Mycobacterium tuberculosis Infection in School Contacts of Tuberculosis Cases: A Systematic Review and Meta-Analysis

Wenjin Wang Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, People’s Republic of China;
Center for Disease Control and Prevention of Yancheng City, Yancheng, People’s Republic of China;

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Aohan Liu Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York;

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Xinjie Liu Department of Epidemiology, School of Public Health, Shandong University, Jinan, People’s Republic of China;

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Nannan You Department of Medical Records and Statistics, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China;

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Zhan Wang Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, People’s Republic of China;

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Cheng Chen Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, People’s Republic of China;

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Limei Zhu Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, People’s Republic of China;

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Leonardo Martinez Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts

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Wei Lu Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, People’s Republic of China;

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Qiao Liu Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, People’s Republic of China;

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ABSTRACT.

Substantial tuberculosis transmission occurs outside of households, and tuberculosis surveillance in schools has recently been proposed. However, the yield of tuberculosis outcomes from school contacts is not well characterized. We assessed the prevalence of Mycobacterium tuberculosis infection among close school contacts by performing a systematic review. We searched PubMed, Elsevier, China National Knowledge Infrastructure, and Wanfang databases. Studies reporting the number of children who were tested overall and who tested positive were included. Subgroup analyses were performed by study location, index case bacteriological status, type of school, and other relevant factors. In total, 28 studies including 54,707 school contacts screened for M. tuberculosis infection were eligible and included in the analysis. Overall, the prevalence of M. tuberculosis infection determined by the QuantiFERON Gold in-tube test was 33.2% (95% CI, 0.0–73.0%). The prevalences of M. tuberculosis infection based on the tuberculin skin test (TST) using 5 mm, 10 mm, and 15 mm as cutoffs were 27.2% (95% CI, 15.1–39.3%), 24.3% (95% CI, 15.3–33.4%), and 12.7% (95% CI, 6.3–19.0%), respectively. The pooled prevalence of M. tuberculosis infection (using a TST ≥5-mm cutoff) was lower in studies from China (22.8%; 95% CI, 16.8–28.8%) than other regions (36.7%; 95% CI, 18.1–55.2%). The pooled prevalence of M. tuberculosis infection was higher when the index was bacteriologically positive (43.6% [95% CI, 16.5–70.8%] versus 23.8% [95% CI, 16.2–31.4%]). These results suggest that contact investigation and general surveillance in schools from high-burden settings merit consideration as means to improve early case detection in children.

INTRODUCTION

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. Approximately 10% of the 9.9 million cases of TB were in children aged under 15 years globally in 2019.1,2 Children with recent Mycobacterium tuberculosis infection have an 8–20% risk to progress to TB disease 2 years after exposure.3,4 Despite this, many children at high risk of developing TB are not identified, screened, and given preventive therapy.5 Historically, children have been largely neglected in TB control efforts. To reduce morbidity and mortality of TB among children, a rigorous evaluation of distinct strategies for case detection and prevention is needed.

The most effective and appropriate TB control program directed at children and adolescents is debated. Whether to target specific high-risk children, settings of high risk, or a more broad-based implementation strategy is unclear. Prior studies have found household contact tracing to have a high yield and to be cost-effective in countries with high TB incidence settings.6,7 However, emerging evidence suggests that M. tuberculosis infections among children are often acquired outside the household, suggesting that complementary interventions and strategies in addition to household contact tracing are needed.8,9 Whether screening approaches in other settings, such as schools, have a substantial yield has not been systematically evaluated.

There has been no published review exploring the prevalence of M. tuberculosis infection among close school contacts of TB cases. We aimed to review the evidence on the yield of school contact investigations in distinct settings. We aimed to collate data from similar settings to provide information that can be used to estimate the benefit of such interventions. We conducted a systematic review and meta-analysis of the prevalence of M. tuberculosis infection in young school contacts of TB cases and by specific subgroups of these children.

MATERIALS AND METHODS

Study design and search strategy.

We conducted a systematic review of studies that included children as school contacts of a person with TB. We first searched the literature for systematic reviews investigating M. tuberculosis infection in school contacts of TB among children. None were found. We then aimed to compile all studies investigating children in close contact with a person with TB in the same school.

A literature search was performed using the PubMed, Elsevier, China National Knowledge Infrastructure, and Wanfang databases. The Medical Subject Headings keywords and terms “pulmonary tuberculosis,” “tuberculosis,” “TB,” “tuberculosis infection,” “latent tuberculosis infection,” “latent TB infection,” “tuberculin skin test,” “interferon-gamma release assays,” “IGRAs,” “QuantiFERON-TB Gold In-Tube,” “QFT,” “T-SPOT,” “students,” “child,” “children,” “adolescent,” “school,” “teenage,” “baby,” “juvenile,” “young,” “pupil,” “infant,” and “kid” were used. Boolean operators (AND and OR) were also used individually or in combinations to conduct a comprehensive search. All search terms were searched in titles, abstracts, and field keywords. Additionally, the search was restricted to papers published from database inception through January 1, 2022, without language restrictions. The literature search was performed by three authors (W. Wang, X. Liu, and A. Liu). Two authors (W. Wang and X. Liu) independently reviewed titles and then abstracts, in parallel and independently, for relevance and included publications identified by either author for full-text review. Two authors (W. Wang and A. Liu) extracted data on methods from included surveys using an electronic form and gathered datasets from supplemental materials.

