Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is a well known and major public health challenge globally, and is the leading cause of death from a single infectious agent1. According to the Global TB Report 20221, an estimated 10.6 million incident cases of TB were reported in 2021. The World Health Organization (WHO) END TB strategy aims to reduce 95 per cent of TB deaths and 90 per cent of new incident cases of TB by 20352. The global TB targets for reductions in disease burden of TB can only be achieved if diagnostic, prevention and treatment services of TB are strengthened3,4. A state of persistent immune response due to stimulation by MTB antigens without any evidence of clinically manifested active TB is defined as TB infection (TBI). TBI can serve as the precursor for the development of full-blown TB disease, particularly among the immunocompromised5. This constitutes a large reservoir of individuals with TBI, and thus, the management of TBI is crucial for global efforts to curb TB burden, particulaly in high TB burden countries such as India.
Geographically, out of the six high-burden countries from south-east Asia region, India accounts for 28 per cent of the global TB burden6. It also has the highest TBI burden globally6. According to the National TB prevalence survey, 2021, the crude prevalence of TBI among individuals >15 yr was 31.3 per cent [95% confidence interval (CI); 30.8-31.9]7. Around 5-10 per cent of those with TBI reportedly develop clinically active TB disease8. A single active case of TB may infect several other individuals before receiving any anti-tubercular treatment due to delayed diagnosis, hence creating a perpetual reservoir of TB-infected individuals9. Since TB-infected individuals constitute a perennial source of risk for progression towards active disease, prevention of active TB disease by treating TB-infected individuals and interrupting the chain of transmission is the chief component of the WHO End TB strategy2,8.
The prevention of TB disease by the treatment of TBI is largely undervalued but remains as an important component of the National Strategic Plan 2017-25 for Ending TB in India by 2025, five year ahead of the sustainable development goals10. The lancet commission on TB mentions that the diagnosis and treatment strategies to end TB would be ineffective unless TB preventive treatment (TPT) is included in the comprehensive strategy11. There is a need to improve the implementation of proven interventions such as effective new regimens for TPT and ensure their efficient and rapid scale-up12. This applies to finding high-risk groups and initiating TPT. Thus, it is essential to estimate the burden of TBI among various states and groups in India, which has programmatic implications. Against this background, this review aimed to estimate the burden of TBI in the Indian population stratified according to geographies and sociodemographic profiles.
Material & Methods
Protocol and inclusion criteria: A systematic review of various studies examining the TBI among Indians was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. All primary studies conducted on Indian residents reporting TBI irrespective of the tests used to measure were included. We considered the use of any available test for identifying TBI including interferon gamma release assay or tuberculin skin test (TST) or T SPOT, TB or C-TB or Cy-TB among the participants. Reviews, case reports, editorials, opinion pieces, study protocols, conference abstracts, posters, thesis, reports or any unpublished material were excluded. TBI for the present study was defined as the immune response to MTB antigen without clinical evidence of active TB.
Databases, study selection and data extraction: We conducted electronic searches of four databases namely: MEDLINE, EMBASE, CINHAL and Scopus limiting the search from January 1, 2013 to December 31, 2022. A comprehensive search was done using the keywords and Medical Subject Headings (MeSH) terminology for Tuberculosis including, TB, Latent Tuberculosis Infection, sub-clinical Tuberculosis, inactive Tuberculosis, Tuberculosis Infection, LTBI, Pulmonary Tuberculosis, Koch’s Tuberculosis, Extra-pulmonary Tuberculosis, Latent TB, Tuberculin Skin test, Mantoux test, TST, Purified protein derivative, Interferon gamma release assay, skin test, IGRA, Enzyme-linked immunospot assay, Quantiferon, Quantiferon-TB Gold, T.SPOT TB, C-TB and Cy-TB. The complete search strategy per database consulted is presented as Appendix I in the Supplementary material.
Two authors independently searched from all four databases mentioned. Reference checking, hand searching of citations and reference lists were done to identify potentially missing literature.
All citations retrieved from the electronic searches were first imported to EndNote where duplicate entries were removed, the resulting entries were then uploaded to the Rayyan software, 201613. Two independent researchers then screened the titles and abstracts of the retrieved studies to identify all the articles that could be eligible for inclusion. Uncertainty or disagreement was settled by a third reviewer’s consensus decision. Two researchers conducted the full-text screening of the previously identified articles, and disagreement was settled by a third reviewer.
The information on study characteristics and the results of the included studies were extracted using a standardized data extraction form. Information on authors, publication, country, study design, study area, sample size, publication year, study year, sociodemographic factors, proportion of TBI and the test used was extracted. In addition, information for assessing the risk of bias was extracted. When the data were insufficient or missing or full text was not available, corresponding authors of the original articles were contacted via e-mail to provide relevant information.
Assessment quality and the risk of bias: Methodological quality and the risk of bias among the included studies were assessed by two independent researchers using the Joanna Briggs Institute (JBI) Critical Appraisal tools designed for use in systematic reviews – set of questionnaires used to asses cross-sectional, cohort and randomized controlled trials13,14. Studies were then graded, and according to the score obtained, these were classified as ‘low’, ‘moderate’ or ‘high’ risk of bias.
