Liver transplantation infection

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Liver trasnsplantation Microchapters
Home
Patient Information
Overview
Historical Perspective
Indications
Pre-surgical management
Choice of donor
Epidemiology and Demographics
Techniques
Complications
Acute rejection
Immune therapy
Post-surgical infection
Prognosis

Liver transplantation infection

EPIDEMIOLOGY In many centers, infection is the most frequent cause of death following liver transplantation even though deaths related to infectious diseases in non-transplant settings have steadily decreased. In an autopsy series, infections were the cause of death in 64 percent of 321 transplant patients who died between 1982 and 1997 [2]. The most common types of infection were bacterial (48 percent), fungal (22 percent), and viral (12 percent).

Donor-derived infections Infections that are derived from donor organ tissues and activated in the recipient are among the most important exposures in transplantation [18-22]. Some of these infections are latent, while others are the result of bad timing (unappreciated active infection in the donor at the time of transplantation). Clusters of infection associated with organ transplantation have also included Mycobacterium tuberculosis, Candida and Aspergillus (and other fungal) species, herpes simplex virus, human herpes virus 8, lymphocytic choriomeningitis virus (LCMV) [24-27], rabies virus [28-30], Trypanosoma cruzi (causing Chagas disease), Balamuthia mandrillaris [31-34], Encephalitozoon cuniculi (causing microsporidiosis) [35], HIV, and hepatitis C virus. Bloodstream infection Some donors may have active infection at the time of procurement. Certain pathogens (eg, staphylococci, pneumococcus, Candida, Salmonella, E. coli) may "stick" to anastomotic sites (vascular, urinary, biliary, tracheal) and produce fever, bloodstream infections, or mycotic aneurysms. Proof of adequate therapy for such infections must be established prior to accepting organs for transplantation.

Inapparent infections accelerated by immunosuppression

Other donor-derived infections may be inapparent or unusual (eg, West Nile virus, leishmaniasis, rabies, lymphocytic choriomeningitis virus, Chagas disease, HIV, herpes simplex virus) and may cause clinical syndromes that are accelerated by immune suppression.

TIMING OF INFECTION POSTTRANSPLANTATION First month after transplantation infection derived from either the donor or recipient and infectious complications of the transplant surgery and hospitalization. Donor-derived infections The risk for infections acquired with the allograft is discussed above (table 3) [18-20,56]. Transmission of donor-derived bacteria and fungi has increased with the emergence of antimicrobial resistance such that vancomycin-resistant enterococci, methicillin-resistant staphylococci, and fluconazole-resistant Candida species may be transmitted from donor to recipient. Graft-associated viral infections (LCMV, West Nile virus, rabies, HIV) and parasitic infections (toxoplasmosis, Chagas disease, Balamuthia mandrillaris) are uncommon but may be amplified in the immunosuppressed host. Endemic infections (eg, histoplasmosis or tuberculosis) should be considered in the differential diagnosis of posttransplant infection or unusual clinical syndromes (eg, encephalitis, hepatitis). (See 'Donor-derived infections' above.) Recurrent infection Infection may have been present in the donor or in the recipient prior to transplantation. An important component of the pretransplant evaluation is to recognize and treat such infections, if possible. (See "Evaluation for infection before solid organ transplantation".) Some common viral infections (eg, hepatitis B virus or hepatitis C virus) may reemerge early after transplantation. Recipient-derived tuberculosis or toxoplasmosis tends to reactivate more than a month after transplantation. Reactivation of Strongyloidesmay be accompanied by gram-negative bacterial sepsis, meningitis, or pneumonia [9]. Infectious complications related to surgery Solid organ transplant recipients develop many of the common postoperative complications, such as aspiration pneumonitis, surgical site (wound) infections, "line sepsis," urinary tract infection, or pulmonary embolus [57]. Transplant recipients are also at unique risk for superinfection of ischemic or injured graft tissues (eg, anastomotic suture lines) or of fluid collections (eg, hematomas, lymphoceles, pleural effusions, urinomas). These patients are at increased risk for infection associated with indwelling vascular access catheters, urinary catheters, and surgical drains. The organisms responsible for such postoperative complications are often the bacteria and fungi that have colonized the recipient or donor (eg, the lungs and/or sinuses in cystic fibrosis) prior to transplantation or the local flora of the hospital. Infections acquired prior to transplantation may include relatively resistant nosocomial pathogens (eg, vancomycin-resistant enterococcus) and pathogens such as Aspergillus spp that are resistant to the usual prophylactic agents. Patients receiving antimicrobial agents are at increased risk for C. difficile colitis. Patients at particular risk of nosocomial infection are those requiring prolonged ventilatory support or those with diminished lung function, persistent ascites, stents of the urinary tract or biliary ducts, with intravascular clot or ischemic graft tissue [49,58]. Individuals with delayed graft function or who require early reexploration or retransplantation are also at increased risk for infection, notably with fungi or bacteria with antimicrobial resistance.

