DOI: 10.1111/tmi.13808 SYSTEMATIC REVIEW Strategies to detect and manage latent tuberculosis infection among household contacts of pulmonary TB patients in high TB burden countries - a systematic review and meta-analysis Karuna Devi Sagili1 | Malaisamy Muniyandi2 | Kalpita Shringarpure3 | Kavita Singh1 | Richard Kirubakaran4 | Raghuram Rao5 | Jamhoih Tonsing6 | Kuldeep Singh Sachdeva1 | 1 International Union Against Tuberculosis and Lung Disease, South East Asia Office, New Delhi, India 2 Indian Council of Medical Research (ICMR), National Institution for Research in Tuberculosis, Chennai, India 3 Department of Community Medicine, Medical College Baroda, Baroda, India 4 Clinical Epidemiology Unit, Christian Medical Centre, Vellore, India 5 National TB Elimination Program, Central TB Division, Ministry of Health, New Delhi, India 6 Technical Advice and Partnerships Department, The Global Fund, Geneva, Switzerland Correspondence Karuna Devi Sagili, Knowledge Management and Research (ACSM-NTSU), International Union Against Tuberculosis and Lung Disease, South East Asia Office, New Delhi, India. Email: drkarunas@gmail.com Funding information UK Government Prathap Tharyan4 Abstract Objective: To summarise latent tuberculosis infection (LTBI) management strategies among household contacts of bacteriologically confirmed pulmonary tuberculosis (TB) patients in high-TB burden countries. Methods: PubMed/MEDLINE (NCBI) and Scopus were searched (January 2006 to December 2021) for studies reporting primary data on LTBI management. Study selection, data management and data synthesis were protocol-driven (PROSPEROCRD42021208715). Primary outcomes were the proportions of LTBI, initiating and completing tuberculosis preventive treatment (TPT). Reported factors influencing the LTBI care cascade were qualitatively synthesised. Results: From 3694 unique records retrieved, 58 studies from 23 countries were included. Most identified contacts were screened (median 99%, interquartile range [IQR] 82%–100%; 46 studies). Random-effects meta-analysis yielded pooled proportions for: LTBI 41% (95% confidence interval [CI] 33%–49%; 21,566 tested contacts); TPT initiation 91% (95% CI 79%–97%; 129,573 eligible contacts, 34 studies); TPT completion 65% (95% CI 54%–74%; 108,679 TPT-initiated contacts, 28 studies). Heterogeneity was significant (I2 ≥ 95%–100%) and could not be explained in subgroup analyses. Median proportions (IQR) were: LTBI 44% (28%–59%); TPT initiation 86% (60%–100%); TPT completion 68% (44%–82%). Nine broad themes related to diagnostic testing, health system structure and functions, risk perception, documentation and adherence were considered likely to influence the LTBI care cascade. Conclusion: The proportions of household contacts screened, detected with LTBI and initiated on TPT, though variable was high, but the proportions completing TPT were lower indicating current strategies used for LTBI management in high TB burden countries are not sufficient. KEYWORDS diagnosis, high TB burden settings, household contacts, isoniazid preventive therapy, latent TB infection, screening, TB preventive therapy, treatment, tuberculosis Sustainable Development Goal: Good Health and Wellbeing. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors Tropical Medicine & International Health Published by John Wiley & Sons Ltd. 842 wileyonlinelibrary.com/journal/tmi Trop Med Int Health. 2022;27:842–863. 843 TROPICAL MEDICINE & INTERNATIONAL HEALTH INTRODUCTION Tuberculosis (TB) is a major public health problem and a leading cause of death worldwide. Over 10 million people are estimated to have developed TB in 2020; the majority were from 30 high TB burden, resource-constrained, lowand middle-income countries (LMICs) [1]. In 2014, the World Health Assembly adopted World Health Organisation’s (WHO) End TB Strategy which aims to eliminate the global TB epidemic by the year 2035 [2]. Latent tuberculosis infection (LTBI) is a condition of persistent immune response to infection by Mycobacterium tuberculosis (M.tb) in people with no evidence of active TB disease [3, 4]. It is estimated that approximately 1.7 billion individuals (nearly a quarter of the global population) were infected with LTBI in 2014, with a 5%–10% lifetime risk of developing active TB; and that over 50% of the household contacts of smear-positive index TB patients in LMICs have LTBI [5, 6]. Hence, WHO recommends that those with LTBI should be treated with tuberculosis preventive therapy (TPT) to realise the goals of the End TB Strategy [7]. Contact investigation is an essential component of the WHO’s TB management algorithms to detect those with LTBI among high-risk groups, and to initiate TPT [4, 7, 8]. WHO guidelines recommend home visits as the preferred mode of contact investigation; however, when home visits are not possible, contact investigation at a health facility is recommended. In either case, WHO advocates that trained staff should elicit the required information from the index TB patients [8] and counsel patients and their family members on the importance of LTBI testing, TPT initiation and completion [4, 7, 8]. WHO recommends the tuberculin skin test (TST) or interferon-gamma release assays (IGRA) to detect LTBI [8]. TST is a reasonably low-cost tool; however, its production is limited. IGRA results in fewer false-positive results than with TST, but has higher cost and supply chain issues that challenge its routine induction in national TB programmes in LMICs [8]. The options for TPT currently recommended by WHO for adults and children with LTBI, regardless of human immunodeficiency virus (HIV) status, include: (1) isoniazid monotherapy daily for 6 or 9 months, (2) rifampicin plus isoniazid daily for 3 months, (3) rifapentine plus isoniazid weekly for 3 months, (4) a 1-month daily regimen of rifapentine or isoniazid, or (5) 4 months of daily rifampicin [8]. As per the recommendations, child contacts under 5 years of age can be provided with TPT irrespective of their LTBI status after excluding TB [4, 7, 8]. The first-ever United Nations high-level meeting (UNHLM) declaration in 2018 envisaged the rapid scale-up of access to LTBI testing and provision of TPT, with a special focus on high TB burden countries, so that at least 30 million people receive TPT by 2022 [9]. In many lowburden, high-income countries, systematic LTBI management has contributed to lower rates of active TB. However, in high TB burden LMICs, this is challenging as it requires the diversion of resources from treating people with active TB. An ideal cascade of care for TPT starts with identifying the eligible population, screening for and excluding active TB, diagnosing LTBI, initiating TPT and ensuring TPT completion. Multiple factors operating at every step of the cascade affect the implementation of TPT. For instance, limited finance and manpower, low rates of contact screening and treatment initiation, inadequate documentation of cascade components and so on are some of the factors that adversely affect TPT implementation in LMICs with a high TB burden [3, 10–13]. Synthesising evidence on implementation strategies and factors that affect TPT in high TB burden settings is imperative to inform attempts to achieve the global targets for managing LTBI. A recent systematic review and metaanalysis found that contact investigation was effective in high-burden settings [14]. Another mixed-methods systematic review discussed the child contact losses that occur through the care cascade, along with the variations in the screening, initiation and completion of isoniazid preventive therapy among child contacts [15]. However, strategies used for child contact management were not described. While these reviews provide information on the prevalence of LTBI and the risk of incident TB, information on effective implementation strategies for the care cascade remains unclear. This systematic review aimed to summarise the strategies used in high TB burden countries for screening and determining the eligibility for TPT among the household contacts