Antibiotic Prophylaxis has no Advantage over Surveillance alone in Terms of the Incidence of Mycobacterium Tuberculosis Infection after Liver Transplantation
Pierluigi Toniutto1*, Davide Bitetto1, Giorgia Corrà2, Nicola Zeni3, Ezio Fornasiere1, Sara Cmet4, Lolita Sasset5, Annarosa Cussigh4, Patrizia Boccagni6, Carmine Gambino3, Paolo Angeli3, Patrizia Burra2 and Edmondo Falleti1
1Department of Medicine, Hepatology and liver transplantation unit, Azienda Sanitaria Universitaria Integrata, University of Udine, Italy
2Department of Surgery, Oncology and Gastroenterology, University of Padua, Italy; Gastroenterology and Mult visceral Transplant Unit, Padua University Hospital, Italy
3Department of Medicine (DIMED), Unit of Internal Medicine and Hepatology, University of Padova, Italy
4Clinical Pathology, Azienda Ospedaliero Universitaria Friuli Centrale, Italy
5Infectious Disease Unit, Padua University Hospital, Italy
6Hepato-Biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Italy
Submission:January 15, 2025;Published:January 20, 2025
*Corresponding author:Pierluigi Toniutto, Hepatology and Liver Transplantation Unit, Azienda Sanitaria Universitaria Integrata, University of Udine, Udine, Italy
How to cite this article:Pierluigi T, Davide B, Giorgia C, Nicola Z, Ezio F, et al. Antibiotic Prophylaxis has no Advantage over Surveillance alone in Terms of the Incidence of Mycobacterium Tuberculosis Infection after Liver Transplantation. Adv Res Gastroentero Hepatol, 2025; 21(2): 556060.DOI: 10.19080/ARGH.2025.21.556060.
Abstract
Screening for latent Mycobacterium tuberculosis (MTB) in liver transplant (LT) candidates and antibiotic prophylaxis in those who test positive is recommended, but its effectiveness remains unclear. This study compared the impact of antibiotic prophylaxis and active surveillance alone on the incidence of MTB infection following LT. Four hundred and ninety-six LT patients that were enrolled in two LT (LT-1 and LT-2) centres were screened for latent MTB infection via the Quantiferon (QTF) test. A total of 88/496 (17.7%) of the QFFs tested positive. Past MTB infection (p=0.030), older age (p<0.001) and hepatocellular carcinoma (p=0.003) were independent predictors of QTF positivity. After LT, 38/59 (64.4%) LT-2 patients and 29/29 (100%) LT-1 QTF-positive patients received antibiotic prophylaxis or active surveillance alone, respectively. MTB infections between LT-2 centres and LT-1 centres were comparable both in all populations (2/262 vs. 1/234, p=0.630) and in QFFs who tested positive (1/59 vs. 1/29, p=0.604). Predictors of MTB infection after LT were hepatitis B virus infection (p=0.004), QTF positivity (p=0.006) and treatment with mycophenolate (p=0.021). All MTB-infected patients were alive after receiving antitubercular treatment. Antibiotic prophylaxis in QTF-positive patients is not superior to observation alone in preventing and determining the clinical outcome of MTB infection following LT.
Keywords:Antibiotic prophylaxis; Surveillance; Mycobacterium tuberculosis; Liver transplantation; Quantiferon; Human immunodeficiency virus
Abbreviations:MTB: Mycobacterium Tuberculosis; LT: Liver Transplant; QTF: Quantiferon; TST: Tuberculin Skin Testing; QFT: QuantiFERON-TB; GESITRA: Group for the Study of Infection in Transplant Recipients; HIV: Human Immunodeficiency Virus; PCR: Polymerase Chain Reaction; IQRs: Interquartile Ranges; HCC: Hepatocellular Carcinoma; IS: Immunosuppressive; HBV: Hepatitis B Virus; CMV: Cytomegalovirus
Introduction
The World Health Organization estimates that approximately one-third of the world’s population is infected with Mycobacterium tuberculosis (MTB) [1] and that up to 10% of infected individuals will develop the symptomatic MTB-related disease during their life [2]. Risk factors for developing MTB-related disease are living in low-income countries, close contact with people with active MTB infection, and impaired immunological function [3,4]. Compared with the general population, liver transplant (LT) recipients are at increased risk of developing MTB infection since their host defense against infections is compromised by immunosuppressive drugs [5]. The acquisition of infection is commonly due to the reactivation of latent infection in patients with previous exposure [4], although reinfection has been described in endemic areas [6]. Furthermore, donor-transmitted MTB accounts for approximately 4% of all cases [7].
Several clinical guidelines recommend systematic screening for latent MTB infection in LT candidates; this can be done by either tuberculin skin testing (TST) or interferon- γ release assays for the detection of the proliferative response of peripheral lymphocytes to specific MTB antigens including the QuantiFERON-TB Gold (QFT) test and chest X-ray findings [8- 11]. In LT candidates who tested positive and after ruling out active MTB disease, the prophylactic antibiotic therapy against MTB reactivation/infection after LT was recommended [12-14]. Scientific societies suggest the use of isoniazid (INH) or rifampin (RIF) for a duration of 6-9 months for all LT recipients who test positive for TST or QFT and suspected latent MTB [13,15-18]. The optimal timing of therapy in relation to the time of LT and the risk of drug-induced hepatotoxicity of INH- and RIF-based regimens in LT recipients continues to be debated [19]. To overcome the potential hepatotoxicity of INH and RIF, a prophylactic regimen based on ethambutol plus either levofloxacin or moxifloxacin for at least 6 months has been suggested by the Group for the Study of Infection in Transplant Recipients (GESITRA) [18]. However, observational studies have shown that the MTB reactivation rate is inferior to the risk of drug-induced hepatotoxicity [20]; thus, some LT centres screen for but do not adopt antibiotic prophylaxis in patients with latent MTB infection [21,22]. Owing to the large variability of prophylactic strategies adopted in LT candidates with latent MTB infection, data regarding their efficacy and safety are still inconclusive. Furthermore, data showing a clear efficacy of antibiotic prophylaxis compared with surveillance alone in reducing the incidence of MTB reactivation/infection after LT are not available. This study evaluated the overall incidence of MTB reactivation/infection after LT to compare the efficacy of antibiotic prophylaxis with that of surveillance alone in preventing MTB reactivation after LT in patients who tested positive for TST or QTF. Furthermore, the safety of antibiotic prophylactic treatment in this population was assessed.
Materials and methods
Patients
All consecutive patients who received an LT from January 1st, 2010, to December 31st, 2018, at two LT centres in northern Italy (the Hepatology and Liver Transplantation Unit, University of Udine, LT-1, and the Gastroenterology and Medicine Departments, University of Padova, LT-2) were enrolled in this study. The inclusion criteria were age ≥18 years, pre-LT diagnostic workup including TST or QFT, post-LT survival of at least 60 days, and post-LT follow-up of at least 1 year. The exclusion criteria were combined solid organ transplantation, active MTB infection for up to one year before LT, and Human Immunodeficiency Virus (HIV) infection. The patients’ main demographic, clinical and laboratory characteristics, as well as the immunosuppressive treatment schedules adopted after LT, were extracted from the electronic medical records of each LT center. Informed consent to participate in the study was obtained from all participants while they agreed to be enlisted for LT. Furthermore, the study was approved by the local internal review boards and ethical committees of the two LT centers. This work was conducted in accordance with the Declaration of Helsinki.
