|Year : 2021 | Volume
| Issue : 1 | Page : 37-42
A multidrug-resistant tuberculosis outbreak in a language school: Tokyo, Japan, 2019–2020
Mariya Itaki1, Masayuki Endo1, Keiko Ikedo1, Aya Kayebeta1, Ikumi Takahashi1, Masaki Ota2, Susumu Hirao2, Yoko Nagata2
1 Shinjuku City Health Office, Research Institute of Tuberculosis, Tokyo, Japan
2 Department of Technical Assistance to National Tuberculosis Programmes, Research Institute of Tuberculosis, Tokyo, Japan
|Date of Submission||28-Dec-2020|
|Date of Acceptance||30-Dec-2020|
|Date of Web Publication||28-Feb-2021|
3-1-24, Matsuyama, Kiyose City, Tokyo 2048533
Source of Support: None, Conflict of Interest: None
Background: Japan has successfully reduced the burden of tuberculosis (TB) in the past seven decades; however, there are still some issues in eliminating TB. Its presence in immigrants, particularly multidrug-resistant (MDR) TB, is one of them. In mid-September 2019, a teenage Chinese male student in a morning class of a Japanese language school in Tokyo, Japan, was diagnosed with sputum smear-positive pulmonary MDR-TB. Method: The outbreak cases were analyzed in a cohort study. Results: We investigated 138 students and 18 teachers, of whom 81 (51.9%) were male, 115 (73.7%) were aged from 20 to 29 years, and 124 (76.9%) were from China. Four other students in the same classroom and another in a different classroom from the index patient in the morning classes were also diagnosed with MDR-TB disease by the end of November 2020. In addition, 31 cases of latent TB infection (LTBI) were detected among the students and teachers. Students in the same classroom had the highest risk of TB infection (78.9%, 95% confidence interval [CI]: 54.4%–93.9%) with a relative risk of 8.6 (95% CI: 3.9–19.0), followed by students in the other classrooms of the morning classes (25.9%, 95% CI: 15.0%–39.7%) with a relative risk of 2.8 (95% CI: 1.2–6.8), compared with the afternoon class students (9.2%, 95% CI: 3.5–19.0) who had minimal contact with the index patient. Conclusion: National TB programs should adopt prophylaxis regimens for MDR-TB LTBI cases and provide prophylaxis to them, particularly if related to an outbreak. The Japanese government should screen immigrants for TB, particularly those from TB-endemic areas.
Keywords: Disease outbreak, epidemiology, immigrants, multidrug-resistance, tuberculosis
|How to cite this article:|
Itaki M, Endo M, Ikedo K, Kayebeta A, Takahashi I, Ota M, Hirao S, Nagata Y. A multidrug-resistant tuberculosis outbreak in a language school: Tokyo, Japan, 2019–2020. Int J Mycobacteriol 2021;10:37-42
|How to cite this URL:|
Itaki M, Endo M, Ikedo K, Kayebeta A, Takahashi I, Ota M, Hirao S, Nagata Y. A multidrug-resistant tuberculosis outbreak in a language school: Tokyo, Japan, 2019–2020. Int J Mycobacteriol [serial online] 2021 [cited 2021 Apr 20];10:37-42. Available from: https://www.ijmyco.org/text.asp?2021/10/1/37/310515
| Introduction|| |
Tuberculosis (TB) remains an important public health concern throughout the world and it is estimated that about 10 million persons develop TB disease annually, of whom about 1.3 million die of it. Drug resistant-TB, particularly multidrug-resistant (MDR) TB, which is resistant to the two most potent anti-TB drugs, rifampicin and isoniazid, is the major contributor to antimicrobial resistance worldwide and continues to be a public health threat. Annually, about half a million persons fall ill with MDR- and rifampicin-resistant TB globally.
