Abstract
The impact of W-Beijing genotype Mycobacterium tuberculosis on treatment outcome was evaluated in 249 newly diagnosed tuberculosis patients. No significant difference in the treatment outcome was found between the W-Beijing and non-W-Beijing groups. However, a poor outcome was more common in the elderly patients (≥65 years) infected with the W-Beijing strain.
Worldwide distribution of W-Beijing strain Mycobacterium tuberculosis has been reported; however, the prevalence and drug resistance patterns of the W-Beijing strain vary widely (6, 8). Contradictory results were reported for studies of the impact of the W-Beijing strain on clinical features and radiological presentations (1, 5, 10, 17, 21). The impact of the W-Beijing strain on treatment outcome has not been well investigated.
The W-Beijing strain is the dominant strain in Southeast Asia and China, including Hong Kong, Taiwan, and mainland China (3, 9, 12). Evaluating the impact of the W-Beijing strain on treatment outcome can be pivotal in M. tuberculosis control. Aging may be a risk factor for unsuccessful treatment in M. tuberculosis-infected patients (7). In this study, we investigated the clinical impact of the W-Beijing strain on M. tuberculosis-infected patients, and the effect of aging was also explored.
Patients with culture-proven M. tuberculosis infection at Taipei Veterans general Hospital were retrospectively evaluated from January 2001 to January 2004. The Institutional Review Board of our hospital approved the study, and informed consent was waived.
The demographic and clinical data and the results of laboratory tests (acid-fast staining, M. tuberculosis culture, drug susceptibility testing, and spoligotyping of M. tuberculosis) were collected and analyzed. The patients were treated with standard antituberculosis (anti-TB) treatment, including isoniazid, rifampin, ethambutol, and pyrazinamide. The dosage of anti-TB drugs and the regimen of anti-TB treatment were modified if clinically indicated.
All patients were followed for 4 years from the start of anti-TB treatment. “Success without relapse” cases were those who completed anti-TB treatment and had no disease relapse during the follow-up period. “Relapse” cases were those who had bacteriologic evidence of recurrence of M. tuberculosis infection during the follow-up period after completion of anti-TB treatment. “Failure” cases were those with persistent positive sputum acid-fast stain and/or M. tuberculosis culture after 5 months of anti-TB treatment. “Expire” cases were those who died during anti-TB treatment. “Default” cases were those with interruption of treatment for at least 2 months. Treatment failure and disease relapse were defined as poor treatment outcomes (11). To evaluate the aging effect, the patients were divided into younger (<65 years old) and elderly (≥65 years old) groups.
Two-group comparisons were analyzed with the χ2 or Fisher exact test for categorical variables and an independent t test for continuous variables. The variables with a P value of <0.05 were subjected to logistic regression analysis. Significance was defined as a P value of <0.05 (two-tailed).
There were 249 patients enrolled, and 144 (57.8%) patients were infected with the W-Beijing genotype. There were 78 (31.3%) and 171 (68.7%) patients, respectively, in the younger and elderly groups. A history of previous anti-TB treatment appeared more commonly in the patients infected with the W-Beijing strain (26.4% versus 9.5%; P = 0.001). There were no significant differences in other demographic data, clinical features, disease severity, positive rate of sputum smear, occurrence of extrapulmonary TB, and chest image findings between the W-Beijing and non-W-Beijing groups (Table 1).
TABLE 1.
