of the above risk factors, the WHO algorithm requires that they be assessed for TB symptoms. If any TB symptom is present (e.g., cough, fever, weight loss, hemoptysis, night sweats), then the focus should be on diagnosing active TB using WHO and RNTCP-endorsed microbiological tests such as smear microscopy, TB cultures, and molecular tests as Xpert MTB/RIF (Cepheid Inc, Sunnyvale, CA, USA), and line probe assays as Genotype MTBDR plus (Hain Life Science, Nehren, Germany). Chest radiography can also be used as part of the work-up for active TB. If the individual has no symptoms, then WHO recommends that either TST or an IGRA be used to test for LTBI in high-income and upper middle-income countries with estimated TB incidence less than 100 per 100 000. TST is preferred and IGRA should not replace TST in low-income and other middle-income countries.[8] If either TST or IGRA is positive, then the next step is to rule out active disease, before starting LTBI treatment. This is done by getting chest radiography done. If the radiogram shows any abnormalities, then it is critical to investigate for active TB, using smear microscopy, TB cultures, and molecular tests. If the radiogram is normal and the individual has no symptoms, then the likelihood of active TB is very low, and LTBI treatment can be initiated. What are the drug regimens available for LTBI treatment? Unlike active TB where four drugs are required in the intensive phase, the burden of bacteria in LTBI is quite low. So, even a single TB drug is sufficient. As shown in the WHO algorithm, treatment options recommended by WHO include 6-9 months of isoniazid, 3-month regimen of weekly rifapentine plus isoniazid, or 3-4 months isoniazid plus rifampicin, or 3-4 months rifampicin alone.[8] All regimens are known to be efficacious, but adherence can be poor with longer regimens such as 9 months of isoniazid.[3] Rifampicin containing regimens may be more suitable in populations with a high background level of isoniazid monoresistance. Regardless of the regimen used for LTBI, it is important to ensure adherence, and provide patients adequate counseling about why they are being treated for LTBI (despite not having symptoms), likely adverse events, and monthly follow-up visits. The risk of toxicity is highest with isoniazid, especially in older individuals, and those who consume alcohol.[3] In India, there is concern that tests such as Mantoux and IGRAs (e.g., TB Gold, TB Platinum) are being misused for active TB diagnosis.[9] The WHO algorithm clearly shows that when doctors suspect active TB, they should test for active TB, not screen for LTBI. In fact, the Standards for TB Care in India (STCI) clearly state that both TST and IGRAs should not be used for the diagnosis of active TB in high endemic settings such as India.[10] If IGRAs are used for active TB diagnosis, this will result in significant overdiagnosis of TB, because of the high background prevalence of LTBI in India. In children, STCI suggests that the Mantoux test may have some value as a test for infection, in addition to chest radiography, symptoms, history of contact, and other microbiological investigations (e.g., gastric juice acid fast bacilli and Xpert MTB/RIF).[10] In conclusion, LTBI screening must be restricted to specific high-risk populations in India, where the benefits of LTBI treatment outweigh any risks. Although either TST or IGRA can be used for LTBI screening, it is important to make sure that these tests are not used for active TB diagnosis. For persons with symptoms or abnormal chest radiograms, physicians should order smears, cultures, and molecular tests (these tests are now available in the public sector, and made more affordable in the private sector in India via the Initiative for Promoting and Affordable Quality TB Tests (IPAQT - www.ipaqt.org)). If LTBI is diagnosed, then physicians must rule out TB disease with chest radiography before starting one of the recommended drug regimens. It is important to ensure adherence, and provide adequate counseling to ensure that patients do not stop therapy prematurely.

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          Most cited references7

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          Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood interferon gamma assay with tuberculin skin testing.

