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Infectious complications remain among the most significant causes of morbidity and mortality in patients undergoing liver transplantation. This review provides the reader with a general approach to the problem of infection after liver transplantation.
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Liver transplantation is associated with a set of technical and medical problems which predispose to a unique set of infectious complications. The abdomen is the most common site of infection in patients undergoing this procedure,1 almost certainly due to the occurrence of local ischemic injury and bleeding, as well as possible soilage with contaminated material.2 Additional factors predisposing to infection can be divided into those that exist prior to transplant and those secondary to intraoperative and posttransplant activities.
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The underlying illnesses that lead to transplantation may be associated with intrinsic risk factors for infection. Some disorders may have required palliative surgery, increasing the technical difficulty of the transplant and enhancing the risk of posttransplant infections.3 Complications of end-stage liver disease may also predispose to infection after transplant. For example, a history of one or more episodes of spontaneous bacterial peritonitis (SBP) pretransplant has been associated with an increased rate of bacterial infections after liver transplantation.4
Age, another pretransplant factor, is an important determinant of susceptibility to certain agents, severity of expression of infection, and immune maturation. Young children undergoing liver transplantation may experience more severe infections with certain viral (eg, respiratory syncytial virus) and bacterial (coagulase-negative staphylococcus) pathogens than the mild infections sustained by adult recipients. In contrast, certain pathogens such as Cryptococcus neoformans uncommonly cause infection before young adulthood.5 Age is also an important factor governing clinical expression of infection with cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Young patients are more likely to be seronegative for these viruses and therefore susceptible to primary infections with these agents; primary infections are more severe than infections due to reactivation.6,7
Donor-related issues must also be considered as pretransplant factors. Transplant recipients are at risk for infections that are active or latent within the donor at the time of organ harvest. Perhaps the most dramatic example of this is CMV, the most frequent and important viral pathogen among transplant recipients.8 Other donor-associated infections are caused by Epstein-Barr virus,9 human immunodeficiency virus,10 and histoplasmosis.11
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Operative factors specific to liver transplantation may predispose to infectious complications. For example, patients who undergo Roux-en-Y choledochoduodenostomy experience more infectious episodes than those who undergo choledochocholedochostomy with T-tube drainage.12,13 Prolonged operative time (>12 hours) during the initial transplant has been associated with an increased risk of infection after transplant.13,14 Finally, intraoperative events such as contamination of the operative field clearly predispose to postoperative infections.
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Technical problems, immunosuppression, indwelling cannulas, and nosocomial exposures are major postoperative risk factors for infectious complications. Thrombosis of the hepatic artery, the most serious technical problem, can cause areas of necrosis within the liver with development of hepatic abscesses and bacteremia.12,15 Bile duct stricture, a sequela of hepatic artery thrombosis with ischemia or due to technical error, may predispose to cholangitis.12
Immunosuppression is the critical postoperative factor that predisposes to infection in transplant recipients. Immunosuppressive regimens have evolved in an attempt to achieve more specific control of rejection with the least impairment of overall immunity. This evolution is aimed not only at improved control of rejection but also at decreased morbidity and mortality from infections. The use of cyclosporine-based regimens has decreased the incidence of infections in renal and cardiac transplant recipients.1,16,17 More recently, the introduction of the immunosuppressant tacrolimus has allowed many patients to be managed without steroids.18,19 Although rates of infection are similar, patients treated with tacrolimus appear to have lower morbidity and mortality, especially from viral pathogens, than those treated with cyclosporine.18,20
The treatment of rejection with additional immunosuppressive agents or higher doses of immunosuppressants increases the risk of invasive and potentially fatal infection. Of particular concern is the use of antilymphocyte preparations, especially OKT3, which is often indispensable in the treatment of steroid refractory rejection.8,13,14 However, the use of these agents has been associated with an increase in the severity and frequency of infection compared to standard immunosuppressive regimens that are routinely used to treat rejection.8,13,14
Prolonged use of indwelling cannulas at any site is an important cause of infection throughout the postoperative course. The presence of central venous catheters is a cause of bacteremia after transplantation. Similarly, urinary tract infections and bacterial pneumonias are associated with the use of indwelling Foley catheters13,14 and prolonged nasotracheal or endotracheal intubation, respectively.