Inclusion and exclusion criteria.

The review included retrospective surveys, cross-sectional studies, and outbreak investigations. Systematic reviews, case reports, case series, editorials, and letters to the editors were excluded. We included studies that showed the prevalence of M. tuberculosis infection among school contacts under 18 years old and used the enzyme-linked immunosorbent assay and/or the enzyme-linked immunosorbent spot-based interferon gamma release assay (IGRA) and/or the tuberculin skin test (TST) with a 5-, 10-, or 15-mm induration diameter as the cutoff for positive results. Furthermore, the unavailability of full text and duplicate publications were also considered exclusion criteria. When we identified more than one study for a single survey, we included the earliest source or most complete dataset and excluded other records. All the processes were independently completed by two reviewers to decrease the risk of errors.

Data extraction.

The data from each study were recorded in a data extraction form designed by the reviewers. The retrieved data included the first author’s name, year of publication, study location, study design, whether the study was an outbreak, sample size, age, sputum smear, school type, whether the study was a boarding school, bacillus Calmette-Guérin (BCG) vaccination, TST induration diameter cutoff, results of the etiological examination, and the number of M. tuberculosis infections among included children. The prevalence of M. tuberculosis infection was the percentage of M. tuberculosis infections among screened contacts.

STATISTICAL ANALYSES

Data analysis was conducted using R statistical software (v. 4.1.2; The R Foundation for Statistical Computing, Vienna, Austria). Wilson’s method was used to calculate 95% CIs; the I2 statistic was used to determine heterogeneity.1012 I2 values greater than 50% were considered to represent substantial heterogeneity; random-effects models were used when substantial heterogeneity was present. Effect sizes were reported as proportions. Subgroup analysis was performed based on country, study design, presence or absence of bacteriological positivity, level of schooling (primary, secondary, or high school), boarding school, and induration diameter cutoff (≥5, ≥10, and 15 mm).

RESULTS

Study selection.

In total, 5,817 articles were reviewed for titles and abstracts, and 3,094 articles were excluded. Of the remaining 2,723 articles, 472 articles were eligible after full-text review. In the end, we identified 28 studies to be included in this meta-analysis that reported data of M. tuberculosis infection in school contacts under 18 years old. The flow diagram of the study selection process is shown in Figure 1.

Figure 1.
Figure 1.

Flow chart of the study inclusion. LTBI = latent tuberculosis infection; TB = tuberculosis; TST = tuberculin skin test.

Citation: The American Journal of Tropical Medicine and Hygiene 110, 6; 10.4269/ajtmh.23-0038

Study characteristics and prevalence of Mycobacterium tuberculosis infection.

The primary characteristics of the studies included in the review are summarized in Table 1. In total, 28 studies with 54,707 school contacts were included in the pooled prevalence of M. tuberculosis infection, of which 19 studies were from China,1331 three were from Italy,3234 two were from Korea,35,36 and four studies each were from Iran,37 Japan,38 Sweden,39 and the United States,40 respectively. In regard to study design, 15 were cross-sectional studies and 11 were retrospective studies. The proportions of students in high school, middle school, and primary school were 47.2% (25,805/54,707), 10.0% (5,471/54,707), and 3.2% (1,774/54,707), respectively. There were 39.3% (21,473/54,707) of unknown school type, and just 0.3% (184/54,707) were children in kindergarten. A total of 36.0% (19,712/54,707) of students were vaccinated with BCG, one study in which students were not vaccinated with BCG, and for 64.0% (34,994/54,707), the vaccination status was unknown.

Table 1

Characteristics of 28 selected studies measuring Mycobacterium tuberculosis infection in close school contacts