Definition of latent MTB infection and antibiotic prophylactic strategy
Both LT-1 and LT-2 centers tested all LT candidates using TST (PPD skin test - Tubersol-Sanofi Pasteur) or QTF (Quantiferon-TB Gold, Cellestis, Inc.) during their pre-LT diagnostic work-up. The diagnosis of latent MTB infection was defined by one or more of the following conditions: positive TST (≥5 mm induration), positive QTF, chest radiography with high-risk abnormalities evaluated by a TB infectious disease and radiologist specialist physicians. Internal clinical policies were followed; in the LT-1 center, TSTor QTF-positive patients did not undergo antibiotic prophylaxis, whereas in the LT-2 center, antibiotic prophylaxis was proposed for all TST- or QTF-positive patients. The antibiotic prophylactic regimen was based on the combination of oral levofloxacin 500mg plus ethambutol 800-1200mg three times per day from Day 1 postsurgical operation to hospital discharge, and then three times a week for 1 year as previously reported [23]. Prophylaxis was discontinued at the discretion of patient’s physicians if symptoms of liver or other significant drug-induced toxicity occurred.
Definition of MTB reactivation/infection
All patients, independent of the TST and QTF results, were followed after LT through regular visits and laboratory and radiological evaluations as determined by the LT centers’ clinical policies. In the occurrence of fever episodes, unexplained graft dysfunction, or clinical deterioration, infections, including bacteria, fungi and MTB, were systematically detected via blood, urine and biological fluid cultures and through the MTB polymerase chain reaction (PCR) test. In cases of suspected respiratory infection, an MTB search was conducted on respiratory secretions or bronchoalveolar lavages obtained during bronchoscopy. Active MTB reactivation/infection was defined by positive microscopic evidence of MTB and MTB positivity of cultures or PCR in examined samples.
Statistical Analysis
Statistical analysis was performed via Stata 15.1 statistical software (StataCorp. 2017. Stata Statistical Software: Release 15.1 College Station, TX: StataCorp LLC). Categorical variables were compared via the Pearson chi-square test and data presented as frequencies (%); continuous variables were compared via the nonparametric rank-sum test (Mann-Whitney), and data are presented as medians and interquartile ranges (IQRs). In multivariate analyses, only univariate factors with a statistical significance determined by p<0.10 were re-evaluated in a stepwise regression model with a forward selection approach.
Results
Four hundred ninety-six LT patients (370 males, median age 57 years) were enrolled in the study. Among them, 234 (47.2%) were enrolled in LT-1 and 262 (52.8%) were enrolled in LT-2. No significant differences in recipient age, sex, or the presence of hepatocellular carcinoma (HCC) were observed between the two LT groups. Compared with those in the LT-1 center, patients in the LT-2 center had significantly higher median Child‒Pugh (10 vs. 8, p<0.001) and Model for End Stage Liver Disease (MELD and MELD-Na) scores (19 vs. 16, p<0.001 and 21 vs. 16, p<0.001). Patients enrolled in the LT-2 center presented a greater frequency of hepatitis B virus (HBV) or hepatitis D virus (HDV) infections (55/262 vs. 24/234, p<0.001) and metabolic dysfunctionassociated steatosis liver disease (MASLD) (30/262 vs. 4/234, p<0.001) than those enrolled in the LT-1 center (Table 1).

BMI: Body Mass Index; MELD: Model of End-Stage Liver Disease; MELD-Na: Model of End-Stage Liver Disease Sodium; HCV: Hepatitis C Virus; HBV: Hepatitis B Virus; HDV: Hepatitis D Virus; KDIGO: Kidney Disease Improving Global Outcomes; ALD: Alcohol-Related Liver Disease; MASLD: Metabolic Dysfunction-Associated Steatotic Liver Disease; HCC: Hepatocellular Carcinoma.
Prevalence of latent MTB infection before LT
All 496 patients underwent the QTF test, and 88 (17.7%), 378 (76.3%), and 30 (6%) tested positive, negative and indeterminate, respectively. Thirty-one (6.1%) patients underwent TST and 8 (25.8%) tested positive. Since all TST-positive patients were also QTF positive, in the following analyses, only the QTF test results were evaluated. Table 2 compares the frequencies of QTF test results and MTB-related past infection, proven source contact, and vaccination between patients enrolled in LT-1 and those enrolled in LT-2 centers. A significantly greater percentage of QTF-positive patients were observed in the LT-2 center than in the LT-1 center (59/262 vs. 29/234, p=0.001). The independent predictors for having a positive QTF test in the whole population studied are presented in Table 3. In the multivariate analysis, in addition to being enrolled in the LT-2 center (p=0.003), past MTB infection (p=0.030), older age at listing (p<0.001) and the presence of HCC (p=0.003) were selected as independent predictors for testing QTF-positivity compared with negative or indeterminate results.