of bacteriologically confirmed pulmonary TB patients, and to evaluate the outcomes of these strategies with respect to TPT initiation and completion. We also sought to ascertain the factors influencing these strategies and outcomes. METHODS This review followed the methods described in the Preferred Reporting Items for a Systematic Review and Meta-analysis (PRISMA) 2020 statement [16] and was based on a protocol registered on the International Prospective Register of Systematic Reviews (PROSPERO ID # CRD42021208715). Search strategy and eligibility criteria We searched PubMed/MEDLINE (NCBI) and SCOPUS (Elsevier) for primary studies published between 1 January 2006 and 31 December 2021 describing the strategies for implementing TPT among household contacts of pulmonary TB patients in high-burden countries that reported data on aspects of the TPT care cascade. The initial search did not yield studies in child contacts; therefore, to ensure that all age groups were covered, the search strategy was rerun with additional keywords (child contacts) and the new output 844 was reviewed for inclusion (Table S1). We included studies published in English that reported data on strategies used in screening household contacts of bacteriologically confirmed pulmonary TB patients for LTBI. The operational definitions we used are provided in Table S2. The permitted study designs included randomised/non-randomised controlled trials (RCTs/non-RCTs), prospective and retrospective cohort studies, cross-sectional studies, longitudinal studies, cost-effectiveness studies and studies with mixed designs. Studies without usable numerical data for any component of the TPT care cascade, as well as those conducted primarily in clinically vulnerable and immunocompromised groups, qualitative studies, and studies published in languages other than English, were excluded. Selection of studies and data management process The search results were exported to the web-application Rayyan (https://www.rayyan.ai/). Three review authors (KS, KDS and MM) independently screened titles and abstracts for eligibility and selected studies. Full texts were evaluated, or study authors were contacted, for additional information to determine eligibility, and disagreements were resolved through discussion. A fourth author (PT) independently checked the appropriateness of study selection. We used a data extraction form that had been pretested by two review authors (KS and KSS). Data were extracted independently by three review authors (KS, MM and KSS) and were checked by a fourth author (PT). From each study, we extracted data regarding the target population, sample size, age of household contacts, setting, study design, screening strategies, tests used, and the proportions with positive test results, proportions initiating and completing TPT among those eligible, loss-to-follow-up, adverse events and treatment failures (incident TB while on TPT). We listed the factors that were reported by study authors as influencing the TPT care cascade. We contacted study authors for clarifications and for missing data. Since different study designs that assessed different aspects of the TPT care cascade were used, a formal risk of bias assessment was not possible, but deficiencies in reporting relevant data were recorded. Data synthesis and statistical analysis Extracted data regarding the characteristics of the included studies were analysed using descriptive statistics with Microsoft Excel. The primary outcomes of interest were the proportions of household contacts who were screened and tested for LTBI, and who initiated and completed TPT. We conducted meta-analyses using the metafor package for the statistical software environment R (https://www.metaforproject.org/doku.php) and generated forest plots of the TROPICAL MEDICINE & INTERNATIONAL HEALTH pooled estimates with 95% confidence intervals (CIs) for the proportions with LTBI (positive either by TST or IGRA or both as defined by study authors), and for the proportions initiating TPT among those eligible, and completing TPT. We anticipated that studies estimating LTBI positivity conducted in different regions of the world over several decades, and using different screening and diagnostic tests, algorithms and treatment protocols would result in substantial heterogeneity, and used the random-effects model in metaanalyses. We quantified heterogeneity using the I 2 statistic with a value more than 50% to denote significant inconsistency in the estimates. This indicates that more than half of the total heterogeneity stems from between-study variance that could not be explained by sampling error. We also reported Tau2 (τ 2) with a value more than zero denoting the absolute value of the true variance (heterogeneity); higher values of τ 2 indicate greater heterogeneity. We explored potential causes for significant heterogeneity in LTBI estimates in the following subgroup analyses: (1) the tests used to diagnose LTBI (TST, IGRA, combination); (2) the place of testing (hospital or health facility, household, both); and (3) the study design used (prospective, cross-sectional or retrospective). We separately analysed the LTBI positivity in studies done in Africa, Asia and South America, sub-grouped by countries within geographical regions within these continents. We also explored LTBI positivity in studies using TST alone sub-grouped by the place of testing, and by the size of the skin induration used to denote a positive TST result (≥5 mm; ≥10 mm). Regarding the proportions initiating and completing TPT, we explored heterogeneity in subgroup analysis of studies including children aged <6 years; <18 years; all age groups. We also reported the range and the median and interquartile range (IQR) of these proportions for the overall pooled results and in the subgroups. Factors reported in the studies that were considered by study authors to have influenced the TPT care cascade outcomes were extracted and grouped under common categories. RESULTS Search results The search yielded 3694 unique records after duplicates were removed. Figure 1 depicts the flow of the search and selection process. After screening the title and abstracts, 3584 records not relevant to this review were excluded (Figure 1). The full texts of 110 potentially eligible studies were assessed, and 52 studies were excluded because disaggregated data for household and non-household contacts were not available (n = 29); or the study designs were inappropriate (n = 9); or there were insufficient data regarding components of the TPT cascade (n = 11). We included 58 studies that satisfied eligibility criteria in qualitative and quantitative synthesis (meta-analysis). 845 TROPICAL MEDICINE & INTERNATIONAL HEALTH FIGURE 1 Flow diagram for study selection. TPT, tuberculosis preventive treatment Study characteristics Table 1 summarises the characteristics of the 58 studies conducted in 23 LMICs that were included in this review. Twenty-eight studies (48%) were conducted in Africa (12 from countries in East Africa, 7 from West Africa and 9 in Southern Africa). Twenty-five studies (43%) were conducted in Asia, of which 17 were conducted in countries in South Asia (with 15 from India); 5 in South East Asia and 3 in East Asia. Three studies were done in South America (all from Brazil). Two were multi-country cost-effectiveness studies (one included countries in Central and West Africa and the other included centres in Asian and African countries). The majority of the studies (45/58, 78%) were published between 2011 and 2020, while six were published before 2010 (2006–2009), and seven were published in 2021. The study designs included prospective cohorts [n = 28], prospectively ascertained programme datasets [n = 6], RCTs [n = 2], cross-sectional studies [n = 19], retrospective cohorts [n = 1] and mixed designs [n = 2]. In 27 (46%) of the studies, the target population was children, with only children <6 years of age included in 25 (43%). Children and adolescents were the target population in 12 (21%), only adult contacts