Data synthesis and analysis: The studies were categorized according to the study design, and then, the study characteristics using percentages and frequencies for categorical variables and standard deviations or median for continuous variables were summarized. The pooled prevalence of TBI was extracted using STATA at 95 per cent confidence interval (CI) to account for small variability between studies. The prevalence of TBI based on geographical location and age group was estimated. Studies were weighted using the random effect model. As two tests (TST and IGRA) were commonly used for estimating TBI prevalence, pooled prevalence was estimated for studies using TST as well as IGRA separately using the random effect model. Sub-group meta-analysis was carried out based on the demography and prevalence of active TBI in India. Effect sizes were expressed as odds ratio for dichotomous data and as weighted mean difference for the continuous data. All effect estimates were expressed using 95 per cent CI. We pooled data using the random effects model (DerSimonian and Laird) in the MetaXL software.
Results
Study characteristics: Initially, 10,521 studies were retrieved. Of these 519 duplicates were excluded and 9996 studies were eligible for screening. Of these, 9836 studies were further excluded after reviewing the title and abstract leaving 160 studies for full text review. Of these, the full text of 55 studies was unavailable. Additionally, 10 studies were included from cross references. So, in all 115 studies met the inclusion criteria for a full-text review. Following the full-text review, 77 studies were finally included for investigation. The PRISMA flow diagram is presented in Figure 1.
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Fig. 1: PRISMA flow diagram. PRISMA, preferred Reporting Items for Systematic Reviews and Meta-Analysis
Out of the 77 articles, 31 were cohort and 46 were cross-sectional studies. According to the zonal divisions of India15, most of the research was conducted in the southern part (15,813 i.e. 40.8% of patients) followed by the northern region (12,527 i.e.; 32.3% of patients), western region (3424 i.e. 8.8% of patients), central region (2296 i.e. 5.9% of patients) and eastern (174 i.e. 0.4% of patients) region of India. TST was used for diagnosing TBI in majority of the studies (70/77), IGRA was used in 10 per cent (7/77) studies and both TST & IGRA were used in 61 per cent (47/77) studies. A total of 59 studies considered TST positivity when reading recorded more than 10 mm induration and 11 studies considered it as more than 5 mm. A total of 38,767 individuals were studied across the included articles ranging from 33 to 2351 individuals. The Table provides an overview of the main characteristics of the included studies. As IGRA is a more specific diagnostic test for TBI compared to TST5, the pooled prevalence of TBI as depicted below was estimated using IGRA data as available. In the absence of the availability of IGRA data, TST results were considered for estimation. Furthermore, the pooled prevalence of TBI in India was estimated based on the community-based cohort studies only since hospital-based and cross-sectional studies generally, have inherent selection biases.
Table: Study characteristics of the included articles
Prevalence of tuberculosis infection based on community-based cohort studies: As per the random-effects model, the pooled community-based cohort study-based prevalence of TBI was found to be 40.8 per cent (95% CI: 29.5-52.6%, Q=1648.9, P<0.0001, I2=99%) (Fig 2). After excluding the risk groups, the pooled prevalence of TBI for community-based general population group was found to be 36 per cent (95% CI: 28-45%, Q=17.38, P<0.0001, I2=83%). Among the general population, TBI prevalence among adults (≥15 yr) was 35 per cent (95% CI: 24-46%, Q=13.93, P<0.0001, I2=86%). Due to the remarkable heterogeneity (P<0.00001, I2=99%), a sensitivity analysis was performed. After excluding the studies causing the heterogeneity, the pooled TBI prevalence was found to be 38 per cent (95% CI: 29-46%, Q=10.72, P=0.02, I2=72%).
Fig. 2: Community-based cohort studies TBI prevalence in India. TBI, tuberculosis infection
Prevalence of tuberculosis infection based on community-based cohort study according to the geography, age, gender and year-wise distribution: According to the available data, the prevalence of TBI based on community-based cohort studies in Delhi was 68 per cent (95% CI: 46-87%), in Tamil Nadu 42 per cent (95% CI: 24-61%) and in Maharashtra 26 per cent (95% CI: 16-36%). The pooled prevalence of TBI in urban areas was 37 per cent (95% CI: 16-60%), in rural areas 27 per cent (95%CI: 11-48%) and in tribal areas 33 per cent (95% CI: 20-47%). Among the paediatric population, the pooled prevalence of TBI was estimated as 33 per cent (95% CI: 24-42%) in under 5-yr-old children and in those aged 6-14 yr, it was 40 per cent (95%CI: 30-51%), respectively. In adult population, ranging from 15-45 yr of age, the TBI prevalence was 52 per cent (95% CI: 39-69%) and among older adults (above 45 yr), it was estimated as 62 per cent (95% CI: 50-74%). The estimated pooled prevalence of TBI was 41 per cent (95% CI: 19-65%) among the male population and in female population, it was 31 per cent (95% CI: 09-59%). A steady trend of TBI over the years was observed according to the data reported by various studies during 2013-2022.
Quality and risk of bias: Majority of the studies (76) were considered having a low risk of bias according to the JBI critical assessment score (>70%). Only one study was considered to have a moderate risk of bias (score 50-69%); Appendix I, Supplementary Table I and II. No articles were excluded based on the quality assessment.
Publication bias: Supplementary Figure presents the Doi plot, which is used to give readers an indication of any possible publication bias in the study. The Doi plot indicates that the included studies had minor asymmetry (LFK index=2.00).
Discussion
The present review appraised available evidence on the burden of TBI among people residing in India based on the results of IGRA as well as TST, which are the tests being used to diagnose and target individuals eligible for TPT. Data were gathered from over 38,767 IGRA and TST results covering the different regions of India. Based on the community-based cohort studies, it was observed that TBI was prevalent in more than one-third of India’s population and it increased with advancing age.
