High-risk Liver Transplant Recipients Research Articles

A practical guide to real-world implementation of pre-emptive therapy for Cytomegalovirus disease prevention in high-risk seronegative liver transplant recipients with seropositive donors.

The Comparison of Antiviral Preventative Strategies In Liver Transplant (CAPSIL) study showed pre-emptive therapy (PET) to be superior to antiviral prophylaxis for Cytomegalovirus (CMV) disease prevention in high-risk CMV seronegative liver transplant recipients (LTRs)with seropositive donors (D+ R- ). Despite the statistical superiority of PET over prophylaxis in research settings, PET is perceived as a logistically more complex strategy that requires careful coordination of weekly CMV PCR testing, prompt initiation of CMV antivirals upon viremia detection, and timely cessation of antivirals following viremia resolution. Transplant centers may be hesitant to use PET for CMV disease prevention in D+ R- LTRs out of concern that PET coordination is not feasible in clinical practice. We recently described our experience using PET in CMV D+ R- LTRs in a real-world setting, and found it to be as effective for CMV disease prevention as PET performed as part of a clinical trial. Here, we describe a systematic approach for PET implementation in real-world settings and provide practical tools to address anticipated challenges. This framework can support transplant programs in overcoming logistical barriers to PET and incorporating an evidence-based and cost-effective CMV prevention strategy into routine care for high-risk CMV D+ R- LTRs.

Invasive Fungal Breakthrough Infections under Targeted Echinocandin Prophylaxis in High-Risk Liver Transplant Recipients

Invasive fungal infections (IFIs) are frequent and outcome-relevant complications in the early postoperative period after orthotopic liver transplantation (OLT). Recent guidelines recommend targeted antimycotic prophylaxis (TAP) for high-risk liver transplant recipients (HR-LTRs). However, the choice of antimycotic agent is still a subject of discussion. Echinocandins are increasingly being used due to their advantageous safety profile and the increasing number of non-albicans Candida infections. However, the evidence justifying their use remains rather sparse. Recently published data on breakthrough IFI (b-IFI) raise concerns about echinocandin efficacy, especially in the case of intra-abdominal candidiasis (IAC), which is the most common infection site after OLT. In this retrospective study, we analyzed 100 adult HR-LTRs undergoing first-time OLT and receiving echinocandin prophylaxis between 2017 and 2020 in a tertiary university hospital. We found a breakthrough incidence of 16%, having a significant impact on postoperative complications, graft survival, and mortality. The reasons for this may be multifactorial. Among the pathogen-related factors, we identified the breakthrough of Candida parapsilosis in 11% of patients and one case of persistent IFI due to the development of a secondary echinocandin resistance of an IAC caused by Candida glabrata. Consequently, the efficacy of echinocandin prophylaxis in liver transplantation should be questioned. Further studies are necessary to clarify the matter of breakthrough infections under echinocandin prophylaxis.

Incidence of Invasive Fungal Infections in Liver Transplant Recipients under Targeted Echinocandin Prophylaxis

Invasive fungal infections (IFIs) are one of the most important infectious complications after liver transplantation, determining morbidity and mortality. Antimycotic prophylaxis may impede IFI, but a consensus on indication, agent, or duration is still missing. Therefore, this study aimed to investigate the incidence of IFIs under targeted echinocandin antimycotic prophylaxis in adult high-risk liver transplant recipients. We retrospectively reviewed all patients undergoing a deceased donor liver transplantation at the Medical University of Innsbruck in the period from 2017 to 2020. Of 299 patients, 224 met the inclusion criteria. We defined patients as being at high risk for IFI if they had two or more prespecified risk factors and these patients received prophylaxis. In total, 85% (190/224) of the patients were correctly classified according to the developed algorithm, being able to predict an IFI with a sensitivity of 89%. Although 83% (90/109) so defined high-risk recipients received echinocandin prophylaxis, 21% (23/109) still developed an IFI. The multivariate analysis identified the age of the recipient (hazard ratio-HR = 0.97, p = 0.027), split liver transplantation (HR = 5.18, p = 0.014), massive intraoperative blood transfusion (HR = 24.08, p = 0.004), donor-derived infection (HR = 9.70, p < 0.001), and relaparotomy (HR = 4.62, p = 0.003) as variables with increased hazard ratios for an IFI within 90 days. The fungal colonization at baseline, high-urgency transplantation, posttransplant dialysis, bile leak, and early transplantation showed significance only in a univariate model. Notably, 57% (12/21) of the invasive Candida infections were caused by a non-albicans species, entailing a markedly reduced one-year survival. The attributable 90-day mortality rate of an IFI after a liver transplant was 53% (9/17). None of the patients with invasive aspergillosis survived. Despite targeted echinocandin prophylaxis, there is still a notable risk for IFI. Consequently, the prophylactic use of echinocandins must be critically questioned regarding the high rate of breakthrough infections, the increased occurrence of fluconazole-resistant pathogens, and the higher mortality rate in non-albicans Candida species. Adherence to the internal prophylaxis algorithms is of immense importance, bearing in mind the high IFI rates in case algorithms are not followed.

