Online Annex 4. Systematic review of the yield of tuberculosis contact investigation in low and middle income countries

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1 Online Annex 4 Systematic review of the yield of tuberculosis contact investigation in low and middle income countries Elizabeth Fair, Cecily Miller, Philip Hopewell Curry International Tuberculosis Center University of California, San Francisco Introduction The aim of this review was to examine the evidence on the yield of household contact investigations in low and middle income countries for finding cases of active tuberculosis and to identify persons with latent tuberculosis infection (LTBI). Many countries share the question of whether or not to undertake contact investigation as a routine component of tuberculosis control programs. The identification and evaluation of persons in close contact with an infectious TB patient (contact investigation) has historically been viewed as an expensive, low-priority endeavor in low and middle income countries. However, increasing concerns with the failure to meet case detection targets, with the spread of Mycobacterium tuberculosis to vulnerable persons such as children and persons with HIV infection, and with transmission of drug-resistant M. tuberculosis, have prompted a reassessment of the potential benefits of contact investigation.this review presents an update of our previously published review (Morrison et al, Lancet ID, 2008)[1] that covered the literature up to 2005, and collates data through August 2011 from low and middle income countries to provide information that can be used by programs to estimate the benefits of such interventions. In particular we were interested in examining studies that included information on drug susceptibility of the index case strain and on HIV status of the index case and contacts. Search strategy Our search strategy aimed to identify all studies reported between 2005 and August, 2011 that assessed the number of cases of active tuberculosis or persons with LTBI found when contact investigation was done in households of people with active pulmonary tuberculosis (index cases). We began by searching the literature for systematic and narrative reviews that assessed the yield of household contact investigation for cases of active tuberculosis and LTBI. No systematic reviews, other than our previous review that covered the literature through 2005, were found. We reviewed all published peer-reviewed articles that reported the yield of household contact investigation efforts, including cross-sectional and prospective studies. We restricted the language of the publications reviewed to English and for the original review searched four electronic databases for primary studies: PubMed, BIOSIS, Embase, and 1

2 Web of Science. Searches in BIOSIS, Embase, and Web of Science included published reports through December, The initial PubMed search was extended to December, The search terms used in both the original and the updated reviews are shown in the box below. In the initial review we supplemented the electronic search with several additional search strategies to identify relevant articles not found in electronic databases. We hand-searched the indices of The International Journal of Tuberculosis and Lung Disease (1997 to 2005) and The n Journal of Tuberculosis (1953 to 2004). We reviewed the reference lists of primary studies, reviews, and editorials. We contacted selected authors of the papers included and requested a complete list of their publications, and reviewed personal databases for relevant citations. Because the yield of relevant studies from these latter searches was minimal, for the update we searched only PubMed and Embase. We excluded the following papers: (1) abstracts, editorials, case studies, outbreak reports; (2) contactinvestigation studies reporting yield for contacts other than household; (3) studies in which the number of contacts screened was not reported; (4) studies using molecular epidemiology in which only contacts with active tuberculosis were included, therefore providing no denominator for calculating yield; and (5)studies that were focused on describing methodological issues, such as those describing the use of interferon gamma release assays (IGRAs). Search Terms for Original and Updated Reviews Search 1 Tuberculosis [MeSH] OR Mycobacterium tuberculosis [MeSH] OR tuberculosis [TI] Search 2 (( Contact tracing [MeSH]) OR ( contact tracing [WORD]) OR ( contact screening [WORD]) OR ( contact examination [WORD]) OR ( household contact* [WORD]) OR ( contact investigation* [WORD]) OR ( tuberculosis contact*[word]) OR ( household transmission [WORD]) OR ( tuberculosis transmission [WORD]) OR ( close family contact* [WORD]) OR ( family contact* [WORD]) OR ( household infection [WORD]) OR ( household screening [WORD]) OR ( close contact* [WORD]) OR ( household cluster* [WORD]) OR ( childhood contact* [TI]) OR ( adult contact* [TI]) OR ( attack contact* [TI]) OR ( attack rate contact* [TI])) Search 3 Search 1 AND Search 2 Initial review of studies The database created from the searches was compiled and all duplicate citations were eliminated. The remaining citations were screened by title and review of the abstract to capture relevant studies. This database was then screened again to include only primary articles, and the full texts of the remaining citations were obtained and reviewed. Studies were eligible for inclusion if they reported the yield of household contact investigations for active tuberculosis or LTBI, including the number of household contacts assessed and number of active cases found, or, for studies reporting LTBI, the number of contacts found to be infected. For both reviews we included only LTBI identified by tuberculin skin testing (TST) and did not include data from IGRAs. In instances in which publications were found to have 2