1 to 6 months after transplantation This is the period when patients are most at risk for the development of opportunistic infections Major infections due to opportunistic pathogens include: ●Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP ●Latent infections, such as the protozoal diseases including toxoplasmosis, leishmaniasis, and Chagas disease [8,47,48,59-61] ●The geographic or endemic fungal infections caused by Histoplasma capsulatum, Coccidioides spp, Cryptococcus gattii, and, rarely, Blastomyces dermatitidis (see "Fungal infections following lung transplantation") ●Viral pathogens, particularly the herpes group viruses but also hepatitis B (HBV) and hepatitis C (HCV). New viruses are recognized as opportunistic pathogens with the use of more sensitive molecular assays (eg, BK polyomavirus, human herpesvirus [HHV]-6, -7, and -8 [Kaposi's sarcoma-associated herpesvirus, KSHV]) (table 5). Respiratory viruses are increasingly important in this population (influenza, parainfluenza, respiratory syncytial virus [RSV], adenovirus, metapneumovirus). ●Tuberculosis and, increasingly, nontuberculous mycobacteria [62] ●Gastrointestinal parasites (Cryptosporidium and Microsporidium) and viruses (cytomegalovirus [CMV], rotavirus) may be associated with diarrhea.

More than 6 to 12 months after transplantation These patients are subject to community-acquired pneumonias due to respiratory viruses, the pneumococcus, Legionella, or other common pathogens. community-acquired infections due to influenza or Listeria monocytogenes.

Pretransplant colonization of liver transplant recipients with organisms such as methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) can lead to posttransplant infection with these organisms [11-13]. An increased prevalence of multidrug-resistant gram-negative bacilli including Escherichia coli and Klebsiella pneumoniae; carbapenem-resistant Enterobacteriaceae) has been observed not only in the general population but also in solid organ transplant recipients [15]. are related to surgical complications of the transplant operation [3]. risk factors for infection included a prolonged operative time (>12 hours) and reoperation [16].

PREVENTION screening potential liver donors and recipients for infection as noted above [8] [9] Vaccination appropriate vaccinations before transplantation since antirejection immunosuppressive medications may prevent optimal responses to vaccination post-transplantation [21]. certain vaccines such as pneumococcal and influenza vaccines should be repeated after transplantation in an attempt to lower the risk for these diseases. live vaccines should be avoided in transplant recipients due to the risk of disseminated disease. Antibacterial and PCP prophylaxis Antibiotics are administered at transplantation in an attempt to prevent SSIs, including wound and intraabdominal infection, although they do not provide complete protection [24]. Skin and intestinal flora are common SSI pathogens, and it is important to recognize local epidemiologic patterns and recent colonizing or infecting organisms in the transplant recipient and donor when choosing antibiotics for prophylaxis. The use of antibacterial agents around the time of transplantation is discussed separately. In patients without sulfonamide allergy, trimethoprim-sulfamethoxazole is generally administered for 6 to 12 months after liver transplantation [25], primarily to reduce the risk of Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP), but it also helps to prevent infections with Listeria monocytogenes, Nocardia asteroides, Toxoplasma gondii, and many common urinary, respiratory, and gastrointestinal bacterial pathogens [8,25-27]. One single-strength tablet is taken daily or one double-strength tablet is taken three times weekly. Routine use of trimethoprim-sulfamethoxazole prophylaxis has virtually eliminated PCP infection in the posttransplant setting in comparison with a 10 to 12 percent incidence in earlier series [26]. The most common adverse effect of trimethoprim-sulfamethoxazole is allergy. Myelosuppression can also occur, Cytomegalovirus (CMV) the most important viral infection in liver transplant recipients. CMV infection, the presence of the virus in blood, tissue, or body fluids, should be distinguished from CMV disease, which is CMV infection accompanied by signs and symptoms of CMV [29]. Ganciclovir and valganciclovir have been incorporated into strategies designed to prevent CMV disease in patients at risk of CMV reactivation [30-32]. As a result, the incidence of CMV disease in the posttransplant setting has declined [33,34].

