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.
EPSTEIN-BARR VIRUS POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE
Epstein-Barr virus-associated posttransplant lymphoproliferative disease is a spectrum of disorders ranging from an infectious mononucleosis syndrome to aggressive malignancy with the potential for death and significant morbidity after liver transplant.29 The timeline of risk varies, but the disease is most common in the first year after transplant.
Risk factors for this disease (Table 1) are:
- Primary Epstein-Barr virus infection
- Cytomegalovirus donor-recipient mismatch
- Cytomegalovirus disease
- Higher levels of immunosuppression, especially with antilymphocyte antibodies.30
The likelihood of Epstein-Barr virus playing a contributing role is lower in later-onset posttransplant lymphoproliferative disease. Patients who are older at the time of transplant, who receive highly immunogenic allografts including a liver as a component of a multivisceral transplant, and who receive increased immunosuppression to treat rejection are at even greater risk of late posttransplant lymphoproliferative disease.31 This is in contrast to early posttransplant lymphoproliferative disease, which is seen more commonly in children as a result of primary Epstein-Barr virus infection.
Recognition and diagnosis. Heightened suspicion is required when considering posttransplant lymphoproliferative disease, and careful evaluation of consistent symptoms and allograft dysfunction are required.
Clinically, posttransplant lymphoproliferative disease should be suspected if a liver transplant recipient develops unexplained fever, weight loss, lymphadenopathy, or cell-line cytopenias.30,32 Other signs and symptoms may be related to the organ involved and may include evidence of hepatitis, pneumonitis, and gastrointestinal disease.31
Adjunctive diagnostic testing includes donor and recipient serology to characterize overall risk before transplantation and quantification of Epstein-Barr viral load, but confirmation relies on tissue histopathology.
Treatment focuses on reducing immunosuppression.30,32 Adding antiviral agents does not seem to improve outcome in all cases.33 Depending on clinical response and histologic classification, additional therapies such as anti-CD20 humanized chimeric monoclonal antibodies, surgery, radiation, and conventional chemotherapy may be required.34
Preventive approaches remain controversial. Chemoprophylaxis with an antiviral such as ganciclovir is occasionally used but has not been shown to consistently decrease rates of posttransplant lymphoproliferative disease. These agents may act in an indirect manner, leading to decreased rates of cytomegalovirus infection, a major cofactor for posttransplant lymphoproliferative disease.24
Passive immunoprophylaxis with immunoglobulin targeting cytomegalovirus has shown to decrease rates of non-Hodgkin lymphoma from posttransplant lymphoproliferative disease in renal transplant recipients in the first year after transplant,35 but data are lacking regarding its use in liver transplant recipients. Monitoring of the viral load and subsequent reduction of immunosuppression remain the most efficient measures to date.36
FUNGAL INFECTIONS
Candida species account for more than half of fungal infections in liver transplant recipients.37 However, a change has been noted in the past 20 years, with a decrease in Candida infections accompanied by an increase in Aspergillus infections.38 Endemic mycoses such as coccidioidomycosis, blastomycosis, and histoplasmosis should be considered with the appropriate epidemiologic history or if disease develops early after transplant and the donor came from a highly endemic region.39Cryptococcus may also be encountered.
Diagnosis. One of the most challenging aspects of fungal infection in liver transplant recipients is timely diagnosis. Heightened suspicion and early biopsy for pathological and microbiological confirmation are necessary. Although available noninvasive diagnostic tools often lack specificity, early detection of fungal markers may be of great use in guiding further diagnostic workup or empiric treatment in the critically ill.
Noninvasive tests include galactomannan, cryptococcal antigen, histoplasma antigen, (1-3)-beta-D-glucan assay and various antibody tests. Galactomannan testing has been widely used to aid in the diagnosis of invasive aspergillosis. Similarly, the (1-3)-beta-D-glucan assay is a non–culture-based tool for diagnosing and monitoring the treatment of invasive fungal infections. However, a definite diagnosis cannot be made on the basis of a positive test alone.40 The complementary diagnostic characteristics of combining noninvasive assays have yet to be fully elucidated.41 Cultures and tissue histopathology are also used when possible.
Treatment is based on targeted specific antifungal drug therapy and reduction of immunosuppressive therapy, when possible. The choice of antifungal agent varies with the pathogen, the site of involvement, and the severity of the disease. A focus on potential drug interactions, their management, and therapeutic drug monitoring when using antifungal medications is essential in the posttransplant period. Combination therapy can be considered in some situations to enhance synergy. The following sections discuss in greater detail Candida species, Aspergillus species, and Pneumocystis jirovecii infections.
Candida infections
Candidiasis after liver transplant is typically nosocomial, especially when diagnosed during the first 3 months (Table 3).37
Risk factors for invasive candidiasis include perioperative colonization, prolonged operative time, retransplant, greater transfusion requirements, and postoperative renal failure.37,42,43 Invasive candidiasis is of concern for its effects on morbidity, mortality, and cost of care.43–46
Organisms. The frequency of implicated species, in particular those with a natural resistance to fluconazole, differs in various reports.37,45,46Candida albicans remains the most commonly isolated pathogen; however, non-albicans species including those resistant to fluconazole have been reported more frequently and include Candida glabrata and Candida krusei.47,48
Signs and diagnosis. Invasive candidiasis in liver transplant recipients generally manifests itself in catheter-related blood stream infections, urinary tract infections, or intra-abdominal infections. Diagnosis can be made by isolating Candida from blood cultures, recovering organisms in culture of a normally sterile site, or finding direct microscopic evidence of the fungus on tissue specimens.49
Disseminated candidiasis refers to the involvement of distant anatomic sites. Clinical manifestations may cause vision changes, abdominal pain or skin nodules with findings of candidemia, hepatosplenic abscesses, or retinal exudates on funduscopy.49
Treatment of invasive candidiasis in liver recipients often involves antifungal therapy and reduction of immunosuppression. Broad-spectrum antifungals are initially advocated in an empirical approach to cover fluconazole-resistant strains of the non-albicans subgroups.50 Depending on antifungal susceptibility, treatment can later be adjusted.
Fluconazole remains the agent of choice in most C albicans infections.47 However, attention should be paid to the possibility of resistance in patients who have received fluconazole prophylaxis within the past 30 days. Additional agents used in treatment may include echinocandins, amphotericin, and additional azoles.
Antifungal prophylaxis is recommended in high-risk liver transplant patients, although its optimal duration remains undetermined.44 Antifungal prophylaxis has been associated with decreased incidence of both superficial and invasive candidiasis.51
Aspergillus infection
Aspergillus, the second most common fungal pathogen, has become a more common concern in liver transplant recipients. Aspergillus fumigatus is the most frequently encountered species.38,52
Risk factors. These infections typically occur in the first year, during intense immunosuppression. Retransplant, renal failure, and fulminant hepatic failure are major risk factors.52 In the presence of risk factors and a suggestive clinical setting, invasive aspergillosis should be considered and the diagnosis pursued.
Diagnosis is suggested by positive findings on CT accompanied by lower respiratory tract symptoms, focal lesions on neuroimaging, or demonstration of the fungus on cultures.49 However, Aspergillus is rarely grown in blood culture. The galactomannan antigen is a noninvasive test that can provide supporting evidence for the diagnosis.41,52 False-positive results do occur in the setting of certain antibiotics and cross-reacting fungi.53
Treatment consists of antifungal therapy and immunosuppression reduction.52
Voriconazole is the first-line agent for invasive aspergillosis. Monitoring for potential drug-drug interactions and side effects is required.54,55 Amphotericin B is considered a second-line choice due to toxicity and lack of an oral formulation. In refractory cases, combined antifungal therapy could be considered.52 The duration of treatment is generally a minimum of 12 weeks.
Prophylaxis. Specific prophylaxis against invasive aspergillosis is not currently recommended; however, some authors suggest a prophylactic approach using echinocandins or liposomal amphotericin B in high-risk patients.51,52 Aspergillosis is associated with a considerable increase in mortality in liver transplant recipients, which highlights the importance of timely management.52,56
Pneumocystis jirovecii
P jirovecii remains a common opportunistic pathogen in people with impaired immunity, including transplant and human immunodeficiency virus patients.
Prophylaxis. Widespread adoption of antimicrobial prophylaxis by transplant centers has decreased the rates of P jirovecii infection in liver transplant recipients.57,58 Commonly used prophylactic regimens after liver transplantation include a single-strength trimethoprim-sulfamethoxazole tablet daily or a double-strength tablet three times per week for a minimum of 6 to 12 months after transplant. Atovaquone and dapsone can be used as alternatives in cases of intolerance to trimethoprim-sulfamethoxazole (Table 2).
Inhaled pentamidine is clearly inferior and should be used only when the other medications are contraindicated.59
Signs and diagnosis. P jirovecii pneumonia is characterized by fever, cough, dyspnea, and chest pain. Insidious hypoxemia, abnormal chest examination, and bilateral interstitial pneumonia on chest radiography are common.
CT may be more sensitive than chest radiography.57 Findings suggestive of P jirovecii pneumonia on chest CT are extensive bilateral and symmetrical ground-glass attenuations. Other less-characteristic findings include upper lobar parenchymal opacities and spontaneous pneumothorax.57,60
The serum (1,3)-beta-D-glucan assay derived from major cell-wall components of P jirovecii might be helpful. Studies report a sensitivity for P jirovecii pneumonia as high as 96% and a negative predictive value of 99.8%.61,62
Definitive diagnosis requires identification of the pathogen. Routine expectorated sputum sampling is generally associated with a poor diagnostic yield. Bronchoscopy and bronchoalveolar lavage with silver or fluorescent antibody staining of samples, polymerase chain reaction testing, or both significantly improves diagnosis. Transbronchial or open lung biopsy are often unnecessary.57
Treatment. Trimethoprim-sulfamethoxazole is the first-line agent for treating P jirovecii pneumonia.57 The minimum duration of treatment is 14 days, with extended courses for severe infection.
Intravenous pentamidine or clindamycin plus primaquine are alternatives for patients who cannot tolerate trimethoprim-sulfamethoxazole. The major concern with intravenous pentamidine is renal dysfunction. Hypoglycemia or hyperglycemia, neutropenia, thrombocytopenia, nausea, dysgeusia, and pancreatitis may also occur.63
Atovaquone might also be beneficial in mild to moderate P jirovecii pneumonia. The main side effects include skin rashes, gastrointestinal intolerance, and elevation of transaminases.64
A corticosteroid (40–60 mg of prednisone or its equivalent) may be beneficial in conjunction with antimicrobial therapy in patients with significant hypoxia (partial pressure of arterial oxygen < 70 mm Hg on room air) in decreasing the risk of respiratory failure and need for intubation.
With appropriate and timely antimicrobial prophylaxis, cases of P jirovecii pneumonia should continue to decrease.
