Invasive fungal infections (IFI) are frequent in patients admitted to the intensive care unit (ICU). The use of first-line antifungals like triazoles or echinocandins may be limited by the global spread of multi-drug resistance species, drug-drug interactions, low organ penetration, and some safety concerns in case of multi-organ failure. Liposomal amphotericin B (L-AmB) is a polyene drug with a broad activity against mold and yeast and an acceptable safety profile. To outline the role of L-AmB in the treatment of IFI in critically ill patients, a panel of experts was invited to draw up an expert opinion paper on the appropriate place in therapy of L-AmB in different clinical scenarios of patients admitted to ICU.

A multidisciplinary group of 16 specialists in infectious disease, microbiology, pharmacology, and intensive care elaborated an expert opinion document through a multi-step approach: (1) the scientific panel defined the items and wrote the statements on the management of IFI in ICU, (2) a survey was submitted to an external panel to express agreement or disagreement on the statements, and (3) the panel reviewed the survey and implemented the final document.

The final document included 35 statements that focused on epidemiology and microbiological rationale of the use of systemic L-AmB in critically ill patients and its potential role in specific clinical scenarios in the ICU.

Systemic L-AmB may represent an appropriate therapeutic choice for IFI in ICU patients with different underlying conditions, especially when the use of first-line agents is undermined. This expert opinion paper may provide a useful guide for clinicians.

This study aimed to investigate the incidence, timing, risk factors, and impacts of invasive Candida infections (ICIs) within 3 months after liver transplantation (LT) on LT recipients' prognosis.

Patients undergoing LT from January 2015 to December 2022 in a tertiary university hospital were investigated the incidence, onset, and risk factors of ICIs and the effects of ICIs on the outcome of LT recipients using statistical methods.

The mean age of involved 389 LT recipients was 47.3 ± 10.5 years, with 322 (82.8%) being men. The incidence of ICIs was 3.3% (13/389), and the median time between LT and onset of ICIs was 5.0 days. The univariate analysis of predictors of ICIs identified that massive blood loss, prolonged duration of central line and urethral catheter, and prophylactic antifungal therapy were related to post-LT ICI risk. Multivariate logistic regression analysis adjusted for men and age identified that intraoperative blood loss ≥5000 mL (odds ratio [OR] = 7.005, 95% CI: 2.084-23.542, P = 0.002) and central line duration >14 days (OR = 5.270, 95% CI: 1.556-17.854, P = 0.008) were independently associated with the development of post-LT ICIs. Post-LT prophylactic antifungal therapy >3 days reduced ICIs (OR = 0.103, 95% CI: 0.021-0.501, P = 0.005). Regarding clinical outcomes, patients with ICIs were more likely to stay in the intensive care unit for 7 days or longer compared with those without ICIs (OR = 6.910, 95% CI: 1.737-27.493, P = 0.006). ICIs had no impact on hospitalization stay and 1-month all-cause mortality after LT.

ICIs are frequent and occur early after LT. Predictors of post-LT ICIs were massive intraoperative blood loss and prolonged duration of the central line. However, post-LT prophylactic antifungal therapy reduced ICIs. Patients with ICIs stayed longer in the intensive care unit than those without ICIs.

To evaluate the predictive performance of metagenomic next-generation sequencing (mNGS) in identifying and predicting pulmonary infections following liver transplantation and to investigate its association with patient outcomes within the initial four-week post-transplantation period.

We retrospectively analyzed 41 liver transplant patients with suspected pulmonary infections from August 2022 to May 2023. Bronchoalveolar lavage fluid (BALF) samples were collected on the first postoperative day for metagenomic next generation sequencing (mNGS) and culture. The predictive capability of mNGS for subsequent infections was assessed by monitoring inflammatory biomarkers and comparing the detection rates with culture methods. Real-time Polymerase Chain Reaction (Rt-PCR) was used to monitor Human betaherpesvirus 5 (CMV) and Human parvovirus B19 (B19) weekly during a four-week postoperative period. Inflammatory biomarkers and blood coagulation function were evaluated on specific days throughout the first, third, fifth, and during four weeks following surgery. The study was conducted until August 2023 to evaluate the patients' prognostic survival outcome, classifying them into groups based on the mortality and survival.

The analysis included a total of 41 patients, comprising 32 males and 9 females, with an average age of 52 (47, 63) years. Within one week after liver transplantation, there were 7 cases of bacterial infections, 5 cases of fungal infections, 19 cases of mixed infections, 8 cases without any infection, and 2 cases with unidentified pathogen-associated infections. mNGS successfully predicted 39 (72 %) strains of pathogens, while culture-based methods only detected 28 (52 %) strains. Among the 8 patients diagnosed as non-infected, culture methods identified positive results in 4 cases (50 %), whereas mNGS yielded positive results in 7 cases (87.5 %). The detection rates of CMV and B19 by Rt-PCR within 4 weeks after liver transplantation were 61 % and 17 %, respectively (25/41, 7/41) among the patients. During the study period, a total of 9 patients succumbed while 32 patients survived. The death group and the survival group exhibited significant differences in CRP, HGB, and INR levels at specific monitoring time points. The proportion of CMV detection in blood was significantly higher in the death group compared to the surviving group. Elevated CRP level was identified as a prognostic risk factor.

