Infectious Complications After Liver

Transplantation
Maria Del Pilar Hernandez, MD, Paul Martin, MD, and Jacques Simkins, MD

Dr Hernandez is an assistant professor of Abstract: Orthotopic liver transplantation (OLT) is the standard
medicine and Dr Martin is a professor of of care for patients with decompensated cirrhosis and for patients
medicine in the Division of Hepatology at with hepatocellular carcinoma. More than 6000 liver transplants
the University of Miami Miller School of
are performed annually in the United States. High patient and
Medicine in Miami, Florida. Dr Simkins
is an assistant professor of medicine in graft survival rates have been achieved in great part due to the
the Division of Infectious Diseases at availability of potent immunosuppressive agents. Systemic immu-
the University of Miami Miller School of nosuppression has rendered the liver recipient susceptible to
Medicine. de novo infections as well as reactivation of preexisting latent
infections. Infections occurring during the first month post-OLT
Address correspondence to:
are usually nosocomial, donor-derived, or the result of a peri-
Dr Jacques Simkins
1120 NW 14th Street, Room #845 operative complication. The development of opportunistic
Miami, FL 33136 infections (OIs) such as Aspergillus and the reactivation of latent
Tel: 305-243-4598 infections such as Mycobacterium tuberculosis are more frequent
Fax: 305-243-4037 1 to 6 months posttransplant, when the net state of immunosup-
E-mail: [email protected] pression is the highest. Immunosuppressive therapy is tapered 6
to 12 months post-OLT; therefore, infections occurring during that
time period and afterward generally resemble those of the general
population. Screening strategies applied to determine the risk of
an infection after transplantation and the use of prophylactic anti-
microbial therapy have reduced the incidence of OIs after OLT.
This article will review the various causes of infection post-OLT
and the therapies used to manage complications.

T
he increased potency of current immunosuppressive agents
has improved graft and patient survival after orthotopic liver
transplantation (OLT) but has also increased the incidence
of opportunistic infections (OIs), which are the leading cause of mor­
bidity and mortality post-OLT.1 Post-OLT infections are estimated
to occur in more than 50% of OLT recipients.2 Bacterial infections
account for most posttransplant infections (up to 70%), followed by
viral and fungal infections.2,3 Fortunately, due to intensive screening
Keywords
practices to detect latent infections in liver transplant candidates,
Orthotopic liver transplantation, immuno­ and with the implementation of appropriate prophylactic therapy,
suppression, mortality, graft survival, infection mortality associated with post-OLT infections is low (<10%).1,2 The

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 HERNANDEZ ET AL

Table 1. Infectious Disease Workup for Orthotopic Liver treated prior to transplant.5 The detection of an infection in
Transplantation Candidates
the donor does not necessarily preclude organ donation; the
Serologic testing  HBV, HAV, HCV, CMV, EBV, VZV, decision is based on the urgent need for transplantation and
HIV, HTLV-1, RPR  the availability of effective therapies to control the infection
Interferon gamma Tuberculosis (via the QuantiFERON-TB after transplant.6-9 Organ donation has been precluded
release assay Gold In-Tube test or the T-SPOT TB test) if the donor has HIV infection (although donation of an
Testing in select Parasitic infections (eg, strongyloidiasis, HIV-infected organ to HIV+ recipients is being considered)
cases Chagas disease, schistosomiasis), endemic and remains contraindicated if infections such as rabies,
mycoses (eg, coccidioidomycosis, WNV, or lymphocytic choriomeningitis are suspected.5,10
histoplasmosis), and viral infections The timing of a specific infection post-OLT is largely
(eg, WNV)  influenced by the net state of immunosuppression, envi­
CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBV, ronmental exposure to a specific organism, and develop­
hepatitis B virus; HCV, hepatitis C virus; HTLV-1, human T-lymphotropic virus type ment of surgical complications (eg, bile leak, hepatic
1; RPR, rapid plasma reagin; VZV, varicella zoster virus; WNV, West Nile virus.
artery stenosis, biliary strictures). Infections differ during
3 different time periods after liver transplant (<1 month,
risk of infection after OLT is strongly influenced by the 1-6 months, and >6 months post-OLT).2,11 OIs are gener­
net state of immunosuppression.2 Other factors known ally absent during the first month after transplantation
to increase the risk of infections after OLT include a pre­ because the full effect of immunosuppression is not yet
transplant Model for End-Stage Liver Disease (MELD) present. The most common infections in this period
score greater than 30, need for a second operation after are nosocomial infections, surgery-related infections
OLT, posttransplant renal replacement therapy (RRT), (eg, wound infections, cholangitis, peritonitis), donor-
and an intensive care unit (ICU) stay longer than 48 derived infections, or recipient-derived infections from
hours.3 It is standard of care to obtain a good patient his­ being colonized with pathogens such as Pseudomonas
tory, perform a thorough physical examination, and order aeruginosa.2,11,12 During the period from 1 to 6 months
a comprehensive infectious disease workup (Table 1) in post-OLT, SOT recipients can develop OIs such as asper­
all solid organ transplant (SOT) candidates.3,4 These steps gillosis, cryptococcosis, or toxoplasmosis. Infections due
allow the clinician to identify active infections that would to Pneumocystis jirovecii or herpesviruses (Cytomegalovirus
require therapy prior to transplantation, latent infections [CMV], Epstein-Barr virus [EBV], herpes simplex virus,
that can reactivate after transplantation, and the need and varicella zoster virus [VZV]) are less likely to appear in
for vaccinations to reduce the risk of de novo infections transplant patients receiving prophylaxis. Viral pathogens
after transplant.3,4 Extended screening for specific infec­ and allograft rejection cause the majority of febrile epi­
tions such as endemic mycoses, West Nile virus (WNV), sodes during this period.9 The late posttransplant period
Chagas disease, and strongyloidiasis is recommended in (after 6 months) is typically associated with a reduced
areas where the organisms that cause these infections are frequency of infections. OIs are almost exclusively seen
endemic (Table 1).3-5 in patients with ongoing rejection that require intensifi­
Due to hepatocellular dysfunction, cirrhotic patients cation of immunosuppressive therapy. For patients with
are at increased risk of infections, including spontaneous stable disease post-OLT, infections resemble those seen in
bacterial peritonitis (SBP), cholangitis, pneumonias, uri­ the general population. The recurrence of chronic infec­
nary tract infections (UTIs), and catheter-related blood­ tions such as EBV, hepatitis C virus (HCV), and hepatitis
stream infections.5 Increased hospitalization rates among B virus (HBV) is also seen during this time period.1-4 
patients with decompensated liver disease also predispose To reduce the risk of infections among OLT recipi­
patients to nosocomial infections, including Clostridium ents, the AASLD recommends that all liver transplant
difficile infection (CDI).5 According to guidelines from candidates receive vaccination to avoid preventable dis­
the American Association for the Study of Liver Diseases eases such as hepatitis A virus, HBV, measles, mumps,
(AASLD), only uncontrolled sepsis and AIDS in the organ rubella, and VZV. Live virus vaccines are not recom­
recipient preclude OLT. However, HIV-infected patients mended following transplantation; if indicated, they
who have a CD4 count greater than 100/µL and a viral should be administered no earlier than 4 weeks prior to
load that is expected to be completely suppressed at the SOT.4 The AASLD also recommends the administration
time of OLT have been considered eligible for transplant.4 of vaccines for diphtheria, tetanus, and pertussis; influ­
According to the American Society of Transplantation enza; and pneumococcus prior to OLT.4 Other measures
(AST), mycobacterial and invasive fungal infections, as well aimed at reducing the risk of infections after OLT include
as strongyloidiasis, are associated with high mortality after antimicrobial prophylaxis, which is described in detail in
SOT. Therefore, it is recommended that these infections be the next section.

