Infections and Sepsis After Liver Transplantation
Despite recent advances, infectious complications remain a significant contributor to morbidity and mortality after liver transplantation, affecting both patient and graft survival. Following transplantation, one third to one half of liver transplant recipients experience an infectious complication with over 80 % of infections occurring within the first 6 months following transplant. Infectious complications are the cause of death in over 15–25 % of all liver transplant recipients but are responsible for over half of deaths in the first year following transplant. Infection remains the most common cause of death for the first 3 years after liver transplant. Bacterial infections predominate and include presentations such as bloodstream, abdominal, wound, or biliary tract infection. Liver transplant patients are also particularly susceptible to fungal infections, predominantly candidemia, invasive aspergillosis, and cryptococcal infection. As with other high-risk populations, multidrug-resistant (MDR) organisms are becoming more prevalent after liver transplantation with an increased mortality than with drug-susceptible infections. With targeted pre-transplant and posttransplant prevention, prophylaxis, and monitoring, many infections may be prevented or identified early allowing for prompt initiation of appropriate therapy.
KeywordsInfection Sepsis Liver transplantation
Since 2004, over 6,000 liver transplants have been performed in the United States each year with reported survival following transplant reaching approximately 88 % at 1 year, 80 % at 3 years, and 75 % at 5 years (www.unos.org). Despite improvement in overall survival, however, infectious complications remain a significant contributor to morbidity and mortality after liver transplantation, affecting both patient and graft survival. Recent studies have found that 35–55 % of liver transplant recipients experience an infectious complication at some point (Kalpoe et al. 2012; Kim et al. 2013b; Rubin 2002; Vera et al. 2011) with up to 83 % of infections occurring within the first 6 months after transplant (Vera et al. 2011). Infection has been found to cause over 15–25 % of deaths of all liver transplant recipients, second only to malignancy of non-hepatic causes of death. Infectious complications are responsible for over half of deaths in the first year, remaining the most common cause of death during the first 3 years following transplant (Avkan-Oguz et al. 2013; Kim et al. 2013; Vera et al. 2011; Watt et al. 2010).
In the initial month after liver transplant, most infections are related to technical or surgical issues and complications or exposure to infectious agents through prolonged hospitalizations before and after transplant (Blair and Kusne 2005). Other risk factors for infectious complications after liver transplant include prolonged intensive care unit stay, need for parenteral nutrition, perioperative blood transfusion requirements, surgical technique, level of immunosuppression, other underlying immune deficiencies such as neutropenia, comorbidities such as diabetes mellitus, and immunomodulating activity of certain viruses such as cytomegalovirus (CMV) (Vera et al. 2011). There are several infectious complications unique to recipients of liver transplants, different from other surgical patients and even other recipients of solid organ transplants that must be taken into consideration when evaluating these patients. The emergence of multidrug-resistant (MDR) pathogens has also become a great concern in the management of liver transplant recipients.
Efforts toward the prevention of infection can begin in the pre-transplant period through the use of donor and recipient screening as well as through recipient vaccine administration. Following liver transplant, targeted prophylaxis in certain patients and close monitoring are the most commonly used methods to prevent infectious complications. With targeted pre-transplant and posttransplant prevention, prophylaxis, and monitoring, many infections may be prevented or identified early allowing for prompt initiation of appropriate therapy.
Pre-transplant Evaluation, Treatment, and Prevention of Infections
Comprehensive guidelines for donor and recipient screening as well as recipient vaccine administration have been published previously (Fischer et al. 2013; Danzinger-Isakov et al. 2013). Pre-transplant evaluation begins primarily with serologic screening which when combined with donor serologic screening, can help determine the risk of infection following transplantation. Viruses, such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV), can all affect the outcome following liver transplantation if present in the donor or recipient prior to transplant. For some infections, such as CMV and EBV, the combined serologic status of the recipient and donor can be an important predictor for infection in the posttransplant period and may indicate the need for prophylactic treatment in high-risk individuals.
