Prevalence of active tuberculosis infection in transplant recipients: A systematic review and meta-analysis

Journal Pre-proof Prevalence of active tuberculosis infection in transplant recipients: A systematic review and meta-analysis Setareh Mamishi, Babak Pourakbari, Mina Moradzadeh, Willem B. van Leeuwen, Shima Mahmoudi PII:

S0882-4010(19)30888-5

DOI:

https://doi.org/10.1016/j.micpath.2019.103894

Reference:

YMPAT 103894

To appear in:

Microbial Pathogenesis

Received Date: 20 May 2019 Revised Date:

24 November 2019

Accepted Date: 25 November 2019

Please cite this article as: Mamishi S, Pourakbari B, Moradzadeh M, van Leeuwen WB, Mahmoudi S, Prevalence of active tuberculosis infection in transplant recipients: A systematic review and metaanalysis, Microbial Pathogenesis (2020), doi: https://doi.org/10.1016/j.micpath.2019.103894. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

Prevalence of active tuberculosis infection in transplant recipients: a systematic review

1

and meta-analysis

2

Setareh Mamishi1,2, Babak Pourakbari1, Mina Moradzadeh1, Willem B. van Leeuwen3, Shima

3

Mahmoudi1*

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1-Pediatric Infectious Disease Research Center, Tehran University of Medical Science,

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Tehran, Iran

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2-Department of Infectious Diseases, Pediatrics Center of Excellence, Children's Medical

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Center, Tehran University of Medical Sciences, Tehran, Iran

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3- Department of Innovative Molecular Diagnostics, University of Applied Sciences Leiden,

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Leiden, the Netherlands

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*Corresponding author:

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Pediatric Infectious Disease Research Center, Tehran University of Medical Sciences,

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Children’s Medical Center Hospital, Dr. Gharib Street, Keshavarz Boulevard, Tehran, Iran

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Tel: +98- 021- 6642- 8996

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Fax: +98- 021- 6642- 8996

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E-mail: [email protected]

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17 18 19 20 21 22 1

Abstract

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Introduction: Tuberculosis (TB) is considered as a serious complication of organ transplant;

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therefore, the detection and appropriate treatment of active TB infection is highly

25

recommended for the reduction of mortality in the future. The aim of this review was to

26

conduct a systematic review and meta-analysis assessing the prevalence of active TB

27

infection in transplant recipients (TRs).

28

Material and methods: Electronic databases, including MEDLINE (via PubMed), SCOPUS

29

and Web of Science were searched up to 24 December 2017. The prevalence of active TB

30

was estimated using the random effects meta-analysis. Heterogeneity was evaluated by

31

subgroup analysis. Data were analyzed by STATA version 14.

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Results: The pooled prevalence of post-transplant active TB was estimated 3% [95% CI: 2-

33

3]. The pooled prevalence of active TB in different transplant forms was as follows: renal,3%

34

[95% CI: 2-4]; stem cell transplant (SCT), 1% [95% CI: 0-3]; lung, 4% [95% CI: 2-6]; heart,

35

3% [95% CI: 2-4]; liver, 1% [95% CI: 1], and hematopoietic stem cell transplant (HSCT),

36

2% [95% CI: 1-3]. The prevalence of different clinical presentations of TB was as follows:

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pulmonary TB (59%; 95% CI: 54-65), extra pulmonary TB (27%; 95% CI: 21-33),

38

disseminated TB (15%; 95% CI: 12-19) and miliary TB (8%; 95% CI: 4-13). The pooled

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prevalence of different diagnostic tests was as follows: chest X-ray, 57% [95% CI, 46-67];

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culture, 56% [95% CI, 45-68]; smear, 49% [95% CI, 40-58]; PCR, 43% [95% CI, 40-58];

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histology,26% [95% CI, 20-32], and tuberculin skin test, 19% [95% CI, 10-28].

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Conclusion: A high suspicion level for TB, the early diagnosis and the prompt initiation of

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therapy could increase the survival rates among SOT patients. Overall, renal and lung TRs

44

appear to have a higher predisposition for acquiring TB than other type of recipients.

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Monitoring of the high-risk recipients, prompt diagnosis, and appropriate treatment are

46

required to manage TB infection among TRs especially in endemic areas.

47

2

Key words: Active tuberculosis infection, transplant recipients, different forms of

48

tuberculosis

49

50

51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71

Introduction

72 73 3

Tuberculosis (TB) is one of the predominant infectious causes of morbidity and mortality

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through the world. According to the World Health Organization (WHO) report, 10.0 million

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people (range, 9.0–11.1 million) developed TB in 2017, and 1.7 million died from this

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disease [1]. TB is one of the major post-transplant infections among transplant recipients

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(TRs). TRs are at increased risk of active TB. The incidence of TB in TRs is 20-50 times

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higher than in the general population, ranging from 0.5% to 1% in North America to 15% in

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developing countries such as India [2].

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TB in transplanted tissue occurs mainly due to reactivation of a former dormant infection and

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it depends on TB burden, the type of organ transplanted, level of immunosuppression and

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concomitant opportunistic infections[3,4].

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Despite the great advances in the field of solid organ transplantation (SOT) over the last few

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decades, diagnosis of active TB after transplantation may be difficult and delayed since

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symptoms and manifestations of disease are often reduced and unusual. The other major

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challenges of TB management are the metabolic interactions between the immunosuppressive

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drugs and the drugs used to treat TB [4,5].

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Sputum microscopy, nucleic acid testing, radiography assay and cultures are the diagnostic

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tests of choice for detection of active TB infection; however, false-positive sputum culture

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results might occur mainly due to laboratory cross-contamination, clerical errors, and

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contamination of clinical equipment [6].

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Since TRs are at risk for reactivating infections transmitted by the donor tissue, screening of

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the TRs and early diagnosis are highly recommended.

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The objective of this review is to conduct a systematic review and meta-analysis of studies

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recognizing the prevalence of active TB in TRs.

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Material and methods

97 4

This systematic review was done according to the guidelines of the preferred reporting items

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for systematic reviews and meta-analyses (PRISMA) statement [7] and the quality

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assessment of the included articles was assessed using the Joanna Briggs Institute (JBI)

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checklist [7,8]. This action was done by two independent reviewers (SM and MM) and any

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dispute was resolved through discussion.

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We searched English -language literature for all case series of active TB in in solid TRs.

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Electronic databases, including MEDLINE (via PubMed), SCOPUS and Web of Science

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were searched systematically. Combinations of the following search terms were applied:

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"Mycobacterium tuberculosis or tuberculosis or TB” AND “transplant OR human organ

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transplant OR organ acquisition OR organ graft OR organ procurement OR transplantation

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and organ OR visceral transplantation”. The databases were searched up to 24 December

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2017 and there was no time limitation. The reference lists of selected articles were also

109

screened manually if deemed relevant. Abstracts of articles published in congresses were not

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explored. These analyses were in accordance with the guidelines proposed by PRISMA [9].

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The following inclusion and exclusion criteria were used for selection of articles for the

112

analyses.

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Inclusion criteria

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We included studies that reported cases of active TB infection following transplantation and

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only patients with post-transplant TB were included. We excluded case reports, case series or

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review articles. Studies were excluded from the systematic review if patients were diagnosed

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with TB prior to transplantation.

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Studies in which the initial TRs population was not reported were also excluded [10].

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Additionally, studies reporting TB caused by nontuberculous mycobacteria (NTM) were also

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excluded.

121 5

Ethics approval was not required for this meta-analysis.

