LIVER TRANSPLANTATION 14:1389-1399, 2008

T.H.E. CORNER

Immunizations and Infectious Diseases in

Pediatric Liver Transplantation
Natasha Halasa1 and Michael Green2
1
Division of Infectious Diseases, Vanderbilt University, Nashville, TN; and 2Division of Infectious Diseases,
Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA

Received April 14, 2008; accepted July 1, 2008.

Liver transplantation (LTx) is an established and effec- Pretransplant Factors

tive treatment for children with end-stage and meta-
bolic liver disease. Improved surgical techniques and
immunosuppressive regimens have led to enhanced
short-term and long-term survival rates, which now
approach or exceed 90%. Consequently, more children
are being referred for LTx, and an increasing numbers
of pediatric centers routinely perform this procedure.
Infectious complications are an important cause of
morbidity and mortality in children undergoing LTx.
However, improvements in immune suppression man-
agement along with the availability of new antimicrobial
agents and diagnostic tools have resulted in improved
treatment and preventative regimens, thus reducing
the impact of infectious complications on these chil-
dren. This review provides an overview of the infectious
complications and prevention strategies for children
undergoing LTx.
FACTORS PREDISPOSING TO INFECTION
LTx is associated with a set of technical and medical
conditions that predispose to infectious complications.
The abdomen is a common site of infection in patients
undergoing this procedure.1 This is almost certainly
due to the occurrence of local ischemic injury and
bleeding as well as potential 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 posttrans-
plant activities.
The underlying illnesses leading to transplantation may
be associated with intrinsic risk factors for infection.
Disorders that require palliative surgery, which in-
creases the technical difficulty of the transplant, may
be associated with an enhanced risk of developing post-
transplant infections.3 For example, children undergo-
ing LTx for biliary atresia may have previously under-
gone a Kasai procedure (choledocojejunostomy), which
may predispose to recurrent episodes of bacterial
cholangitis prior to transplantation, increasing the like-
lihood of colonization with multiple antibiotic–resistant
bacteria, which can cause infection following trans-
plantation. Similarly, children undergoing LTx for cys-
tic fibrosis may have an increased risk of developing
invasive aspergillosis if they were colonized with this
pathogen prior to transplant. Complications of end-
stage liver disease may also predispose to infection after
transplant. A history of 1 or more episodes of sponta-
neous bacterial peritonitis pre-transplant in patients
with ascites has been associated with an increased rate
of bacterial infections after LTx.4
Age, another important pretransplant factor, is a ma-
jor determinant of susceptibility to certain pathogens,
severity of expression of infection, and immune matu-
ration. Young children undergoing LTx may experience
moderate to severe infection with certain viral [eg, re-
spiratory syncytial virus (RSV)] or bacterial (coagulase-
negative staphylococci) pathogens versus the more mild
illness experienced by adult recipients infected with

Abbreviations: CMV, cytomegalovirus; DTaP, diphtheria, tetanus, and acellular pertussis vaccine; EBV, Epstein-Barr virus; HHV6,
human herpesvirus 6; HHV7, human herpesvirus 7; HiB, Haemophilus influenzae type B vaccine; LTx, liver transplantation; MMR,
measles, mumps, and rubella vaccine; MPV, meningococcal polysaccharide vaccine; PCP, Pneumocystis jirovecii pneumonia; PCR,
polymerase chain reaction; PCV7, 7-valent pneumococcal conjugate vaccine; PPV23, pneumococcal polysaccharide vaccine; PTLD,
posttransplant lymphoproliferative disease; RSV, respiratory syncytial virus; TB, tuberculosis.
Address reprint requests to Michael Green, M.D., M.P.H., Division of Infectious Diseases, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue,
Pittsburgh, PA 15213. Telephone: 412-692-6111; FAX: 412-629-6116; E-mail: michael.green@chp.edu
DOI 10.1002/lt.21605
Published online in Wiley InterScience (www.interscience.wiley.com).

© 2008 American Association for the Study of Liver Diseases.

1390 HALASA AND GREEN
these pathogens. In contrast, other pathogens, such as
Cryptococcus neoformans, uncommonly manifest infec-
tion before young adulthood.5 Age is also an important
factor governing the clinical expression of infection with
cytomegalovirus (CMV) and Epstein-Barr virus (EBV).