Clinical features, radiological presentations, and disease severity in patients infected with W-Beijing and non-W-Beijing strainsa
| Characteristic | No. of patients
|
P value | |
|---|---|---|---|
| W-Beijing strain | Non-W-Beijing strain | ||
| Symptoms and signsb | |||
| Cough | 74 (51.4) | 63 (60.0) | 0.177 |
| Hemoptysis | 15 (10.4) | 13 (12.4) | 0.628 |
| Fever | 44 (30.6) | 34 (32.4) | 0.759 |
| Weight loss | 12 (8.3) | 11 (10.5) | 0.564 |
| Asymptomatic | 15 (10.4) | 9 (8.6) | 0.626 |
| Smear positive | 70 (48.6) | 45 (42.9) | 0.368 |
| Extrapulmonary TB | 15 (10.4) | 15 (14.3) | 0.354 |
| Chest X-ray findingsc | |||
| Bilateral lesion | 77 (55.8) | 45 (44.6) | 0.086 |
| Cavitary lesion | 22 (15.9) | 13 (12.9) | 0.507 |
| Caseous pneumonia | 16 (11.6) | 13 (12.9) | 0.250 |
| Miliary lesion | 1 (0.7) | 3 (3.0) | 0.313 |
| Disseminated TB | 3 (2.1) | 3 (2.9) | 0.699 |
| Hospitalization for >1 mo | 28 (19.4) | 23 (21.9) | 0.635 |
| Use of ventilator | 14 (9.7) | 12 (11.4) | 0.664 |
| Organ failured | 19 (13.2) | 16 (15.2) | 0.647 |
| Death within 1 mo | 5 (3.5) | 7 (6.7) | 0.245 |
| Albumin [g/liter; mean (SD)] | 3.36 (0.56) | 3.26 (0.54) | 0.266 |
| Lymphocyte count/mm3 [mean (SD)] | 1,066 (542) | 1,212 (927) | 0.220 |
The data are presented as number (%) unless otherwise stated.
W-Beijing strain, n = 144; non-W-Beijing strain, n = 105.
W-Beijing strain, n = 138; non-W-Beijing strain, n = 101.
Failure of more than one organ, except for respiratory failure, including renal failure, hepatic failure, cardiovascular failure, and central nervous system failure.
Rates of resistance to anti-TB drugs showed no significant differences between W-Beijing and non-W-Beijing strains, except that the pyrazinamide resistance rate was significantly higher in W-Beijing than in non-W-Beijing strains (31.9% versus 17.1%; P = 0.008) (Table 2). There was no significant difference in the rates of resistance to anti-TB drugs between W-Beijing and non-W-Beijing strains in the elderly group; however, higher rates of resistance to ethambutol and streptomycin were found in the patients infected with the W-Beijing strain in the younger group (Table 2).
TABLE 2.
Results of drug susceptibility tests between W-Beijing and non-W-Beijing strainsa
| Drug resistance | Overall no. of patientsc (n = 202)
|
P value | No. of elderly patients (n = 171)
|
P value | No. of younger patients (n = 78)
|
P value | |||
|---|---|---|---|---|---|---|---|---|---|
| W-B (n = 144) | N-W-B (n = 105) | W-B (n = 76) | N-W-B (n = 54) | W-B (n = 47) | N-W-B (n = 31) | ||||
| Isoniazid | 45 (31.3) | 32 (30.5) | 0.896 | 33 (34.0) | 25 (33.8) | 0.974 | 12 (25.5) | 7 (22.6) | 0.766 |
| Rifampin | 34 (21.5) | 21 (20.0) | 0.770 | 20 (20.6) | 17 (23.0) | 0.711 | 11 (23.4) | 4 (12.9) | 0.249 |
| Ethambutol | 39 (27.1) | 22 (21.0) | 0.267 | 24 (24.7) | 19 (25.7) | 0.889 | 15 (31.9) | 3 (9.7) | 0.028 |
| Streptomycin | 39 (27.1) | 21 (20.0) | 0.197 | 25 (25.8) | 18 (24.3) | 0.829 | 14 (29.8) | 3 (9.7) | 0.035 |
| Pyrazinamide | 46 (31.9) | 18 (17.1) | 0.008 | 29 (29.9) | 13 (17.6) | 0.063 | 17 (36.2) | 5 (16.1) | 0.054 |
| MDRb | 30 (20.8) | 20 (19.0) | 0.728 | 20 (20.6) | 16 (21.6) | 0.873 | 10 (21.3) | 4 (12.9) | 0.346 |
| Any drug | 79 (54.9) | 51 (48.6) | 0.326 | 52 (53.6) | 38 (51.4) | 0.770 | 27 (57.4) | 13 (41.9) | 0.180 |
The data are presented as number (%) unless otherwise stated.
MDR, multiple drug resistance.