Evaluation of patients after liver transplantation
Immunosuppression schedules adopted. Table 4 shows the immunosuppressive (IS) treatment regimens adopted in each LT center. Compared to those in the LT-2 center, patients in the LT-1 center received the following: more frequent IS treatment with cyclosporine (43/234 vs. 11/262, p<0.001) and less frequent treatment with tacrolimus (173/234 vs. 235/262, p<0.001), MMF (33/234 vs. 85/262, p<0.001) and mammalian target of rapamycin (mTOR) drugs (102/262 vs. 23/234, p<0.001).

LT-1: Liver Transplant Centre 1; LT-2: Liver Transplant Centre 2; MTB: Mycobacterium Tuberculosis; QTF: QuantiFERON

MTB: Mycobacterium Tuberculosis; BMI: Body Mass Index; KDIGO: Kidney Disease Improving Global Outcomes; MELD: Model of End-Stage Liver Disease; MELD-Na: Model of End-Stage Liver Disease-Sodium; ALD: Alcohol-Related Liver Disease; MASLD: Metabolic Dysfunction-Associated Steatotic Liver Disease; HCC: Hepatocellular Carcinoma. Logistic Regression Model: pseudo-R2= 0.111 (p<0.001), Akaike’s Information Criterion = 422.

IS: Immunosuppressive; MTB: Mycobacterium Tuberculosis; mTOR: Mammalian Target of Rapamycin
Duration and safety of antibiotic prophylaxis
Among the 59 QTF-positive patients enrolled in the LT-2 center, only 38 (64.4%) received antibiotic prophylaxis against MTB reactivation/infection. The reasons why twenty-one patients did not receive antibiotic prophylaxis were as follows: were judged too sick at the time of the LT operation (N=10), refused the indication to assume prophylaxis (N=7) and were positive for the Quantiferon test, which became available only after LT (N=4). Furthermore, in 5 patients, owing to a proven past allergy to fluoroquinolones, antibiotic prophylaxis included INH (300 mg/ day) along with 25–50 mg of vitamin B6 starting from the first week after LT and then continuing for 6 months. The median duration of antibiotic prophylaxis was 12 months, and only 2 patients had levofloxacin and ethambutol suspended by their physicians who followed the patients within 3 months after LT for the appearance of fluroquinolone-related tendinopathy. No grade >1 hepatoxicity was recorded in either the 5 patients receiving INH or in those receiving levofloxacin and ethambutol.
Incidence and clinical characteristics of MTB reactivation/infection during follow-up
The median follow-up time was significantly longer in the LT-2 center than in the LT-1 center (78 vs. 71 months; p=0.027). During the follow-up period, the incidence of MTB reactivation/ infection in the whole population was 3/496 (0.6%), and 2/88 (2.3%) of the QTFs tested positive while one patient experienced MTB reactivation/infection despite a negative QTF test. MTB reactivations/infections were comparable between LT-2 and LT-1 centers for both the whole population (2/262 vs. 1/234, p=0.630) and in QTFs that tested positive (1/59 vs. 1/29, p=0.622). In the periodical chest X-ray or computed tomography (CT) scan evaluations, a pulmonary suspected MTB-related picture was observed in 33 (6.6%) patients without significant differences between LT-1 and LT-2 centers (15/234 vs. 18/262, p=0.837; data not shown). MTB pulmonary reactivation/infection after LT was confirmed through a positive PCR for MTB in the bronchoalveolar lavage fluid of 1 patient at each LT center and at 46 and 10 months in LT-2 and LT-1, respectively. One additional patient, who experienced extrapulmonary (peritoneal) MTB reactivation, was observed at the LT-2 center 44 months after LT.