Japan has successfully reduced the burden of TB in the past seven decades from 590,684 cases (698/100,000 population) in 1951 to 15,590 cases (12.3/100,000 population) in 2018., However, there are still some issues in eliminating TB in Japan. Imported TB from immigrants is one of these challenges, as seen in Europe and North America,,, because Japan has an increasing number of immigrants (2.1 million at the end of 2014), mainly from Asia. The proportion of immigrants among all TB cases in Japan has steadily increased from 2.4% in 2000 to 10.7% in 2018. Immigrants accounted for 70% of the TB cases among those aged 20–29 years in 2018. The proportion of MDR-TB in all types of previously untreated TB in Japan was 0.4% in 2018; however, for those born in other countries, the proportion is much higher (8.6%).
There have also been TB outbreaks involving hospitals, workplaces, military training, schools, casinos, and homeless persons,,,,,, fueled by the about 6000 smear-positive pulmonary TB cases still being reported in Japan annually, and these infectious TB cases pose a public health threat to the community. MDR-TB and extensively drug-resistant (XDR) TB outbreaks involving a factory and health facilities were also reported in Japan., The practice of investigations of TB contacts in Japan is similar to that recommended elsewhere. Briefly, once a TB case is reported to a local health office by a physician, a public health nurse of the health office where the patient lives visits the patient to conduct an interview about his or her contacts. When the case is smear positive, the health office initiates a contact investigation. Normally, interferon-γ release assay (IGRA), rather than tuberculin skin testing, is used to screen for latent TB infection (LTBI) among the contacts because IGRA is more specific without interference caused by Bacillus Calmette–Guérin vaccination.,, For an LTBI patient, prophylaxis using isoniazid for 6–9 months or rifampicin for 4–6 months is normally prescribed; however, no standard regimens are currently recommended for LTBI patients with presumed MDR-TB.
In mid-September 2019, a teenage male student of Chinese origin in a Japanese language school in Shinjuku, Tokyo, Japan, was diagnosed with sputum smear-positive pulmonary TB (Pt 1). It was later determined that he had MDR-TB. He came to Tokyo in early July 2019 and started participating in morning Japanese classes 5 days a week in the school on arrival. Although he had had a cough for almost a year, he did not seek health care before he underwent a chest X-ray examination offered by the Shinjuku City Health Office. The city health office started a contact investigation on his diagnosis as patient 1 (Pt 1). This study aims to characterize the cases found in the TB outbreak and share the lessons learnt from the outbreak investigation.
| Method|| |
Shinjuku is a special ward of Tokyo, Japan. It is a major commercial and administrative center, housing the northern half of the busiest railway station in the world (Shinjuku Station) and the Tokyo Metropolitan Government Building, the administrative center for the government of Tokyo. As of 2015, the ward had an estimated population of 338,000, and a population density of 18,500 people/km2. The total area is 18 km2. Since the end of World War II, Shinjuku has been a major secondary center of Tokyo. Historically, it has had Korean and then Chinese communities and now has 43,000 foreign residents, making up 12.4% of the total population. It also has over 50 Japanese language schools within its jurisdiction and there are sometimes TB outbreaks related to the schools. The city health office has been conducting TB screening through chest X-ray three times a year for foreign-born students participating in the Japanese language schools. The TB notification rate for all types of TB in Shinjuku was 33.7/100,000 population in 2016, which was 2.4 times as high as that of the entire country, with peaks in the young (66.5/100,000 population in those aged 20–29 years) and elderly (68.0/100,000 population in those aged 80 years or older). However, the treatment outcomes of its intensive directly observed therapy program have been relatively good (88.2% treatment success for all types of TB for the 2015 cohort).
In our study, a TB case was defined as one in which a patient had (1) bacteriologically positive TB in a sputum sample determined by smear microscopy, culture, or nucleic acid amplification, or (2) a patient was determined to have TB by a physician through a chest X-ray and/or chest computed tomography (CT) and who had an epidemiological link with the index patient. An LTBI case was defined as one in which a patient had contact with the index patient and tested positive in an IGRA test but had no chest X-ray findings suggestive of TB. A case of TB infection was defined as either a TB case, regardless of the availability of IGRA, or an LTBI case. Those who had close contact with the index patient outside the school were excluded from the study because we wanted to focus on the risk of TB disease and infection within the school setting.