Reference, Year Country Study Design No. of Initial Cases Sputum Smear* Age (years) Level of School Boarding School BCG Vaccination (%) Diagnostic Test Used and Cutoff Total, N Total with Outcome Prevalence (%)
Fang et al.,13 2021 China Outbreak investigation 1 Positive 16–17 High school No 100 TST ≥15 mm 405 30 7.4
You et al.,14 2019 China Outbreak investigation 2 ATB 17–20 High school Yes 100 TST ≥5 mm 845 44 5.2
TST ≥10 mm 845 65 7.7
Kim et al.,35 2018 Korea Cross-sectional study 43 ATB 17–18 High school No 65 TST ≥10 mm 947 282 29.8
QFT, 0.35 IU/mL 947 258 27.2
Kim et al.,36 2015 Korea Retrospective study NS ATB 12–19 High school NS 70 TST ≥10 mm 7,475 1,861 24.9
Wei et al.,15 2020 China Retrospective study 6 ATB NS NS NS NS TST ≥5 mm 7,702 742 9.6
Jing et al.,16 2020 China Retrospective study 26 ATB ≥15 Primary school, middle school, high school NS NS TST ≥5 mm 10,062 101 1.0
<15 1,555 28 1.8
Ou et al.,17 2020 China Retrospective study 1 Positive NS Middle school No NS TST ≥15 mm 1,753 70 4.0
High school 1,046 32 3.1
Zhang,18 2015 China Retrospective study 5 ATB NS Primary school, middle school NS NS TST ≥15 mm 524 41 7.8
Ding and Zhang,19 2015 China Cross-sectional study 2 ATB NS High school No NS TST ≥5 mm 4,258 141 3.3
Weng and Wang,20 2014 China Retrospective study 34 ATB NS NS No NS TST ≥5 mm 710 475 66.9
Wang et al.,21 2019 China Retrospective study NS ATB NS High school NS NS TST ≥15 mm 193 13 6.7
Yuan et al.,22 2014 China Cross-sectional study NS ATB NS NS NS NS TST ≥5 mm 802 572 71.3
Ma,23 2019 China Retrospective study 9 ATB NS Secondary school No NS TST ≥5 mm 443 50 11.3
Chen et al.,24 2018 China Cross-sectional study 1 ATB NS Secondary school NS NS TST ≥5 mm 841 132 15.7
Xu et al.,25 2021 China Cross-sectional study 4 ATB NS High school Yes NS TST ≥5 mm 462 134 29.0
Pu et al.,26 2018 China Cross-sectional study 1 Positive NS High school Yes NS TST ≥15 mm 506 48 9.5
Ma et al.,27 2021 China Retrospective study 11 ATB NS High school NS 100 TST ≥5 mm 342 72 21.1
Hou et al.,28 2020 China Cross-sectional study 1 ATB 16–18 High school Yes 100 TST ≥15 mm 395 130 32.9
Filia et al.,32 2011 Italy Cross-sectional study 1 ATB 2–6 Kindergarten NS NS TST ≥5 mm 184 19 10.3
5–11 Primary school 199 24 12.1
Faccini et al.,33 2013 Italy Cross-sectional study 1 Positive NS Primary school NS NS TST ≥5 mm 977 188 19.2
Baghaie et al.,37 2012 Iran Cross-sectional study 1 Negative 15 High school NS 100 TST ≥10 mm 52 17 32.7
Fang et al.,29 2013 China Retrospective study 1 Positive NS High school NS 100 TST ≥15 mm 476 122 25.6
Higuchi et al.,38 2009 Japan Cross-sectional study 1 Positive 8–12 Primary school NS 100 TST ≥5 mm 306 200 65.4
TST ≥10 mm 306 90 29.4
QFT 308 6 2.0
Pan et al.,30 2019 China Retrospective study 117 ATB NS High school NS 100 TST ≥5 mm 4,078 625 15.3
Middle school TST ≥5 mm 2,434 559 23.0
Müller et al.,39 2008 Sweden Cross-sectional study 1 ATB 6–15 Primary school NS 100 TST ≥15 mm 261 35 13.4
Molicotti et al.,34 2008 Italy Cross-sectional study 1 Positive 10 Primary school NS NS TST ≥5 mm 29 19 65.5
QFT 29 21 72.4
Huang et al.,31 2018 China Cross-sectional study NS ATB 16–18 High school NS 100 TST ≥15 mm 4,325 352 8.1
Adler-Shohet et al.,40 2014 USA Cross-sectional study 1 Positive NS NS NS NS TST ≥5 mm 118 31 26.3

NS = not shown; QFT = QuantiFERON-TB Gold In-Tube; TST = tuberculin skin test.

For sputum smears, we divided studies into two groups according to the bacteriological results of index tuberculosis patients: ATB = active tuberculosis included studies with no detailed information of the bacteriological results of cases; Positive = bacteriologically positive.

Boarding school.

The vast majority of studies used TST screening, whereas only three studies used both the TST and the QuantiFERON-TB Gold In-Tube (QFT). There was high heterogeneity between studies; M. tuberculosis infection prevalence ranged from 1.1% to 72.4%. When a random-effects model was applied, we found that the pooled M. tuberculosis infection prevalences determined by the TST with induration cutoffs of ≥5 mm, ≥10 mm, and ≥15 mm and the QFT were 27.2% (95% CI: 15.1–39.3%, I2 = 100%), 24.3% (95% CI: 15.3–33.4%, I2 = 99%), 12.7% (95% CI: 6.3–19.0%, I2 = 97%), and 33.2% (95% CI: 0.0–73.0%, I2 = 99%), respectively (Figure 2). Twenty studies described the TB prevalence at baseline among contacts screened, and 11 studies described TB incidence during the follow-up time. The TB prevalence ranged from 0.0% to 15.0%, and the pooled TB prevalence among contacts screened was 0.7% (95% CI, 0.5–0.9%). The pooled TB incidence rate among contacts screened was 1.2% (95% CI, 0.8–1.6%), and ranged from 0.0% to 12.9% (Supplemental Table S1; Supplemental Figures 1 and 2).

Figure 2.
Figure 2.

Forest plot of the prevalence of Mycobacterium tuberculosis infection based on distinct diagnostic tests and cutoffs. QFT = QuantiFERON-TB Gold In-Tube; TST = tuberculin skin test.

Citation: The American Journal of Tropical Medicine and Hygiene 110, 6; 10.4269/ajtmh.23-0038

Percentage prevalences of Mycobacterium tuberculosis infection by location.