The diagnosis of MTB reactivation/infection in this patient was confirmed by microscopic detection of MTB in the ascitic fluid. These three patients did not have a history of past MTB-related infection, contact or vaccination before LT. Only one of the two QTFpositive patients enrolled in the LT-2 center received antibiotic prophylaxis with levofloxacin plus ethambutol since the second patient did not agree to receive prophylaxis. Immunosuppressive treatment in the three patients who experienced MTB reactivation/ infection involved tacrolimus in combination with MMF in two patients and with everolimus in one patient. All LT recipients who developed MTB reactivation/infection received antitubercular treatment with the combination of RIF, INH, pyrazinamide, and ethambutol for two months, which was followed by 4 months of continuation therapy with daily INH and RIF since none of them presented with MTB drug-resistant strains. During this period, periodical and strict evaluation of the blood immunosuppressive drug levels as well as a liver function test was performed. All patients who experienced MTB reactivation were alive at the last follow-up visit with a preserved graft function (Table 5). According to the multivariate analysis, the independent predictors of MTB reactivation/infection following LT were hepatitis B virus (HBV) infection (p=0.004), a positive QTF test (p=0.006) and receipt of IS treatment with MMF (p=0.021) (Table 6).

LT: Liver Transplantation; MTB: Mycobacterium Tuberculosis; QTF: Quantiferon; IS: Immunosuppressive; HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; TAC: Tacrolimus; EVR: Everolimus; MMF: Mycophenolate Mofetil; LVF: Levofloxacin; ETH: Ethambutol

MTB: Mycobacterium tuberculosis; QTF: quantiferon; BMI: body mass index; KDIGO: Kidney Disease Improving Global Outcomes; MELD: model of end-stage liver disease; MELD-Na: model of end-stage liver disease-Sodium; HCV: hepatitis C virus; HBV/HDV; hepatitis B/hepatitis D; ALD: alcoholrelated liver disease; MASLD: metabolic dysfunction-associated steatotic liver disease; HCC: hepatocellular carcinoma; IS: immunosuppressive; mTOR: mammalian target of rapamycin. Logistic regression model: pseudo-R2= 0.267 (p=0.013), Akaike’s information criterion = 34.8
Overall clinical outcomes at the post LT follow-up
No significant differences between LT centers were observed regarding post-LT survival rates, the incidence of chronic rejection, cytomegalovirus (CMV) infection, or the development of de novo cancers. Among the well-known metabolic complications present after LT, KDIGO stage III or IV renal insufficiency was more frequently observed in patients enrolled in the LT-2 center than those in the LT-1 center (25/262 vs. 1/234; p<0.001) (Table 7).

LT: Liver Transplant; CMV: Cytomegalovirus; KDIGO: Kidney Disease Improving Global Outcomes.
Discussion
The prevalence of latent MTB infection in LT candidates ranges from 11% to 44% in several studies adopting the QTF test [11,24,25], which was similar to the 17.7% reported in our study. A significantly greater number of LT patients that were enrolled in the LT-2 center compared to the LT-1 center tested QTF positive and this difference was confirmed by multivariate analysis in addition to past MTB infection, older age, and the presence of HCC. The higher prevalence of latent MTB infection in older patients and in those with past MTB infection is not unexpected since it has been previously demonstrated [26]. More interestingly, latent MTB infection appeared to be more common in patients with HCC and more severe liver disease. MTB infection may play a role in carcinogenesis [27], and simultaneous MTB infection and HCC can occur [28]. These features could explain the increased prevalence of HCC in QTF-positive patients as previously reported [25]. In contrast with our findings, some reports indicate that patients with liver cirrhosis harbor systemic immunodepression, which leads to a lower detection rate of latent MTB infection [25]. However, these results have been obtained via the TST instead of the QTF test and have not been confirmed by analysing the severity of liver disease via the CPT score.