in 1 (2%), only adolescents and adults in 1 (2%) and contacts of all ages in 17 (29%) of the studies. Household screening strategies were used in 19 (33%), and facility-based screening was used in 35 (60%) of the studies. Three studies used both approaches, and the approach was unclear in one. Thirty-six (62%) of the studies reported data on screening and LTBI diagnosis, of which 14 also reported on TPT initiation/completion. Thirty-four (59%) reported on components of TPT initiation/completion, of which 20 did not report data for LTBI diagnosis. Twenty-eight studies (48%) provided information on the factors that may have affected the outcomes of the TPT cascade. Components of the TPT care cascade The implementation of the recommended sequence of steps that formed the strategy used to implement TPT among household contacts varied in the 58 studies from the high TB burden, LMIC countries included in the review. Characteristics of the included studies 846 TABLE 1 No. Study ID Geographic region TB incidence/100,000 peoplea 1. Bonnet_Uganda_2017 [17] East Africa 196 Children <5 years 2. Chandrasekaran_India_2018 [18] South Asia 188 Adults + children 3. Machado_Brazil_2009 [19] South America 45 Adults + children 4. MacPherson_South Africa_2020 [20] Southern Africa 554 Adults + children 5. Odera_Kenya_2020 [21] East Africa 259 Adults ≥18 years 6. Praveen_India_2020 [22] South Asia 188 7. Ronge South Africa_2021 [23] Southern Africa 8. Rutherford_Indonesia_2012 [24] 9. Target population Household contacts screened among those identified (%) Diagnostic Screening test(s) TPT initiated/ completed Both Place/setting Study design HC/urban Prospective cohort V + CXR TST HC/NR Prospective cohort CXR TST + IGRA NR 261/301 (86.7) HC/NR Prospective cohort NR TST 2725/2985 (91.3) HH/NR RCT V + CXR TST NR 175/NR HC/semi-urban Crosssectional NR IGRA NR Adults + children ≥12 years 220/NR HH/NR Crosssectional V TST NR 554 Children ≤15 years 669/669 (100) HH/urban Crosssectional CXR IGRA NR South East Asia 301 Children 6 months to 9 years 320/320 (100) HC/urban Prospective cohort V TST + IGRA NR Shah_South Africa_2011 [25] Southern Africa 554 Children 6–16 years 270/270 (100) HH + HC/NR Prospective cohort NR TST + IGRA NR 10. Sharma_India_2017 [26] South Asia 188 Adults + children 1– 65 years 1511/1511 (100) HH/NR Prospective cohort V + CXR TST + IGRA NR 11. Stein_Uganda_2018 [27] East Africa 196 Adults + children 2585/3102 (83.3) HH/NR Prospective cohort V 12. Zhang_China_2019 [28] East Asia 59 Adults + adolescents >14 years 196/196 (100) HC/NR Prospective cohort V + CXR IGRA NR 13. Akhtar_Pakistan_2009 [29] South Asia 259 Adults + ≥3 months 385/385 (100) HH/rural Crosssectional V NR 14. Hu_China_2013 [30] East Asia 59 Children + adolescents 9–18 years School/urban Crosssectional V + CXR IGRA NR 15. Araujo_Brazil_2020 [31] South America 554 Adults + children 394/NR HC/urban Retrospective cohort V TST Both 16. Maraise_South Africa_2006 [32] Southern Africa 554 Children <5 years 260/274 (94.9) HC/urban Prospective cohort CXR TST Both 17. Nakaoka_Nigeria_2006 [33] West Africa 219 Children <15 years 161/161 (100) HH/urban Crosssectional V TST + IGRA NR 18. Oxlade_Multicentric_2021 [34]b South East Asia (Indonesia, Vietnam), West Africa (Ghana) Indonesia = 301, Viet Nam = 176, Ghana = 143 Children <5 years 1619/1619 (100) 281/339 (82.9) 1048/NR HC/rural + urban RCT TST V + CXR TST NR Initiated (Continues) TROPICAL MEDICINE & INTERNATIONAL HEALTH 1120/1136 (98.6) TST Both (Continued) No. Study ID Geographic region TB incidence/100,000 peoplea 19. Sun_China_2021 [35] East Asia 59 Children + adolescents ≤18 years 20. Triasih_Indonesia_2016 [36] South East Asia 301 Children ≤15 years 21. Adjobimey_Benin_2016 [37] West Africa 55 22. Amisi_Kenya_2021 [38] East Africa 23. Silva_Brazil_2016 [39] 24. Target population Household contacts screened among those identified (%) 95/95 (100) Place/setting Study design Diagnostic Screening test(s) TPT initiated/ completed HC/rural + urban Prospective cohort V 269/413 (65.1) HC/NR Prospective cohort V + CXR TST Both Children <5 years 497/499 (99.6) HC/urban Prospective cohort V ND Both 259 Children <5 years 553/NR HC/rural + urban Programme data V + CXR ND Both South America 45 Children ≤15 years 1078/NR HC/NR CXR TST Both Burmen_Kenya_2014 [40] East Africa 259 Children <5 years 337/345 (97.7) NR/rural + urban Programme data V ND Initiated 25. Garie_Ethiopia_2011 [41] East Africa 132 Children <15 years 184/184 (100) HC/urban Prospective cohort V TST Both 26. Ginderdeuren_South Africa_2021 [42] Southern Africa 554 Children <15 years 77/170 (45.1) HC/urban Prospective cohort V ND Both 27. Krishnamoorthy_India_2021 [43] South Asia 188 Adults + children HC/NR Prospective cohort V + CXR TST 28. Narasimhan_India_2017 [44] South Asia 188 Adults + children 359/491 (73.1) HH/NR Prospective cohort V TST + IGRA NR 29. Paradkar_India_2020 [45] South Asia 188 Adults + children ≥1 year 997/1009 (98.8) HH + HC/NR Prospective cohort V TST + IGRA NR 30. Okwara_Kenya_2017 [46] East Africa 259 Children <5 428/428 (100) HC/rural Prospective cohort V TST Both 31. Paul_Nigeria_2019 [47] West Africa 219 Children ≤5 years 63/NR HC/NR Prospective cohort V + CXR TST Both 32. Rekha_India_2009 [13] South Asia 188 Children ≤14 years 31/220 (14.1) HC/rural + urban Crosssectional V NR Both 33. Rutherford _Indonesia_2012 [48] South East Asia 301 Children <5 years 150/150 (100) HC/NR Prospective cohort V TST + IGRA Both 34. Sulis_Burkina Faso_2018 [49] West Africa 46 Children <5 years 956/1166 (82.0) HH/ Programme rural + urban data V ND Initiated 35. Pothukuchi _India_2011 [10] South Asia 188 Children <6 years 116/172 (67.4) HH/ Crossrural + urban sectional V ND Both 36. Rekha_India_2013 [50] South Asia 188 Children <6 years 53/87 (60.9) HH/ Prospective rural + urban cohort U ND Both 37. Shivaramakrishna_India_2014 [51] South Asia 188 Children <6 years 218/271 (80.4) HH/rural U ND Both 1523/NR Crosssectional NR (Continues) 847 Crosssectional TST + IGRA NR TROPICAL MEDICINE & INTERNATIONAL HEALTH TABLE 1 (Continued) 848 TABLE 1 No. Study ID Geographic region TB incidence/100,000 peoplea 38. Seid_Ethiopia_2020 [52] East Africa 132 Children <5 years 39. Singh_India_2017 [12] South Asia 188 40. Tadesse_Ethiopia_2016 [53] East Africa 41. Belgaumkar_India_2018 [11] 42. Target population Household contacts screened among those identified (%) Diagnostic Screening test(s) TPT initiated/ completed Study design 125/129 (96.9) HC/urban Mixed methods U ND Both Children <5 years 51/59 (86.4) HH/rural Mixed methods U ND Both 132 Children <5 years 237/282 (84.0) HC/NR Programme data U ND Both South Asia 188 Children <6 years 53/178 (29.8) HC/NR Crosssectional U ND Both Birungi_Rwanda _2019 [54] East Africa 58 Children <5 years 94/94 (100) HC/NR Prospective cohort V + CXR ND Both 43. Black_South Africa_2018 [55] Southern Africa 554 Children <5 years 184/261 (70.5) HC/NR Crosssectional V + CXR TST Both 44. Chauhan_India_2013 [56] South Asia 188 Children <5 years 253/NR HC/NR Prospective cohort V + CXR TST NR 45. Datiko_Ethiopia_2017 [57] East Africa 132 Adults + Children 24,267/24,267 (100) HC/rural Prospective cohort V + CXR ND Both 46. Egere_Gambia_2016 [58] West Africa 157 Children <5 years 404/404 (100) HH/ Prospective rural + urban cohort V TST Both 47. Wysocki_Brazil_2016 [59] South America 554 Adults + children 267/326 (81.9) HC/urban Crosssectional V TST Both 48. Fentahun_Ethiopia_2020 [60] East Africa 132 Children <5 years 149/230 (64.8) HC/urban Crosssectional V ND Initiated 49. Faksri_Thailand_2015 [61] South East Asia 150 Adults + children 100/100 (100) HC/NR Crosssectional V TST + IGRA NR 50. Sayedi_Afghanistan_2020 [62] South Asia 193 Adults + Children Programme data V ND Both 51. Schwoebel_Multicentric_2020 [63] Central Africa (Bangui, 815 Cameroon), West Africa (Benin, Burkina Faso) Children <5 years HH/urban Prospective cohort V + CXR TST Both 52. Sharma_India_2021 [64] South Asia 188 Children <5 years 86/NR HH/urban Prospective cohort V ND Both 53. Soelen_South Africa_2012 [65] Southern Africa 554 Children <5 years 39/NR HC/urban Programme data NR ND Initiated 54. Gomes_Guinea-Bissau_2011 [66] 361 Children <15 years HH/urban Prospective cohort V TST Both West Africa 586,292/856,782 (68.4) HH/urban 1965/1965 (100) 1895/1904 (99.5) (Continues) TROPICAL MEDICINE & INTERNATIONAL HEALTH Place/setting 849 Abbreviations: CXR, only chest x-ray; HC, health centre; HH, house-to-house; IGRA, interferon-gamma release assay; ND, not done; NR, not reported; RCT, randomised controlled trial; TB, tuberculosis; TST, tuberculin skin test; U, unclear; V, only verbal screening; V + CXR, verbal screening + chest x-ray. a TB Incidence: The World Bank Data, 2020, https://data.worldbank.org/indicator/SH.TBS.INCD?locations=BJ. b Data only for children <5 years from the low- and middle-income countries evaluated. NR IGRA Crosssectional 1809/NR 554 Southern Africa Mzembe_South Africa_2020 [70] 58. Children + adolescents 10–19 years HH + HC/rural NR NR TST Crosssectional 148/148 (100) 149 South East Asia Nguyen_Laos_2009 [69] 57. Adults + children HH/urban NR NR IGRA Crosssectional 112/112 (100) West Africa 143 Mensah_Ghana_2017 [68] 56. Adults + children ≥6 months HC/urban NR NR TST V Crosssectional HC/urban 56/56 (100) 141 Southern Africa Hector_Malawi_2017 [67] 55. Children <15 years Study design Place/setting Target population Geographic region No. Study ID Household contacts screened among those identified (%) TB incidence/100,000 peoplea TABLE 1 (Continued) Diagnostic Screening test(s) TPT initiated/ completed TROPICAL MEDICINE & INTERNATIONAL HEALTH Screening strategies Twelve (21%) of the 58 included studies did not report the proportion of household contacts screened among those identified as contacts. In the 46 (79%) studies that provided these data, the proportion of household contacts screened among those identified ranged from 14% to 100% (Table 1). Thirty-six studies (78%) screened >80% of identified contacts, 27 (59%) screened ≥95% and 20 (44%) screened 100% of the identified contacts. Only three studies (7%) reported screening <50% of the identified contacts. The median proportion of eligible contacts screened across the studies was 99% (IQR 82%–100%). Of the 45 studies that reported on the method used to screen out active TB, only verbal screening for symptoms was used in 26 (58%) studies and chest x-rays were used in 19 (42%) of the studies (Table 1). Diagnosis of LTBI Of the 58 studies, 22 (38%) did not test for TB; most of them included children under 5–6 years of age where LTBI testing was not required to initiate TPT (Table 2). Of the 36 studies that tested for LTBI, 21 (58%) used only TST, with 17 requiring a skin induration size of ≥10 mm to denote a positive TST result, while an induration size of ≥5 mm was used in the remainder. Four studies (11%) used only IGRA, while 11 (31%) used both TST and IGRA to aid diagnosis. In the studies where both tests were used, we reported the proportions diagnosed as having LTBI based on the study authors’ definitions. If this was not reported, we used the IGRA results to denote LTBI positivity (Table 2). Estimates of LTBI positivity among household contacts Estimates of the proportions with LTBI among the 21,566 household contacts from 36 studies are presented in the forest plot in Figure 2, sub-grouped by studies that used TST alone or IGRA alone or a combination of the two to diagnose LTBI. The pooled random-effects estimate for LTBI positivity in the 36 studies was 41% (95% CI 33%–49%); however, there was significant heterogeneity in these estimates that far exceeded what could be accounted for by chance (I 2 = 99%; τ 2 = 1.0; p = 0). The proportions diagnosed with LTBI varied considerably among the studies and ranged from 5% to 81%. In 15/36 studies (42%; TST 9, IGRA 1, both 5), the upper and lower bounds of the 95% CI for the LTBI positivity estimates did not overlap with the 95% CI of the pooled estimates for the proportions with LTBI in the sample (Figure 1). The median LTBI positivity estimate across the studies was 44%, with an IQR of 28%–59% (Table 3). Diagnosis of LTBI among household contacts No. Study_ID Eligible household contacts 850 TABLE 2 Number tested (%) Test used (TST/IGRA) TST positive, IGRA TST + IGRA n (%) positive, n (%) positive, n (%) Testing LTBI diagnosed (%, 95% CI) personnel 1. Bonnet_Uganda_2017 [17] 281 278 (98.9) TST 144 (51.8)a NA NA 2. Chandrasekaran_India_2018 [18] 869 869 (100) Both 478 (55)a 468(53.9) 300 (34.5) 3. Machado_Brazil_2009 [19] 301 261 (86.4) TST 145 (55.6)c NA NA 145 (49.5–61.5) Trained nursing and lab staff 4. MacPherson_South Africa_2020 [20] 2725 2725 (100) TST 458 (16.8)a ND ND 458 (16.8, 15.5–18.3) Nurse 111 (39.9, 34.4–45.8) 646b (74.3, 71.3–77.1) Doctor Trained lab staff 5. Odera_Kenya_2020 [21] 175 174 (99.4) IGRA NA 97 (55.6) NA 97 (55.6, 48.3–62.9) NR 6. Praveen_India_2020 [22] 220 220 (100) TST 96 (43.6)c NA NA 96 (43.6, 37.3–50.2) Trained staff 7. Ronge_South Africa_2021 [23] 669 669 (100) Both 302 (45.1)c 500 (74.7) NA 500 (74.7, 71.3–77.9) Nurse 8. Rutherford_Indonesia_2012 [24] 304 302 (99.3) Both 145 (48)c 152 (50.8) 180 (59.2) 180 (59.2, 54.6–64.6) Project staff 9. Shah_South Africa_2011 [25] 270 270 (IGRA) (100) Both 71/254 (28)a 79 (29) QFT NR 71/254 (28.0, 23.0–34.0) Project staff 263 (TST) (97.4) 10. Sharma_India_2017 [26] 1511 1511 (100) QFT 79/270 (29.3, 24.0–35.0) Both 732 (48.4)c c 917 (60.7) 540 (35.7) 917 (60.7, 58.2–63.1) Trained staff 11. Stein_Uganda_2018 [27] 2585 2562 (99.1) TST 1683 (65.7) NA NA 1683 (65.7, 63.8–67.5) 12. Zhang_China_2019 [28] 159 159 (100) Both 72 (45.3)c 75 (47.2) NR 75 (47.2, 39.6–55.0) Trained staff 13. Akhtar_Pakistan_2009 [29] 385 359 (93.3) TST 179 (49.9)c NA NA 179 (49.9, 44.7–55.0) Project staff 1120 1106 (98.8) IGRA NA 52 (4.7) NA 475 435 (91.6) TST 351 (80.7)a NA NA 351 (80.7, 76.7–84.1) NR c NA NA 122 (50.2, 44.0–56.4) NR 61 (42.1) NA 61 (42.1, 34.3–50.2) 14. Hu_China_2013 [30] 15. Araujo_Brazil_2020 [31] Maraise_South Africa_2006 [32] 260 243 (93.5) TST 122 (50.2) 17. Nakaoka_Nigeria_2006 [33] 161 TST 161 (100) Both 51 (31.9)c 18. Sun_China_2021 [35] Both 17 (17.9)c Trained staff Trained staff IGRA 145 (90.1) 19. Triasih_Indonesia_2016 [36] 20. Silva_Brazil_2016 [39] 21. Garie_Ethiopia_2011 [41] 95 413 1078 184 95 (100) 269 (65.1) 981d (91) 184 (100) 5 (5.3) 4 (4.2) TST 119 (44.2) c 5 (5.3, 2.3–11.7) NR NA TST 322 (32.8)c NA NA 102 (37.9, 32.3–43.8) NR NA 321 (32.7, 29.9–35.7) TST 106 (57.6)c NR NA NA 106 (57.6, 50.4–64.5) a NR NA NA 801 (52.6, 50.1–55.1) NR Trained lab staff 22. Krishnamoorthy_India_2021 [43] 1523 1523 (100) TST 801 (52.6) 23. Narasimhan_India_2017 [44] 359 TST 357 (99.4) Both 193 (54.1)c 143 (44.1) NR 143 (44.1, 38.8–49.6) Both 524 (52.6)a 485 (48.5) 301 (30.2) 707 (70.9, 68.0–73.7)b Trained lab staff IGRA 324 (90.1) Both 323 (90) 24. Paradkar_India_2020 [45] 997 997 (100) (Continues) TROPICAL MEDICINE & INTERNATIONAL HEALTH 16. 