When transplants are performed in young patients,
there is a high likelihood that they will be seronegative
for CMV and EBV and therefore susceptible to primary
infections, which are more severe than infections due to
reactivation.6,7
Donor-related issues represent another set of pre-
transplant factors. Transplant recipients are at risk for
acquiring infections that may be active or latent within
the donor organ. The best described examples of donor-
associated infections are CMV and EBV.8,9 Although
the frequency of some donor-associated pathogens (eg,
human immunodeficiency virus, hepatitis B, and hep-
atitis C) have decreased substantially with better diag-
nostic screening tests,10 recent evidence now demon-
strates donor-associated transmission of West Nile
virus and rabies.11,12 Because organs from a single
donor often go to disparate sites, it is important for the
recipient center to report back to the United Network for
Organ Sharing any unusual infections that might pos-
sibly have come from the donor.
Intraoperative Factors
Operative factors may predispose to infectious complica-
tions. For example, LTx recipients undergoing Roux-en-Y
choledocoduodenostomy experience more infectious epi-
sodes than those who undergo a choledochocholedocho-
stomy with T-tube drainage.13,14 However, only the
former option is usually performed in children because of
the small size of their bile ducts or because of require-
ments associated with technical variants of LTx (eg, split,
reduced, and living donor organs). A prolonged operative
time (⬎12 hours) during the transplant has been associ-
ated with an increased risk of infection13,15 and is likely a
surrogate marker for the technical difficulty of the sur-
gery. Intraoperative events, such as contamination of the
operative field, also predispose to postoperative infec-
tions. Finally, the inability to close the abdomen after
transplantation appears to increase the risk for postoper-
ative infections. This circumstance tends to occur more
frequently when larger grafts are placed in smaller chil-
dren.
Posttransplant Factors
Technical problems, immunosuppression, the presence
of indwelling cannulas, and nosocomial exposures are
the major posttransplant factors predisposing to infec-
tious complications. Hepatic artery thrombosis is the
most serious technical problem following LTx, predis-
posing to areas of necrotic liver and the development of
hepatic abscesses and bacteremia.14,16 Bile duct stric-
tures, developing as sequelae of a thrombosed hepatic
artery and ischemia or because of technical difficulties,
may predispose to cholangitis.16
Immunosuppression is the critical posttransplant
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
factor predisposing to infection in transplant recipi-
ents. Immunosuppressive regimens have evolved in an
attempt to achieve more specific control of rejection
with the least impairment of immunity. Thus, this evo-
lution is aimed not only at improved control of rejection
but also at decreased morbidity and mortality from in-
fections. The use of cyclosporine-based regimens has
resulted in a decreased incidence of infections in renal
and cardiac transplant recipients.1,17,18 The introduc-
tion of tacrolimus has allowed many patients to be
managed without steroids.19,20 The use of tacrolimus in
LTx recipients has been associated with an apparent
decrease in morbidity and mortality, especially from
viral pathogens, in comparison with recipients receiv-
ing cyclosporine.19,21 Although some centers have re-
ported an increased rate of EBV-associated posttrans-
plant lymphoproliferative disease (PTLD) in patients
receiving tacrolimus,22 data from the University of
Pittsburgh suggest that the short-term and long-term
incidence of PTLD is similar in pediatric LTx recipients
treated with either cyclosporine or tacrolimus.23
The treatment of rejection with additional or higher
doses of immunosuppressants increases the risk of an
invasive and potentially fatal infection. Of particular
concern is the use of anti-lymphocyte preparations,
especially OKT3.6,13,15 Newer anti-lymphocyte antibod-
ies (eg, Thymoglobulin®) are also likely to be associated
with an increased risk of infection.
The prolonged use of indwelling cannulas at any site
is an important cause of bacterial and fungal infections
throughout the postoperative course. The presence of
central venous catheters is associated with bacteremia,
whereas the development of urinary tract infections
and bacterial pneumonia are associated with the use of
urethral catheters and prolonged nasotracheal or en-
dotracheal intubation, respectively.13,15
Nosocomial exposures constitute the final group of
postoperative risk factors. Children undergoing LTx
may be exposed to many common viral pathogens (eg,
rotavirus and RSV) while in the hospital. Uncommonly,
they are also at risk of exposure to transfusion-associ-
ated pathogens (eg, hepatitis B, hepatitis C, and CMV).
