LIVER TRANSPLANTATION 15:894-906, 2009 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 Ruoss2 Center for Primary Care and Outcomes Research, Stanford University, Stanford, CA; Divisions of Pulmonary and Critical Care Medicine and 3Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA; 4VA Palo Alto Health Care System, Palo Alto, CA; and 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 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 or more drugs for MTB induction therapy (P ϭ 0.003) and to have been diagnosed within 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 hospitalizations each year.1,2 Liver transplantation is an effective treatment for irreversible liver failure Approxi- mately 90% of transplant recipients survive the first year, and 70% survive 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 immunosuppression 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 Mycobacterium 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: jholty@stanford.edu DOI 10.1002/lt.21709 Published online in Wiley InterScience (www.interscience.wiley.com) © 2009 American Association for the Study of Liver Diseases TUBERCULOSIS IN LIVER TRANSPLANT RECIPIENTS 895 third of the world’s population is infected with Mycobacterium tuberculosis (MTB).6 Approximately 10% of infected individuals will develop active tuberculosis at some time in their lives.7,8 A decreased immune response enhances the risk of developing active MTB disease and is associated with higher disease-specific mortality.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 However, because existing studies have described small samples, we not have a clear understanding of the extent to which patient characteristics and treatment factors affect mortality Furthermore, although isoniazid therapy for latent Mycobacterium tuberculosis infection (LTBI) significantly reduces the rate of MTB reactivation,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 consequences that could arise from reactivation of a previously 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 between 1963 (the first report of a liver transplant) and 2007 to evaluate the effectiveness of pretransplant tuberculosis skin testing and LTBI treatment, the prevalence and outcome of MTB infections, and the effects of patient factors and treatment on mortality from MTB infection PATIENTS AND METHODS plant chest roentgenogram, a previous history of untreated MTB, or a recent high-risk MTB exposure history) Patients receiving or more months of isoniazid 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 additional potentially relevant studies Two investigators independently abstracted data from each article We resolved abstraction discrepancies by repeated discussion If 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 abstracted data about patient characteristics, transplantrelated factors, and MTB infection–specific factors Active pulmonary MTB infection was defined as including lung or mediastinal lymph node involvement We defined multiorgan (ie, miliary) MTB infection as involvement of or more organs (lymph nodes draining infected organs were not considered to be separate organs) Patients with both pulmonary and pleural involvement were not considered to have disseminated MTB infection unless nonthoracic organ involvement was noted We classified patients who received antibiotics that 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 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 bibliographies to identify liver transplant recipients with MTB infection (Appendix Fig A1) We considered all reports of MTB infection (latent or active) in liver transplant candidates or recipients eligible for inclusion, regardless of language 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 comparisons, we considered a P value less than 0.05 to be statistically significant For multiple group comparisons, we applied a Bonferroni correction We plotted Kaplan-Meier curves to estimate the time from transplant to symptom onset and diagnosis of MTB for patients with pretransplant risk factors for MTB exposure Study Selection Evaluating Predictors of Mortality 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 tuberculin skin test (TST) result in the absence of symptoms or clinical findings suggestive of active infection In analyzing LTBI treatment, we included studies reporting 10 or more patients with a known pretransplant MTB infection risk factor (positive TST, an abnormal pretrans- We used a multivariate logistic regression model to examine the association between the following variables and survival: age (continuous variable), gender, indication for transplant, whether MTB therapy was given, whether patients received a Ն3-drug MTB induction regimen, whether the MTB infection was limited to pulmonary 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 (Ն3drug regimen) or inadequate MTB induction drug ther- LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases 896 HOLTY ET AL Figure Literature search and selection 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 additional references from our manual search of the bibliographies 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.11,1318,20-90 We included an additional liver transplant patient 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 studies11,13,15,16,18,20,21,23,28-34,39,43,44,46,47,51-58,65,66,76,77,81, 82,87,90 provided sufficient information to calculate the prevalence of MTB in liver transplant recipients, and 15 reports of studies15,16,43-46,51-53,55,61,62,91-93 evaluated latent MTB treatment in liver transplant candidates or recipients We excluded 15 studies with pretransplant active MTB patients who developed fulminant hepatic failure 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 From the 20 studies that provided sufficient information, the prevalence of active MTB infection in liver transplant recipients was 1.3% (104/8296) The prevalence was lower at US or Canadian 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 transplant recipients The incidence was lower at US transplant 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 sufficient 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 LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases TUBERCULOSIS IN LIVER TRANSPLANT RECIPIENTS 897 TABLE Patient and MTB Characteristics Characteristics (n) Patient characteristics Mean age (years; n ϭ 98) Male (%; n ϭ 94) Location of transplant center (%; n ϭ 139) United States or Canada Europe Outside of United States or Europe Year of transplant (n ϭ 139) Reason for liver transplantation (%; n ϭ 80) Hepatitis B virus Hepatitis C virus Cryptogenic cirrhosis Primary biliary cirrhosis Biliary atresia MTB risk factors Pretransplant TST performed (%; n ϭ 97) Positive TST (n ϭ 38) Negative TST (n ϭ 38) Anergic TST (n ϭ 38) History of untreated/improperly treated MTB (%; n ϭ 93) Abnormal pretransplant chest roentgenogram (%; n ϭ 87) Pre-MTB moderate to severe acute rejection (%; n ϭ 86) MTB clinical characteristics Transplant MTB (%; n ϭ 82)* Pulmonary MTB (%; n ϭ 102) Extrapulmonary MTB (%; n ϭ 102) Liver Pleural Nonthoracic lymphadenitis Genitourinary Nonhepatic gastrointestinal Brain/meningitis Multiorgan MTB (n ϭ 102) Time to MTB diagnosis post–liver transplant (months; n ϭ 100) Overall mortality (%; n ϭ 127) Time from MTB diagnosis to death (months; n ϭ 20) Mortality from active MTB infection (%; n ϭ 22) Time from MTB diagnosis to death (months; n ϭ 12) Follow-up (survivors) Time from transplant (months; n ϭ 72) Time from MTB diagnosis (months; n ϭ 72) 40 Ϯ 19.2 72 27 37 36 1995 Ϯ 4.7 35 14 10 39 37 53 11 13 23 34 60 67 26 23 10 10 27 8.5 Ϯ 8.9 31 7.5 Ϯ 14.6 65 1.7 Ϯ 3.2 30 Ϯ 25.3 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) 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 pretransplant chest roentgenograms (Table 1) Of the 10 patients with a positive TST and pretransplant radiograph, (30%) had abnormal pretransplant chest roentgenograms (2 had apical fibrotic opacities, and 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 hepatitis C virus infection, P ϭ 1.0) We identified only studies that retrospectively provided TST status in all liver transplant recipients.15,16,43-46,76,77 Two of studies were at US transplant 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 factors.15,16,43-46,51-53,55,61,62,91-93 Two studies were prospective, were retrospective, and none used a ran- LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases 898 HOLTY ET AL domized protocol Of 224 patients with a positive pretransplant TST result, 61 received Ն6 months of isoniazid, 16 received less than months of isoniazid, 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, patients not receiving LTBI treatment developed active MTB infection (0.0% versus 5.1%, P ϭ 0.079) during a mean follow-up of approximately 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 significantly associated with a reduction in developing active MTB (0.0% versus 8.2%, P ϭ 0.022, absolute risk reduction: 8.2%) Five of 84 patients (including patients with negative TST results and patients with unknown TST results) had isoniazid discontinued because of hepatotoxicity (6.0%), with only patient having drug-induced liver failure requiring liver transplantation (1.2%) Posttransplant Active MTB Infection Clinical Characteristics In of the 139 included cases, MTB infection was suspected to have arisen from the transplanted organ Of 17 patients with a posttransplant TST (none had a pretransplant 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 treatment regimen Seven patients received no MTB drug therapy Of the 86 patients with known MTB induction