Impact of high MELD scores on CMV viremia following liver transplantation.

Advanced liver disease or cirrhosis is associated with an increased risk of infections; however, the impact of high pretransplant model for end-stage liver disease (MELD) score on cytomegalovirus (CMV) viremia after liver transplantation is unknown. This single-center, retrospective, cohort study evaluated CMV high-risk (CMV immunoglobulin G D+/R-) liver transplant recipients who received valganciclovir prophylaxis for 3 months between 2009 and 2019. Patients were stratified by pretransplant MELD score of <35 (low MELD) and ≥35 (high MELD). The primary outcome was 12-month CMV viremia, and secondary outcomes included CMV resistance and tissue invasive disease, mortality, biopsy-proven acute rejection (BPAR), leukopenia, and thrombocytopenia. Multivariable Cox proportional-hazards modeling was used to assess the association of MELD score with the time to CMV viremia. There were 162 and 79 patients in the low and high MELD groups, respectively. Pretransplant MELD score ≥35 was associated with an increased risk of CMV viremia (hazard ratio [HR] 1.73; confidence interval 1.06-2.82, p=.03). CMV viremia occurred at 162±61 days in the low MELD group and 139±62 days in the high MELD group. Although BPAR occurred early at 30 days (13-59) in the low-MELD group and at 18 days (11-66) in the high-MELD group (p=.56), BPAR was not associated with an increased risk of CMV viremia (HR 1.55 [0.93-2.60], p=.1). MELD scores ≥35 were associated with an increased hazards of CMV viremia. In liver transplant recipients with MELD scores ≥35 who are CMV high-risk, additional CMV intervention may be warranted.

Carbapenems versus Cephalosporin or Piperacillin-Tazobactam as Perioperative Antibiotic Prophylaxis in Liver Transplant Recipients with Model for End-Stage Liver Disease Scores of ≥30: A Retrospective Study in a Chinese Population.

ObjectivePerioperative prophylaxis, commonly with a third-generation cephalosporin plus ampicillin or piperacillin-tazobactam, is usually employed to prevent infections in liver transplantation (LT) recipients. Patients with a high Model for End-Stage Liver Disease (MELD) score have an increased infection risk after LT. However, whether carbapenems could be used as surgical prophylaxis in these high-risk patients remains unclear. Therefore, this study aimed at comparing the effectiveness of carbapenems with that of cephalosporin or piperacillin-tazobactam for surgical prophylaxis in high-risk LT recipients with a MELD score ≥30.Design or MethodsThis retrospective study included adult patients with a MELD score ≥30 who underwent LT between May 2018 and September 2020. We comparatively analyzed the infection rate and outcome between patients using cefoperazone-sulbactam or piperacillin-tazobactam and those using carbapenems as surgical prophylaxis.ResultsThis study included 105 LT recipients. Seventy-eight and 27 patients used non-carbapenem and carbapenem antibiotics, respectively, as surgical prophylaxis. The corresponding infection incidence rates within 30 days were 38.5% and 66.7% (p = 0.011). Multivariate analysis revealed that reoperation and the Child–Pugh score were independent risk factors for infections within 30 days after LT. The following four risk factors were associated with the 180-day post-LT survival: MELD score, vascular complication, intra-abdominal bleeding, and infection with carbapenem-resistant organisms (CROs). There was no significant difference in CRO infection incidence between the carbapenem and non-carbapenem groups (18.5% vs 11.5%; p = 0.345).ConclusionCarbapenem use as surgical prophylaxis was not associated with infection incidence within 30 days after LT, 180-day post-LT survival or CRO infection. Therefore, carbapenems are not superior to cephalosporin or piperacillin-tazobactam for perioperative antibiotic prophylaxis in LT recipients with a MELD score ≥30.

