Is there a relationship between Mycobacterium tuberculosis strain type and TB paradoxical reaction
http://www.100md.com
《胸》
1 Department of Thoracic Medicine, Royal Free Hospital, London NW3 2QG, UK
2 Centre for Medical Microbiology, Royal Free & University College Medical School, London NW3 2PF, UK
Correspondence to:
Dr F M R Perrin
Department of Thoracic Medicine, Royal Free Hospital, London NW3 2QG, UK; f.perrin@medsch.ucl.ac.uk
Keywords: tuberculosis; paradoxical reaction; strain type; IS6110 RFLP typing
Paradoxical reaction (PR) in tuberculosis (TB) is defined as transient worsening of symptoms and signs or the appearance of new lesions after beginning appropriate anti-tuberculosis chemotherapy. Recent studies suggest that PR occurs in 10–35% of patients. It is more common and more severe in HIV co-infected individuals with disseminated disease.1 PR is thought to be an immune mediated phenomenon but the reasons for its occurrence are unknown.1
Infection by Mycobacterium tuberculosis (MTB) results in highly variable outcomes between individuals. The characterisation of MTB strains by molecular typing techniques suggests this may be a reflection of the infecting organism, as well as host response and environmental factors. MTB strains with distinct genotypes have been shown to evoke different immunopathological events in mouse models2 and variable clinical manifestations in human population based studies.3 Furthermore, individual strain types have been linked to particular clinical outcomes; for example, a significant association was seen between the Beijing MTB lineage and transient fever unrelated to disease severity, toxicity, or drug resistance in early treatment.4
We sought to investigate the hypothesis that the risk of PR may be strain dependent as defined by IS6110 restriction fragment length polymorphism (RFLP) typing.
Between January 2002 and December 2003 all adult patients seen at our centre with culture positive MTB had IS6110 RFLP typing performed on one isolate. A case note review was performed retrospectively for clinical evidence of PR.1 IS6110 RFLP typing was undertaken using a modification of the standard international protocol.5 All patterns were entered onto a database using Bionumerics Edition 3.0 package (Applied Maths, Kourtrai, Belgium). Comparison of DNA fingerprints and cluster analysis of profiles was performed by calculation of the Dice coefficient; optimisation was set at 1% and position tolerance at 1.2%. A cluster was defined as a series of isolates with 100% identity. A putative lineage was identified as a series of isolates with 70% or greater similarity.6
145 patients had isolates that were typed. 100 (69%) sets of notes were reviewed. 45 were excluded (24 were unavailable or incomplete; 21 patients were lost to follow up or care was transferred). Of the 100 patients’ notes reviewed, 52 were male, age range 16–81 years. 48% were black African, 16% Asian, and 19% from the UK. Table 1 shows the TB site and HIV status of the patients. PR occurred in 20 patients (20%) (HIV positive 10/26 (38%); HIV negative or unknown 10/74 (14%)). All patients with PR had distinct IS6110 RFLP profiles suggesting 20 separate strains.
Table 1 Site of TB and HIV status of patients with and without clinically evident paradoxical reactions (PR)
There was only one identified lineage with a similarity of 70% within the whole patient cohort. This was not associated with increased risk of PR. The group comprised 10 patients who were all black African, only one of whom had a PR. The similarity is likely to represent an original strain of African descent (data not shown).
IS6110 typing is the recognised gold standard for MTB strain typing and has widespread application in epidemiological and outbreak investigations of TB.5 Using this method we found one lineage, but no association between strain type and PR. The power of our study is limited by its small sample size and retrospective nature. However, the rate of PR (20% and three times higher in HIV positive subjects: 38% v 14%) is in line with previous work.1 IS6110 typing is not a definitive phylogenetic marker and other molecular techniques such as single nucleotide polymorphism may demonstrate an association.
The possibility exists that paradoxical TB reactions may be a consequence of specific host response genes. Particular MHC haplotypes have been linked to "immune reconstitution disease" in HIV positive patients starting antiretroviral therapy.7 A larger study is needed to focus on both strain type and consequent host immune response.
References
Breen RA, Smith CJ, Bettison H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004;59:704–7.
Dormans J, Burger M, Aguilar D, et al. Correlation of virulence, lung pathology, bacterial load and delayed type hypersensitivity responses after infection with different Mycobacterium tuberculosis genotypes in a BALB/c mouse model. Clin Exp Immunol 2004;137:460–8.
Dale JW, Bothamley GH, Drobniewski F, et al. Origins and properties of Mycobacterium tuberculosis isolates in London. J Med Microbiol 2005;54:575–82.
Van Crevel R, Nelwan RHH, de Lenne W, et al. Mycobacterium tuberculosis Beijing genotype strains associated with febrile response to treatment. Emerg Infect Dis 2001;7:880–3.
Maguire H, Dale JW, McHugh TD, et al. Molecular epidemiology of tuberculosis in London 1995–7 showing low rate of active transmission. Thorax 2002;57:617–22.
McHugh TD, Batt SL, Shorten RJ, et al. Mycobacterium tuberculosis lineage: a naming of the parts. Tuberculosis (Edinb) 2005;85:27–136.