Despite the presence of false positives, mNGS still presents a potential advantage in predicting pulmonary infection pathogens following liver transplantation. Furthermore, the levels of CRP and CMV carrier status within four weeks post-surgery exhibit significant associations with patient survival and prognosis.

Liver transplantation (LT) has emerged as an effective therapy for severe forms of acute-on-chronic liver failure (ACLF), an entity characterized by the development of multiorgan failure and high short-term mortality. The aim of critical care management of ACLF patients is to rapidly treat precipitating events and aggressively support failing organs to ensure that patients may successfully undergo LT or, less frequently, recover. Malnutrition and sarcopenia are frequently present, adversely impacting the prognosis of these patients. Management of critical care patients with ACLF is complex and requires the participation of different specialties. Once the patient is stabilized, a rapid evaluation for salvage LT should be performed because the time window for LT is often narrow. The development of sepsis and prolonged organ support may preclude LT or diminish its chances of success. The current review describes strategies to bridge severe ACLF patients to LT, highlights the minimal evaluation required for listing and the currently suggested contraindications to proceed with LT, and addresses different aspects of management during the perioperative and early posttransplant period.

The primary objective of this study was to assess the incidence, timing, risk factors of fungal infections (FIs) within 3 months after liver transplantation (LT). The secondary objective was to evaluate the impact of FIs on outcomes. Four hundred and ten patients undergoing LT from January 2015 until January 2023 in a tertiary university hospital were included in the present retrospective cohort study to investigate the risk factors of FIs and to assess the impacts of FIs on the prognosis of LT recipients using logistic regression. The incidence of FIs was 12.4% (51/410), and median time from LT to the onset of FIs was 3 days. By univariate analysis, advanced recipient age, prolonged hospital stay prior to LT, high Model for End Stage Liver Disease (MELD) score, use of broad-spectrum antibiotics, and elevated white blood cell (WBC) count, increased operating time, massive blood loss and red blood cell transfusion, elevated alanine aminotransferase on day 1 and creatinine on day 3 after LT, prolonged duration of urethral catheter, prophylactic antifungal therapy, the need for mechanical ventilation and renal replacement therapy were identified as factors of increased post-LT FIs risk. Multivariate logistic regression analysis identified that recipient age ≥ 55 years[OR = 2.669, 95%CI: 1.292-5.513, P = 0.008], MELD score at LT ≥ 22[OR = 2.747, 95%CI: 1.274-5.922, P = 0.010], pre-LT WBC count ≥ 10 × 109/L[OR = 2.522, 95%CI: 1.117-5.692, P = 0.026], intraoperative blood loss ≥ 3000 ml [OR = 2.691, 95%CI: 1.262-5.738, P = 0.010], post-LT duration of urethral catheter > 4 d [OR = 3.202, 95%CI: 1.553-6.602, P = 0.002], and post-LT renal replacement therapy [OR = 5.768, 95%CI: 1.822-18.263, P = 0.003] were independently associated with the development of post-LT FIs. Post-LT prophylactic antifungal therapy ≥ 3 days was associated with a lower risk of the development of FIs [OR = 0.157, 95%CI: 0.073-0.340, P < 0.001]. As for clinical outcomes, FIs had a negative impact on intensive care unit (ICU) length of stay ≥ 7 days than those without FIs [OR = 3.027, 95% CI: 1.558-5.878, P = 0.001] but had no impact on hospital length of stay and 1-month all-cause mortality after LT. FIs are frequent complications after LT and the interval between the onset of FIs and LT was short. Risk factors for post-LT FIs included high MELD score at LT, advanced recipient age, pre-LT WBC count, massive intraoperative blood loss, prolonged post-LT duration of urethral catheter, and the need for post-LT renal replacement therapy. However, post-LT prophylactic antifungal therapy was independently associated with the reduction in the risk of FIs. FIs had a significant negative impact on ICU length of stay.

After liver transplantation (LTx), the most common cause of death in the long-term is de-novo malignancy (DNM). The aim is to review the gender differences in the standardized incidence ratio (SIR) of DNM within the same geographical locations.

Four studies were identified comparing post-LTx SIR between males and females.

