Common infectious complications of liver transplant
ABSTRACTMajor improvements in the care of liver transplant recipients have mitigated but not eliminated the risk of potentially life-threatening infectious complications. This review provides general information about risk factors, prophylactic strategies, diagnostic workup, and therapy for some of the most commonly encountered infections after liver transplant.
KEY POINTS
- After liver transplant, the risk of infection and the likely causal organisms vary with the patient’s state of immunosuppression and the time of infection.
- Recurrent or newly acquired infections may jeopardize the survival of the graft and the recipient.
- Because infections with viruses, fungi, and atypical pathogens can alter the prognosis, they need to be prevented and carefully managed.
- An ongoing assessment of each patient’s risk of infection allows the clinician to constantly and efficiently adapt immunosuppressive, prophylactic, and therapeutic strategies.
TUBERCULOSIS
Development of tuberculosis after transplantation is a catastrophic complication, with mortality rates of up to 30%.65 Most cases of posttransplant tuberculosis represent reactivation of latent disease.66 Screening with tuberculin skin tests or interferon-gamma-release assays is recommended in all liver transplant candidates. Chest radiography before transplant is necessary when assessing a positive screening test.67
The optimal management of latent tuberculosis in these cases remains controversial. Patients at high risk or those with positive screening results on chest radiography warrant treatment for latent tuberculosis infection with isoniazid unless contraindicated.67,68
The ideal time to initiate prophylactic isoniazid therapy is unclear. Some authors suggest delaying it, as it might be associated with poor tolerance and hepatotoxicity.69 Others have found that early isoniazid use was not associated with negative outcomes.70
Risk factors for symptomatic tuberculosis after liver transplant include previous infection with tuberculosis, intensified immunosuppression (especially anti-T-lymphocyte therapies), diabetes mellitus, and other co-infections (Table 1).71
The increased incidence of atypical presentations in recent years makes the diagnosis of active tuberculosis among liver transplant recipients challenging. Sputum smears can be negative due to low mycobacterial burdens, and tuberculin skin testing and interferon-gamma-release assays may be falsely negative due to immunosuppression.67
Treatment of active tuberculosis consists initially of a four-drug regimen using isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months. Adjustments are made in accordance with culture and sensitivity results. Treatment can then be tapered to two drugs (isoniazid and rifampin) for a minimum of 4 additional months. Prolonged treatment may be required in instances of extrapulmonary or disseminated disease.65,72
Tuberculosis treatment can be complicated by hepatotoxicity in liver transplant recipients because of direct drug effects and drug-drug interactions with immunosuppressive agents. Close monitoring for rejection and hepatotoxicity is therefore imperative while liver transplant recipients are receiving antituberculosis therapy. Drug-drug interactions may also be responsible for marked reductions in immunosuppression levels, especially with regimens containing rifampin.71 Substitution of rifabutin for rifampin reduces the effect of drug interactions.66
VIRAL HEPATITIS
Hepatitis B virus
Hepatitis B virus-related end-stage liver disease and hepatocellular carcinoma are common indications for liver transplant in Asia. It is less common in the United States and Europe, accounting for less than 10% of all liver transplant cases. Prognosis is favorable in recipients undergoing liver transplant for hepatitis B virus, with excellent survival rates. Prevention of reinfection is crucial in these patients.
Treatment with combination antiviral agents and hepatitis B immunoglobulin (HBIG) is effective.73 Lamivudine was the first nucleoside analogue found to be effective against hepatitis B virus. Its low cost and relative safety are strong arguments in favor of its continued use in liver transplant recipients.74 In patients without evidence of hepatitis B viral replication at the time of transplant, monotherapy with lamivudine has led to low recurrence rates, and adefovir can be added to control resistant viral strains.75
The frequent emergence of resistance with lamivudine favors newer agents such as entecavir or tenofovir. These nucleoside and nucleotide analogues have a higher barrier to resistance, and thus resistance to them is rare. They are also more efficient, potentially allowing use of an HBIG-sparing protocol.76 However, they are associated with a higher risk of nephrotoxicity and require dose adjustments in renal insufficiency. Data directly comparing entecavir and tenofovir are scarce.