This is a retrospective cohort study. The cohort consisted of the teachers and the students who participated in the school for at least 1 day from July to September 2019. The proportions of the teachers and students who developed TB disease or who were infected with TB were compared using four categories: (1) students in the same classroom with the index patient (same-classroom students), (2) students in the morning classes except those in the same classroom indicated in (1) (morning class students), (3) students in the afternoon class (afternoon class students), and (4) teachers, with the afternoon class students as a reference.
All the IGRA-positive contacts were screened by chest X-ray and those who had abnormal findings were referred to chest physicians who were familiar with TB for further investigation. Since there is no standard regimen for LTBI prophylaxis for MDR- or rifampicin-resistant TB, those with IGRA positivity were followed up with chest X-rays, and chest CT, if indicated, every 3 months up to 3 years (i.e., until September 2022).
The information on the index patient was retrieved from the Nakano City Health Office where the patient was registered as a TB patient. The information on the contacts at the school was retrieved from the school records or derived from interviews with the school officials. The results of the IGRA tests were obtained from the Tokyo Metropolitan Institute of Public Health where the IGRA tests for the contacts were processed. The results of the chest X-ray examinations were obtained from chest physicians. The results of 24 loci variable numbers tandem repeat (VNTR) tests were obtained from the reference laboratory through the chest physicians. After the line lists of the TB and LTBI patients and the contacts were completed, the identity information, including the name, address, and cellphone number, was removed from the list and it was analyzed.
Statistical tests, including calculations of 95% confidence intervals (CIs) were conducted using R (Ver. x64 4.0.2. The R Foundation for Statistical Computing, Vienna, Austria). Fisher's exact test was employed for comparison of proportions. The Cochran–Armitage test was used for the trend of proportions among the groups. P < 0.05 was considered statistically significant.
| Results|| |
There were 150 students and 20 teachers who had contact with the index patient from July to September 2019. Twelve students and two teachers did not take IGRA tests at all, including one student who had a TB treatment history before, and they were excluded from the analysis. A total of 156 individuals were enrolled in the analysis [138 students and 18 teachers, [Table 1]]. Eighty-one (51.9%) of those analyzed were males, 115 (73.7%) were aged from 20 to 29 years, and 124 (76.9%) were from China.
|Table 1: Summary of the population analyzed in a tuberculosis outbreak investigation at a Japanese language school: Tokyo, Japan, 2019-2020|
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An epidemic curve of TB patients found during the outbreak investigation is shown in [Figure 1]. A student (Pt 2) from the same classroom was found to have TB in December 2019 with rifampicin-resistance through the GeneXpert test. A morning class student (Pt 3) was found to have rifampicin-resistant TB in January 2020. In addition, three other same-classroom students were found to have TB in March 2020 (Pts 4 and 5) and September 2020 (Pt 6) through chest CT and sputum and/or gastric fluid examinations. Pt 6 had been suspected to have TB disease through IGRA test and chest CT since January 2020; however, he was under observation and followed up because the sputum tests had not yielded TB bacilli before September 2020. Pt 3 was found to be sputum smear positive (scanty positive) and culture positive, whereas Pts 2, 4, 5, and 6 were found to be sputum smear negative and culture positive. All six patients (Pts 1–6) had isoniazid, rifampicin, and streptomycin resistance. Active case finding efforts of the city health office also found that one student (Pt 7) had developed TB disease in December 2018, about 9 months before the index patient developed TB. However, a further investigation concluded that this was not an outbreak case because he had sputum smear-negative pulmonary TB and did not have any epidemiological links with the other patients, including the index one, before he developed the disease. One teacher was found to have LTBI in March 2020, but none developed TB disease.