From 6663 males and 2780 females LTx recipients, the mean SIR from each of the four studies for males is 2.8, 2.0, 1.94, and 3.4, and 3.5, 1.3, 1.95, and 2.3 for females. On meta-analysis using a random effect model for each gender group. No significant difference was revealed after logarithmic transformation and subgroup meta-analysis. Overall mean SIR with 95% Confidence Interval (CI) for males is 2.53 (95% CI 1.65-3.88) and 2.3 (1.25-4.24) for females. lung malignancy, 1.97 (1.14-3.41) for males and 2.65 (0.67-10.47) for females. For colorectal malignancy, the combined SIR for males is 1.98 (0.58-6.78) and 1.85 (1.02-3.37) for females. The SIR for female gender-specific malignancies; SIR for breast is 1.1 ± 4.4, cervix 2.9 ± 1.9, uterus 2.8, and ovarian 0.7, and for males, testis 1.6 ± 1.3, prostate 1.2 ± 0.4. However, rare malignancies, male breast cancers (n = 1, SIR, 22.6), and Kaposi's sarcoma, in males (n = 6) and in females (n = 1), had SIR 120. and 212.7, respectively.

Overall, there are no statistical differences between male and female DNM. Female-specific cervix, uterus, ovarian, and male-specific testis and prostate have similar SIR. Rare malignancies have very high SIR.

Liver transplantation (LT) is the standard treatment for end- stage liver disease. Patient and graft survival have improved significantly in the last three decades owing to improvement in surgical technique, better perioperative management and better immunosuppressive regimens. However, LT recipients are at increased risk of infections, particularly in the first year after transplantation. The risk of infection is directly proportional to immunosuppressive regimen and graft function. In this review, we will briefly discuss the timeline of infections after liver transplant, preventive strategies and management of infectious complications.

Organ transplantation stands as a pivotal achievement in modern medicine, offering hope to individuals with end-stage organ diseases. Advancements in immunology led to improved organ transplant survival through the development of immunosuppressants, but this heightened susceptibility to fungal infections with nonspecific symptoms in recipients. This review aims to establish an intricate balance between immune responses and fungal infections in organ transplant recipients. It explores the fundamental immune mechanisms, recent advances in immune response dynamics, and strategies for immune modulation, encompassing responses to fungal infections, immunomodulatory approaches, diagnostics, treatment challenges, and management. Early diagnosis of fungal infections in transplant patients is emphasized with the understanding that innate immune responses could potentially reduce immunosuppression and promise efficient and safe immuno-modulating treatments. Advances in fungal research and genetic influences on immune-fungal interactions are underscored, as well as the potential of single-cell technologies integrated with machine learning for biomarker discovery. This review provides a snapshot of the complex interplay between immune responses and fungal infections in organ transplantation and underscores key research directions.

Patients with liver diseases, including decompensated cirrhosis, alcohol-associated hepatitis, and liver transplant recipients are at increased risk of acquiring invasive fungal infections (IFIs). These infections carry high morbidity and mortality. Multiple factors, including host immune dysfunction, barrier failures, malnutrition, and microbiome alterations, increase the risk of developing IFI. Candida remains the most common fungal pathogen causing IFI. However, other pathogens, including Aspergillus, Cryptococcus, Pneumocystis, and endemic mycoses, are being increasingly recognized. The diagnosis of IFIs can be ascertained by the direct observation or isolation of the pathogen (culture, histopathology, and cytopathology) or by detecting antigens, antibodies, or nucleic acid. Here, we provide an update on the epidemiology, pathogenesis, diagnosis, and management of IFI in patients with liver disease and liver transplantation.

Liver transplantation is a standard of care and a life-saving procedure for end-stage liver diseases and certain malignancies. The evidence on predictors and risk factors for poor outcomes is lacking. Therefore, we aimed to identify potential risk factors for mortality and to report on overall 90-day mortality after orthotopic liver transplantation (OLT), especially focusing on the role of fungal infections.

We retrospectively reviewed medical charts of all patients undergoing OLT at a tertiary university center in Europe.

From 299 patients, 214 adult patients who received a first-time OLT were included. The OLT indication was mainly due to tumors (42%, 89/214) and cirrhosis (32%, 68/214), including acute liver failure in 4.7% (10/214) of patients. In total, 8% (17/214) of patients died within the first three months, with a median time to death of 15 (1-80) days. Despite a targeted antimycotic prophylaxis using echinocandins, invasive fungal infections occurred in 12% (26/214) of the patients. In the multivariate analysis, patients with invasive fungal infections had an almost five times higher chance of death (HR 4.6, 95% CI 1.1-18.8; p = 0.032).

Short-term mortality after OLT is mainly determined by infectious and procedural complications. Fungal breakthrough infections are becoming a growing concern. Procedural, host, and fungal factors can contribute to a failure of prophylaxis. Finally, invasive fungal infections may be a potentially modifiable risk factor, but the ideal perioperative antimycotic prophylaxis has yet to be determined.

To develop evidence-based recommendations for clinicians caring for adults with acute liver failure (ALF) or acute on chronic liver failure (ACLF) in the ICU.

The guideline panel comprised 27 members with expertise in aspects of care of the critically ill patient with liver failure or methodology. We adhered to the Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development.

