Infection In Liver Transplant Patients Research Articles

Fulminant septic shock due to Clostridium perfringens skin and soft tissue infection eight years after liver transplantation

Bacterial and fungal infections are the main cause of death within the first year after liver transplantation. Clostridium perfringens is the most common germ causing gas gangrene. Infections with Clostridium perfringens may present in a variety of clinical manifestations, reaching from asymptomatic infections to massive intravascular haemolysis and multiple organ failure due to septic shock. We here report on a 55-year old male liver transplant patient suffering from skin and soft tissue infection eight years after liver transplantation. The patient was referred to our department from a community hospital. Upon admission in our department the infection had been ongoing for at least three days. Laboratory analyses demonstrated severe infection and impaired liver function. Tomogram and computed tomography scan of his right limb showed typical images of gas gangrene. The patient was immediately scheduled for surgical debridement. During surgery the patient developed septic shock with severe coagulopathy and died six hours after the operation due to uncontrolled septic shock. The histopathological and microbiologic work-up of the resected skin and soft tissue showed necrotic areas infiltrated with Clostridium perfringens. Even long-term survivors of liver transplantation are at major risk for life-threatening infections. The reported clinical scenario of Clostridium perfringens infection indicates the narrow therapeutic window. Clostridium perfringens should always be considered as a cause of infection in liver transplant patients.

Three-month pegylated interferon-alpha-2a therapy for chronic hepatitis E virus infection in a haemodialysis patient

Hepatitis E virus (HEV) can induce chronic hepatitis in immunosuppressed patients. There is no established treatment for HEV infection. Pegylated interferon-alpha-2a (Peg-IFN-alpha-2a) has been successfully used for treating HEV infection in liver transplant patients with chronic hepatitis. A kidney transplant patient with chronic HEV infection evolved to end-stage kidney disease and started haemodialysis. Three months after immunosuppressive therapy was stopped, HEV RNA was still detected both in serum and in stools. Before considering a retransplantation, we decided to initiate Peg-IFN-alpha-2a therapy to eradicate the virus. A 3-month course of Peg-IFN-alpha-2a was scheduled, and the latter was started at the weekly dose of 135 microg. Serum HEV RNA became negative by Week 3 of Peg-IFN-alpha-2a therapy, and remained negative until the last follow-up, i.e. 6 months after anti-viral therapy was stopped. Hence, we report the first known case of a 3-month course of Peg-IFN-alpha-2a inducing a sustained virological response in this HEV-positive and RNA-positive haemodialysis patient who had failed to be cleared of the virus after immunosuppressant withdrawal.

Antifungal prophylaxis in liver transplant recipients

Although the overall incidence of fungal infections in liver transplant recipients has declined, these infections still contribute significantly to the morbidity and mortality of patients with risk factors for infection. Although antifungal prophylaxis has been widely studied and practiced, no consensus exists on which patients should receive prophylaxis, with which agent, and for what duration. Numerous studies have attempted to ascertain independent risk factors for invasive fungal infections in liver transplant patients, and these data, in addition to clinical trials, identify several patient groups at exceedingly high risk of fungal infection. These include retransplant patients, patients with renal failure requiring hemodialysis or renal replacement therapy, and those requiring reoperations after transplant. Because the majority of infections occur in the first month after transplantation, prophylaxis should be continued for 4-6 weeks. However, local epidemiology and research should guide decisions regarding choice of agent as well as overall development of interinstitutional guidelines, because the incidence and spectrum of infection may differ dramatically among institutions. Liver Transpl 15:842-858, 2009. (c) 2009 AASLD.

Studies with Inulin-Type Fructans on Intestinal Infections, Permeability, and Inflammation