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Case definition

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Active TB was defined by one or more of the following diagnostic methods: (1) detection and

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identification of M. tuberculosis in culture from any clinical specimen and/or demonstration

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of acid-fast bacilli in bronchoalveolar lavage (BAL), sputum, endotracheal aspirates and

126

pleural fluid; (2) caseating granuloma documented in histologic examination of tissue

127

specimens; (3) detection of M. tuberculosis DNA using polymerase chain reaction (PCR) ;(4)

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survey thorax X-ray in combination with clinical symptoms[1,8].

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Pulmonary TB (PTB)

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PTB was defined when the acid-alcohol-fast bacilli (AFB) was present in sputum, pleural

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fluid or tissue; detection of M. tuberculosis in the culture or presence of caseating granuloma

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in lung tissue or clinically diagnosed case of TB involving the lung parenchyma or the

133

tracheobronchial tract [1,11].

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Extra pulmonary TB (EPTB) Refer to any bacteriologically confirmed or clinically diagnosed case of TB involving organs

135 136 137

other than the lungs, e.g. pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and

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bones and meninges [1].

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Tuberculous intra-thoracic lymphadenopathy (mediastinal and/or hilar) or tuberculous pleural

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effusion, without radiographic abnormalities in the lungs, constitutes a case of EPTB. A

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patient with both PTB and EPTB should be classified as a case of PTB [1].

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Disseminated TB

143

6

Disseminated TB was defined when M. tuberculosis have spread from the primary focus

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(lungs) to other parts of the body through the blood or lymph system, when cultures of

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specimens from two or more noncontiguous organ sites were positive for M. tuberculosis and

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when smears from one more organ sites were positive for acid fast bacilli [1,12] .

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Miliary TB

148

Miliary TB is characterized by the wide dissemination of M. tuberculosis into the human

149

body and by the small size of the lesions [1].

150

Data extraction

151

Two reviewers (SM, MM) extracted data and analyzed all selected articles independently.

152

The extracted data was then crosschecked. In cases of deviations, final documentation of

153

information was based on consensus. The following data were collected: author, period of the

154

study, country in which the study was conducted, sex distribution, age of study population,

155

total transplantation population, type of transplantation, number of post TB cases, type of TB,

156

method of active TB detection, history of TB contact, mortality rate, number of positive/total

157

individuals with each test (culture, AFB smear, histology, chest x-ray and PCR assay,

158

although tuberculin skin test (TST) was not considered as a test to rule out active TB, the

159

result of TST were also assessed. Data was reviewed and differences resolved by a third

160

reviewer.

161

Meta-analysis

162

A random-effects meta-analysis model using the ‘metaprop’ routine in Stata V.14 was

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performed in order to account for the expected between study variability for each study,

164

along with a pooled estimate. Results of the meta-analysis were revealed as a forest plot

165

diagram which represents the estimated prevalence and their relevant 95% confidence

166

7

interval (CI). The subgroup meta-analysis was used to compare the prevalence of active TB

167

on the basis of geographic distribution of studies, the overall prevalence of culture positive in

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active TB patients, method of detection (AFB smear/ biopsy/ chest x-ray / PCR and other

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methods), type of the transplant, quality score of the studies (the study score <5 (low quality)

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vs. the study score ≥ 5 (high quality)). The Cochran’s heterogeneity statistic (Q -test) and I2

171

statistic was assessed to examine the heterogeneity among studies. The I2 values were

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considered into three categories: low (25%), moderate (50%) and high (75%), respectively.

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The Q and I2 statistics values were calculated for each subgroup to determine the effective

174

factors on the prevalence of active TB and heterogeneity of the studies. Publication bias was

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assessed by Egger’s regression test [13].

176

Results

177

Study selection and characteristics

178

In our initial search strategy we identified 13,558 papers for screening. After excluding 9,216

179

duplicates, 585 articles were selected for full-text review and 60 studies met the inclusion

180

criteria and were included in the systematic review and meta-analysis. The summary of the

181

screening and selection strategy is shown in Figure 1.

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Patient characteristics and prevalence of active TB infection

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Table 1A, B and C (supplementary materials) summarizes the main characteristics of the 60

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selected studies included in this review. The studies included in the analysis were conducted

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in 22 different countries: Brazil [2,5,14,15,16,17,18,19] and Spain were the most frequently

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represented countries [20,21,22,23,24,25,26,27]. Seven studies included populations in

187

Taiwan [28,29,30,31,32,33,34]. Five studies were conducted in India [35,36,37,38,39] and

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[40,41], Turkey [42,43,44]. Four studies were done in China [29,45,46,47]. Three studies

189

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conducted in Tunisia [12,48,49] and South Africa [11,50,51]. Two studies were performed in

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Iran [52,53], Japan[8,54] and United States [55,56]. The remaining studies were from

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Thailand [57], Australia [58], Belgium [59], Egypt [60] , Finland [61], France [62], Germany

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[63], Hong Kong [64], and Pakistan [65].

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Based on the data of the included studies, median age range of the patients was from 60

194

studied was 24.2±7.4 to 57 ± 8.2 years and most of them were male (n=1025/1524, 67/25%).

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Positive past history of TB was detected in 103/2969 (3/5%) patients and the mortality rate

196

was 20% [95% CI, 16-24]. The pooled prevalence of different diagnostic tests used was as

197

follows: chest x-ray, 57% [95% CI, 46-67]; culture, 56% [95% CI, 45-204 68]; AFB smear,

198

49% [95% CI, 40-58]; PCR, 43% [95% CI, 40-58]; histology, 26% [95% CI, 20-32] and

199

TST, 19% [95% CI, 10-28].

200

Post-transplant TB

201

According to the results of the meta-analysis, the pooled prevalence of post-transplant active

202

TB was estimated at 2% [95% CI: 2%] (Figure2).

203

Prevalence of active TB based on transplant types

204

The pooled prevalence of active TB in different transplant types was as follows: renal,3%

205

[95% CI: 2-4]; stem cell transplant (SCT), 1% [95% CI: 0-3]; lung (4%; 95% CI: 2-6); heart,

206

3% [95% CI: 2-4]; liver, 1% [95% CI: 1] and hematopoietic stem cell transplant (HSCT), 2%

207

[95% CI: 1-3].

208

Prevalence of active TB based on TB types

209

9

Prevalence of active TB based on TB clinical presentations was as follows: miliary TB, 8%

210

[95% CI: 4-13]; disseminated TB, 15% [95% CI: 12-19]; EPTB, 27% [95% CI: 21-33]) and

211

PTB, 59% [95% CI: 54-65].

212

The prevalence of different types of transplant in patients with PTB were: renal , 57% [95%

213

CI: 50-63]; SCT,80% [95% CI: 66-94]; liver,64% [95% CI: 46-81] and HSCT,85% [ 95%

214

CI: 75-95].

215

The prevalence of different forms of transplant in patients with EPTB were: heart, 50% [95%

216

CI: 17-84]; renal, 30% [95% CI: 22-38]; SCT,20% [95% CI: 4-36]; liver, 18% [95% CI: 3-

217

32] and HSCT, 15% [95% CI: 5-25].

218

The prevalence of different forms of transplant in patients with disseminated TB were: renal,

219

19% [95% CI: 9-17] and liver, 16%

220

[95% CI: 2-29]. Patients with miliary TB only

underwent renal transplant (80%; 95% CI: 13).

221

Subgroup analysis

222

The subgroup results analysis are presented in Table 2. The results revealed a strong

223

heterogeneity (I2 = 94.67%; P <0.001) among the selected studies (Figure 2).

224

PTB

225

The type of transplantation influences the occurrence of PTB, which is more prevalent in

226

liver TRs (64%; 95% CI: 46-81).