In part 2 of this guideline, the panel was divided into four subgroups: neurology, peri-transplant, infectious diseases, and gastrointestinal groups. We developed and selected Population, Intervention, Comparison, and Outcomes (PICO) questions according to importance to patients and practicing clinicians. For each PICO question, we conducted a systematic review and meta-analysis where applicable. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements.

We report 28 recommendations (from 31 PICO questions) on the management ALF and ACLF in the ICU. Overall, five were strong recommendations, 21 were conditional recommendations, two were best-practice statements, and we were unable to issue a recommendation for five questions due to insufficient evidence.

Multidisciplinary, international experts formulated evidence-based recommendations for the management ALF and ACLF patients in the ICU, acknowledging that most recommendations were based on low quality and indirect evidence.

Invasive fungal infections represent a major challenge in patients who underwent organ transplantation. Overall, the most common fungal infections in these patients are candidiasis, followed by aspergillosis and cryptococcosis, except in lung transplant recipients, where aspergillosis is most common. Several risk factors have been identified, which increase the likelihood of an invasive fungal infection developing after transplantation. Liver transplant recipients constitute a high-risk category for invasive candidiasis and aspergillosis, and therefore targeted prophylaxis is favored in this patient population. Furthermore, a timely implemented therapy is crucial for achieving optimal outcomes in transplanted patients. In this article, we describe the epidemiology, risk factors, prophylaxis, and treatment strategies of the most common fungal infections in organ transplantation, with a focus on liver transplantation.

Liver transplantation is increasing worldwide with underlying pathologies dominated by metabolic and alcoholic diseases in developed countries.

We provide a narrative review of invasive aspergillosis (IA) in liver transplant (LT) recipients. We searched PubMed and Google Scholar for references without language and time restrictions.

The incidence of IA in LT recipients is low (1.8%), while mortality is high (∼50%). It occurs mainly early (<3 months) after LT. Some risk factors have been identified before (corticosteroid, renal, and liver failure), during (massive transfusion and duration of surgical procedure), and after transplantation (intensive care unit stay, re-transplantation, re-operation). Diagnosis can be difficult and therefore requires full radiological and clinicobiological collaboration. Accurate identification of Aspergillus species is recommended due to the cryptic species, and susceptibility testing is crucial given the increasing resistance of Aspergillus fumigatus to azoles. It is recommended to reduce the dose of tacrolimus (50%) and to closely monitor the trough level when introducing voriconazole, isavuconazole, and posaconazole. Surgery should be discussed on a case-by-case basis. Antifungal prophylaxis is recommended in high-risk patients. Environmental preventative measures should be implemented to prevent outbreaks of nosocomial aspergillosis in LT recipient units.

IA remains a very serious disease in LT patients and should be promptly sought and, if possible, prevented by clinicians when risk factors are identified.

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.

At present, there is still a lack of effective invasive fungal prophylaxis therapy in liver transplant recipients (LTRs). This study aimed to analysis the latest evidence on efficacy of current prophylactic anti-fungal therapy, and systematically compare between anti-fungal agents and placebo by a fixed-effects meta-analysis in all randomised controlled trials. A network meta-analysis was performed for invasive fungal infection (IFI) among different agents in 14 randomised controlled trials, in which 10 anti-fungal approaches were identified. Overall, anti-fungal prophylaxis reduced the rate of IFI (RR 0.30, 95% CI 0.18-0.52) and proven IFI (RR 0.27, 95% CI 0.14-0.53) when compared to placebo. In the network meta-analysis, an equivalent reduction in the rate of IFI was observed in fluconazole (OR 4.70, 95% CI 1.22-18.10), itraconazole (OR 5.82, 95% CI 1.10-30.71) and Liposomal amphotericin B (LAmB, OR 5.74, 95% CI 1.29-25.58) groups when compared with placebo. Anidulafungin might be the most effective agents in IFI prevention; however, this superiority did not meet statistically significance. Our study indicated that fluconazole, echinocandins and LAmB are equivalent in efficacy. Of which, fluconazole is recommended for the prevention of IFI in LTRs due to its efficacy, economics and compliance.

Antimicrobial prophylaxis is well-accepted in the liver transplant (LT) setting. Nevertheless, optimal regimens to prevent bacterial, viral, and fungal infections are not defined.

To identify the optimal antimicrobial prophylaxis to prevent post-LT bacterial, fungal, and cytomegalovirus (CMV) infections, to improve short-term outcomes, and to provide international expert panel recommendations.

Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central.

Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel.

CRD42021244976.

Of 1853 studies screened, 34 were included for this review. Bacterial, CMV, and fungal antimicrobial prophylaxis were evaluated separately. Pneumocystis jiroveccii pneumonia (PJP) antimicrobial prophylaxis was analyzed separately from other fungal infections. Overall, eight randomized controlled trials, 21 comparative studies, and five observational noncomparative studies were included.