Symbiosis between host and gut bacteria can be optimized by prebiotics. Inulin-type fructans have been shown to improve the microbial balance of the intestinal ecosystem by stimulating the growth of bifidobacteria and lactobacilli. These changes have been associated with several health benefits, including the prevention of gastrointestinal and systemic infections in animal models and human studies. Inulin-type fructans induce changes of the intestinal mucosa characterized by higher villi, deeper crypts, increased number of goblet cells, and a thicker mucus layer on the colonic epithelium. Bacterial antagonism and competition of bifidobacteria and lactobacilli with pathogens, as well as the trophic effects on the intestinal epithelium, may explain the protective role of inulin against enteric infections. In contrast, studies with rats fed a low-calcium diet suggested a negative effect of prebiotics on intestinal barrier function. However, the adverse effect was clearly ascribed to the strong reduction of dietary calcium, as it could be reversed by oral administration of calcium. The adverse effect of a low-calcium diet on intestinal permeability has not been observed in humans. Inulin and oligofructose are now being tested in human studies aimed at prevention of bacterial translocation in critical health conditions. Mixtures of probiotics and prebiotics including inulin or oligofructose significantly reduced the rate of postoperative infections in liver transplant patients. Finally, inulin and oligofructose have proven useful to prevent mucosal inflammatory disorders in animal models and in patients with inflammatory bowel disease.

HHV-6-DNAemia Related to CMV-DNAemia After Liver Transplantation

In addition to cytomegalovirus (CMV), activation of other betaherpesviruses, especially human herpesvirus 6 (HHV-6), has been reported in liver transplant patients. The purpose of this study was to investigate the posttransplant HHV-6-DNAemia in relation to CMV-DNAemia in liver transplant patients. Thirty-one adult liver allograft recipients were regularly monitored for CMV and HHV-6 during the first 3 months after transplantation. For the diagnosis of CMV infections, pp65-antigenemia assay and quantitative DNA-PCR were used. HHV-6 was demonstrated by using quantitative DNA-PCR and HHV-6 antigenemia test. Altogether 253 blood specimens of 31 recipients were analyzed. In addition, CMV and HHV-6 specific antigens were demonstrated by immunohistochemistry in liver biopsy specimens in the case of graft dysfunction. Thirteen patients (40%) developed a clinically significant CMV infection, at a mean of 33 days (range 5 to 62 days) after transplantation and were treated with intravenous ganciclovir. The peak viral loads of these symptomatic CMV infections were high (CMV-DNA 34210 ± 37557 copies/mL plasma). Six additional asymptomatic patients demonstrated significantly lower CMV-DNAemia levels (1020 ± 1008 copies/mL, P < .05), and were not treated. Concurrently with CMV, HHV-6 DNAemia and antigenemia were detected in 17 of 19 patients, mean 11 days (range 6 to 24 days) after transplantation. HHV-6 appeared prior to CMV in most cases (12 of 17). However, the peak viral loads were low (HHV-6-DNA <1500 copies/mL blood), even in the five patients who demonstrated HHV-6 antigens on liver biopsy. All CMV infections were successfully treated with ganciglovir and the CMV DNAemia/antigenemia subsided. HHV-6 also responded to the antiviral treatment, but more slowly and less clearly. In conclusion, HHV-6 activations were common and usually associated with CMV infection in liver transplant patients. Further investigation of the clinical significance of HHV-6 DNAemia/antigenemia is necessary.

Adefovir treatment in posttransplant hepatitis B virus infection resistant to lamivudine plus hepatitis B virus immunoglobulin

Failure of prophylaxis for hepatitis B virus (HBV) recurrence in liver transplant patients with HBV immunoglobulin (HBIG) or lamivudine or both can be associated with rapid development of liver failure. Some of these patients develop a devastating clinicopathological state characterized by jaundice and rapidly progressive liver failure or fibrosing cholestatic hepatitis. We present two liver transplant recipients who experienced HBV recurrence while they were under lamivudine and HBIG prophylaxis. One of them had finding of severe HBV infection; the other, fibrosing cholestatic hepatitis. After commencing adefovir dipivoxil both patients showed improvements in clinical status and laboratory data. At month 4 of treatment, HBV DNA values became negative and liver function tests almost normalized. In addition, in one case showed HBs ag/anti-HBs seroconversion. When failure of prophylaxis with lamivudine and HBIG occurs, adefovir dipivoxil should be considered to be a safe and effective choice for recurrent HBV infections in liver transplant patients.

The CARI guidelines. CMV disease and kidney transplant: pre-emptive treatment of cytomegalovirus.

The CARI guidelines. CMV disease and kidney transplant: pre-emptive treatment of cytomegalovirus.

HHV-6-DNAEMIA RELATED TO CMV-DNAEMIA AFTER LIVER TRANSPLANTATION

O173 Aims: In addition to cytomegalovirus (CMV), activation of other betaherpesviruses, especially human herpesvirus 6 (HHV-6), have been reported in liver transplant patients. HHV-6 may cause fever, hepatitis and neurological disorders, but most activations are asymptomatic. The purpose of this study was to investigate the post transplant HHV-6-DNAenemia in relation to CMV-DNAemia in liver transplant patients. Methods: Thirty-one adult liver allograft recipients transplanted during 2002-2003 were regularly monitored for CMV and HHV-6 during the first three months after transplantation. For the diagnosis of CMV infections pp65-antigenemia assay and quantitative DNA-PCR were used, in parallel. HHV-6 was demonstrated, by using quantitative DNA-PCR and the HHV-6 antigenemia test for the both variants A and B, from the same blood specimens which were obtained for CMV monitoring. Altogether 253 blood specimens of 31 recipients analyzed were analyzed. In addition, CMV and HHV-6 specific antigens were demonstrated by immunohistochemistry in liver biopsy specimens obtained for routine histopathological examination, in the case of graft dysfunction. Results: Thirteen patients (40%) developed a clinically significant CMV infection during the first 3 months (first pp65/DNA-positive finding mean 33 days, range 5-62 days) after transplantation and were treated with intravenous ganciclovir. The peak viral loads of these symptomatic CMV infections were high (CMV-DNA 34210±37557 copies/ml plasma) and one patient even developed CMV-hepatitis. Six additional asymptomatic patients demonstrated significantly lower CMV-DNAemia levels (1020±1008 copies/ml, p<0.05), and were not treated. Concurrently with CMV, HHV-6 DNAemia and antigenemia was detected in 17/19 patients (first positive finding mean 11 days, range 6-24 days) after transplantation. Most HHV-6 cases were of variant B, but also two HHV-6A activations were recorded. HHV-6 appeared prior to CMV in most cases (12/17). However, the peak viral loads were low (HHV-6-DNA <1500 copies/ml blood), even in the 5 patients who demonstrated HHV-6 antigens in the liver biopsies. All CMV infections were successfully treated with ganciglovir and the CMV DNAemia/antigenemia subsided. HHV-6 also responded to the antiviral treatment, but more slowly and less clearly, and recurrences were common. Conclusions: HHV-6 activations were common and usually associated with CMV infection in liver transplant patients. The findings demonstrate that not only CMV but also the other betaherpesviruses may activate in transplant patients. Further investigation of the clinical significance of HHV-6 DNAemia/antigenemia is necessary.

Recurrence of HCV infection in liver transplant patients: evaluation of IgM anti-HCV and IgM anti-CMV

Recurrence of HCV infection in liver transplant patients: evaluation of IgM anti-HCV and IgM anti-CMV

Diagnosis and monitoring of hepatitis virus infection in liver transplant patients

Diagnosis and monitoring of hepatitis virus infection in liver transplant patients

Early differentiation between rejection and infection in liver transplant patients by serum and biliary cytokine patterns.

Differentiation between acute liver graft rejection and infection remains a clinical challenge during the early posttransplantation period. Although cytokines play a pivotal role in mediating allograft rejection, previous studies demonstrate that most cytokines are not specific for liver graft rejection or infections. However, other studies suggest that adhesion molecules and cytokines in bile reflect the immunologic activity within the liver more closely. Therefore, we postulated that by combining cytokine patterns in serum and bile, early recognition of acute liver graft rejection and differentiation from infectious complications can be improved. We performed a prospective study in 45 patients who were monitored daily for clinical events and cytokine patterns in serum and bile during the first month after liver transplantation. Soluble intercellular adhesion molecule-1 (sICAM-1) in serum and interleukin-8 in bile were specifically increased at the onset of acute rejection (P<0.001), whereas serum soluble tumor necrosis factor-receptor II was also significantly increased in patients with infectious complications and serum interleukin-6 only in patients with rejection during infection. In 68% of patients with increased sICAM-1, acute rejection was diagnosed within 10 days, whereas rejection occurred in only 26% of patients with low serum levels of sICAM-1. In patients with increased sICAM-1, the relative risk for rejection was 4.8 (P=0.009). Cytokine patterns in bile do not provide rejection markers with higher specificity compared with serum cytokines. Daily monitoring of sICAM-1 in serum could identify patients at risk for rejection; therefore, acute liver graft rejection may be recognized earlier in those patients.