Nosocomial exposures constitute the final group of postoperative risk factors. Transplant recipients, especially children, may be exposed to many common viral pathogens (eg, rotavirus, respiratory syncytial virus, influenza) while in hospital. Transplant recipients may also be exposed to transfusion-associated pathogens (eg, hepatitis B and C and HIV). Finally, the presence in the hospital of areas of heavy contamination with pathogenic fungi such as Aspergillus may increase the risk of invasive fungal disease in these patients.
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The majority of clinically important infections following transplantation occur within the first 180 days.13,21 The time of onset of infection with various pathogens tends to be predictable, although some may occur throughout the postoperative course. The timing of infections can be divided into three intervals: early (0 to 30 days after transplantation), intermediate (31 to 180 days after transplantation), and late (more than 180 days after transplantation). These divisions, although arbitrary, are generally useful in approaching a patient with fever and can serve as a guide to differential diagnosis.
Early infections tend to be associated with preexisting conditions or surgical manipulation. In general, they are caused either by bacteria or yeast. Cholangitis or SBP presenting at or near the time of liver transplantation may lead to intraabdominal infection after the transplant. Herpes simplex infection can also reactivate and cause early symptomatic disease.13 Technical difficulties (ie, thrombosis of the hepatic artery or portal vein, biliary strictures) predispose to early bacterial infections. Likewise, re-exploration of the abdomen is associated with an increased rate of fungal infection.13
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The intermediate period is the typical time of onset for infections associated with donor transmission (either organ or blood products), reactivated viruses, and opportunistic infections. CMV peaks in incidence during this period.8,13 EBV-associated posttransplant lymphoproliferative disorders (PTLD)7 and Pneumocystis carinii pneumonias (PCP)13 also begin to appear at this time.
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Late infections after liver transplantation are less well characterized, because patients have usually been discharged from the transplant center to their homes, often quite far away. Accumulation of accurate data on these late infections is therefore difficult. Nonetheless, problems such as recurrent episodes of bacterial cholangitis (typically associated with underlying problems in the biliary tree) and PTLD22 occur in this time period and usually require the patient to return to the transplant center for definitive diagnosis and management.
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Iatrogenic factors are an important cause of bacterial and fungal infections at all times, but they predominate in the early transplant period. Central venous lines are maintained for a variable duration; the risk of infection persists for the entire time the catheter remains in place. As previously noted, indwelling Foley catheters and endotracheal tubes also increase the risk of infection.
Nosocomial acquisition of community viruses (such as RSV, rotavirus, and influenza A and B) can occur at any time after transplant. These viruses spread easily in hospital environments from personnel or other hospitalized patients to transplant recipients. It is therefore important to modify diagnostic considerations according to local epidemiologic considerations.
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Bacterial and fungal infections are frequent and early problems after liver transplantation.12-14,23,24 Bacterial infection rates of 40 to 70%12-14,23,24 and fungal infection rates of up to 63%24-26 have been reported. Bacteremia is a frequent problem and may be associated with central venous catheters, intraadominal infection, or with no obvious source. Enteric gram-negative organisms account for more than 50% of episodes.6,13,24 Bacterial infection involving the abdomen or wound occurs frequently in most series. Infectious complications of the transplanted liver also occur,27 the most important of which is hepatic abscess, associated with hepatic artery or portal vein thrombosis13 and often accompanied by refractory bacteremia. Urgent retransplantation in addition to antimicrobial therapy is necessary if the patient is to survive.12,23 Percutaneous drainage of the intrahepatic abscess may stabilize the patient prior to retransplantation.15
Another common infection after transplantation is ascending cholangitis, usually associated with biliary abnormalities. This diagnosis is made on clinical grounds in a patient with fever and biochemical evidence of bile duct disease. Empiric antibiotic treatment is chosen to cover enteric gram-negative bacteria and enterococcal species.
