Tuberculosis in Liver Transplant Recipients: A Systematic Review and Meta-Analysis of Individual Patient Data doc

ORIGINAL ARTICLE
Tuberculosis in Liver Transplant Recipients: A
Systematic Review and Meta-Analysis of
Individual Patient Data
Jon-Erik C. Holty,
1,2
Michael K. Gould,
1,2,4
Laura Meinke,
5
Emmet B. Keeffe,
3
and Stephen J. Ruoss
2
1
Center for Primary Care and Outcomes Research, Stanford University, Stanford, CA; Divisions of
2
Pulmonary and Critical Care Medicine and
3
Gastroenterology and Hepatology, Department of Medicine,
Stanford University School of Medicine, Stanford, CA;
4
VA Palo Alto Health Care System, Palo Alto, CA; and
5
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Arizona, Tucson,
AZ
Mycobacterium tuberculosis (MTB) causes substantial morbidity and mortality in liver transplant recipients. We examined the
efficacy of isoniazid latent Mycobacterium tuberculosis infection (LTBI) treatment in liver transplant recipients and reviewed
systematically all cases of active MTB infection in this population. We found 7 studies that evaluated LTBI treatment and 139
cases of active MTB infection in liver transplant recipients. Isoniazid LTBI treatment was associated with reduced MTB
reactivation in transplant patients with latent MTB risk factors (0.0% versus 8.2%, P ϭ 0.02), and isoniazid-related

hepatotoxicity occurred in 6% of treated patients, with no reported deaths. The prevalence of active MTB infection in transplant
recipients was 1.3%. Nearly half of all recipients with active MTB infection had an identifiable pretransplant MTB risk factor.
Among recipients who developed active MTB infection, extrapulmonary involvement was common (67%), including multiorgan
disease (27%). The short-term mortality rate was 31%. Surviving patients were more likely to have received 3 or more drugs
for MTB induction therapy (P ϭ 0.003) and to have been diagnosed within 1 month of symptom onset (P ϭ 0.01) and were less
likely to have multiorgan disease (P ϭ 0.01) or to have experienced episodes of acute transplant rejection (P ϭ 0.02).
Compared with the general population, liver transplant recipients have an 18-fold increase in the prevalence of active MTB
infection and a 4-fold increase in the case-fatality rate. For high-risk transplant candidates, isoniazid appears safe and is
probably effective at reducing MTB reactivation. All liver transplant candidates should receive a tuberculin skin test, and
isoniazid LTBI treatment should be given to patients with a positive skin test result or MTB pretransplant risk factors, barring
a specific contraindication. Liver Transpl 15:894-906, 2009.
© 2009 AASLD.
Received August 11, 2008; accepted November 16, 2008.
See Editorial on Page 834
Chronic liver disease leading to cirrhosis is the twelfth
leading cause of death in the United States, accounting
for approximately 26,500 deaths and 513,000 hospital-
izations each year.
1,2
Liver transplantation is an effec
-
tive treatment for irreversible liver failure. Approxi-
mately 90% of transplant recipients survive the first
year, and 70% survive 5 years post-transplantation.
3,4
Infections are an important cause of morbidity and
mortality, accounting for more than 50% of deaths in
this patient population.
5
Predisposing factors include

malnutrition, impaired immunity, leukopenia, and im-
munosuppression.
The World Health Organization estimates that one-
Additional supporting information may be found in the online version of this article.
Abbreviations: BCG, bacille Calmette-Guerin; CI, confidence interval; HIV, human immunodeficiency virus; LTBI, latent Mycobacte-
rium tuberculosis infection; MTB, Mycobacterium tuberculosis; OR, odds ratio; TST, tuberculin skin test. This project was supported
in part by the Department of Veterans Affairs.
Address reprint requests to Jon-Erik C. Holty, M.D., M.S., Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford
University School of Medicine, 300 Pasteur Drive, H3143, Stanford, CA 94305-5236. Telephone: 650-723-6381; FAX: 650-725-5489;
E-mail:
DOI 10.1002/lt.21709
Published online in Wiley InterScience (www.interscience.wiley.com).
LIVER TRANSPLANTATION 15:894-906, 2009
© 2009 American Association for the Study of Liver Diseases.
third of the world’s population is infected with Mycobac-
terium tuberculosis (MTB).
6
Approximately 10% of in
-
fected individuals will develop active tuberculosis at
some time in their lives.
7,8
A decreased immune re
-
sponse enhances the risk of developing active MTB dis-
ease and is associated with higher disease-specific mor-
tality.
9
The prevalence of MTB infection in liver
transplant recipients is uncertain, with published rates