Fungal infection in liver transplantation.

Infection is the common cause of death following transplantation. Fungal infections are associated with high morbidity and mortality, and make up a significant proportion of infectious complications. Unfortunately, the diagnosis is usually made late--symptoms may be mild and non-specific, even with dissemination. Mortality associated with disseminated fungal infections is high, while those associated with limited fungal infections is low. Although the risk factors for invasive fungal infections in liver transplant patients are well identified, early diagnosis is challenging, and commonly used diagnostic methods lack sensitivity and specificity. Although the incidence of fungal infections following liver transplantation appears to be falling, mortality and morbidity associated with fungal infections suggests that future developments should focus on enhancing earlier diagnosis, implementing more effective and less toxic anti-fungal therapies.

Genogrouping and incidence of virulence factors of Enterococcus faecalis in liver transplant patients differ from blood culture and fecal isolates.

Enterococcus faecalis is a leading cause of infections in liver transplant patients. This study reviewed the incidence of virulence factors such as hemolysin, gelatinase, aggregation substances (asa1 and asa373), or the enterococcal surface protein (Esp) in isolates from liver transplant patients. In total, 133 isolates from liver transplant patients were compared with 47 isolates from feces of healthy volunteers and 66 isolates from blood cultures. Amplified fragment length polymorphism (AFLP) analysis indicates that the isolates from different clinical subgroups can be divided into genogroups with an AFLP similarity of >80% and different virulence factors. Hemolysin and asa1 might be associated with infection, as they are more frequent in isolates from blood cultures and transplant patients. Esp might be associated with colonization and spread, because it is more frequent in isolates from feces of healthy volunteers and transplant patients. An epidemic esp gene-positive strain among liver transplant patients supports this hypothesis.

Infección precoz en el paciente con trasplante hepático: incidencia, gravedad, factores de riesgo y sensibilidad antibiótica de los aislados bacterianos

To conduct a descriptive study with an analysis of risk factors for early infection in liver transplant patients, and to determine the resistance of the bacteria involved. The study included 149 liver transplant recipients. All cases of infection occurring 0-90 days after transplantation were considered early infection. Pre-, intra- and postoperative variables were analyzed, and isolated microorganisms were studied. Selective bowel decontamination with quinolones, and perioperative and antifungal prophylaxis were carried out in all patients. The incidence of infection was 73.1%: bacterial (49.7%), viral (35.5%), fungal (10.1%) and mixed (4.5%). In the first postoperative month the most frequent infections were bacterial and in the second and third months, viral (p = 0.001). Multivariate analysis of risk factors identified the following: days of parenteral nutrition, duration of surgery > 5 hours, rejection and CMV seronegative status. Among 1278 cultures, the following microorganisms were isolated: 77.9% gram-positive cocci (GP) and 19% aerobic gram-negative bacilli (GNB). Sensitivity of Staphylococcus to vancomycin was 99.6-100% and to teicoplanin 97.9-100%. VAN resistance was observed in 1.2% of E. faecalis and 4.5% of E. faecium. Among S. aureus strains, 68.7% were MRSA. The resistance rate of GNB to quinolones was 38.8%. Incidence of infection was higher the first 30 days after transplantation, with bacterial infection predominating. Duration of surgery > 5 hours was the most important risk factor for acquiring bacterial infection. GP were the most frequently isolated bacteria. Empirical treatment of early bacterial infection should include vancomycin or teicoplanin. Selective bowel decontamination resulted in a low incidence of GNB infections, among which there was 38.8% resistance to quinolones.

Abstension from treatment of low-level pp65 cytomegalovirus antigenemia after liver transplantation: a prospective study.