therapy, 94% received drug regimens including isoniazid, 81% received drug regimens including ethambutol, 76% received drug regimens including rifampin or rifabutin, 51% received drug regimens including pyrazinamide, 31% received drug regimens including a fluoroquinolone, and 17% received drug regimens including streptomycin Induction drug regimens consisted of drugs in 5% of regimens, drugs in 43%, drugs in 45%, and more than drugs in 7% Maintenance MTB therapy regimens (n ϭ 56) consisted of isoniazid in 70% of treated patients, ethambutol in 73%, rifampin or rifabutin in 45%, any fluoroquinolone in 52%, pyrazinamide in 18%, and streptomycin in 14% Most maintenance regimens consisted of 2-drug (46%) or 3-drug (29%) regimens No patients received single-drug MTB therapy during induction or maintenance therapy Of 50 surviving patients who completed MTB drug therapy, the mean duration 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 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 effect attributed to drug therapy Of these 30 patients, 24 (73%) had hepatotoxicity, and (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 rifabutin Hepatotoxicity was not associated with hepatitis 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 versus 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 immunosuppressive regimen did not have a significant impact on this effect (35% for cyclosporine versus 42% for tacrolimus, P ϭ 0.57) The mean time from initiation of MTB antibiotic therapy to identification of hepatotoxicity was 3.1 months (range: 0.2-18) Most cases of hepatotoxicity were reversible, although patients required liver retransplantation Of these, patient died months post–MTB diagnosis, whereas the other patients 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 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-specific mortality are shown in Table Statistically significant predictors of mortality in the 22 deaths attributed to MTB infection included diagnosis of MTB greater than 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 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- LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases TUBERCULOSIS IN LIVER TRANSPLANT RECIPIENTS 899 TABLE Predictors of Mortality (Univariate Analysis) MTB Mortality‡ Overall Mortality Characteristics Patient characteristics Mean age (years) Male (%) Transplant center (%) US or Canadian European Non-US or European Year of transplantation Ն 1995 (%) Indication for liver transplantation (%) Primary biliary cirrhosis Cryptogenic cirrhosis Other Type of maintenance immunosuppressive regimen Cyclosporine-based versus tacrolimusbased (%)§ Pre-MTB diagnosis of acute rejection (%) MTB clinical and treatment characteristics Type of MTB (%) Pulmonary involvement versus no pulmonary involvement Disseminated MTB (Ն1 organ) Transplant MTB࿣ Symptoms to diagnosis Ͻ month (versus Ն1 month; %) MTB induction regimen (%) No drugs Two drug versus other drug regimen ՆThree drugs versus other drug regimen Post-MTB complications Isoniazid hepatotoxicity (%) Rifampin hepatotoxicity (%) Post-MTB diagnosis of acute rejection (%) Requiring liver retransplant Lived (n)* Died (n)* Lived (n)* Died (n)* 40 (53) 74 (54) (66) 27 39 33 60 (70) (52) 10 85 40 (21) 55 (20) (24) 33 29 38 54 (26) (19) 21 16 63 43 (14) 54 (13) (17) 35 35 29 50 (18) (13) 23 15 62 0.60 0.15 0.10 40 (53) 74 (54) (66) 27 39 33 60 (70) (52) 10 85 44 (45) 44 (18) 1.0 44 (45) 42 (12) 0.86 26 (62) 45 (20) 0.11 26 (62) 31 (13) 0.71 37 (65) 18 (22) 0.10 37 (65) 20 (15) 0.21 26 (65) (62) 50 (36) 41 (22) (20) 17 (12) 0.19 0.81 0.04 26 (65) (62) 50 (36) 53 (15) (13) (7) 0.04 0.35 0.014 (61) (61) 95 (61) 16 (19) (16) 94 (16) 0.002 0.83 0.83 (61) (61) 95 (61) 25 (12) 11 (9) 67 (12) Ͻ0.001 0.45 0.002 25 13 13 13 33 (9) (9) (12) (12) 0.09 0.43 0.64 0.46 (61) (61) (45) (45) (16) (16) (18) (18) P Value† 0.88 0.12 0.67 0.59 0.30 0.43 0.07 0.85 25 13 (61) (61) (45) (45) P Value† 0.81 0.44 0.11 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) dent predictors of overall mortality included the presence of acute cellular rejection following MTB infection diagnosis [odds ratio (OR): 5.0] and the use of MTB treatment regimens containing 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 or more drugs (OR: 0.04) Kaplan-Meier analysis demonstrated a statistically significant association with the type of MTB induction drug regimen and mortality (Fig 2) DISCUSSION Isoniazid LTBI treatment for TST-positive liver transplant 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 exposure history; 0% versus 8.2%, P ϭ 0.02) over a short follow-up period of 53 months Two previous randomized 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 LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases 900 HOLTY ET AL TABLE Effects of Patient and Disease Progression