Various researchers previously reported a similar prevalence of TBI in India, using Bayesian model. Woodruff et al15 and Collins et al93 estimated 31.9 per cent and 33.9 per cent prevalence among Indians, respectively whereas Houben and Dodd94 by mathematical modeling presented a 31 per cent estimate of TBI in the south-east Asian region94. The national TB prevalence survey in 2019-2021 also recorded a crude TBI prevalence of 31 per cent7. Considered together, all these evidences indicate that India has a huge reservoir of TBI, a considerable proportion of whom may progress to TB disease. This review noted a rising TBI prevalence with age, especially among adults and older adults. High prevalence among such groups is an impediment to the national TB elimination efforts. Chong et al95 in their mathematical model, pertaining to countries with intermediate TB prevalence, suggested that screening and providing TPT to 20-40 per cent of the elderly could result in 50 per cent overall decline of TB incidence.
We noted a steady trend of TBI maintained over the last decade suggesting the persistence of TB incidence. TBI treatment rates among the high-risk groups in India was sub-optimal (12%)6. The World Health Organization (WHO) recommends the prevention and treatment as key interventions to achieve, the End TB targets. End TB targets2 India’s National Strategic plan (2017-25) rests on prevent, detect and treat as the core pillars for the elimination of TB10. The treatment of active TB reduces the prevalence of infectious TB, eventually cutting down the transmission and lowering the incidence4, whereas treatment of TBI prevents the progression of latent infection to disease and directly reduces the incidence3. Evidence suggests the treatment of TBI and active TB act synergistically to reduce TB incidence96,97. Hence, when the treatment levels of active TB are high (95%)6, a similar payoff could accrue by stepping up the treatment of TBI. Thus, scaling up of the TPT will hasten the lowering of TB incidence and to achieve the EndTB targets in India98.
The current review recorded remarkable regional differences in TBI prevalence. A high burden was found in those areas with prevalent active TB (Delhi, Tamil Nadu, etc.) implying that TBI probably has a high conversion rate to active TB disease7. TBI case-finding has high implementation cost99. However, in the absence of TBI case-finding, the number of infectious individuals will grow demanding increased need for active case-finding and case-holding efforts99. At present, India’s National TB Elimination Programme (NTEP) recommends active case-finding and case-holding efforts for areas with high TB prevalence leading to a longer implementation period100. Considering, both active as well as TBI case-finding having similar cost-sensitivities, TBI case-finding has a shorter implementation period. TBI case-finding relies on the use of diagnosis and treatment of TBI99. Evidence suggests that there is no ideal way of testing for and diagnosing TBI101–103. The two main tests in use are TST and IGRA, both of which measure the immunological response to MTB antigens101. TST, although inexpensive, is logistically challenging, produces variable results depending on the type of purified protein derivative (PPD) used and shortage of quality-assured tuberculin posing an impediment globally104,105. On the other hand, IGRA has high specificity, demands single facility visit; however, it is costly and there are issues related to the reproducibility of the results102. Recently, validity of both the tests has been questioned with evidence, suggesting only 10 per cent patients who harbour viable MTB organisms capable of causing disease showing immunoreactivity to these tests12,106. Further, issues related to testing hesitancy challenges the implementation of widespread screening107,108. Growing experience from clinical studies and implementation in the field suggests newer regimens such as three-month weekly rifapentine and isoniazid (3HP) regimen and one-month daily rifapentine and isoniazid (1HP) regimens, both of these appear to have a similar efficacy as the daily isoniazid dosing-based preventive therapy but with a better safety profile, higher acceptance and completion rate3. Thus, faced with operational issues related to the TBI diagnostics and considering the consequences of missing positive cases leading to increase in number of infectious individuals, increased efforts for active case-finding and high case-holding efforts in high prevalence areas and with recent 3HP implementation in the programme7,100, ‘no test, treat only approach’ after ruling out active TB needs to be contemplated109,110.
The present review is a comprehensive review that reports the prevalence of TBI in India, wherein an extensive systematic literature search with hand-searching of references was performed with a multidisciplinary team. The pooled prevalence was estimated only for community-based cohort studies. This increased the validity and offered a deeper and comprehensive understanding of the burden of TBI among different groups as well as the general population. However, the evidence reflected all the parts of India except the eastern region thus limiting the comprehensive depiction of the findings across India. There were also some limitations. For TST, studies were not separated based on the strength of PPD or use of standardization of PPD used in the studies. Furthermore, there was a lack of uniformity in the diagnosis of TBI, especially while using TST method as some studies reported more than 5 mm as TBI positivity irrespective of the immunocompromised patient inclusion. Further, there is a possibility of poor detection of true heterogeneity, especially when small number of studies are analyzed using Cochran’s Q, Higgins and Thompson’s I2 test.
Implications and way-forward: Prioritization of initiation of TPT is required for the regions with a high prevalence of TBI. This is important as the chances of missing positive patients are high owing to the less predictive value of diagnostic tests and their high operational costs. A more robust approach is needed with consideration of ‘No test, treat only’ approach after ruling out active TB for specific high disease burden geographies in comparison to the current strategy of active TB case-finding and case-holding approach for such regions. Research is further needed to identify the prevalence of TBI among individuals with multimorbidity (presence of two or more chronic conditions in one person), e.g. diabetic with cardiovascular disease or rheumatoid arthritis. Further evidence needs to be generated related to TBI among migrants, prisoners and residents of mental health homes. Prioritization of States with high TB disease burden and TBI prevalence for community-based screening to rule out active TB and implement TPT policy at the population levels is needed. As the treatment of TBI is a pre-requisite for achieving TB elimination goals, the evidence presented in this review will pave way for a more strengthened programmatic management of TBI in India.