227

EPTB

228

In patients with EPTB, renal transplantation was more common other than other types of

229

transplant (30%; 95% CI: 22-38), but in patients with disseminated TB, there was no

230

10

significant difference between the types of transplantation (P ˃ 0.05)

231

and only in patients who had undergone, renal transplantation, miliary TB was observed.

232

There was no significant difference between the sex of the patients and the type of

233

transplantation (P ˃ 0.05).

234

According to the results of the meta-analysis, the pooled rate of mortality among post-

235

transplant active TB was estimated at 20% [95% CI: 16-24%].

236

Based on the results of funnel plot and Egger’s regression test (Figure 3-A and B), the

237

publication bias among included studies could not be ignored (P < 0.0001).

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Discussion

239

To our knowledge, this systematic review and meta-analysis is the first to examine the pooled

240

prevalence of active TB after transplantation.

241

Studies from different geographic areas were recognized, including countries with high,

242

medium, and low TB prevalence rates. No difference was seen between mean/median age of

243

TRs in Asian, the USA, Africa and European countries.

244

Countries with high TB prevalence rates were found to have higher rates of infection. This

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correlation was expected, as transplant patients use immunosuppressor drugs and therefor are

246

at higher risk of acquiring infections such as TB.

247

In our investigation the pooled prevalence of post-transplant active TB was estimated at 3%

248

[95% CI: 2-3] but the highest rate was observed among patient who submitted to lung, 4%

249

[95% CI= 2-6] and renal transplant, 3% [95% CI= 2-3]. Our result are similar to the

250

systematic review studies conducted by Reis-Santos et al [66] and K. Al-Efraij et al.,[67] in

251

11

which the prevalence rates of active TB in renal TRs was 2.51% [95% CI = 2.17-2.85] and

252

3.62 [95% CI = 1.79–7.33], respectively.

253

According to published articles, the incidence rates of TB after heart transplant ranges from

254

0% to 3.3 %. A nearest result was reported by Chou N.-K. et al., ,[30] and Chen CH . et al.,

255

from Taiwan [31] and Munoz which showed 2.8%, 2.8% and 2.08% rates, respectively [24]..

256

Incidence of TB in lung transplantation in the reported series ranges from 6.5% to 10%

257

[68,69]. In our investigation only two studies had been done in Spain on lung TRs that report

258

6.41% and 2.58 % prevalence rates, respectively. Based on the random effects models, the

259

pooled prevalence was 3% [95% CI: 2-5] which indicates a very low prevalence of TB in

260

lung TRs.

261

Several reasons have described as risk factors for the development of different forms of TB

262

in TRs such as immunosuppressive treatment, diabetes mellitus, chronic liver disease (in

263

kidney transplant recipients) and coexisting infections (e.g., cytomegalovirus infection, deep

264

mycosis, and Nocardia infection)[20].

265

About the type of transplantation, post-transplant of active TB was more common in renal

266

recipients (3%,95% CI= 2-4) than in liver TRs (1%, 95% CI= 1-1), it might be due to the fact

267

that who receive kidney grafts are increasing the risk for the development of mycobacterial

268

disease,

the

269

immunosuppressant used in the post transplantation) period, all of which interfere with T-cell

270

function that can be increasing risk of occurrence of active TB in this group [53].

271

According to our study among different forms of TB, PTB was more common while miliary

272

TB had the lowest prevalence (59%; 95% CI: 54-65 versus 8%; 95% CI: 4-13). These results

273

are not unexpected.

274

because

of

widespread

immune

12

system

dysfunction,

uremia

and

The diagnosis of TB in TRs may be delayed, because EPTB is not uncommon and co-

275

infection with other pathogens such as cytomegalovirus and Nocardia spp. make it difficult

276

[70].

277

The higher prevalence rates of active TB were found when it was used chest x-ray (57%,

278

95% CI, 46-67) and culture (56%, 95% CI, 45-68) for the diagnosis. This result could be

279

expected because culture is the gold standard method. As such, is advisable to perform

280

routinely mycobacterial cultures after transplantation that together with chest x-ray as a

281

supplementary test can be of help in early diagnosis of TB in TRs. Although TST testing has

282

a low efficacy it can be the first step in the evaluation of M. tuberculosis infection in TRs. TB

283

often develops within the first year after surgery in SOT recipients. The mean interval

284

between transplantation and TB is 32 months; however, in renal TRs, the average time is

285

higher than in liver TRs (19.15 month). A possible explanation is that renal TRs are less

286

immunosuppressed than other TRs [37,70].

287

According to other study done the mortality rate among patients with SOT and TB may reach

288

about 30 % [68] and in our study pooled rate of mortality was 20% [95% CI: 16-24%].

289

In a study involving 66 kidney TRs with tuberculosis, John et al. [36] also showed that

290

diabetes and chronic liver disease increased the mortality.

291

In conclusion, a high suspicion level for TB, the early diagnosis and the prompt initiation of

292

therapy could increase the survival rates among SOT patients. In this preliminary study, renal

293

recipients were found to have a higher risk of TB infection than other type of TRs.

294

The use of most adequate immunosuppressive agents to reduce acute rejection, monitoring of

295

high-risk recipients, prompt diagnosis, and appropriate treatment are required to manage TB

296

infection among SOT patients especially in endemic areas.

297 298

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299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314

References

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15

330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379

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46. Liu J, Yan J, Wan Q, Ye Q, Huang Y (2014) The risk factors for tuberculosis in liver or kidney transplant recipients. BMC infectious diseases 14: 387. 47. Zhang X, Lv Y, Xue W, Wang B, Liu C, et al. Mycobacterium tuberculosis infection in solid organ transplant recipients: experience from a single center in China; 2008. Elsevier. pp. 1382‐ 1385. 48. Dridi A, Kaaroud H, Boubaker K, Abdallah T, Ei‐Younsi F, et al. Tuberculosis in renal transplant recipients; 2003. Elsevier. pp. 2682‐2683. 49. Kaaroud H, Beji S, Boubaker K, Abderrahim E, Hamida FB, et al. Tuberculosis after renal transplantation; 2007. Elsevier. pp. 1012‐1013. 50. Hall CM, Willcox PA, Swanepoel CR, Kahn D, Smit RVZ (1994) Mycobacterial Infection in Renal Transplant Recipients: A Delphi Survey. Chest 106: 435‐439. 51. Costa J, Meyers AM, Botha JR, Conlan AA, Myburgh A (1988) Mycobacterial infections in recipients of kidney allografts. A seventeen‐year experience. Acta medica portuguesa 1: 51‐ 57. 52. Basiri A, Moghaddam SH, Simforoosh N, Einollahi B, Hosseini M, et al. Preliminary report of a nationwide case‐control study for identifying risk factors of tuberculosis following renal transplantation; 2005. Elsevier. pp. 3041‐3044. 53. Ghafari A, Makhdoomi K, Ahmadpoor P, Afshari A, Fallah M, et al. Tuberculosis in Iranian kidney transplant recipients: a single‐center experience; 2007. Elsevier. pp. 1008‐1011. 54. Maeda T, Kusumi E, Kami M, Kawabata M, Le Pavoux A, et al. (2005) Disseminated tuberculosis following reduced‐intensity cord blood transplantation for adult patients with hematological diseases. Bone marrow transplantation 35: 91. 55. Klote MM, Agodoa LY, Abbott K (2004) Mycobacterium tuberculosis infection incidence in hospitalized renal transplant patients in the United States, 1998–2000. American Journal of Transplantation 4: 1523‐1528. 56. Lopez de Castilla D, Schluger N (2010) Tuberculosis following solid organ transplantation. Transplant Infectious Disease 12: 106‐112. 57. Ruangkanchanasetr P, Natejumnong C, Kitpanich S, Chaiprasert A, Luesutthiviboon L, et al. Prevalence and manifestations of tuberculosis in renal transplant recipients: a single‐center experience in Thailand; 2008. Elsevier. pp. 2380‐2381. 58. Lattes R, Radisic M, Rial M, Argento J, Casadei D (1999) Tuberculosis in renal transplant recipients. Transplant Infectious Disease 1: 98‐104. 59. Vandermarliere A, Audenhove AV, Peetermans WE, Vanrenterghem Y, Maes B (2003) Mycobacterial infection after renal transplantation in a Western population. Transplant Infectious Disease 5: 9‐15. 60. El‐Agroudy AE, Refaie AF, Moussa OM, Ghoneim MA (2003) Tuberculosis in Egyptian kidney transplant recipients: study of clinical course and outcome. Journal of nephrology 16: 404‐ 411. 61. Riska H, Kuhlbäck B (1979) Tuberculosis and kidney transplantation. Journal of Internal Medicine 205: 637‐640. 62. Canet E, Dantal J, Blancho G, Hourmant M, Coupel S (2011) Tuberculosis following kidney transplantation: clinical features and outcome. A French multicentre experience in the last 20 years. Nephrology Dialysis Transplantation 26: 3773‐3778. 63. Grauhan O, Lohmann R, Lemmens P, Schattenfroh N, Jonas S, et al. (1995) Mycobacterial infection after liver transplantation. Langenbecks Archiv für Chirurgie 380: 171‐175. 64. Chan AC, Lo CM, Ng KKC, Chan SC, Fan ST (2007) Implications for management of Mycobacterium tuberculosis infection in adult‐to‐adult live donor liver transplantation. Liver International 27: 81‐85. 65. Naqvi A, Rizvi A, Hussain Z, Hafeez S, Hashmi A, et al. Developing world perspective of posttransplant tuberculosis: morbidity, mortality, and cost implications; 2001. Elsevier. pp. 1787‐1788. 17