The pooled M. tuberculosis infection percentage, when a TST ≥5-mm induration cutoff was used, in studies from China was lower than that in studies from other regions (22.8%, 95% CI: 16.8–28.8%, versus 36.7%, 95% CI: 18.1–55.2%). The pooled M. tuberculosis infection percentage, based on a TST ≥15-mm cutoff, in China was 12.3% (95% CI: 8.4–16.1%, I2 = 97.7%). The pooled M. tuberculosis infection percentages detected by a TST ≥10-mm cutoff and QFT were 28.0% (95% CI: 24.3–31.8%, I2 = 77.3%) and 31.9% (95% CI: 9.0–54.7%, I2 = 99.3%), respectively, in other regions (Table 2; Supplemental Figure 3).

Table 2

Subgroup analysis of studies measuring Mycobacterium tuberculosis infection in close school contacts from a meta-analysis of 28 studies published

Stratum* No. of Studies Pooled Prevalence (%) 95% CI (%) I2 (%) References
All studies using different tests
 TST ≥5 mm 16 27.2 15.1–39.3 100 1416,19,20,2225,27,30,3234,38,40
 TST ≥10 mm 5 24.3 15.3–33.4 99 14,3538
 TST ≥15 mm 9 12.7 6.3–19.0 97 13,17,18,21,26,28,29,31,39
 QFT 3 33.2 0.0–73.0 99 34,35,38
Locations
 China
  TST ≥5 mm 11 22.8 16.8–28.8 100 1416,19,20,2225,27,30
  TST ≥15 mm 8 12.3 8.4–16.1 98 13,17,18,21,26,28,29,31
 Other countries
  TST ≥5 mm 5 36.7 18.1–55.2 99 3234,38,40
  TST ≥10 mm 4 28.0 24.3–31.8 77 3538
  QFT 3 31.9 9.0–54.7 99 34,35,38
Case types
 Bacteriologically positive TB
  TST ≥5 mm 4 43.6 16.5–70.8 99 33,34,38,40
  TST ≥15 mm 4 11.3 4.2–18.5 98 13,17,26,29
 Active TB
  TST ≥5 mm 11 23.8 16.2–31.4 100 14,15,19,20,2225,27,30,32
  TST ≥10 mm 3 20.8 8.3–33.2 99 14,35,36
  TST ≥15 mm 5 13.5 7.5–19.5 96 18,21,28,31,39
Levels of school
 Primary school
  TST ≥5 mm 4 39.8 15.7–63.9 99 3234,38
 Secondary school
  TST ≥5 mm 2 19.4 12.3–26.5 96 24,30
 High school
  TST ≥5 mm 5 14.5 7.4–21.6 99 14,19,25,27,30
  TST ≥10 mm 3 27.7 23.2–32.2 81 3537
  TST ≥15 mm 7 12.9 8.3–17.6 81 13,17,21,26,28,29,31

QFT = QuantiFERON-TB Gold In-Tube; TB = tuberculosis; TST = tuberculin skin test.

The induration cutoff is shown with TST.

Percentage prevalences of Mycobacterium tuberculosis infection by index TB patient characteristics.

We divided studies into three groups according to the bacteriological results of index TB patients. The group of “active TB” included studies that had no detailed information of the bacteriological results of cases. M. tuberculosis infection percentages in contacts with bacteriologically positive TB (43.6%, 95% CI: 16.5–70.8%, I2 = 98.8%) was higher than that in contacts with active TB (23.8%, 95% CI: 16.2–31.4%, I2 = 99.7%) when a TST induration cutoff of ≥5 mm was used. The percentage prevalence of M. tuberculosis infection in contacts with bacteriologically positive TB (11.3%, 95% CI: 4.2–15.8%, I2 = 97.8%) was similar to that in contacts with active TB (13.5%, 95% CI: 7.5–19.5%, I2 = 96.5%) when a TST cutoff of ≥15 mm was used (Table 2; Supplemental Figure 4).

Percentage prevalences of Mycobacterium tuberculosis infection by school grade.

The pooled M. tuberculosis infection percentages detected using a TST cutoff of ≥5 mm in high school, secondary school, and primary school were 14.5% (95% CI: 7.4–21.6%, I2 = 99.3%), 19.4% (95% CI: 12.3–26.5%, I2 = 95.7%), and 39.8% (95% CI: 15.7–63.9%, I2 = 99.0%), respectively. The analysis revealed that the overall percentage prevalences of M. tuberculosis infection were 27.7% (95% CI: 23.2–32.2%, I2 = 81.7%) in high school students when a TST cutoff of ≥10 mm was used and 12.9% (95% CI: 8.3–17.6%, I2 = 97.8%) in high school students when a TST cutoff of ≥15 mm was used. Only one study of high school students and no study of secondary school students were performed to calculate M. tuberculosis infection percentage prevalences detected using QFT (Table 2; Supplemental Figure 5).

Percentage prevalences of Mycobacterium tuberculosis infection by boarding school.

We divided studies into two groups, one which focused on studies of boarding schools and one which focused on studies that did not. The pooled percentage prevalence of M. tuberculosis infection, based on the results of a TST induration cutoff of ≥5 mm, was 17.2% (95% CI: 0.0–39.7%, I2 = 98.6%) in boarding schools. A TST cutoff of ≥5 mm was not used in any of the included studies to calculate the percentage prevalence of M. tuberculosis infection among nonboarding school students. QFT was not used in any of the included studies to calculate the prevalence of M. tuberculosis infection among boarding school students or nonboarding school students.