ranging from 1% to 6% in some case series.
10,11
How
-
ever, because existing studies have described small
samples, we do not have a clear understanding of the
extent to which patient characteristics and treatment
factors affect mortality. Furthermore, although isonia-
zid therapy for latent Mycobacterium tuberculosis infec-
tion (LTBI) significantly reduces the rate of MTB reacti-
vation,
12
some transplant centers neither test for nor
treat LTBI because of the perceived lack of efficacy and
potential toxicity of drug therapy in liver transplant
candidates.
13-18
Given the substantial clinical conse
-
quences that could arise from reactivation of a previ-
ously unrecognized LTBI in a liver transplant recipient,
it is of considerable importance to better understand
the relevant clinical issues in these patients.
We performed a systematic review of reports of MTB
infection in liver transplant recipients published be-
tween 1963 (the first report of a liver transplant) and
2007 to evaluate the effectiveness of pretransplant tu-
berculosis skin testing and LTBI treatment, the preva-
lence and outcome of MTB infections, and the effects of
patient factors and treatment on mortality from MTB

infection.
PATIENTS AND METHODS
Search Strategy
We searched Medline (1/1950 to 11/2007), Embase
(1/1974 to 12/2006), ISI SciSearch (1/1945 to 12/
2006), BIOSIS (1/1969 to 12/2006), and the Cochrane
Database of Systematic Reviews and Central Register of
Controlled Trials and manually searched retrieved bib-
liographies to identify liver transplant recipients with
MTB infection (Appendix Fig. A1). We considered all
reports of MTB infection (latent or active) in liver trans-
plant candidates or recipients eligible for inclusion, re-
gardless of language.
Study Selection
We included studies that reported (1) cases of active
MTB infection following liver transplantation or (2)
cases of liver transplant candidates or recipients who
received LTBI treatment prior to transplantation. We
excluded cases of pretransplant active MTB infection
that developed fulminant hepatic failure requiring
transplantation due to MTB drug therapy. We defined
LTBI as the clinical circumstance of a positive tubercu-
lin skin test (TST) result in the absence of symptoms or
clinical findings suggestive of active infection. In ana-
lyzing LTBI treatment, we included studies reporting 10
or more patients with a known pretransplant MTB in-
fection risk factor (positive TST, an abnormal pretrans-
plant chest roentgenogram, a previous history of un-
treated MTB, or a recent high-risk MTB exposure
history). Patients receiving 6 or more months of isoni-

azid were counted as having received LTBI treatment.
Data Abstraction
One investigator vetted potentially relevant articles to
determine whether they met inclusion criteria and
searched bibliographies and review articles for addi-
tional potentially relevant studies. Two investigators
independently abstracted data from each article. We
resolved abstraction discrepancies by repeated discus-
sion. If 2 or more studies presented the same data from
a single patient, we included these data only once in our
analyses.
For each included case of MTB infection, we ab-
stracted data about patient characteristics, transplant-
related factors, and MTB infection–specific factors. Ac-
tive pulmonary MTB infection was defined as including
lung or mediastinal lymph node involvement. We de-
fined multiorgan (ie, miliary) MTB infection as involve-
ment of 2 or more organs (lymph nodes draining in-
fected organs were not considered to be separate
organs). Patients with both pulmonary and pleural in-
volvement were not considered to have disseminated
MTB infection unless nonthoracic organ involvement
was noted. We classified patients who received antibi-
otics that do not have significant anti-MTB activity as
having received no MTB treatment. Major MTB drug
toxicity was defined as drug therapy discontinued or
changed because of an adverse effect attributed to MTB
therapy by the reporting authors.
Statistical Analyses
We used SAS software, version 9.1 for Windows (SAS,

Cary, NC). We compared categorical variables with
Fisher’s exact test and continuous variables with a
2-tailed Wilcoxon-Mann-Whitney test. For single com-
parisons, we considered a P value less than 0.05 to be
statistically significant. For multiple group compari-
sons, we applied a Bonferroni correction. We plotted
Kaplan-Meier curves to estimate the time from trans-
plant to symptom onset and diagnosis of MTB for pa-
tients with pretransplant risk factors for MTB exposure.
Evaluating Predictors of Mortality
We used a multivariate logistic regression model to ex-
amine the association between the following variables
and survival: age (continuous variable), gender, indica-
tion for transplant, whether MTB therapy was given,
whether patients received a Ն3-drug MTB induction
regimen, whether the MTB infection was limited to pul-
monary involvement (ie, lung, pleural, or mediastinal
lymph node involvement), development of multiorgan
MTB infection, development of isoniazid or rifampin
hepatotoxicity, and presence of acute cellular hepatic
rejection. We adopted the definition of the Centers for
Disease Control and Prevention for appropriate (Ն3-
drug regimen) or inadequate MTB induction drug ther-
TUBERCULOSIS IN LIVER TRANSPLANT RECIPIENTS 895
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
apy.
19
We assessed each variable by stepwise backward
regression using a P value cutoff of Յ0.1. Because
Ͻ50% of cases reported year of transplant, we excluded