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66. Reis‐Santos B, Gomes T, Horta BL, Maciel ELN (2013) Tuberculosis prevalence in renal transplant recipients: systematic review and meta‐analysis. Jornal Brasileiro de Nefrologia 35: 206‐213. 67. Al‐Efraij K, Mota L, Lunny C, Schachter M, Cook V, et al. (2015) Risk of active tuberculosis in chronic kidney disease: a systematic review and meta‐analysis. The International Journal of Tuberculosis and Lung Disease 19: 1493‐1499. 68. Verma A, Dhawan A, Wade JJ, Lim WH, Ruiz G, et al. (2000) Mycobacterium tuberculosisinfection in pediatric liver transplant recipients. The Pediatric infectious disease journal 19: 625‐630. 69. John GT, Shankar V, Talaulikar G, Mathews MS, Abraham MA, et al. (2003) Epidemiology of systemic mycoses among renal‐transplant recipients in India. Transplantation 75: 1544‐1551. 70. Muñoz P, Rodríguez C, Bouza E (2005) Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clinical infectious diseases 40: 581‐587. 71. Chen CH, Lian JD, Cheng CH, Wu MJ, Lee WC, et al. (2006) Mycobacterium tuberculosis infection following renal transplantation in Taiwan. Transplant Infectious Disease 8: 148‐156. 72. Higgins R, Cahn A, Porter D, Richardson A, Mitchell R, et al. (1991) Mycobacterial infections after renal transplantation. QJM: An International Journal of Medicine 78: 145‐153. 73. Qunibi WY, Al‐sibai MB, Taher S, Harder EJ, De Vol E, et al. (1990) Mycobacterial infection after renal transplantation—report of 14 cases and review of the literature. QJM: An International Journal of Medicine 77: 1039‐1060.

482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501

502 503 504

18

Table1-A. Characteristics of the included studies Type of TB Author

Country

Year

N

Type of transplantation

post TB cases

n/N

(%)

Renal

45/1200

3.75

6326

Renal/Liver/Heart *

51/6326

1981-2002

982

Renal

Turkey

1986-1998

274

Alpdogan T.B[43]

Turkey

1988-1998

351

Atasever A[44]

Turkey

1994-2002

444

Agrawal N[35]

India

2012-2015

175

Biz E[5]

Brazil

1976-1996

Iran

1984-2003

Extrapulmonary

Disseminated

Miliary

Not determine d n/ (%) N

(%)

n/N

(%)

n/N

(%)

n/N

(%)

n/N

(%)

32.6 ± 10.5

40/45

89

-

-

41/45

91

4/45

8.8

-

-

-

-

0.8

45.3 (23-67)

30/51

59

32/51

63

6/51

11.7

13/51

25

-

-

-

-

44/982

4.48

36±10.85

ND

ND

23/44

52

20/44

45

-

-

-

-

1/4 4

2.2

Renal

16/274

5.83

31 ( 22± 51)

14/16

87.5

8/16

50

-

-

3/16

18.7

5/16

31.2

-

-

alloSCT*

5/351

1.42

27/4

4/5

80

4/5

80

1/5

20

-

-

-

-

-

-

Renal

13/328

4

38.9±10.6

8/13

61.5

5/13

38

3/13

23

5/13

38

-

-

-

-

Renal

7/116

6.03

24.2±7.4

4/7

57

2/7

29

1/7

14.2

4/7

57

-

-

-

-

SCT

5/175

2.8

45 (38-54)

3/5

60

4/5

80

-

-

1/5

20

-

-

-

-

1264

Renal

30/1264

2.37

33 (16 - 60)

21/130

70

24/30

80

-

-

6/30

20

-

-

-

-

12820

Renal

120/1282

1

38.6

62/120

51.6

82/120

68.3

29/120

24.2

9/120

7.5

-

-

-

-

Egypt

1976-1999

1200

Aguado JM [20]

Spain

1980-1994

Azevedo Matuck T[14]

Brazil

Apaydin S[42]

Boubaker K[12]

Pulmonary n/N

el-Agroudy A.E[60]

Basiri A[52]

Mean/ Median age

Sex (male)

Tunisia

1986-2009

491

Renal

16/491

3.2

32,5 ± 12,7

14/16

87.5

10/16

62.6

3/16

18.7

3/16

18.7

-

-

-

-

Bravo C[21]

Spain

1990-2002

187

Lung

12/187

6.41

43.9 (4–67)

7/13

58.3

12/12

100

-

-

-

-

-

-

-

-

Clifford M[50]

South Africa

1980-1992

487

Renal

21/487

4.3

37.1 (22-50)

14/21

66.6

20/21

95

-

-

-

-

1/21

5

-

-

Chen C.H[71]

Taiwan

1983-2003

727

Renal

31/727

4.26

40.6 ± 12.1

ND

ND

22/31

71

7/31

22.5

1/31

3

1/31

3

-

-

2000-2009

4835

Renal

153/4835

3.2

46.6 ± 12.7

95/153

62.1

-

-

15/15

100

-

-

-

-

-

-

Chen C.H[31]

Taiwan 1983-2012

1176

Renal

33/1176

2.8

43.69 ± 15.53

23/33

69.7

-

-

33/33

100

-

-

-

-

-

-

Canet E[62]

France

1986-2006

16146

Renal

49/16146

0.3

51.8 (41.3– 60.2)

27/49

55.1

16/49

32.6

18/49

37

-

-

15/49

30.6

-

-

Chou N.K[30]

Taiwan

1989- 2003

177

Heart

5/177

2.8

57 ± 8.2

4/5

80

3/5

60

2/5

40

0/5

0

0/5

0

-

-

Hong Kong

1991-2004

397

Liver

8/397

2

47(34–56)