Are split liver grafts a suitable option in high-risk liver transplant recipients?

To assess the outcomes of split liver transplantation (SLT) in adults and children and evaluate its role in high-risk recipients with a high model for end-stage liver disease (MELD) score, an urgent indication or requiring retransplantation. Split liver grafts in general have equivalent long-term survival outcomes to whole grafts despite an increase in biliary complications. Recent success and technical advances have encouraged use of these grafts in high-risk recipients. Split liver grafts can be used successfully in recipients with a high MELD score if there is adequate weight-matching. There are mixed results in urgent indication recipients and for retransplantation such that use in this group of patients remains controversial. SLT addresses donor shortages by facilitating the transplant of two recipients from the same donor liver. By using careful donor and recipient selection criteria, SLT can achieve equivalent long-term outcomes to whole grafts. These grafts have been used successfully in recipients with a high MELD score, but should be used selectively in urgent indication recipients and for retransplantation.

Breakthrough invasive fungal infections in liver transplant recipients exposed to prophylaxis with echinocandins vs other antifungal agents: A systematic review and meta-analysis.

IntroductionAlthough echinocandins are recommended as first‐line prophylaxis for high‐risk orthotopic liver transplant (OLT) recipients, occurrence of breakthrough‐invasive fungal infections (IFIs) remains a serious concern. We aim to assess the risk of breakthrough IFIs among OLT recipients exposed to prophylaxis with echinocandins compared to other antifungals.Materials and methodsTwo authors independently searched PubMed‐MEDLINE, Embase, study registries and reference lists from inception to March 2021, to retrieve randomised controlled trials (RCTs) or observational studies comparing efficacy and safety of echinocandins vs other antifungals for prophylaxis in OLT recipients. Data were independently extracted from two authors, and the quality of included studies was independently assessed according to ROB 2.0 tool for RCTs and ROBINS‐I tool for observational studies. The primary outcome was occurrence of breakthrough IFI at the end of prophylaxis (EOP).Results698 articles were screened, and ten studies (3 RCTs and 7 observational) were included. No difference between echinocandins and other antifungals in terms of breakthrough IFIs at the EOP emerged both from RCTs (odds ratio [OR] 0.85, 95% CI 0.24–2.99) and observational studies (OR 1.43, 95% CI 0.28–7.40). No difference emerged also for secondary outcomes. In the subgroup comparison between echinocandins and polyenes, a trend for higher risk of breakthrough IFI at the EOP (OR 4.82, 95% CI 0.97–24.03) was noted.ConclusionsEchinocandins do not seem to be associated with increased risk of breakthrough IFIs in OLT recipients. However, the large diversity in the comparator group hinders a definitive interpretation. Further studies exploring the relationship between echinocandin use and breakthrough IFIs according to specific comparators are warranted.

Interleukin-2 receptor antibody induction with early low dose tacrolimus preserves post-liver transplant renal function in at risk individuals

BackgroundRenal dysfunction post liver transplantation (LT) is common. We report our real-world experience of IL2Ra induction with immediate exposure to reduced dose tacrolimus used for patients with chronic kidney disease (CKD) and evolving acute kidney injury (AKI). MethodA single-centre retrospective analysis of elective adult LT from 1/1/17 to 31/12/17. The primary outcome measure was increase in CKD stage at month 6 post-LT, and secondary outcome was early biopsy proven acute rejection (BPAR). Results161 patients were included: 17 planned-IL2Ra for CKD; 38 unplanned-IL2Ra for AKI; and 106 standard immunosuppression. IL2Ra group had lower trough tacrolimus levels till month 3 post-LT. Patients receiving IL2Ra did not have an increased risk of increase in CKD class at month 6 (aOR 0.95, 95% CI 0.34–2.75, P = 0.92), or of early BPAR (aOR 0.53, 95% CI 0.19–1.32, P = 0.19). ConclusionIL2Ra induction with immediate exposure to reduced dose tacrolimus can be given to patients with CKD or early evolving AKI post-LT, with no greater attrition of renal function at 6 months or an increased risk of early BPAR when compared to standard IS. Longer-term outcome data is required, however this regimen can be considered for high risk LT recipients with CKD and AKI.