W-B, W-Beijing strain; N-W-B, non-W-Beijing strain.
The final outcome could be assessed in 224 patients. Twenty-three of 144 (16.0%) patients infected with the W-Beijing strain and 24 of 105 (22.9%) patients infected with the non-W-Beijing strain died during anti-TB treatment, but no significant difference in mortality cases was found between the W-Beijing and non-W-Beijing groups (Table 3). The treatment outcome for those who completed anti-TB treatment showed no significant difference between the W-Beijing and non-W-Beijing groups, irrespective of age. For the elderly group, poorer treatment outcomes (25.0% versus 7.4%; P = 0.01) and a lower success rate (75.0% versus 92.6%; P = 0.01) were found in the patients infected with the W-Beijing strain. These findings were not found in the younger group. The independent risk factors for poor treatment outcome in the elderly group included chronic obstructive pulmonary disease, W-Beijing strain infection, and drug resistance to isoniazid.
TABLE 3.
Treatment outcomes between patients infected with W-Beijing and non-W-Beijing strainsa
| Treatment outcome | Overall no. of patientsc (n = 202)
|
P value | No. of elderly patients (n = 171)
|
P value | No. of younger patients (n = 78)
|
P value | |||
|---|---|---|---|---|---|---|---|---|---|
| W-B (n = 144) | N-W-B (n = 105) | W-B (n = 76) | N-W-B (n = 54) | W-B (n = 47) | N-W-B (n = 31) | ||||
| Mortality | 23 (16.0) | 24 (22.9) | 0.170 | 21 (21.6) | 20 (27) | 0.484 | 2 (4.3) | 4 (12.9) | 0.167 |
| Within 1 mo | 5 (3.5) | 7 (6.7) | 0.559 | 4 (4.1) | 6 (8.1) | 0.414 | 1 (2.1) | 1 (3.2) | 0.208 |
| After 1 mo | 18 (12.5) | 17 (16.2) | 17 (17.5) | 14 (18.9) | 1 (2.1) | 3 (9.7) | |||
| Success | 99 (68.8) | 72 (68.6) | 0.976 | 57 (58.8) | 50 (67.6) | 0.238 | 42 (89.4) | 22 (71.0) | 0.038 |
| Relapse | 19 (13.2) | 7 (6.7) | 0.096 | 17 (17.5) | 4 (5.4) | 0.017 | 2 (4.3) | 3 (9.7) | 0.381 |
| Failure | 2 (1.4) | 1 (1.0) | 1.000 | 2 (2.1) | 0 | 0.506 | 0 (0.0) | 1 (3.2) | 0.397 |
| Default | 1 (0.7) | 1 (1.0) | 1.000 | 0 | 0 | 1 (2.1) | 1 (3.2) | 1.000 | |
| Poorb | 21 (14.6) | 8 (7.6) | 0.091 | 19 (19.6) | 4 (5.4) | 0.007 | 2 (4.3) | 4 (12.9) | 0.161 |
The data are presented as number (%) unless otherwise stated.
Combination of treatment failure and disease relapse.
W-B, W-Beijing strain; N-W-B, non-W-Beijing strain.
No definite relationship between W-Beijing strain infection and previous anti-TB treatment was reported previously (1, 4, 5, 19). Because genotyping of M. tuberculosis was not done in the previous M. tuberculosis infection, the genotyping of the M. tuberculosis strains responsible for previous and recent M. tuberculosis infections could not be evaluated in this study.
The W-Beijing genotype is reported to have a higher rate of drug resistance and different drug resistance patterns in different areas (6, 8). The varying mutation rates in the rpoB, katG, and inhA genes between W-Beijing and non-W-Beijing strains and a unique missense alteration of DNA repair genes in the W-Beijing strain may be possible reasons (14, 15). The drug resistance pattern of the W-Beijing strain in most East and Southeast Asian countries appears to be the endemic pattern without a higher drug resistance rate. Despite a high prevalence rate, the drug resistance pattern of the W-Beijing strain in Chinese society remains unclear. The effect of the W-Beijing strain on drug resistance was studied in Hong Kong (3), mainland China (12), and Taiwan (9) with inconclusive results. In this study, a higher pyrazinamide resistance rate was found in the W-Beijing strain. The inconsistent results may indicate that the biologic behavior of the W-Beijing strain is area dependent.