Characteristics on Mortality Model Coefficient Overall mortality Intercept Pre-MTB acute rejection* Post-MTB acute rejection† ՆThree-drug MTB induction regimen‡ MTB-specific mortality Intercept ϾOne-organ MTB§ ՆThree-drug MTB induction regimen‡ P Value Odds Ratio 95% CI 0.15 1.1 1.6 Ϫ2.3 — 0.07 0.02 0.009 — 3.0 5.0 0.1 — 0.9–10 1.2–20 0.02–0.6 0.07 2.1 Ϫ3.2 — 0.01 0.003 — 8.5 0.04 — 1.6–45 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 or more drugs § More than organ was infected with MTB (ie, disseminated extrapulmonary or miliary MTB) TABLE Summary of Key Findings for Tuberculosis Infection in Liver Transplant Recipients Approximately 1% of liver transplant recipients develop active MTB infection 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 More than 60% of liver transplant recipients with active MTB have extrapulmonary involvement 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 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 month of symptom onset and are less likely to have disseminated disease or experience episodes of acute transplant rejection 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 significant hepatotoxicity related to LTBI treatment in liver transplant candidates was relatively uncommon, with 6% of patients requiring LTBI treatment discontinuation, 1% requiring emergent liver transplantation (ie, for drug-induced hepatotoxicity with acute liver failure), and no associated deaths Forty-four percent of transplant recipients with active MTB infection (excluding the cases of MTB infection with a source from the transplanted organ) had a pretransplant positive TST result, an abnormal pretransplant chest roentgenogram, a previous history of untreated MTB infection, or a recent high-risk MTB exposure history (ie, direct patient 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 current 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-transplant.10,52,109 Given the 10% lifetime risk of progression 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 active 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 solidorgan 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 LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases TUBERCULOSIS IN LIVER TRANSPLANT RECIPIENTS 901 Figure Kaplan-Meier estimate of death Overall mortality was statistically significantly associated with the type of MTB drug regimen (P < 0.001 by logrank test) The observed shortterm mortality was higher in patients given no MTB drug therapy (100%; n ‫ )3 ؍‬versus patients given 2-drug (25%; n ‫,)4 ؍‬ 3-drug (15%; n ‫ ,)62 ؍‬or >4drug regimens (11%; n ‫.)63 ؍‬ Abbreviation: MTB, Mycobacterium tuberculosis compared to the US general population (17.1% versus 4.5%) The mortality rate for untreated active MTB infection 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 recommend 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, barring a specific contraindication (ie, previous isoniazid hepatotoxicity) Our recommendation to provide isoniazid LTBI treatment to at-risk liver transplant candidates is supported by the American Society of Transplantation123 as well as experts at other transplant centers.61,62,91,93 Furthermore, person with active MTB infects to 30 other individuals,124,125 with higher transmission rates for hospitalized patients not in respiratory isolation.126 The mean time from symptom onset to diagnosis of active MTB infection in our review was weeks, and this demonstrates the presence of a significant risk period during which a patient with active MTB disease might infect others before diagnosis and therapy are established Both the Centers for Disease Control and Prevention and the American Society of Transplantation prefer months of isoniazid for LTBI treatment over other potential therapies (rifampin or rifampin-pyrazinamide) because of its lower hepatoxicity and the higher quality of the evidence supporting efficacy.123,127,128 A rifampin-containing regimen may be considered in patients at risk for isoniazid-resistant LTBI Some centers have recommended initiating LTBI treatment after transplant once liver function is stable in at-risk patients.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 months post-transplant versus liver transplant recipients who developed active MTB infection after months (36% versus 17%, P ϭ 0.04) Immunosuppression due to HIV infection and immunosuppressive therapy in solid-organ transplant recipients are recognized risk factors for false-negative TST reactions.130 A TST reaction Ն mm defines LTBI in these immunosuppressed patients.131 Whether chronic liver disease or hepatitis is a risk factor for false-negative TST reactions is controversial.132-134 Two recent studies found no association between a positive TST result and hepatitis B virus135 or hepatitis C virus infection.