Finally, the presence in the hospital of heavy areas of
contamination with pathogenic fungi, such as aspergil-
lus, may increase the risk of invasive fungal disease in
these patients. The rate of fungal colonization increases
during times of hospital reconstruction. Therefore, in-
fection control policies to limit exposure to these patho-
gens are warranted.
TIMING OF INFECTIONS
The time of onset of infection with various pathogens
after transplantation tends to be predictable. The ma-
jority of clinically important infections occur within the
first 180 days following transplantation.13,19 The tim-
ing of infections can be divided into 3 intervals: early
(0-30 days after transplantation), intermediate (30-180
days after transplantation), and late (greater than 180
days after transplantation). In addition, some infections
may occur throughout the postoperative course. These

divisions, while arbitrary, are generally useful in ap-
proaching a patient with fever after transplantation and
can be used as a guide to differential diagnoses.
Early Infections (0-30 Days)
Early infections tend to be associated with pre-existing
conditions and surgical manipulation. In general, they
are caused by either bacteria or yeast. As many as half
of these early infections develop in the first 2 weeks
following LTx.24 Cholangitis or spontaneous bacterial
peritonitis presenting at or near the time of transplan-
tation may lead to intra-abdominal infection after the
transplant. Herpes simplex infection can also reactivate
and cause early symptomatic disease,13 although this
is uncommon in children. Technical difficulties (eg,
thrombosis of the hepatic artery or portal vein and
biliary strictures) predispose to early bacterial infec-
tions. Likewise, the development of bile leaks and bowel
perforations are associated with polymicrobial intra-
abdominal infections in the first month after LTx.25
Finally, re-exploration of the abdomen is associated
with increased rates of fungal infection.13
Intermediate Period (31-180 Days)
The intermediate period is the typical time of onset of
donor-related infections, reactivated viruses, and op-
portunistic infections. The peak incidence of CMV in-
fection occurs in this period.6,13 However, the use of
CMV prophylaxis has resulted in shifting the time of
presentation of CMV disease so that some patients will
present with this infection after 180 days. The interme-
diate period is also when patients begin to present with
EBV-associated PTLD7 and Pneumocystis jirovecii
pneumonia (PCP).13
Late Infections (⬎180 Days)
Late infections after LTx are less well characterized
than infections of other periods because patients have
usually been discharged from the transplant center to
their respective homes, which are often quite far away.
This makes the accurate accumulation of data on these
late infections difficult. Nonetheless, problems such as
recurrent episodes of bacterial cholangitis (in patients
with underlying problems of the biliary tree) and
PTLD26 occur in this time period. In addition, the use of
CMV prophylaxis may delay the onset of CMV disease to
the late period.27 Finally, it is important to remember
that these children are at risk for common community-
acquired infections.
Infections Occurring Throughout the
Postoperative Course
Iatrogenic factors are important causes of bacterial and
fungal infections at all times but predominate in the
early transplant period. The use of central venous lines,
urethral catheters, and endotracheal tubes increases
the risk of infections whenever they are in use. Nosoco-
mial acquisition of community viruses, such as RSV,
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
T.H.E. CORNER 1391
rotavirus, and influenza, can occur at any time after
transplantation. These viruses, which can have differ-
ent manifestations and severity in immunocompro-
mised children, spread easily in hospital environments.
It is therefore important to modify diagnostic consider-
ations according to local epidemiologic considerations.
BACTERIAL AND FUNGAL INFECTIONS
Bacterial and fungal infections are a common early
problem after LTx.28-31 Rates for bacterial infection of
40% to 70% have been reported.13,14,19 Bacteremia of-
ten occurs in association with intra-abdominal infec-
tion or with the use of central venous catheters. Enteric
gram-negative organisms account for more than one-
half of episodes. Bacterial infections involving the ab-
domen or surgical wound are common in most series.
Infectious complications of the transplanted liver also
occur. The most important complication is hepatic ab-
scess associated with hepatic artery or portal vein
thrombosis, which is often accompanied by persistent
bacteremia. However, the use of frequent surveillance
Doppler studies early after transplant to monitor for the
development of thrombosis, coupled with the use of
operative thrombectomy and thrombolysis, has signifi-
cantly reduced the development of hepatic abscesses in
this population.
Ascending cholangitis is common after LTx and is
usually associated with biliary abnormalities. This di-
agnosis typically is made on clinical grounds in a pa-
tient with fever and biochemical evidence of biliary in-
flammation. Because this clinical picture can be
identical to that of acute graft rejection, a liver biopsy
should be performed to differentiate these processes.
Outbreaks of colonization and disease due to multi-
ple antibiotic–resistant bacteria are increasingly com-
mon among liver transplant recipients. Examples of
multiple antibiotic–resistant bacteria include vancomy-
cin-resistant Enterococcus faecium, extended spectrum
beta-lactamase–producing Klebsiella pneumoniae, and
Enterobacter cloacae.32-34 These resistant bacteria can
be transmitted from patient to patient, and this should
prompt the imposition of strict infection control proce-
dures. The increasing prevalence of these resistant or-
ganisms limits the therapeutic options available for the
treatment of bacterial infections following LTx.
As many as 40% of children undergoing LTx may
develop a fungal infection during their first year follow-
ing this procedure.30 Candida spp. are the most com-
mon fungal pathogens, and infection usually is associ-
ated with an intra-abdominal focus or indwelling
catheter. Candida infections are most commonly recog-
nized in the first month following transplantation, with
Candida peritonitis most likely presenting in the first 2
weeks post-LTx in association with a bile leak or bowel
perforation. Additional risk factors for Candida infec-
tions include prolonged duration of intubation after
transplantation, hepatic artery thrombosis, a high vol-
ume of blood transfused, and exposure to steroids and
antibiotics. The recovery of Candida from a Jackson-
Pratt drain in the early postoperative period may occur
1392 HALASA AND GREEN
prior to the onset of clinical symptoms of intra-abdom-
inal infection.25 Such a recovery should prompt initia-
tion of antimicrobial therapy and an aggressive evalu-
ation of the presence of the source of the infection. Early
initiation of treatment is particularly important, given
an attributable mortality rate of up to 33% for Candida
infections in pediatric liver transplant recipients.25 The
availability of fluconazole and the newer echinocandin
antifungal agents (eg, caspofungin and micofungin) has
increased the number of therapeutic options for Can-
dida infections. However, resistance to the azoles is an
increasing concern, as are drug-drug interactions be-
tween azoles and echinocandins with both cyclosporine
and tacrolimus.
Episodes of invasive aspergillosis are uncommon but
can be fatal.35 Children undergoing LTx for cystic fibro-
sis are at particular risk of developing infection due to
aspergillus.35 A history of recovery of aspergillus prior
to transplant should prompt the use of antifungal pro-
phylaxis in liver recipients with cystic fibrosis. Data
defining the precise duration of prophylaxis are not
available, and prophylactic treatment has ranged from
1 month of intravenous amphotericin to prolonged use
of an oral azole agent (ie, voriconazole).
VIRAL INFECTIONS
Viral pathogens, especially herpesviruses, are a major
source of morbidity and mortality after LTx. The fre-
quency, mode of presentation, and relative severity of
these infections can differ according to the intensity of
immunosuppression and the serologic status of the re-
cipient.
CMV
CMV is one of the most common and important viral
pathogens following LTx in children. CMV infection can
be asymptomatic or symptomatic and may be due to
primary infection (either from the donor graft or blood
products), reactivation of latent infection, or superin-
fection with a different CMV strain in a previously se-
ropositive child. Prior to the use of prophylaxis, the
incidence of symptomatic CMV infection was reported
to be as high as 40% in these patients.8 Use of ganci-
clovir prophylaxis has resulted in a decreased rate and
severity of CMV disease.36 Primary CMV infection, typ-
ically acquired from the donor organ (or donor leuko-
cytes that accompany the organ), is associated with the
greatest degree of morbidity and mortality.6,36 Accord-
ingly, CMV-seronegative recipients of organs from
CMV-seropositive donors are considered at high risk of
developing CMV disease. Reactivation of CMV or super-
infection with CMV tends to result in milder illness.6
Patients treated with unusually high doses of immuno-
suppressants, especially anti-lymphocyte antibody
preparations, experience an increased rate of CMV dis-
ease, regardless of previous immunity.8,13
Symptomatic CMV disease typically presents be-
tween 1 and 3 months after transplantation. However,
the use of prophylactic regimens may delay the onset of
CMV disease. A characteristic constellation of fever and
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
hematologic abnormalities (including leukopenia, atyp-
ical lymphocytosis, and thrombocytopenia) is fre-
quently seen. This CMV syndrome occurs in 25% to
50% of patients with symptomatic CMV infection. Inva-
sive CMV disease is manifested by visceral organ in-
volvement; common sites include the liver, gastrointes-
tinal tract, and lungs, with hepatitis being the most
common among LTx recipients.