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Table 2. Risk Factors Associated With Bacterial Infections complications such as hepatic artery thrombosis and biliary
After Orthotopic Liver Transplantation
strictures increase the risk of cholangitis.17,19-21
Older age Over the past 15 years, there has been an increased
Length of preoperative stay incidence of infections caused by multidrug-resistant
organisms (MDROs).22-32 These infections are common
CMV infection
and cause high mortality rates among OLT recipients.13,22-24
Duration of surgery Extended use of preoperative broad-spectrum antibiotics,
Retransplantation preoperative fecal carriage, surgical reexploration, and a
Volume of transfused blood products MELD score greater than 25 are known to increase the
Preoperative MELD and CTP scores
risk of posttransplant infections with MDROs.22,23
Chronic use of quinolones for SBP prophylaxis has
Bilioenteric anastomosis
led to a decrease in infections caused by enteric gram-
Technical complications (eg, biliary leak, HAT)  negative bacteria, but an increase in Staphylococcus aureus
Renal replacement therapy colonization and subsequent methicillin-resistant S aureus
Hyperglycemia (MRSA) infections after OLT.24-27 A high prevalence of
CMV, Cytomegalovirus; CTP, Child-Turcotte-Pugh; HAT, hepatic artery
MRSA infections among OLT recipients has been docu­
thrombosis; MELD, Model for End-Stage Liver Disease. mented.24,26,27 Nearly one-third of all MRSA infections
Adapted from Sun HY et al3 and Kim SI.13 occur within 14 days of transplantation. MRSA infections
appear to increase the mortality risk after OLT.24,27 Mor­
tality rates have been reported as high as 86% among
Bacterial Infections patients with MRSA bacteremia and MRSA-related
abdominal infections.27 Parallel to an increase in MRSA,
Bacterial organisms are the leading cause of infection the emergence of vancomycin-resistant enterococci
post-OLT, with an incidence that ranges from 53% to (VRE) has been widely documented as an important
70%.2,13 Although infections can occur at any time after pathogen in OLT recipients.25,31 Several studies have also
liver transplant, their incidence is highest during the first reported a high prevalence of extended-spectrum beta-
postoperative month due to factors such as alteration of lactamase (ESBL)-producing Enterobacteriaceae infec­
the mucocutaneous barrier and the use of invasive devices tions in SOT recipients.26,30 The most commonly isolated
and immunosuppression.2,12,13 It is believed that OLT ESBL-­producing species are Klebsiella pneumoniae and
recipients are more susceptible to bacterial infections than Escherichia coli. The reported incidence of post-OLT
any other SOT recipients, in part due to the complexity ESBL infections is 5.5% to 7%.26
of the surgical procedure involved.13 Antimicrobial agents Colonization with K pneumoniae carbapenemase
that provide coverage for skin flora, Enterococcus species, (KPC)-producing bacteria after OLT has been reported
anaerobic organisms, and Enterobacteriaceae are routinely with increased frequency.28,32 More than 50% of patients
used as prophylactic treatments in the immediate postop­ colonized with KPC will present with bacteremia.
erative period. The effect of pretransplant infections on Reported mortality rates associated with KPC infections
the incidence and severity of posttransplant infections has are as high as 89%.28 The most common therapeutic
been investigated and has shown conflicting results.14,15 options for patients with KPC infection are colistin (poly­
It is well known that SBP is the most common infection myxin E), a known nephrotoxic agent, and tigecycline,
among patients awaiting liver transplantation, followed which is usually not effective for bacteremia.28
by bloodstream infections, cellulitis, pneumonia, and Despite the increased incidence of infections caused
UTIs.16,17 However, pretransplant infections are not asso­ by MDROs after OLT, the use of broad-spectrum
ciated with a reduced patient or graft survival post-OLT.18 prophylactic antimicrobial agents with activity against
The most common risk factors for bacterial infections MRSA and other MDROs varies by transplant center.17,21
post-OLT are listed in Table 2.3,13 Selective bowel decontamination remains a controversial
Bacterial colonization during the perioperative period approach to the prevention of infections in critically ill
results in same-pathogen infections among some OLT patients awaiting OLT. A meta-analysis of OLT recipients
recipients. Factors directly associated with liver transplanta­ showed that while selective bowel decontamination did
tion that contribute to the risk of infection include the devel­ not lead to a reduction in the overall incidence of infec­
opment of ischemia-reperfusion injury or issues directly tions, it significantly reduced gram-negative bacterial
related to the graft (eg, steatosis).1,2,4,17,18 The amount of infections.33 There has been an increased interest on the
blood transfused intraoperatively is directly correlated with effect of chronic rifaximin (Xifaxan, Salix) therapy and the
the risk of infection immediately after OLT. Postsurgical incidence of infections after OLT. A retrospective study