Potential Role of Adjuvant Lenvatinib in Improving Disease-Free Survival for Patients With High-Risk Hepatitis B Virus-Related Hepatocellular Carcinoma Following Liver Transplantation: A Retrospective, Case Control Study

Background and AimAlthough liver transplantation (LT) is one of the most effective treatments for the patients with hepatocellular carcinoma (HCC), the high-risk patients suffer from a high ratio of tumor recurrence after LT. Lenvatinib, as a novel targeted drug, has shown an excellent effect in the treatment of advanced HCC, but there is no study on its effect in preventing HCC recurrence in the patients undergoing transplantation. Therefore, this study was designed to evaluate the role of adjuvant lenvatinib in preventing recurrence of high-risk LT recipients with HBV-related HCC.MethodsWe retrospectively analyzed 23 high-risk patients consisting of lenvatinib group (n=14) and control group (n=9) with HBV-related HCC who underwent LT in our center. Disease-free survival (DFS) and HCC recurrence of the two groups were compared. The adverse events (AEs) and drug tolerance of lenvatinib were evaluated.ResultsThe median DFS in lenvatinib group was 291 (95%CI 204–516) days, significantly longer than 182 (95%CI 56–537) days in control group (P=0.04). Three patients in lenvatinib group (21.4%) and five patients in control group (55.6%) had short-term HCC recurrence (P=0.11). All patients in lenvatinib group could tolerate oral lenvatinib for at least three cycles except six cases (42.9%) of dose reduction and 1 case of interruption (14.3%). Thirteen patients (92.9%) taking lenvatinib experienced AEs. The most common AEs were hypertension (64.3%) and proteinuria (42.9%), and the most serious AEs were Grade 3 for 4 cases (28.5%) according to common terminology criteria for adverse events (CTCAE) version 5.0. Additionally, no influence of lenvatinib on the dosage and blood concentration of FK506 was observed.ConclusionsAdjuvant lenvatinib had a potential benefit on prolonging the DFS and reducing the recurrence of high-risk HBV-related HCC patients following liver transplantation with an acceptable drug safety and patient tolerance.

Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors

Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients. To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease. Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018. Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105). The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia. Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, -9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, -14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46). Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes. ClinicalTrials.gov Identifier: NCT01552369.

Prevalence of Perineural Invasion in keratinocyte cancer in the general population and among organ transplant recipients

Basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs) are the most commonly encountered cancers in fair-skinned populations worldwide. Perineural invasion is associated with worse outcomes for patients with BCC or SCC. Estimates of perineural invasion prevalence range widely, likely reflecting non-representative patient samples. We sought to determine the prevalence of perineural invasion in BCC and SCC in the general population, as well as among cancers arising in solid organ transplant recipients. We retrospectively analysed histopathology reports of BCC and SCC from patients enrolled in the QSkin Study (a population-based cohort of 43794 Queensland residents recruited 2010-2011) and the Skin Tumours in Allograft Recipients (STAR) study (a cohort of 509 high-risk kidney or liver transplant recipients at the Princess Alexandra Hospital, Brisbane, recruited 2012-2014.) We estimated the prevalence of perineural invasion (and 95% confidence interval) in BCC and SCC, respectively, and identified clinical factors associated with perineural invasion. In QSkin, we observed 35 instances of perineural invasion in 9850 histopathologically confirmed BCCs (0.36%) and 9 instances of perineural invasion in 3982 confirmed SCC (0.23%) lesions. In the STAR cohort, we identified 4 lesions with perineural invasion in 692 BCCs (0.58%) and 16 reports of perineural invasion in 875 SCC lesions (1.9%). These data suggest that the overall prevalence of perineural invasion in keratinocyte cancer is low, although perineural invasion prevalence may be slightly higher among organ transplant recipients when compared to the general population.

Renal Outcomes of Liver Transplantation Recipients Receiving Standard Immunosuppression and Early Renal Sparing Immunosuppression: A Retrospective Single Center Study.