3 reported the same cohort of index cases and contacts at several time points, the most recent publication was used and all others were excluded. The relevant citations were classified, according to current World Bank definitions, by whether the studies had been done in low-income, middle-income, or high-income countries. Because the community incidence of tuberculosis was not reported in most of the studies reviewed, the World Bank income classification was used as a proxy for incidence. For the purposes of both the original and update reviews, only those studies from low- and middle-income countries were included. Data extraction A data extraction form was developed in consultation with experts in the area of contact investigation, and was designed and pilot tested by two reviewers. The same form was used for the update. Five of the initial 41 studies were reviewed by two reviewers and an inter-reviewer agreement of 100% was obtained for the data from these studies. Data extraction for the update was completed by one reviewer (PH) and reviewed by a second investigator (EF). The data extracted included the following information: study design, description of index cases, description of contacts, and outcomes among contacts including bacteriologically confirmed tuberculosis (sputum-smear microscopy and/or culture positivity), clinical and radiological diagnoses of tuberculosis, and LTBI. We also recorded the definition of an index case principally by their bacteriological status (sputum smear positive with or without positive culture, sputum smear negative/culture positive, smear and culture negative) and definition of household contacts, generally by age and by the proximity and duration of exposure. Where available we also recorded the HIV status of the index case and contacts and whether or not the index case had multiple drug resistant (MDR) TB. Determination of outcomes For confirmed tuberculosis among contacts, in nearly all studies the process of diagnosis began with assessment of symptoms among household contacts. The symptoms for which contacts were screened varied little among the studies and included cough, fevers, night sweats, weight loss, and hemoptysis. The process of diagnosis for confirmed tuberculosis then proceeded to sputum studies (smear and/or culture) for those with symptoms. For children radiographic examination was also commonly used. A case of confirmed tuberculosis was defined as a person with smear and/or culture positive for M tuberculosis. If possible, cases of infection by mycobacteria other than M. tuberculosis were excluded. Cases of smear-positive but culture-negative disease were excluded, but a number of studies included smear-positive cases for which cultures were not done. These cases were included in our analysis. The yield of confirmed tuberculosis among contacts was defined as the percentage of contacts assessed and found to have confirmed tuberculosis. For clinical and radiological diagnoses of active tuberculosis among contacts, the process of diagnosis for each reviewed study included assessment of symptoms, followed by chest radiograph and sputum 3