ttt CMV liver transplant recipients who are seronegative for CMV and receive an organ from a CMV-seropositive donor have the highest risk for developing CMV disease, while CMV-seropositive recipients (R+) have a modest risk, and CMV D-/R- recipients have the lowest risk [36]. CMV infection has been associated with an accelerated course of hepatitis C virus recurrence and allograft loss after liver transplantation [41,42]. CMV prophylaxis refers to giving an anti-CMV drug to those at increased risk of CMV reactivation (eg, CMV D+/R-, D+/R+, D-/R+), while preemptive therapy refers to giving an anti-CMV drug only when there is evidence of CMV replication (eg, by detection of CMV nucleic acids in serum via polymerase chain reaction [PCR] or CMV antigenemia). Both strategies reduce the risk of CMV disease [47,48]. Valganciclovir, at doses of 900 mg daily a clinical trial showed an increased incidence of CMV disease compared with those who received oral ganciclovir in patients who had undergone liver transplantation [34,37]. Universal CMV prophylaxis has additional benefits since ganciclovir and valganciclovir are CMV prophylaxis reduced the risk of biopsy-proven rejection in liver transplant recipients [50]. CMV prophylaxis in CMV R+ individuals, although preemptive therapy is an acceptable alternative. [52,53] use antiviral CMV prophylaxis for three to six months after transplant and during intensification of immunosuppression for rejection [8]. In patients who do not receive CMV prophylaxis, an antiviral with activity against HSV and VZV (acyclovir, valacyclovir, famciclovir) should be given during the first three to six months after transplantation and during periods of intensified immunosuppression (treatment of graft rejection) [53].

Fungal infection Candida is the predominant fungal infection encountered after liver transplantation [56]. Aspergillus infections occur in patients with certain risk factors Candida prophylaxis for adult liver transplant recipients with ≥2 of the following risk factors [57]: ●Prolonged or repeat operation ●Retransplantation ●Renal failure ●High transfusion requirement (ie, transfusion of ≥40 units of cellular blood products including platelets, packed red blood cells, and auto transfusion) ●Choledochojejunostomy ●Candida colonization during the perioperative period Fluconazole 400 mg orally (or IV if the patient is not taking oral medications) daily is appropriate for many patients, but an echinocandin (micafungin, caspofungin, anidulafungin) or a lipid formulation of amphotericin B 3 to 5 mg IV daily should be used if there is a high rate of non-albicans Candida infections or intolerance to fluconazole. The duration of Candida prophylaxis should be one to four weeks or for as long as risk factors persist. risk factors for Aspergillus infection after liver transplantation include fulminant hepatic failure, reoperation, retransplantation, posttransplant renal or hepatic failure, concurrent cytomegalovirus infection, hepatitis C infection, and high-dose glucocorticoids [58]. antifungal prophylaxis did not reduce total mortality, although fluconazole prophylaxis decreased invasive fungal infections by 75 percent [66].

Tuberculosis it is optimal to treat latent tuberculosis prior to transplantation, it is challenging in liver transplant candidates who may not tolerate the potential hepatotoxicity of isoniazid.