Antimicrobial prophylaxis is recommended to prevent bacterial, CMV, and fungal infection to improve outcomes after LT. Universal antibiotic prophylaxis is recommended to prevent postoperative bacterial infections. The choice of antibiotics should be individualized and length of therapy should not exceed 24 hours (Quality of Evidence; Low | Grade of Recommendation; Strong). Both universal prophylaxis and preemptive therapy are strongly recommended for CMV prevention following LT. The choice of one or the other strategy will depend on individual program resources and experiences, as well as donor and recipient serostatus. (Quality of Evidence; Low | Grade of Recommendation; Strong). Antifungal prophylaxis is strongly recommended for LT recipients at high risk of developing invasive fungal infections. The drug of choice remains controversial. (Quality of Evidence; High | Grade of Recommendation; Strong). PJP prophylaxis is strongly recommended. Length of prophylaxis remains controversial. (Quality of Evidence; Very Low | Grade of Recommendation; Strong).

With increasing morbidity and mortality from chronic liver disease and acute liver failure, the need for liver transplantation is on the rise. Most of these patients are extremely vulnerable to infections as they are immune-compromised and have other chronic co-morbid conditions. Despite the recent advances in practice and improvement in diagnostic surveillance and treatment modalities, a major portion of these patients continue to be affected by post-transplant infections. Of these, fungal infections are particularly notorious given their vague and insidious onset and are very challenging to diagnose. This mini-review aims to discuss the incidence of fungal infections following liver transplantation, the different fungi involved, the risk factors, which predispose these patients to such infections, associated diagnostic challenges, and the role of prophylaxis. The population at risk is increasingly old and frail, suffering from various other co-morbid conditions, and needs special attention. To improve care and to decrease the burden of such infections, we need to identify the at-risk population with more robust clinical and diagnostic parameters. A more robust global consensus and stringent guidelines are needed to fight against resistant microbes and maintain the longevity of current antimicrobial therapies.

Although 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.

Two 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).

698 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.

Echinocandins 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.

Liver transplantation (LT) has revolutionized outcomes for cirrhotic patients. Current liver allocation policies dictate patients with highest short-term mortality receive the highest priority, thus, several patients become increasingly ill on the waitlist. Given cirrhosis is a progressive disease, it can be complicated by the occurrence of acute-on-chronic liver failure (ACLF), a syndrome defined by an acute deterioration of liver function associated with extrahepatic organ failures requiring intensive care support and a high short-term mortality. Successfully bridging to transplant includes accurate prognostication and prioritization of ACLF patients awaiting LT, optimizing intensive care support pre-LT, and tailoring immunosuppressive and anti-infective therapies post-LT. Furthermore, predicting futility (too sick to undergo LT) in ACLF is challenging. In this review, we summarize the role of LT in ACLF specifically highlighting (a) current prognostic scores in ACLF, (b) critical care management of the ACLF patient awaiting LT, (c) donor issues to consider in transplant in ACLF, and (d) exploring of recent post-LT outcomes in ACLF and potential opportunities to improve outcomes including current care gaps and unmet research needs.

Invasive infections are a major complication before liver transplantation (LT) and in the early phase after surgery. There has been an increasing prevalence of invasive fungal disease (IFD), especially among the sickest patients with decompensated cirrhosis and acute-on-chronic liver failure, who suffer from a profound state of immune dysfunction and receive intensive care management. In such patients, who are listed for LT, development of an IFD often worsens hepatic and extra-hepatic organ dysfunction, requiring a careful evaluation before surgery. In the post-transplant setting, the burden of IFD has been reduced after the clinical advent of antifungal prophylaxis, even if several major issues still remain, such as duration, target population and drug type(s). Nevertheless, the development of IFD in the early phase after surgery significantly impairs graft and patient survival. This review outlines presentation, prophylactic and therapeutic strategies, and outcomes of IFD in LT candidates and recipients, providing specific considerations for clinical practice.

Invasive fungal disease (IFD) in liver transplant recipients causes significant morbidity and mortality. We aim to describe institutional epidemiology and risk factors for IFD in the liver transplant population.

We conducted a retrospective cohort study of all adult liver transplant recipients in our institution from 2005 to October 2015 to describe the epidemiology of patients with proven and probable IFD according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. To determine risk factors for IFD, a case-control study was also conducted. Cases were defined as liver transplant recipients with proven or probable IFD, and controls were defined as liver transplant recipients without IFD. Each case was matched to two controls by age (±10 years of age), gender, and time of transplant (within one year of the case).

28/554 (5.1%) patients developed IFD. Candidiasis (n = 11; 39.3%), Aspergillosis (n = 10; 35.7%), and Cryptococcosis (n = 3; 10.7%) were the most common fungal infections in the proven and probable IFD groups. Mold infections occurred in 13 (46.4%) cases. Reoperation, roux-en-y anastomosis, and massive intraoperative transfusion of ≥40 units of cellular blood products were major risk factors for IFD in the multivariate analysis.