4 studies among those with symptoms. A diagnosis of clinical and radiological active tuberculosis was defined as a person with symptoms and a chest radiograph showing findings characteristic of tuberculosis (eg, opacities, cavitation, or, in children < 5 years, hilar or mediastinal adenopathy). Diagnoses based on histopathology were not reported in any of the included studies. The yield for all active tuberculosis among contacts was defined as the percentage of contacts assessed that either met the clinical and radiological criteria for active tuberculosis or had bacteriological confirmation. For LTBI, the process of diagnosis for each reviewed study included the use of a TST and exclusion of active tuberculosis by symptom and sputum assessment for those who had a positive test. A number of the recent studies reported the results of IGRAs as well as TSTs, but the results of IGRAs were not taken into account. (In fact, many of the recent studies from which the results of contact investigation were derived were designed to evaluate the performance of IGRAs.) Persons who had been previously treated for tuberculosis were generally excluded from the analysis. The history of BCG vaccination was not reported in most studies. A case of LTBI was defined in most studies as an individual with TST induration greater than 10 mm after hours in whom active tuberculosis was excluded. Other studies, particularly in HIV infected populations, reported outcomes for TST results greater than 5 mm. For the purposes of data extraction, a case of LTBI was defined as an individual with TST induration greater than 10 mm (or, if 10 mm was not used, the publication cut-off was used) and in whom active tuberculosis had been excluded. Yield for LTBI was defined as the percentage of contacts assessed who met the criteria. Data collation and meta-analysis For each study, the yield of contact investigation for all active tuberculosis, confirmed tuberculosis, and LTBI was calculated. Meta-analysis of the yield data was done using Stata version 11.2 (StataCorp 2009, College Station, TX). Because the yield data are simple proportions, we used methods appropriate for pooling rates and proportions. A meta-analysis was done with studies weighted by the number of contacts screened in each study to pool (summarise) yields for active tuberculosis and LTBI across studies. In addition we conducted sub-analyses for the yield of active tuberculosis for contacts of HIV-positive index patients and for contacts of index patients with multidrug resistant tuberculosis (MDR-TB). The presence of heterogeneity across studies was assessed by use of the conventional chi-squared test for heterogeneity and by computing the I 2 statistic. This heterogeneity may indicate differences in community incidence of tuberculosis, index-case characteristics, or contact characteristics. In the initial study we investigated sources of heterogeneity by pre-specified subgroup analyses. We stratified study results by the geography of the study setting (Africa, Asia, and the Americas), World Bank income classification (low income, gross national income per head <US$ 825 per year; middle income, US$ per year), year of study publication (before 1980, 1980 and later), sputum-smear status of the index case, HIV status of the index case, and age of household contacts. The age of the index case and HIV status of contacts were also considered, but there were insufficient studies with these outcomes to warrant analysis. 4

5 Results For the initial review the study selection process identified 1237 unique citations, 41 of which were selected for inclusion. (figure 1) For the update, 3187 unique citations were identified and 19 were included. (figure 2) Of the combined 60 studies, 27 from the original review and 15 from the update[2-16] (42 total) reported the yield of all active tuberculosis (clinical/radiological diagnoses with or without bacteriological confirmation, (figure 3). Twenty three of the original studies and 11 of the update studies[2, 5, 6, 8-10, 12-16] (34 total) reported the yield of bacteriologically confirmed active tuberculosis (figure 4). Nineteen of the original studies and 12 of the update studies[2, 4, 7, 9, 11-13, 15, 17-20] (31 total) reported the yield of LTBI (figure 5). Four of the original studies and one of the update studies[19] (5 total) reported the yield for all active tuberculosis among household contacts of HIV-positive index cases (figure 6). Five of the original studies and one of the update studies[19] (6 total) reported the yield of LTBI among household contacts of HIV-positive index patients (figure 7). Fifteen of the original studies and 4 of the update studies[2, 7, 9, 13] (19 total) reported the yield of all active tuberculosis among pediatric contacts (figure 8). Sixteen of the original studies and 6 of the update studies[2, 7, 9, 13, 18, 20] (22 total) reported the yield of LTBI among pediatric contacts (figure 9). Two of the original and three of the update studies[3, 6, 16] (5 total) reported the yield of all active tuberculosis among contacts of MDR-TB index patients (figure 10), and two of the original and two of the update studies[6, 16] (4 total) reported the yield of bacteriologically confirmed active tuberculosis among contacts of MDR-TB index patients (figure 11). The original 41 studies were done in 17 countries: 20 (48%) were done in Africa, 12 (30%) in Asia, and nine (23%) in Central or South America. By use of the World Bank classification system, 26 (63%) studies were from 11 low-income nations, and 15 (37%) were from seven middle-income nations. Eight (20%) of the studies reviewed were published before 1980 and 33 (80%) were published in 1980 or later. The 19 studies included in the update are from 13 countries; 8 (42%) were done in Africa[7, 9, 10, 14, 16, 18-20], 5 (26% were done in South America[3-6, 12], and 6 (32%) were done in Asia[2, 8, 11, 13, 15, 17]. Two studies (11%) were from two low-income countries[18, 19], 6 studies (32%) were from 6 low/middleincome countries[10, 13-15, 17, 20], and 11 studies (58%) were from 5 different upper/middle-income countries[2-9, 11, 12, 16]. Figure 1 shows the results of the studies that reported yield for all active tuberculosis (with or without bacteriological confirmation) among all household contacts. The pooled yield was 4 5% (95% CI %).The pooled yield of the 34 studies reporting the yield for confirmed tuberculosis (figure 2) among all household contacts was 2.2% (95% CI % ). Figure 3 shows the results of the 31 studies reporting the yield for LTBI. The pooled yield was 50.5% (95% CI %). All the above meta-analyses had substantial statistical heterogeneity. 5

6 Of the subgroups examined, the pooled yield of all active tuberculosis from contacts of HIV-positive index cases (figure 4) was 9.4% (95% CI %), and the pooled yield of LTBI from HIV-positive index cases (figure 5) was 46.6% (95% CI %). The pooled yield of all active tuberculosis among pediatric contacts (figure 6) was 7.0% (95% CI %), and the pooled yield of LTBI among pediatric contacts (figure 7) was 39.7% (95% CI %). The pooled yield of all active tuberculosis among contacts of MDR-TB index patients (figure 8) was 3.4% (95% CI %), and the pooled yield of bacteriologically confirmed active tuberculosis among contacts of MDR-TB index patients (figure 9) was 4.9% (95% CI %).. There was significant statistical heterogeneity in all subgroups. Discussion The literature describing the results of contact investigations is not easy to summarize systematically. There are substantial differences in study designs with many of the recent studies focused on examining test performance for IGRAs rather than on contact investigation per se. Overall the quality of the literature is poor with studies often lacking critical details. Moreover, many local factors, often operating at the neighbourhood level, including differences in tuberculosis epidemiology, HIV prevalence, local living circumstances and culture, and social mixing patterns, which cannot be captured in single studies, let alone systematic reviews of many studies, make generalization difficult. However, some generalizations can be made, that for the most part are consistent with observations made many years ago. Index cases with higher bacillary burdens as indicated by a positive sputum smear are clearly more likely to transmit the infection. Generally there is a dose response relationship between the degree of smear positivity and the risk of infection and active disease among contacts. However, molecular epidemiological studies have shown that transmission also occurs from smear negative cases. For example in a study from San Francisco 17% of incident cases could be attributed to a smear negative index case. A similar study from the Netherlands found that 12% of cases were the result of transmission from a smear negative case. Also there is a fairly consistent relationship between the proximity of contact-sleeping in the same bed versus living in the same compound, for example-and risk. But, there are many examples of transmission occurring out of the household, in social settings (informal bars in and Mexico for example); in workplaces, residential facilities, prisons, hospitals and other congregate settings, all clearly demonstrated by molecular epidemiological studies. The overall results of contact investigations conducted in the past 5.5 years are similar to those found in the earlier review but provide more information on transmission from HIV+ index cases and patients with MDR-TB. These findings suggest that contact investigation may improve early case detection and decrease transmission of M. tuberculosis in high-incidence areas. In addition there should be focus on evaluation of contacts of HIV+ index cases and contacts of persons with MDR-TB. 6

7 Figure legends Figure 1. Flow diagram of paper selection for original review Figure 2. Flow diagram of paper selection for updated review Figure 3. Forest plot showing yield of all active TB cases The lower portion of the figure under the heading New data presents the updated review from December, 2005 through August, Figure 4. Forest plot showing yield of bacteriologically confirmed active tuberculosis. The lower portion of the figure under the heading New data presents the updated review from December, 2005 through August, Figure 5. Forest plot showing yield of LTBI. The lower portion of the figure under the heading New data presents the updated review from December, 2005 through August, Figure 6. Yield of active TB from contacts of HIV-positive index cases. Figure 7. Yield of LTBI from contacts of HIV-positive index cases Figure 8. Yield of active tuberculosis among pediatric contacts. The lower portion of the figure under the heading New data presents the updated review from December, 2005 through August, Figure 9. Yield of LTBI among pediatric contacts. The lower portion of the figure under the heading New data presents the updated review from December, 2005 through August, Figure 10. Yield of active tuberculosis among contacts of MDR-TB index patients. Figure 11. Yield of bacteriologically confirmed active tuberculosis among contacts of MDR-TB index patients 7