The diagnosis of CMV disease may be confirmed by a
positive culture, pp65 antigenemia assay,37 and/or
CMV DNA polymerase chain reaction (PCR) in a patient
with a compatible clinical syndrome.38 However, clini-
cians must be aware that the results of viral cultures of
the urine and even bronchoalveolar lavage specimens
may be difficult to interpret in previously infected pa-
tients because CMV is frequently shed asymptomati-
cally in these secretions. Similarly, the presence of
pp65 antigen and CMV DNA in the blood can be mis-
leading, as these assays are often positive in asymp-
tomatic patients. Although a quantitative determina-
tion of the CMV load improves specificity, a histologic
examination of potentially involved organs to confirm
the presence of CMV is critical when the diagnosis of
invasive CMV is being entertained.
Antiviral agents with activity against CMV have dra-
matically improved the survival of transplant recipients
with CMV disease. Fatal, disseminated CMV disease
occurred in 19% of infected children8 undergoing LTx in
the preganciclovir era. Currently, mortality attributable
to CMV rarely occurs in these patients. CMV disease is
treated with ganciclovir in conjunction with reduction
of immunosuppression unless evidence of rejection is
present. Clinical response usually occurs 5 to 7 days
after initiation of therapy. Baseline immunosuppres-
sion levels are typically restored at the time of initial
clinical response or upon recognition of rejection.
Treatment with ganciclovir is usually continued until
the CMV viral load is nondetectable.39,40 The role of
CMV hyperimmune globulin in combination with gan-
ciclovir in the treatment of CMV disease is controver-
sial, although some evidence for improved outcome has
been reported in the treatment of CMV pneumonia in
adult liver transplant recipients.41 Finally, because of
drug-associated nephrotoxicity, the use of foscarnet
and cidofovir should be restricted to only patients with
apparent or proven resistance to ganciclovir.
EBV
EBV infection is an important cause of morbidity and
mortality following pediatric LTx.7,42-44 Symptomatic
EBV disease most commonly occurs among patients
experiencing primary EBV infection. Accordingly, chil-
dren undergoing transplantation are disproportion-
ately affected by EBV in comparison with their adult
counterparts.45 As many as 80% of children who are
EBV-seronegative prior to LTx will develop a primary
EBV infection following this procedure; however, clini-
cal disease develops in less than one-third of these
children.46,47
A wide spectrum of EBV diseases are recognized, in-

cluding nonspecific viral illness, mononucleosis, and
PTLD (including lymphoma). Asymptomatic serocon-
version also occurs. Variation in the severity and extent
of disease is related to the degree of immunosuppres-
sion and adequacy of the host immune response. Al-
though EBV disease and PTLD may present with in-
volvement of many different clinical sites, there is a
tendency for involvement of the transplanted organ.
Thus, hepatic involvement is common among LTx re-
cipients. The onset of viral syndrome, mononucleosis,
and PTLD occur primarily within the first year, whereas
lymphoma tends to present later. Immunosuppressive
regimens based on the use of tacrolimus appear to have
affected a shift in the timing of PTLD; only rare cases
occur more than 18 months after transplantation.44,48
The diagnosis of EBV-associated PTLD is made on the
basis of clinical, laboratory, and histopathologic exam-
ination and should be suspected in patients with pro-
tracted fever, exudative tonsillitis, lymphadenopathy,
organomegaly, leukopenia, or atypical lymphocyto-
sis.49,50 Gastrointestinal involvement should be sus-
pected in patients with persistent fever and diarrhea. In
addition, the present of occult blood in the stool, hema-
tochezia, and/or hypoalbuminemia should also prompt
consideration of gastrointestinal involvement. Serologic
diagnosis is often unreliable as it is confounded by the
presence of passive antibodies. Measurement of the
EBV load in peripheral blood by PCR has gained wide
acceptance as a method to predict the risk for or pres-
ence of EBV or PTLD.50-53 Although extremely sensi-
tive, these assays are limited by their lack of specificity;
they are often elevated in asymptomatic patients.54 Ac-
cordingly, every effort should be made to histologically
confirm the diagnosis of EBV or PTLD. Occult sites of
PTLD are assessed by performance of computed tomog-
raphy of chest, abdomen and brain. Palpable nodes or
lesions (or both) identified by radiographic surveillance
should be biopsied. Endoscopic evaluation should be
considered in patients with diarrheal illnesses and ele-
vated viral loads.