Candida and Aspergillus are the most common causes of IFD in liver transplantation in our center. There is significant overlap in risk factors for such infections post-transplantation. In our cohort, critically ill patients with complicated perioperative course seem to predispose them to mold infections post-transplantation, but larger studies are required to better delineate risk factors for mold infection as well as determine the efficacy and optimal duration of mold prophylaxis in liver transplantation. With increasing echinocandin use for antifungal prophylaxis, it is also important to monitor for emerging antifungal resistance.

Mold infections in liver transplant are associated with high mortality. Guidelines recommend prophylaxis targeted against mold based upon risk factors of fulminant hepatic failure, retransplantation, reoperation, and renal replacement therapy post-transplant. It is not known if these factors identify risk of mold infection at every center.

A retrospective study was conducted of adult liver transplant recipients at a single center from 2010 to 2014. The association between risk factors and invasive mold infection and effect of antifungal prophylaxis were determined.

Five hundred thirty-four liver transplant recipients were identified. The overall incidence of invasive mold infection was 0.9% (N = 5). The incidence in patients with (N = 128) and without (N = 406) risk factors was 0.78% and 0.98%, respectively. Antifungal prophylaxis with mold activity was administered to 23/128 (18%) with risk factors, and none developed infection. No mold-active prophylaxis was given to 105/128 (82%) with risk factors, and incidence of mold infection was 0.95% (N = 1). Number needed to treat was 105.

Traditional risk factors for mold infection in liver transplant performed poorly. These results underscore the importance of transplant center-specific data to inform adoption of an antifungal prophylactic strategy. Studies are needed to determine alternative risk factors to facilitate appropriate targeting of antifungals.

Invasive fungal infection (IFI) after liver transplant (LTx) is associated with extensive morbidity and mortality. Targeted prophylaxis reduces risk, but qualifying criteria, drug of choice and regimen are unclear and compliance is inconsistent.

Assess the impact of a risk factor-based fungal prophylaxis protocol (FPP) after LTx on fungal infection rates, fungal epidemiology, and transplant outcomes.

Observational cohort study of adult LTx recipients between July 1, 2009, and June 30, 2017. Patients in the FPP group were given a set dose of 400 mg fluconazole without renal adjustment on POD 1-14 via pharmacist delegation protocol.

One hundred and eighty-nine patients met inclusion criteria; 50 in the FPP and 139 in the pre-implementation comparator group. Of those who would be considered high-risk, 22.3% received antifungal prophylaxis prior to FPP implementation vs 92% after implementation (P < .0001). There were significantly fewer fungal infections in the FPP group at 1 year (12.5% vs 26.6%, P = .03). IFI in the pre-implementation control group was due to Candida species in 95% of cases; 30% were species with reduced fluconazole susceptibility. IFI in the FPP group was due to Candida species in all cases, and no isolates had reduced fluconazole susceptibility. Aspergillus did not account for any IFI between the groups. One-year patient and graft survival were similar between groups. In a multivariable model accounting for patient and donor age, donor type, MELD, and cold ischemic time, FPP was protective against fungal infection (HR 0.3, P = .015). FPP did not significantly impact graft survival (HR 0.4, P = .14), but trended toward improved patient survival. (HR 0.18, P = .06).

Implementation of a targeted FPP utilizing static dosing of fluconazole 400 mg × 14 days to those that meet high-risk criteria significantly reduces invasive fungal infection after liver transplant. Use of this protocol did not adversely affect fungal epidemiology and may have a positive impact on allograft and patient survival. Future large prospective studies are needed to better evaluate survival impact.

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice provide recommendations for the diagnosis and management of Candida infections in solid organ transplant recipients. Candida infections manifest primarily as candidemia and invasive candidiasis and cause considerable morbidity and mortality. Early diagnosis and initiation of treatment are necessary to reduce mortality. For both candidemia and invasive candidiasis, an echinocandin is recommended for initial therapy. However, early transition to oral therapy is encouraged when patients are stable and the organism is susceptible. Candida prophylaxis should be targeted for high-risk patients in liver, small bowel, and pancreas transplant recipients. Future research should address which patient groups may benefit most from preventative antifungal therapy strategies.

The epidemiology of invasive fungal infections (IFIs) after liver transplantation (LT) is continuing to evolve in the current era of antifungal prophylactic therapy. This multicenter retrospective cohort study aimed to evaluate the epidemiology, risk factors, and outcomes of IFIs among LT recipients in the current era.We analyzed a total of 482 LT recipients aged 18 years and older who were admitted to 3 tertiary hospitals in Korea between January 2009 and February 2012.Twenty-four episodes of IFIs occurred in 23 patients (4.77%; 23/482). Of these episodes, 20 were proven cases and 4 were probable cases according to EORTC/MSG criteria. Among these cases, IFI developed within 30 days of transplantation in 47.8% of recipients, from 31 to 180 days in 34.8% of recipients, and from 181 to 365 days in 17.4% of recipients. The most common isolates were Candida species (n = 12, 52.2%; Candida albicans, 6 cases; Candida tropicalis, 1 case; Candida glabrata, 1 case; Candida parapsilosis, 1 case; and unspecified Candida species, 1 case) and Aspergillus species (n = 7, 30.4%). The mortality in patients with IFIs was significantly higher than that in patients without IFIs (47.83% [11/23] vs 7.18% [33/459], P < .001). The incidence of late-onset IFIs is increasing in the antifungal prophylactic era, and fluconazole-resistant non-albicans Candida species have not yet emerged in Korea.