8 Figure 1. Flow diagram of paper selection for original review 8

9 Figure 2. Flow diagram of paper selection for updated review 9

10 Figure 3. Updated review for yield of all active TB cases authoryear country Percent (95% CI) % Weight Prior Data Alfonja 1973 Nigeria Aluoch 1978 Kenya Aluoch 1982 Kenya Andrews 1960 Aziz 1985 Pakistan Bayona 2003 Peru Becerra 2005 Peru Claessens 2002 Malawi Devadatta 1970 Egsmose 1965 Kenya Espinal 2000 Dominican Republic Gilpin 1987 Guwatudde 2003 Uganda Kamat 1966 Klausner 1993 Kritski 1996 Zaire Kumar 1984 Lemos 2004 Narain 1966 Nsanzumuhiree 1981 Kenya Nunn 1994 Kenya Saunders 1984 Suggaravetsiri 2003 Thailand Teixeira 2001 Wares 2000 Nepal WHO 1961 Kenya Zachariah 2003 Malawi Subtotal (I-squared = 95.6%, p = 0.000). New Data Ottmani 2009 Morocco Kruk 2007 Gazetta 2006 Bakir 2008 Turkey Cavalcante 2010 Kilicaslan 2009 Becerra 2011 Lin 2008 Turkey Peru China Maciel 2009 Nguyen 2009 Laos Sia 2010 Philippines Vella 2011 Grandjean 2011 Peru Kasambria 2011 Lienhardt 2010 Senegal Subtotal (I-squared = 96.5%, p = 0.000). Overall (I-squared = 95.9%, p = 0.000) (9.51, 17.66) 0.48 (0.10, 1.39) 1.67 (0.67, 3.41) 6.93 (5.15, 9.08) 9.22 (6.67, 12.34) 7.62 (6.01, 9.50) 0.91 (0.44, 1.67) 2.02 (1.53, 2.62) 8.46 (6.70, 10.50) (9.32, 13.94) 5.74 (4.23, 7.58) 3.03 (0.83, 7.58) 6.30 (5.00, 7.82) 9.06 (7.13, 11.30) 4.45 (3.36, 5.77) 7.80 (4.61, 12.19) 5.45 (3.21, 8.58) 3.55 (1.71, 6.42) 2.22 (1.52, 3.12) 2.39 (0.88, 5.13) 5.88 (3.68, 8.85) 5.45 (4.67, 6.31) 4.83 (3.69, 6.20) 4.17 (2.45, 6.59) 0.61 (0.33, 1.02) (7.28, 13.43) 0.91 (0.42, 1.73) 5.03 (4.02, 6.04) 2.50 (2.47, 2.53) (9.19, 17.90) 1.81 (0.37, 5.19) 1.54 (0.85, 2.57) 3.72 (2.44, 5.40) 6.71 (5.88, 7.61) 2.60 (2.15, 3.11) 0.37 (0.12, 0.86) 3.23 (1.06, 7.37) 1.26 (0.34, 3.20) (10.50, 14.95) 3.62 (2.80, 4.60) 5.11 (4.21, 6.14) (13.65, 25.07) 2.14 (1.61, 2.80) 4.03 (3.13, 4.93) 4.51 (3.95, 5.08)

