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Human tuberculosis caused by Mycobacterium bovis, Taiwan.

To the Editor: Mycobacterium bovis is one of the causative agents of tuberculosis (TB) in humans and animals. Drinking unpasteurized milk, eating undercooked meat, and close contact with infected animals are the main sources of infection for humans. Currently, 119 M. bovis spoligotypes are contained in the fourth international spoligotyping database (SpolDB 4) and are categorized into 3 main sublineages corresponding to ST prototypes 482,683, and 479 (1).

Although an M. bovis surveillance program for farm animals has been implemented by the Taiwan Council of Agriculture, no surveillance system exists for human TB cases caused by M. bovis. To monitor the epidemiology of M. bovis in domestic animals, a regular tuberculin skin test (TST) is compulsory for cattle and sheep and optional for deer in Taiwan (2). In 2005, screening of Mycobacterium spp. infections by TST was performed for 111,412 cattle and 73,396 caprint and ovine herds, of which 188 (0.17%) and 148 (0.2%), respectively, were positive (2). We used spacer oligonucleotide typing (spoligotyping) and mycobacterial interspersed repetitive units-variable number tandem repeat (MIRU-VNTR) methods to investigate human TB caused by M. bovis in Taiwan.

During 2004-2005, a total of 3,321 mycobacteria isolates from individual patients were sent to the reference laboratory for strain typing. Of the 3,321 patients, 2,427 (73.1%) were male, 903 (27.2%) were from eastern Taiwan, and 513 (15.4%) were aboriginal persons. The mean age of the patients was 58.7 years: 224 (6.7%) were <25 years of age, 667 (20.1%) were 25-44 years of age, 906 (27.3%) were 45-64 years of age, and 1,524 (45.9%) were >65 years of age.

Isolates were screened by using a GenoType kit (3) and multiplex PCR (4). To differentiate between M. bovis and M. bovis BCG strains, presence or absence of region of difference 1 was analyzed (5). Spoligotyping was performed with a commercial kit (Isogen Bioscience BV, Maarssen, the Netherlands) following the manufacturer's instructions (6). Spoligotyping profiles were analyzed by using Bionumerics software, version 4.51 (Applied Maths, Kortijk, Belgium). The resolved spoligotype was designated by comparing it to SpolDB4 (1). The MIRU-VNTR assay was performed by using a modified, high-throughput, 15-loci MIRU typing system that we developed (7).

Of the 3,321 patient isolates, 3,306 (99.5%) were M. tuberculosis and only 15 (0.5%) were M. bovis. Mean age of the 15 M. bovis-infected patients was 62.2 years (Table). Twelve (80%) patients were male, and 3 (20%) were female. Of these 15 patients, 10 (66.7%) had newly diagnosed TB and 5 (33.3%) had been treated with anti-TB drugs. Most (11/15, 73%) of the patients were from eastern Taiwan, where the reporting rate for TB was the highest among the 4 regions of Taiwan; 60% (9/15) were aboriginal persons. Of the 15 patients, 13 (86.7%) had pulmonary TB, 1 had both pulmonary and extrapulmonary TB, and 1 had extrapulmonary TB. Only 2 patients (cases 2 and 3) had known contact with farm animals. Univariate analysis showed that region (eastern region 1.2% vs. other region 0.2%; odds ratio [OR] 7.4, 95% confidence interval [CI] (2.4-23.4) and ethnicity (aboriginal 1.8% vs. nonaboriginal 0.2%; OR 8.3, 95% CI 3.0 23.5) were associated with M. bovis infection but not age and sex. The association between region and M. bovis disappeared after controlling for age and ethnicity. Aboriginal ethnicity was the only factor significantly associated with TB caused by M. bovis after controlling for age (adjusted OR 12.7, 95% CI 4.2-38.9).

Spoligotyping profiles of the 15 M. bovis isolates were typical of M. bovis with the absence of spacers 3, 6, 9, 16, 21, and 39-43 (8). Although 15 cases were reported separately from different regions of Yaiwan, only 1 spoligotyping profile was identical to spoligotype ST 684 of the bovis sublineage. In addition, we identified 2 similar MIRU-VNTR profiles: 523-23232-42533-22 (13/14, 92.9%, cases 1-9, 11-13, and 15) and 523-22232-42523-22 (1/14, 7.1%, case 14). We were unable to obtain sufficient DNA from 1 strain (case 10) for MIRU-VNTR typing.