These updated AST-IDCOP guidelines provide information on epidemiology, diagnosis, and management of Aspergillus after organ transplantation. Aspergillus is the most common invasive mold infection in solid-organ transplant (SOT) recipients, and it is the most common invasive fungal infection among lung transplant recipients. Time from transplant to diagnosis of invasive aspergillosis (IA) is variable, but most cases present within the first year post-transplant, with shortest time to onset among liver and heart transplant recipients. The overall 12-week mortality of IA in SOT exceeds 20%; prognosis is worse among those with central nervous system involvement or disseminated disease. Bronchoalveolar lavage galactomannan is preferred for the diagnosis of IA in lung and non-lung transplant recipients, in combination with other diagnostic modalities (eg, chest CT scan, culture). Voriconazole remains the drug of choice to treat IA, with isavuconazole and lipid formulations of amphotericin B regarded as alternative agents. The role of combination antifungals for primary therapy of IA remains controversial. Either universal prophylaxis or preemptive therapy is recommended in lung transplant recipients, whereas targeted prophylaxis is favored in liver and heart transplant recipients. In these guidelines, we also discuss newer antifungals and diagnostic tests, antifungal susceptibility testing, and special patient populations.

Invasive fungal infections (IFIs) are a major threat to patients undergoing solid organ transplantation (SOT). Owing to improvements in surgical techniques, immunosuppression therapy and antifungal prophylaxis, the incidence of IFIs has been decreasing in recent years. However, IFI-associated morbidity and mortality remain significant. Invasive candidiasis (IC) and aspergillosis (IA) are the main IFIs after SOT. Risk factors for IC and IA continue to evolve, and thus strategies for their prevention should be constantly updated and targeted to both individual patient risk factors and local epidemiology. In this review, we discuss the current epidemiology and risk factors for IFIs in SOT recipients in the context of actual approaches to antifungal prophylaxis, including experience with the use of echinocandins, after SOT.

The study aims to assess the population pharmacokinetics of fluconazole and the adequacy of current dosages and breakpoints against Candida albicans and non-albicans spp. in liver transplant (LT) patients.

Patients initiated i.v. fluconazole within 1 month from liver transplantation (LTx) for prevention or treatment of Candida spp. infections. Multiple assessments of trough and peak plasma concentrations of fluconazole were undertaken in each patient by means of therapeutic drug monitoring. Monte Carlo simulations were performed to define the probability of target attainment (PTA) with a loading dose (LD) of 400, 600, and 800 mg at day 1, 7, 14, and 28 from LTx, followed by a maintenance dose (MD) of 100, 200, and 300 mg daily of the pharmacokinetic/pharmacodynamic target of AUC_24h/MIC ratio ≥ 55.2.

Nineteen patients were recruited. A two-compartment model with first-order intravenous input and first-order elimination was developed. Patient's age and time elapsed from LTx were the covariates included in the final model. At an MIC of 2 mg/L, a LD of 600 mg was required for optimal PTAs between days 1 and 20 from LTx, while 400 mg was sufficient from days 21 on. A MD of 200 mg was required for patients aged 40-49 years old, while a dose of 100 mg was sufficient for patients aged ≥ 50 years.

Fluconazole dosages of 100-200 mg daily may ensure optimal PTA against C. albicans, C. parapsilosis, and C. tropicalis. Higher dosages are required against C. glabrata. Estimated creatinine clearance is not a reliable predictor of fluconazole clearance in LT patients.

Hospitalized patients with cirrhosis have a high rate of mortality. In the report by Bajaj et al., the negative impact of fungal infections (FI) on outcomes in a large US cohort of hospitalized cirrhotics is highlighted. Risk factors for FI are identified. Increasing awareness of FI along with the application of new diagnostic tools in species identification will provide the opportunity to improve patient outcomes.

Mycotic aneurysm of the hepatic artery (HA) is a rare, unpredictable, and potentially lethal complication of liver transplantation (LT). Pediatric LT is not exempt from it but the related literature is rather scanty. We present our experience with post-LT mycotic aneurysm of the HA in pediatric age, describing four cases occurred with a special focus on the possible risk factors for its development and a proposal for the management of high-risk recipients.

Invasive fungal infection (IFI) is a severe complication of liver transplantation burdened by high mortality. Guidelines recommend targeted rather than universal antifungal prophylaxis based on tiers of risk.

We aimed to evaluate IFI incidence, risk factors, and outcome after implementation of a simplified two-tiered targeted prophylaxis regimen based on a single broad-spectrum antifungal drug (amphotericin B). Patients presenting 1 or more risk factors according to literature were administered prophylaxis. Prospectively collected data on all adult patients transplanted in Turin from January 2011 to December 2015 were reviewed.

Patients re-transplanted before postoperative day 7 were considered once, yielding a study cohort of 581 cases. Prophylaxis was administered to 299 (51.4%) patients; adherence to protocol was 94.1%. Sixteen patients developed 18 IFIs for an overall rate of 2.8%. All IFI cases were in targeted prophylaxis group; none of the non-prophylaxis group developed IFI. Most cases (81.3%) presented within 30 days after transplantation during prophylaxis; predominant pathogens were molds (94.4%). Only 1 case of candidemia was observed. One-year mortality in IFI patients was 33.3% vs 6.4% in patients without IFI (P = .001); IFI attributable mortality was 6.3%. At multivariate analysis, significant risk factors for IFI were renal replacement therapy (OR = 8.1) and re-operation (OR = 5.2).

The implementation of a simplified targeted prophylaxis regimen appeared to be safe and applicable and was associated with low IFI incidence and mortality. Association of IFI with re-operation and renal replacement therapy calls for further studies to identify optimal prophylaxis in this subset of patients.

Targeted antifungal prophylaxis against Candida species or against Candida species and Aspergillus species, according to individual patient risk factors (RFs), is recommended by experts. However, recent studies have reported fluconazole is as effective as broader spectrum antifungals for preventing invasive fungal infection (IFI) after liver transplantation (LT).

We performed a retrospective cohort study of all adult patients who underwent LT at our 1420-bed tertiary teaching hospital, from June 2010 to December 2014, to assess the rate and etiology of IFI within 100 days after LT, to investigate the compliance with targeted prophylaxis, and to analyze risk factors for developing IFI.

In total, 303 patients underwent LT. Patients were classified as having low (no RFs), intermediate (1 RF for invasive candidiasis [IC]), and high risk (1 RF for invasive aspergillosis [IA] or ≥2 RFs for IC) for IFI in 20%, 30%, and 50% of cases, respectively. A total of 139 patients received antifungal prophylaxis: 98 with a mold-active drug and 41 with fluconazole. Overall adherence to targeted prophylaxis was 53%. Nineteen patients (6.3%) developed IFI: 7 IC and 12 IA. Multivariate Cox regression analysis, adjusted for median model for end-stage liver disease score at LT, stratification risk group, and adherence to targeted prophylaxis, showed that graft dysfunction, renal replacement therapy, and prophylaxis with fluconazole were independent risk factors for IFI. Seven of the 9 patients who received fluconazole prophylaxis and developed IFI were classified as having high risk for IFI, and 6 developed IA.

Recommended stratification is accurate for predicting patients at very high risk for IFI, who should receive prophylaxis with a mold-active drug.

Targeted prophylaxis has proven to be an efficient strategy in liver transplantation recipients (LTRs). The aim of this study was to compare the effectiveness and safety of caspofungin with that of fluconazole in high-risk (HR) LTRs. Caspofungin and fluconazole were compared in a multicenter, retrospective, cohort study in HR-LTRs in Spain. Outcomes were assessed at 180 days after transplantation. A propensity score approach was applied. During the study period (2005-2012), we analyzed 195 HR-LTRs from 9 hospitals. By type of prophylaxis, 97 patients received caspofungin and 98 received fluconazole. Of a total of 17 (8.7%) global invasive fungal infections (IFIs), breakthrough IFIs accounted for 11 (5.6%) and invasive aspergillosis (IA) accounted for 6 (3.1%). By univariate analysis, no differences were observed in the prevention of global IFIs. However, caspofungin was associated with a significant reduction in the rate of breakthrough IFIs (2.1% versus 9.2%, P = 0.04). In patients requiring dialysis (n = 62), caspofungin significantly reduced the frequency of breakthrough IFIs (P = 0.03). The propensity score analysis confirmed a significant reduction in the frequency of IA in patients receiving caspofungin (absolute risk reduction, 0.06; 95% confidence interval [CI], 0.001-0.11; P = 0.044). Linear regression analysis revealed a significant decrease in blood alanine aminotransferase levels and a significant increase in bilirubin levels after administration of caspofungin. Caspofungin and fluconazole have similar efficacy for the prevention of global IFIs in HR-LTRs in this observational, multicenter cohort study. However, caspofungin was associated with a significant reduction of breakthrough IFIs and, after adjusting for confounders, caspofungin was associated with a lower rate of IA. This benefit is probably more favorable in patients on dialysis. Caspofungin is safe in HR-LTRs, although bilirubin levels may be increased.