11 Figure 4. Updated review for yield of bacteriologically confirmed active tuberculosis authoryear country Proportion (95% CI) % Weight Prior Data Aluoch 1978 Kenya Aluoch 1982 Kenya Andrews 1960 Aziz 1985 Pakistan Bayona 2003 Peru Becerra 2005 Peru Claessens 2002 Malawi Devadatta 1970 Egsmose 1965 Kenya Espinal 2000 Dominican Republic Gilpin 1987 Guwatudde 2003 Uganda Kamat 1966 Klausner 1993 Zaire Kritski 1996 Kumar 1984 Narain 1966 Nsanzumuhire 1981 Kenya Suggaravetsiri 2003 Thailand Teixeira 2001 Wares 2000 Nepal WHO 1961 Kenya Zachariah 2003 Malawi Subtotal (I-squared = 91.2%, p = 0.000). New Data Ottmani 2009 Morocco Kruk 2007 Gazetta 2006 Bakir 2008 Turkey Kilicaslan 2009 Turkey Maciel 2009 Nguyen 2009 Laos Sia 2010 Philippines Vella 2011 Grandjean 2011 Peru Lienhardt 2010 Senegal Subtotal (I-squared = 94.8%, p = 0.000). Overall (I-squared = 92.5%, p = 0.000) 0.48 (0.10, 1.39) 1.67 (0.67, 3.41) 4.18 (2.82, 5.95) 2.30 (1.11, 4.20) 7.62 (6.01, 9.50) 0.91 (0.44, 1.67) 2.02 (1.53, 2.62) 3.31 (2.23, 4.73) 1.42 (0.71, 2.53) 2.87 (1.83, 4.27) 3.03 (0.83, 7.58) 3.32 (2.38, 4.49) 2.85 (1.79, 4.28) 4.45 (3.36, 5.77) 7.80 (4.61, 12.19) 2.56 (1.11, 4.99) 0.28 (0.08, 0.71) 2.39 (0.88, 5.13) 1.08 (0.58, 1.85) 4.17 (2.45, 6.59) 0.61 (0.33, 1.02) 3.02 (1.57, 5.21) 0.20 (0.02, 0.73) 2.37 (1.80, 2.95) 1.10 (1.08, 1.12) (7.18, 15.21) 0.60 (0.02, 3.31) 0.33 (0.07, 0.96) 5.02 (4.30, 5.81) 3.23 (1.06, 7.37) 0.95 (0.20, 2.74) 2.23 (1.37, 3.42) 1.87 (1.29, 2.61) 3.84 (3.06, 4.74) 1.65 (1.18, 2.24) 2.30 (1.48, 3.11) 2.24 (1.86, 2.62)

12 Figure 5. Updated review for yield of LTBI % authoryear country Percent (95% CI) Weight Prior Data Andrews 1960 Aziz 1985 Pakistan Devadatta 1970 Elliot 1993 Zambia Espinal 2000 Dominican Republic Gilpin 1987 Guwatudde 2003 Uganda Hill 2004 Gambia Kamat 1966 Klausner 1993 Zaire Kritski 1996 Lemos 2004 Lienhardt 2003 (AJRCCM) Gambia Lutong 2000 China Narain 1966 Rathi 2002 Pakistan Suggaravetsiri 2003 Thailand Teixeira 2001 WHO 1961 Kenya Subtotal (I-squared = 98.7%, p = 0.000). New Data Kruk 2007 Bakir 2008 Turkey Cavalcante 2010 Nakaoka 2006 Nigeria Gustafson 2007 Guinea Bissau Akhtar 2009 Pakistan Lin 2008 China Mutsvangwa 2010 Zimbabwe Maciel 2009 Nguyen 2009 Laos Sia 2010 Philippines Kasambria 2011 Subtotal (I-squared = 98.9%, p = 0.000). Overall (I-squared = 98.8%, p = 0.000) (40.33, 48.13) (51.41, 60.95) (67.49, 73.63) (43.14, 54.60) (67.93, 74.31) (18.77, 38.62) (63.67, 69.08) (37.24, 44.47) (35.79, 50.46) (58.95, 64.49) (88.34, 96.23) (57.89, 69.68) (38.79, 42.42) (37.35, 45.08) (30.38, 35.29) (44.25, 54.46) (52.75, 58.47) (34.77, 45.07) (58.11, 67.82) (46.10, 60.50) (47.60, 60.24) (57.75, 64.20) (69.81, 77.12) (25.65, 40.82) (38.28, 44.30) (44.25, 54.46) (21.08, 25.65) (66.15, 78.28) (15.19, 26.17) (24.98, 40.61) (61.05, 68.09) (22.52, 33.90) (34.57, 57.73) (44.39, 56.68)

13 Figure 6. Updated review for yield of active TB from contacts of HIV-positive index cases % Study Country Percent (95% CI) Weight Nunn 2004 Kenya 7.84 (3.45, 14.87) Espinal 2000 Dominican Republic 5.16 (2.78, 8.66) Suggaravetsiri 2003 Thailand 4.08 (2.51, 6.23) Klausner 1993 Zaire 4.99 (3.29, 7.23) Mutsvangwe 2010 Zimbabwe (38.80, 66.35) 8.52 Overall (I-squared = 91.7%, p = 0.000) 9.41 (4.49, 14.34)