this variable from our model. We plotted Kaplan-Meier
curves to estimate the time from MTB diagnosis to
death for patients treated with different MTB induction
drug regimens.
RESULTS
We identified 886 titles of potentially relevant articles
from our search of computerized databases and 58 ad-
ditional references from our manual search of the bib-
liographies of retrieved articles. Of the 944 potentially
relevant articles, 81 reports met our inclusion criteria
(Fig. 1). This included 78 reports describing 138 cases
of post–liver transplant active MTB infection.
11,13-
18,20-90
We included an additional liver transplant pa
-
tient whom we treated for pulmonary MTB and who was
not previously reported in the peer-reviewed literature.
Information about the 139 included cases is presented
in Appendix Table A1. Eighty-two of the 139 cases were
described in detail. Additionally, 36 reports of 20 stud-
ies
11,13,15,16,18,20,21,23,28-34,39,43,44,46,47,51-58,65,66,76,77,81,
82,87,90
provided sufficient information to calculate the
prevalence of MTB in liver transplant recipients, and 15
reports of 7 studies
15,16,43-46,51-53,55,61,62,91-93
evaluated
latent MTB treatment in liver transplant candidates or

recipients. We excluded 15 studies with pretransplant
active MTB patients who developed fulminant hepatic fail-
ure requiring transplant due to MTB drug therapy.
94-108
Patient Characteristics and Prevalence of
Active MTB Infection
Patient and disease characteristics for the 139 included
liver transplant patients with active MTB infection are
summarized in Table 1. From the 20 studies that pro-
vided sufficient information, the prevalence of active
MTB infection in liver transplant recipients was 1.3%
(104/8296). The prevalence was lower at US or Cana-
dian centers (0.6%) compared with European (1.4%)
and non-US/European centers (2.2%, P Ͻ 0.001). The
estimated annual incidence of active MTB infection at
all transplant centers was 450 per 100,000 liver trans-
plant recipients. The incidence was lower at US trans-
plant centers (85 per 100,000).
Pretransplant Tuberculosis Risk Factors and
Treatment for LTBI
Our review identified 82 cases in which active MTB
infection developed in transplanted patients and suffi-
cient accompanying clinical information was available
for additional interpretation. Pretransplant TST status
was provided for 15 additional cases. Of these 97 cases,
38 had a known pretransplant TST result (39%). Of
Figure 1. Literature search
and selection.
896 HOLTY ET AL.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

these, 37% were positive, 53% were negative, and 11%
were interpreted by the original publication authors as
representing anergy. Twenty-three percent of patients
had abnormalities reported by the authors on pretrans-
plant chest roentgenograms (Table 1). Of the 10 pa-
tients with a positive TST and pretransplant radio-
graph, 3 (30%) had abnormal pretransplant chest
roentgenograms (2 had apical fibrotic opacities, and 1
had fibrotic pleural thickening). Twenty-seven percent
of patients reported a history of untreated active MTB
infection or recent high-risk MTB exposure (ie, a family
member with active MTB). Pre-existing viral hepatitis
did not seem to affect TST results (33% positive with
versus 33% positive without hepatitis B virus or hepa-
titis C virus infection, P ϭ 1.0).
We identified only 3 studies that retrospectively pro-
vided TST status in all liver transplant recipi-
ents.
15,16,43-46,76,77
Two of 3 studies were at US trans
-
plant centers. Of 2972 patients in these studies who
underwent liver transplantation, 926 had a TST placed
(31%), and 124 were positive (13% of those tested).
Seven studies evaluated the efficacy of isoniazid LTBI
treatment in liver transplant candidates and recipients
with a known TST result or other latent MTB risk fac-
tors.
15,16,43-46,51-53,55,61,62,91-93
Two studies were pro

-
spective, 5 were retrospective, and none used a ran-
TABLE 1. Patient and MTB Characteristics
Characteristics (n)
Patient characteristics
Mean age (years; n ϭ 98) 40 Ϯ 19.2
Male (%; n ϭ 94) 72
Location of transplant center (%; n ϭ 139)
United States or Canada 27
Europe 37
Outside of United States or Europe 36
Year of transplant (n ϭ 139) 1995 Ϯ 4.7
Reason for liver transplantation (%; n ϭ 80)
Hepatitis B virus 35
Hepatitis C virus 14
Cryptogenic cirrhosis 10
Primary biliary cirrhosis 9
Biliary atresia 8
MTB risk factors
Pretransplant TST performed (%; n ϭ 97) 39
Positive TST (n ϭ 38) 37
Negative TST (n ϭ 38) 53
Anergic TST (n ϭ 38) 11
History of untreated/improperly treated MTB (%; n ϭ 93) 13
Abnormal pretransplant chest roentgenogram (%; n ϭ 87) 23
Pre-MTB moderate to severe acute rejection (%; n ϭ 86) 34
MTB clinical characteristics
Transplant MTB (%; n ϭ 82)* 6
Pulmonary MTB (%; n ϭ 102) 60
Extrapulmonary MTB (%; n ϭ 102) 67

Liver 26
Pleural 23
Nonthoracic lymphadenitis 10
Genitourinary 10
Nonhepatic gastrointestinal 9
Brain/meningitis 8
Multiorgan MTB (n ϭ 102) 27
Time to MTB diagnosis post–liver transplant (months; n ϭ 100) 8.5 Ϯ 8.9
Overall mortality (%; n ϭ 127) 31
Time from MTB diagnosis to death (months; n ϭ 20) 7.5 Ϯ 14.6
Mortality from active MTB infection (%; n ϭ 22) 65
Time from MTB diagnosis to death (months; n ϭ 12) 1.7 Ϯ 3.2
Follow-up (survivors)
Time from transplant (months; n ϭ 72) 30 Ϯ 25.3
Time from MTB diagnosis (months; n ϭ 72) 22 Ϯ 22.5
NOTE: Plus or minus values are means (or percentages) Ϯ the standard deviation. Values in parentheses are the numbers of
patients evaluated.
Abbreviations: MTB, Mycobacterium tuberculosis; TST, tuberculin skin test.
*The reporting authors determined that the MTB infection was from the transplanted organ(s) (n ϭ 5).
TUBERCULOSIS IN LIVER TRANSPLANT RECIPIENTS 897
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domized protocol. Of 224 patients with a positive
pretransplant TST result, 61 received Ն6 months of
isoniazid, 16 received less than 6 months of isoniazid, 5
received rifampin, and 143 received no LTBI treatment.
None of the TST-positive patients who received Ն6
months of isoniazid LTBI treatment developed active
MTB infection; however, 7 patients not receiving LTBI
treatment developed active MTB infection (0.0% versus
5.1%, P ϭ 0.079) during a mean follow-up of approxi-

mately 54 months. Of 238 patients identified as having
any pretransplant latent MTB risk factors (positive TST,
radiographic abnormality, or clinical history), isoniazid
LTBI treatment (Ն6 months) was statistically signifi-
cantly associated with a reduction in developing active
MTB (0.0% versus 8.2%, P ϭ 0.022, absolute risk re-
duction: 8.2%). Five of 84 patients (including 5 patients
with negative TST results and 2 patients with unknown
TST results) had isoniazid discontinued because of hep-
atotoxicity (6.0%), with only 1 patient having drug-in-
duced liver failure requiring liver transplantation
(1.2%).
Posttransplant Active MTB Infection Clinical
Characteristics
In 5 of the 139 included cases, MTB infection was sus-
pected to have arisen from the transplanted organ. Of
17 patients with a posttransplant TST (none had a pre-
transplant TST), 35% were positive. Sixty-one (60%)
patients presented with pulmonary MTB infection,
whereas 68 (67%) had extrapulmonary involvement
(Table 1). Of 59 cases for which sufficient information
was available, the mean time from symptom onset to
diagnosis of MTB infection was 1.1 months (range:
0-3.2).
Active MTB Case Treatment Characteristics
Cases were highly heterogeneous with respect to treat-
ment regimen. Seven patients received no MTB drug
therapy. Of the 86 patients with known MTB induction
therapy, 94% received drug regimens including isonia-
zid, 81% received drug regimens including ethambutol,

76% received drug regimens including rifampin or ri-
fabutin, 51% received drug regimens including pyrazin-
amide, 31% received drug regimens including a fluoro-
quinolone, and 17% received drug regimens including
streptomycin. Induction drug regimens consisted of 2
drugs in 5% of regimens, 3 drugs in 43%, 4 drugs in
45%, and more than 4 drugs in 7%.
Maintenance MTB therapy regimens (n ϭ 56) con-
sisted of isoniazid in 70% of treated patients, ethambu-
tol in 73%, rifampin or rifabutin in 45%, any fluoro-
quinolone in 52%, pyrazinamide in 18%, and
streptomycin in 14%. Most maintenance regimens con-
sisted of 2-drug (46%) or 3-drug (29%) regimens. No
patients received single-drug MTB therapy during in-
duction or maintenance therapy. Of 50 surviving pa-
tients who completed MTB drug therapy, the mean du-
ration of total drug therapy was 11.1 months (range:
4-24). One surviving patient who underwent a wedge
resection for pulmonary tuberculosis and was followed
for 12 months post–MTB diagnosis received only 4
months of MTB drug therapy consisting of isoniazid
and rifampin.
Thirty-five percent of patients (30/86) had MTB drug
therapy stopped or changed because of an adverse ef-
fect attributed to drug therapy. Of these 30 patients, 24
(73%) had hepatotoxicity, and 9 (30%) had interference
with immunosuppressive drug levels. Twenty-two of 24
patients with hepatotoxicity received isoniazid; 18 of
these patients received isoniazid with rifampin or ri-
fabutin. Hepatotoxicity was not associated with hepa-

titis B virus or hepatitis C virus infection (29% with
versus 28% without, P ϭ 0.94), MTB liver involvement
(29% with versus 26% without, P ϭ 0.80), or acute
cellular rejection prior to MTB diagnosis (30% with ver-
sus 26% without, P ϭ 0.68). However, patients with
acute transplant rejection after MTB diagnosis were
more likely to have had MTB drug hepatotoxicity (58%
versus 25%, P ϭ 0.026). Of the 52 patients treated with
rifampin or rifabutin, 39% required adjustments to
their immunosuppressive dosing. The type of immuno-
suppressive regimen did not have a significant impact
on this effect (35% for cyclosporine versus 42% for ta-
crolimus, P ϭ 0.57). The mean time from initiation of
MTB antibiotic therapy to identification of hepatotoxic-
ity was 3.1 months (range: 0.2-18). Most cases of hep-
atotoxicity were reversible, although 3 patients re-
quired liver retransplantation. Of these, 1 patient died 2
months post–MTB diagnosis, whereas the other 2 pa-
tients were alive at a mean follow-up of 29 months.
Associations Between Treatment, Patient
Characteristics, and Mortality
The observed short-term overall mortality rate was 31%
at a mean follow-up of 26.6 (Ϯ24.9) months. Patients
who were diagnosed with active MTB infection within 5
months post-transplant had higher observed mortality
(36% versus 17%, P ϭ 0.042). Of the 39 patients who
died, 22 deaths (65%) were directly attributed to MTB
infection. Bivariate predictors of overall and MTB-spe-
cific mortality are shown in Table 2. Statistically signif-
icant predictors of mortality in the 22 deaths attributed

to MTB infection included diagnosis of MTB greater
than 1 month after symptom onset (28% versus 0%
mortality, P ϭ 0.014), the absence of any MTB antibiotic
therapy (100% versus 13% mortality, P Ͻ 0.001), and
the presence of fewer than 3 drugs in the initial MTB
treatment regimen (57% versus 12% mortality, P ϭ
0.002). Interestingly, liver transplant recipients at US
centers who were born outside the United States had
statistically significantly lower MTB mortality rates in
comparison with recipients born in the United States
with MTB infection (0% versus 55% mortality, P ϭ
0.002). The interval between MTB infection symptom
onset and diagnosis was shorter for patients not born in
the United States than for patients born in the United
States at US transplant centers (mean: 0.3 versus 1.3
months, P ϭ 0.005).
In multivariate logistic regression analysis, indepen-
898 HOLTY ET AL.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
dent predictors of overall mortality included the pres-
ence of acute cellular rejection following MTB infection
diagnosis [odds ratio (OR): 5.0] and the use of MTB
treatment regimens containing 3 or more drugs (OR:
0.1; Table 3). Independent predictors of MTB infection–
specific mortality included the presence of multiorgan
MTB infection (OR: 8.5) and the use of MTB treatment
regimens containing 3 or more drugs (OR: 0.04).
Kaplan-Meier analysis demonstrated a statistically sig-
nificant association with the type of MTB induction
drug regimen and mortality (Fig. 2).

DISCUSSION
Isoniazid LTBI treatment for TST-positive liver trans-
plant candidates is controversial.
13-18,109-112
The prev
-
alence of isoniazid-induced acute liver failure within
the general population is low (between 3.2 and 14 per
100,000 treated patients).
113-116
However, patients
with abnormal liver biochemical tests at baseline are at
higher risk for developing isoniazid hepatotoxicity.
117
Our meta-analysis reveals an association between LTBI
treatment and reduced prevalence of active MTB in liver
transplant candidates with latent MTB risk factors (a
pretransplant positive TST, an abnormal pretransplant
chest roentgenogram, or a recent high-risk MTB expo-
sure history; 0% versus 8.2%, P ϭ 0.02) over a short
follow-up period of 53 months. Two previous random-
ized studies of isoniazid LTBI treatment in 184 and 85
renal transplant candidates showed similar reductions
in active MTB infection.
118,119
In our review, clinically
TABLE 2. Predictors of Mortality (Univariate Analysis)
Characteristics
Overall Mortality MTB Mortality
‡

Lived
(n)*
Died
(n)* P Value
†
Lived
(n)*
Died
(n)* P Value
†
Patient characteristics
Mean age (years) 40 (53) 40 (21) 0.88 40 (53) 43 (14) 0.60
Male (%) 74 (54) 55 (20) 0.12 74 (54) 54 (13) 0.15
Transplant center (%) (66) (24) (66) (17)
US or Canadian 27 33 27 35
European 39 29 39 35
Non-US or European 33 38 0.67 33 29 0.81
Year of transplantation Ն 1995 (%) 60 (70) 54 (26) 0.59 60 (70) 50 (18) 0.44
Indication for liver transplantation (%) (52) (19) (52) (13)
Primary biliary cirrhosis 6 21 6 23
Cryptogenic cirrhosis 10 16 10 15
Other 85 63 0.10 85 62 0.11
Type of maintenance immunosuppressive
regimen
Cyclosporine-based versus tacrolimus-
based (%)
§
44 (45) 44 (18) 1.0 44 (45) 42 (12) 0.86
Pre-MTB diagnosis of acute rejection (%) 26 (62) 45 (20) 0.11 26 (62) 31 (13) 0.71
MTB clinical and treatment characteristics