DISCUSSION

To our knowledge, this is the first study to systematically collect and analyze the prevalence of M. tuberculosis infection in school contacts of TB cases. M. tuberculosis infection among school contacts was high overall but largely varied from 27.2% to 24.3% to 12.7% when TST cutoffs of 5 mm, 10 mm, and 15 mm were used. The prevalence of M. tuberculosis infection was highest (33.2%) among children from studies that used QFT tests. These study results show that the prevalence is substantially higher than the background prevalence of M. tuberculosis infection among young children,4144 suggesting that considerable transmission is occurring among school contacts of TB cases, representing an important population for targeted intervention.

Surprisingly, we found a lower prevalence of M. tuberculosis infection in studies from China than in those from other countries. This remained the case regardless of the TST induration cutoff used to define M. tuberculosis infection. The reason for this result is not immediately clear but may be related to BCG vaccination. In China, all newborns were BCG vaccinated due to a strong immunization program.45 BCG vaccination has been found to protect against both M. tuberculosis infection and TB disease in young children.46,47 The strong BCG vaccination coverage in China may partially explain this result by protecting young school contacts in these studies. Alternatively, many of the studies outside of China included bacteriologically positive index cases. Bacteriological status was often not mentioned in studies from China. This may also explain the lower M. tuberculosis infection prevalence in studies from China.

Our results suggest a high prevalence of M. tuberculosis infection among school contacts irrespective of school grade. But it is worth noting that primary school contacts may have a higher likelihood of developing M. tuberculosis infection, and the prevalence reached 40% when a TST induration cutoff of ≥5 mm was used. A meta-analysis involving children with M. tuberculosis infection in Europe, the United States, Asia, and Africa showed that the infection rate of M. tuberculosis infection children with close family contact with TB was nearly four times that of children without close family contact.48,49 These studies indicate that children are the high-risk group for M. tuberculosis infection and that preventive measures for young children are urgently needed.

Additionally, our study revealed that there was little difference in prevalence of M. tuberculosis infection between boarding and nonboarding schools, implying that boarding school attendance may not be an important factor in M. tuberculosis infection. One study indicated a higher risk of M. tuberculosis infection in boarding schools (19%) than day schools (5%)9; ventilation and time spent in the classroom may play an important role in TB transmission and acquisition.9,50 However, there were too few boarding school studies in our study, potentially impacting the final result.

This review has several limitations. First, less information was available among index cases from included studies, limiting our ability to understand how disease severity impacted subsequent transmission. We recommend that future social contact surveys collect and report school-based data, ideally using standardized tools to indicate the bacteriological status of TB cases. Second, substantial between-study variability was present. Enduring heterogeneity suggests that secondary factors that were not collected (or not collected systematically by all studies) may have impacted this analysis. These may include undocumented secondary exposures among school contacts, reliability of the diagnostic tests performed,51 and BCG vaccination status, among others. Third, most studies from China used a TST induration cutoff of ≥15 mm to define M. tuberculosis infection; differential classification of M. tuberculosis infection status by study and region may have impacted our pooled results. Fourth, we included only studies that evaluated M. tuberculosis infection immunologically, and results would differ based on different screening methods. Thus, our conclusion may not generalize to some regions that lack the ability to screen TB infection by IGRA or TST. Generally, these regions have a high burden of TB, so our results may underestimate TB infection among school contacts.

CONCLUSION

In summary, we found a high prevalence of M. tuberculosis infection among school contacts. The excess burden of TB among school contacts has serious implications for M. tuberculosis transmission. High between-study heterogeneity suggests that local transmission dynamics are critical for understanding high-transmission locations. However, if confirmed, an integrated and consistent facility-based and community-based effort addressing prevention, early detection, and management of M. tuberculosis infection should be further investigated and strengthened for control of TB among young children.

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    Weng LX , Wang Y , 2014. Analysis of screening and prophylactic drug effect of close contact with smear positive pulmonary tuberculosis in school (in Chinese). Int J Epidemiol Infect Dis 41: 258260.

    • PubMed
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    • Export Citation
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    Wang J , Yu FY , Zhong H , Tang L , Xu CH , 2019. Analysis of screening results of close contacts of tuberculosis in schools in Fengxian District and countermeasures (in Chinese). Med Front 9: 240241.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Yuan LL , Tan SQ , Li JZ , Wu ZL , 2014. The analysis of bacillus Calmette-Guerin purified protein derivative and tuberculin purified protein derivative in tuberculosis screening among tuberculosis close contacts in school (in Chinese). J Tuberc Lung Health 3: 115119.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Ma B , 2019. Investigation and analysis of a tuberculosis epidemic in a middle school of Longxi County (in Chinese). Chin J Health Nutr 29: 317.

  • 24.

    Chen HJ , Tian JR , An BO , 2018. Analysis of tuberculosis cluster in a middle school in Guizhou Province (in Chinese). Chin J Sch Health 39: 460462.

  • 25.