Overall, this review demonstrated a high prevalence of TBI, commensurate with active TB prevalence suggesting conversion of TBI to active TB-disease. A high burden among people residing in the northern and southern regions was observed, indicating the need for the TBI country-specific strategies targeting population-level interventions.
Conflicts of Interest: Authors (MP, HS, SC and KR) are affiliated to the World Health Organization (WHO). The views expressed in this article are their own and not an official position of their respective institutions.
Supplementary Files
References
1. World Health Organization. Global TB report 2022. Geneva: WHO; 2022
3. World Health Organization. WHO consolidated guidelines on tuberculosis:Module 1:Prevention. Tuberculosis preventive treatment. Geneva: WHO; 2020
4. World Health Organization. WHO consolidated guidelines on tuberculosis:Module 4:Treatment:Drug-susceptible tuberculosis treatment. Geneva: WHO; 2022
5. Blumberg HM, Ernst JD. The challenge of latent TB infection. JAMA 2016;316:931-3
6. Ministry of Health and Family Welfare, Government of India. INDIA TB REPORT 2022. Available from:
https://tbcindia.gov.in/WriteReadData/IndiaTBReport2022/TBAnnaulReport 2022.pdf, [accessed on February 20 2023]
7. Indian Council of Medical Research. Central TB Division, Ministry of Health and Famly Welfare, Government of India, National TB
prevalence survey in India. Available from:
https://tbcindia.gov.in/showfile.php?lid=3659, [accessed on February 20 2023]
8. Rajpal S, Arora VK. Latent TB (LTBI) treatment:Challenges in India with an eye on 2025: “To Treat LTBI or not to treat, that is the question”. Indian J Tuberc 2020;67:S43-7
9. Sharma N, Basu S, Chopra KK. Achieving TB elimination in India:The role of latent TB management. Indian J Tuberc 2019;66:30-3
10. Central TB Division, Directorate General of Health Services, Ministry of Health and Famly Welfare, Government of India. National strategic plan for tuberculosis elimination 2017-2025. Available from:
https://tbcindia.gov.in/WriteReadData/NSP Draft 20.02.20171.pdf, [accessed on February 20, 2023]
11. Reid MJA, Arinaminpathy N, Bloom A, Bloom BR, Boehme C, Chaisson R, et al. Building a tuberculosis-free world:The Lancet Commission on tuberculosis. Lancet 2019;393:1331-84
12. Harries AD, Kumar AMV, Satyanarayana S, Thekkur P, Lin Y, Dlodlo RA, et al. The growing importance of tuberculosis preventive therapy and how research and innovation can enhance its implementation on the ground. Trop Med Infect Dis 2020;5:61
13. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016;5:210
14. Tufanaru C, Munn Z, Aromataris E, Campbell J, Hopp L. Ch. 3. Systematic reviews of effectiveness Aromataris E, Munn Z. JBI manual for evidence synthesis. New York: JBI; 2020
15. Yelk Woodruff R, Hill A, Marks S, Navin T, Miramontes R. Estimated latent
tuberculosis infection prevalence and tuberculosis reactivation rates among Non-U.S.-born residents in the United States, from the. 2011-2012 National Health And Nutrition Examination Survey. J Immigr Minor Health 2021;23:806-12
16. Agarwal S, Das SK, Agarwal GG, Srivastava R. Steroids decrease
prevalence of positive tuberculin skin test in rheumatoid arthritis: Implications on Anti-TNF therapies. Interdiscip Perspect Infect Dis 2014 2014; 430134
17. Agarwal SK, Singh UB, Zaidi SH, Gupta S, Pandey RM. Comparison of interferon gamma release assay &tuberculin skin tests for diagnosis of latent tuberculosis in patients on maintenance haemodialysis. Indian J Med Res 2015;141:463-8
18. Arya S, Kumar SK, Nath A, Kapoor P, Aggarwal A, Misra R, et al. Synergy between tuberculin skin test and proliferative T cell responses to PPD or cell-membrane antigens of Mycobacterium tuberculosis for detection of latent TB infection in a high disease-burden setting. PLoS One 2018;13:e0204429
19. Aravindhan V, Bobhate A, Sathishkumar K, Patil A, Kumpatla S, Viswanathan V. Unique reciprocal association seen between latent
tuberculosis infection and diabetes is due to immunoendocrine modulation (DM-LTB-1). Front Microbiol 2022;13:884374
20. Bajgai P, Sharma K, Bansal R, Gupta N, Sharma A, Gupta A. Detection of Mycobacterium tuberculosis genome in subretinal fluid of patients with latent
tuberculosis infection. Ocul Immunol Inflamm 2016;24:615-20
21. Bapat PR, Husain AA, Daginawala HF, Agrawal NP, Panchbhai MS, Satav AR, et al. The assessment of cytokines in Quantiferon supernatants for the diagnosis of latent TB infection in a tribal population of Melghat, India. J Infect Public Health 2015;8:329-40
22. Bekken GK, Ritz C, Selvam S, Jesuraj N, Hesseling AC, Doherty TM, et al. Identification of subclinical tuberculosis in household contacts using exposure scores and contact investigations. BMC Infect Dis 2020;20:96
23. Benachinmardi KK, Sangeetha S, Rao M, Prema R. Validation and clinical application of interferon-gamma release assay for diagnosis of latent
tuberculosis infection in children. Int J Appl Basic Med Res 2019;9:241-5
24. Benachinmardi K, Sampath S, Rao M. Evaluation of a new interferon gamma release assay, in comparison to tuberculin skin tests and quantiferon tuberculosis goldplus for the detection of latent
tuberculosis infection in children from a high tuberculosis burden setting. Int J Mycobacteriol 2021;10:142-8