52 (4.7, 3.6–6.1) NR (Continued) No. Study_ID Eligible household contacts Number tested (%) Test used (TST/IGRA) TST positive, IGRA TST + IGRA n (%) positive, n (%) positive, n (%) Testing LTBI diagnosed (%, 95% CI) personnel 428 428 (100) TST 96 (22.4)c NA NA 96 (22.4, 18.7–26.6) NR 63 62 (98.4) TST 6 (9.7)c NA NA 6 (9.7, 4.5–19.6) NR Chauhan_India_2013 [56] 240 200 (83.3) TST 78 (39)c NA NA 78 (39.0, 32.5–45.9) Project staff 28. Egere_Gambia_2016 [58] 404 328 (81.2) TST 63 (19.2)c NA NA 63 (19.2, 15.3–23.8) NR 29. Wysocki_Brazil_2016 [59] 336 267 (79.5) TST 106/221 (48.0)a NA NA 106 (48.0, 41.5–54.5) NR 30. Faksri_Thailand_2015 [61] 70 70 (100) Both NR 25. Okwara_Kenya_2017 [46] 26. Paul_Nigeria_2019 [47] 27. NR 15 (21.4)c c NA NA 520 (27.9, 25.9–30.0) Nurse NA NA 253 (21.8, 19.6–24.3) NR 15 (21.4, 13.4–32.4) Trained nurse 31. Schwoebel_Multicentric_2020 [63] 1965 1866 (95.0) TST 520 (27.9) 32. Gomes_Guinea-Bissau_2011 [66] 1159 1159 (100) TST 253 (21.8)c 33. Hector_Malawi_2017 [67] 56 56 (100) TST 37 (66.1)c NA NA 37 (66.1, 53.0–77.1) NR 34. Mensah_Ghana_2017 [68] 112 100 (89.3) IGRA NA 65 (65) NA 65 (65.0, 55.1–73.6) NR 35. Nguyen_Laos_2009 [69] 148 148 (100) TST 46 (31.1)c NA NA 46 (31.1, 24.2–39.0) Project staff 36. Mzembe_South Africa_2020 [70] 1809 266 (14.7) IGRA NA 78 (29.3) NA 78 (29.3, 24.2–35.1) NR TROPICAL MEDICINE & INTERNATIONAL HEALTH TABLE 2 Abbreviations: IGRA, interferon-gamma release assay; LTBI, latent tuberculosis infection; NA, not applicable; ND, not done; NR, not reported; TST, tuberculin skin test. TST positive = induration ≥5 mm. b LTBI diagnosed if either TST or IGRA or both were positive (as defined by study authors); in other studies where both tests were done and authors had not defined LTBI diagnosis, IGRA positives were diagnosed to have LTBI. c TST positive = induration ≥10 mm. d Ninety-seven children did not return for TST reading. a 851 852 TROPICAL MEDICINE & INTERNATIONAL HEALTH F I G U R E 2 Forest plot of the latent tuberculosis infection positivity estimates in studies using tuberculin skin test or interferon-gamma release assay or a combination of tests Exploration of heterogeneity in the estimates of LTBI Table 3 summarises the results of subgroup analyses exploring heterogeneity in the LTBI positivity estimates. The pooled estimates for the proportions with LTBI in the subgroup of studies using TST alone, IGRA alone or a combination of tests were similar to the pooled overall estimates, with no significant differences between the subgroups, as evident from the overlapping 95% CIs, and formal tests for 853 TROPICAL MEDICINE & INTERNATIONAL HEALTH T A B L E 3 Summary of LTBI positivity using TST, IGRA or both and exploration of heterogeneity based on the tests used, the place of testing, the study design and geographical location of the studies LTBI diagnosis: all (TST/IGRA/both) Proportion with LTBI (%) Pooled LTBI positivity (random effects) Range Median (IQR) % (95% CI) I 2, τ 2; p Forest plot Studies Household contacts LTBI positive 36 21,566 9290 4.7–80.7 43.9 (28.3–58.8) 41.0 (33.0–49.0) 99%, 1.0; <0.01 Figure 2, Figures S1 and S2 Subgroups analysis 1: diagnostic tests used TST alone 21 14,509 5670 9.7–80.7 39.9 (25.2–51.4) 40.0 (32.0–49.0) 99%, 0.67; <0.01 Figure 2, subgroup 1 4 1646 292 4.7–65.0 42.5 (10.9–62.7) 32.0 (10.0–65.0) 99%, 1.98; <0.01 Figure 2, subgroup 2 11 5411 3328 5.3–74.7 47.2 (29.3–70.9) 47.0 (37.0–62.0) 98%, 1.2; <0.01 Figure 2, subgroup 3 8236 4235 9.7–80.7 49.5 (35.3–62.1) 44.0 (35.0–55.0) 98%, 0.96; <0.01 Figure S1, subgroup 1 4846 16.8–74.7 43.6 (27.9–60.7) 43.0 (32.0–54.0) 99%, 0.65; <0.01 Figure S1, subgroup 2 1642 209 4.7–29.3 29.3 (4.7–29.3) 17.0 (6.0–39.0) 99%, 0.99; <0.01 Figure S1, subgroup 3 IGRA alone Both Subgroup analysis 2: place of testing Health facility 22 Household 11 Both/school 3 11.688 Subgroup analysis 3: study design Prospective 22 16,616 7286 9.7–74.3 44.1 (25.2–58.4) 39.0 (30.0–49.0) 99%, 0.89; <0.01 Figure S2, subgroup 1 Not prospective 14 4950 2004 4.7–80.7 45.8 (30.7–65.3) 44.0 (31.0–58.0) 99%, 1.14; <0.01 Figure S2, subgroup 2 LTBI diagnosis (TST/IGRA/both): geographical regions Africa 17 11,516 4325 9.7–74.7 39.9 (22.1–61.3) 39.0 (29.0–50.0) 99%, 0.81; <0.01 Figure S3 Subgroup analysis: regions West and Central Africa 6 3660 958 9.7–65.0 24.9 (16.8–47.8) 28.0 (16.0–44.0) 96%, 0.72; <0.01 Figure S3, subgroup 1 East Africa 5 3627 2093 22.4–65.7 55.6 (31.2–61.7) 48.0 (34.0–62.0) 96%, 0.44; <0.01 Figure S3, subgroup 2 Southern Africa 6 4229 1274 16.8–74.7 39.8 (26.2–68.3) 43.0 (26.0–62.0) 99%, 0.88; <0.01 Figure S3, subgroup 3 15 8152 4042 4.7–74.3 44.1 (21.4–51.2) 40.0 (27.0–54.0) 99%, 1.24; <0.01 Figure S4 Asia Subgroup analysis: regions South Asia 8 6003 3567 39.0–74.3 51.3 (43.7–58.4) 55.0 (46.0–64.0) 97%, 0.26; <0.01 Figure S4, subgroup 1 East Asia 3 1360 132 4.7–47.2 5.3 (4.7 to –) 12.0 (3.0–39.0) 99%, 1.82; <0.01 Figure S4, subgroup 2 South East Asia 4 789 343 5.3–59.2 29.7 (9.3–53.9) 37.0 (25.0–52.0) 95%, 0.34; <0.01 Figure S4, subgroup 3 4 1898 923 32.7–80.7 48.8 (36.5–72.9) 55.0 (36.0–73.0) 99%, 0.60: <0.01 Figure S5 South America Brazil Abbreviations: CI, confidence interval; IGRA, interferon-gamma release assay; IQR, interquartile range; LTBI, latent tuberculosis infection; TST, tuberculin skin test. subgroup differences (Table 3; Figure 2). Significant heterogeneity was also present within the subgroups, indicating that the inconsistency in LTBI estimates was not explained by the tests used. Similarly, neither the place of testing (Table 3; Figure S1), nor the study designs (Table 3; Figure S2) explained the heterogeneity in LTBI estimates. LTBI estimates did not also appear to be influenced by the year of publication of the studies (Figure 2). The median and IQR for the proportions with LTBI in these subgroups also overlapped (Table 3). Geographical variations in screening and testing protocols and in resources were also explored as potential causes of heterogeneity in subgroup analyses. LTBI estimates from studies among household contacts in Africa were 854 TROPICAL MEDICINE & INTERNATIONAL HEALTH TABLE 4 Summary of LTBI positivity using TST only and exploration of heterogeneity based on place of testing and the size of skin induration LTBI diagnosis: TST only Proportion with LTBI (%) Pooled LTBI positivity (random effects) Range Median (IQR) % (95% CI) Studies Household contacts LTBI positive 22 14,811 5850 5.3–80.7 39.9 (25.2–51.4) 41.0 (33.0–49.0) 99%, 0.66; <0.01 Figures S6 and S7 I 2, τ 2; p Forest plot Subgroup analysis 1: place of testing Health facility 15 5772 2625 9.7–80.7 48.0 (32.7–57.6) 44.0 (34.0–54.0) 97%, 0.68; <0.01 Figure S6, subgroup 1 Household 7 9039 3225 5.3–65.7 27.9 (16.8–49.9) 36.0 (24.0–48.0) 100%, 0.53; <0.01 Figure S6, subgroup 2 Subgroup analysis 2: size of induration Induration ≥5 mm 5 5182 1827 16.8–80.7 39.9 (28.4–66.7) 47.0 (28.0–68.0) 100%, 0.94; <0.01 Figure S7, subgroup 1 Induration ≥10 mm 17 9629 4023 5.3–66.1 39.0 (22.1–53.9) 39.0 (31.0–48.0) 99%, 0.55; <0.01 Figure S7, subgroup 2 Abbreviations: CI, confidence interval; IQR, interquartile range; LTBI, latent tuberculosis infection; TST, tuberculin skin test. separately analysed, sub-grouped by countries in West and Central Africa, East Africa and Southern Africa (Table 3; Figure S3). Studies from Asia were sub-grouped by studies from countries in South Asia, East Asia and South East Asia (Table 3; Figure S4). Pooled estimates from studies from South America were represented by three studies from Brazil (Table 3; Figure S5). None of these sub-group analyses adequately explained the heterogeneity in LTBI estimates. Additionally, we explored heterogeneity in LTBI estimates in studies using TST alone sub-grouped by the place of testing (Table 4; Figure S6) and the size of skin induration (Table 4; Figure S7). These sub-group analyses also did not explain the heterogeneity in LTBI estimates. Tuberculosis preventive treatment Table 5 provides summary estimates of the proportion of household contacts in whom TPT was initiated and the proportion completing TPT in the studies that reported these outcomes. Of the 58 included studies, 34 (59%) reported data regarding treatment initiation among the 129,573 household contacts considered eligible for TPT. Twenty-six of these studies initiated TPT in children ≤6 years of age, four studies included children and adolescents and four included contacts of all ages (Table 5). Eighteen studies were conducted in Africa. Ten studies were conducted in Asia (seven in India). Four studies were from Brazil, and two were multi-country studies (Table 5). Twenty-two studies used a prospective design, while nine studies were cross-sectional, one was a retrospective cohort study, and two used mixed methods. Of the 34 studies reporting on TPT initiation, 28 (82%) also reported the proportions completing TPT. Six of the 26 studies that initiated TPT in children ≤6 years of age did not report treatment completion rates, with three reporting that they had referred household contacts with LTBI elsewhere after treatment initiation. The methods used to facilitate treatment adherence were reported in only 13/34 studies (38%) and the proportions actually