          Mycobacterium tuberculosis infection in health care workers has not been adequately studied in developing countries using newer diagnostic tests. To estimate latent tuberculosis infection prevalence in health care workers using the tuberculin skin test (TST) and a whole-blood interferon gamma (IFN-gamma) assay; to determine agreement between the tests; and to compare their correlation with risk factors. A cross-sectional comparison study of 726 health care workers aged 18 to 61 years (median age, 22 years) with no history of active tuberculosis conducted from January to May 2004, at a rural medical school in India. A total of 493 (68%) of the health care workers had direct contact with patients with tuberculosis and 514 (71%) had BCG vaccine scars. Tuberculin skin testing was performed using 1-TU dose of purified protein derivative RT23, and the IFN-gamma assay was performed by measuring IFN-gamma response to early secreted antigenic target 6, culture filtrate protein 10, and a portion of tuberculosis antigen TB7.7. Agreement between TST and the IFN-gamma assay, and comparison of the tests with respect to their association with risk factors. A large proportion of the health care workers were latently infected; 360 (50%) were positive by either TST or IFN-gamma assay, and 226 (31%) were positive by both tests. The prevalence estimates of TST and IFN-gamma assay positivity were comparable (41%; 95% confidence interval [CI], 38%-45% and 40%; 95% CI, 37%-43%, respectively). Agreement between the tests was high (81.4%; kappa = 0.61; 95% CI, 0.56-0.67). Increasing age and years in the health profession were significant risk factors for both IFN-gamma assay and TST positivity. BCG vaccination had little impact on TST and IFN-gamma assay results. Our study showed high latent tuberculosis infection prevalence in Indian health care workers, high agreement between TST and IFN-gamma assay, and similar association between positive test results and risk factors. Although TST and IFN-gamma assay appear comparable in this population, they have different performance and operational characteristics; therefore, the decision to select one test over the other will depend on the population, purpose of testing, and resource availability.
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            Guidelines on the management of latent tuberculosis infection

            (2015)
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              Preventive chemotherapy. Where has it got us? Where to go next?

              The World Health Organization estimates that a third of the world's population is infected with Mycobacterium tuberculosis. Every second, one person becomes newly infected with tuberculosis (TB). In the past two decades, the spread of human immunodeficiency virus infection, worsening poverty and deteriorating health services have resulted in a steady increase in the overall incidence of TB globally. With treatment of latent TB infection (LTBI), the number of infected persons who develop active TB can be significantly diminished. Prevention through treatment of LTBI should therefore be an integral part of the control of TB. Although only a minority of those with LTBI will develop active disease, the risk varies substantially according to the time since infection and medical risk factors. If persons at low risk for TB are selected for preventive chemotherapy, the individual and public health benefits are low, and a large number will have to be treated to prevent a single active case. It is therefore important to identify and treat patients who are at high risk of disease. Tools for rapid and reliable identification of persons with LTBI who are most likely to progress to active disease are urgently needed, as this will permit rational use of preventive treatment by restricting treatment to those patients with the most favourable risk/benefit ratio. The major challenges are efficient identification of those at highest risk of developing disease and ensuring treatment completion with a non-toxic regimen. If these can be overcome, preventive treatment holds the promise to substantially assist in the achievement of global control of TB.
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                Author and article information

                Journal
                Lung India
                Lung India
                LI
                Lung India : Official Organ of Indian Chest Society
                Medknow Publications & Media Pvt Ltd (India )
                0970-2113
                0974-598X
                May-Jun 2015
                : 32
                : 3
                : 205-207
                Affiliations
                [1] Department of Epidemiology and Biostatistics, McGill International TB Centre, McGill University, Montreal, Quebec, Canada. E-mail: madhukar.pai@ 123456mcgill.ca
                [1 ] Department of Microbiology, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra, India
                Article
                LI-32-205
                10.4103/0970-2113.156210
                4429378
                25983402
                dfbee683-7f48-4624-9e6f-8632b4ec067f
                Copyright: © Lung India

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Respiratory medicine
                Respiratory medicine

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