25. Boddu D, Verghese VP, Michael JS, Chacko A, Jeyaseelan V. Utility of QuantiFERON
(®)-TB gold In-Tube test compared with tuberculin skin test in diagnosing tuberculosis in Indian children with malnutrition. Indian J Med Microbiol 2019;37:433-7
26. Chandrasekaran P, Mave V, Thiruvengadam K, Gupte N, Shivakumar SVBY, Hanna LE, et al. Tuberculin skin test and QuantiFERON-Gold In Tube assay for diagnosis of latent TB infection among household contacts of pulmonary TB patients in high TB burden setting. PLoS One 2018;13:e0199360
27. Chauhan S, Gahalaut P, Rathi AK. Tuberculin Skin Test, chest radiography and contact screening in children ≤5 y:Relevance in Revised National Tuberculosis Control Programme (RNTCP). Indian J Pediatr 2013;80:276-80
28. Christopher DJ, Shankar D, Datey A, Zwerling A, Pai M. Safety of the two-step tuberculin skin test in Indian health care workers. Int J Mycobacteriol 2014;3:247-51
29. Dayal R, Agarwal D, Bhatia R, Bipin C, Yadav NK, Kumar S, et al. Tuberculosis burden among household pediatric contacts of adult tuberculosis patients. Indian J Pediatr 2018;85:867-71
30. Dabhi PA, Thangakunam B, Gupta R, James P, Thomas N, Naik D, et al. Screening for
prevalence of current TB disease and latent TB infection in type 2 diabetes mellitus patients attending a diabetic clinic in an Indian tertiary care hospital. PLoS One 2020;15:e0233385
31. Dinkar PK, Kumar S, Kumar S, Verma SK, Kumar S. To study the
prevalence of latent
tuberculosis infection among medical students. Indian J Community Health 2022;34:5-9
32. Dolla CK, Padmapriyadarsini C, Thiruvengadam K, Lokhande R, Kinikar A, Paradkar M, et al. Age-specific
prevalence of TB infection among household contacts of pulmonary TB:Is it time for TB preventive therapy?. Trans R Soc Trop Med Hyg 2019;113:632-40
33. Dorjee K, Topgyal S, Dorjee C, Tsundue T, Namdol T, Tsewang T, et al. High
prevalence of active and latent tuberculosis in children and adolescents in Tibetan schools in India:The Zero TB kids initiative in Tibetan refugee children. Clin Infect Dis 2019;69:760-8
34. Faujdar SS, Singh U, Kumar S, Mehrishi P, Sharma A, Dutta A. Mantoux test defaulters in rural population attending tertiary care hospital in a tuberculosis endemic area. J Family Med Prim Care 2022;11:677-9
35. Girish S, Kinikar A, Pardesh G, Shelke S, Basavaraj A, Chandanwale A, et al. Utility of the interferon-gamma release assay for latent
tuberculosis infection screening among Indian health-care workers. Indian J Community Med 2021;46:281-4
36. Gupta A, Swindells S, Kim S, Hughes MD, Naini L, Wu X, et al. Feasibility of identifying household contacts of Rifampin-and multidrug-resistant tuberculosis cases at high risk of progression to tuberculosis disease. Clin Infect Dis 2020;70:425-35
37. Gupta A, Sural S, Gupta A, Rousa S, Koner BC, Bhalotra A, et al. Positive QuantiFERON test and the severity of COVID-19 disease:A prospective study. Indian J Tuberc 2021;68:474-80
38. Jain SK, Ordonez A, Kinikar A, Gupte N, Thakar M, Mave V, et al. Pediatric tuberculosis in young children in India:A prospective study. Biomed Res Int 2013 2013; 783698
39. James PM, Ganaie FA, Kadahalli RL. The performance of quantiferon-TB gold in-tube (QFT-IT) test compared to tuberculin skin test (TST) in detecting latent
tuberculosis infection (LTBI) in the presence of HIV coinfection in a high TB-burden area with BCG-vaccinated population. J Int Assoc Provid AIDS Care 2014;13:47-55
40. Janagond AB, Ganesan V, Vijay Kumar GS, Ramesh A, Anand P, Mariappan M. Screening of health-care workers for latent
tuberculosis infection in a Tertiary Care Hospital. Int J Mycobacteriol 2017;6:253-7
41. Jenum S, Selvam S, Mahelai D, Jesuraj N, Cárdenas V, Kenneth J, et al. Influence of age and nutritional status on the performance of the tuberculin skin test and QuantiFERON-TB gold in-tube in young children evaluated for tuberculosis in Southern India. Pediatr Infect Dis J 2014;33:e260-9
42. Mukherjee A, Saini S, Kabra SK, Gupta N, Singh V, Singh S, et al. Effect of micronutrient deficiency on QuantiFERON-TB Gold In-Tube test and tuberculin skin test in diagnosis of childhood Intrathoracic tuberculosis. Eur J Clin Nutr 2014;68:38-42
43. Syed Ahamed Kabeer B, Paramasivam P, Raja A. Interferon gamma and interferon gamma inducible protein-10 in detecting
tuberculosis infection. J Infect 2012;64:573-9
44. Kashyap RS, Nayak AR, Gaherwar HM, Husain AA, Shekhawat SD, Jain RK, et al. Latent TB infection diagnosis in population exposed to TB subjects in close and poor ventilated high TB endemic zone in India. PLoS One 2014;9:e89524
45. Kashyap RS, Nayak AR, Husain AA, Shekhawat SD, Satav AR, Jain RK, et al. Impact of socioeconomic status and living condition on latent tuberculosis diagnosis among the tribal population of Melghat:A cohort study. Lung India 2016;33:372-80
46. Kaul S, Nair V, Birla S, Dhawan S, Rathore S, Khanna V, et al. Latent
tuberculosis infection diagnosis among household contacts in a high tuberculosis-burden area:A comparison between transcript signature and interferon gamma release assay. Microbiol Spectr 2022;10:e0244521
47. Kinikar A, Chandanwale A, Kadam D, Joshi S, Basavaraj A, Pardeshi G, et al. High risk for latent
tuberculosis infection among medical residents and nursing students in India. PLoS One 2019;14:e0219131