Ganciclovir is a highly effective and relatively safe drug to treat cytomegalovirus (CMV) infection in liver transplant patients; CMV resistance to ganciclovir is progressively emerging due to the extensive use of the drug in transplant and AIDS patients; CMV pp65 antigenemia allows early diagnosis of CMV infection and quantitation of the viral load; preemptive antigenemia-guided therapy of CMV infection can prevent CMV disease but the threshold of antigenemia value above which treatment has to be instituted is unclear. To demonstrate the safety of abstention from preemptive treatment in the presence of low levels of antigenemia 77 consecutive liver transplant recipients were prospectively evaluated. Antigenemia was tested twice a week from transplantation until discharge, then once a week until the third postoperative month. In absence of risk factors for CMV disease, namely donor positive/recipient negative CMV serology, treatment with antibodies to lymphocytes and retransplantation, only patients with antigenemia of more than 50 or symptoms possibly related to CMV infection had preemptive treatment. A total of 32 patients had at least one positive antigenemia test with a value less than 50; 22 (68.7%) spontaneously cleared the virus, 3 were treated with i.v. ganciclovir for the presence of fever, and the other 7 (21,8%) progressed to values of antigenemia of more than 50 and were treated even if asymptomatic. No CMV disease was observed in these patients. CMV antigenemia less than 50 in liver transplant recipients with low and intermediate risk for CMV disease does not mandate preemptive ganciclovir treatment. Close surveillance with repeated determination of antigenemia until its negativization and careful clinical and laboratory monitoring is advisable.

HHV-6 reactivation is often associated with CMV infection in liver transplant patients

Abstract Human herpesvirus 6 (HHV-6) infection has been recently reported in liver transplant patients. HHV-6 is closely related to cytomegalo-virus (CMV), and some interaction between the viruses has been suggested. In this study, the post-transplant HHV-6 antigenemia was investigated in relation to symptomatic CMV infections in adult liver transplant patients. CMV infections were diagnosed by the pp65 antigenemia test and by viral cultures. HHV-6 infections were demonstrated by the HHV-6 antigenemia test and by serology. Significant symptomatic CMV infection was diagnosed in 42 of 75 patients during the first 6 months after transplantation. All CMV infections were successfully treated with ganciclovir. Concurrent HHV-6 antigenemia was detected in 21 (50%) of 42 patients with CMV infection. All HHV-6 infections were reactivations. HHV-6 also responded to the antiviral treatment, but with less clear effect. In conclusion, HHV-6 reactivation is often associated with CMV infection in liver transplant patients. The results support the suggestion that CMV and HHV-6 may have interactions.

HHV-6 reactivation is often associated with CMV infection in liver transplant patients.

Human herpesvirus 6 (HHV-6) infection has been recently reported in liver transplant patients. HHV-6 is closely related to cytomegalo-virus (CMV), and some interaction between the viruses has been suggested. In this study, the post-transplant HHV-6 antigenemia was investigated in relation to symptomatic CMV infections in adult liver transplant patients. CMV infections were diagnosed by the pp65 antigenemia test and by viral cultures. HHV-6 infections were demonstrated by the HHV-6 antigenemia test and by serology. Significant symptomatic CMV infection was diagnosed in 42 of 75 patients during the first 6 months after transplantation. All CMV infections were successfully treated with ganciclovir. Concurrent HHV-6 antigenemia was detected in 21 (50%) of 42 patients with CMV infection. All HHV-6 infections were reactivations. HHV-6 also responded to the antiviral treatment, but with less clear effect. In conclusion, HHV-6 reactivation is often associated with CMV infection in liver transplant patients. The results support the suggestion that CMV and HHV-6 may have interactions.

Incidence, prevalence, and clinical outcome of hepatitis GB-C virus infection in liver transplant patients.

A novel RNA virus of the Flaviviridae family has been discovered recently and designated hepatitis GB-C virus (GBV-C). Previous studies have reported that GBV-C is associated with posttransfusion hepatitis, chronic viral hepatitis, and cryptogenic hepatitis. However, the clinical significance of GBV-C infection has been questioned increasingly in patients not undergoing transplantation. To investigate whether GBV-C infection under immunosuppression affects the clinical or the histological outcome in liver transplant recipients, we determined the prevalence and incidence of GBV-C infections and the clinical and histological signs in patients after orthotopic liver transplantation (OLT). The presence of GBV-C was tested in sera from patients before and in regular intervals up to 6 years after OLT by nested reverse transcription-polymerase chain reaction using primers derived from the NS3 region. A total of 72 patients were studied. Before OLT, 8 of 72 (11.1%) patients were positive for GBV-C. After OLT, 7 of 8 (87.5%) remained positive. Of 64 patients who were negative for GBV-C before OLT, 23 became positive after OLT, resulting in a de novo rate of GBV-C infection of 35.9%. We could not detect a higher rate of histologically proven hepatitis in GBV-C-positive patients (29.1%) than in GBV-C-negative patients (14.6%, P > 0.057). Comparing GBV-C-positive with GBV-C-negative liver transplant patients, we could not find any differences in age, gender, liver function tests, number of blood transfusions, histological degree of hepatitis, or number of rejection episodes. Survival was not negatively influenced by GBV-C positivity. In conclusion, the presence of GBV-C did not influence the clinical or histological outcome in liver transplant patients.