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performed in 2012 showed that pretransplant rifaximin Fungal Infections

use appeared to reduce early infections post-OLT among
patients with severe liver disease (MELD score >30).34 Invasive fungal infections (IFIs) are a major cause of mor­
Finally, CDI is a major problem in SOT recipients. bidity and mortality among OLT recipients,2,36 although
Fulminant colitis is more frequent in SOT recipients than the overall incidence of IFIs after SOT has decreased in
in the general population (13% vs 8%, respectively).35 The recent years. The annual cumulative incidence of IFIs
incidence of CDI is estimated to be 3% to 19% in OLT is 1.9% among SOT recipients.37-39 IFIs occur in 5%
recipients (incidence <1% in the general population).35 to 42% of OLT recipients and are associated with an
The incidence of CDI in SOT recipients is higher during increased mortality rate. Candidiasis (60%-80%) and
the first 3 months after transplant, which is explained by aspergillosis (1%-8%) are the most common mycoses,
the increased antimicrobial exposure, intense immunosup­ with associated mortality rates of 30% to 50% and 65%
pression, and more frequent hospitalizations. Exposure to 90%, respectively.2,37-40 IFIs are more common in OLT
to antimicrobial agents has continued to be the most recipients who require surgical reexploration or retrans­
important risk factor associated with the development of plantation and in those who receive transfusions of large
CDI.35 Selection of the antimicrobial agent to treat CDI is amounts of blood products. Retransplantation confers a
largely based on the severity of the infection.35 For patients 30-fold increased risk of IFIs.41-43 Other factors associated
with mild to moderate infection, oral metronidazole is with the development of IFIs include the preoperative use
the drug of choice. Patients with severe CDI are recom­ of broad-spectrum antibiotics, pretransplant diagnosis
mended to receive oral vancomycin 125 mg every 6 hours. of fulminant hepatic failure, CMV or HCV infection,
In cases of severe CDI complicated with reduced gastroin­ creatinine level greater than 3 mg/dL, long ICU stay, and
testinal motility, an increased dose of vancomycin (up to surgical time greater than 11 hours.40-43
500 mg every 6 hours), the addition of intravenous (IV) The increased mortality associated with IFIs is in
metronidazole, or the use of vancomycin rectal enemas are part attributed to delayed diagnosis and historically
frequently used to increase chances for response. limited therapeutic options.40-43 Diagnosis relies on the
identification of suggestive signs and symptoms, as well
Reducing Bacterial Infections After Liver as on laboratory isolation of the causative microorganism.
Transplantation  Laboratory identification of a fungal pathogen is difficult
Prophylactic antimicrobial therapy is universally used because some fungi have slow growth, and others can
in the immediate posttransplant period to reduce the be colonizers in the absence of disease (eg, Candida).43-49
incidence of bacterial infections. The selection of an An overall reduction in the incidence of IFIs after OLT
appropriate antimicrobial agent is typically guided by the is believed to be the result of improved surgical methods
local epidemiology. Transplant prophylactic antibiotics and techniques as well as advances in immunosuppressive
should not be used beyond 48 hours posttransplantation. therapy that has led to the limited use of corticosteroids
Prolonged use of broad-spectrum antibiotics without after transplant.40-45 Furthermore, the rapid initiation of
evidence of an active infection is always discouraged.13-15 antifungal therapy when IFIs are suspected has also reduced
The use of broad-spectrum antimicrobials suppresses nor­ mortality rates among patients with fungal infections.45,46     
mal gastrointestinal flora and increases stool concentra­
tion of VRE, which increases the susceptibility for VRE Antifungal Prophylaxis  
acquisition and subsequent infection. Moreover, the use Antifungal prophylaxis in SOT recipients remains a com­
of broad-spectrum antimicrobial agents increases the risk plex and controversial issue. A targeted prophylactic strat­
of MRSA colonization and CDI.22,23,26 Other preventive egy is used to prevent fungal infections.43-46 Fluconazole
measures recommended to reduce the risk of infections and echinocandins are both used for targeted prophylaxis,
post-OLT include the implementation of a strict hand but the latter have become the leading choice as they have
hygiene regimen among all medical personnel. Isolation fungicidal activity, prevent against fluconazole-resistant
and contact precautions are recommended for all patients Candida species, and have no interaction with calcineurin
with a history of colonization or infection of MDROs. inhibitors (CNIs).37 Candidates for targeted antifungal
Gloves and gowns should be worn at all times when enter­ prophylaxis include patients with a prolonged and com­
ing the patient’s room.22-26,32,35 Other interventions aimed plicated liver transplant surgery, patients who received
at reducing the risk of posttransplant bacterial infections multiple blood products, and patients with renal insuffi­
include limiting invasive devices such as urinary catheters ciency requiring RRT.2,36 In high-risk patients, antifungal
for a minimum period of time22,23 and decolonization of prophylaxis is recommended for 7 to 14 days after SOT.47 
patients colonized with MRSA, which can  decrease the The use of antifungal prophylaxis in high-risk patients
incidence of postoperative S aureus infections.24 has reduced the incidence of fungal infections, but has

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not led to improvement in overall mortality in most airborne spores that result in pulmonary infection, with
series.37-39 In a meta-analysis of 10 trials of antifungal pro­ extrapulmonary dissemination to the central nervous
phylaxis that included 1106 OLT recipients, fluconazole system and virtually any other organ.47 Extrapulmonary
prophylaxis decreased IFIs by 75%, but did not reduce dissemination is common, appearing in 50% to 60% of
mortality.45 Echinocandins appear to have an acceptable cases of Aspergillus infection. Isolation of Aspergillus from
safety profile44 and prevent IFIs in more than 90% of the respiratory secretions of patients who are not immu­
OLT recipients. In the absence of any form of antifungal nosuppressed usually indicates colonization, but its pres­
prophylaxis, invasive mycoses typically occur in 36% to ence in transplant recipients should not be ignored unless
50% of high-risk OLT recipients.44-49    invasive disease can be excluded.48,49 The diagnosis of
aspergillosis can be difficult. When Aspergillus infection is
Candida suspected, a computed tomography scan of the chest can
Candidiasis is the most frequent fungal infection encoun­ help in the diagnosis, as invasive pulmonary aspergillosis
tered post-OLT and is the leading cause of IFIs. Candida can manifest early as a nodular opacity with surround­
albicans is the most common isolated species, followed by ing attenuation (halo sign).48,49 Molecules that have been
Candida glabrata and Candida tropicalis. Risk factors for used as diagnostic markers of Aspergillus infection include
invasive candidiasis include the use of prophylactic anti­ galactomannan and beta-D-glucan.47-49 The galactoman­
biotics to prevent SBP, the need for RRT postoperatively, nan test is an enzyme-linked immunosorbent assay that
and retransplantation. CMV infection is a clear risk factor detects galactomannan, an antigen released from hyphae
for all types of invasive candidal infections, and effective upon host tissue invasion.47-49 Beta-D-glucan is another
CMV prophylaxis among high-risk patients has been surrogate marker of IFIs. Glucan is the most important
shown to significantly decrease the incidence of invasive and abundant polysaccharide component of the fungal
Candida infection. Routine use of fluconazole prophylaxis cell wall.47-49
is associated with an increased occurrence of infections Aspergillus infection is seen more frequently among
with Candida species other than C albicans (eg, C glabrata patients who experience retransplantation and patients
and Candida krusei).42-46 Treatment of invasive Candida who require RRT.48,49 A study conducted at a large trans­
infections in OLT recipients should reflect the type and plant center showed that 25% of patients with invasive
severity of Candida infection and its susceptibilities, as aspergillosis had undergone liver retransplantation, 82%
well as the comorbid conditions of the patient.42    of whom required hemodialysis at the onset of infection.
Fluconazole remains an appropriate treatment Infection with CMV is also known to increase the risk of
choice for mild to moderate candidemia. All azoles show invasive aspergillosis.47-49 The risk of invasive aspergillosis
significant drug-drug interactions, especially with CNIs. is highest during the first 30 days following retransplan­
Careful monitoring of the levels of CNIs is recommended tation; 53% of all Aspergillus infections occur within this
while patients are on azoles.  Echinocandins have time period. Therefore, some transplant centers recom­
proven to be effective and safe when used to treat IFIs mend beginning antifungal prophylaxis during this high-
among OLT recipients. Echinocandins are the agents risk period.47-49 The mortality risk associated with Asper-
of choice for severe candidemia or infections caused by gillus infection has been reported to be as high as 92%.
azole-resistant Candida species.42,44 Other interventions Due to high mortality rates associated with this infection,
recommended in patients with candidemia include it is recommended that empiric antifungal therapy be
the removal of all central venous catheters and the initiated with any clinical suspicion of aspergillosis.47-49
administration of a fundoscopic eye examination to Voriconazole is the recommended drug of choice because
exclude endophthalmitis.44  Therapy is recommended it has been shown to lead to better responses, improved
for 2 weeks after the first negative blood culture. The survival, and fewer severe side effects when compared to
extension of therapy is recommended when candidemia amphotericin B.50
is complicated by endocarditis or endophthalmitis.44    Combination therapy with voriconazole and echino­
candins is reserved for refractory aspergillosis.47-49 
Aspergillus
Aspergillus is the second most common fungal infection Cryptococcus 
observed post-OLT, accounting for approximately one- Cryptococcus infection is not commonly seen post-OLT.2
fourth of IFIs.47-49 According to reports, infection occurs Symptoms caused by cryptococcal infection develop at
at a median of 17 days posttransplantation. Aspergillus a mean of 30 months after transplant. Posttransplant
infection is characterized by angioinvasion, resulting in cryptococcal infection can manifest as pneumonia (46%),
tissue infarcts that limit the eradication of infection with isolated meningitis (36%), disseminated disease (11%),
antifungal therapy. Disease is caused by the inhalation of and, less frequently, involvement of another single organ

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(eg, lymph node; 7%). The mortality rate associated with infection or reactivation of prior infection.55 Transmission
this infection is reported to be as high as 25% among from an infected liver allograft has also been reported.57
transplant recipients. Cryptococcal infection can be However, histoplasmosis is rare in SOT recipients.55,58
diagnosed by isolation of the fungus in blood. Detec­ SOT recipients with mild to moderate infection can
tion of the serum cryptococcal antigen is helpful for the be treated with itraconazole, and for those with mod­
diagnosis of meningitis or disseminated disease, but lacks erately severe and severe infection, initial therapy with
sensitivity in the diagnosis of cryptococcal pneumonia.51 amphotericin B is recommended. Treatment is usually
Patients without overt central nervous system symptoms continued until stabilization of the infection, followed
should undergo lumbar puncture because of the possibil­ by de-escalation to itraconazole to complete a total of 12
ity of subclinical meningitis.51 Cryptococcal meningitis months.55 Itraconazole decreases the metabolism of CNIs,
is treated with a combination of amphotericin B and and mammalian target of rapamycin inhibitors and levels
flucytosine for 2 weeks, followed by fluconazole 400 to need to be monitored on therapy. Pretransplant screen­
800 mg/day for 8 weeks, and fluconazole 200 to 400 mg/ ing for prior histoplasmosis infection in endemic areas is
day for 6 to 12 months.51 Maintenance treatment can be usually not recommended based on the low chances for
extended in some patients based on their net status of subsequent infection.59 
immunosuppression.51 
  Coccidioidomycosis
Pneumocystis jirovecii Coccidioidomycosis is endemic in parts of South and Cen­
P jirovecii is an opportunistic pathogen that can cause tral America, as well as in the southwestern region of the
a severe form of pneumonitis in SOT recipients.1,2 The United States.55,60 Coccidioidomycosis is caused by Coccidi-
incidence of P jirovecii pneumonia (PJP) is reported to be oides immitis and Coccidioides posadasii; in OLT recipients,
as high as 10% during the first 6 months after transplan­ coccidioidomycosis can result from primary infection or
tation in the absence of prophylaxis.52 Treatment with cor­ reactivation of prior infection, although donor-derived coc­
ticosteroids, CNIs, and sirolimus may initially suppress cidioidomycosis has also been reported.55,61 SOT recipients
some of the early clinical findings, including dyspnea and are more likely to develop severe pneumonia and dissemi­
hypoxemia, which can lead to delay in the diagnosis of nated infection.55 Cutaneous, osteoarticular, and central
this infection.2 The risk of PJP is higher during periods of nervous systems are the most common extrapulmonary
increased immunosuppression (acute rejection). Prophy­ sites.55 In a large study from Arizona, 4% of the OLT
lactic therapy with trimethoprim (TMP)-sulfamethoxa­ recipients developed coccidioidomycosis, mostly during
zole (SMX) has been shown to be safe and effective against the first year posttransplant. One-third of the patients had
PJP in OLT recipients. It is well known that the incidence disseminated disease, and the mortality rate was 13%.60
of P jirovecii declines after the first year in SOT patients.52 Fluconazole or itraconazole is usually used to treat mild to
Thus, prophylaxis beyond the first year should be targeted moderate coccidioidomycosis, amphotericin B is used to
only at patients receiving treatment for allograft rejection. treat severe pneumonia or disseminated infection, and pro­
Of note, TMP-SMX may not only prevent PJP, but may phylactic antifungal therapy is recommended for all SOT
also prevent infections by Toxoplasma gondii and Listeria recipients with a history of coccidioidomycosis or positive
species, as well as common respiratory, skin, urinary, and Coccidioides serologies.55 Prophylaxis is recommended for 6
gastrointestinal pathogens.37 If TMP-SMX cannot be to 12 months post-OLT.60 
used (due to intolerance or allergy), alternative treatments
include pentamidine, clindamycin-primaquine, TMP- Blastomycosis 
dapsone, and atovaquone.52-54 Blastomycosis is caused by Blastomyces dermatitidis,
and it is endemic in the midwestern, southeastern, and
Endemic Mycoses  south central regions of the United States.55 It has also
been reported in Canada and Africa.62 Blastomycosis can
Histoplasmosis  present as a primary infection or reactivation of prior
Histoplasmosis is caused by Histoplasma capsulatum and infection.55 Cases transmitted by donors have not been
is found in different areas such as South America, India, reported. SOT recipients are more likely to present with
and Bangladesh.55 Within the United States, H capsulatum severe pulmonary or disseminated infection. Therefore,
is endemic in the Ohio and Mississippi River valleys.55,56 amphotericin B is considered the drug of choice.
Any organ can be affected by H capsulatum, but the most Itraconazole can be used for mild infection, but close
common clinical findings are pneumonia, hepatospleno­ clinical monitoring is required.55 Blastomycosis is rare
megaly, gastrointestinal involvement, and pancytopenia.55 after SOT; therefore, primary or secondary antifungal
In OLT recipients, histoplasmosis can result from primary prophylaxis after OLT is not recommended.55

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Tuberculosis patients.73 Sixty-seven percent of OLT recipients had

extrapulmonary involvement in 1 study.74 The standard
It is estimated that one-third of the world’s population treatment recommended for active tuberculosis is a
has latent tuberculosis infection (LTBI).63 SOT recipi­ 4-drug regimen of isoniazid, rifampin, pyrazinamide, and
ents are at significant risk for tuberculosis reactivation, ethambutol for the first 2 months, followed by isoniazid
as they are up to 74 times more likely to develop active and rifampin for an additional 4 months. Ethambutol can
tuberculosis as compared to the general population.64 be discontinued if the M tuberculosis isolate is susceptible to
Therefore, screening for LTBI prior to SOT with tuber­ isoniazid, rifampin, and pyrazinamide. Fluoroquinolones
culin skin testing (TST) or the quantiFERON-TB Gold are useful antituberculosis agents in OLT recipients
In-Tube test (Quest Diagnostics) is the standard of care.64 with poor hepatic function. Despite known drug-drug
A thorough clinical evaluation should be performed to interactions with CNIs, a rifamycin-containing regimen
rule out active tuberculosis before the initiation of LTBI is strongly preferred given its potent sterilizing activity.64
treatment. Therapeutic options for LTBI include isonia­ Rifampin is usually replaced by rifabutin, which is
zid daily for 9 months, isoniazid/rifapentine weekly for associated with fewer drug-drug interactions. The
12 weeks, and rifampin daily for 4 months.64 Isoniazid- treatment duration should be longer than 6 months for
containing regimens are effective approximately 90% of bone and joint disease, central nervous system disease,
the time.65,66 The treatment completion rate for 9-month severe disseminated disease, and for patients with cavitary
isoniazid therapy is low (45%-60%).67 Therefore, the lesions in whom sputum cultures are still positive at the
shorter regimens of rifampin and isoniazid/rifapentine completion of 2 months of treatment.64 OLT recipients
are appealing; however, they should not be continued should be monitored closely, as 50% of them may develop
after OLT because of drug-drug interactions with CNIs. drug-induced hepatotoxicity during treatment for active
Isoniazid monotherapy for 9 months is the preferred tuberculosis.74 Compared with the general population,
regimen for patients who are likely to undergo a liver OLT recipients with active tuberculosis have a 4-fold
transplant within the next few months.64 Isoniazid-related increase in the case-fatality rate.74 In terms of prevention,
hepatotoxicity in patients with compensated cirrhosis is all SOT candidates should be evaluated for LTBI and
uncommon.68 The data on isoniazid/rifapentine therapy treated if testing is positive.64 Organs from potential
in OLT candidates are limited to 1 small study in which donors with active tuberculosis disease should not be used.
treatment was completed in the majority of patients, and Living donors should also be tested for LTBI. Treating
none developed significant transaminase elevations or living donors for LTBI prior to organ donation should
clinical hepatotoxicity.69 LTBI treatment can also begin be considered, especially for recent TST or interferon
after OLT, depending on the patient’s risk for LTBI treat­ gamma release assay converters.64
ment-induced hepatotoxicity and for progression to active  
tuberculosis. OLT candidates and recipients should have Nontuberculous Mycobacteria 
their transaminases checked every 2 weeks for the first 6 Most nontuberculous mycobacteria (NTM) are ubiqui­
weeks of treatment and then monthly.64 LTBI treatment tous free-living saprophytic organisms.75 The number of
should be stopped with a 3-fold increase in transaminases NTM species has significantly increased over time.76 Infec­
plus signs and symptoms of hepatotoxicity, or a 5-fold tions develop following exposure in the environment,
elevation without symptoms and signs.70 although nosocomial infections of water-contaminated
Active tuberculosis in SOT recipients is usually medical devices have also been reported.75 Because NTM
the result of LTBI reactivation, which typically occurs infections are not reportable, the real incidence of NTM
during the first year after SOT.64 Donor-derived active infections is uncertain, although it was estimated to be
tuberculosis has also been reported; however, it accounts 0.04% in OLT recipients.77 In a case series of 34 SOT
for less than 5% of cases.64 A study from Spain reported recipients, including 4 OLT patients, the median time
an active tuberculosis incidence of 512 cases per 100,000 to NTM disease was 8 months posttransplant. The most
patients per year among SOT recipients.71 This incidence common pathogens were Mycobacterium abscessus and
is suspected to be higher in countries where tuberculosis Mycobacterium avium complex, and pleuropulmonary
is endemic. Compared with the general population, OLT disease was the most common presentation, followed
recipients have an 18-fold increase in the prevalence by disseminated disease.78 Also reported in the literature
of active tuberculosis.72 The clinical picture of active are skin, soft tissue, musculoskeletal, catheter-associated,
tuberculosis can be different in SOT, as 33% to 50% and lymphadenitis infection sites.79,80 A multidrug regi­
of all active tuberculosis cases after transplantation men is recommended for 3 months to 2 years (depend­
are disseminated or extrapulmonary, compared with ing on the type of infection) to treat NTM infections.
approximately 15% of cases in immunocompetent Two-drug therapy can be used; however, 3 agents are

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 HERNANDEZ ET AL

recommended when the illness is life-threatening, the phosphoprotein 65 antigen every week for 12 weeks after
burden of organisms is high, or the patient has a rapidly OLT, and if a positive result is obtained, treatment with
growing mycobacteria whose identification and suscep­ valganciclovir or IV ganciclovir is indicated.85 In the event
tibilities are not yet known.77 Surgery may be required of treatment for allograft rejection with antilymphocyte
to treat localized infections because NTM infections therapy or high-dose corticosteroids, the reinitiation of
may persist despite antimycobacterial therapy.77 Second­ antiviral prophylaxis is recommended.
ary prophylaxis after completion of NTM treatment is  
sometimes used. However, it is not recommended by the Epstein-Barr Virus 
AST due to the lack of data.77 Primary EBV infection is uncommon in the general adult
population in the United States, as more than 80% of
Viral Infections individuals at age 19 are seropositive.87 Therefore, the
majority of OLT recipients have already been infected at
Cytomegalovirus  the time of transplantation. EBV can also be transmitted
CMV is the most common viral infection that influences to OLT recipients from seropositive donors and blood
outcomes after OLT.81 The risk of infection is strongly transfusions when nonleukoreduced blood products are
dependent on the serologic status of both the organ donor used.88 EBV infection can lead to posttransplant lym­
and the recipient. In the study by Singh and colleagues,82 phoproliferative disease (PTLD) in SOT recipients.88
CMV infection resulted in 85% of donor-positive/ The most common risk factors for PTLD after OLT are
recipient-negative OLT patients, 33% of donor-positive EBV-seronegativity in the recipient age 18 years or older,
or -negative/recipient-positive OLT patients, and 4% of the degree of immunosuppression, and the first year post­
donor-negative/recipient-negative OLT patients. CMV transplant. PTLD can occur in up to 3% of adults and
usually occurs during the first 3 months after OLT.83 The 15% of pediatric OLT recipients.89 Some of the prognos­
incidence of CMV infection for OLT (donor-positive/ tic factors for poor PTLD are high-grade, monoclonal,
recipient-negative) decreases to approximately 30% and multisite, EBV-negativity; graft or central nervous system
15% with 3 months and 6 months of CMV prophylactic involvement; coinfection with HBV or HCV; and poor
treatment, respectively.84 CMV syndrome accounts for performance status.87-89 Mortality has been reported to
over 60% of CMV diseases after OLT, and it is usually be as high as 50%.89 Treatment options are immunosup­
manifested by fever, malaise, and bone marrow suppres­ pression reduction, rituximab (Rituxan, Genentech) for
sion.84 Less frequently, CMV may manifest as a tissue- CD20-positive PTLD cases, and chemotherapy.90 Local
invasive disease (eg, colitis, enteritis, esophagitis, gastritis, control (surgical resection and radiotherapy) can be useful
hepatitis, pneumonitis, encephalitis, retinitis).84 CMV for localized liver PTLD.89 Antiviral medications such as
can also cause indirect effects, such as allograft rejection, ganciclovir and acyclovir have been used as part of the
vanishing bile duct syndrome, chronic ductopenic rejec­ treatment for early PTLD.88 SOT recipients at high risk
tion, HCV recurrence, and allograft hepatitis. In addition, for PTLD should be monitored carefully for symptoms
CMV has immunomodulatory effects, which can make and signs of PTLD such as fever, lymphadenopathy,
patients more susceptible to developing OIs.84 The reduc­ diarrhea, allograft dysfunction, weight loss, and spleno­
tion of immunosuppression should be considered in SOT megaly.88 PTLD can be prevented by reducing immuno­
patients with moderate to severe CMV disease.85 IV ganci­ suppression in patients with a high EBV viral load; in 1
clovir is preferred in patients with severe or life-threatening study, the incidence of PTLD decreased from 16% to 2%
disease. Valganciclovir is frequently used as a step-down in pediatric OLT recipients.91
treatment when clinical symptoms have resolved after an  
initial course with IV ganciclovir.84 The duration of treat­ Varicella Zoster Virus 
ment for induction has varied from 2 to 4 weeks based VZV infection can present as chickenpox or herpes zoster
on clinical and virologic response.86 After completion of (HZ). VZV infection has a low likelihood for organ dis­
induction treatment, 1 to 3 months of maintenance treat­ semination among OLT recipients.92-96 OLT recipients
ment is recommended to prevent relapse.85 In terms of with chickenpox, disseminated HZ, organ-invasive disease,
prevention, antiviral prophylaxis for 3 to 6 months is rec­ HZ ophthalmicus, or Ramsay-Hunt syndrome should be
ommended for donor-positive/recipient-negative patients treated with IV acyclovir, and localized nonsevere derma­
after OLT. Antiviral prophylaxis for 3 months or preemp­ tomal HZ can be treated with valacyclovir or famciclovir
tive therapy are both accepted for recipient-positive OLT in an outpatient setting.97 Acyclovir, valacyclovir, and fam­
recipients.84 Valganciclovir and oral and IV ganciclovir ciclovir can be used for short-term treatment after OLT to
can be used for antiviral prophylaxis.84 Preemptive therapy prevent VZV reactivation in patients who are not receiving
consists of checking CMV polymerase chain reaction or CMV prophylaxis.97

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Herpes Simplex Virus  Parvovirus B19 

Herpes simplex virus hepatitis has been reported in Parvovirus B19 (PVB19) infection is a common illness
OLT recipients. It appears to occur very early in the of childhood.105 PVB19 is usually transmitted via respi­
posttransplant course (20±12 days), suggesting early ratory secretions, but it can also be transmitted through
reactivation of the virus because of immunosuppressive transplantation. In immunocompetent patients, PVB19
drugs or donor-acquired primary infection.96 The clinical can cause erythema infectiosum in children and acute
presentations are usually nonspecific (eg, fever, highly symmetric polyarthropathy in adults. Anemia is present
abnormal liver function test results without jaundice, in 99% of immunocompromised patients with PVB19
right superior quadrant abdominal pain, leukopenia), and infection.105 In 1 study, pure red cell anemia was reported
mucocutaneous lesions are seen in less than one-third of in 8 OLT recipients, all of whom improved with intra­
OLT patients. Early diagnosis and treatment are essential venous immunoglobulin (IVIG).106 PVB19 should be
to improve survival.98  Prophylaxis with acyclovir is suspected in OLT recipients with erythropoietin-resistant
recommended for the first 3 months after OLT in patients anemia. PVB19 can also cause pancytopenia, hepatitis,
not receiving CMV prophylaxis. myocarditis, pneumonitis, neurologic disease, or vasculi­
  tis.105 IVIG is recommended for treatment, although the
Human Herpesvirus 6  optimal dosing and duration have not been established.
Primary infection with human herpesvirus 6 (HHV-6)
usually occurs during the first 2 years of life; most patients Parasitic Infections
are asymptomatic or might present with fever followed
by a maculopapular rash (exanthema subitum).99 HHV-6 Strongyloidiasis
infection after OLT is usually caused by viral reactivation, Approximately 100 million people worldwide have
transmission from the transplanted allograft or blood strongyloidiasis.107 SOT patients with latent infection
products, or through natural transmission in children are at risk for hyperinfection syndrome and disseminated
who have never been exposed.99 HHV-6 infections typi­ disease, both of which are associated with high
cally occur during the first 2 to 8 weeks after OLT, when mortality.108,109 Donor-derived infections have also been
the level of immunosuppression is most intense.99 OLT reported.110 Strongyloidiasis can present with acute and
recipients with HHV-6 can present with a febrile illness severe abdominal disease, bloody diarrhea, intestinal
(sometimes associated with rash), myelosuppression, obstruction, gastrointestinal hemorrhage, pulmonary
pneumonitis, neurologic diseases, and hepatitis.99-101 involvement, bacterial sepsis, or bacterial meningitis
HHV-6 can predispose OLT recipients to certain infec­ due to gram-negative rods or Enterococcus species, and it
tions such as CMV.99 HHV-6 hepatitis is commonly asso­ is most likely to occur in the initial months after SOT
ciated with acute rejection.100 Ganciclovir, cidofovir, and when immunosuppression is higher.108 Ivermectin is the
foscarnet have been used for the treatment of HHV-6– drug of choice, as it has an efficacy greater than 90%.111
associated diseases.99 The administration of 2 doses of ivermectin given 2 weeks
  apart is recommended by the AST for uncomplicated
Adenovirus  strongyloidiasis; for hyperinfection syndrome and
In immunocompetent patients, adenovirus is usually disseminated disease, daily doses of ivermectin should be
associated with self-limited respiratory, gastrointestinal, or administered until parasitic clearance, and then for 7 to
conjunctival disease; however, in immunocompromised 14 days afterward to prevent relapse.108
patients, adenovirus can cause severe and disseminated
infections.102 Adenovirus infections can be acquired de Toxoplasmosis
novo, through reactivation of a latent infection, or from It is estimated that 30% to 50% of the world population
the transplanted organ.103 In 1 study, the incidence of ade­ is infected with T gondii.112 Its prevalence in the United
novirus infection in adult OLT recipients was 6%.104 Four States is 10% to 20%.113 The majority of infected patients
patients (36%) were asymptomatic, 3 patients (27%) had have latent toxoplasmosis.112 Toxoplasmosis in OLT
UTIs, 3 patients (27%) had pneumonia and disseminated recipients can occur through contaminated food, cat
disease, and 1 patient (9%) had fulminant hepatitis.104 exposure, infected allograft, or  reactivation of latent infec­
The mean time to the initial detection of adenovirus was tion.108 In a matched case-control study by Fernàndez-
2.2 months posttransplantation.104 The most important Sabé and colleagues, the most common manifestations
component of therapy is supportive care and a decrease in of toxoplasmosis for OLT recipients were pneumonitis,
immunosuppression. IV cidofovir is considered the drug myocarditis, and brain abscesses.114 The time to diagnosis
of choice for the treatment of severe, progressive, or dis­ was approximately 3 months posttransplantation, and
seminated adenovirus.103 the crude mortality rate was 14%.114 The recommended

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 HERNANDEZ ET AL

treatment for active toxoplasmosis in SOT patients is AE are typically symptomatic, with the most common
pyrimethamine/leucovorin and sulfadiazine for at least symptoms being malaise, weight loss, and right upper
6 weeks followed by chronic suppressive therapy.108 quadrant discomfort.108 OLT is usually considered for
Universal screening for OLT candidates is recommended patients with AE who have hilar involvement, recurrent
only in high-prevalence areas.108 The recommended biliary infections, secondary biliary cirrhosis, or lesions
duration of prophylactic treatment with TMP/SMX is that invade the hepatic veins and the inferior vena cava.
uncertain for OLT recipients.108 AE has been reported in parts of central Europe, central
   Asia, China, the northwestern portion of Canada, and
Chagas Disease  western Alaska.119 AE is difficult to treat post-OLT, as only
Chagas disease is endemic in most Latin American coun­ approximately half of the patients who receive antipara­
tries, as approximately 9 million people are currently sitic treatment for residual AE have favorable responses.120
infected with this disease.108 OLT recipients can become OLT candidates can receive livers with CH as long as the
infected with Trypanosoma cruzi from contaminated feces livers have a single and calcified cyst with no biliary tree
of a triatomine insect vector, or by receiving blood or involvement that is amenable for resection without dam­
organs from T cruzi–infected donors.108,115 The transmis­ aging the main vascular and biliary structures.121
sion rate from seropositive donors to seronegative OLT
recipients is approximately 20%.115 Chagas cardiomyopa­ Summary
thy should also be considered in the differential diagnosis
of patients who develop cardiac complications after liver Comprehensive pretransplant infectious diseases workup,
transplantation when there is positive epidemiology for immunizations, and perioperative and prophylactic anti­
Chagas disease.116 Patients who are not treated for acute microbials are vital to decrease the rate of infections after
Chagas disease may become chronically infected, and OLT. Early diagnosis and treatment of infections are usu­
one-third will become symptomatic (2/3 with chagasic ally associated with improved outcomes.
cardiomyopathy and 1/3 with megacolon and mega­
esophagus).117 Liver transplant programs are allowed to The authors have no relevant conflicts of interest to disclose.
use livers from T cruzi–infected donors with informed
consent from recipients, although it is recommend to References 
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63. Lönnroth K, Raviglione M. Global epidemiology of tuberculosis: prospects for Epstein-Barr virus infection in U.S. children ages 6-19, 2003-2010. PLoS One.
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