7/8

87.5

6/8

75

1/8

12.5

1/8

12.5

-

-

-

-

China

1991-2007

2333

Renal

41/2333

1.76

42(11-64)

31/41

75.6

16/41

39.02

21/41

51.2

3/41

7.3

1/41

2.4

-

-

Chan C.Y.A[64] Chen S.Y[29]

19

Clemente W.T[15]

Brazil

1994 -2007

319

Liver

5/319

1.57

39.6±16.5

0/5

0

2/5

40

1/5

20

2/5

40

-

-

-

-

Costa S.D[2]

Brazil

1994-2014

1604

Renal

34/1604

2.1

41.0 ± 12.7

24/34

70.6

15/34

44.1

14/34

41.17

4/34

11.8

-

-

1/3 4

2.94

1690

Liver

0

1.1

43.2 ± 19.3

14/19

73.7

ND

ND

ND

ND

ND

ND

ND

ND

-

-

Chen C.H[28]

Taiwan

2000-2009 938

Heart

26/938

2.8

45.2 ±16.6

19/26

73.1

ND

ND

ND

ND

ND

ND

ND

ND

-

-

De la Ca´mara R[22]

Spain

1976-1998

8013

SCT

20/8013

0.24

37(19–57)

9/20

45

16/20

80

4/20

20

-

-

-

-

-

-

Dridi. A[48]

Tunisia

1980-2002

368

Renal

5/368

1.3

34 (26-40)

3/5

60

4/5

80

1/5

20

-

-

-

-

-

-

Edelstein C. L[11]

South Africa

1988-1992

110

Renal

9/110

8.2

ND

ND

ND

9/9

100

-

-

-

-

-

-

-

-

Ergun I[40]

Turkey

1990-2004

283

Renal

10/283

3.5

41 ± 9

7/10

70

5.10

50

5/10

50

-

-

-

-

-

-

Fan W.C[32]

Taiwan

1997-2006

2040

HSCT

39/204

1.9

*

27/39

69.2

34/39

87.2

5/39

12.8

-

-

-

-

-

-

Guida J.P.S[16]

Brazil

1984 2007

1342

Renal

23/1342

1.71

ND

ND

ND

10/23

43

12/23

52.1

1/23

7.6

-

-

-

-

Garcı´a-Goez J. F [23]

Spain

1988-2007

4634

Renal, Liver, Renal-Pancreas, Heart*

21/4634

0.45

49.38 ± 13.99

15/21

71.4

10/21

48

6/21

29

5/21

24

-

-

-

-

Grauhan O[63]

Germany

1988-1994

420

Liver

5/420

1.2

45(3- 66)

ND

ND

3/5

60

1/5

20

1/5

20

-

-

-

-

Ghafari A[53]

Iran

1989-2005

1350

Renal

52/1350

3.9

32.6 ± 10.5

40/52

76.9

20/52

38

29/52

55.7

1/5

2

2/52

3.9

-

-

United kingdom

1975-1989

674

Renal

10/674

1.4

44.1

7/10

70

2.10

20

4/10

40

4/10

40

-

-

-

-

Japan

1990-2007

1222

Liver

9/1222

0.74

48(0.83-–67)

5/9

55.5

6/9

66.6

2/9

22

1/9

11

-

-

-

-

-

26/ 17

15.6

Higgins R.M[72] Imai S[8] John G.T[36]

India

1986-1999

1251

Renal

166/1251

13.2

34.5 (10.3)

138/166

83.1

80/166

48.2

28/166

16.8

32/166

19.3

Koseoglu F[41]

Turkey

1975-1999

935

Renal

Kaaroud H[49]

Tunisia

1986-2006

359

Renal

Ku S.C[33]

Taiwan

1994-2000

350

M M Klote[55]

United States

1998-2000

Lezaic V[37]

India

Lattes R[58]

Asturias

19/935

2

38.6 (20-55)

14/19

73.7

9/19

47.3

4/19

21.1

6/19

31.6

-

-

-

-

9/359

2.5

37.8 (15-53)

7/9

77.7

5/9

55.5

4/9

44.5

-

-

-

-

-

-

HSCT

8/350

2.3

42(11-50)

6/8

75

5/8

62.5

3/8

37.5

-

-

-

-

-

-

16257

Renal

66/16257

0.4

ND

ND

ND

41/66

62

21/66

32

-

-

4/66

6.06

-

-

1980-1998

456

Renal

16/456

3.13

34.9

10/16

62.5

13/16

81.25

2/16

12.5

1/16

6.25

-

-

-

-

1986-1995

384

Renal

14/384

3.64

35

10/14

71

10/14

71.4

3/14

21.4

1/14

7.1

-

-

-

-

20

-

Lopez de Castilla .D [56]

United States

1988-2007

4925

*

13/4925

0.26

47 (12.5)

10/13

77

7/13

53.8

1/13

7.6

5/13

38.5

-

-

-

-

Lui S.L[45]

China

1991-2002

440

Renal

23/440

5.2

39.3 ± 13.4

18/23

78.2

20/23

87

1/23

4.3

2/23

8.7

-

-

-

-

Liu J[46]

China

2000 -2013

1914

Renal, Liver

45/1914

2.3

37.9 (37.9 ± 10.0)

34/45

75

28/45

62.2

4/45

8.9

13/45

28.9

-

-

-

-

Malhotra K.K[38]

India

1986

95

Renal

9/95

9.47

29± 9.15

9/9

100

5/9

55.5

-

-

-

-

1/9

11.1

3/9

33.3

Munoz P[24]

Spain

1989-1993

144

Heart

3/144

2.08

52

2/3

67

-

-

2/3

67

1/3

33.3

-

-

-

-

Morales P[25]

Spain

1990-2004

271

Lung

7/271

2.58

26(13± 55)

3/7

43

7/7

100

-

-

-

-

-

-

-

-

Melchor J.L[17]

Brazil

1992-2000

545

Renal

10/545

1.8

36 (20- 45)

3/10

30

6/10

60

4/10

40

-

-

-

-

-

-

Marques I.D.B[18]

Brazil

2000-2010

1549

Renal

43/1549

2.7

40 ± 16

28/43

65

32/43

74

5/43

12

6/43

14

-

-

-

-

Maeda T[54]

Japan

2002-2004

113

RI-UCBT*

3/113

2.65

50

1/3

33.4

-

-

-

-

-

-

3/3

100

-

-

Nascimentocosta J.M[51]

South Africa

1966-1983

519

Renal

10/519

1.92

27-45(36.8)

9/10

90

10/10

100

-

-

-

-

-

-

-

-

Naqvi A[65]

Pakistan

1985-2000

850

Renal

130/850

15.2

ND

ND

ND

70/130

54

38/130

29.2

4/130

3.1

-

-

0

14

Neto R.S [19]

Brazil

2005-2015

1853

Liver

19/1853

1.02

57 (23-65)

12/19

63

19/19

100

-

-

-

-

-

-

-

-

Ou S.M[34]

Taiwan

1997-2006

4554

Renal

109/4554

2.4

47.6 ± 11.2

63/109

57.8

75/109

68.8

16/109

31.2

-

-

13/10 9

11.9

5/1 09

4.6

Spain

1980-2000

1261

Renal

20/1261

74

39.55

12/20

60

8/20

40

5/20

25

7/20

35

-

-

-

-

Riska H[61]

Finland

1964- 1978

584

Renal

10/584

1.7

30-67

6/10

60

10/10

100

-

-

-

-

-

-

-

-

Ruangkanchanas etr P[57]

Thailand

1987-2007

151

Renal

5/151

3.3

49(38–55)