Background.New-onset stage 4–5 chronic kidney disease (CKD) after liver transplantation (LT) is associated with high morbidity, mortality, and economic burden. In 2010, we instituted an early renal sparing immunosuppression (RSI) protocol for LT recipients with severe renal dysfunction (pre-LT dialysis/estimated glomerular filtration rate (eGFR)<30mL/min/1.73 m2 or post-LT acute kidney injury) consisting of 2 doses of basiliximab for induction and delaying tacrolimus to post-LT day 4–7. We examined the effect of early RSI on post-LT renal outcomes.Methods.Data on all adults who had LT between January 1, 2010, and December 12, 2014 were collected. We calculated the renal risk index (RRI) score for each LT recipient (https://rri.med.umich.edu). Primary outcome was new-onset post-LT stage 4–5 CKD.Results.Of 214 LT recipients, 121 (57%) received early RSI and 93 (43%) received standard immunosuppression. Cumulative incidence of new-onset stage 4–5 CKD was higher in early RSI compared with standard immunosuppression (P = 0.03). Female sex and RRI score were the significant risk factors for development of post-LT stage CKD in the entire study cohort as well as the LT recipients with RRI ≥ sixth decile (high-risk group).Conclusions.Delaying tacrolimus initiation combined with basiliximab induction did not have a durable effect on long-term renal outcomes in high-risk LT recipients. Further studies are needed to identify the effective strategies to preserve renal function by targeting patients at high risk for CKD progression.

Epidemiological features of invasive mold infections among solid organ transplant recipients: PATH Alliance® registry analysis.

Epidemiological characteristics of 333 proven and probable invasive mould infections (IMIs) among solid organ transplant recipients (SOTRs) identified between 2004 and 2008 from the Prospective Antifungal Therapy Alliance (PATH) registry are presented. Liver transplant recipients (LTRs) had the lowest median time to IMIs (109 days; interquartile range [IQR] 24-611 days), the highest rate of disseminated disease (n/N = 18/33; 55%), and highest mortality (n/N = 21/33; 64%). Lung transplant recipients had highest median time to IMIs (486 days; IQR 117-1358 days) and lowest mortality (n/N = 31/184; 17%). Complete or partial response at week 12 in patients with invasive aspergillosis (IA) was 67% (n/N = 189/281), and 41% (n/N = 9/22) in mucormycosis patients. In the composite outcome of death or no response to therapy, LTRs had the worst outcome. Higher suspicion of mold infection and institution of appropriate antifungal prophylactic strategies are warranted, especially in high risk LTRs.

Intraoperative Management of High-Risk Liver Transplant Recipients: Concerns and Challenges.

Liver transplantation (LT) offers patients with liver disease a real chance for long-term survival. In the past decade, successful survival after LT along with the Model for End-Stage Liver Disease-based allocation policy have increased willingness to accept patients with a higher risk profile and marginal organs and to prioritize the sickest patients on the waiting list. Therefore, the anesthesiologist now deals with very challenging patients. In the present review, we aimed to highlight key aspects of intraoperative LT management in high-risk patients and to place these aspects in the perspective of their impact on perioperative outcomes. Conservative standardized perioperative strategies mandate a switch toward accurate and tailored perioperative anesthetic care to maintain the steady improvement in recipient survival rates after LT. In our opinion, continuous assessment of fluid status and cardiac performance, strategies promoting graft decongestion, rational hemostatic management, and the identification of LT recipients with potential risk of vascular complications should constitute the cornerstone of intraoperative management.

Sa1624 Risk Factors for Delayed-Onset Cytomegalovirus Disease in High Risk Liver Transplant Recipients Who Receive Antiviral Prophylaxis

Sa1624 Risk Factors for Delayed-Onset Cytomegalovirus Disease in High Risk Liver Transplant Recipients Who Receive Antiviral Prophylaxis

Prevalence of Skin Cancer and Related Skin Tumors in High-Risk Kidney and Liver Transplant Recipients in Queensland, Australia