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 apparent immunosuppression and with active MTB infection.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 previously or if the induration is Ն10 mm.139 The new gamma-interferon release assays have shown promise in distinguishing positive TST due to BCG vaccination from positive TST due to MTB infection.140 However, LIVER TRANSPLANTATION.DOI 10.1002/lt Published on behalf of the American Association for the Study of Liver Diseases 902 HOLTY ET AL these assays have not been well studied in liver transplant 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 involvement, 27% had multiorgan (miliary) disease, and only 33% had isolated active pulmonary MTB infection It is known that immunosuppression from HIV predisposes to extrapulmonary and miliary MTB infection.142 Because of the relatively high prevalence of MTB disease 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 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 MTBspecific mortality (0% versus 55%, P ϭ 0.002) in comparison 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 not receive LTBI treatment despite pretransplant MTB infection risk factors and who develop acute cellular rejection (requiring aggressive 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 efficacy of specific MTB drug regimens in this patient population No patient received single-drug MTB therapy, but 5% received induction regimens containing only drugs Given the rise of multidrug-resistant MTB strains, the Centers for Disease Control and Prevention recommends MTB induction regimens containing at least 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 nationality 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 patient in our review had alcohol-related 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 prevalence 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 infection in liver transplant recipients is relatively common 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 justification for a test and treat strategy In order to establish a timely diagnosis and initiate appropriate therapy, a high degree of suspicion for MTB infection is needed in liver transplant candidates and recipients REFERENCES Minino AM, Heron MP, Smith BL Deaths: preliminary ˜ data 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reported case and review of the literature Am J Transplant 2003;3:88-93 Al-Moamary MS, Al-Baz S, Alothman A, Memish Z, AlJahdali H, Al-Abdulkareem A Does tuberculin skin test predict tuberculosis in patients with end-stage liver disease? 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cure of disseminated infection with nonconventional regimens Transplantation 2000;69:64-69 52 Meyers BR, Halpern M, Sheiner P, Mendelson MH, Neibart E, Miller C Tuberculosis in liver transplant patients Transplantation 1994;58:301-306 53 Meyers BR, Halpern M, Sheiner P, Mendelson MH, Neibart E Increased incidence of tuberculosis in orthotopic liver transplant (OLT) patients: clinical aspects/ strategies for prevention and treatment Abstr Intersci Conf Antimicrob Agents Chemother 1994;34:197 54 Bronster DJ, Emre S, Boccagni P, Sheiner PA, Schwartz ME, Miller CM Central nervous system complications in liver transplant recipients—incidence, timing, and longterm follow-up Clin Transplant 2000;14:1-7 55 Schluger LK, Sheiner PA, Jonas M, Guarrera JV, Fiel IM, Meyers B, Berk PD Isoniazid hepatotoxicity after orthotopic liver transplantation Mt Sinai J Med 1996;63:364369 56 Kahn D, Spearman CW, Millar AJ History of liver transplantation at the University of Cape Town and Groote Schuur Hospital S Afr J Surg 2000;38:88-90 57 Verma A, Dhawan A, Wade JJ, Lim WH, Ruiz G, Price JF, et al Mycobacterium tuberculosis infection in pediatric liver transplant recipients Pediatr Infect Dis J 2000;19: 625-630 58 Verma A, Lim WH, Dhawan A, Baker AJ, Hadzic N, Ruiz G, Wade I, Price JF, Rela M, Heaton ND Mycobacterium tuberculosis infection in paediatric liver transplant recipients [abstract] Hepatology 1999;30(pt 2):667A 59 D’Antiga L, Dhawan A, Portmann B, Francavilla R, Rela M, Heaton N, Mieli-Vergani G Late cellular rejection in paediatric liver transplantation: aetiology and outcome Transplantation 2002;73:80-84 60 Revald P, Olsen BS, Gronbaek H, Duel P Intramedullary tuberculous abscess in a patient with liver transplantation [in Danish] Ugeskr Laeger 2000;162:502-503 61 Chaparro S, Montoya J, Keeffe E, Rhee J, Small P Risk of tuberculosis in tuberculin-positive liver transplant patients Tuber Lung Disease 2000;80:97-98 62 Chaparro SV, Montoya JG, Keeffe EB, Rhee JT, Small PM Risk of tuberculosis in tuberculin skin test-positive liver transplant patients Clin Infect Dis 1999;29:207208 63 Coelho JCU, Wiederkehr JC, Parolin MB, Balbi E, Nassif AE Isolated tuberculosis of the pancreas after orthotopic liver transplantation Liver Transpl Surg 