4/5

80

5/5

100

-

-

-

-

-

-

-

-

Spain

1976-2004

2012

Renal

16/2012

0.79

39.8 ± 13.2

10/16

62.5

9/16

56.2

3/16

18.7

4/16

25

-

-

-

-

Belgium

1963-2001

2502

Renal

9/2502

0.35

45.7

6/9

66.6

5/9

55.5

4/9

44.5

-

-

-

-

-

-

India

1989-1991

109

Renal

16/109

14.6

33.4 ±11.9

12/16

75

7/16

43.7

2/16

12.5

-

-

-

-

7/1 6

43.7

Wajeh Y[73]

Saudi Arabia

1990

403

Renal

14/403

3.4

37(19-69)

11/14

78.5

4/14

28.5

1/14

7.1

9/14

64.3

-

-

-

-

1986-2006

1947

Renal

25/1947

1.28

Zhang X.F[47]

China

45(19-72)

22/28

78.5

20/28

71.4

5/28

17.86

3/28

10.71

-

-

-

-

2000-2006

85

Liver

3/85

3.5

Queipo J.A[26]

Torres J[27] Vandermarliere A[59] Vachharajani T[39]

21

*Aguado, Jose M; (Renal, n=4539); (liver, n=1202); (heart, n=585),*Alpdogan T.B;allogeneic stem cell transplant,* Garcı´a-Goez J.F; (Renal, n=2757); (liver, n=1334); (heart, n=182); (Renal-pancreas, n=361), * Lopez de Castilla .D; (Renal, n=1858); (liver, n=857); (heart, n=1714); (Renal-pancreas, n=361),(Lung,n=460),(Hear,Lung.n=36), * Maeda T; reduced-intensity unrelatedcord blood transplantation

Table1-B. Characteristics of the included studies Diagnostic assays for detection of active TB Author

culture positive

AFB smear

Histology

0

TST

chest x-ray posetive

PCR

other

n/N

(%)

n/N

(%)

n/N

(%)

cut off

Positive( n)

el-Agroudy A.E[60]

25/45

56

36/45

80

5/45

11

-

-

-

17/45

37

-

-

34/45

76**

Aguado JM [20]

45/51

88

34/51

67

13/51

25

≥5

6/51

12

36/51

71

-

-

-

-

Azevedo Matuck T[14]

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

Apaydin S[42]

7/16

43.7

5/16

31.2

-

-

>10

-

-

15/16

93.7

5/16

31.2

4/16

25

Alpdogan T.B[43]

4/5

80

-

-

-

-

≥15

-

-

-

-

-

-

-

-

-

4/2

20

-

-

-

-

1/5

20

Atasever A[44] Agrawal N[35]

-

-

-

-

-

-

(%)

n/N

(%)

n/N

(%)

n/N

(%)

≥5

4/5

80

4/5

80

3/5

60

ND

-

-

4/5

80

-

-

-

-

-

-

11/30

36

19/30

64

ND

-

-

26/30

87

-

-

-

-

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

Boubaker K[12]

9/16

56.25

7/16

43.75

-

-

≥10

2/5

40

14/16

87.5

-

-

-

-

Bravo C[21]

6/12

50

5/12

41.6

-

-

≥5

-

-

5/12

41.6

-

-

-

-

Clifford M[50]

2/21

9/5

6/21

28.5

5/21

23

ND

-

-

21/21

100

-

-

19/21

90.4

Chen C.H[71]

26/31

83/9

14/31

45.2

-

-

ND

-

-

22/31

71

-

-

-

-

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

36/49

73.5

-

-

-

-

ND

-

-

13/43

26.5

-

-

-

-

Chou N.K[30]

5/5

100

-

-

-

-

ND

-

-

5/5

100

-

-

-

-

Chan C.Y.A[64]

4/8

50

4/8

50

-

-

ND

-

-

4/8

50

-

-

-

-

Chen S.Y[29]

ND

ND

7/41

17.1

-

-

≥5

-

-

32/41

78

-

-

-

-

Biz E[5] Basiri A[52]

Chen C.H[31] Canet E[62]

22

Clemente W.T[15]

4/5

80

-

-

-

-

-

-

-

1/5

20

-

-

-

-

Costa S.D[2]

4/34

11.7

16/34

47

10/34

29.4

≥5

-

-

-

-

-

-

-

-

Chen C.H[28]

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

De la Ca´mara R[22]

19/20

95

9/20

45

-

-

ND

-

-

19/20

95

-

-

-

-

2/5

40

-

-

1/5

20

ND

-

-

2/5

40

-

-

-

-

Dridi. A[48] Edelstein C. L[11]

3/9

33.4

5/9

55.6

1/9

11

ND

-

-

4/9

44

-

-

-

-

10/10

100

-

-

-

-

ND

-

-

-

-

-

-

-

-

Fan W.C[32]

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

Guida J.P.S[16]

3/23

13

4/23

17.3

6/23

26

ND

-

-

-

-

-

-

-

-

Garcı´a-Goez J. F [23]

19/21

91

12/21

57

6/21

29

≥5

2/21

10

-

-

-

-

1/21

5

Grauhan O[63]

3/5

60

-

-

1/5

20

ND

-

-

1/5

20

-

-

-

-

Ghafari A[53]

-

-

22/52

42

-

-

ND

-

-

32/52

61.5

-

-

-

-

Higgins R.M[72]

8/10

80

8/10

80

2/10

20

ND

-

-

2/10

20

-

-

-

-

Imai S[8]

7/9

78

-

-

2/9

22

ND

-

-

-

-

-

-

-

-

-

-

-

-

34/166

20.4

ND

-

-

-

-

-

-

-

-

Ergun I[40]

John G.T[36] Koseoglu F[41]

8/19

42

-

-

9/19

47.3

ND

-

-

9/19

47.3

7/19

36.8

-

-

Kaaroud H[49]

6/9

66.6

-

-

1/9

11

ND

-

-

6/9

66.6

-

-

-

-

Ku S.C[33]

6/8

75

1/8

12.5

-

-

ND

-

-

7/8

87.5

-

-

-

-

M M Klote[55]

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

Lezaic V[37]

16/16

100

-

-

1/16

6.25

ND

-

-

5/16

31.2

-

-

-

-

Lattes R[58]

14/14

100

6/14

43

-

-

ND

-

-

-

-

-

-

-

-

Lopez de Castilla .D [56]

13/13

100

-

-

-

-

ND

-

-

-

-

-

-

-

-

Lui S.L[45]

21/23

91.3

11/23

48

5/23

22

ND

-

-

22/23

95.6

-

-

-

-

Liu J[46]

23/38

60.5

15/36

41.7

-

-

≥5

10/36

27.8

10/45

22.2

12/20

60

-

-

23

Malhotra K.K[38]

5/6

84

-

-

-

-

ND

-

-

6/9

66.67

-

-

-

-

Munoz P[24]

1/3

33.3

1/3

33.3

1/3

33.3

≥15

1/3

33.3

1/3

33.3

-

-

-

-

Morales P[25]

1/7

14

6/7

86

-

-

≥5

-

-

-

-

-

-

-

-

Melchor J.L[17]

10/10

100

1/10

10

5/10

50

ND

-

-

-

-

-

-

-

-

Marques I.D.B[18]

7/43

16

37/43

86

18/43

42

ND

-

-

-

-

30/43

70

-

-

-

-

3/3

100

-

-

ND

-

-

1/3

33.4

3/3

100

-

-

Nascimentocosta J.M[51]

1/10

10

3/10

30

4/10

40

ND

-

-

7/10

70

-

-

2/10

20

Naqvi A[65]

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

Neto R.S [19]