A wide range of histologic findings may be present in
patients with EBV disease and PTLD. The tissue spec-
imen should be interpreted by a pathologist or hema-
topathologist familiar with histopathologic features of
EBV and PTLD. Ranges of EBV infection notable in
tissue biopsy include early lesions (reactive plasmacytic
hyperplasia, infectious mononucleosis-like), polymor-
phic PTLD, monomorphic PTLD, B cell neoplasms, T
cell neoplasms, Hodgkin’s lymphoma, and Hodgkin’s
lymphoma-like PTLD. The histologic evaluation for typ-
ical features may be augmented by the use of the Ep-
stein-Barr encoded RNA probe.55
Management of patients with PTLD is controver-
sial.48-50 Reduction of immunosuppression is recom-
mended widely. Antiviral agents (eg, ganciclovir) typi-
cally are used,49,56 although their role has not been
studied formally. Reduction of immunosuppression,
alone or in combination with antiviral agents, results in
an approximately 67% cure rate of EBV disease and
PTLD. Several different strategies have been proposed
for patients who fail to respond to withdrawal of initial
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
T.H.E. CORNER 1393
immunosuppression. Experience to date suggests that
as many as two-thirds of patients who fail initial with-
drawal of immunosuppression will respond to a 4-week
course of the anti-CD20 monoclonal agent rituximab.57
However, relapse of EBV disease has been observed in
20% to 25% of treated patients 6 to 8 months following
completion of therapy. An alternative, chemotherapy-
based approach for patients who fail to respond to ini-
tial reduction or withdrawal of immunosuppression has
also been proposed.58 This strategy, which uses modi-
fied doses of cyclophosphamide and prednisone, has
also achieved success in approximately two-thirds of
treated patients. Unfortunately, as with rituximab, re-
lapse of PTLD has been seen in 22% of treated patients,
and outright treatment failures have occurred in pa-
tients presenting with fulminant disease. Definitive
studies comparing these 2 second-line therapies are
needed to define the best option for those children who
fail to respond to initial therapeutic modification of im-
munosuppression.
Other Herpesviruses
Herpes simplex can reactivate early after surgery or
after augmentation of immunosuppression, but pro-
phylaxis with acyclovir has been beneficial in these
situations. Varicella in nonimmune transplant recipi-
ents can lead to disseminated, fatal disease59 and
should be treated early and aggressively with intrave-
nous acyclovir. Recent interest has focused on deter-
mining what role, if any, human herpesvirus 6 (HHV6)
and human herpesvirus 7 (HHV7) may play in causing
disease in transplant recipients. Several groups of in-
vestigators have now identified a potential interaction
between the development of HHV6 and HHV7 and CMV
infection in organ transplant recipients.60,61 Reactiva-
tion of HHV6 infection following LTx has been associ-
ated with the development of an increased CMV viral
load and a greater likelihood of developing CMV dis-
ease.61 It has also been suggested that some or all of the
symptoms typically associated with CMV syndrome in
patients with proven CMV infection may be attributable
in part to HHV6 or HHV7. Studies in children have
suggested that infection due to HHV6 alone is a rela-
tively common cause of unexplained fever in pediatric
LTx recipients.62,63 The full spectrum of HHV6 and
HHV7 diseases and their potential therapies remain to
be determined.