Type of MTB (%)
Pulmonary involvement versus no
pulmonary involvement
37 (65) 18 (22) 0.10 37 (65) 20 (15) 0.21
Disseminated MTB (Ն1 organ) 26 (65) 41 (22) 0.19 26 (65) 53 (15) 0.04
Transplant MTB
࿣
7 (62) 5 (20) 0.81 7 (62) 0 (13) 0.35
Symptoms to diagnosis Ͻ 1 month (versus
Ն1 month; %)
50 (36) 17 (12) 0.04 50 (36) 0 (7) 0.014
MTB induction regimen (%)
No drugs 0 (61) 16 (19) 0.002 0 (61) 25 (12) Ͻ0.001
Two drug versus other drug regimen 5 (61) 6 (16) 0.83 5 (61) 11 (9) 0.45
ՆThree drugs versus other drug regimen 95 (61) 94 (16) 0.83 95 (61) 67 (12) 0.002
Post-MTB complications
Isoniazid hepatotoxicity (%) 25 (61) 13 (16) 0.30 25 (61) 0 (9) 0.09
Rifampin hepatotoxicity (%) 7 (61) 13 (16) 0.43 7 (61) 0 (9) 0.43
Post-MTB diagnosis of acute rejection (%) 13 (45) 33 (18) 0.07 13 (45) 8 (12) 0.64
Requiring liver retransplant 4 (45) 6 (18) 0.85 4 (45) 0 (12) 0.46
Abbreviation: MTB, Mycobacterium tuberculosis.
*
The number of patients used in each analysis is shown in parentheses.
†
The P value is for the comparison between cases that lived and died.
‡
Cases were excluded when the reporting authors determined that the cause of death was not directly caused by MTB (n ϭ 17).
§
All reported immunosuppressive regimens were either cyclosporin-based or tacrolimus-based.
࿣

The reporting authors determined that the MTB infection was from transplant organs (n ϭ 5).
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significant hepatotoxicity related to LTBI treatment in
liver transplant candidates was relatively uncommon,
with 6% of patients requiring LTBI treatment discontin-
uation, 1% requiring emergent liver transplantation (ie,
for drug-induced hepatotoxicity with acute liver fail-
ure), and no associated deaths. Forty-four percent of
transplant recipients with active MTB infection (exclud-
ing the 5 cases of MTB infection with a source from the
transplanted organ) had a pretransplant positive TST
result, an abnormal pretransplant chest roentgeno-
gram, a previous history of untreated MTB infection, or
a recent high-risk MTB exposure history (ie, direct pa-
tient contact with active MTB infection).
Non–human immunodeficiency virus (HIV)–infected
but actively immunosuppressed patients are at high
risk for developing active MTB infection.
120
We found
that the prevalence of active MTB infection (both cur-
rent and past) in liver transplant recipients (1.3%) is
similar to the reported prevalence in other solid-organ
transplant recipients (ϳ1%) over an estimated mean
follow-up of approximately 3.1 years post-trans-
plant.
10,52,109
Given the 10% lifetime risk of progres
-

sion from latent MTB infection to active MTB infection
even in the absence of chronic immune suppression,
the prevalence in this population may increase over
longer follow-up.
7,8,12,121
The reported incidence of ac
-
tive MTB infection in the US general population for the
year 2006 was 4.6 per 100,000.
2,122
We observed an
18-fold increase of active MTB disease incidence in liver
transplant recipients at US centers (85 per 100,000
annually) compared to the general US population.
We observed short-term 31% overall and 18% MTB
infection–specific mortality rates (mean follow-up of 27
months). A review by Singh et al.
10
similarly found an
overall MTB infection mortality rate of 29% in all solid-
organ transplant recipients. In 2004, 657 deaths and
14,517 cases of MTB infection were reported in the
United States, with an estimated mortality rate of
4.5%.
2
We observed a 3.8-fold increase in mortality in
US liver transplant recipients with active MTB infection
TABLE 3. Effects of Patient and Disease Progression Characteristics on Mortality
Model Coefficient P Value Odds Ratio 95% CI
Overall mortality

Intercept 0.15 — — —
Pre-MTB acute rejection* 1.1 0.07 3.0 0.9–10
Post-MTB acute rejection
†
1.6 0.02 5.0 1.2–20
ՆThree-drug MTB induction regimen
‡
Ϫ2.3 0.009 0.1 0.02–0.6
MTB-specific mortality
Intercept 0.07 — — —
ϾOne-organ MTB
§
2.1 0.01 8.5 1.6–45
ՆThree-drug MTB induction regimen
‡
Ϫ3.2 0.003 0.04 0.005–0.3
NOTE: This table presents the results of the logistic regression analysis. The Hosmer and Lemeshow statistics for overall
mortality (P ϭ 0.33) and MTB-specific mortality (P ϭ 0.93) models support the models’ adequacy for the data.
Abbreviations: CI, confidence interval; MTB, Mycobacterium tuberculosis.
*One or more episodes of moderate to severe acute rejection prior to the diagnosis of active MTB.
†
One or more episodes of moderate to severe acute rejection after the diagnosis of active MTB.
‡
The MTB induction drug regimen consisted of 3 or more drugs.
§
More than 1 organ was infected with MTB (ie, disseminated extrapulmonary or miliary MTB).
TABLE 4. Summary of Key Findings for Tuberculosis Infection in Liver Transplant Recipients
1. Approximately 1% of liver transplant recipients develop active MTB infection.
2. Less than one-third of all liver transplant recipients have a known TST result. Of patients with active MTB and
known TST, 37% have a positive test. Even though it is a preventable disease, few liver transplant recipients receive

latent tuberculosis therapy. Isoniazid latent MTB treatment appears effective, causing severe hepatotoxicity in ϳ1%
of patients.
3. More than 60% of liver transplant recipients with active MTB have extrapulmonary involvement.
4. Approximately 35% of patients will have active MTB drug regimens altered or stopped because of hepatotoxicity. The
long-term sequela of antibiotic-related hepatoxicity is rare.
5. The short-term mortality rate for liver transplant recipients with active tuberculosis is 31%. Surviving patients are
more likely to have received multidrug tuberculosis induction regimens or to have been diagnosed within 1 month of
symptom onset and are less likely to have disseminated disease or experience episodes of acute transplant rejection.
6. The available data support establishing a standard approach to liver transplant candidates, which should include
MTB testing, with appropriate pretransplantation treatment for patients who are found to have MTB infection (latent
or active).
Abbreviations: MTB, Mycobacterium tuberculosis; TST, tuberculin skin test.
900 HOLTY ET AL.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
compared to the US general population (17.1% versus
4.5%). The mortality rate for untreated active MTB in-
fection was 100%.
Given the relatively high prevalence and mortality of
posttransplant active MTB infection compared with the
relatively low rate of observed toxicity associated with
LTBI treatment in liver transplant candidates, we rec-
ommend that all liver transplant candidates receive a
TST and that isoniazid LTBI treatment be given to all
patients with a positive TST result or pretransplant risk
factors for MTB infection prior to transplantation, bar-
ring a specific contraindication (ie, previous isoniazid
hepatotoxicity). Our recommendation to provide isoni-
azid LTBI treatment to at-risk liver transplant candi-
dates is supported by the American Society of Trans-
plantation

123
as well as experts at other transplant
centers.
61,62,91,93
Furthermore, 1 person with active
MTB infects 2 to 30 other individuals,
124,125
with
higher transmission rates for hospitalized patients not
in respiratory isolation.
126
The mean time from symp
-
tom onset to diagnosis of active MTB infection in our
review was 4 weeks, and this demonstrates the pres-
ence of a significant risk period during which a patient
with active MTB disease might infect others before di-
agnosis and therapy are established.
Both the Centers for Disease Control and Prevention
and the American Society of Transplantation prefer 9
months of isoniazid for LTBI treatment over other po-
tential therapies (rifampin or rifampin-pyrazinamide)
because of its lower hepatoxicity and the higher quality
of the evidence supporting efficacy.
123,127,128
Ari
-
fampin-containing regimen may be considered in pa-
tients at risk for isoniazid-resistant LTBI. Some centers
have recommended initiating LTBI treatment after

transplant once liver function is stable in at-risk pa-
tients.
43,129
This recommendation is problematic, given
the observed mean time of 8.5 months from transplant
to MTB infection diagnosis, with a higher associated
mortality in liver transplant recipients who developed
active MTB infection within 5 months post-transplant
versus liver transplant recipients who developed active
MTB infection after 5 months (36% versus 17%, P ϭ
0.04).
Immunosuppression due to HIV infection and immu-
nosuppressive therapy in solid-organ transplant recip-
ients are recognized risk factors for false-negative TST
reactions.
130
A TST reaction Ն 5 mm defines LTBI in
these immunosuppressed patients.
131
Whether chronic
liver disease or hepatitis is a risk factor for false-nega-
tive TST reactions is controversial.
132-134
Two recent
studies found no association between a positive TST
result and hepatitis B virus
135
or hepatitis C virus in
-
fection.