19/19

100

15/19

78

-

-

ND

-

-

-

-

-

-

-

-

ND

ND

ND

ND

ND

ND

ND

-

-

-

-

-

-

-

-

20/20

100

6/20

30

-

-

ND

9/20

45

2/20

10

-

-

-

-

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

-

-

4/5

80

-

-

ND

-

-

-

-

-

-

-

-

6/16

37.5

14/16

87.5

5/16

31.2

ND

-

-

-

-

-

-

-

-

ND

ND

ND

ND

ND

ND

ND

-

-

-

-

-

-

-

-

-

-

4/16

25

2/16

12.5

-

-

-

7/16

43.7

-

-

-

-

Wajeh Y[73]

13/14

93

11/14

78.5

-

-

ND

-

ND

11/14

78.5

-

-

-

-

Zhang X.F[47]

10/28

35.7

12/28

42.86

7/28

25

≥5

2/28

7.1

24/28

85.7

5/28

17.8

-

-

Maeda T[54]

Ou S.M[34] Queipo J.A[26] Riska H[61] Ruangkanchanasetr P[57] Torres J[27] Vandermarliere A[59] Vachharajani T[39]

**Aguado, Jose M;( 33 renal , 12 liver ,6 heart) TST: Tuberculin skin test

24

Table1-C. Characteristics of the included studies

Author

el-Agroudy A.E[60] Aguado JM [20] Azevedo Matuck T[14] Apaydin S[42] Alpdogan T.B[43] Atasever A[44] Agrawal N[35] Biz E[5] Basiri A[52] Boubaker K[12] Bravo C[21] Clifford M[50] Chen C.H[71] Chen C.H[31]

Previous history of active TB

Mean interval between transplantation and TB(month) diagnosis

mortality rate

Total score

N

(%)

N

(%)

N

ND

ND

49.8 ± 41.5( 2-180)

12/45

26

9

12/51

23

23(0.5-156)

12/51

23

ND

ND

36

15/44

34.9

8 3

ND

ND

6(3-119)

5/16

31

5

0

0

13(10-47)

0

0

5

0

0

53.1±73.1

0

0

3

0

0

46.1±55.8

2/7

28.6

ND

ND

8.6 (5.2-21.3)

0

0

4

ND

ND

1.6-216

3/.30

10

5

4/12

3.3

ND

ND

ND

4

3/16

18.75

36.6

2/16

12.5

3

ND

ND

0.83(0.53-1.2)

3/6

50

8 6

1/21

4.7

14 (2-74)

1/21

5

ND

ND

57.9 ± 42.3

12/29

41.4

5

ND

ND

ND

ND

ND

-1

ND

ND

ND

ND

ND

Canet E[62] Chou N.K[30] Chan C.Y.A[64] Chen S.Y[29]

9/49

18.4

10

3/49

6.1

0

0

3.5- 85(46.5 ±34.9)

0

0

5

1/8

12.5

9 (4–20 )

1/8

12.5

3

4/41

9.7

8 ( 1-156 )

9/41

22

5

Clemente W.T[15]

2/5

40

8

0

0

25

3

5

Costa S.D[2]

ND

ND

25.5 (1-168)

ND

ND

Chen C.H[28]

ND

ND

ND

ND

ND

De la Ca´mara R[22] Dridi. A[48] Edelstein C. L[11] Ergun I[40] Fan W.C[32] Guida J.P.S[16]

1.20

5

10.8

3/20

15

7

ND

ND

27 (3-63)

1/5

20

6

ND

ND

5

2/9

22.3

5

ND

ND

38 (3-81)

0

20

4

ND

ND

0(0)

20/39

51.3

5

7/23

30.4

53 ± 49

3/23

13

3

Garcı´a-Goez J. F [23]

2/21

10

21.7 (0.3–164.4)

3/21

14

Grauhan O[63]

1/5

20

6.18

1/5

20

5

Ghafari A[53]

20/52

38.2

54.6 ± 48.23 (4-140)

12/52

23

6

Higgins R.M[72] Imai S[8] John G.T[36] Koseoglu F[41] Kaaroud H[49] Ku S.C[33] M M Klote[55]

1/10

10

16.5

1/10

10

7

ND

ND

5(1–45)

2/9

22

5

-

-

-

53/166

31.9

5

0

0

35.8

0

0

6

ND

ND

49.6

3/9

33.3

5

ND

ND

3.8(1-33.5)

4/8

50

5

ND

ND

ND

2/66

3.03

4

Lezaic V[37]

3/16

18.7

40.5(1.5-300)

2/16

12.5

0

0

21.8 ( 2–98)

2/14

14.2

3

ND

ND

11.2 (4.4-23.0)

2/13

15.3

7

0

0

27 ± 12 ( 7–56 )

1/23

4.3

5

1/45

2.2

20(5-70)

4/45

8.9

7

3/9

33

6- 32

2/9

22.2

3

Munoz P[24]

2/3

66.6

2.5 (1.8-3.4 )

0

0

Morales P[25] Melchor J.L[17]

2/7

29

16(6-25)

3/7

43

5

ND

ND

22.5(2 - 88)

5/10

50

5

Lattes R[58] Lopez de Castilla .D [56] Lui S.L[45] Liu J[46] Malhotra K.K[38]

26

9 1

3

5

6

Marques I.D.B[18]

3/43

7

7.6 ( 0.63–4.2)

5/43

12

0

0

1.6

2/3

66.7

Nascimentocosta J.M[51]

7/10

70

10.9 (3-33 )

2/10

20

Naqvi A[65] Neto R.S [19] Ou S.M[34] Queipo J.A[26] Riska H[61] Ruangkanchanasetr P[57] Torres J[27] Vandermarliere A[59] Vachharajani T[39] Wajeh Y[73]

ND

ND

12

38/130

29

5

6/19

31.5

2.6 (0.2-5.1)

ND

ND

3

Maeda T[54]

Zhang X.F[47]

8 3 5

ND

ND

ND

25/109

22.9

3

3/20

15

25.9

3/20

15

7

1/10

10

1-3

4/10

40

2

ND

ND

23

0

0

3

1/16

6.25

41.9±18.2

ND

ND

3

1/9

11.1

64±80

ND

ND

8

ND

ND

6.5 ± 4.8 (1–18)

3/16

18.7

3

0

0

16.5(1-84)

ND

ND

7

4/25

15.38

1/3

33.3

2/28

7.1

32(1-142)

27

5

Table 2. Subgroup meta-analysis of the prevalence of Active TB in transplant recipients by potential predictors

Prevalence (95% CI)

I2 (%)

Heterogeneity (χ χ 2)

P value

Interaction test (χ χ 2)

P value

culture chest X-ray smear

0.56 (0.45-0.68) 0.57 (0.46-0.67) 0.49 (0.40-0.58)

93.36 91.59 86.01

380.36 497.17 235.81

< 0.001 < 0.001 < 0.001

497.17 380.36 235.81

< 0.001 < 0.001 < 0.001

histology

0.26 (0.20-0.32)

59.91

59.86

< 0.001

59.86

< 0.001

PCR

0.43 (0.21-0.65)

86.82

30.34

< 0.001

30.34

< 0.001

PPD Renal Liver Renal Liver Renal Liver Renal Liver Renal Renal Liver

0.19 (0.10-0.28) 0.03 (0.02-0.03) 0.01 (0.01-0.01) 0.57 (0.50-0.63) 0.64 (0.46-0.81) 0.30 (0.22-0.38) 0.18 (0.03-0.32) 0.13 (0.09-0.17) 0.16 (0.02-0.29) 0.80 (0.04-0.13) 0.68 (0.60-0.76) 0.72 (0.59-0.84) 2(2)