adherent was infrequently reported. Adverse event monitoring and management were also poorly reported. Various TPT regimens were used, though daily isoniazid for 6 months was the most commonly used regimen. In the 28 studies reporting treatment initiation and completion, 108,679 contacts were initiated on TPT. The numbers considered to be TPT treatment failures (incident TB developed while on TPT) were reported in 12 (43%) of these studies. Treatment failures were rare, affecting 25 of 74,991 (0.03%) contacts completing treatment in the 28 studies (Tables 5 and 6). As with the estimates of LTBI, the proportions that initiated and completed TPT varied considerably in the studies reporting these estimates. The proportions initiated on TPT in the 34 studies ranged from 15% to 100%; and in the 28 studies that also reported treatment completion, the proportions ranged from 5% to 94% (Tables 5 and 6). Figure 3 displays the forest plot of the proportions initiating TPT, and Figure 4 displays the forest plot of the proportions completing TPT; sub-grouped by the age of the household contacts included. Table 6 summarises the pooled estimates for the proportions initiating and completing treatment and the results of subgroup analyses exploring heterogeneity, as well as the median proportions (with the IQR) for treatment initiation and completion. Figure 3 displays the estimates for treatment initiation rates among 129,573 household contacts who were eligible for treatment in the 34 studies. The pooled estimate for the proportions initiating TPT was 91% (95% CI 79%–97%). There was significant heterogeneity in the estimates (I 2 = 99%; τ 2 = 7.79; p < 0.01), that was not explained by subgroup analysis. The median proportion that was initiated on TPT was 86% (IQR 60%–100%) (Table 6). No. Tuberculosis preventive therapy (TPT) initiation and completion among household contacts Study_ID Age (years) Eligible for treatment (n) Treatment initiated, n (%, 95% CI) Adherence monitoring Treatment completion, n (%, 95% CI) Treatment regimen used Treatment failurea 1. Bonnet_Uganda_2017 [17] <5 234 234 (100, 98.0–100) NR 188 (80.3, 74.8–84.9) 6HZ 1 2. Machado_Brazil_2009 [19] All 101 101 (100. 96.0–100) NR 54 (53.5, 43.8–62.9) 6H NR 233 (82.9, 78.1–86.9) 3. Araujo_Brazil_2020 [31] All 320 281 (87.8, 83.8–91.0) NR 6HZ 1 4. Maraise_South Africa_2006 [32] <5 236 180 (76.3, 74.5–81.2) Yes 36 (20.0, 14.8 to 26.4) 6H 4 5. Oxlade_Multicentric_2021 [34]b <5 347 250 (72.1, 67.1–76.5) Yes NR 6H NR 6. Triasih_Indonesia_2016 [36] ≤5 99 86 (86.9, 78.8–92.2) NR 50 (58.1, 47.6–68.0) 6H None 7. Adjobimey_Benin_2016 [37] <5 497 496 (99.8, 98.9–99.99) Yes 427 (86.1, 82.8–88.9) 9H 3 8. Amisi_Kenya_2021 [38] <5 472 427 (90.5, 87.5–92.8) NR 205 (48.0, 43.3–52.7) 6H 6 9. Silva_Brazil_2016 [39] ≤15 322 109 (33.9, 28.9–39.2) Yes 73 (67.0, 57.7–75.1) 9H, 6H 1 10. Burmen_Kenya_2014 [40] <5 337 51 (15.1, 11.7–19.4) NR NR 6H NR 11. Garie_Ethiopia_2011 [41] <15 82 82 (100, 95.5–100) Yes 10 (12.2, 6.8–21.0) 6H 1 12. Ginderdeuren_South Africa_2021 [42] <15 56 56 (100, 93.5–100) NR 24 (42.9, 30.8–52.9) 6H 1 13. Paul_Nigeria_2019 [47] ≤5 55 55 (100, 93.5–100) Yes 24 (43.6, 31.4–56.7) 6H NR 14. Rekha_India_2009 [13] ≤6 84 16 (19.1, 12.1–28.7) NR NR 6H NR 15. Rutherford _Indonesia_2012 [48] <5 82 82 (100, 95.5–100) Yes 21 (25.6, 17.4–36.0) 6H NR 16. Sulis_Burkina Faso_2018 [49] <5 941 852 (90.5, 88.5–92.6) NR NR 6H NR 17. Pothukuchi _India_2011 [10] <6 116 97 (83.6, 75.8–85.3) NR 83 (85.6, 77.2–91.2) 6H NR 18. Rekha_India_2013 [50] <6 53 53 (100, 93.2–100) NR 39 (73.6, 60.4–83.6) 6H NR 19. Shivaramakrishna_India_2014 [51] <6 209 70 (33.5, 27.4–40.1) NR 16 (22.9, 14.6–40.0) 6H NR NR 20. Seid_Ethiopia_2018 [52] <5 125 94 (75.2, 67.0–81.9) NR 74 (78.7, 69.4–85.8) 6H 21. Singh_India_2017 [12] <5 50 11 (22.0 1.8–35.2) NR 10 (90.9, 62.3–98.4) 6H NR 22. Tadesse_Ethiopia_2016 [53] <5 221 142 (64.3, 57.7–70.3) NR 114 (80.3, 73.0–84.0) 6H None 23. Belgaumkar_India_2018 [11] <6 33 28 (84.9, 69.1–93.1) NR 21 (75.0, 56.6–87.3) 6H NR 24. Birungi_Rwanda_2019 [54] <5 94 84 (89.4, 81.5–94.1) Yes 74 (88.1, 79.5–93.4) 6H 1 74 (40.7, 33.8–48.0 NR 25. Black_South Africa_2018 [55] <5 182 NR 4 (5.4, 2.1–13.1) 6H 26. Datiko_Ethiopia_2017 [57] All 3027 1761 (58.2, 56.4–60.0) Yes 1574 (89.4, 87.9–90.7) 6H 3 27. Egere_Gambia_2016 [58] <5 368 328 (89.1, 85.5–91.9) Yes 255 (77.7, 72.9–81.9) 6H NR 28. Wysocki_Brazil_2016 [59] All 106 64 (60.4, 50.9–69.2) NR 36 (56.3, 44.1–67.7) 6H NR 29. Fentahun_Ethiopia_2020 [60] <5 138 44 (31.9, 24.7–40.1) NR NR 6H NR 30. Sayedi_Afghanistan_2020 [62] <5 117,593 101,084 (86.0, 85.8–86.2) NR 6H NR 69,273 (68.5, 68.2–68.8) 855 (Continues) TROPICAL MEDICINE & INTERNATIONAL HEALTH TABLE 5 856 NR 6H 9H 378 (46.1, 42.71–49.5) Abbreviations: CI, confidence interval; H, isoniazid; NR, not reported; R, rifampicin; TPT, tuberculosis preventive treatment; Z, pyrazinamide; the numbers before the drug names denote the number of months of treatment. Treatment failure: incident tuberculosis disease during the course of treatment. b Data only for children <5 years from the low- and middle-income countries evaluated. a 989 Gomes_Guinea-Bissau_2011 [66] 34. <15 820 (82.9, 80.4–85.1) Yes 2 NR 6H 42 (67.7, 55.4–78.1) 20 (37.0, 25.4–50.4) NR Yes 62 (72.1, 61.8–80.5) 54 (100, 93.4–100) 54 86 <5 Sharma_India_2021 [64] Soelen_South Africa_2012 [65] 32 33. <5 1 3RH, 6H <5 Schwoebel_Multicentric_2020 [63] 31. 1909 1746 (91.5, 90.1–92.6) Yes 1642 (94.0, 92.8–95.1) Treatment failurea Study_ID No. TABLE 5 (Continued) Age (years) Eligible for treatment (n) Treatment initiated, n (%, 95% CI) Adherence monitoring Treatment completion, n (%, 95% CI) Treatment regimen used TROPICAL MEDICINE & INTERNATIONAL HEALTH Compared to the more than 90% pooled estimates for TPT initiation, the pooled estimate for the proportions completing TPT (Figure 4) was considerably lower (65%, 95% CI 54%–74%), with significant heterogeneity in the estimates (I 2 = 98%, τ 2 = 1.48, p < 0.01). The pooled treatment completion proportions did not significantly differ between the subgroups based on age; and did not explain the heterogeneity in the estimates of the proportions completing treatment. The true estimates of treatment completion with TPT are uncertain, but the median estimate for proportions completing treatment was 68% (IQR 44%–82%) (Table 6). Factors affecting the TPT care cascade The factors reported in 28 studies which the authors considered to have affected one or more components of the TPT care cascade are summarised in Table 7. For the diagnosis of LTBI, short duration of the followup, and the type of tests used were reported as potentially important (Table 7). The time of testing was reported as another factor that might have affected the results since contacts incubating the infection might test negative if tested early, thus leading to an underestimation of the infection prevalence. In studies where data were collected retrospectively, inadequate documentation of the care cascade components was reported to have likely impacted the study outcomes. In many settings, the information on the household contacts (especially for child contacts) was retrieved from the index patient’s card, thus inadequate documentation could have led to selection bias for household contacts. Furthermore, in studies that collected information from the participants, recall bias, and the general tendency to provide socially desirable responses were reported as factors that could have resulted in over/underestimation of the findings of the studies. For preventive treatment, factors such as higher cost of transportation, medication palatability, treatment duration, social support and the knowledge and beliefs of healthcare workers were thought to have influenced the reported treatment outcomes. Where described, treatment adherence was defined based on pill count or the monthly prescription of the medicines collected from the subjects. This might have led to an overestimation of treatment adherence. Another factor that might have impacted the results was the risk perception