Price P, Keane NM, Stone SF, et al. MHC haplotypes affect the expression of opportunistic infections in HIV patients. Hum Immunol 2001;62:157–64.(F M R Perrin1, R A M Bree)
2 Centre for Medical Microbiology, Royal Free & University College Medical School, London NW3 2PF, UK
Correspondence to:
Dr F M R Perrin
Department of Thoracic Medicine, Royal Free Hospital, London NW3 2QG, UK; f.perrin@medsch.ucl.ac.uk
Keywords: tuberculosis; paradoxical reaction; strain type; IS6110 RFLP typing
Paradoxical reaction (PR) in tuberculosis (TB) is defined as transient worsening of symptoms and signs or the appearance of new lesions after beginning appropriate anti-tuberculosis chemotherapy. Recent studies suggest that PR occurs in 10–35% of patients. It is more common and more severe in HIV co-infected individuals with disseminated disease.1 PR is thought to be an immune mediated phenomenon but the reasons for its occurrence are unknown.1
Infection by Mycobacterium tuberculosis (MTB) results in highly variable outcomes between individuals. The characterisation of MTB strains by molecular typing techniques suggests this may be a reflection of the infecting organism, as well as host response and environmental factors. MTB strains with distinct genotypes have been shown to evoke different immunopathological events in mouse models2 and variable clinical manifestations in human population based studies.3 Furthermore, individual strain types have been linked to particular clinical outcomes; for example, a significant association was seen between the Beijing MTB lineage and transient fever unrelated to disease severity, toxicity, or drug resistance in early treatment.4
We sought to investigate the hypothesis that the risk of PR may be strain dependent as defined by IS6110 restriction fragment length polymorphism (RFLP) typing.
Between January 2002 and December 2003 all adult patients seen at our centre with culture positive MTB had IS6110 RFLP typing performed on one isolate. A case note review was performed retrospectively for clinical evidence of PR.1 IS6110 RFLP typing was undertaken using a modification of the standard international protocol.5 All patterns were entered onto a database using Bionumerics Edition 3.0 package (Applied Maths, Kourtrai, Belgium). Comparison of DNA fingerprints and cluster analysis of profiles was performed by calculation of the Dice coefficient; optimisation was set at 1% and position tolerance at 1.2%. A cluster was defined as a series of isolates with 100% identity. A putative lineage was identified as a series of isolates with 70% or greater similarity.6
145 patients had isolates that were typed. 100 (69%) sets of notes were reviewed. 45 were excluded (24 were unavailable or incomplete; 21 patients were lost to follow up or care was transferred). Of the 100 patients’ notes reviewed, 52 were male, age range 16–81 years. 48% were black African, 16% Asian, and 19% from the UK. Table 1 shows the TB site and HIV status of the patients. PR occurred in 20 patients (20%) (HIV positive 10/26 (38%); HIV negative or unknown 10/74 (14%)). All patients with PR had distinct IS6110 RFLP profiles suggesting 20 separate strains.
Table 1 Site of TB and HIV status of patients with and without clinically evident paradoxical reactions (PR)
There was only one identified lineage with a similarity of 70% within the whole patient cohort. This was not associated with increased risk of PR. The group comprised 10 patients who were all black African, only one of whom had a PR. The similarity is likely to represent an original strain of African descent (data not shown).
IS6110 typing is the recognised gold standard for MTB strain typing and has widespread application in epidemiological and outbreak investigations of TB.5 Using this method we found one lineage, but no association between strain type and PR. The power of our study is limited by its small sample size and retrospective nature. However, the rate of PR (20% and three times higher in HIV positive subjects: 38% v 14%) is in line with previous work.1 IS6110 typing is not a definitive phylogenetic marker and other molecular techniques such as single nucleotide polymorphism may demonstrate an association.
The possibility exists that paradoxical TB reactions may be a consequence of specific host response genes. Particular MHC haplotypes have been linked to "immune reconstitution disease" in HIV positive patients starting antiretroviral therapy.7 A larger study is needed to focus on both strain type and consequent host immune response.
References
Breen RA, Smith CJ, Bettison H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004;59:704–7.
Dormans J, Burger M, Aguilar D, et al. Correlation of virulence, lung pathology, bacterial load and delayed type hypersensitivity responses after infection with different Mycobacterium tuberculosis genotypes in a BALB/c mouse model. Clin Exp Immunol 2004;137:460–8.
Dale JW, Bothamley GH, Drobniewski F, et al. Origins and properties of Mycobacterium tuberculosis isolates in London. J Med Microbiol 2005;54:575–82.
Van Crevel R, Nelwan RHH, de Lenne W, et al. Mycobacterium tuberculosis Beijing genotype strains associated with febrile response to treatment. Emerg Infect Dis 2001;7:880–3.
Maguire H, Dale JW, McHugh TD, et al. Molecular epidemiology of tuberculosis in London 1995–7 showing low rate of active transmission. Thorax 2002;57:617–22.
McHugh TD, Batt SL, Shorten RJ, et al. Mycobacterium tuberculosis lineage: a naming of the parts. Tuberculosis (Edinb) 2005;85:27–136.
Price P, Keane NM, Stone SF, et al. MHC haplotypes affect the expression of opportunistic infections in HIV patients. Hum Immunol 2001;62:157–64.(F M R Perrin1, R A M Bree)