55.87 95.91 0 81.71 0 91.45 0 75.28 0 69.51 90.38 12 94.67

15.86 1002.08 5.77 185.87 1.78 362.73 0.34 93.06 1.55 26.24 353.40 3.41 1182.32

0.03 < 0.001 0.45 < 0.001 < 0.062 < 0.001 < 0.095 < 0.001 0.67 < 0.001 < 0.001 0.33 < 0.001

15.86

< 0.001

249.55

< 0.001

29.22

< 0.001

21.52

0.01

12.13

0.10

0

< 0.001

9.21

0.51

Subgroup variable

Diagnostic test

Type of transplant Pulmonary TB Extra pulmonary TB Disseminated TB Miliary TB Male All studies

28

29

Study

ES (95% CI)

% Weight

Renal el-Agroudy A.E (1976-1999) Azevedo Matuck T (1981-2002) Apaydin S (1986-1998) Atasever A (1994-2002) Atasever A (1994-2002) Biz E (1976-1996) Basiri A (1984-2003) Boubaker K (1986-2009) Clifford M (1980-1992) Chen C.H (1983-2003) Chen C.H (2000-2009) Chen C.H (1983-2012) Canet E (1986-2006) Chen S.Y (1991-2007) Costa S.D (1994-2014) Dridi. A (1980-2002) Edelstein C. L (1988-1992) Ergun I (1990-2004) Guida J.P.S (1984 - 2007) Ghafari A (1989-2005) Higgins R.M (1975-1989) John G.T (1986-1999) Koseoglu F (1975-1999) Kaaroud H (1986-2006) Klote M M (1998-2000) Lezaic V (1980-1998) Lattes R (1986-1995) Lui S.L (1991-2002) Malhotra K.K (1986) Melchor J.L (1992-2000) Marques I.D.B (2000-2010) Nascimentocosta J.M (1966-1983) Naqvi A (1985-2000) Ou S.M (1997-2006) Queipo J.A (1980-2000) Riska H (1964- 1978) Ruangkanchanasetr P (1987-2007) Torres J (1976-2004) Vandermarliere A (1963-2001) Vachharajani T (1989-1991) Wajeh Y (1990) Zhang X.F (1986-2006) Subtotal (I^2 = 97.38%, p = 0.00)

0.04 (0.03, 0.05) 0.04 (0.03, 0.06) 0.06 (0.03, 0.09) 0.04 (0.02, 0.07) 0.06 (0.02, 0.12) 0.02 (0.02, 0.03) 0.01 (0.01, 0.01) 0.03 (0.02, 0.05) 0.04 (0.03, 0.07) 0.04 (0.03, 0.06) 0.03 (0.03, 0.04) 0.03 (0.02, 0.04) 0.00 (0.00, 0.00) 0.02 (0.01, 0.02) 0.02 (0.01, 0.03) 0.01 (0.00, 0.03) 0.08 (0.04, 0.15) 0.04 (0.02, 0.06) 0.02 (0.01, 0.03) 0.04 (0.03, 0.05) 0.01 (0.01, 0.03) 0.13 (0.11, 0.15) 0.02 (0.01, 0.03) 0.03 (0.01, 0.05) 0.00 (0.00, 0.01) 0.04 (0.02, 0.06) 0.04 (0.02, 0.06) 0.05 (0.03, 0.08) 0.09 (0.04, 0.17) 0.02 (0.01, 0.03) 0.03 (0.02, 0.04) 0.02 (0.01, 0.04) 0.15 (0.13, 0.18) 0.02 (0.02, 0.03) 0.02 (0.01, 0.02) 0.02 (0.01, 0.03) 0.03 (0.01, 0.08) 0.01 (0.00, 0.01) 0.00 (0.00, 0.01) 0.15 (0.09, 0.23) 0.03 (0.02, 0.06) 0.01 (0.01, 0.02) 0.03 (0.02, 0.04)

1.69 1.67 1.44 1.49 1.15 1.69 1.77 1.57 1.57 1.63 1.75 1.69 1.77 1.73 1.71 1.51 1.13 1.45 1.70 1.70 1.62 1.69 1.66 1.51 1.77 1.56 1.52 1.55 1.07 1.59 1.71 1.58 1.65 1.75 1.69 1.60 1.25 1.72 1.73 1.12 1.53 1.72 66.42

Renal/Liver/Heart Aguado JM (1980-1994)

0.01 (0.01, 0.01)

1.76

SCT Alpdogan T.B (1988-1998) Agrawal N (2012-2015) De la Ca?mara R (1976-1998) Subtotal (I^2 = .%, p = .)

0.01 (0.00, 0.03) 0.03 (0.01, 0.07) 0.00 (0.00, 0.00) 0.01 (0.00, 0.03)

1.50 1.30 1.76 4.57

Lung Bravo C (1990-2002) Morales P (1990-2004) Subtotal (I^2 = .%, p = .)

0.06 (0.03, 0.11) 0.03 (0.01, 0.05) 0.04 (0.02, 0.06)

1.33 1.44 2.77

Heart Chou N.K (1989- 2003) Chen C.H (2000-2009) Munoz P (1989-1993) Subtotal (I^2 = .%, p = .)

0.03 (0.01, 0.06) 0.03 (0.02, 0.04) 0.02 (0.00, 0.06) 0.03 (0.02, 0.04)

1.31 1.66 1.23 4.21

Liver Chan C.Y.A (1991-2004) Clemente W.T (1994 -2007) Chen C.H (2000-2009) Grauhan O (1988-1994) Imai S (1990-2007) Neto R.S (2005-2015) Zhang X.F (2000-2006) Subtotal (I^2 = 27.86%, p = 0.22)

0.02 (0.01, 0.04) 0.02 (0.01, 0.04) 0.01 (0.01, 0.02) 0.01 (0.00, 0.03) 0.01 (0.00, 0.01) 0.01 (0.01, 0.02) 0.04 (0.01, 0.10) 0.01 (0.01, 0.01)

1.53 1.48 1.71 1.54 1.69 1.72 1.02 10.69

HSCT Fan W.C (1997-2006) Ku S.C (1994-2000) Subtotal (I^2 = .%, p = .)

0.02 (0.01, 0.03) 0.02 (0.01, 0.04) 0.02 (0.01, 0.03)

1.72 1.50 3.23

Renal, Liver, Renal-Pancreas, Heart* Garci?a-Goez J.F (1988-2007)

0.00 (0.00, 0.01)

1.75

* Lopez de Castilla .D (1988-2007)

0.00 (0.00, 0.00)

1.75

Renal, Liver Liu J (2000 -2013)

0.02 (0.02, 0.03)

1.72

RI-UCBT* Maeda T (2002-2004)

0.03 (0.01, 0.08)

1.14

Heterogeneity between groups: p = 0.000 Overall (I^2 = 96.64%, p = 0.00);

0.03 (0.02, 0.03)

100.00

-.1

0

.1

30

.2

.3

Figure 2. Forest plot diagram of the total prevalence post-transplant of active TB in transplant recipients around the world. The middle point of each line indicates the prevalence rate and the length of line indicates 95% confidence interval of each study. The opened diamond is representatives of the overall prevalence of the studies

31

Figure 3-A. The Egger’s test graph to test for publication bias (P value < 0.0001)

32

Figure 3-B. The Egger’s test graph to test for publication bias (P value < 0.0001)

33

Highlights •

Post-transplant tuberculosis is a major problem worldwide.

•

The incidence of tuberculosis in transplant recipients is 20 to 50 times higher than in the general population.

•

Renal and lung transplant recipients appear to have a higher predisposition for acquiring tuberculosis.

•

Prompt diagnosis of tuberculosis infection can decrease the mortality rate among patients with solid organ transplantation.