Aboriginal persons in Taiwan were more likely to have TB caused by M. bovis and had a 5-fold higher reporting rate for TB (9) than nonaboriginal persons. Environmental and genetic factors may be associated with a higher reporting rate for TB among aboriginal populations (10), but the contribution of M. bovis infection needs to be investigated. Because only 1 major spoligotype and 2 similar MIRU patterns were found in this case series, spread of a predominant clone in Taiwan is likely. In addition, because of insufficient epidemiologic data, we were unable to determine the proportion of cases caused by reactivation of latent infection and those caused by recent transmission. In our study population, M. bovis infection in humans appeared to be predominately indigenous in Taiwan because no imported case was noted. We are now genotyping M. bovis strains isolated from farm animals to help elucidate the source of infection and transmission of M. bovis in Taiwan.


We thank Chen-Che Chiu and Pei-Ju Chin for excellent technical assistance.

This work was supported by grant DOH95-DC-2011 from the Taiwan Centers for Disease Control, Department of Health, and joint grant 95-0324-19-F-01-00-00-00-35 from National Science Council and Department of Health, Taiwan, Republic of China.


(1.) Brudey K, Driscoll JR, Rigouts L, Prodinger WM, Gori A, Al-Hajoj SA, et al. Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology. BMC Microbiol. 2006;6:23-39.

(2.) Bureau of Animal and Plant Health Inspection and Quarantine, Council of Agriculture, Executive Yuan, Taiwan. Annual report. Taipei: The Bureau; 2005.

(3.) Richter E, Weizenegger S, Rusch-Gerdes S, Niemann S. Evaluation of genotype MTBC assay for differentiation of clinical Mycobacterium tuberculosis complex isolates. J Clin Microbiol. 2003;41:2672-5.

(4.) Yeboah-Manu D, Yates MD, Wilson SM. Application of a simple multiplex PCR to aid in routine work of the mycobacterium reference laboratory. J Clin Microbiol. 2001;39:4166-8.

(5.) Behr MA, Wilson MA, Gill WP, Salamon H, Schoolnik GK, Rane S, et al. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science. 1999;284:1520-3.

(6.) Kamerbeek J, Schouls L, Kolk A, van Agterveld M, van Soolingen D, Kuijper S, et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol. 1997;35:907-14.

(7.) Chin P J, Jou R. A modified automated high-throughput mycobacterial interspersed repetitive unit method for genotyping Mycobacterium tuberculosis. Diagn Microbiol Infect Dis. 2005;53:325-7.

(8.) Aranaz A, Lie'bana E, Mateos A, Dominguez L, Vidal D, Domingo M, et al. Spacer oligonucleotide typing of Mycobacterium boris strains from cattle and other animals: a tool for studying epidemiology of tuberculosis. J Clin Microbiol. 1996;34: 2734-40.

(9.) Hsu YH, Chen CW, Sun HS, Jou R, Lee JJ, Su IJ. Association of NRAMP 1 gene polymorphism with susceptibility to tuberculosis in Taiwanese aboriginals. J Formos Med Assoc. 2006;105:363-9.

(10.) Wang WH, Chang SJ, Wang TN, Cheng LS, Feng YP, Chen C J, et al. Complex segregation and linkage analysis of familial gout in Taiwanese aborigines. Arthritis Rheum. 2004;50:242-6.

Ruwen Jou,* Wei-Lun Huang,* and Chen-Yuan Chiang ([dagger])

* Centers for Disease Control, Taipei, Taiwan, Republic of China; and ([dagger]) International Union Against Tuberculosis and Lung Disease, Paris, France

Address for correspondence: Ruwen Jou, Reference Laboratory of Mycobacteriology, Research and Diagnostic Center, Department of Health, Centers for Disease Control, 161 Kun-Yang St, Nan-Kang, Taipei 115, Taiwan, Republic of China; email:
Table. Characteristics of 15 patients with tuberculosis caused by
Mycobacterium bovis, Taiwan, 2004-2005

 Age at
Patient no. diagnosis, y Sex Type of tuberculosis

1 53 M Pulmonary
2 71 M Pulmonary
3 76 M Pulmonary
4 84 M Pulmonary
5 71 F Pulmonary
6 55 M Pulmonary
7 51 M Pulmonary
8 65 F Pulmonary
9 51 M Pulmonary
10 90 M Pulmonary
11 34 M Pulmonary
12 81 M Pulmonary
13 64 F Pulmonary
14 44 M Bladder/urinary
15 43 M Pulmonary/miliary

Patient no. Ethnicity Region

1 Aboriginal Northern
2 Han Central
3 Han Central
4 Han Southern
5 Aboriginal Eastern
6 Aboriginal Eastern
7 Aboriginal Eastern
8 Aboriginal Eastern
9 Han Eastern
10 Han Eastern
11 Aboriginal Eastern
12 Han Eastern
13 Aboriginal Eastern
14 Aboriginal Eastern
15 Aboriginal Eastern
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Title Annotation:LETTERS
Author:Ruwen, Jou; Wei-Lun, Huang; Chen-Yuan, Chiang
Publication:Emerging Infectious Diseases
Article Type:Letter to the editor
Date:Mar 1, 2008
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