Recipients should be screened and tested when clinically appropriate for infections that have the potential for reactivation in the setting of immunosuppression. Information regarding previous infections, locations of travel or residence, and exposures to environmental pathogens through animals or activities can help direct targeted screening for infections. Treponema pallidum (the bacteria responsible for syphilis), Strongyloides stercoralis, Mycobacterium tuberculosis (TB), and endemic fungi such as Histoplasma capsulatum, Coccidioides immitis, and various Cryptococcus species are a few examples of infections for which a provider may screen and test in a potential liver transplant recipient. Active infections that are found generally require initiation of treatment and possibly completion of therapy prior to transplantation.
Limiting the transmission of infections through the donated organ is also crucial to the success after liver transplant. Unexpected disease transmission through the donor can lead to significant morbidity and mortality. As discussed by Ison et al. (2013), risk of donor disease transmission can be mitigated by a three-pronged approach: (1) use of donor medical and social history for risk stratification, (2) physical assessment of the donor and donor organs, and (3) laboratory screening of the donor for infection. If a donor-derived infection is suspected, coordination of care with the local organ procurement organization (OPO), if in the United States, or other national organ procurement authorities is essential so that quality control is ensured and that the providers of other organ recipients from the same donor may be notified and begin appropriate evaluation and treatment if needed.
Vaccine administration is an important part of the prevention of infectious complications after transplant. As vaccines are generally less effective in end-stage organ failure and while on immunosuppression after transplant, early administration of vaccines prior to transplant is preferred. If needed, inactive vaccines are safe after transplant and generally felt to be most effective once recipients have achieved a baseline level of immunosuppression, usually 3–6 months after transplant. Live vaccines are considered contraindicated after transplant due to the immunosuppressed state; thus, vaccines such as MMR (measles, mumps, and rubella) and varicella should be administered prior to transplant if needed.
Characterization of Post-Liver Transplant Bacterial Infections
Bacterial infections are the most common infectious complication after liver transplant, comprising 69–78 % of all posttransplant infections (Chen et al. 2011; Kim et al. 2013; Kim 2014; Vera et al. 2011) with nearly half of all bacterial infections occurring within the first 2 months following liver transplant (Kim 2014). Early in the postoperative phase (<1 month), posttransplant infections are frequently healthcare associated caused by bacteria that are routinely seen with nosocomial infections (Kim 2014). Risk factors for the development of a bacterial infection after liver transplant include pre- or posttransplant renal replacement therapy, operation-related or biliary complications, graft rejection, reoperation including re-transplantation, perioperative blood transfusion requirements, or prolonged time spent in the intensive care unit (Chen et al. 2011; Kim et al. 2013).
While the spectrum of infection varies regionally and among centers, infections caused by gram-negative bacteria are generally most common, causing 50–70 % of bacterial infections (Kalpoe et al. 2012; Kim et al. 2013; Shi et al. 2009; Vera et al. 2011; Zhong et al. 2012), although nearly a third of infections may be polymicrobial (Kalpoe et al. 2012). Common organisms include Escherichia coli; various species of Pseudomonas, Klebsiella, Acinetobacter, and Enterobacter; as well as gram-positive organisms such as Staphylococcus aureus and Enterococcus species.
As the worldwide prevalence of multidrug-resistant (MDR) organisms has increased, the prevalence has also increased among liver transplant recipients (Bert et al. 2010; Mrzljak et al. 2010; Shi et al. 2009). An estimated 52 % of all organisms and up to 56–66 % of gram-negative infections after liver transplant are resistant to more than one antibiotic (Dganga et al. 2012; Kalpoe et al. 2012; Zhong et al. 2012). With this increased incidence of multi-drug resistance comes an increased risk mortality due to infections. Kalpoe et al. (2012) studied carbapenem-resistant Klebsiella pneumonia (CRKP) infections in liver transplant recipients and found the mortality following CRKP infections was 71 % versus 14 % of non-CRKP infections. Of liver transplant recipients with CRKP infections, 86 % had a bloodstream infection, and 79 % had an intra-abdominal infection or peritonitis, with 82 % having both an intra-abdominal infection and peritonitis in conjunction with a bloodstream infection. CRKP infections occurred on average 12 days following liver transplantation with 93 % of infections occurring within 1 month and were associated with a 64 % mortality within 30 days of developing the infection. An increased mortality is not with CRKP infections alone. Shi et al. (2009) found a mortality of 39 % in liver transplant recipients with any gram-negative MDR infection as opposed to 15 % of patients without a gram-negative MDR infection.
