Clinical and pathological characteristics of the Uganda genotype of Mycobacterium tuberculosis
Author: Wamala, Dan
Date: 2016-03-07
Location: Lecture hall IHRE, floor 0, Södersjukhuset
Time: 13.00
Department: Inst för klinisk forskning och utbildning, Södersjukhuset / Dept of Clinical Science and Education, Södersjukhuset
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Thesis (1.321Mb)
Abstract
Mycobacterium tuberculosis (Mtb), the aetiological agent of tuberculosis (TB) is the leading
infectious cause of death globally. The outcome of Mtb infection is variable and depends on
host, bacterial and environmental factors. Mtb has evolved into a number of lineages and sublineages exhibiting phylogeographical population structuring and diverse clinical
consequences after infection. The Mtb Uganda genotype is the commonest cause of
pulmonary TB (PTB) in Kampala, Uganda. Prominent inherited host factors that determine
the outcome of TB are human leukocyte antigens (HLA).
To investigate the impact of Mtb genomic diversity and host HLA allelic variability on the clinical outcome of TB infection in Ugandan patients, the clinical and pathological outcome of Mtb Uganda genotype, and the association between HLA II alleles and PTB due to Mtb were studied. The Uganda genotype was found less frequently in extrapulmonary TB (EPTB) than previously reported in PTB in the same setting (Paper I), and tuberculous lymphadenitis patients infected with Mtb Uganda genotype were significantly less prone to have abdominal lymphadenopathy (Paper IV). This may imply that Mtb Uganda genotype has reduced potential to disseminate.
A study of the evolutionary relationships and worldwide distribution of the spoligotypes of Mtb isolates from Ugandan patients with tuberculous lymphadenitis indicated an ongoing evolution of the Uganda genotype, with Uganda at the center of this evolution (Paper II).
HIV negative patients with pulmonary TB and their genetically related healthy household controls were typed for HLA class II alleles (Paper III). The HLA- DQB1*03:03 allele was significantly less frequent in patients compared to healthy controls suggesting that the HLADQB1*03:03 allele may be associated with resistance to TB.
To establish the cause and pathology of fatal mycobacterial disease, the mycobacteria and pathology associated with fatal TB were studied (Paper IV). One quarter of fatal mycobacterial disease was associated with non tuberculous mycobacteria (NTM). Pleural effusions were significantly associated with Mtb disease compared to NTM infection (Paper IV).
To explore the potential use of the CD4+ and CD8+ T cell immunoprofile to diagnose tuberculous effusion, CD4+ and CD8+ T cells from pleural effusions were characterized. CD4+ T cells were significantly more abundant in individuals with TB, and the CD4+/CD8+T cell ratios were significantly higher in tuberculous pleural effusion compared to non tuberculous effusion, however this significance was lost after adjusting for age and ethnicity. Analysis of pleural fluid for the quantity of CD4+ and CD8+ T cells may be useful for establishing a diagnosis of TB in suspicious cases (Paper V).
In conclusion, this thesis highlights the genetic diversity of Mtb with Mtb Uganda as the predominant genotype in EPTB patients in Uganda. Both NTM and Mtb are associated with fatal mycobacterial disease and the pathology findings are indistinguishable, though NTM are significantly less likely to cause pleural effusion. Mycobacterial genetic diversity together with host HLA variability may have clinical consequences. This can be exploited in designing TB diagnostic, management and prevention strategies.
To investigate the impact of Mtb genomic diversity and host HLA allelic variability on the clinical outcome of TB infection in Ugandan patients, the clinical and pathological outcome of Mtb Uganda genotype, and the association between HLA II alleles and PTB due to Mtb were studied. The Uganda genotype was found less frequently in extrapulmonary TB (EPTB) than previously reported in PTB in the same setting (Paper I), and tuberculous lymphadenitis patients infected with Mtb Uganda genotype were significantly less prone to have abdominal lymphadenopathy (Paper IV). This may imply that Mtb Uganda genotype has reduced potential to disseminate.
A study of the evolutionary relationships and worldwide distribution of the spoligotypes of Mtb isolates from Ugandan patients with tuberculous lymphadenitis indicated an ongoing evolution of the Uganda genotype, with Uganda at the center of this evolution (Paper II).
HIV negative patients with pulmonary TB and their genetically related healthy household controls were typed for HLA class II alleles (Paper III). The HLA- DQB1*03:03 allele was significantly less frequent in patients compared to healthy controls suggesting that the HLADQB1*03:03 allele may be associated with resistance to TB.