of the participants; parents’ or caregivers’ own experience concerning TB disease and its health consequences that could have motivated them to initiate treatment among their close contacts; whereas, in studies where adherence was poor, absence of signs and symptoms among contacts could have adversely impacted the treatment-related decisions. In some studies, participants’ characteristics in terms of their immune status were reported to have likely impacted the findings. Health worker-related factors such as high patient to health worker ratio and their working hours could compromise the quality of care. The timing of household visits by the 857 TROPICAL MEDICINE & INTERNATIONAL HEALTH TABLE 6 Summary of the proportions initiating and completing TPT for LTBI and exploration of heterogeneity based on age of household contacts TPT initiation Proportion on TPT (%) Pooled proportion on TPT (random effects) Range Median (IQR) % (95% CI) I 2, τ 2; p Forest plot 109,974 15.1–100.0 85.5 (59.9–100) 91.0 (79.0–97.0) 99%, 7.79; 0.00 Figure 3 Studies Eligible household contacts On TPT 34 129,573 Subgroup analysis: age <6 years 26 124,570 106,700 15.1–100.0 85.5 (58.4–98.9) 90.0 (75.0–97.0) 99%, 7.54; <0.01 Figure 3, subgroup 1 <18 years 4 1449 1067 33.9–100.0 91.5 (46.2–100.0) 98.0 (32.0–100.0) 99%, 14.88; <0.01 Figure 3, subgroup 2 All ages 4 3554 2207 58.2–100.0 74.1 (58.8–97.0) 89.0 (45.0–99.0) 97%, 4.63; <0.01 Figure 3, subgroup 3 28 108,679 74,991 5.4–94.0 68.1 (44.2–82.3) 65.0 (54.0–74.0) 98%, 1.48; <0.01 Figure 4 TPT completion Subgroup analysis: age <6 years 20 105,159 72,364 5.4–94.0 71.1 (38.7–84.3) 64.0 (49.0–76.0) 98%, 1.95; <0.01 Figure 4, subgroup 2 <18 years 4 1313 730 42.9–77.7 56.6 (43.7–75.2) 60.0 (44.0–73.0) 97%, 0.38; <0.01 Figure 4, subgroup 2 All ages 4 2207 1897 53.5–89.4 69.6 (54.2–87.8) 74.0 (55.0–87.0) 98%, 0.71; <0.01 Figure 4, subgroup 2 Abbreviations: CI, confidence interval; IQR, interquartile range; LTBI, latent tuberculosis infection; TPT, tuberculosis preventive treatment. workers could lead to under-representation of certain age groups (especially school-going children) as many might not be available at that time (Table 7). As reported in the studies, factors operating at multiple levels can facilitate or hinder the execution of each component of the care cascade. Therefore, for a successful realisation of the care cascade, it is imperative to address these factors in contextually appropriate ways. DISCUSSION This systematic review aimed to describe the strategies used in studies from high TB burden countries for detecting LTBI in household contacts of people with bacteriologically confirmed pulmonary TB who were not immunocompromised, and to ascertain the proportions initiated on and completing TPT. The 58 included studies provide updated estimates to supplement estimates from existing systematic reviews in this area [3, 6, 14, 15]. The pooled estimates for LTBI positivity of 41% (95% CI 33%– 49%), using a combination of TST or IGRA or both, in 21,566 household contacts of people with bacteriologically confirmed pulmonary TB in the 36 studies provide a timely reminder of the hidden burden of TB infection. Even though there was significant heterogeneity in these estimates, the median LTBI positivity estimates (44%, IQR 28%–59%) indicate that between a third to over half of the household contacts of people with bacteriologically proven TB are likely to have LTBI. Over half of these studies used TST alone to detect LTBI. Since most studies also used only verbal screening of symptoms to rule out active TB, concerns exist about the potential for false negative results with the use of TST alone. The number of studies that used IGRA (alone or in combination with TST) to diagnose LTBI was fewer. The relatively higher LTBI yield in these studies (albeit with wide 95% CI that overlapped with the TST-diagnosed LTBI estimates), coupled with the likelihood of fewer false-positive results, suggest that increasing the use of imaging modalities and molecular tests could augment the utility of contact tracing for LTBI management. However, this would need to be balanced against available resources and other programmatic considerations. WHO recommends that contact investigation be conducted through home visits but the data in this review did not find the LTBI diagnostic yield to differ significantly with health facility-based versus home-based contact investigations. The other notable finding in this review was the higher proportions of contacts with LTBI initiating TPT compared to the lower proportions completing treatment. The pooled estimates for treatment initiation in 129,573 eligible household contacts in the 34 studies was an impressive 91% (95% CI 79%–97%), compared to the pooled estimates of the proportions completing treatment (65%, 95% CI 54%–74%) among 108,679 contacts who commenced TPT in 28 of these studies. In spite of the significant heterogeneity in these estimates, the nearly 20% difference in the median proportion completing compared to initiating treatment, reveals a flaw in the TPT care cascade that can adversely impact the effectiveness of LTBI management among household contacts. The qualitative synthesis of the factors reported by study investigators provide complementary insights about the factors related to the various components of the cascade of care that could have contributed to heterogeneity in LTBI estimates and TPT outcomes. These factors can also inform strategies to improve the effectiveness of LTBI management. No single factor or intervention can be considered pre-eminent to improve the LTBI cascade, and many incremental strategic adjustments will be needed to reduce losses that can occur throughout the LTBI cascade of care [71]. 858 FIGURE 3 TROPICAL MEDICINE & INTERNATIONAL HEALTH Forest plot of the proportions initiating tuberculosis preventive treatment sub-grouped by the age of household contacts Limitations A major limitation in this review was the lack of adequate details provided in the included studies regarding the processes used in screening, testing or treatment initiation due to which we were unable to adequately assess the quality of implementation of LTBI management strategies. The variety of included study designs precluded valid assessments of the risk of bias uniformly applicable across these designs. The possibility of reporting biases is also high with systematic reviews using observational data. 859 TROPICAL MEDICINE & INTERNATIONAL HEALTH FIGURE 4 Forest plot of the proportions completing tuberculosis preventive treatment sub-grouped by the age of household contacts Another major limitation was the significant heterogeneity in the pooled estimates from meta-analysis for the diagnostic yield. This was not explained in subgroup analyses based on the diagnostic tests used and the place of testing. Additional post hoc sub-group analyses based on the study designs employed and geographical differences in the countries where the studies were conducted also did not explain the heterogeneity. Significant heterogeneity in the estimates for TPT outcomes was also a serious limitation that was not explained in pre-stated subgroup analyses based on the age of the household contacts. The prevalence of TB (and LTBI) varies across different populations within 860 TABLE 7 TROPICAL MEDICINE & INTERNATIONAL HEALTH Factors reported to affect the TPT care cascade Study reference Factors Description Duration of follow-up Short duration of follow-up could have affected the assessment of TPT effectiveness and the magnitude of the true burden of Mycobacterium tuberculosis infection. [17, 26, 59] Type of test used Using TST could have resulted in low yield for M. tuberculosis infection, since IGRA correlates better with recent M. tuberculosis exposure and has higher accuracy in diagnosing infection in children. [18, 23] Timing of tests The timing of conducting tests could have affected the results in terms of LTBI positivity as the average time for developing hypersensitivity reactions is 4–12 weeks, thus some household contacts who might have been incubating the infection might have tested negative on the tests. [24, 29] Inadequate documentation Retrospective studies and studies on programmatic data reported that the lack of proper documentation on the care cascade for TB management could have affected their assessment and findings. Collecting data from the programme registers and from reports that lack rigour in documenting the information could lead to selection bias for the number of household contacts. [32, 38, 52, 53, 62] Adherence to TPT The common factors related to TPT adherence included: higher cost of transportation, medication palatability, longer treatment duration, social support, and the knowledge and beliefs of HCWs and carers. Further, treatment adherence reported in the studies could be an overestimation as it depended on pill count or on the monthly collection of prescriptions. [37, 39, 42, 48, 66] Risk perception of the participants Parents’ or caregivers’ own experience concerning TB disease and its long-term health consequences was reported as a motivating factor for TPT initiation and completion. Further, participants’ perception regarding the risk related to LTBI influences the treatment initiation and adherence among HH contacts, especially among child contacts. Parents were unable to comprehend the relevance of initiating TPT among asymptomatic children. [40, 41, 55, 60] Recall bias Studies that ascertained information on the care cascade from the participants reported that recall bias or the tendency to provide socially desirable answers could have resulted in under- or over-estimation of the results in the study. [12, 43, 51, 60, 70] Participants’ characteristics One study reported that HIV positivity reduces the likelihood of completing testing, whereas in another, it was reported that HIV-infected participants were more likely to get their contacts screened as they visit the health facility regularly and are aware of the benefits of early contact screening. Another study mentioned that subjects’ immunological status could also impact the testing outcomes as the T-SPOT.TB assay was based on the individual activated T cell. [20, 30, 60] HCWs’ related In one study, the high patient to health worker ratio was thought to have compromised the quality of care, whereas another reported that the working hours of the HCWs could have resulted in underrepresentation of certain age group (especially school-going children). [40, 57] Abbreviations: HCWs, healthcare workers; HH, house-to-house; IGRA, interferon-gamma release assay; IPT, isoniazid preventive therapy; LTBI, latent tuberculosis infection; TB, tuberculosis; TST, tuberculin skin test. and between countries and between geographical regions, as was also evident in other systematic reviews and metaanalysis of TB contact tracing [3, 6, 14, 15]; their results were similar to the estimates in this review. This highlights the inherent difficulty in accurately estimating, with the available data, the effects of strategies like TB contact tracing among diverse populations. Anticipating that meta-analysis of studies of disease prevalence would result in significant heterogeneity, we chose to use the random-effects model for meta-analysis. The random-effects model adjusts the weights assigned to each study to account for within-study and between-study variability, and results in wider 95% CIs for the prevalence estimates. With the magnitude of heterogeneity observed (I 2 > 95%–100%), the weights assigned to each study in random-effects meta-analysis are nearly equal, regardless of the sample size and study variance. Therefore, the point estimates for LTBI and TPT outcomes in these studies generated through random-effects meta-analysis only represent the mean of a wide range of possible estimates [72]. In spite of the significant heterogeneity, we chose to retain the meta- analysis estimates in order to explore heterogeneity, but caution against relying on these pooled estimates alone. The median estimates (with the IQR) that accompany each analysis offer a more conservative interpretation of LTBI positivity and TPT outcomes in the included studies. Recommendations for LTBI management scale up In spite of these limitations, the evidence synthesised in this review provides important information that can inform the national TB programmes in high TB burden countries while scaling up LTBI management. Firstly, a more systematic approach is needed for screening TB symptoms (to exclude active TB). There are already comprehensive guidelines on contact investigations provided by WHO that most programmes have integrated into their systems. However, the recording and reporting for TPT eligibility need to be strengthened. Information regarding the personnel doing the screening and their training; 861 TROPICAL MEDICINE & INTERNATIONAL HEALTH details on the timing and frequency of screening, particularly in relation to the timing since the index case was diagnosed, also need to be documented as these can impact detection and implementation. Screening should not depend only on verbal screening of symptoms to rule out active TB, and imaging and molecular tools should be optimally utilised. Secondly, diagnostic testing for LTBI among the household contacts should be mandatory and TPT should not be initiated without a positive result (except for those <5 years and for those with HIV infection, or on the recommendation of a consulting physician), since, on an average, only a third to a little more than half of household contacts may have LTBI. Irrespective of the diagnostic test used or considered feasible, ensuring consistent protocols and adequately trained staff in administrating the tests will result in better outcomes. Thirdly, mechanisms to ensure better integration of TPT initiation with mechanisms to encourage and monitor adherence, detect and manage adverse events, provide counselling, to record treatment completion and follow-up after TPT are required. Many of these problems already exist in national TB programmes for active TB case finding, and common solutions are needed for LTBI and TB case detection and management [73]. For optimum utilisation of resources, adherence mechanisms integrated with active TB management may work well, however real-world experience indicates that this may overburden health workers who support TB treatment. TPT scale-up, as recommended by WHO and the commitments at UNHLM, is important. However, in high-TB burden, resource-constrained countries, this would require attending to approximately four-times more people than the total number of TB patients diagnosed. Integrating TPT in the current active TB programmes, without providing additional human resources, risks overburdening of existing staff, while leaving large numbers without completing their treatment, and wasting already limited resources in terms of free testing and treatment provided under the programmes. While shorter treatment regimens may aid in treatment completion, the systems to support this need to be in place for this to work. Follow-up mechanisms for those household contacts who complete TPT to document any further episodes of TB also need to be in place. proportions initiated on TPT were reassuringly high, treatment completion proportions were worryingly lower. The qualitative data collected alongside the quantitative data provide heuristic insights about factors that could reduce losses in the LTBI cascade of care. A C K N O W L E D G E M E N TS We acknowledge Prof. Paul Garner, Director – Research, Evidence and Development Initiative (READ-IT), Liverpool School of Tropical Medicine, Liverpool for his support during the initial phase of prioritising the research question and protocol development for systematic review. We thank the authors who responded promptly and shared their full papers for screening and inclusion in the review. FUNDING INFORMATION This publication is associated with the Research, Evidence and Development Initiative (READ-It). 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