|Figure 1: Epidemic curve of tuberculosis cases in a language school: Tokyo, Japan, 2019–2020. The numbers indicated in each box are the patients' IDs. Patient 7, who was diagnosed in December 2018 before the outbreak, was eventually excluded from the analysis because the patient did not have any epidemiological links with the other outbreak-related TB patients. TB: Tuberculosis|
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A schematic map of the classrooms of the language school is shown in [Figure 2]. The language school had four classrooms of about 30 m2 each on one floor of a building. One batch of students studied in the morning and another in the afternoon. Each class had about 20 students. The index patient participated in the classes in classroom (CR) 1 in the mornings from Monday to Friday. CR 1 had five TB (Pts 1, 2, 4, 5, and 6) and 11 LTBI student patients. CR 2 had one TB (Pt 3) and four LTBI student patients. CRs 3 and 4 had two and seven LTBI student patients, respectively.
|Figure 2: Distribution of cases of tuberculosis disease and latent tuberculosis infection in a language school: Tokyo, Japan, 2019–2020|
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[Table 2] shows the proportions of TB disease and TB infection (TB disease plus LTBI) by different subgroups, and the relative risks of the subgroups, with the afternoon class students as a reference. The same-classroom students had the highest risk of TB infection (78.9%, 95% CI: 54.4%–93.9%) with a relative risk of 8.6 (95% CI: 3.9–19.0), followed by the morning class students (25.9%, 95% CI: 15.0%–39.7%) with a relative risk of 2.8 (95% CI: 1.2–6.8) compared with the afternoon class students (9.2%, 95% CI: 3.5–19.0). The Cochran–Armitage test revealed that there were statistically significant trends in TB disease and TB infection, assuming the same-classroom students had the highest risk of developing TB disease and/or TB infection, followed by the morning class students, afternoon class students, and teachers (P = 0.0004 and P < 0.0001, respectively). VNTR analysis revealed that five patients (Pts 1 through 5, though the analysis for Pt 6 was not yet done as of this writing) had the same strain of TB bacilli.
|Table 2: Proportions of cases with tuberculosis disease and latent tuberculosis infection by different subgroups: Tokyo, Japan, 2019-2020|
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The city health office conducted three phases of contact investigation starting from the same-classroom students (n = 19), to the morning class students (n = 54), and finally to the afternoon class students (n = 65). The same-classroom students and the morning class students were re-examined by the IGRA in March 2020. All the teachers were also investigated from December 2019 to January 2020 and in March 2020. As of the end of November 2020, no further cases of TB disease or LTBI were found with regard to this outbreak.
| Discussion|| |
We investigated an MDR-TB outbreak in a language school in Tokyo from 2019 to 2020 and found five TB disease and 31 LTBI patients in addition to the index patient as of November 2020. The same-classroom students and the morning class students had 8.6 and 2.8 times, respectively, more risk of TB infection than the afternoon class students.
The reason why the same-classroom students had a high risk of TB infection is that they shared an airspace that contained a higher concentration of TB bacilli spread by the index patient. Even the morning class students had a slightly higher risk of TB infection, probably because air containing TB bacilli was circulated in all the classrooms on the floor during the morning hours. It is also possible that the students of all the classrooms in the morning sessions mingled with each other in shared spaces such as the elevator hall, during the break time, and may have inhaled the TB bacilli. The afternoon class students had a lower risk of TB infection because they shared much less time with the index patient, but the air might still have contained a number of TB bacilli in the afternoon. The teachers also had a lower risk of TB infection, possibly because the time they shared the air with the index patient might have been shorter, and almost all of them escaped infection., Another factor that might have heightened the infectivity in this outbreak was the low air change rate of the classrooms in the summer in Tokyo (late June to early September) when the index patient was infectious. The ventilation of the classrooms might have been quite low, with windows shut to keep the cool air inside. It was reported that the same index patient (a teacher) spreads TB to eight of 155 persons (5.2%), including one who developed TB disease, in a classroom with an air change rate of about 0.5–1.0 times per hour (ACH), but to no one in a classroom with an ACH of about 4–7.
Several TB outbreaks involving schools and universities that young students attended have been reported and the findings are quite similar to those in our study. When a student is the index patient, mostly fellow students are affected, whereas the risk to employees teaching them is very small.,, A TB outbreak in which 55 students and no staff member developed TB disease was reported in a middle school in 2013 in Henan Province of China. The students in the same class and on the same teaching floor were more at risk of developing TB disease and TB infection. In a Norwegian educational institution, a TB outbreak in which a student was the index patient and eight other individuals, including six students, developed TB disease was reported in 2013. In a TB outbreak in a Serbian grammar school in 2016, 17 students, including the index patient, but no staff member, developed TB disease.
