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Department of Clinical Pharmacy, Shanghai Tenth Peoples Hospital, Tongji University School of Medicine, Shanghai 200072, China;
2
Department of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
*Corresponding author. Tel: +86-2166302761; Fax: +86-2166307668; E-mail: xuhongbin119@yahoo.cn
These authors contributed equally to this work.
Received 2 March 2011; returned 7 April 2011; revised 27 April 2011; accepted 1 May 2011
Downloaded from http://jac.oxfordjournals.org/ by guest on April 20, 2014
Objectives: Multidrug-resistant tuberculosis (MDR-TB) has become an emerging global public health crisis.
Several studies have suggested that pulmonary resection has efficacy in the treatment of MDR-TB. A systematic
review of the available therapeutic studies was conducted to determine the treatment outcome among
patients with MDR-TB who underwent pulmonary resection.
Methods: To evaluate pulmonary resection for MDR-TB, a random-effect meta-analysis of the available studies
was used to assess the overall treatment outcome. Subgroup analyses were also conducted by separating
studies based on each characteristic independently.
Results: After screening 4996 articles, 15 clinical reports with a mean of 63 patients per report met the
inclusion criteria. Analysis of the studies showed that the estimated pooled treatment success rate of pulmonary resection for patients with MDR-TB was 84% [95% confidence interval (CI) 78% 89%]. The rates of failure,
relapse, death and default were 6% (95% CI 4%8%), 3% (95% CI 1%4%), 5% (95% CI 2% 8%) and 3%
(95% CI 1% 5%), respectively. The proportion of patients treated successfully did not differ significantly on
the basis of any of the individual study characteristics.
Conclusions: Substantial heterogeneity in the study characteristics prevented a more conclusive determination
of what factors had the greatest effect on the proportion of patients that achieve treatment success and
limited the validity of this analysis. Some important variables, including patient HIV status, were inconsistently
reported between studies. These results underscore the importance of strong patient support and treatment
follow-up systems to develop successful MDR-TB treatment programmes.
Keywords: pulmonary surgical procedures, MDR-TB, treatment outcome
Introduction
Tuberculosis (TB) is a major global health problem, with 9 million
new cases and almost 2 million deaths per year.1 Most patients
with TB can be successfully treated using short-course medical
chemotherapy, which consists of a four-drug regimen including
isoniazid, rifampicin, pyrazinamide and ethambutol.2 However,
a small proportion of patients with pulmonary TB require surgical
treatment.3 The indications for surgery usually include the management of complications of TB (including haemoptysis, bronchiectasis, bronchial stenosis, bronchopleural fistula and
aspergilloma) and the management of drug-resistant forms of
the disease.4 7 A wide variety of procedures have been reported,
including surgical resection and thoracoplasty.8 Patients usually
do well with surgery, with cure rates of 60% 100% being
achieved.9,10
# The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
1687
Systematic review
Methods
The meta-analysis was conducted in accordance with QUOROM
guidelines.32
Data sources
PubMed, Embase and the Cochrane Library for were searched for studies
through July 2010. There was no limit put on the earliest date of publication. The search terms included were as follows: tuberculosis; pulmonary resection; pneumonectomy; surgery; surgical treatment;
lung resection; drug-resistant; multidrug resistant; multi-drug resistant; MDR; and multiple drug-resistant. In addition, the online archives
of the International Journal of Tuberculosis and Lung Disease were
reviewed for applicable studies not found in the previous search. The
reference lists of identified original articles and reviews were searched
for other relevant articles. Abstracts, chapters of books, conference proceedings or correspondence were not included. The initial search had
no language restrictions, but studies not published in the English
language were excluded from the data extraction process. As very
small studies may be vulnerable to selection bias, only studies including
10 patients were selected for inclusion in the analysis.
Study selection
Two reviewers (H.-B. X. and R.-H. J.) selected articles in the following two
stages: titles and abstracts; and then full-text articles. Discrepancies
between the two reviewers were resolved by consensus or through discussion with a third reviewer (L. L.). Two reviewers (H. B. X. and R. H. J.)
performed data extraction for all the articles and a third reviewer (L. L.)
independently performed data extraction for one-third of the articles to
assess accuracy in the data extraction. Studies were required to meet
the following inclusion criteria: (i) confirmation that patients had
MDR-TB using drug-susceptibility testing of cultured M. tuberculosis; (ii)
treatment outcome definitions specified by mycobacterial culture endpoints; and (iii) outcomes reported according to WHO classifications of
success (cure or treatment completion), failure, relapse, death and
default (treatment interruption).30 Because this study was a systematic
review, ethics committee approval or written informed consent from
the participants was not required. The methodological quality of the
eligible studies was assessed mainly according to Cochrane-based
criteria.
1688
Data extraction
We recorded treatment outcomes according to WHO classifications of
treatment success (cure or treatment completion), failure, relapse,
death and default (treatment interruption).30 Patients still on treatment
who were classified as probable cure or probable failure were added to
the success and failure categories, respectively. Patients who remained
on treatment but were not assigned an interim outcome were not
included in this analysis. All patients who were classified as transfer
out were added to the default category.