The overall MTB reactivation rate we observed was 0.6%, which was similar to that reported in LT patients in developed countries where MTB endemicity is low [12,29,30]. Only 2/88 QTFpositive patients developed MTB reactivation/infection, which confirms the suboptimal accuracy of pretransplant positive QTF tests in selecting patients with a greater risk of MTB reactivation after LT [31,32]. The positive and negative predictive values of the QTF test for identifying patients with latent MTB infection are <3% and 97%, respectively [8]. This implies that a positive and negative QTF test indicates a nearly 3% risk of MTB reactivation/ infection as shown in our study. Pulmonary MTB reactivation was detected in only 2/3 of our patients, which supports data reported in other LT centres where extrapulmonary MTB reactivation was described [7,30].
A novel and interesting observation is that among QTFpositive patients, the incidence of MTB reactivation/infection in our series was similar in patients regardless of whether they did or did not receive antibiotic prophylaxis (1/38 vs. 1/50, p=0.844). This finding contrasts with a systematic literature review demonstrating that antibiotic prophylaxis versus no treatment was associated with a significant reduction in MTB reactivation after LT [7]. However, these data referred to INH prophylaxis, which was used in our series in only a limited number of patients owing to its potentially severe hepatotoxicity in LT recipients [11,19]. Our data seem to confirm previous results obtained in Japan, which showed that no MTB reactivations after LT were observed despite the absence of antibiotic prophylaxis in patients considered at the highest risk of MTB reactivation such as those treated for active MTB infection several years before LT [22]. In our experience, no grade >1 hepatotoxicity was recorded in either the few patients receiving INH or in patients receiving levofloxacin, which confirms the reported good safety profile of fluroquinolone-based prophylaxis in LT patients [23,33-35]. In two of our patients, levofloxacin was prematurely discontinued due to the development of tendinopathy, which has been reported as a more frequent side effect in other studies [33,34].
A further novel feature of our study is its identification of an independent predictor of MTB reactivation/infection, which included not only being positive for QTF but also being positive for HBV infection and receiving immunosuppressive treatment with MMF. With respect to HBV infection, 2/3 of patients who experienced MTB reactivation/infection after LT were positive for HBV. This finding agrees with a recent large epidemiological study conducted in the U.S. in HBV-positive patients showing that the prevalence of latent MTB infection was 23.1% and was highest among persons born in high-incidence countries [36]. The increased risk of MTB reactivation in patients treated with MMF, to our knowledge has only been previously described in kidney transplant recipients [37]. MMF inhibits de novo purine synthesis, which leads to profound selective lymphocyte inhibition, and its use in LT recipients has increased in recent years due to its negative impact on renal, glucose and lipid parameters [38]. However, despite these favourable properties, MMF has been recently reported to be the main factor involved in reducing the immune response for coronavirus disease (COVID-19) after LT [39]. Furthermore, it has been demonstrated that the restoration of humoral and cellular immune responses to COVID-19 vaccination were achieved only after the interruption of MMF [40]. Thus, MMF may reduce the ability of lymphocytes to maintain immunological control of latent MTB infection and increase the probability of reactivation after LT.
All patients who experienced MTB reactivation completed antitubercular treatment without significant drug-induced side effects or amenable interactions and all of them were alive at the last follow-up. This excellent survival rate seems to confirm data reported in other studies with post-LT mortality ranging from 9% [21] to 30% [4]. The absence of MTB exposure was identified as the only factor associated with longer survival in patients who experienced reactivated MTB infection after solid organ transplantation [30]. This observation can explain why our patients, who did not have MTB contact, had excellent clinical outcomes.
Our study has several limitations. First, it was retrospective and not randomized. Second, we cannot rule out that some QTFpositive patients were not included because their data were missing or incomplete in the electronic records. However, the present study also presents several strengths since, to our knowledge, this is the first study to compare the impact of antibiotic prophylaxis with that of observation alone in conditioning the incidence of MTB reactivation/infection in LT patients from two large series.
In summary, MTB reactivation after LT is rare. The QTF test remains a suboptimal tool for selecting patients with latent MTB who should be considered at increased risk of MTB reactivation after LT. Moreover, antibiotic prophylaxis in QTF-positive patients does not seem superior to observation alone for both preventing and determining the clinical outcome of MTB reactivation/ infection after LT.
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