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

We examined the efficacy of isoniazid latent Mycobacterium tuberculosis infection LTBI treatment in liver transplant recipients and reviewed systematically all cases of active MTB infecti

ORIGINAL ARTICLE

Tuberculosis in Liver Transplant Recipients: A

Systematic Review and Meta-Analysis of

Individual Patient Data

Jon-Erik C Holty,1,2Michael K Gould,1,2,4Laura Meinke,5Emmet B Keeffe,3and Stephen J Ruoss2

1Center for Primary Care and Outcomes Research, Stanford University, Stanford, CA; Divisions of

2

Pulmonary and Critical Care Medicine and3Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA;4VA Palo Alto Health Care System, Palo Alto, CA; and

5Division 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 ⫽ 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 ⫽ 0.003) and to have been diagnosed within 1 month of symptom onset (P ⫽ 0.01) and were less likely to have multiorgan disease (P ⫽ 0.01) or to have experienced episodes of acute transplant rejection (P ⫽ 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.1,2Liver 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.5Predisposing 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, MycobacteMycobacte-rium 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: jholty@stanford.edu

DOI 10.1002/lt.21709

Published online in Wiley InterScience (www.interscience.wiley.com)

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 disdis-ease-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 ⱖ3-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 ( ⱖ3-drug regimen) or inadequate MTB induction ⱖ3-drug

ther-LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases

apy.19We assessed each variable by stepwise backward

regression using a P value cutoff of ⱕ0.1 Because

⬍50% 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.

11,13-18,20-90We 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-ies11,13,15,16,18,20,21,23,28-34,39,43,44,46,47,51-58,65,66,76,77,81,

82,87,90 provided sufficient information to calculate the

prevalence of MTB in liver transplant recipients, and 15

reports of 7 studies15,16,43-46,51-53,55,61,62,91-93evaluated

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⬍ 0.001) The estimated annual incidence of active MTB infection at all transplant centers was 450 per 100,000 liver 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.

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⫽ 1.0)

We identified only 3 studies that retrospectively pro-vided TST status in all liver transplant recipi-ents.15,16,43-46,76,77Two 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 retropro-spective, and none used a

ran-TABLE 1 Patient and MTB Characteristics Characteristics (n)

Patient characteristics

Location of transplant center (%; n⫽ 139)

Reason for liver transplantation (%; n⫽ 80)

MTB risk factors

History of untreated/improperly treated MTB (%; n⫽ 93) 13

Abnormal pretransplant chest roentgenogram (%; n⫽ 87) 23

Pre-MTB moderate to severe acute rejection (%; n⫽ 86) 34

MTB clinical characteristics

Time to MTB diagnosis post–liver transplant (months; n⫽ 100) 8.5⫾ 8.9

Time from MTB diagnosis to death (months; n⫽ 20) 7.5⫾ 14.6

Time from MTB diagnosis to death (months; n⫽ 12) 1.7⫾ 3.2

Follow-up (survivors)

NOTE: Plus or minus values are means (or percentages)⫾ 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⫽ 5)

LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases

domized protocol Of 224 patients with a positive

pretransplant TST result, 61 received ⱖ6 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 ⱖ6

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⫽ 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 (ⱖ6 months) was statistically

signifi-cantly associated with a reduction in developing active

MTB (0.0% versus 8.2%, P⫽ 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 ⫽ 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 hepahepa-titis C virus infection (29% with

versus 28% without, P⫽ 0.94), MTB liver involvement

(29% with versus 26% without, P ⫽ 0.80), or acute cellular rejection prior to MTB diagnosis (30% with

ver-sus 26% without, P ⫽ 0.68) However, patients with acute transplant rejection after MTB diagnosis were more likely to have had MTB drug hepatotoxicity (58%

versus 25%, P⫽ 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⫽ 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 (⫾24.9) months Patients who were diagnosed with active MTB infection within 5 months post-transplant had higher observed mortality

(36% versus 17%, P⫽ 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⫽ 0.014), the absence of any MTB antibiotic

therapy (100% versus 13% mortality, P⬍ 0.001), and the presence of fewer than 3 drugs in the initial MTB

treatment regimen (57% versus 12% mortality, P ⫽ 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 ⫽ 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⫽ 0.005)

In multivariate logistic regression analysis,

indepen-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.13-18,109-112The

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⫽ 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

Year of transplantationⱖ 1995 (%) 60 (70) 54 (26) 0.59 60 (70) 50 (18) 0.44 Indication for liver transplantation (%) (52) (19) (52) (13)

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 (ⱖ1 organ) 26 (65) 41 (22) 0.19 26 (65) 53 (15) 0.04

Symptoms to diagnosis⬍ 1 month (versus

0.014 MTB induction regimen (%)

Two drug versus other drug regimen 5 (61) 6 (16) 0.83 5 (61) 11 (9) 0.45 ⱖThree 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⫽ 17)

§All reported immunosuppressive regimens were either cyclosporin-based or tacrolimus-based

㛳The reporting authors determined that the MTB infection was from transplant organs (n⫽ 5)

LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases

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.120We 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 (⬃1%) 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.7,8,12,121The 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.10similarly 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%.2We 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

Overall mortality

Post-MTB acute rejection†

ⱖThree-drug MTB induction regimen‡ ⫺2.3 0.009 0.1 0.02–0.6 MTB-specific mortality

⬎One-organ MTB§

ⱖThree-drug MTB induction regimen‡ ⫺3.2 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 ⫽ 0.33) and MTB-specific mortality (P ⫽ 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⬃1%

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.

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-plantation123 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.126The 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 A

ri-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.43,129This 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⫽ 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 reactionⱖ 5 mm defines LTBI in these immunosuppressed patients.131Whether 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 virus135or hepatitis C virus in-fection.136We 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 (⬃80%) in patients without appar-ent immunosuppression and with active MTB infec-tion.137In 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).138BCG-vaccinated patients are more likely have

a true-positive TST if BCG was givenⱖ10 years previ-ously or if the induration isⱖ10 mm.139The 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 ⴝ 3) versus

pa-tients given 2-drug (25%; n ⴝ 4),

3-drug (15%; n ⴝ 26), or

>4-drug regimens (11%; n ⴝ 36).

Abbreviation: MTB,

Mycobacte-rium tuberculosis.

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 ⫽ 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⫽ 0.005) with an associated decreased

MTB-specific mortality (0% versus 55%, P⫽ 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,3only 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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