For each study, data were gathered on patients characteristics, treatment protocols and study definitions. Patients characteristics included
previous TB treatment history, HIV prevalence, and the mean number
of drugs to which patients isolates were resistant. Data on treatment
protocols included the indication for surgery, pre-operative lung lesion
type and type of pulmonary resection. In addition, the length of
follow-up and definition of cure were recorded, if available. If no data
on the above-mentioned characteristics were reported in the primary
studies, the information was requested from the original authors.
Results
Study characteristics
As summarized in Figure 1, 15 studies (Table 1) were selected for
inclusion in the analysis,26 29,37 47 including 12 studies of pulmonary resection for patients with MDR-TB26 29,37 40,43 46 and
3 studies for patients with MDR-TB or XDR-TB.41,42,47 Because
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Systematic review
Treatment outcomes
Across all studies, the estimated pooled treatment success rate,
defined as the proportion of patients who were cured or completed treatment, was 84% [95% confidence interval (CI)
78% 89%]. The pooled treatment failure, relapse, death and
default rates were 6% (95% CI 4%8%), 3% (95% CI 1%
4%), 5% (95% CI 2%8%) and 3% (95% CI 1% 5%), respectively (Figure 2). However, the heterogeneity in the study characteristics led to significant variation in the reported treatment
outcome. Among the 12 reports of pulmonary resection for
patients with MDR-TB (mean 69 patients; range 23 172), the
mean proportion of patients achieving treatment success was
83% (95% CI 77% 89%; Figure 3 and Table 3). Among the
three studies involving patients with MDR-TB or XDR-TB (mean
42 patients; range 1972), the mean proportion achieving treatment success was higher than that for the studies with MDR-TB
patients, but the difference was not significant at 89% (95% CI
86% 92%; Figure 3 and Table 3).
We also analysed the effect of each of the other study characteristics independently (Table 3). The analysis showed that the
proportion of patients treated successfully did not differ significantly on the basis of any of the following individual study
characteristics: start year of the study; cure definition; national
income status; geographic region; or type of pulmonary resection
(Table 3). Differences in population characteristics, including
1689
Study location
Years
Sample
size
Proportion
previously
treated (%)
HIV
prevalence
Median resistance
[n drugs (range)]
Definition of cure
Pomerantz
et al. 26
Park et al. 27
USA
1983 2000
172
100
NR
NR
South
Korea
1995 1999
49
100
4.7
Chan et al. 28
USA
1984 1998
130
100
NR
Somocurcio
et al. 29
USA
1999 2004
121
95
1%
7 (3 11)
Leuven
et al. 37
South
Africa
1990 1995
61
100
Sung et al. 38
South
Korea
1994 1998
27
100
NR
4.4 (2 10)
Chiang
et al. 39
China
1990 1999
26
100
NR
3.9 (3 6)
Naidoo
et al. 40
South
Africa
1996 2000
23
100
17%
NR
1995 2004
35
100
NR
5 (3 6)
1998 2004
19
100
4.7 (2 8)
1993 2005
79
100
NR
Mohsen
Egypt
et al. 44
Wang et al. 45 China
1995 2005
23
100
1995 2006
56
100
Japan
2000 2007
56
South
Korea
1996 2008
72
Shiraishi
et al. 46
Kang et al. 47
culture negative
Follow-up
(months)
4 204
6 36
NR
19 103
24
3 45
15 80
18
NR
68
18 24
4 (3 6)
3.5 (2 4)
9 137
100
5.6 (2 10)
100
6 (5 8)
2 months of
consecutive
negative cultures
pneumonectomy 22, lobectomy 33, culture negative
segmentectomy 6
pneumonectomy 23, lobectomy 38, Laserson definition
segmentectomy 10, wedge
resection 1
14 27
8 105
18 24
Systematic review
1690
JAC
Systematic review
Study
location
Incomplete
outcome data
addressed
Prospective
USA
NR
yes
no
South Korea
USA
USA
NR
NR
NR
yes
no
yes
no
no
yes
South Africa
NR
yes
no
South Korea
China
consecutive
NR
yes
yes
no
no
South Africa
NR
yes
no
South Korea
South Korea
Turkey
Egypt
NR
NR
NR
consecutive
no
yes
no
yes
no
yes
no
no
China
Japan
consecutive
consecutive
yes
yes
no
no
South Korea
NR
yes
no
Publication bias
The result of the Egger test for publication bias was significant
(P 0.020). The funnel plots for publication bias (Figure 4) also
showed asymmetry. These results indicate a presence of
potential for publication bias.
Discussion
MDR-TB ultimately develops from the inadequate treatment of
active pulmonary TB. There are multiple reasons for inadequate
therapy; poor prescribing practices with insufficient treatment
duration and poor drug selection are well-recognized contributors.48,49 Systemic problems, through inadequate public health
resources and unpredictable drug supplies, also play a role.50
In addition, irregular medication intakewhether due to insufficient patient education, adverse events or socioeconomic determinantscontributes to resistance. Also, a significant proportion
of patients acquire the drug-resistant disease because they live
in an environment with a high prevalence of drug-resistant TB.