1999;5:153155 64 Lalonde RG, Barkun J Prolonged ciprofloxacin therapy fails to prevent reactivation tuberculosis Clin Infect Dis 1998;27:913-914 65 Quereda Navarro DC, Navas Elorza E, Lopez San Roman A, Moreno Caparros A Febrile syndrome and adrenal lesion in a patient receiving a hepatic transplant [in Spanish] Rev Clin Esp 1998;198:690-700 66 Aguado JM, Herrero JA, Gavalda J, Torre-Cisneros J, ´ Blanes M, Rufı G, et al Clinical presentation and out´ come of tuberculosis in kidney, liver, and heart transplant recipients in Spain Spanish Transplantation Infection Study Group, GESITRA Transplantation 1997;63: 1278-1286 67 Aguado JM, Gavalda J, Torre-Cisneros J, Blanes M, Carvatala J, Moreno A, Munoz P, Gurgui M, Lumbreras C 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 Incidence, risk factors and outcome from tuberculosis in solid organ transplantation: a case-control study Abstr Intersci Conf Antimicrob Agents Chemother 1997;37:206 Folgueira L, Delgado R, Palenque E, Aguado JM, Noriega AR Rapid diagnosis of Mycobacterium tuberculosis bacteremia by PCR J Clin Microbiol 1996;34:512-515 Aguado JM, Hayek M, Palenque E, Lumbreras C, Lizasoain M, Noriega AR Tuberculosis (TB) in solid organ transplantation (SOT): an increasing problem with serious clinical consequences [abstract] Abstr Intersci Conf Antimicrob Agents Chemother 1994;34:107 Abstract J116 Kiuchi T Liver transplantation and tuberculosis [in Japanese] Kekkaku 2000;75:685-690 Kiuchi T, Inomata Y, Uemoto S, Satomura K, Egawa H, Okajima H, et al A hepatic graft tuberculosis transmitted from a living-related donor Transplantation 1997; 63:905-907 Kiuchi T, Tanaka K, Inomata Y, Uemoto S, Satomura K, Egawa H, et al Experience of tacrolimus-based immunosuppression in living-related liver transplantation complicated with graft tuberculosis: interaction with rifampicin and side effects Transplant Proc 1996;28:31713172 Willemart T, Godfraind C, Pieters A, Lerut J, Laterre C Cerebellar tuberculous abscess in a liver transplant patient Acta Neurol Belg 1997;97:55-55 Nishizaki T, Yanaga K, Soejima Y, Kishikawa K, Kajiyama K, Uchiyama H, et al Tuberculosis following liver transplantation: report of a case and review of the literature Transpl Int 1996;9:589-592 Chusid MJ, Splaingard ML, Tweddell JS, Rice TR, Adams M, Havens PL, Kehl KS Pulmonary tuberculosis after lung-liver transplantation for cystic fibrosis Pediatr Infect Dis J 1996;15:462-464 Wada S, Kusne S, Fung J, Rakela J Foreign born is the most important risk factor for tuberculosis infection in adult liver transplant recipients Abstr Intersci Conf Antimicrob Agents Chemother 1996;36:195 Kusne S, Irish W, Geary K, Ondick L, Rakela J, Fung J Anergy panel and purified protein derivative (PPD) skin testing are poor tuberculosis (TB) screening method in adult liver transplant candidates Abstr Intersci Conf Antimicrob Agents Chemother 1995;35:262 Paterson DL, Singh N, Gayowski T, Marino IR Pulmonary nodules in liver transplant recipients Clin Infect Dis 1997;25:486 Ferrell LD, Lee R, Brixko C, Bass NM, Lake JR, Roberts JP, et al Hepatic granulomas following liver transplantation Transplantation 1995;60:926-933 Sokal EM, Silva ES, Hermans D, Reding R, de Ville de Goyet J, Buts JP, Otte JB Orthotopic liver transplantation for Crigler-Najjar type I disease in six children Transplantation 1995;60:1095-1098 Stoblen F, Neuhaus R, Neumann K, Grauhan O, Bechă stein WO, Klein E, et al Tuberculosis in liver transplant recipients: recurrence after transplantation? 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report of three cases and review of the literature Clin Transplant 1992;6:55-61 87 Vajro P, Vegnente A, Devincenzo A, Lorio R, Fontanella A, Guida S, Tedesco M Follow-up of 25 children who underwent liver transplantation [in Italian] Ital J Pediatr 1992;18:44-49 88 Lie TS, Hofer M Tuberculosis following liver transplantation [in German] Dtsch Med Wochenschr 1988;113: 731-734 89 Lie TS, Hofer M, Hohnke C Successful treatment of tuberculosis after liver transplantation Langenbecks Arch Chir 1987;372:893-894 90 Piza F, Funovics J, Muhlbacher F Lebertransplantation—indikation und postoperativer verlauf Wien Klin Wochenschr 1986;98:838-842 91 Jahng AW, Tran T, Bui L, Joyner JL Safety of treatment of latent tuberculosis infection in compensated cirrhotic patients during transplant candidacy period Transplantation 2007;83:1557-1562 92 Singh N, Wagener MM, Gayowski T Safety and efficacy of isoniazid (INH) chemoprophylaxis administered during liver transplant candidacy for the prevention of 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Sepulveda A, Oliveira AC, Bacchella T, Machado MCC, Abdala E Tuberculosis in liver transplant recipients [abstract] World Transplant Congress 2006 Poster Abstracts American Journal of Transplantation... 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