Specific Bacterial Infections After Liver Transplant
Intra-Abdominal and Surgical Site Infections
Intra-abdominal and surgical site infections are the most common infection after liver transplant, comprising over half of all infections (Kim et al. 2013) and occurring in 18–51 % of all liver transplant recipients (Freire et al. 2013; Hellinger et al. 2009; Kim et al. 2013; Kim et al. 2008). The infections range from superficial and deep incisional infections to peritonitis, cholangitis, and intra-abdominal abscesses. Posttransplant intra-abdominal and surgical site infections are associated with longer hospital stays and higher medical costs (Hollenbeak et al. 2001) as well as increased death and graft loss (Hellinger et al. 2009).
Risk factors for the development of intra-abdominal and surgical site infections include a higher model for end-stage liver disease (MELD) score at the time of transplant, duration of transplant surgery, Roux-en-Y biliary anastomosis, need for renal replacement therapy following transplant, extended postoperative intensive care unit (ICU) stay, need for reoperation, or extended preoperative hospital stay (Avkan-Oguz et al. 2013).
The biliary tract is a common source for intra-abdominal infections, contributing to the development of cholangitis, abscess, or bilomas. Risk factors for the development of biliary complications in particular, specifically biliary necrosis, strictures, and leaks, include hepatic artery thrombosis, hepatic artery stenosis, Roux-en-Y biliary anastomosis, and T-tube placement (Safdar et al. 2004). As surgical techniques have improved, so too has the incidence of biliary tract complications following liver transplantation. Greif et al. (1994) reported an initial biliary complication rate at their institution of 19 % in 1983 which had fallen to 11.5 % in 1994. Other studies have shown an incidence of 5–25 % (Akamatsu et al. 2011; Chen et al. 2011; Gastaca 2012; Safdar et al. 2004). Of all biliary complications, strictures and leaks are most common, occurring predominantly in the first 3 months after transplant (Akamatsu et al. 2011; Chen et al. 2011; Safdar et al. 2004).
The presentation of intra-abdominal and surgical site infections can range from erythema and pain of the incisional site to fever, abdominal pain, elevated white blood cell (WBC) count and/or liver enzymes, or sepsis . At times, laboratory abnormalities may be the only presenting sign of an intra-abdominal infection. Infections can be caused by a spectrum of bacteria most commonly including Staphylococcus aureus (both methicillin sensitive and methicillin resistant), enterococci, anaerobic bacteria, Escherichia coli, Pseudomonas sp., Enterobacter sp., Klebsiella sp., and Acinetobacter sp. Most infections are managed by surgical or interventional procedures as needed and drainage if a fluid collection is present. Broad-spectrum antibiotics should be initiated immediately and tailored once microbiologic data is available. Treatment should extend for at least 2 weeks once any necessary drainage has occurred.
Bloodstream infections are the second most common infection following liver transplant, occurring in 17–30 % of liver transplant recipients, with mortality reaching 28–36 % (Chen et al. 2011; Kalpoe et al. 2012; Kim et al. 2013; Lee et al. 2011; Singh et al. 2000, 2004). Most bloodstream infections occur within the first 60 days following transplant, although they can occur at any time (Dganga et al. 2012). There are conflicting reports of the predominant bacteria causing bloodstream infections following liver transplant, likely due to center-specific epidemiology, with some documenting primarily gram-negative bacteria (Dganga et al. 2012; Kim et al. 2013; Singh et al. 2004) and others reporting a predominance of gram-positive bacteria (Lee et al. 2011). The timing of bacteremia following liver transplant may play a role, however, as shown by Lee et al. (2011). They found over 92 % of gram-positive bloodstream infections occurred within the first 30 days following transplant, whereas over 41 % of gram-negative bloodstream infections occurred after the first 30 days. For episodes of bacteremia occurring within the first 30 days after transplant, nosocomial bacteria were more common than in episodes of bacteremia occurring after 30 days. Polymicrobial bloodstream infections may also be common, occurring in up to 28 % of liver transplant recipients, primarily comprised of staphylococci, enterococci, and Candida (Kim et al. 2013).
