Common infectious complications of liver transplant

THE IMMUNOSUPPRESSED STATE of liver transplant recipients makes them vulnerable to infections after surgery.¹ These infections are directly correlated with the net state of immunosuppression. Higher levels of immunosuppression mean a higher risk of infection, with rates of infection typically highest in the early posttransplant period.

Common infections during this period include operative and perioperative nosocomial bacterial and fungal infections, reactivation of latent infections, and invasive fungal infections such as candidiasis, aspergillosis, and pneumocystosis. Donor-derived infections also must be considered. As time passes and the level of immunosuppression is reduced, liver recipients are less prone to infection.¹

The risk of infection can be minimized by appropriate antimicrobial prophylaxis, strategies for safe living after transplant,² vaccination,³ careful balancing of immunosuppressive therapy,⁴ and thoughtful donor selection.⁵ Drug-drug interactions are common and must be carefully considered to minimize the risk.

This review highlights common infectious complications encountered after liver transplant.

INTRA-ABDOMINAL INFECTIONS

Intra-abdominal infections are common in the early postoperative period.^6,7

Risk factors include:

• Pretransplant ascites
• Posttransplant dialysis
• Wound infection
• Reoperation⁸
• Hepatic artery thrombosis
• Roux-en-Y choledochojejunostomy anastomosis.⁹

Signs that may indicate intra-abdominal infection include fever, abdominal pain, leukocytosis, and elevated liver enzymes. But because of their immunosuppressed state, transplant recipients may not manifest fever as readily as the general population. They should be evaluated for cholangitis, peritonitis, biloma, and intra-abdominal abscess.

Organisms. Intra-abdominal infections are often polymicrobial. Enterococci, Staphylococcus aureus, gram-negative species including Pseudomonas, Klebsiella, and Acinetobacter, and Candida species are the most common pathogens. Strains are often resistant to multiple drugs, especially in patients who received antibiotics in the weeks before transplant.^8,10

Liver transplant recipients are also particularly susceptible to Clostridium difficile-associated colitis as a result of immunosuppression and frequent use of antibiotics perioperatively and postoperatively.¹¹ The spectrum of C difficile infection ranges from mild diarrhea to life-threatening colitis, and the course in liver transplant patients tends to be more complicated than in immunocompetent patients.¹²

Diagnosis. Intra-abdominal infections should be looked for and treated promptly, as they are associated with a higher mortality rate, a greater risk of graft loss, and a higher incidence of retransplant.^6,10 Abdominal ultrasonography or computed tomography (CT) can confirm the presence of fluid collections.

Treatment. Infected collections can be treated with percutaneous or surgical drainage and antimicrobial therapy. In the case of biliary tract complications, retransplant or surgical correction of biliary leakage or stenosis decreases the risk of death.⁶

Suspicion should be high for C difficile-associated colitis in cases of posttransplant diarrhea. C difficile toxin stool assays help confirm the diagnosis.¹² Oral metronidazole is recommended in mild to moderate C difficile infection, with oral vancomycin and intravenous metronidazole reserved for severe cases. Colectomy may be necessary in patients with toxic megacolon.

CYTOMEGALOVIRUS INFECTION

Cytomegalovirus is an important opportunistic pathogen in liver transplant recipients.¹³ It causes a range of manifestations, from infection (viremia with or without symptoms) to cytomegalovirus syndrome (fever, malaise, and cell-line cytopenias) to tissue-invasive disease with end-organ disease.¹⁴ Without preventive measures and treatment, cytomegalovirus disease can increase the risk of morbidity, allograft loss and death.^15,16

Risk factors for cytomegalovirus infection (Table 1) include:

• Discordant serostatus of the donor and recipient (the risk is highest in seronegative recipients of organs from seropositive donors)
• Higher levels of immunosuppression, especially when antilymphocyte antibodies are used
• Treatment of graft rejection
• Coinfection with other human herpesviruses, such as Epstein-Barr virus.^4,17

Preventing cytomegalovirus infection

The strategy to prevent cytomegalovirus infection depends on the serologic status of the donor and recipient and may include antiviral prophylaxis or preemptive treatment (Table 2).¹⁸

Prophylaxis involves giving antiviral drugs during the early high-risk period, with the goal of preventing the development of cytomegalovirus viremia. The alternative preemptive strategy emphasizes serial testing for cytomegalovirus viremia, with the goal of intervening with antiviral medications while viremia is at a low level, thus avoiding potential progression to cytomegalovirus disease. Both strategies have pros and cons that should be considered by each transplant center when setting institutional policy.

A prophylactic approach seems very effective at preventing both infection and disease from cytomegalovirus and has been shown to reduce graft rejection and the risk of death.¹⁸ It is preferred in cytomegalovirus-negative recipients when the donor was cytomegalovirus-positive—a high-risk situation.¹⁹ However, these patients are also at higher risk of late-onset cytomegalovirus disease. Higher cost and potential drug toxicity, mainly neutropenia from ganciclovir-based regimens, are additional considerations.

Preemptive treatment, in contrast, reserves drug treatment for patients who are actually infected with cytomegalovirus, thus resulting in fewer adverse drug events and lower cost; but it requires regular monitoring. Preemptive methods, by definition, cannot prevent infection, and with this strategy tissue-invasive disease not associated with viremia does occasionally occur.²⁰ As such, patients with a clinical presentation that suggests cytomegalovirus but have negative results on blood testing should be considered for tissue biopsy with culture and immunohistochemical stain.

The most commonly used regimens for antiviral prophylaxis and treatment in liver transplant recipients are intravenous ganciclovir and oral valganciclovir.²¹ Although valganciclovir is the most commonly used agent in this setting because of ease of administration, it has not been approved by the US Food and Drug Administration in liver transplant patients, as it was associated with higher rates of cytomegalovirus tissue-invasive disease.^22–24 Additionally, drug-resistant cytomegalovirus strains have been associated with valganciclovir prophylaxis in cytomegalovirus-negative recipients of solid organs from cytomegalovirus-positive donors.²⁵

Prophylaxis typically consists of therapy for 3 months from the time of transplant. In higher-risk patients (donor-positive, recipient-negative), longer courses of prophylaxis have been extrapolated from data in kidney transplant recipients.²⁶ Extension or reinstitution of prophylaxis should also be considered in liver transplant patients receiving treatment for rejection with antilymphocyte therapy.

Routine screening for cytomegalovirus is not recommended while patients are receiving prophylaxis. High-risk patients who are not receiving prophylaxis should be monitored with nucleic acid or pp65 antigenemia testing as part of the preemptive strategy protocol.

Treatment of cytomegalovirus disease

Although no specific threshold has been established, treatment is generally indicated if a patient has a consistent clinical syndrome, evidence of tissue injury, and persistent or increasing viremia.

Treatment involves giving antiviral drugs and also reducing the level of immunosuppression, if possible, until symptoms and viremia have resolved.

The choice of antiviral therapy depends on the severity of disease. Intravenous ganciclovir (5 mg/kg twice daily adjusted for renal impairment) or oral valganciclovir (900 mg twice daily, also renally dose-adjusted when necessary) can be used for mild to moderate disease if no significant gastrointestinal involvement is reported. Intravenous ganciclovir is preferred for patients with more severe disease or gastrointestinal involvement. The minimum duration of treatment is 2 weeks and may need to be prolonged until both symptoms and viremia completely resolve.¹⁸

Drug resistance can occur and should be considered in patients who have a history of prolonged ganciclovir or valganciclovir exposure who do not clinically improve or have persistent or rising viremia. In such cases, genotype assays are helpful, and initiation of alternative therapy should be considered. Mutations conferring resistance to ganciclovir are often associated with cross-resistance to cidofovir. Cidofovir can therefore be considered only when genotype assays demonstrate specific mutations conferring an isolated resistance to ganciclovir.²⁷ The addition of foscarnet to the ganciclovir regimen or substitution of foscarnet for ganciclovir are accepted approaches.

Although cytomegalovirus hyperimmunoglobulin has been used in prophylaxis and invasive disease treatment, its role in the management of ganciclovir-resistant cytomegalovirus infections remains controversial.²⁸