14 Figure 7. Updated review for yield of LTBI from contacts of HIV-positive index cases authoryear country Percent (95% CI) Weight Espinal 2000 Dominican Republic (54.39, 66.78) Suggaravetsiri 2003 Thailand (41.44, 50.45) Klausner 1993 Zaire (55.73, 64.31) Elliot 1993 Zambia (31.06, 44.66) Teixeira (13.15, 35.50) Mutsvangwe 2010 Zimbabwe (35.35, 62.93) Overall (I-squared = 92.9%, p = 0.000) (36.66, 56.56)

15 Figure 8. Updated review for yield of active tuberculosis among pediatric contacts % authoryear country Percent (95% CI) Weight Prior Data Andrews 1966 Bayona 2003 Peru Beyers 1997 Devadatta 1970 Espinal 2000 Dominican Republic Guwatudde 2003 Uganda Kamat 1966 Klausner 1993 Zaire Kumar 1984 Nunn 1994 Kenya Salazar-Vergera 2003 Philippines Saunders 1984 Schaaf 2002 Singh 2005 Zachariah 2003 Malawi Subtotal (I-squared = 86.4%, p = 0.000). New Data Kruk 2007 Bakir 2008 Turkey Nguyen 2009 Laos Kasambria 2011 Subtotal (I-squared = 95.2%, p = 0.000). Overall (I-squared = 91.2%, p = 0.000) 5.45 (3.26, 8.48) 1.49 (0.41, 3.76) 8.39 (4.54, 13.92) (8.34, 14.35) 7.00 (4.58, 10.16) (7.90, 14.90) (11.05, 20.06) 4.78 (3.31, 6.65) 3.52 (1.15, 8.03) (5.27, 24.48) 3.27 (1.07, 7.46) (8.03, 15.02) (6.26, 18.08) 3.20 (1.47, 5.99) 1.67 (0.46, 4.23) 6.85 (4.83, 8.87) (9.19, 17.90) 1.38 (0.75, 2.30) 0.68 (0.02, 3.71) (13.65, 25.07) 7.62 (2.48, 12.76) 6.96 (5.05, 8.87)

16 Figure 9. Updated review for yield of LTBI among pediatric contacts % authoryear country Percent (95% CI) Weight Prior Data Almeida 2001 Andrews 1966 Beyers 1997 Espinal 2000 Dominican Republic Gilpin 1987 Klausner 1993 Zaire Lienhardt 2003 Gambia Madico 1995 Peru Narain 1966 Nunn 1994 Kenya Rathi 2002 Pakistan Salazar-Vergera 2003 Philippines Schaaf 2002 Singh 2005 Teixeira 2001 Topley 1996 Malawi Subtotal (I-squared = 96.7%, p = 0.000). New Data Kruk 2007 Bakir 2008 Turkey Nakaoka 2006 Nigeria Gustafson 2007 Guinea Bissau Nguyen 2009 Laos Kasambria 2011 Subtotal (I-squared = 97.8%, p = 0.000). Overall (I-squared = 97.2%, p = 0.000) (39.05, 56.09) (33.47, 44.38) (9.69, 21.92) (50.98, 61.52) (18.77, 38.62) (47.50, 55.09) (21.48, 30.46) (47.74, 62.93) (15.83, 21.37) (35.35, 62.93) (30.97, 48.03) (60.54, 77.02) (43.67, 61.79) (28.30, 39.67) (23.80, 38.88) (23.18, 34.02) (31.79, 47.86) (47.60, 60.24) (57.75, 64.20) (25.65, 40.82) (23.84, 32.03) (24.98, 40.61) (22.52, 33.90) (25.15, 53.69) (32.73, 46.72)