    Xu Z , Fang LH , Wang X , Cheng QL , Lai YH , Chen P , Zhou WQ , 2021. Survey of a school clustering epidemic of pulmonary tuberculosis (in Chinese). J Med Pest Control 37: 275279.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Pu AQ , Yang ZQ , Tang WQ , Chen YZ , Lu ZX , Yao XJ , Yang CQ , 2018. Investigation and treatment of a cluster tuberculosis epidemic in vocational high school. World Latest Med Information 18: 180181.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Ma JF , Wu JZ , Liu Q , Wang JM , Lu F , 2021. Epidemiological investigation analysis of a tuberculosis epidemic in a middle school in Qidong, Jiangsu (in Chinese). China Trop Med 21: 531534.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Hou J , Pang Y , Yang X , Chen T , Yang H , Yang R , Chen L , Xu L , 2020. Outbreak of Mycobacterium tuberculosis Beijing strain in a high school in Yunnan, China. Am J Trop Med Hyg 102: 728730.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Fang Y et al., 2013. Outbreak of pulmonary tuberculosis in a Chinese high school, 2009–2010. J Epidemiol 23: 307312.

  • 30.

    Pan D et al., 2019. Infectivity of Mycobacterium tuberculosis genotypes and outcome of contact investigation in classroom in Guangxi, China. BioMed Res Int 2019: 3980658.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Huang H , Yuan G , Du Y , Cai X , Liu J , Hu C , Liang B , Hu G , Tang X , Zhou Y , 2018. Effects of preventive therapy for latent tuberculosis infection and factors associated with treatment abandonment: A cross-sectional study. J Thorac Dis 10: 43774386.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Filia A , Ciarrocchi G , Belfiglio R , Caferri M , Bella A , Piersimoni C , Cirillo D , Grilli G , Mancini C , Greco D , 2011. Tuberculosis in kindergarten and primary school, Italy, 2008–2009. Emerg Infect Dis 17: 514516.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Faccini M et al., 2013. Tuberculosis outbreak in a primary school, Milan, Italy. Emerg Infect Dis 19: 485487.

  • 34.

    Molicotti P , Bua A , Mela G , Olmeo P , Delogu R , Ortu S , Sechi LA , Zanetti S , 2008. Performance of QuantiFERON-TB testing in a tuberculosis outbreak at a primary school. J Pediatr 152: 585586.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Kim Y et al., 2017. Lessons learned from continued TB outbreaks in a high school. PLoS One 12: e0188076.

  • 36.

    Kim HJ et al., 2015. The prevalence rate of tuberculin skin test positive by contacts group to predict the development of active tuberculosis after school outbreaks. Tuberc Respir Dis (Seoul) 78: 349355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Baghaie N , Khalilzadeh S , Bolursaz MR , Parsanejad N , 2012. Contact tracing of a 15-year-old girl with smear-negative pulmonary tuberculosis in Tehran. East Mediterr Health J 18: 399401.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Higuchi K , Kondo S , Wada M , Hayashi S , Ootsuka G , Sakamoto N , Harada N , 2009. Contact investigation in a primary school using a whole blood interferon-gamma assay. J Infect 58: 352357.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Müller LL , Bennet R , Gaines H , Zedenius I , Berggren I , 2008. Complexity in estimating recent tuberculosis transmission among predominantly immigrant school children in Stockholm, Sweden 2006. Scand J Infect Dis 40: 709714.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Adler-Shohet FC , Low J , Carson M , Girma H , Singh J , 2014. Management of latent tuberculosis infection in child contacts of multidrug-resistant tuberculosis. Pediatr Infect Dis J 33: 664666.

    • PubMed
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    • Export Citation
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    WHO , 2021. Global Tuberculosis Report 2021. Available at: https://www.who.int/publications/i/item/9789240037021. Accessed March 14, 2023.

    • PubMed
    • Export Citation
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    Lin P, Zhang C, 2020. Current situation and intervention progress of latent tuberculosis infection in students. JTLD1: 170173.

  • 43.

    Aksenova VA , Vasilyeva IA , Kasaeva TC , Samoilova AG , Pshenichnaya NY , Tyulkova TE , 2020. Latent tuberculosis infection in children and adolescents in Russia. Int J Infect Dis 92s: S26S30.

    • PubMed
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    • Export Citation
  • 44.

    Mumpe-Mwanja D , Verver S , Yeka A , Etwom A , Waako J , Ssengooba W , Matovu JK , Wanyenze RK , Musoke P , Mayanja-Kizza H , 2015. Prevalence and risk factors of latent tuberculosis among adolescents in rural Eastern Uganda. Afr Health Sci 15: 851860.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Lu P , Lu F , Liu Q , Tang L , Ding X , Kong W , Lu W , Zhu L , 2021. High rate of transmission in a pulmonary tuberculosis outbreak in a junior high school in China, 2020. IJID Reg 1: 117123.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Martinez L , Cords O , Liu Q , Acuna-Villaorduna C , Bonnet M , Fox GJ , Carvalho ACC , Chan P-C , Croda J , Hill PC , 2022. Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: A systematic review and individual participant data meta-analysis. Lancet Glob Health 10: e1307e1316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Roy A , Eisenhut M , Harris R , Rodrigues L , Sridhar S , Habermann S , Snell L , Mangtani P , Adetifa I , Lalvani A , 2014. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: Systematic review and meta-analysis. BMJ 349: g4643.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Martinez L , Shen Y , Mupere E , Kizza A , Hill PC , Whalen CC , 2017. Transmission of Mycobacterium tuberculosis in households and the community: A systematic review and meta-analysis. Am J Epidemiol 185: 13271339.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Fernandes P et al., 2018. Sex and age differences in Mycobacterium tuberculosis infection in Brazil. Epidemiol Infect 146: 15031510.