Amphotericin B lipid complex in the treatment of invasive fungal infections in liver transplant patients

F UNGAL infections continue to be a major source of morbidity and mortality following liver transplantation (LTx). Infection rates have been reported to bc as high as X3.8%,’ with an associated mortality of up to 500/r.‘.” Liver disease and the transplant procedure itself have inherent risks that increase the likelihood for fungal infection. These include portal occlusion and hypertension, hypoalbuminemia, bowel edema. immunosuppression. and wide disscction.’ ’ In addition. several risk factors have been identified that further increase the risk for fungal infection. Among these risks are the patient’s preoperative status. lengthy operations, transfusion requirement, Roux-Y biliary reconstruction, retransplantation, reoperations, and bacterial infcctions.’ -’ Amphotericin B (AmB) has been the main pharmaccutical agent used in the treatment of invasive mycoscs owing to its wide spectrum and fungicidal activity. Its USC, howcvcr, is limited by its narrow therapeutic index. Its renal toxicity is particularly disturbing, especially when given with other nephrotoxic drugs, which most transplant patients require for immunosuppression. In addition, certain organisms. eg, Aspqihs species, have been resistant to AmB treatment in vivo despite demonstrated sensitivity in vitro. This may be due to inadequate availability of the drug at the site of infection. Amphotcricin B lipid complex (ABLC) was designed to increase the etficacy of AmB while simultaneously decreasing its toxicity. ABLC is a lipid complex consisting of AmB and lipid in a l-to-l molar ratio. The lipids arc dimyristoylphosphatidycholine (DMPC) and dimyristoylphosphatidyglyccrol (DMPG) in a 7-to-3 ratio. The complex itself has been found to interact minimally with mammalian cells. possibly explaining its reduced toxicity. At the site of infection, howcvcr, lipases, relcascd by either the fungi or macrophages and ncutrophils. break down the complex and release the active drug.” Our objective was to test the eticacy and safety of ABLC in the treatment of fungal infections in LTx patients. ABLC was made available to 13 patients on a compassionate use basis for the treatment of 15 episodes of fungal infection.

De novo and apparent de novo hepatitis B virus infection after liver transplantation

Background/Aims: The aim of this study was to clarify the aetiology of apparent de novo HBV infection after liver transplantation. Methods: Twenty out of 570 HBsAg negative patients (3.5%) became HBsAg positive after transplantation and were studied. Donor and recipient sera were retrospectively tested for HBsAg, anti-HBs, anti-HBc, and HBV DNA by PCR. Donor and recipient livers were tested for HBV DNA by PCR on paraffin-embedded tissue. Results: Group 1: HBV infection of donor origin (eight patients): one donor serum was HBsAg positive, three were serum HBV DNA positive, four were liver HBV DNA positive. Group 2: reactivation of latent HBV infection (eight patients) with detection of HBV DNA in pretransplant serum (seven patients) or in native liver (one patient): three were anti-HBs positive, two anti-HBc positive, and three with fulminant hepatitis had no serological HBV markers. Group 3: undetermined origin (four patients) defined by absence of HBV DNA in pretransplant donor and/or recipient sera and liver; however, acquired infection was suspected from two anti-HBs and anti-HBc positive donors. Two patients became HBsAg negative, and five HBV DNA negative. One died from HBV-cirrhosis and two were retransplanted. In the others, the last histology showed cirrhosis (three), chronic hepatitis (nine), acute hepatitis (one), and non-specific change (four patients). Conclusions: The prevalence of de novo HBV infection in liver transplant patients was 3.5%; the aetiology was determined in 16 20 patients: from the donor in eight, and from the recipient in eight. One should be cautions when donors or recipients are anti-HBc or both anti-HBs and anti-HBc positive.