Prophylaxis. Most studies support an individualized approach for prevention of hepatitis B virus reinfection. High-risk patients, ie, those positive for HBe antigen or with high viral loads (> 100,000 copies/mL) are generally treated with both HBIG and antiviral agents.77 Low-risk patients are those with a negative HBe antigen, low hepatitis B virus DNA levels, hepatitis B virus-related acute liver failure, and cirrhosis resulting from coinfection with both hepatitis B and hepatitis D virus.75 In low-risk patients, discontinuation of HBIG after 1 to 2 years of treatment is appropriate, and long-term prophylaxis with antiviral agents alone is an option. However, levels of hepatitis B DNA should be monitored closely.78,79
Hepatitis C virus
Recurrence of hepatitis C virus infection is the rule among patients who are viremic at the time of liver transplant.80,81 Most of these patients will show histologic evidence of recurrent hepatitis within the first year after liver transplant. It is often difficult to distinguish between the histopathological appearance of a recurrent hepatitis C virus infection and acute cellular rejection.
Progression to fibrosis and subsequently cirrhosis and decompensation is highly variable in hepatitis C virus-infected liver transplant recipients. Diabetes, insulin resistance, and possibly hepatitis steatosis have been associated with a rapid progression to advanced fibrosis. The contribution of immunosuppression to the progression of hepatitis C virus remains an area of active study. Some studies point to antilymphocyte immunosuppressive agents as a potential cause.82 Liver biopsy is a useful tool in this situation. It allows monitoring of disease severity and progression and may distinguish recurrent hepatitis C virus disease from other causes of liver enzyme elevation.
The major concern with the recurrence of hepatitis C virus infection after liver transplant is allograft loss. Rates of patient and graft survival are reduced in infected patients compared with hepatitis C virus-negative patients.83,84 Prophylactic antiviral therapy has no current role in the management of hepatitis C virus disease. Those manifesting moderate to severe necroinflammation or mild to moderate fibrosis indicative of progressive disease should be treated.81,85
Sustained viral clearance with antiviral agents confers a graft survival benefit.
The combination of peg-interferon and weight-based ribavirin has been the standard of treatment but may be associated with increased rates of rejection.86,87 The sustained virologic response rates for hepatitis C virus range from 60% in genotypes 4, 5, and 6 after 48 weeks of treatment to 60% to 80% in genotypes 2 and 3 after 24 weeks, but only about 30% in genotype 1.88
Treatment with the newer agents, especially protease inhibitors, in genotype 1 (peg-interferon, ribavirin, and either telaprevir or boceprevir) has been evaluated. Success rates reaching 70% have been achieved.89 Adverse effects can be a major setback. Serious complications include severe anemia, renal dysfunction, increased risk of infection, and death.
Triple therapy should be carefully considered in liver transplant patients with genotype 1 hepatitis C virus.90 Significant drug-drug interactions are reported between hepatitis C virus protease inhibitors and immunosuppression regimens. Additional new oral direct- acting antivirals have been investigated. They bring promising advances in hepatitis C virus treatment and pave the way for interferon-free regimens with pangenotypic activity.
IMMUNIZATION
Immunization can decrease the risk of infectious complications in liver transplant recipients, as well as in close contacts and healthcare professionals.3
Influenza. Pretransplant influenza vaccine and posttransplant annual influenza vaccines are necessary.
Pneumococcal immunization should additionally be provided prior to transplant and repeated every 3 to 5 years thereafter.3,91
A number of other vaccinations should also be completed before transplant, including the hepatitis A and B vaccines and the tetanus/diphtheria/acellular pertussis vaccines. However, these vaccinations have not been shown to be detrimental to patients after transplant.91
Varicella and zoster vaccines should be given before liver transplant—zoster in patients over age 60, and varicella in patients with no immunity. Live vaccines, including varicella and zoster vaccines, are contraindicated after liver transplant.3
Human papillomavirus. The bivalent human papillomavirus vaccine can be given before transplant in females ages 9 to 26; the quadrivalent vaccine is beneficial in those ages 9 to 26 and in women under age 45.3,91
IMMUNOSUPPRESSION CARRIES RISK OF INFECTION
Most liver transplant patients require prolonged immunosuppressive therapy. This comes with an increased risk of new or recurrent infections, potentially causing death and significant morbidity.
Evaluation of existing risk factors, appropriate prophylaxis and immunization, timely diagnosis, and treatment of such infections are therefore essential steps for the successful management of liver transplant recipients.