  • 50.

    Coleman M , Martinez L , Theron G , Wood R , Marais B , 2022. Mycobacterium tuberculosis transmission in high-incidence settings—New paradigms and insights. Pathogens 11: 1228.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Lu P , Liu Q , Zhou Y , Martinez L , Kong W , Ding X , Peng H , Zhu T , Zhu L , Lu W , 2021. Predictors of discordant tuberculin skin test and QuantiFERON-TB Gold in-tube results in eastern China: A population-based, cohort study. Clin Infect Dis 72: 20062015.

    • PubMed
    • Search Google Scholar
    • Export Citation

Author Notes

Financial support: This study was supported by the National Nature Science Foundation of China (Grant no. 82003516), the Medical Scientific Research General Project of Jiangsu Health Commission (Grant no. M2020020/ZD2021052/ZDA2020022), and the Jiangsu Provincial Medical Key Discipline (Grant no. ZDXK202250).

Data availability: Please contact W. Wang for data requests.

Authors’ contributions: Q. Liu and W. Lu conceived the study and revised the manuscript. W. Wang, A. Liu, X. Liu, and Z. Wang analyzed the data and drafted the manuscript. L. Zhu, C. Chen, and J. Wang participated in the study design. L. Martinez and N. You participated in the study design and helped draft the manuscript. All authors contributed to the study and have read and approved the final manuscript.

Authors’ addresses: Wenjin Wang, Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, People’s Republic of China, and Center for Disease Control and Prevention of Yancheng City, Yancheng, People’s Republic of China, E-mail: 736539878@qq.com. Aohan Liu, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, E-mail: al4403@cumc.columbia.edu. Xinjie Liu, Department of Epidemiology, School of Public Health, Shandong University, Jinan, People’s Republic of China, E-mail: dlamlxj2021@163.com. Nannan You, Department of Medical Records and Statistics, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, E-mail: yourseu@163.com. Zhan Wang, Cheng Chen, Limei Zhu, Wei Lu, and Qiao Liu, Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, People’s Republic of China, E-mails: 3305078663@qq.com, chencheng128@gmail.com, lilyam0921@163.com, weiluxx@163.com, and liuqiaonjmu@163.com. Leonardo Martinez, Department of Epidemiology, School of Public Health, Boston University, Boston, MA, E-mail: leomarti@Stanforduga.edu.

Address correspondence to Wei Lu or Qiao Liu, Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, No. 172 Jiangsu Rd., Nanjing 210009, People’s Republic of China. E-mails: weiluxx@163.com or liuqiaonjmu@163.com
  • Figure 1.

    Flow chart of the study inclusion. LTBI = latent tuberculosis infection; TB = tuberculosis; TST = tuberculin skin test.

  • Figure 2.

    Forest plot of the prevalence of Mycobacterium tuberculosis infection based on distinct diagnostic tests and cutoffs. QFT = QuantiFERON-TB Gold In-Tube; TST = tuberculin skin test.

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    • Export Citation
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    Yuan LL , Tan SQ , Li JZ , Wu ZL , 2014. The analysis of bacillus Calmette-Guerin purified protein derivative and tuberculin purified protein derivative in tuberculosis screening among tuberculosis close contacts in school (in Chinese). J Tuberc Lung Health 3: 115119.

    • PubMed
    • Search Google Scholar
    • Export Citation
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    Ma B , 2019. Investigation and analysis of a tuberculosis epidemic in a middle school of Longxi County (in Chinese). Chin J Health Nutr 29: 317.

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    Chen HJ , Tian JR , An BO , 2018. Analysis of tuberculosis cluster in a middle school in Guizhou Province (in Chinese). Chin J Sch Health 39: 460462.

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    Xu Z , Fang LH , Wang X , Cheng QL , Lai YH , Chen P , Zhou WQ , 2021. Survey of a school clustering epidemic of pulmonary tuberculosis (in Chinese). J Med Pest Control 37: 275279.

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    • Export Citation
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    Pu AQ , Yang ZQ , Tang WQ , Chen YZ , Lu ZX , Yao XJ , Yang CQ , 2018. Investigation and treatment of a cluster tuberculosis epidemic in vocational high school. World Latest Med Information 18: 180181.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Ma JF , Wu JZ , Liu Q , Wang JM , Lu F , 2021. Epidemiological investigation analysis of a tuberculosis epidemic in a middle school in Qidong, Jiangsu (in Chinese). China Trop Med 21: 531534.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Hou J , Pang Y , Yang X , Chen T , Yang H , Yang R , Chen L , Xu L , 2020. Outbreak of Mycobacterium tuberculosis Beijing strain in a high school in Yunnan, China. Am J Trop Med Hyg 102: 728730.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Fang Y et al., 2013. Outbreak of pulmonary tuberculosis in a Chinese high school, 2009–2010. J Epidemiol 23: 307312.