48. Krishnamoorthy Y, Ezhumalai K, Murali S, Rajaa S, Jose M, Sathishkumar A, et al.
Prevalence and risk factors associated with latent
tuberculosis infection among household contacts of smear positive pulmonary tuberculosis patients in South India. Trop Med Int Health 2021;26:1645-51
49. Vijay Kumar GS, Gopalakrishnan R. Detection of latent
tuberculosis infection in nursing students by combined TST and IGRA serial testing. J Med Sci Clin Res 2014;2:567-74
50. Kumar MG, Joseph B, Goud BR, Joseph M, Rajitha M. Risk of
tuberculosis infection among healthcare workers in a tertiary care hospital in Bengaluru City. Indian J Occup Environ Med 2019;23:83-9
51. Kumar P, Vuyyuru SK, Kante B, Sahu P, Goyal S, Madhu D, et al. Stringent screening strategy significantly reduces reactivation rates of tuberculosis in patients with inflammatory bowel disease on anti-TNF therapy in tuberculosis endemic region. Aliment Pharmacol Ther 2022;55:1431-40
52. Madan M, Baldwa B, Raja A, Tyagi R, Dwivedi T, Mohan A, et al. Impact of latent tuberculosis on severity and outcomes in admitted COVID-19 patients. Cureus 2021;13:e19882
53. Madan K, Sryma PB, Pattnaik B, Mittal S, Tiwari P, Hadda V, et al. Clinical profile of 327 patients with Sarcoidosis in India:An Ambispective cohort study in a Tuberculosis (TB) endemic population. Lung India 2022;39:51-7
54. Malaviya AN, Aggarwal VK, Rawat R, Baghel S, Thakran R, Zaheer Q, et al. Screening for latent
tuberculosis infection among patients with rheumatoid arthritis in the era of biologics and targeted synthetic disease-modifying anti-rheumatic drugs in India, a high-burden TB country:The importance of Mantoux and Quantiferon-TB Gold tests. Int J Rheum Dis 2018;21:1563-71
55. Malaviya AN, Thakaran R, Rawat R, Kapoor S, Garg S, Baghel SS, et al. Real life experience of a screening strategy for latent tuberculosis before treatment with biologicals in Indian patients with rheumatic diseases. Indian J Rheumatol 2018;13:233-9
56. Mantri AK, Meena P, Puri AS, Kumar A, Sachdeva S, Srivastava S, et al. Comparison of interferon-gamma release assay and tuberculin skin test for the screening of latent tuberculosis in inflammatory bowel disease patients:Indian Scenario. Tuberc Res Treat 2021 2021; 6682840
57. Mathad JS, Bhosale R, Sangar V, Mave V, Gupte N, Kanade S, et al. Pregnancy differentially impacts performance of latent tuberculosis diagnostics in a high-burden setting. PLoS One 2014;9:e92308
58. Mathad JS, Bhosale R, Balasubramanian U, Kanade S, Mave V, Suryavanshi N, et al. Quantitative IFN-γand IL-2 response associated with latent tuberculosis test discordance in HIV-infected pregnant women. Am J Respir Crit Care Med 2016;193:1421-8
59. Mave V, Chandrasekaran P, Chavan A, Shivakumar SVBY, Danasekaran K, Paradkar M, et al. Infection free “resisters” among household contacts of adult pulmonary tuberculosis. PLoS One 2019;14:e0218034
60. Mishra S, Singh SK, Mohan U, Sahu R, Verma AK. Risk factors associated with
tuberculosis infection among household children contacts of sputum smear positive tuberculosis cases. Indian J Community Health 2017;29:162-7