To establish the cause and pathology of fatal mycobacterial disease, the mycobacteria and pathology associated with fatal TB were studied (Paper IV). One quarter of fatal mycobacterial disease was associated with non tuberculous mycobacteria (NTM). Pleural effusions were significantly associated with Mtb disease compared to NTM infection (Paper IV).
To explore the potential use of the CD4+ and CD8+ T cell immunoprofile to diagnose tuberculous effusion, CD4+ and CD8+ T cells from pleural effusions were characterized. CD4+ T cells were significantly more abundant in individuals with TB, and the CD4+/CD8+T cell ratios were significantly higher in tuberculous pleural effusion compared to non tuberculous effusion, however this significance was lost after adjusting for age and ethnicity. Analysis of pleural fluid for the quantity of CD4+ and CD8+ T cells may be useful for establishing a diagnosis of TB in suspicious cases (Paper V).
In conclusion, this thesis highlights the genetic diversity of Mtb with Mtb Uganda as the predominant genotype in EPTB patients in Uganda. Both NTM and Mtb are associated with fatal mycobacterial disease and the pathology findings are indistinguishable, though NTM are significantly less likely to cause pleural effusion. Mycobacterial genetic diversity together with host HLA variability may have clinical consequences. This can be exploited in designing TB diagnostic, management and prevention strategies.
List of papers:
I. Wamala D, Asiimwe B, Kigozi E, Mboowa G, Joloba M, Källenius G. Clinico-pathological features of tuberculosis due to Mycobacterium tuberculosis Uganda genotype in patients with tuberculous lymphadenitis: a cross sectional study. BMC Clinical Pathololgy, 2014;14(1):14.
Fulltext (DOI)
Pubmed
II. Wamala D, Okee M, Kigozi E, Nalin R , Couvin D, Joloba M, Källenius G. Predominance of Mycobacterium tuberculosis Uganda genotype in Ugandan patients with tuberculous lymphadenitis. BMC Research Notes, 2015, 8:398
Fulltext (DOI)
Pubmed
III. Wamala D, Buteme H, Kirimundu S, Joloba M, Källenius G. Association between Human Leukocyte Antigen Class II and pulmonary tuberculosis due to Mycobacterium tuberculosis in Uganda. BMC Infectious Dis. 2016;16(1):016-1346. 23
Fulltext (DOI)
Pubmed
IV. Wamala D, Källenius G, Joloba M. Morbid anatomy of patients with mycobacterial infections, a cross sectional autopsy study at a tertiary hospital in a high disease burden setting. [Manuscript]
V. Wamala D, Joloba M, Hjerpe A. Potential use of CD4+ and CD8+ T cell immunoprofile from pleural fluid to diagnose tuberculous effusions. [Manuscript]
I. Wamala D, Asiimwe B, Kigozi E, Mboowa G, Joloba M, Källenius G. Clinico-pathological features of tuberculosis due to Mycobacterium tuberculosis Uganda genotype in patients with tuberculous lymphadenitis: a cross sectional study. BMC Clinical Pathololgy, 2014;14(1):14.
Fulltext (DOI)
Pubmed
II. Wamala D, Okee M, Kigozi E, Nalin R , Couvin D, Joloba M, Källenius G. Predominance of Mycobacterium tuberculosis Uganda genotype in Ugandan patients with tuberculous lymphadenitis. BMC Research Notes, 2015, 8:398
Fulltext (DOI)
Pubmed
III. Wamala D, Buteme H, Kirimundu S, Joloba M, Källenius G. Association between Human Leukocyte Antigen Class II and pulmonary tuberculosis due to Mycobacterium tuberculosis in Uganda. BMC Infectious Dis. 2016;16(1):016-1346. 23
Fulltext (DOI)
Pubmed
IV. Wamala D, Källenius G, Joloba M. Morbid anatomy of patients with mycobacterial infections, a cross sectional autopsy study at a tertiary hospital in a high disease burden setting. [Manuscript]
V. Wamala D, Joloba M, Hjerpe A. Potential use of CD4+ and CD8+ T cell immunoprofile from pleural fluid to diagnose tuberculous effusions. [Manuscript]
Institution:
- Karolinska Institutet
- Makerere University
Supervisor: Källenius, Gunilla
Issue date: 2016-02-15
Rights:
Publication year: 2016
ISBN: 978-91-7676-137-3
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