Studies of the impact of the W-Beijing stain on treatment outcome are limited. The W-Beijing genotype was reported to be a significant risk factor for treatment failure and disease relapse in Vietnam (11). Our results indicated no significant difference in treatment outcome between the W-Beijing and non-W-Beijing groups, irrespective of age. However, treatment failure and disease relapse occurred more frequently in the elderly patients infected with the W-Beijing strain. Drug resistance gene mutation and different immune responses induced by the W-Beijing strain may explain this in part (2, 13-18, 20).
In summary, the W-Beijing strain had a limited impact on clinical features, radiological findings, results of drug susceptibility tests, and treatment response in M. tuberculosis-infected patients irrespective of age. However, a poor treatment outcome occurred more commonly in the aged patients infected with the W-Beijing strain.
Acknowledgments
We thank Yu-Hua Liu, Nursing Department, Taipei Veterans General Hospital, for data collection and analysis.
Footnotes
Published ahead of print on 2 July 2008.
REFERENCES
- 1.Borgdorff, M. W., H. Van Deutekom, P. E. De Haas, K. Kremer, and D. Van Soolingen. 2004. Mycobacterium tuberculosis, Beijing genotype strains not associated with radiological presentation of pulmonary tuberculosis. Tuberculosis 84337-340. [DOI] [PubMed] [Google Scholar]
- 2.Caws, M., G. Thwaites, K. Stepniewska, T. N. Nguyen, T. H. Nguyen, T. P. Nguyen, N. T. Mai, M. D. Phan, H. L. Tran, T. H. Tran, D. van Soolingen, K. Kremer, V. V. Nguyen, T. C. Nguyen, and J. Farrar. 2006. Beijing genotype of Mycobacterium tuberculosis is significantly associated with human immunodeficiency virus infection and multidrug resistance in cases of tuberculous meningitis. J. Clin. Microbiol. 443934-3939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Chan, M. Y., M. Borgdorff, C. W. Yip, P. E. de Haas, W. S. Wong, K. M. Kam, and D. Van Soolingen. 2001. Seventy percent of the Mycobacterium tuberculosis isolates in Hong Kong represent the Beijing genotype. Epidemiol. Infect. 127169-171. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Cox, H. S., T. Kubica, D. Doshetov, Y. Kebede, S. Rüsch-Gerdess, and S. Niemann. 2005. The Beijing genotype and drug resistant tuberculosis in the Aral Sea region of central Asia. Respir. Res. 6134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Drobniewski, F., Y. Balabanova, V. Nikolayevsky, M. Ruddy, S. Kuznetzov, S. Zakharova, A. Melentyev, and I. Fedorin. 2005. Drug-resistant tuberculosis, clinical virulence, and the dominance of the Beijing strain family in Russia. JAMA 2932726-2731. [DOI] [PubMed] [Google Scholar]
- 6.European Concerted Action on New Generation Genetic Markers and Techniques for the Epidemiology and Control of Tuberculosis. 2006. Beijing/W genotype Mycobacterium tuberculosis and drug resistance. Emerg. Infect. Dis. 12736-743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Farah, M. G., A. Tverdal, T. W. Steen, E. Heldal, A. B. Brantsaeter, and G. Bjune. 2005. Treatment outcome of new culture positive pulmonary tuberculosis in Norway. BMC Public Health 514. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Glynn, J. R., J. Whiteley, P. J. Bifani, K. Kremer, and D. van Soolingen. 2002. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg. Infect. Dis. 8843-849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Jou, R., C. Y. Chiang, and W. L. Huang. 2005. Distribution of the Beijing family genotypes of Mycobacterium tuberculosis in Taiwan. J. Clin. Microbiol. 