61. Munisankar S, Rajamanickam A, Balasubramanian S, Muthusamy S, Menon PA, Ahamed SF, et al.
Prevalence of proximate risk factors of active tuberculosis in latent
tuberculosis infection:A cross-sectional study from South India. Front Public Health 2022;10:1011388
62. Murthy M, Selvam S, Jesuraj N, Bennett S, Doherty M, Grewal HM, et al. Two-step tuberculin skin testing in school-going adolescents with initial 0-4 millimeter responses in a high tuberculosis
prevalence setting in South India. PLoS One 2013;8:e71470
63. Narasimhan P, MacIntyre CR, Mathai D, Wood J. High rates of latent TB infection in contacts and the wider community in South India. Trans R Soc Trop Med Hyg 2017;111:55-61
64. Neema S, Radhakrishnan S, Dabbas D, Vasudevan B. Latent tuberculosis in psoriasis patients planned for systemic therapy –A prospective observational study. Indian Dermatol Online J 2021;12:429-32
65. Neema S, Sandhu S, Mukherjee S, Vashisht D, Vendhan S, Sinha A, et al. Comparison of interferon gamma release assay and tuberculin skin test for diagnosis of latent tuberculosis in Psoriasis Patients Planned for Systemic Therapy. Indian J Dermatol 2022;67:19-25
66. Pattnaik B, Pb S, Verma M, Kumar S, Mittal S, Arava S, et al. Patient profile and comparison of three diagnostic criteria for cardiac sarcoidosis in a tuberculosis endemic population. Sarcoidosis Vasc Diffuse Lung Dis 2022;38:e2021040
67. Pandey A, Warade JP. Role of QuantiFERON-TB QuantiFERON TB gold in diagnosis of tuberculosis. IAIM 2014;1:9-12
68. Paradkar M, Padmapriyadarsini C, Jain D, Shivakumar SVBY, Thiruvengadam K, Gupte AN, et al. Tuberculosis preventive treatment should be considered for all household contacts of pulmonary tuberculosis patients in India. PLoS One 2020;15:e0236743
69. Prabhavathi M, Kabeer BS, Deenadayalan A, Raja A. Role of QuantiFERON-TB gold antigen-specific IL-1βin diagnosis of active tuberculosis. Med Microbiol Immunol 2015;204:567-74
70. Prabhavathi M, Ahamed Kabeer BS, Deenadayalan A, Raja A. In vitro QuantiFERON-TB gold antigen specific interleukin-1beta to diagnose TB among HIV-positive subjects. Tuberculosis (Edinb) 2016;96:27-30
71. Patil S, Phutane M, Mundkar S. Role of tuberculin skin test in latent
tuberculosis infection in HIV patients in a tertiary care hospital of India. J Transl Intern Med 2014;2:136-42
72. Rajamanickam A, Kumar NP, Padmapriyadarsini C, Nancy A, Selvaraj N, Karunanithi K, et al. Latent tuberculosis co-infection is associated with heightened levels of humoral, cytokine and acute phase responses in seropositive SARS-CoV-2 infection. J Infect 2021;83:339-46
73. Ramaraj SM, Nagendra K, Gopal G, Majgi SM. Need for different cutoff values for reading Mantoux Test with 2TU and 5TU PPD. Indian J Pediatr 2017;84:677-80
74. Rajalakshmi KV, Viknesh Prabu A.
Prevalence of latent
tuberculosis infection in type 2 diabetic and non- diabetic individuals. J Med Sci Clin Res 2017;5:23617-23
75. Reddy D, Ma Y, Lakshminarayanan S, Sahu S, White LF, Reshma A, et al. Severe undernutrition in children affects tuberculin skin test performance in Southern India. PLoS One 2021;16:e0250304
76. Sawhney N, Mehta S, Shinu P, Singh V.
Prevalence of Latent
Tuberculosis infection among hospital workers in a tertiary care referral centre. Int J Adv Health Sci 2015;2:585-91
77. Shah I, Raut V, Shetty NS. Interpretation of tuberculin skin test in Bacillus calmette –Guerin-Vaccinated children. Med J DY Patil Vidyapeeth 2021;14:512-6
78. Shah I, Kathwate J, Shetty NS. Comparison of tuberculin skin test and QuantiFERON-TB Gold In-Tube test in Bacillus Calmette-Guerin-vaccinated children. Lung India 2020;37:24-9
79. Sharma SK, Vashishtha R, Chauhan LS, Sreenivas V, Seth D. Comparison of TST and IGRA in diagnosis of latent
tuberculosis infection in a high TB-Burden setting. PLoS One 2017;12:e0169539
80. Shivakumar SVBY, Chandrasekaran P, Kumar AMV, Paradkar M, Dhanasekaran K, Suryavarshini N, et al. Diabetes and pre-diabetes among household contacts of tuberculosis patients in India:Is it time to screen them all?. Int J Tuberc Lung Dis 2018;22:686-94
81. Shobha V, Chandrashekara S, Rao V, Desai A, Jois R, Dharmanand BG, et al. Biologics and risk of tuberculosis in autoimmune rheumatic diseases:A real-world clinical experience from India. Int J Rheum Dis 2019;22:280-7
82. Srivastava G, Faridi MMA, Gupta SS. Tubercular infection in children living with adults receiving Directly Observed Treatment Short Course (DOTS):A follow up study. BMC Infect Dis 2020;20:720
83. Siddiqui MK, Khan S, Bhutia R, Nair V, Gurung N, Yamphel T, et al.
Prevalence and factors associated with latent
tuberculosis infection among residents of a monastery situated in a high-TB burden area :A cross sectional study, Sikkim, India. Res Square 2022. Doi:10.21203/rs.3.rs-1872450/v1
84. Singh J, Sankar MM, Kumar S, Gopinath K, Singh N, Mani K, et al. Incidence and
prevalence of tuberculosis among household contacts of pulmonary tuberculosis patients in a Peri-Urban population of South Delhi, India. PLoS One 2013;8:e69730
85. Singh R, Fatima N, Shukla I, Shameem M. Evaluation of role of interferon gamma release assays in the diagnosis of latent tuberculosis in human immunodeficiency virus-infected patients. Indian J Sex Transm Dis AIDS 2021;42:111-7
86. Surve S, Bhor V, Naukariya K, Begum S, Munne K, Tipre P, et al. Discordance between TST and QFT-TBGold plus for latent tuberculosis screening among under-five children:An interim analysis. J Trop Pediatr 2021;67:fmab103
87. Thamke R, Kamale V, Rajan R. Assessment of children in contact with sputum positive adult patients with respect to TB disease and latency. New Indian J Pediatr 2018;7:229-38
88. Thomas L, Verghese VP, Chacko A, Michael JS, Jeyaseelan V. Accuracy and agreement of the Tuberculin Skin Test (TST) and the QuantiFERON-TB Gold In-tube test (QFT) in the diagnosis of tuberculosis in Indian children. Indian J Med Microbiol 2022;40:109-12
89. Uppada DR, Selvam S, Jesuraj N, Bennett S, Verver S, Grewal HM, et al. The tuberculin skin test in school going adolescents in South India:Associations of socio-demographic and clinical characteristics with TST positivity and non-response. BMC Infect Dis 2014;14:571
90. Vyas S, Thangakunam B, Gupta R, Michael JS, Christopher DJ. Interferon gamma release assay and tuberculin skin test positivity in Sarcoidosis. Lung India 2015;32:91-2
91. Zwerling A, Pai M, Michael JS, Christopher DJ. Serial testing using interferon-γrelease assays in nursing students in India. Eur Respir J 2014;44:257-60
92. Abdullah Z, Kumar A, Khan MA, Kumar U, Vyas S, Vishwakarma VK, et al. The interplay of disease modifying anti rheumatic drugs and tuberculin skin test. Curr Rev Clin Exp Pharmacol 2021;16:350-6
93. Collins JM, Stout JE, Ayers T, Hill AN, Katz DJ, Ho CS, et al.
Prevalence of latent
tuberculosis infection among Non-US-Born persons by country of Birth-United States 2012-2017. Clin Infect Dis 2021;73:e3468-75
94. Houben RM, Dodd PJ. The global burden of latent
tuberculosis infection:A Re-estimation using mathematical modelling. PLoS Med 2016;13:e1002152
95. Chong KC, Leung CC, Yew WW, Zee BCY, Tam GCH, Wang MH, et al. Mathematical modelling of the impact of treating latent
tuberculosis infection in the elderly in a city with intermediate tuberculosis burden. Sci Rep 2019;9:4869
96. Dye C, Williams BG. Eliminating human tuberculosis in the twenty-first century. J R Soc Interface 2008;5:653-62
97. Hill AN, Becerra J, Castro KG. Modelling tuberculosis trends in the USA. Epidemiol Infect 2012;140:1862-72
98. Centrl TB Division. Ministry of Health and Family Welfare, Government of India. Guidelines for programmatic management of tuberculosis preventive treatment in India. New Delhi: MoHFW, GoI; 2021
99. Kim S, de Los Reyes AA 5th, Jung E. Mathematical model and intervention strategies for mitigating tuberculosis in the Philippines. J Theor Biol 2018;443:100-12
100. Central TB Division. Ministry of Health & Family Welfare, Government of India. India TB report 2023. New Delhi: MoHFW, GoI; 2023
101. Muñoz L, Stagg HR, Abubakar I. Diagnosis and Management of Latent
Tuberculosis Infection. Cold Spring Harb Perspect Med 2015;5:a017830
102. Carranza C, Pedraza-Sanchez S, de Oyarzabal-Mendez E, Torres M. Diagnosis for latent
tuberculosis infection:New alternatives. Front Immunol 2020;11:2006
103. Al-Orainey IO. Diagnosis of latent tuberculosis:Can we do better?. Ann Thorac Med 2009;4:5-9
104. Yang H, Kruh-Garcia NA, Dobos KM. Purified protein derivatives of tuberculin –Past, present, and future. FEMS Immunol Med Microbiol 2012;66:273-80
105. Tebruegge M, Bogyi M, Soriano-Arandes A, Kampmann B Paediatric Tuberculosis Network European Trials Group. Shortage of purified protein derivative for tuberculosis testing. Lancet 2014;384:2026
106. Behr MA, Edelstein PH, Ramakrishnan L. Is Mycobacterium
tuberculosis infection life long?. BMJ 2019;367:l5770
107. Goode JV, Upshur R, Grimes MB, Nadpara P. Patient satisfaction with pharmacist-administered Mantoux tuberculin skin test in a community-based pharmacy setting. J Am Pharm Assoc 2019;59:S77-80.e2
108. Brien K, Ikram S, Burman M, Kunst H. Barriers and facilitators of a latent tuberculosis screening and treatment programme of recent migrants. Eur Respir J 2020;56 Suppl 64:508
109. Huynh GH, Klein DJ, Chin DP, Wagner BG, Eckhoff PA, Liu R, et al. Tuberculosis control strategies to reach the 2035 global targets in China:The role of changing demographics and reactivation disease. BMC Med 2015;13:88
110. Sumner T, White RG. The predicted impact of tuberculosis preventive therapy:The importance of disease progression assumptions. BMC Infect Dis 2020;20:880