The increased skin cancer incidence in organ transplant recipients is well-known, but the skin cancer burden at any one time is unknown. Our objective was to estimate the period prevalence of untreated skin malignancy and actinic keratoses in high-risk kidney and liver transplant recipients and to assess associated factors. Organ transplant recipients underwent full skin examinations by dermatologically trained physicians. The proportion of examined organ transplant recipients with histopathologically confirmed skin cancer in the 3-month baseline period was estimated. Prevalence ratios with 95% confidence intervals indicated significant associations. Of 495 high-risk organ transplant recipients (average age= 54 years, time immunosuppressed= 8.9 years), 135 (27%) had basal cell carcinoma, squamous cell carcinoma or Bowen's disease (intraepidermal carcinoma) present and confirmed in the baseline period, with respective prevalence proportions of 10%, 11%, and 18% in kidney transplant recipients and 10%, 9%, and 13% in liver transplant recipients. Over 80% had actinic keratosis present, with approximately 30% having 5 or more actinic keratoses. Organ transplant recipients with the highest skin cancer burden were Australian born, were fair skinned (prevalence ratio= 1.61, 95% confidence interval= [1.07, 2.43]), reported past skin cancer (prevalence ratio=3.39, 95% confidence interval= [1.93, 5.95]), and were receiving the most frequent skin checks (prevalence ratio= 1.76, 95% confidence interval= [1.15, 2.70]). In conclusion, high-risk organ transplant recipients carry a substantial measurable skin cancer burden at any given time and require frequent review through easily accessible, specialized services.

Advantage of tacrolimus/mycophenolate mofetil regimen for cytotoxic T cell-mediated defence and its inhibition by additive steroid administration in high-risk liver transplant recipients.

Our previous work revealed that the recipients with the highest pre-existing numbers of CD8(+) effector T cells (TE ) [hyperparathyroidism (HPT)E recipients] occupied approximately 30% of adult transplant recipients performed in our hospital. HPTE recipients demonstrated very poor clinical outcome compared with the remaining 70% of recipients with the lowest pre-existing TE (LPTE recipient). This study aimed to clarify the best combined immunosuppressive regimen related to function of cytotoxic T lymphocytes (CTLs) for HPTE recipients. Eighty-one HPTE recipients were classified into three types, according to the immunosuppressive regimens: type 1, tacrolimus (Tac)/glucocorticoid (GC); type 2, Tac/mycophenolate mofetil (MMF)/GC; and type 3, Tac/MMF. Frequencies of severe infection, rejection and hospital death were the highest in types 1 and 2, whereas the lowest occurred in type 3. The survival rate in type 3 was the highest (100%) during follow-up until post-operative day 2000. Regarding the immunological mechanism, in type 1 TE perforin and interferon (IFN)-γ were generated through the self-renewal of CD8(+) central memory T cells (TCM ), but decreased in the early post-transplant period due to marked down-regulation of interleukin (IL)-12 receptor beta-1 of TCM. In type 2, the self-renewal TCM did not develop, and the effector function could not be increased. In type 3, in contrast, the effectors and cytotoxicity were correlated inversely with IL-12Rβ1(+) TCM levels, and increased at the highest level around the pre-transplant levels of IL-12Rβ1(+) TCM . However, the immunological advantage of Tac/MMF therapy was inhibited strongly by additive steroid administration.

Efficacy and cost-effectiveness of voriconazole prophylaxis for prevention of invasive aspergillosis in high-risk liver transplant recipients.

Aspergillus infection remains a significant and deadly complication after liver transplantation (LT). We sought to determine whether the antifungal prophylactic use of voriconazole reduces the incidence of invasive aspergillosis (IA) in high-risk LT recipients without prohibitively increasing cost. During the study era (April 2008 to April 2014), 339 deceased donor LTs were performed. Of those patients, 174 high-risk recipients were administered antifungal prophylaxis with voriconazole. The median biological Model for End-Stage Liver Disease score at the time of LT was 33 (range, 18-49) with 56% requiring continuous renal replacement therapy and 50% requiring ventilatory support immediately before transplantation. Diagnosis of IA was stratified as proven, probable, or possible according to previously published definitions. No IA was documented in patients receiving voriconazole prophylaxis. At 90 days after LT, the institutional cost of prophylaxis was $5324 or 5.6% of the predicted cost associated with post-LT aspergillosis. There was no documentation of resistant strains isolated from any recipient who received voriconazole. In conclusion, these data suggest that voriconazole prophylaxis is safe, clinically effective, and cost-effective in high-risk LT recipients.