17 Figure 10. Updated review for yield of active tuberculosis among contacts of MDR-TB index patients Study Country Percent (95% CI) Weight Becerra 2011 Peru 2.60 (2.15, 3.11) Vella (2.80, 4.60) Grandjean 2011 Peru 5.11 (4.21, 6.14) Bayona 2003 Peru 7.62 (6.01, 9.50) 4.62 Kritski (4.61, 12.19) 0.98 Overall (I-squared = 92.1%, p = 0.000) 3.44 (3.06, 3.81)

18 Figure 11. Updated review for yield of bacteriologically confirmed active tuberculosis among contacts of MDR-TB index patients Study Country Percent (95% CI) Weight Vella (1.29, 2.61) Grandjean 2011 Peru 3.84 (3.06, 4.74) Bayona 2003 Peru 7.62 (6.01, 9.50) Kritski (4.61, 12.19) Overall (I-squared = 93.7%, p = 0.000) 4.91 (2.51, 7.31)

19 REFERENCES 1. Morrison, J., M. Pai, and P.C. Hopewell, Tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary tuberculosis in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Infect Dis, (6): p Bakir, M., et al., Prognostic value of a T-cell-based, interferon-gamma biomarker in children with tuberculosis contact. Ann Intern Med, (11): p Becerra, M.C., et al., Tuberculosis burden in households of patients with multidrugresistant and extensively drug-resistant tuberculosis: a retrospective cohort study. Lancet, (9760): p Cavalcante, S.C., et al., Community-randomized trial of enhanced DOTS for tuberculosis control in Rio de Janeiro,. Int J Tuberc Lung Dis, (2): p Gazetta, C.E., et al., Investigation of tuberculosis contacts in the tuberculosis control program of a medium-sized municipality in the southeast of in J Bras Pneumol, (6): p Grandjean, L., et al., Tuberculosis in household contacts of multidrug-resistant tuberculosis patients. Int J Tuberc Lung Dis, (9): p , i. 7. Kasambira, T.S., et al., QuantiFERON-TB Gold In-Tube for the detection of Mycobacterium tuberculosis infection in children with household tuberculosis contact. Int J Tuberc Lung Dis, (5): p Kilicaslan, Z., et al., Risk of active tuberculosis in adult household contacts of smearpositive pulmonary tuberculosis cases. Int J Tuberc Lung Dis, (1): p Kruk, A., et al., Symptom-based screening of child tuberculosis contacts: improved feasibility in resource-limited settings. Pediatrics, (6): p. e Lienhardt, C., et al., Evaluation of the prognostic value of IFN-gamma release assay and tuberculin skin test in household contacts of infectious tuberculosis cases in Senegal. PLoS One, (5): p. e Lin, X., et al., Dose-response relationship between treatment delay of smear-positive tuberculosis patients and intra-household transmission: a cross-sectional study. Trans R Soc Trop Med Hyg, (8): p Maciel, E.L., et al., Juvenile household contacts aged 15 or younger of patients with pulmonary TB in the greater metropolitan area of Vitoria, : a cohort study. J Bras Pneumol, (4): p Nguyen, T.H., et al., Risk of latent tuberculosis infection in children living in households with tuberculosis patients: a cross sectional survey in remote northern Lao People's Democratic Republic. BMC Infect Dis, : p Ottmani, S., et al., TB contact investigations: 12 years of experience in the National TB Programme, Morocco East Mediterr Health J, (3): p Sia, I.G., et al., Tuberculosis attributed to household contacts in the Philippines. Int J Tuberc Lung Dis, (1): p Vella, V., et al., Household contact investigation of multidrug-resistant and extensively drug-resistant tuberculosis in a high HIV prevalence setting. Int J Tuberc Lung Dis, (9): p , i. 19

20 17. Akhtar, S. and S.K. Rathi, Multilevel modeling of household contextual determinants of tuberculin skin test positivity among contacts of infectious tuberculosis patients, Umerkot, Pakistan. Am J Trop Med Hyg, (3): p Gustafson, P., et al., Clinical predictors for death in HIV-positive and HIV-negative tuberculosis patients in Guinea-Bissau. Infection, (2): p Mutsvangwa, J., et al., Identifying recent Mycobacterium tuberculosis transmission in the setting of high HIV and TB burden. Thorax, (4): p Nakaoka, H., et al., Risk for tuberculosis among children. Emerg Infect Dis, (9): p

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