Transplant to one month The two major sites of infection during this time period are the abdomen and the lungs, both of which may be associated with bacteremia [16,77]. ●Abdominal abscesses and infections of the peritoneum can result from operative complications including biliary leaks or hematomas, with the predominant pathogens being enteric organisms [3,4]. ●Intrahepatic abscesses may manifest as the result of hepatic artery thrombosis or bile duct ischemia occurring in the perioperative period. ●Cholangitis may occur after T-tube obstruction. ●Wound infections are common [3,24]. Nosocomial pneumonias are particularly frequent in patients who require prolonged mechanical ventilation. Pseudomonas aeruginosa and Enterobacter species may be recovered from bronchoalveolar lavage specimens. Other common bacterial pathogens associated with pneumonia include Staphylococcus aureus, Klebsiella pneumonia, Stenotrophomonas maltophilia, and Citrobacter freundii [4]. Clostridium difficile colitis can also occur, particularly in the early period following transplantation and in patients requiring prolonged hospitalization. In fact, liver transplantation has been identified as a significant risk factor for C. difficile acquisition in the hospital [78]. If a bacterial infection is suspected in a liver transplant recipient, empiric broad-spectrum antibiotics should be initiated until the specific bacterium and its sensitivities can be identified. Antibiotic regimens used for empiric therapy in the early posttransplantation period should include coverage for gram-positive cocci, gram-negative bacilli and anaerobes, with selection of agents that cover resistant organisms that have already been documented in the patient while awaiting microbiological test results. Candida is also an important pathogen during the first month after transplantation. The bloodstream, surgical wounds, and the urinary tract are common sites for primary infection, which may then disseminate [56]. Candida infections may also manifest as esophagitis and superficial infections of the skin (folliculitis) or oral cavity [4]. (See "Biology of Candida infections".) Candidemia should be treated aggressively since fungemia is associated with high mortality [56]. In addition, as noted above, a greater proportion of invasive Candida infections among liver transplant recipients in recent years have been due to non-albicansCandida spp, a finding that has significant implications for outcome and treatment as these organisms have been associated with higher mortality and may be less susceptible to fluconazole than C. albicans [56]. One to six months Cytomegalovirus

Cytomegalovirus (CMV) is one of the most common pathogens causing disease during this period [37]. In the absence of prophylaxis, CMV reactivation occurs in approximately 50 to 60 percent of patients; 20 to 30 percent of these will develop CMV-related disease such as pneumonitis, enteritis, or hepatitis [3]. As noted above, the timeline of infections following transplantation has been altered due to prophylactic therapies. In many cases, primary CMV infection is merely delayed rather than prevented and often occurs after prophylaxis has been stopped [51,86].

CMV disease can present with a variety of symptoms, the most common of which are fever, leukopenia, thrombocytopenia, malaise, and arthralgias [87]. Less frequent manifestations include pneumonia, gastroenteritis, hepatitis, encephalitis, and retinitis. CMV hepatitis may be difficult to distinguish from graft rejection, which is also common during this period. A liver biopsy is helpful in this setting. Findings on liver biopsy suggesting CMV disease include the presence of viral inclusions associated with a mononuclear cell infiltrate and microabscesses. Although somewhat controversial, CMV has also been implicated as a risk factor for ductopenic (ie, chronic) rejection [88]. Other viruses Varicella-zoster virus (VZV), Epstein-Barr virus (EBV), respiratory syncytial virus (RSV), human herpesvirus 6 (HHV-6), influenza, and adenovirus may also occur during the period of one to six months following transplant. Of these, EBV is the most important because of its potential to cause posttransplant lymphoproliferative disease (PTLD). Aspergillus species The most common site of aspergillosis is the lung, although it may disseminate to other sites including the central nervous system (CNS). It is the most common cause of CNS infection in liver transplant recipients, accounting for 55 percent of brain abscesses in one series [99]. Mortality of aspergillosis in early series of liver transplant recipients approached 100 percent [100], but more recent data suggest the outcomes may be improving [97,101]. After six months Opportunistic infections are uncommon beyond six months post-transplant in patients who have good graft function since immunosuppression has generally been tapered to a maintenance regimen. These patients usually develop the same types of community-acquired infections seen in the general population, although at an increased rate [8]. Transplant recipients may be more susceptible to some pathogens such as Legionella [103] and may experience more severe manifestations of certain infections such as West Nile virus infection [104]. Patients on chronic immunosuppression often initially have only subtle findings of infection due to attenuation of inflammatory responses by immunosuppressants, but this may be followed by a precipitous decline in status and severe manifestations of infection. Respiratory infections due to pathogens such as Streptococcus pneumoniae and Haemophilus influenzae can be life threatening if not promptly treated. Patients who have chronic rejection are also more susceptible to chronic viral infections, possibly from the increased immunosuppressive regimens. Chronic or recurrent viral infections including those due to EBV, CMV, hepatitis B (HBV), hepatitis C (HCV), and human herpesviruses 6 and 7 also can lead to complications in the late posttransplant period. Chronic viral infections can also produce damage to the liver allograft (HBV and HCV) or cause secondary tumors during this period, including posttransplant lymphoproliferative disease due to EBV and hepatocellular carcinoma due to HBV or HCV [35]. Hepatitis E virus (HEV) can also cause chronic hepatitis in liver transplant recipients and should be considered in patients with unexplained liver enzyme elevations [105].