Plasma IL-10 Levels to Guide Antiviral Prophylaxis Prevention of Late-Onset Cytomegalovirus Disease, in High Risk Solid Kidney and Liver Transplant Recipients.

Immune measurements that distinguish solid organ transplantation (SOT) recipients who control cytomegalovirus (CMV) infection from those who progress to CMV-disease (CMV-dz) may be clinically useful in guiding tailored prevention strategies. We previously reported that elevated plasma levels of the immune-modulator IL-10 are associated with late CMV-dz. Here we evaluate whether IL-10 levels measured soon after prophylaxis discontinuation are predictive of CMV-dz risk. Plasma IL-10 levels were quantitatively measured by ELISA kit in 40 D/R SOT patients. All 40 D/R high-risk patients were prospectively followed for at least 12 months post-SOT: 13 subjects developed CMV-dz, all within 6 months of prophylaxis discontinuation. IL-10 was detectable at the first post-prophylaxis measurement for 11 of 13 subjects who developed CMV-dz. In contrast, IL-10 was detectable in only 6 of 27 CMV asymptomatic patients. Monitoring IL-10 plasma levels within 1 month prophylaxis suspension appeared to have clinically useful level of 85% sensitivity and 78% specificity. The exact role of IL-10 with its multiple immunoregulatory effects during CMV infection is not clear. Moreover, IL-10 production can be influenced by pathological and infectious contexts, and/or anti-rejection immunosuppressant therapy. Despite mechanisms of IL-10 dysregulation may substantially differ among SOT patients, our findings suggest that measurable plasma IL-10 soon after prophylaxis discontinuation may be an adequate indicator of subsequent CMV-dz. If a similar prognostic performance is confirmed in a larger D/R cohort, IL-10 plasma levels could be used to guide the length of prophylaxis, providing a clinically useful means to reduce the incidence of CMV-dz in high risk patients.

Antibiotic prophylaxis for surgical site infection in people undergoing liver transplantation.

Surgical site infection is more frequent in liver transplantation than in other types of solid organ transplantation with different antibiotics. Studies have shown that the rate of surgical site infection varies from 8.8% to 37.5% after liver transplantation. Therefore, antimicrobial prophylaxis is likely an essential tool for reducing these infections. However, the literature lacks evidence indicating the best prophylactic antibiotic regimen that can be used for liver transplantation. To assess the benefits and harms of antibiotic prophylactic regimens for surgical site infection in people undergoing liver transplantation. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded and Latin American Caribbean Health Sciences Literature (LILACS). The most recent search was performed on 11 September 2015. All eligible randomised clinical trials comparing any antibiotic regimen versus placebo, versus no intervention or versus another antibiotic regimen for surgical site infection in liver transplant recipients, regardless of age, sex and reason for transplantation. Quasi-randomised studies and other observational studies were considered for data on harm if retrieved with search results for randomised clinical trials. Two review authors selected relevant trials, assessed risk of bias of studies and extracted data. The electronic search identified 786 publications after removal of duplicates. From this search, only one seemingly randomised clinical trial, published in abstract form, fulfilled the inclusion criteria of this review. This trial was conducted at Shiraz Transplant Centre, Shiraz, Iran, where investigators randomly assigned a total of 180 consecutive liver transplant recipients. We judged the overall risk of bias of the trial published in abstract form as high. Researchers reported no numerical data but mentioned that 163 participants met the inclusion criteria after randomisation, and hence were included in the analyses. Most probably, the 17 excluded participants were high-risk liver transplant recipients. Trial authors concluded that they could find no differences between the two antibiotic regimens - ceftriaxone plus metronidazole versus ampicillin-sulbactam plus ceftizoxime - when given to liver transplant recipients. Review authors could not reconfirm the analyses because, as it has been mentioned, trial authors provided no trial data for analyses. Benefits and harms of antibiotic prophylactic regimens for surgical site infection in liver transplantation remain unclear. Additional well-conducted randomised clinical trials adhering to SPIRIT (Spirit Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) guidelines are needed to determine the exact role of antibiotic prophylactic regimens in patients undergoing liver transplantation.