136
We similarly found no association between a
positive TST result and liver transplant recipients with
or without hepatitis B or C infection. Additionally, TST
has poor sensitivity (ϳ80%) in patients without appar-
ent immunosuppression and with active MTB infec-
tion.
137
In liver transplant recipients with a known TST
result and active MTB infection, we found only 37% had
a positive pretransplant TST and 35% had a positive
posttransplant TST. Clearly, the lack of a positive TST
does not exclude the possibility of latent or active MTB
infection in this unique patient population.
Most false-positive TST reactions are due to antigen
cross-reactions with nontuberculous mycobacteria or
prior vaccination with bacille Calmette-Guerin
(BCG).
138
BCG-vaccinated patients are more likely have
a true-positive TST if BCG was given Ն10 years previ-
ously or if the induration is Ն10 mm.
139
The new gam
-
ma-interferon release assays have shown promise in
distinguishing positive TST due to BCG vaccination
from positive TST due to MTB infection.
140
However,

Figure 2. Kaplan-Meier esti-
mate of death. Overall mortality
was statistically significantly
associated with the type of MTB
drug regimen (P < 0.001 by log-
rank test). The observed short-
term mortality was higher in pa-
tients given no MTB drug
therapy (100%; n ؍ 3) versus pa-
tients given 2-drug (25%; n ؍ 4),
3-drug (15%; n ؍ 26), or >4-
drug regimens (11%; n ؍ 36).
Abbreviation: MTB, Mycobacte-
rium tuberculosis.
TUBERCULOSIS IN LIVER TRANSPLANT RECIPIENTS 901
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
these assays have not been well studied in liver trans-
plant candidates or recipients.
25,141
In the United States, 28% of all active MTB cases have
extrapulmonary involvement.
2
In our series of liver
transplant recipients, 67% had extrapulmonary in-
volvement, 27% had multiorgan (miliary) disease, and
only 33% had isolated active pulmonary MTB infection.
It is known that immunosuppression from HIV predis-
poses to extrapulmonary and miliary MTB infection.
142
Because of the relatively high prevalence of MTB dis-

ease in liver transplant recipients, and because these
patients are more likely to present with nonpulmonary
symptoms, a high degree of suspicion for MTB infection
is warranted. Patients diagnosed within 1 month after
symptom onset have reduced MTB mortality (0% versus
25%, P ϭ 0.01). We observed that at US transplant
centers, recipients not born in the United States were
diagnosed sooner after symptom onset (0.3 versus 1.3
months, P ϭ 0.005) with an associated decreased MTB-
specific mortality (0% versus 55%, P ϭ 0.002) in com-
parison with recipients born in the United States. This
finding may reflect a higher degree of suspicion for MTB
in patients with identifiable pretransplant risk factors.
We observed that 34% of liver transplant recipients
had an episode of moderate to severe allograft rejection
(usually treated with high-dose steroids) prior to MTB
diagnosis. Patients who do not receive LTBI treatment
despite pretransplant MTB infection risk factors and
who develop acute cellular rejection (requiring aggres-
sive immunosuppression) may be at higher risk for
MTB reactivation.
Because of the overall heterogeneity and relatively
few reported cases, we were unable to assess the effi-
cacy of specific MTB drug regimens in this patient pop-
ulation. No patient received single-drug MTB therapy,
but 5% received induction regimens containing only 2
drugs. Given the rise of multidrug-resistant MTB
strains, the Centers for Disease Control and Prevention
recommends MTB induction regimens containing at
least 3 drugs followed by de-escalation.

19
Our analysis has several potential limitations. First,
because we did not have access to the original medical
records, our analyses depended on the completeness
and accuracy of the reporting physicians. Second,
cases were highly heterogeneous with respect to nation-
ality and MTB treatment regimen. Thus, our findings
may be attributed to patient characteristics, MTB drug
efficacy, or other confounding factors that we could not
assess or control. Third, despite an exhaustive search,
we may not have identified all cases of active MTB
infection in liver transplant recipients. Patients who
have heavy alcohol consumption are at higher risk for
developing active MTB infection.
2,125,143-145
Although
nearly half of all liver transplants in the United States
are performed for chronic hepatitis C or alcoholic liver
disease,
3
only 1 patient in our review had alcohol-re
-
lated liver failure. Given the association between heavy
alcohol consumption and MTB reactivation, the lack of
alcohol-related liver disease in our review may reflect
an underreporting of MTB infection, and the true prev-
alence of active MTB infection in liver transplant recip-
ients may be higher. Fourth, because of the limited
number of cases, we could not include all potential
interaction terms in our regression models. Finally,

these data did not allow us to assess the potential
effects of antibiotic resistance on MTB therapy in this
population.
Despite being a preventable disease, active MTB in-
fection in liver transplant recipients is relatively com-
mon with a very high associated mortality. On the basis
of the available evidence, the benefits of treating latent
MTB appear to exceed the risks, and this provides jus-
tification for a test and treat strategy. In order to estab-
lish a timely diagnosis and initiate appropriate therapy,
a high degree of suspicion for MTB infection is needed
in liver transplant candidates and recipients.
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