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Journal of Clinical Microbiology, April 2008, p. 1363-1368, Vol. 46, No. 4
0095-1137/08/$08.00+0     doi:10.1128/JCM.02180-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Relationship between Mycobacterium tuberculosis Genotype and the Clinical Phenotype of Pulmonary and Meningeal Tuberculosis

Guy Thwaites,^1,2* Maxine Caws,^2,3 Tran Thi Hong Chau,^2,4 Anthony D'Sa,⁵ Nguyen Thi Ngoc Lan,⁶ Mai Nguyet Thu Huyen,⁶ Sebastien Gagneux,^7, Phan Thi Hoang Anh,⁶ Dau Quang Tho,² Estee Torok,^2,3 Nguyen Thi Quynh Nhu,² Nguyen Thi Hong Duyen,² Phan Minh Duy,² Jonathan Richenberg,⁵ Cameron Simmons,^2,3 Tran Tinh Hien,⁴ and Jeremy Farrar^2,3

Centre for Molecular Microbiology and Infection, Imperial College, London, United Kingdom,¹ Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 190 Ben Ham Tu, District 5, Ho Chi Minh City, Vietnam,² Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Old Road, Headington, Oxford, United Kingdom,³ The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam,⁴ Department of Radiology, Brighton, and Sussex University Hospitals, Eastern Road, Brighton, United Kingdom,⁵ Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases, Huong Vuong, District 5, Ho Chi Minh City, Vietnam,⁶ Institute for Systems Biology, 1441 N. 34th Street, Seattle, Washington⁷

Received 11 November 2007/ Returned for modification 23 December 2007/ Accepted 4 February 2008

We used large sequence polymorphisms to determine the genotypes of 397 isolates of Mycobacterium tuberculosis from human immunodeficiency virus-uninfected Vietnamese adults with pulmonary (n = 235) or meningeal (n = 162) tuberculosis. We compared the pretreatment radiographic appearances of pulmonary tuberculosis and the presentation, response to treatment, and outcome of tuberculous meningitis between the genotypes. Multivariate analysis identified variables independently associated with genotype and outcome. A higher proportion of adults with pulmonary tuberculosis caused by the Euro-American genotype had consolidation on chest X-ray than was the case with disease caused by other genotypes (P = 0.006). Multivariate analysis revealed that meningitis caused by the East Asian/Beijing genotype was independently associated with a shorter duration of illness before presentation and fewer cerebrospinal fluid (CSF) leukocytes. Older age, fewer CSF leukocytes, and the presence of hemiplegia (but not strain lineage) were independently associated with death or severe disability, although the East Asian/Beijing genotype was strongly associated with drug-resistant tuberculosis. The genotype of M. tuberculosis influenced the presenting features of pulmonary and meningeal tuberculosis. The association between the East Asian/Beijing lineage and disease progression and CSF leukocyte count suggests the lineage may alter the presentation of meningitis by influencing the intracerebral inflammatory response. In addition, increased drug resistance among bacteria of the East Asian/Beijing lineage might influence the response to treatment. This study suggests the genetic diversity of M. tuberculosis has important clinical consequences.

Published ahead of print on 20 February 2008.

Present address: Division of Mycobacterial Research, Medical Research Council, National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom.