Liver transplantation is the standard therapy for end-stage liver disease in pediatric patients with biliary atresia (BA), congenital and metabolic conditions, and for an unresectable malignant tumor like hepatoblastoma (HB). BA is the leading indication for pediatric liver transplantation, while HB is the most common childhood liver cancer. Despite improved outcomes through advanced surgical techniques and novel immunosuppression, pediatric liver transplantation (pLT) is complicated by post-transplant infections.

A retrospective review was performed of pLT recipients at Cincinnati Children's Hospital Medical Center (CCHMC) and stratified patients by underlying disease to assess impact on post-transplant infectious events.

BA patients were youngest at pLT (12.5 months; p < 0.001) compared to other disease cohorts (HB 30.8, other 43.7). All HB patients received organs from deceased donors. In the year following pLT, 93% of the patients experienced at least one infectious event (IE). HB patients had the highest mean number of IE across disease groups (5.5 IE/patient vs. BA 4.5, other 4.0; p = 0.055), with significantly more patients with fever and neutropenia (p < 0.001) and EBV infections (p = 0.012). HB patients were more likely to develop IE earlier after pLT than non-HB groups (p = 0.013), especially Clostridioides difficile (p < 0.01) and fever and neutropenia (p < 0.01). Despite having variable IE experiences, 1-and-5-year survival across disease groups were similar.

IE were frequently observed in HB patients after pLT, possibly related to pre-and-postoperative chemotherapy and associated neutropenia. Underlying disease may help inform targeted infection-related patient management following pLT.

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.

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.

To investigate the role of diffusion-weighted imaging (DWI) for diagnosis and posttreatment assessment of hepatic fungal infection in patients with acute leukemia.

Patients with acute leukemia and highly suspected hepatic fungal infection were collected in the study. All the patients underwent MRI examination, including initial and follow-up DWI. The apparent diffusion coefficient (ADC) values of the lesions and the normal liver parenchyma were compared using Student's t-test. The ADC values of the hepatic fungal lesions of pretreatment and posttreatment were compared using paired t-test.

A total of 13 patients with hepatic fungal infections have enrolled this study. Hepatic lesions were rounded or oval shaped, measured from 0.3 to 3 cm in diameter. The lesions showed significantly hyperintense signal on DWI and markedly hypointense signal on the ADC map, reflecting a marked restricted diffusion. The mean ADC values of the lesions were significantly lower than those of normal liver parenchyma (1.08 ± 0.34 × 10-3 vs. 1.98 ± 0.12 × 10-3  mm2 /s, p < 0.001). After treatment, the mean ADC values of the lesions were significantly increased when comparing with those of pretreatment (1.39 ± 0.29 × 10-3 vs. 1.06 ± 0.10 × 10-3 mm2 /s, p = .016).

DWI can provide diffusion information of hepatic fungal infection in patients with acute leukemia, which could be taken as a valuable tool for diagnosis and therapy response assessment of these patients.

Chronic liver disease is often associated with testosterone deficiency. However, testosterone replacement does not improve hepatic function or survival with diseased liver. So far, to our knowledge, testosterone replacement therapy after successful livertransplantforfunctional sarcopenia has not been studied. We had 3 goals: (1) define postoperative functional sarcopenia afterlivertransplant with serum testosterone level; (2) examine the role of short-term testosterone replacement therapy with active in-bed exercise of upper and lower extremity joints; and (3) correlate functional sarcopenia with skeletal muscle index and skeletal muscle density in relation to ascites, pleural effusion subtracted body mass index.

We evaluated 16 liver transplant recipients who had been receiving posttransplanttestosterone replacementtherapy with functional sarcopenia. Preoperative and postoperative demographics and laboratory and radiological data were retrieved; body mass index, skeletal muscle index, and skeletal muscle density were calculated. For this retrospective study, institutional review board approval was obtained before the electronic database was reviewed and analyzed.

Mean testosterone level was 28.3 ng/dL (<5% of expected). Twelve patients received 1 dose, and the remaining 4 patients received >1 dose oftestosterone cypionate, 200 mg. Mean hospital stay was 26 days. Seven patients were discharged home, with the remaining patients to a rehabilitation facility or nursing home. One patient died from a cardiac event, and another patient died from recurrent metastatic malignancy. The 1-year and 5-year actuarial patient and graft survival rates were 93.8% and 87.5%, respectively. Overall, 5 patients were sarcopenic by skeletal muscle index, and 6 patients had poor muscle quality by skeletal muscle density.

Testosterone deficiency after liver transplant exists with functional sarcopenia. Two- thirds of such recipients have low skeletal muscle index and/or have low skeletal muscle density. Short- term testosterone replacement therapy with in-bed active exercise provides 5-year patient and graft survival of 87.5%.

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 invasive fungal infections (IFIs) contribute to substantial morbidity and mortality in liver transplant recipients, only a few randomized studies analyzed the results of antifungal prophylaxis with echinocandins. The aim of this open-label, non-inferiority study was to evaluate the efficacy and safety of micafungin in the prophylaxis of IFIs in living-donor liver transplantation recipients (LDLTRs), with fluconazole as the comparator.

LDLTRs (N = 172) from five centers were randomized 1:1 to receive intravenous micafungin 100 mg/day or fluconazole 100~200 mg/day (intravenous or oral). A non-inferiority of micafungin was tested against fluconazole.

The per-protocol set included 144 patients without major clinical trial protocol violations: 69 from the micafungin group and 75 from the fluconazole group. Mean age of the study patients was 54.2 years and mean model for end-stage liver disease (MELD) score amounted to 16.5. Clinical success rates in the micafungin and fluconazole groups were 95.65% and 96.10%, respectively (difference: - 0.45%; 90% confidence interval [CI]: - 6.93%, 5.59%), which demonstrated micafungin's non-inferiority (the lower bound for the 90% CI exceeded - 10%). The study groups did not differ significantly in terms of the secondary efficacy endpoints: absence of IFIs at the end of the prophylaxis and the end of the study, time to proven IFI, fungal-free survival, and adverse reactions. A total of 17 drug-related adverse events were observed in both groups; none of them was serious and all resolved.

Micafungin can be used as an alternative to fluconazole in the prevention of IFIs in LDLTRs.

NCT01974375.

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.

Chronic liver disease has been associated with pulmonary dysfunction both before and after liver transplantation. Post-liver transplantation pulmonary complications can affect both morbidity and mortality often necessitating intensive care during the immediate postoperative period. The major pulmonary complications include pneumonia, pleural effusions, pulmonary edema, and atelectasis. Poor clinical outcomes have been known to be associated with age, severity of liver dysfunction, and preexisting lung disease as well as perioperative events related to fluid balance, particularly transfusion and fluid volumes. Delineating each and every one of these pulmonary complications and their associated risk factors becomes paramount in guiding specific therapeutic strategies.

Invasive fungal infection (IFI) is associated with high mortality after living donor liver transplant (LDLT). The aim of this study was to identify the risk factors for post-LDLT IFI for early diagnosis and improvement of antifungal treatment outcome.

Risk analysis data were available for all 153 patients who underwent LDLT between January 2005 and April 2012.

During the follow-up period (1,553 ± 73 days, range 20-2,946 days), 15 patients (9.8%) developed IFI classified as "proven" (n = 8) and "probable" (n = 7) with fungal pathogens including Candida spp. (n = 10), Aspergillus spp. (n = 4), and Trichosporon (n = 2). Of these patients, 7 patients with IFI died despite treatment. The 1-, 3-, and 5-year survival rates were lower in patients with IFI than those without IFI (66.7/59.3/44.4 vs. 90.4/85.7/81.8%, respectively; p = 0.0026). Multivariate analysis identified model for end-stage liver disease score of ≥26 (OR 16.0, p = 0.0012) and post-transplant acute kidney injury (RIFLE criteria I- or F-class; OR 4.87, p = 0.047) as independent risk factors for IFI.

Preoperative recipients' status and postoperative kidney dysfunction can affect an occurrence of post-transplant IFI. These risk factors would be taken into consideration for designation of proper antifungal therapy.

Background:Heliotropium strigosum Willd. (Chitiphal) is a medicinally important herb that belongs to the Boraginaceae family. Traditionally, this plant was used in the medication therapy of various ailments in different populations of the world. The aim of the study is to probe the therapeutic aspects of H. strigosum described in the traditional folklore history of medicines. Methods: In the present study, the dichloromethane crude extract of this plant was screened to explore the antimicrobial, cytotoxic, phytotoxic and antioxidant potential of H. strigosum. For antibacterial, antifungal and antioxidant activities, microplate alamar blue assay (MABA), agar tube dilution method and diphenyl picryl hydrazine (DPPH) radical-scavenging assay were used, respectively. The cytotoxic and phytotoxic potential were demonstrated by using brine shrimp lethality bioassay and Lemna minor assay. Results: The crude extract displayed positive cytotoxic activity in the brine shrimp lethality assay, with 23 of 30 shrimps dying at the concentration of 1000 µg/mL. It also showed moderate phytotoxic potential with percent inhibition of 50% at the concentration of 1000 µg/mL. The crude extract exhibited no significant antibacterial activity against Staphylococcus aureus, Shigella flexneri, Escherichia coli and Pseudomonas aeruginosa. Non-significant antifungal and radical scavenging activity was also shown by the dichloromethane crude extract. Conclusion: It is recommended that scientists focus on the identification and isolation of beneficial bioactive constituents with the help of advanced scientific methodologies that seems to be helpful in the synthesis of new therapeutic agents of desired interest.

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.

Early hepatic artery thrombosis after liver transplant may be complicated by aggressive aspergillosis and bacterial infections that may cause morbidity and mortality. The definitive treatment of hepatic artery thrombosis is revision transplant. However, sepsis may be a contraindication to revision transplant. A 37-year-old man developed hepatic artery thrombosis at 3 days after liver transplant. During the treatment of hepatic artery thrombosis, he developed multiple biliary, bacterial, and fungal infections. Evaluation showed aspergillosis with multiple intrahepatic abscesses. He was treated with antibiotic and antifungal drugs. Despite active sepsis, revision transplant was performed and the infection resolved. Although sepsis may be a contraindication for transplant surgery, revision transplant was successful, probably because the primary transplanted liver was the source of infection.

Liver transplant seems to be an effective option to prolong survival in patients with end-stage liver disease, although it still can be followed by serious complications. Invasive fungal infections (ifi) are related to high rates of morbidity and mortality. The epidemiology of fungal infections in Brazilian liver transplant recipients is unknown. The aim of this observational and retrospective study was to determine the incidence and epidemiology of fungal infections in all patients who underwent liver transplantation at Albert Einstein Israeli Hospital between 2002-2007. A total of 596 liver transplants were performed in 540 patients. Overall, 77 fungal infections occurred in 68 (13%) patients. Among the 77 fungal infections, there were 40 IFI that occurred in 37 patients (7%). Candida and Aspergillus species were the most common etiologic agents. Candida species accounted for 82% of all fungal infections and for 67% of all IFI, while Aspergillus species accounted for 9% of all fungal infections and for 17% of all IFI. Non-albicans Candida species were the predominant Candida isolates. Invasive aspergillosis tended to occur earlier in the post-transplant period. These findings can contribute to improve antifungal prophylaxis and therapy practices in Brazilian centres.

Invasive fungal infections (IFIs) in immunocompromised patients, particularly liver transplant recipients, are the subject of increasing clinical attention. Although the overall incidence of fungal infections in liver transplant recipients has declined due to the early treatment of high-risk patients, the overall mortality rate remains high, particularly for invasive candidiasis and aspergillosis. IFIs after liver transplantation are strongly associated with negative outcomes, increasing the cost to recipients. Numerous studies have attempted to determine the independent risk factors related to IFIs and to reduce the morbidity and mortality with empirical antifungal prophylaxis after liver transplantation. Unfortunately, fungal infections are often diagnosed too late; symptoms can be mild and non-specific even with dissemination. Currently, no consensus exists on which patients should receive antifungal prophylaxis, when prophylaxis should be given, which antifungal agents should be used, and what duration is effective. This review highlights the types of IFI, risk factors, diagnosis, antifungal prophylaxis, and treatment after liver transplantation. With the early identification of patients at high risk for IFIs and the development of new molecular diagnostic techniques for early detection, the role of antifungal compounds in fungal infection prophylaxis needs to be established to improve the survival rate and quality of life in liver transplant patients.

Candida tropicalis has been identified as the most prevalent pathogenic yeast species of the Candida-non-albicans group. Historically, Candida albicans has been the major species responsible for causing candidiasis in immunocompromised and immunocompetent patients. However, infections (candidiasis) due to C. tropicalis have increased dramatically on a global scale thus proclaiming this organism to be an emerging pathogenic yeast. The reasons for this organism's dominance and its resistance to fluconazole have been difficult to elucidate. In addition, the mechanism of this organism's pathogenicity and the consequent immune response remain to be clarified. This paper describes certain predisposing factors potentially responsible for these characteristics and presents a 'root cause analysis' to explain the increasing prevalence of C. tropicalis in developed and undeveloped countries, as well as the organism's acquired drug resistance. Control measures against fluconazole resistance in clinical management have also been discussed.

Antifungal prophylaxis for liver transplant recipients (LTRs) is common among patients considered at high risk of infection, but optimal prophylaxis duration and drug has not been defined. This study aimed to assess the effects of 14 days of antifungal therapy prophylaxis in reducing proven invasive fungal infections (IFI) in high-risk subjects. Eligible subjects who met 2 or more risk criteria were randomized 1:1 to the treatment arms (liposomal amphotericin B or fluconazole) and were followed for 100 days post transplantation for evidence of IFI. The study was designed to enroll 300 subjects, but was closed early for insufficient enrollment. A total of 71 subjects were enrolled and randomized. Two-thirds of subjects completed 14 days of study therapy. Ten subjects developed proven or probable IFI with Candida species (9 subjects) and Cryptococcus neoformans (1 subject); rates were similar in the 2 treatment arms. Eleven subjects died, but no death was attributed to study drug or IFI. In summary, high-risk LTRs tolerated antifungal prophylaxis well, and rates of IFI were lower than previously reported in untreated high-risk LTRs.

There is a rapidly growing population of immunocompromised organ transplant recipients. These patients are at risk of a large variety of infections that have significant consequences on mortality, graft dysfunction, and graft loss. The diagnosis and treatment of these infections are facilitated by an understanding of the preoperative, perioperative, and postoperative risk factors; the typical pathogens; and their characteristic time of presentation. On the basis of these factors, we put forth an algorithm for diagnosing and treating suspected infections in solid organ transplant recipients.

Fungal infection is a major cause of death in patients who undergo organ transplantation. The incidence of Aspergillus or Mucor infection is low compared with Candida species. We report a case in which Aspergillus and Mucor infected both the hepatic and renal arteries, leading the 2 arteries to rupture at the same time. The patient died 4 days after the second operation. We review the recent literature about this topic and explore the possible route of transmission in our patient. We also discuss the prophylactic methods for Aspergillus and Mucor infections.

Infectious complications occur in approximately 50% of cadaveric liver transplant (CDLT) recipients. Living-donor liver transplantation (LDLT) is an established alternative to shorten the waiting time. Currently, the incidence of pulmonary infections after LDLT and the microbiologic causes are unknown. In the present cohort study, we compared the incidence and profiles of pulmonary and blood stream infections (BSI) between LDLT and CDLT recipients. We hypothesized a lower incidence in LDLT recipients.

The clinical course of 55 LDLT recipients consecutively transplanted between January 2003 and December 2006 was analyzed. The 173 CDLT recipients who were transplanted in the same period served as a control group. Patients were treated in a single Intensive Care Unit, applying standardized postoperative care.

Mean model for end-stage liver disease score did not differ between LDLT and CDLT recipients (14.2 vs. 13.3). The overall incidence of pulmonary and BSI for both groups was 8% and 24%, respectively. Pulmonary infections were experienced by 18% of LDLT versus 5% of CDLT recipients (P=0.005) and BSI occurred in 33% of LDLT versus 21% of CDLT recipients (P=0.1).

In contrast to our hypothesis, LDLT recipients experienced significantly more pulmonary infections and a trend toward increased higher incidence of BSI. These findings emphasize the need for future research on the causative agents and prevention of infection in LDLT recipients. The observation that patients with pulmonary infection had a significantly reduced 1-year survival rate underscores the importance of our observations.

We sought to determine whether the prophylactic use of amphotericin B products (conventional amphotericin B and liposomal amphotericin B) reduces the incidence of fungal infections in high-risk liver transplant recipients, and if so, whether this lowers the cost of care. The study sample comprised 232 adult orthotopic liver transplants performed from 1994 to 2005 at a single center for patients classified as being at high risk for fungal infections. High-risk patients who received transplants with a prophylaxis regimen of amphotericin B (n=58 transplants) were compared with high-risk patients who received no prophylaxis (n=174 transplants). Fungal infections occurred in 3 transplants (5.17%) of those who received amphotericin B and 28 transplants (16.09%) in those without prophylaxis (P=0.0432). Regression models were used to analyze fungal infection and costs for the 232 high-risk transplants. Failure to offer prophylaxis conferred a 4-fold greater risk of fungal infection (P=0.046) compared with those who received amphotericin B. A fungal infection in a high-risk recipient increased mean costs by 46.48%. The indirect effect of prophylaxis (operating through infection reduction) is estimated to reduce overall costs in high-risk patients by 8.73%.

Invasive fungal infections after liver transplantation (LT) have resulted in high mortality and potentially fatal complications. This study was undertaken to determine the accuracy of the panfungal polymerase chain reaction enzyme link immunosorbent assay (PCR-ELISA) method in early diagnosis of invasive fungal infections in liver transplant recipients (LTRs). A total of 48 liver recipients (cadaver donors) were followed for fungal infections for a period of at least 6 months. All clinical samples were cultured and a direct microscopic examination was performed. Blood samples were cultured by bedside inoculation onto BACTEC medium. Whole blood specimens were collected prospectively once per week and were evaluated for any invasive fungal infections by panfungal PCR and PCR-ELISA. Among 48 transplant recipients between September 2004 and January 2006 (22 females, 28 males, mean age = 34.4 yr), 40 recipients (83.3%) had Candida colonization in different sites of their body before LT. In proven and probable recipients for panfungal PCR-ELISA, the sensitivity, specificity, and positive and negative predictive values were 83.3%, 91.7%, 76.9%, and 94.3%, respectively. By PCR assay, fungal infections were diagnosed in 10 recipients (20.8%). The mean interval time from transplantation to development of fungal infection was 61.4 days (range, 20-150 days) and time of infection in blood before any clinical signs was 7-70 days with mean of 21.4 days. The etiologic agents were Candida albicans (9 cases) and Aspergillus fumigatus (1 case). Use of PCR-ELISA in LTRs may not only improve the ability of early diagnosis of invasive fungal infections (IFIs) when positive results are obtained, but also would provide more confidence to exclude a diagnosis of IFIs when negative results are obtained.

The magnitude of drug interactions between azole antifungals and immunosuppressants is drug and patient specific and depends on the potency of the azole inhibitor involved, the resulting plasma concentrations of each drug, the drug formulation, and interpatient variability. Many factors contribute to variability in the magnitude and clinical significance of drug interactions between an immunosuppressant such as cyclosporine, tacrolimus, or sirolimus and an antifungal agent such as ketoconazole, fluconazole, itraconazole, voriconazole, or posaconazole. By bringing similarities and differences among these agents and their potential interactions to clinicians' attention, they can appreciate and apply these findings in a individualized patient approach rather than follow only the one-size-fits-all dosing recommendations suggested in many tertiary references. Differences in metabolism and in the inhibitory potency of cytochrome P450 3A4 and P-glycoprotein influence the onset, magnitude, and resolution of drug interactions and their potential effect on clinical outcomes. Important issues are the route of administration and the decision to preemptively adjust dosages versus intensive monitoring with subsequent dosage adjustments. We provide recommendations for the concomitant use of these agents, including suggestions regarding contraindicated combinations, those best avoided, and those requiring close monitoring of drug dosages and plasma concentrations.

A systematic review and meta-analysis was performed to evaluate the benefits and harms of antifungal prophylaxis in liver transplant recipients. Ten randomised trials comparing any prophylactic antifungal regimen with no antifungal agent or with another antifungal regimen were identified from Medline, EMBASE, the Cochrane Library, and other sources. Together, the studies included a total of 1,106 patients. In general, results were consistent across trials despite clinical and methodological heterogeneity. Antifungal prophylaxis did not reduce total mortality (RR 0.84, 95% CI: 0.54-1.3). Fluconazole prophylaxis reduced invasive fungal infections by about 75% (RR 0.28, 95% CI: 0.13-0.57). Although fewer data on prophylactic itraconazole and liposomal amphotericin B were available, indirect comparisons and three direct comparative trials suggested similar efficacy. Fluconazole prophylaxis did not significantly increase colonisation or infection with azole-resistant fungi, although data were limited. A subgroup analysis suggested a dose and duration effect. In conclusion, fluconazole prophylaxis significantly reduces invasive fungal infections in liver transplant recipients and should be instituted in patients at increased risk in the early postoperative period.

Candida spp. are responsible for most of the fungal infections in humans. Available since 1990, fluconazole is well established as a leading drug in the setting of prevention and treatment of mucosal and invasive candidiasis. Fluconazole displays predictable pharmacokinetics and an excellent tolerance profile in all groups, including the elderly and children. Fluconazole is a fungistatic drug against yeasts and lacks activity against moulds. Candida krusei is intrinsically resistant to fluconazole, and other species, notably Candida glabrata, often manifest reduced susceptibility. Emergence of azole-resistant strains as well as discovery of new antifungal drugs (new triazoles and echinocandins) have raised important questions about its use as a first line drug. The aim of this review is to summarize the main available data on the position of fluconazole in the prophylaxis or curative treatment of invasive Candida spp. infections. Fluconazole is still a major drug for antifungal prophylaxis in the setting of transplantation (solid organ and bone marrow), intensive care unit, and in neutropenic patients. Prophylactic fluconazole still has a place in HIV-positive patients in viro-immunological failure with recurrent mucosal candidiasis. Fluconazole can be used in adult neutropenic patients with systemic candidiasis, as long as the species identified is a priori susceptible. Among non-neutropenic patients with candidaemia fluconazole is one of the first line drugs for susceptible species. Cases reports and uncontrolled studies have also reported its efficacy in the setting of osteoarthritis, endophthalmitis, meningitis, endocarditis and peritonitis caused by Candida spp. among immunocompetent adults. In paediatrics, fluconazole is a well tolerated and major prophylactic drug for high-risk neonates, as well as an alternative treatment for neonatal candidiasis. Importantly 15 years after its introduction in the antifungal armamentarium, fluconazole is still a first line treatment option in several cases of invasive candidiasis. Its prophylactic use should however be limited to selected high-risk patients to limit the risk of emergence of azole-resistant strains.

Viral and fungal infections in liver transplant recipients are important to recognize and treat early because of their association with substantial morbidity and mortality. Some viruses, such as cytomegalovirus and human herpesvirus 6, have immunomodulatory properties and can facilitate other infections, including fungal infections. Cytomegalovirus has long been recognized as an important virus in transplantation, but in the past decade other viruses have also received attention in the medical literature because of their association with particular clinical syndromes. Although human herpesvirus 6 has been associated with fever, rash, and encephalitis, a direct cause-and-effect relationship is still lacking. Human herpesvirus 8 has been found to be the cause of Kaposi sarcoma. Molecular techniques (e.g., pp65 antigenemia and polymerase chain reaction) that have been introduced for routine diagnosis of viruses have facilitated the diagnosis of asymptomatic viral infections and the institution of preemptive therapy. Nonetheless, the diagnosis of invasive fungal infections in liver transplant recipients is often delayed and thus associated with high mortality. Despite the use of new antifungal agents in clinical practice and the reduced incidence of fungal infections because of antifungal prophylaxis regimens, mortality has not decreased. Future patient outcomes may improve with early identification of patients who have risk factors for invasive fungal infections and with the development of new molecular diagnostic techniques for early detection.

This two-part review provides a comprehensive summary of clinical and research literature on paediatric liver transplantation. Part 1 outlines the peri-operative issues of liver transplantation, covers a brief history, discusses the indications and methods of transplantation and outlines the physical complications which can occur either as a result of the surgery or the subsequent immunosuppressive therapy required to maintain graft integrity. Post-liver transplantation care may require prolonged admission in hospital due to the complications that can occur during surgery and as a result of immunosuppression. This can have a further impact on the emotional status of the child and family. Health care professionals in all settings require greater knowledge about paediatric liver transplantation, its associated complications and long-term health implications.

To investigate the possibilities that: (i) organ toxicity of amphotericin B-deoxycholate (AMB-DOC) is related to induction of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and apoptosis in target organs; and (ii) the reduced toxicity resulting from the conjugation of AMB with water-soluble arabinogalactan (AMB-AG), is related to modulation of these parameters.

Organ expression of IL-1beta and TNF-alpha was evaluated by enzyme-linked immunosorbent assay (ELISA) in mouse organ biological fluids and in situ by immunohistochemistry. Tissue damage was evaluated histologically, and apoptosis was demonstrated by terminal dUTP nick end-labelling (TUNEL) staining. AMB-AG conjugate was compared with the micellar (AMB-DOC) and liposomal (AmBisome) AMB formulations.

Treatment with AMB-AG or AmBisome caused no observable histopathological damage in the kidneys. In contrast, treatment with AMB-DOC resulted in disruptive changes and apoptosis in renal tubular cells. These effects were found to correlate with induction of high levels of IL-1beta and TNF-alpha in kidney lysates. Unlike AMB-AG, AMB-DOC also induced enhanced IL-1beta and TNF-alpha expression in lysates of lungs, brain, liver and spleen. The marked elevation of these inflammation-apoptosis-promoting cytokines after treatment with AMB-DOC may mediate its systemic and local renal damage. Treatment with AMB-AG (but not AmBisome) appears to uniquely modulate the in situ expression of IL-1beta and enhance secretion of TNF-alpha in kidneys, effects possibly involved in prevention of apoptosis.

AMB-related toxicity is associated with induction of IL-1beta, TNF-alpha and apoptosis in organs. These effects were not observed with AMB-AG conjugate, suggesting its potential as a safer formulation for therapy.

Advances in surgical technique, immunosuppression, and medical management have greatly improved clinical results after liver transplantation (LTx). Fungal infections in LTx-patients still represent serious complications and are associated with a significant decrease in survival. The majority of fungal infections in LTx-patients are caused by Candida species, which is explained by the major abdominal surgery. Aspergillus infections are second common, whereas other fungal infections such as pneumocystosis, cryptococcosis, or zygomycosis represent rare events. The high mortality of invasive fungal infections in LTx-recipients is explained by the severity of the underlying medical condition and by difficulties in diagnosis and medical therapy. Currently available diagnostic tests do not allow a timely and reliable diagnosis of invasive fungal infections in LTx-patients. Amphotericin B has been the standard treatment for invasive candidiasis and aspergillosis for many years but the high frequency of side effects limits its application. Fluconazole is widely used due to better tolerability and fewer drug interactions. Disadvantages are the lack of activity against Aspergillus species and the selection of resistant Candida strains. Progress is to be expected from new antimycotic agents belonging to azoles (voriconazole) and echinocandins (caspofungin) as these are less toxic and have a broad range of antimycotic activity. Analysis of prognostic factors allows identifying LTx-patients at high risk for invasive fungal infection. Antimycotic prophylaxis or pre-emptive therapy may improve clinical outcome in this patient subgroup.

Fungal infection (FI) is a major and potentially fatal complication in liver transplantation (LT). Published experience of FI in paediatric LT is limited. We therefore reviewed case records of 79 children, aged between 0.16 and 16 yr, who underwent LT between 1997 and 1998 to document the incidence of, and identify risk factors for, FI. Sixty-eight pre-, peri- and post-LT variables were assessed in relation to FI by univariate and multivariate analyses. The major indications for LT were biliary atresia in 26 (33%) patients, fulminant hepatic failure in 16 (20%) and intrahepatic cholestasis in 11 (14%); eight patients required re-LT. Thirty-two (40.5%) children developed a FI within 1 yr of LT. The median time to FI was 42 days (range 1-342 days). Candida spp. caused 29 (90.7%) FIs; 21 (66%) of these were Candida albicans. Although FI was associated with increased mortality, most patients responded well to antifungal treatment. The variables independently associated with FI were pre-LT fungal colonization and pyrexia and, post-LT, bacterial infection, Epstein-Barr virus (EBV) infection and tacrolimus administration. Identifying risk factors for FI should contribute to the development of strategies for prophylaxis or preemptive therapy.

Invasive fungal infections (IFIs) are important causes of morbidity and mortality in solid organ transplant recipients.

This study aims to systematically identify and summarise the effects of antifungal prophylaxis in solid organ transplant recipients.

The Cochrane Central Register of Controlled Trials (Issue 3, 2003), MEDLINE (1966-June 2003), and EMBASE (1980-June 2003) were searched. Reference lists, abstracts of conference proceedings and scientific meetings (1998-2003) were handsearched. Authors of included studies and pharmaceutical manufacturers were contacted.

Randomised controlled trials (RCTs) in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen.

Two reviewers independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. Differences were resolved by discussion. Data were synthesised using the random effects model and expressed as relative risk (RR) with 95% confidence intervals (95% CI).

Fourteen unique trials with 1497 randomised participants were included. Antifungal prophylaxis did not reduce mortality (RR 0.90, 95% CI 0.57 to 1.44). In liver transplant recipients, a significant reduction in IFIs was demonstrated for fluconazole (RR 0.28, 95% CI 0.13 to 0.57). Although less data were available for itraconazole and liposomal amphotericin B, indirect comparisons and one direct comparative trial suggested similar efficacy. Fluconazole prophylaxis did not significantly increase invasive infections or colonisation with fluconazole-resistant fungi. In renal and cardiac transplant recipients, neither ketoconazole nor clotrimazole significantly reduced invasive infections. Overall, the strength and precision of comparisons however were limited by a paucity of data.

For liver transplant recipients, antifungal prophylaxis with fluconazole significantly reduces the incidence of IFIs with no definite mortality benefit. Given a 10% incidence of IFI, 14 liver transplant recipients would require fluconazole prophylaxis to prevent one infection. In transplant centres where the incidence of IFIs is high, or in situations where the individual risk is great, antifungal prophylaxis should be considered.