The medical treatment of MDR-TB is complex and costly, and
is associated with relatively low cure rates, high relapse,
increased toxicity, and high morbidity and mortality. Two previous systematic reviews evaluated the existing evidence regarding medical treatment regimens for MDR-TB. The authors used a
meta-analysis of the available therapeutic studies to assess
treatment outcomes. The results of the two reviews showed
that the pooled treatment success estimate, defined as the
Success (95% CI)
al.26
Pomerantz et
Park et al.27
Chan et al.28
Somocurcio et al.29
Leuven et al.37
Sung et al.38
Chiang et al.39
Naidoo et al.40
Kwon et al.41
Park et al.42
Kir et al.43
Mohsen et al.44
Wang et al.45
Shiraishi et al.46
Kang et al.47
92 (8796)
94 (8399)
76 (6883)
63 (5471)
77 (6587)
74 (5489)
88 (7098)
96 (78100)
89 (7397)
84 (6097)
89 (7995)
91 (7299)
88 (7695)
91 (8097)
90 (8196)
Summary
84 (7889)
I 2 = 79
20
60
80
40
Treatment success (%)
Failure (%)
Default (%)
2
4
7
11
10
19
8
4
9
5
1
0
9
0
6
2
2
0
1
10
7
4
0
0
5
1
4
4
9
0
6 (48)
3 (14)
5 (28)
I 2 = 77
I 2 = 73
(P = 0.004)
(P = 0.003)
(P < 0.001)
(P < 0.001)
I 2 = 56
I 2 = 57
3
0
8
18
3
0
0
0
3
0
3
4
0
0
1
3
0
6
0
5
0
0
0
7
0
0
0
0
9
0
3 (15)
Figure 2. Treatment success and other treatment outcomes for pulmonary resection of multidrug-resistant tuberculosis. Treatment effects and
summaries were calculated using a random-effects model weighted by study population. The 95% confidence intervals (95% CI) are shown.
1691
Pomerantz
et al. 26
Park et al. 27
Chan et al. 28
Somocurcio
et al. 29
Leuven
et al. 37
Sung et al. 38
Chiang
et al. 39
Naidoo
et al. 40
Kwon et al. 41
Park et al. 42
Kir et al. 43
Mohsen
et al. 44
Wang et al. 45
Shiraishi
et al. 46
Kang et al. 47
Sampling
method
Systematic review
(a)
Pomerantz et al.26
Park et al.27
Chan et al.28
Somocurcio et al.29
Leuven et al.37
Sung et al.38
Chiang et al.39
Naidoo et al.40
Kir et al.43
Mohsen et al.44
Wang et al.45
Shiraishi et al.46
92 (8796)
94 (8399)
76 (6883)
63 (5471)
77 (6587)
74 (5489)
88 (7098)
96 (78100)
89 (7995)
91 (7299)
88 (7695)
91 (8097)
83 (7789)
I 2 = 83
0
20
40
60
80
100
P < 0.001
89 (7397)
84 (6097)
90 (8196)
Summary
89 (8692)
I2=0
(P < 0.768)
20
40
60
80
100
1692
Summary
JAC
Systematic review
HIV prevalence
0%27,37,42 47
.0% and not reported26,28,29,38 41
8
7
0.250
,0.001
23
88
Average resistanceb
4.928,29,41,46,47
,4.927,37 39,42,44,45
not reported26,40,43
5
7
3
,0.001
0.126
0.453
87
40
0
9
6
,0.001
,0.001
83
77
5
10
,0.001
0.0012
89
67
9
6
,0.001
0.213
86
30
Geographic region
Asia27,37,39,41,42,45 47
Africa38,40,44
Europe and America26,28,29,43
8
3
4
0.440
0.046
,0.001
0
6
93
4
11
10
5
0.017
,0.001
,0.001
0.025
71
82
84
64
Type of studiesd
studies including MDR patients26 29,37 40,43 46
studies including MDR +XDR patients41,42,47
12
3
,0.001
0.768
83
0.0
Definition of cure
5 months of negative cultures required29,40,41,43,47
,5 months of negative cultures required26 28,37 39,42,44 46
I 2 (%)
heterogeneity in TB epidemics and associated treatment strategies. Thus, the lack of significant findings associated with
certain variables in this analysis may be due to reporting insufficiency, rather than the absence of a real association. Furthermore, these variations in the recording of data necessary for
assessing treatment outcomes underscore the need for standardized data collection and reporting in programmes and
studies of MDR-TB, possibly through the use of an international
registry of treatment outcomes.56 The absence of a registry of
individual treatment outcomes or outcome studies precluded
the possibility of estimating publication bias in this
meta-analysis. Standards in outcome reporting are particularly
important in light of the emergence of XDR-TB.
Our systematic review and meta-analysis had several
strengths. The comprehensive search strategy enabled us to
1693
Reports (n)a
Systematic review
Acknowledgements
Log OR
Funding
This work was supported by the Scientific Research Foundation of Shanghai Pharmaceutical Society (Grant No. 2009-YY-01-13).
2
0
0.5
SE of log OR
1694
None to declare.
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