One of the difficulties in relation to containing MDR- and XDR-TB outbreaks is often the lack of a standard regimen for prophylaxis. An MDR-TB outbreak was reported in a high school in 2017 in northern China, with 12 students among the close contacts developing TB disease. Five students who had close contact with the index patient had LTBI and were provided with isoniazid, and two of them developed TB disease. Several fluoroquinolone-based regimens are proposed and some are effective and tolerable, as reported for MDR-TB outbreaks in Micronesia and other places.,, In future MDR-TB outbreaks, fluoroquinolone-based prophylaxis regimens should be administered to LTBI patients to contain the outbreaks earlier.
There are a few limitations in this study. First, we were able to follow-up the contacts for only 1 year and 2 months to monitor who developed TB disease. However, the authors believe that the situation and the extent of the TB infection among the contacts have already been revealed and will not change much even in 2–3 years, thanks to the use of IGRA tests. Second, since we did not conduct baseline IGRA tests for students and teachers, we were not able to show the conversion of IGRA test results. However, considering that the duration of the index patient's symptoms before his diagnosis was more than 2 months, most, if not all, of the same-classroom students must have converted. In addition, the proportion of those infected with TB among the same-classroom students was very high (over three-fourths) and since the study showed a decreasing trend in the proportions of TB disease and infection for the subgroups of the students and teachers, we believe that most of the students with LTBI were infected in this outbreak, not before arriving in Japan. Third, this study deals with one TB outbreak in a school setting in a country with a lower medium burden of TB, and the findings might not be generalizable to other countries. However, as we have already discussed above, some of the findings of this study are quite similar to those for TB outbreaks at schools and universities in other countries and the authors believe that the findings of our study are still important to note.
| Conclusion|| |
Based on this and the past studies on TB and MDR-TB outbreaks in schools, we have several recommendations. National TB programs, particularly those that accept immigrants from countries where the proportion of MDR-TB is high, should formulate a prophylaxis regimen for LTBI patients with presumed MDR-TB and provide prophylaxis to them, particularly if it is related to an outbreak. Since many Japanese language schools with students from countries with a high burden of TB have experienced TB outbreaks, they should screen students for TB at entry using chest X-rays.
Financial support and sponsorship
This study was partially supported by the Japan Agency for Medical Research and Development (Grant #: JP20fk0108127).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Katsuda N, Hirosawa T, Reyer JA, Hamajima N. Roles of public health centers (Hokenjo) in tuberculosis control in Japan. Nagoya J Med Sci 2015;77:19-28.
van de Berg S, Erkens C, van Rest J, van den Hof S, Kamphorst M, Keizer S, et al
. Evaluation of tuberculosis screening of immigrants in the Netherlands. Eur Respir J 2017;50:1700977.
Räisänen PE, Soini H, Vasankari T, Smit PW, Nuorti JP, Ollgren J, et al
. Tuberculosis in immigrants in Finland, 1995–2013. Epidemiol Infect 2016;144:425-33.
Menzies NA, Hill AN, Cohen T, Salomon JA. The impact of migration on tuberculosis in the United States. Int J Tuberc Lung Dis 2018;22:1392-403.
Ota M, Isshiki M. An outbreak of tuberculosis in a long-term care unit of a mental hospital. Kekkaku 2004;79:579-86.
Seki N. A suspected case of mass outbreak of tuberculosis infection in a small company separated into two floors. Kekkaku 2003;78:395-9.
Fujikawa A, Fujii T, Mimura S, Takahashi R, Sakai M, Suzuki S, et al
. Tuberculosis contact investigation using interferon-gamma release assay with chest x-ray and computed tomography. PLoS One 2014;9:e85612.
Ota M, Uchimura K, Hirao S. A community tuberculosis outbreak that could be detected earlier using surveillance data, Japan, 2012–2014. Int J Mycobacteriol (in printing) [doi: 10.4103/ijmy.ijmy_215_20].
Endo M, Ota M, Kayebeta A, Takahashi I, Nagata Y. A tuberculosis outbreak at an insecure, temporary housing facility, manga café, Tokyo, Japan, 2016–2017. Epidemiol Infect 2019;147:E222.
Ogata H, Sugita H, Kobayashi N, Takahashi M, Abe C, Mori T, et al
. An outbreak of multidrug-resistant tuberculosis in a family-run factory. Kekkaku 1997;72:329.
Kobayashi H, Koyanagi K, Kato O, Oe T. Outbreak of extensively drug-resistant pulmonary tuberculosis in a hemodialysis facility. Kekkaku 2013;88:477-84.
Centers for Disease Control and Prevention. Guidelines for the investigation of contacts of persons with infectious tuberculosis; recommendations from the National Tuberculosis Controllers Association and CDC, and Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis
infection, United States. Morb Mortal Wkly Rep Recomm Rep 2005;54:1-37.
Diel R, Loddenkemper R, Nienhaus A. Evidence-based comparison of commercial interferon-gamma release assays for detecting active TB: A metaanalysis. Chest 2010;137:952-68.
Sester M, Sotgiu G, Lange C, Giehl C, Girardi E, Migliori GB, et al
. Interferon-γ release assays for the diagnosis of active tuberculosis: A systematic review and meta-analysis. Eur Respir J 2011;37:100-11.
Higuchi K, Sekiya Y, Igari H, Watanabe A, Harada N. Comparison of specificities between two interferon-gamma release assays in Japan. Int J Tuberc Lung Dis 2012;16:1190-2.
Murase Y, Mitarai S, Isamu S, Kato S, Maeda S. Promising loci of variable numbers of tandem repeats for typing Beijing family Mycobacterium tuberculosis
. J Med Microbiol 2008;57:873-80.
Bargman C, Reves R, Parker M, Belknap R, Bettridge J, Bedell DT, et al
. Transmission of Mycobacterium tuberculosis
in a high school and school-based supervision of an isoniazid-rifapentine regimen for preventing tuberculosis – Colorado, 2011–2012. Morb Mortal Wkly Rep 2013;62:8059.
Caley M, Fowler T, Welch S, Wood A. Risk of developing tuberculosis from a school contact: Retrospective cohort study, United Kingdom, 2009. Euro Surveill 2010;15:19510.
Matsumoto K, Tatsumi T, Arima K, Koda S, Yoshida H, Kamiya N, et al
. [An outbreak of tuberculosis in which environmental factors influenced tuberculosis infection]. Kekkaku 2011;86:487-91.
Xu J, Wang G, Zhang Y, Zhang G, Xing J, Qi L, et al
. An outbreak of tuberculosis in a middle school in Henan, China: Epidemiology and risk factors. PLoS One 2019;14:e0225042.
Arnesen TM, Seterelv S, Norheim G, Helgebostad SR, Mannsåker T, Ly IN, et al
. Tuberculosis outbreak in Eastern Norway. Tidsskr Nor Legeforen 2015;135:2160-5.
Ilic M, Spahic S, Spahic M, Spahic O, Ilic I, Tiodorovic B. Tuberculosis outbreak in a grammar school, Serbia, 2016. Ann Ist Super Sanità 2019;55:55-8.
Wu X, Pang Y, Song Y, Dong W, Zhang T, Wen S, et al
. Implications of a school outbreak of multidrug-resistant tuberculosis in Northern China. Epidemiol Infect 2018;146:584-8.
Bamrah S, Brostrom R, Dorina F, Setik L, Song R, Kawamura LM, et al
. Treatment for LTBI in contacts of MDR-TB patients, Federated States of Micronesia, 2009–2012. Int J Tuberc Lung Dis 2014;18:912-8.
Trieu L, Proops DC, Ahuja SD. Moxifloxacin prophylaxis against MDR TB, New York, New York, USA. Emerg Infect Dis 2015;21:500-3.
[Figure 1], [Figure 2]
[Table 1], [Table 2]