Patients with bloodstream infections may present with a variety of signs and symptoms including fever, rigors, elevated WBC count, sepsis , or localizing symptoms of the primary source. Risk factors for developing bloodstream infections include extended postoperative ICU stay, an MELD score of greater than 20 at the time of transplant, preoperative albumin level of less than 2.8 g/dL, and the need for reoperation (Avkan-Oguz et al. 2013; Singh et al. 2000).
The primary sources of bloodstream infections include intra-abdominal or biliary tract infections, pneumonia, urinary tract infection, intravascular catheter-related infection, or wound infection. Kim et al. (2013) found the primary sources for bacteremia include the biliary tract in 36 %, abdominal or wound in 28 %, and intravascular catheters in 19 % of liver transplant recipients. In patients who developed biliary complications, 42 % developed a concurrent bloodstream infection (OR 2.91 (95 % CI)). Bloodstream infections were found to be an independent risk factor for death with 1 year survival being 60 % in patients who developed a bloodstream infection and 90 % in those who did not (HR 3.93 (95 % CI)). Among patients who developed a bloodstream infection, the risk factors for death included hepatocellular carcinoma (HCC) (HR 3.82), candidemia (HR 3.71), polymicrobial bacteremia (HR 3.18), and posttransplant need for renal replacement therapy (HR 2.44).
Treatment for bloodstream infections involves identification and management of the primary source if possible, removing any indwelling catheters that may be involved and providing broad-spectrum antibiotic coverage that may be tailored once microbiologic data is available. Initial antimicrobial coverage should take into consideration the prevalence of MDR bacteria at each individual institution.
Beyond the use of routine antibacterial prophylaxis, perioperative antibiotics may also be used to minimize the risk of postoperative bacterial infections. Perioperative antibiotics in the first 48 h after transplant are a widely used practice; however, more tailored therapy can be considered for patients in whom there is a previously documented donor or recipient bacterial infection. While active infection in a recipient is generally considered a contraindication for transplant, no consensus has been reached regarding the optimal timing of transplant after initiation of treatment and/or resolution of the infection (Kim 2014). Screening for bacterial infection should be performed in both the donor and recipient prior to transplantation; however, laboratory limitations often prevent full information to be available at the time of transplant (Fischer and Avery 2009). As such, close follow-up of outstanding laboratory studies and microbiologic cultures is essential so that appropriate therapy may be given as soon as possible if an infection is identified. Recipients of organs from a donor with a documented infection will also need to be monitored closely as infection may recur despite appropriate antibacterial therapy (Coucette 2013).
Fungal infections are the third most common infection following liver transplant with an estimated incidence of 7–9 % (Chen et al. 2011; Fung 2002; Vera et al. 2011). The incidence has decreased significantly over time, from 42 % at a single center between 1981 and 1983 falling to 7 % between 1989 and 1992 (Fung 2002; Wajszczuk et al. 1985). Fungal infections in liver transplant recipients are generally due to Candida (33–73 %), followed by Aspergillus (16–33 %) and Cryptococcus (16–33 %). Mortality is high following a fungal infection, reaching 55–69 % (Fung 2002; Wajszczuk et al. 1985).
Risk factors for the development of a fungal infection after liver transplant include a choledochojejunostomy anastomosis, serum creatinine >3 mg/dL, prolonged transplant operative time, re-transplantation, early fungal colonization, and development of cytomegalovirus (CMV) infection or disease (Collins et al. 1994; George et al. 1997; San-Juan et al. 2011). In liver transplant recipients without any of these risk factors, the incidence of fungal infection has been found to be 1–2 %, whereas in recipients with two or more risk factors, the incidence is 67 % (Collins et al. 1994; San-Juan et al. 2011).
Prophylaxis for fungal infection can be considered in liver transplant recipients, particularly those who are at high risk; however, universal prophylaxis is likely not warranted. San-Juan et al. (2011) found an incidence of fungal infection in low-risk liver transplant recipients to be 1.9 % in those who received prophylaxis and 1 % in those who do not receive prophylaxis. The MELD score may be a helpful predictor for the need of antifungal prophylaxis. Saliba et al. (2013) found a twofold increased risk for fungal infection in liver transplant recipients who had a pre-transplant MELD score between 20 and 30 and an over fourfold increased risk in those with a pre-transplant MELD score of greater than 30. Current recommendations for fungal prophylaxis include fluconazole or liposomal amphotericin B for 4 weeks or until resolution of the risk factors predisposing for fungal infection (Silveira and Kusne 2013). A recent study has reported that an echinocandin, anidulafungin, may also have a similar efficacy as fluconazole for the prevention of fungal infection following liver transplant (Winston et al. 2014).
Candidal infections are the most common fungal infection following liver transplantation with the highest incidence within the first 30 days and nearly all episodes occurring within the first 6 months following transplant (Vera et al. 2011). The mean onset of Candida infections has been found to be 12 days after transplant (Kime et al. 2013). Risk factors for the development of invasive candidal infections include a prolonged operative time, need for early reoperation, choledochojejunostomy anastomosis, need for more than 40 units of blood products during surgery, need for renal replacement therapy, early colonization with Candida or previously documented colonization, and acute fulminant liver failure (Fagiuoli et al. 2014). Candida albicans is the most common infecting organism; however, non-albicans species are becoming more frequent, some of which are inherently resistant to fluconazole (Romero and Razonable 2011).
The most common presentation of a Candida infection is mucocutaneous candidiasis; however, invasive candidiasis is the more worrisome infection in liver transplant recipients and usually presents as candidemia related to an intravascular catheter or an intra-abdominal infection (Huprikar 2007). Caution should be used when starting empiric treatment for invasive candidiasis due to the increasing resistance of certain Candida species, particularly to fluconazole. An echinocandin may be preferred in a hemodynamically unstable liver transplant recipient, particularly if there has been prior azole exposure (Fagiuoli et al. 2014). Liposomal amphotericin is an alternative as empiric treatment, although its use may be limited in patients with renal dysfunction. Once the organism has been identified, sensitivity testing and local epidemiology may help guide targeted treatment choices. Management of a potential source of the candidal infection (i.e., infected intravascular catheter, abdominal abscess, etc.) is also crucial in the resolution of the infection.
Prophylaxis for infections caused by Candida in high-risk individuals is currently recommended by the American Society of Transplantation (Silveira and Kusne 2013). A recent meta-analysis showed antifungal prophylaxis reduced the rates of colonization and infection with Candida albicans and reduced the mortality due to Candida albicans infection but did not reduce overall mortality (Cruciani et al. 2006).
Invasive aspergillosis is the second most common fungal infection in liver transplant recipients but has the highest rates of mortality. Invasive aspergillosis occurs in 1–9 % of patients following liver transplant with mortality reaching 33–100 % (Barchiesi et al. 2014; Brown et al. 1996; Singh et al. 2003). In a literature review by Barchiesi et al. (2014), the median diagnosis of invasive aspergillosis was found to be 25 days following transplant, and the primary site of infection was the lung (66 %), followed by the central nervous system (39 %) and osteoarticular infections (29 %). Aspergillus fumigatus caused the majority of infections (73 %), followed by Aspergillus flavus (14 %), and Aspergillus terreus (8 %). The mortality in this study was 66 %, with a large proportion of those who did not survive having pulmonary infection or infection in unusual sites such as in the kidney, heart, liver, eye, thyroid, muscles, or pancreas. Survival was improved in those who were transplanted after the year 2000, in those diagnosed with invasive aspergillosis more than 30 days after transplant, in patients who did not have renal failure, and in those who received voriconazole. Although data would suggest that the majority of infections with Aspergillus following liver transplant occur early posttransplant, other reports indicate an increasing number of infections beyond 6 months posttransplant and even 1 year posttransplant (Singh et al. 2006).
Risk factors for post-liver transplant invasive aspergillosis include need for dialysis, re-transplantation, CMV infection, prior colonization with Aspergillus, and acute fulminant liver failure (Fagiuoli et al. 2014). Diagnosis occurs with identification of the mold in a clinical specimen and/or clinical signs or symptoms consistent with the disease. There has been an attention on the use of Aspergillus antigens such as galactomannan in the diagnosis of invasive aspergillosis; however, there is a data to suggest that this test does not perform well in solid organ transplant recipients (Pfeiffer et al. 2006).