4395-100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Kong, Y., M. D. Cave, L. Zhang, B. Foxman, C. F. Marrs, J. H. Bates, and Z. H. Yang. 2007. Association between Mycobacterium tuberculosis Beijing/W lineage strain infection and extrathoracic tuberculosis: insights from epidemiologic and clinical characterization of the three principal genetic groups of M. tuberculosis clinical isolates. J. Clin. Microbiol. 45409-414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lan, N. T. N., H. T. K. Lien, L. B. Tung, M. W. Borgdorff, K. Kremer, and D. van Soolingen. 2003. Mycobacterium tuberculosis Beijing genotype and risk for treatment failure and relapse, Vietnam. Emerg. Infect. Dis. 91633-1635. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Li, W. M., S. M. Wang, C. Y. Li, Y. H. Liu, G. M. Shen, X. X. Zhang, T. G. Niu, Q. Gao, D. van Soolingen, K. Kremer, and H. J. Duanmu. 2005. Molecular epidemiology of Mycobacterium tuberculosis in China: a nationwide random survey in 2000. Int. J. Tuberc. Lung. Dis. 91314-1319. [PubMed] [Google Scholar]
- 13.López, B., D. Aguilar, H. Orozco, M. Burger, C. Espitia, V. Ritacco, L. Barrera, K. Kremer, R. Hernandez-Pando, K. Huygen, and D. van Soolingen. 2003. A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes. Clin. Exp. Immunol. 3330-37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Park, Y. K., S. Shin, S. Ryu, S. N. Cho, W. J. Koh, O. J. Kwon, Y. S. Shim, W. J. Lew, and G. H. Bai. 2005. Comparison of drug resistance genotypes between Beijing and non-Beijing family strains of Mycobacterium tuberculosis in Korea. J. Microbiol. Methods 63165-172. [DOI] [PubMed] [Google Scholar]
- 15.Rad, M. E., P. Bifani, C. Martin, K. Kremer, S. Sampe, J. Rauzier, B. Kreiswirth J. Blazquez, M. Jouan, D. van Soolingen, and B. Gicquel. 2003. Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family. Emerg. Infect. Dis. 9838-845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Ríos-Barrera, V. A., V. Campos-Peña, D. Aguilar-León, L. R. Lascurain, M. A. Meraz-Ríos, J. Moreno, V. Figueroa-Granados, and R. Hernández-Pando. 2006. Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence. Eur. J. Immunol. 36345-353. [DOI] [PubMed] [Google Scholar]
- 17.Sun, Y. J., T. K. Lim, A. K. Ong, B. C. Ho, G. T. Seah, and N. I. Paton. 2006. Tuberculosis associated with Mycobacterium tuberculosis Beijing and non-Beijing genotypes: a clinical and immunological comparison. BMC Infect. Dis. 6105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Theus, S., K. Eisenach, N. Fomukong, R. F. Silver, and M. D. Cave. 2007. Beijing family Mycobacterium tuberculosis strains differ in their intracellular growth in THP-1 macrophages. Int. J. Tuberc. Lung. Dis. 111087-1093. [PubMed] [Google Scholar]
- 19.Toungoussova, O. S., P. Sandven, A. O. Mariandyshev, N. I. Nizovtseva, G. Bjune, and D. A. Caugant. 2002. Spread of drug-resistant Mycobacterium tuberculosis strains of the Beijing genotype in the Archangel Oblast, Russia. J. Clin. Microbiol. 401930-1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Tsenova, L., E. Ellison, R. Harbacheuski, A. L. Moreira, N. Kurepina, M. B. Reed, B. Mathema, C. E. Barry III, and G. Kaplan. 2005. Virulence of selected Mycobacterium tuberculosis clinical isolates in the rabbit model of meningitis is dependent on phenolic glycolipid produced by the bacilli. J. Infect. Dis. 19298-106. [DOI] [PubMed] [Google Scholar]
- 21.van Crevel, R., R. H. Nelwan, W. de Lenne, Y. Veeraragu, A. G. van der Zanden, Z. Ami, J. W. van der Meer, and D. van Soolingen. 2001. Mycobacterium tuberculosis Beijing genotype strains associated with febrile response to treatment. Emerg. Infect. Dis. 7880-883. [DOI] [PMC free article] [PubMed] [Google Scholar]