Candida is the most common fungal pathogen and is usually associated with intraabdominal or catheter-associated infections. Episodes of invasive aspergillosis occur infrequently but may be fatal.28
Viral infections, especially herpesviruses, are a major source of morbidity and mortality after liver transplantation. CMV accounts for symptomatic infection in up to 22% of adult13 and 40% of pediatric8 liver transplant recipients. Infection may be related to primary acquisition (either from the donor graft or blood products), reactivation of latent infection, or reinfection with a new strain. Primary CMV infection is associated with substantial morbidity and death; it occurs more commonly in pediatric recipients. Reactivation or reinfection occurs frequently in seropositive patients and generally causes no symptoms or mild disease.6 However, the use of heavy immunosuppression, especially with antilymphocyte preparations, may increase the severity of CMV infections, including those occurring in seropositive patients.8,13
Patients with symptomatic CMV disease present with constitutional symptoms of varying severity. The "CMV syndrome" occurs in 25%-50% of patients with symptomatic infection and is characterized by fever, leukopenia, thrombocytopenia, and atypical lymphocytosis. Invasive CMV disease occurs when involvement of the gastrointestinal tract, liver, and/or lung is noted. CMV hepatitis appears to be more common among liver transplant recipients than in recipients of other transplanted organs. Diagnosis of invasive disease is confirmed by tissue biopsy or bronchoalveolar lavage.
Fatal, disseminated CMV disease occurred in 19% of infected children8 and 5% of infected adults in the pre-ganciclovir era.29 The use of ganciclovir has led to an improved outcome of CMV infection in liver transplant recipients.18,30 However, episodes of CMV disease recur in approximately 25% of patients treated with ganciclovir.30 Recurrences appear about one month after primary infection and may be associated with invasive disease. Clinical response usually occurs five to seven days after initiation of therapy. In addition to ganciclovir therapy, we also recommend a reduction in immunosuppression for approximately one week or until the patient shows a clinical response or has evidence of rejection.
EBV and PTLD represent important problems after liver transplantation.7,31-33 PTLD is more common after primary EBV infection, placing seronegative recipients of organs from seropositive donors at higher risk. Several schemas describing the clinical syndromes of PTLD have been proposed,7,22,23 including three distinct presentations: a self-limited form of mononucleosis, a similar syndrome progressing to disseminated lymphoproliferation, and isolated extranodal lymphoma.7 Usually, the first and second syndromes appear within the first year; extranodal lymphoma tends to occur later. Histologic classification schemes generally describe whether the lesions are poly- or monomorphic. Special stains or gene rearrangement studies are used to determine the clonality of PTLD lesions.
The management of PTLD is controversial, but reduction of immunosuppression is recommended.7,22,23 Although widely used, antiviral agents have not been formally studied, and along with monoclonal antibodies, interferon, and chemotherapy, await formal clinical trials to fully determine their impact on PTLD.
Other herpesvirus infections can present serious problems following transplantation. Herpes simplex can reactivate early after surgery or after augmentation of immunosuppression. Prophylaxis with acyclovir has been beneficial in these situations. Varicella in nonimmune transplant recipients can lead to disseminated fatal disease34 and should be treated early and aggressively with intravenous acyclovir.
Other classes of viruses can cause disease, particularly early after transplantation or in naive hosts. Adenovirus was found in 10% of our series of 484 pediatric liver transplant recipients.35 Serious consequences were more likely if infection occurred within three months of the transplant. However, this pathogen is rarely a problem in adult transplant recipients. Respiratory viruses such as influenza, parainfluenza, and RSV led to more severe disease in children early after transplantation and during periods of heavy immunosuppression.36,37
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Pneumocystis carinii is a well documented cause of pneumonia in immunocompromised patients including liver transplant recipients. Prophylactic trimethoprim-sulfamethoxazole is safe, inexpensive, and effective.38 Alternative prophylactic regimens for the sulfa-allergic patient include aerosolized pentamidine (for patients >5 years of age)39 and dapsone.40 This prophylactic strategy has eliminated PCP in liver transplant recipients at our center.