Preferred treatment for Aspergillus species is voriconazole followed by amphotericin B as second-line therapy (Romero and Razonable 2011). While antifungal prophylaxis is recommended following liver transplant in individuals with identifiable risk factors (Singh et al. 2013), there is evidence to suggest that antifungal prophylaxis has no effect on the incidence of invasive aspergillosis (Cruciani et al. 2006).
Cryptococcus neoformans is the third most common fungal infection in liver transplant recipients with a reported incidence of 2.4 % and mortality of up to 40 % (Husain et al. 2001). While cryptococcal infection following solid organ transplantation generally occurs 16–21 months following transplant, early cases have been reported that may be related to unrecognized cryptococcal disease in the recipient or due to a donor-derived infection (Sun et al. 2010). These early cryptococcal infections have been found to occur primarily in liver transplant recipients with the infection presenting in the allograft or at the surgical site (Sun et al. 2010). Risk factors for cryptococcal infection include the administration of corticosteroids or antilymphocyte antibodies (Patel and Hhuprikar 2012).
Diagnosis of cryptococcal infection is made with either identification of the organism on culture or biopsy or with the use of serum and/or cerebrospinal fluid (CSF) antigen assay. Liver transplant recipients may develop cutaneous involvement with Cryptococcus at the surgical site or other cutaneous sites and present with a non-resolving skin infection unresponsive to standard therapy for cellulitis. A skin biopsy may be needed for the diagnosis of cryptococcal cellulitis, which likely represents a disseminated disease. A lumbar puncture should be performed to exclude CNS involvement, particularly as liver transplant recipients are more likely to present with disseminated disease than other solid organ transplant recipients (Singh et al. 2007).
Per the Infectious Diseases Society of America, recommended treatment for disseminated cryptococcosis includes liposomal amphotericin plus flucytosine or amphotericin B lipid formulation (Perfect et al. 2010). Consolidation may be accomplished with fluconazole for 8 weeks followed by maintenance fluconazole for 6–12 months. Cryptococcal infection limited to the lungs may be managed with fluconazole therapy alone for 6–12 months.
Following bacterial infections, viral infections are the second most common infection in liver transplant recipients, occurring in 12–19 % of patients (Chen et al. 2011; Vera et al. 2011). Cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV) are the most common viral agents to cause infection after liver transplant, although numerous other viruses can also cause significant morbidity and mortality after transplantation (Ison 2005).
CMV will be discussed in full detail elsewhere. Briefly, CMV can occur following liver transplant as either new primary infection or reactivation of latent infection. Nearly two thirds of CMV episodes occur between 2 and 6 months posttransplant (Vera et al. 2011). Clinical presentations can range from asymptomatic viremia, CMV syndrome with fever, leukopenia and/or thrombocytopenia, or CMV disease with end-organ disease such as hepatitis, pneumonitis, and/or gastritis/colitis. The highest-risk patient for the development of CMV reactivation or disease is a CMV seronegative recipient of a CMV seropositive donated organ. Antiviral agents are key for the treatment of CMV infection and may be considered for the posttransplant prophylaxis of CMV infection.
Herpes Simplex Virus (HSV)
Herpes simplex virus can appear as either a new primary infection, reactivation of latent infection, or as a donor-derived infection with clinical presentations of orolabial, genital, or perianal lesions. More severe disease can present as fulminant hepatitis, pneumonitis, or keratitis. A recent review of liver transplant recipients who developed HSV hepatitis found the average presentation to be 20 ± 12 days following transplant (Côté-Daigneault et al. 2014) with 67 % of cases occurring within the first 30 days (Vera et al. 2011). Mortality from HSV hepatitis reaches 55 % following liver transplantation (Côté-Daigneault et al. 2014). Fever, leukopenia, elevated liver enzymes, and/or abdominal pain are the most common presenting signs and symptoms. Treatment involves administration of antiviral therapy, supportive care, and reduction of immunosuppression when feasible. It is recommended that liver transplant recipients receive a period of antiviral prophylaxis with HSV coverage for at least 1 month following transplant given the high rate of HSV infection during times of significant immunosuppression (Wilck et al. 2013).
Varicella-Zoster Virus (VZV)
Varicella-zoster virus can occur in liver transplant recipients either as a new primary infection, reactivation of latent infection, or as a donor-derived infection. Following liver transplantation, the incidence of herpes zoster has been reported to be 1.2–12 % (Ignacio Herrero et al. 2004; Gourishankar et al. 2004; Levitsky et al. 2005). While most patients present with herpes zoster, or shingles, there have been reports of fulminant liver failure due to the infection (Roque-Alfonso et al. 2008). Treatment includes antiviral therapy, supportive care, and reduction of immunosuppression when feasible. Key preventative measures for herpes zoster are the pre-transplant administration of a varicella-zoster virus vaccine as well as consideration of antiviral prophylaxis for a period of time following transplant.
Adenovirus is a double-stranded, non-enveloped DNA virus that primarily causes self-limited conjunctival, respiratory, and gastrointestinal infection in immunocompetent hosts. In immunocompromised patients such as liver transplant recipients, adenovirus can lead to hepatitis and acute liver failure, pneumonitis and respiratory failure, hemorrhagic cystitis, and disseminated disease (disease in more than two end organs). Infection can occur via new infection, including nosocomial infection, as well as reactivation of latent infection (Ison 2006). Of adult solid organ transplant recipients, adenoviral infection occurs most commonly following liver transplantation, with a reported incidence of 6 % and mean time to disease of 55 days after transplant (McGrath et al. 1998). There is no definitive treatment of adenoviral infections; however, management includes supportive care, reduction of immunosuppression when feasible, and consideration of antiviral therapy and/or intravenous immunoglobulin in severe cases.
Toxoplasma gondii is a parasitic protozoan transmitted to humans through the ingestion of contaminated food or water. Following liver transplant, infection can occur as reactivation of latent disease or as a donor-derived infection. While toxoplasmosis is well described following cardiac transplantation, a number of cases in noncardiac solid organ transplant recipients have also been reported (Gourishankar et al. 2008; Wendum et al. 2002). Clinical presentations can range from a nonspecific syndrome of fever, myalgias, lymphadenopathy, rash, and/or hepatosplenomegaly to central nervous system (CNS) lesions, pneumonitis, or chorioretinitis. While little data exists regarding treatment in solid organ transplant recipients, treatment recommendations generally follow those for patients with human immunodeficiency virus (HIV) which includes pyrimethamine plus leucovorin and sulfadiazine. Prophylaxis for Pneumocystis jirovechii (PJP) with trimethoprim-sulfamethoxazole also provides prophylactic coverage for Toxoplasma (Schwartz et al. 2013).
Strongyloides stercoralis is an intestinal helminth which is found worldwide, predominantly in tropical or subtropical regions. Infection occurs via direct inoculation by larvae in the soil, and infection in the host is perpetuated by an autoinfective cycle. Following liver transplant, strongyloidiasis occurs primarily by reactivation of latent infection or as a donor-derived infection. Liver transplant patients, as with all immunosuppressed patients, are at risk for the development of hyperinfection and disseminated disease which have a mortality rate up to 85 % (Le et al. 2014). Treatment in immunocompromised patients is not well established but may include ivermectin and/or albendazole (Rodriguez-Hernandez et al. 2009). The American Society for Transplantation recommends serologic screening for Strongyloides in at-risk recipients, living donors, and at-risk deceased donors whenever possible so appropriate therapy may be given prior to or just following transplantation (Schwartz et al. 2013).
Despite recent advances, infectious complications remain a significant contributor to morbidity and mortality after liver transplantation. Infection is the most common cause of death for the first 3 years after liver transplant and limits both patient and graft survival. Bacterial infections predominate; however, liver transplant recipients are also particularly susceptible to fungal infections. As with other high-risk populations, multidrug-resistant (MDR) organisms are becoming more prevalent after liver transplantation with increased mortality than with drug-susceptible infections. With targeted pre-transplant and posttransplant prevention, prophylaxis, and monitoring, many infections may be prevented or identified early allowing for prompt initiation of appropriate therapy.
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