  • 30.

    Pan D et al., 2019. Infectivity of Mycobacterium tuberculosis genotypes and outcome of contact investigation in classroom in Guangxi, China. BioMed Res Int 2019: 3980658.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Huang H , Yuan G , Du Y , Cai X , Liu J , Hu C , Liang B , Hu G , Tang X , Zhou Y , 2018. Effects of preventive therapy for latent tuberculosis infection and factors associated with treatment abandonment: A cross-sectional study. J Thorac Dis 10: 43774386.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Filia A , Ciarrocchi G , Belfiglio R , Caferri M , Bella A , Piersimoni C , Cirillo D , Grilli G , Mancini C , Greco D , 2011. Tuberculosis in kindergarten and primary school, Italy, 2008–2009. Emerg Infect Dis 17: 514516.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Faccini M et al., 2013. Tuberculosis outbreak in a primary school, Milan, Italy. Emerg Infect Dis 19: 485487.

  • 34.

    Molicotti P , Bua A , Mela G , Olmeo P , Delogu R , Ortu S , Sechi LA , Zanetti S , 2008. Performance of QuantiFERON-TB testing in a tuberculosis outbreak at a primary school. J Pediatr 152: 585586.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Kim Y et al., 2017. Lessons learned from continued TB outbreaks in a high school. PLoS One 12: e0188076.

  • 36.

    Kim HJ et al., 2015. The prevalence rate of tuberculin skin test positive by contacts group to predict the development of active tuberculosis after school outbreaks. Tuberc Respir Dis (Seoul) 78: 349355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Baghaie N , Khalilzadeh S , Bolursaz MR , Parsanejad N , 2012. Contact tracing of a 15-year-old girl with smear-negative pulmonary tuberculosis in Tehran. East Mediterr Health J 18: 399401.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Higuchi K , Kondo S , Wada M , Hayashi S , Ootsuka G , Sakamoto N , Harada N , 2009. Contact investigation in a primary school using a whole blood interferon-gamma assay. J Infect 58: 352357.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Müller LL , Bennet R , Gaines H , Zedenius I , Berggren I , 2008. Complexity in estimating recent tuberculosis transmission among predominantly immigrant school children in Stockholm, Sweden 2006. Scand J Infect Dis 40: 709714.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Adler-Shohet FC , Low J , Carson M , Girma H , Singh J , 2014. Management of latent tuberculosis infection in child contacts of multidrug-resistant tuberculosis. Pediatr Infect Dis J 33: 664666.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    WHO , 2021. Global Tuberculosis Report 2021. Available at: https://www.who.int/publications/i/item/9789240037021. Accessed March 14, 2023.

    • PubMed
    • Export Citation
  • 42.

    Lin P, Zhang C, 2020. Current situation and intervention progress of latent tuberculosis infection in students. JTLD1: 170173.

  • 43.

    Aksenova VA , Vasilyeva IA , Kasaeva TC , Samoilova AG , Pshenichnaya NY , Tyulkova TE , 2020. Latent tuberculosis infection in children and adolescents in Russia. Int J Infect Dis 92s: S26S30.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Mumpe-Mwanja D , Verver S , Yeka A , Etwom A , Waako J , Ssengooba W , Matovu JK , Wanyenze RK , Musoke P , Mayanja-Kizza H , 2015. Prevalence and risk factors of latent tuberculosis among adolescents in rural Eastern Uganda. Afr Health Sci 15: 851860.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Lu P , Lu F , Liu Q , Tang L , Ding X , Kong W , Lu W , Zhu L , 2021. High rate of transmission in a pulmonary tuberculosis outbreak in a junior high school in China, 2020. IJID Reg 1: 117123.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Martinez L , Cords O , Liu Q , Acuna-Villaorduna C , Bonnet M , Fox GJ , Carvalho ACC , Chan P-C , Croda J , Hill PC , 2022. Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: A systematic review and individual participant data meta-analysis. Lancet Glob Health 10: e1307e1316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Roy A , Eisenhut M , Harris R , Rodrigues L , Sridhar S , Habermann S , Snell L , Mangtani P , Adetifa I , Lalvani A , 2014. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: Systematic review and meta-analysis. BMJ 349: g4643.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Martinez L , Shen Y , Mupere E , Kizza A , Hill PC , Whalen CC , 2017. Transmission of Mycobacterium tuberculosis in households and the community: A systematic review and meta-analysis. Am J Epidemiol 185: 13271339.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Fernandes P et al., 2018. Sex and age differences in Mycobacterium tuberculosis infection in Brazil. Epidemiol Infect 146: 15031510.

  • 50.

    Coleman M , Martinez L , Theron G , Wood R , Marais B , 2022. Mycobacterium tuberculosis transmission in high-incidence settings—New paradigms and insights. Pathogens 11: 1228.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Lu P , Liu Q , Zhou Y , Martinez L , Kong W , Ding X , Peng H , Zhu T , Zhu L , Lu W , 2021. Predictors of discordant tuberculin skin test and QuantiFERON-TB Gold in-tube results in eastern China: A population-based, cohort study. Clin Infect Dis 72: 20062015.

    • PubMed
    • Search Google Scholar
    • Export Citation
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