Tuberculosis (TB) is a particular concern in immunosuppressed hosts, including recipients of liver transplants. Although only limited published information is available describing TB in these patients, transplant recipients known to have a positive PPD or who come from an area endemic for TB appear to be at increased risk for symptomatic reactivation after transplantation.41,42 Additional factors predisposing to the development of TB after transplantation include severe hepatic failure at the time of transplant, aggressive anti-rejection therapy, and concurrent HIV infection.41,42 Experience among renal transplant recipients suggests that although the risk appears greatest in patients who received inadequate or no prior TB therapy,43,44 the disease can also occur in patients who received appropriate anti-TB therapy pretransplant.43-45 Current practice at the University of Pittsburgh includes a careful screen for TB by history, and placement of a PPD with anergy panel, along with review of the chest radiograph for lesions consistent with healed TB. Patients with a positive TB history and/or a positive PPD receive isoniazid for 6 to 12 months after transplant, although some experts recommend continuing therapy for the duration of immunosuppressive treatment. Attempts at a more definitive diagnosis are indicated in patients from endemic areas with a negative PPD but a suspicious chest radiograph. Careful evaluation for evidence of side effects, particularly hepatotoxicity, is maintained, and isoniazid is discontinued when unacceptable toxicity supervenes.
Other opportunistic infections include cryptococcosis, coccidioidomycosis, and histoplasmosis. Prior infection with these pathogens is associated with travel or residence in endemic areas. Because patients often travel to transplant centers at a distance from their homes, transplant physicians must be cognizant of the local environmental risks for each patient. Experience with coccidioidomycosis suggests that a minimum of four months of antifungal therapy (with fluconazole, for example) should be given to transplant recipients with a history of coccidioidomycosis.46 Similarities between coccidioidomycosis and other fungal pathogens suggest that the prolonged use of antifungal therapy may be necessary for patients with a history of prior fungal infection with pathogens known to recur after resolution of the primary infection. However, the need for and duration of such therapy has not been proven.
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A pretransplant evaluation is helpful in the management of infectious complications in liver transplant recipients. A complete history and physical examination should be performed with particular attention to previous infections, immunizations, and drug allergies. An intermediate strength tuberculin skin test, along with an anergy panel, should be performed on all patients.
We recommend obtaining serologies for CMV, EBV, varicella, herpes simplex virus, hepatitis A, B, and C, and human immunodeficiency virus on all candidates. Serologic tests on the donor should include HIV, hepatitis B and C, CMV, and EBV. Donors positive for HIV or hepatitis B should be excluded. The use of organs from hepatitis C-positive donors is controversial. Knowledge of donor and recipient status for these viruses allows one to anticipate infection, identify patients who might benefit from prophylactic regimens, and guide the diagnostic evaluation of fever.
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Prophylactic regimens vary widely among transplant centers. These strategies have been divided into perioperative and long-term prophylaxis; our own program has evolved to reflect the infectious complications seen at our institution.
Perioperative prophylaxis is designed to prevent intraoperative sepsis and wound infection. It is based on individual patient characteristics and expected normal flora. If sepsis is suspected in the donor, antibiotics are chosen to cover the organisms identified from the donor, and treatment is usually extended to a therapeutic course of 10 to 14 days.
Long-term prophylaxis against infections occurring beyond the perioperative period depends on several factors: the risk and severity of infection; and the toxicity, cost, and efficacy of a given prophylactic strategy. Nystatin is used in all transplant recipients in an effort to prevent oropharyngeal candidiasis. SMZ/TMP is used to prevent PCP.
The frequency and severity of CMV infection in transplant recipients prompt consideration of prophylactic strategies. Although acyclovir was used initially,47 many centers now use ganciclovir which has greater in vitro activity against CMV. Several centers have also evaluated intravenous immunoglobulin (both high-titer anti-CMV and commercially available products) in the prevention of CMV disease in liver transplant recipients.47-49 Further studies evaluating cost-benefit ratios, dosage, duration, and identification of transplant recipients most likely to benefit are necessary.
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Infections remain an important problem following liver transplantation. Knowledge of the type, timing, and predisposing risk factors for these infectious complications allows for their timely and appropriate diagnosis and management. Further studies, particularly controlled trials to evaluate prophylactic strategies for the prevention of viral (CMV, EBV) and fungal infection, will improve the outcome in these patients.
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