Adenovirus
Adenovirus has been reported to be the third most im-
portant virus affecting pediatric LTx recipients, occur-
ring in 10% of 484 children undergoing LTx under cy-
closporine-based immunosuppression.64 Symptomatic
disease (ranging from self-limited fever, gastroenteritis,
or cystitis to devastating illness with necrotizing hepa-
titis or pneumonia) occurred in over 60% of these in-
fected patients, and infection occurred within the first 3
months after transplantation. However, the frequency
of invasive adenovirus infection after pediatric LTx has
1394 HALASA AND GREEN
decreased markedly since the introduction of tacroli-
mus-based immunosuppression.19 In a recent report,
only 4.2% of pediatric LTx recipients using tacrolimus-
based therapy developed adenovirus disease.65
A presumptive diagnosis of adenovirus infection in
pediatric LTx recipients is difficult as fever, hepatitis,
and pneumonia may be caused by a variety of other
pathogens. The presence of high-grade fevers, unex-
plained elevations in hepatocellular enzymes sugges-
tive of hepatitis, and symptoms suggestive of adenovi-
rus infection should prompt serial cultures for viruses
(including adenovirus) and/or PCR investigation, as
well as the possibility of graft biopsies. A histologic
examination for the presence of adenoviral inclusions
as well as the use of immunohistochemical stains of
biopsy specimens should be undertaken to help con-
firm this diagnosis.
Unfortunately, there is no definitive treatment for ad-
enoviral infection at this time. The most important com-
ponent of therapy is supportive care along with a de-
crease in immunosuppression. The role of antiviral
agents is unproven. Although early case reports fo-
cused on the use of ribavirin,66-69 more recent reports
have described the use of cidofovir as a potential treat-
ment for adenoviral disease in immunocompromised
hosts, including organ transplant recipients.70-72 Un-
fortunately, no conclusive evidence of the efficacy can
be drawn from these reports.
Common Community-Acquired Viruses
Although the course of illness has been poorly docu-
mented, most children who undergo LTx experience the
usual respiratory viruses and gastrointestinal illness
without significant problems. However, infections due
to influenza, parainfluenza, and RSV can cause more
severe disease in young children, especially if infection
occurs soon after transplantation and during periods of
maximal immunosuppression.73-76 The diagnosis of
these viral pathogens is accomplished through the per-
formance of viral cultures, antigen detection, and/or
nucleotide amplification testing (eg, PCR). Antiviral
therapy may be of value for influenza, but there are few
data to confirm the efficacy of treating RSV and para-
influenza with antivirals in this population.
OPPORTUNISTIC INFECTIONS
P. jirovecii is a well-documented cause of pneumonia in
immunocompromised patients, including liver trans-
plant recipients. Prophylactic trimethoprim/sulfame-
thoxazole is safe, inexpensive, and effective.77 The use
of this strategy has eliminated PCP at the Children’s
Hospital of Pittsburgh. Alternative prophylactic regi-
mens for the sulfa-allergic patient include aerosolized
pentamidine (for patients ⬎ 5 years of age)78 and dap-
sone.79
Tuberculosis (TB) is of concern in recipients of LTx.
Development of TB after pediatric LTx is extremely un-
common, with only 11 cases reported to date,80-82 al-
though the incidence of TB after LTx in adults in Europe
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
and the United States has ranged from 0.9% to
2.3%.81,82 Not surprisingly, higher rates (up to 15% of
organ transplant recipients) have been reported from
areas of high-level endemnicity of TB.82 Recognition of
TB among organ transplant recipients is critical as mor-
tality rates ranging from 25% to 40% have been re-
ported in this population.81,82 Recommendations for
the management of TB in transplant recipients were
included in the American Society for Transplantation
Guidelines for the Prevention and Treatment of Infec-
tious Complications of Organ Transplantation.83
Cryptococcosis, coccidiomycosis, and histoplasmosis
have been infrequently reported among pediatric LTx
recipients. Prior infection with these pathogens is com-
mon in geographic areas where they are endemic. Ex-
perience with coccidiomycosis in transplant recipients
suggests that a minimum of 4 months of antifungal
therapy, such as fluconazole, should be given to trans-
plant recipients found to have serologic evidence of this
pathogen.84 Similarities between coccidiomycosis and
other fungal pathogens suggest that similar strategies
may be necessary for patients with a positive history of
prior fungal infection with pathogens known to recur
after resolution of the primary infection.
PROPHYLACTIC REGIMENS
Perioperative prophylaxis is used to prevent intraoper-
ative sepsis and wound infection. We consider pipera-
cillin/tazobactam to be an appropriate agent for peri-
operative prophylaxis for children undergoing LTx. If
infection is suspected in the donor, antibiotics are cho-
sen to cover those organisms identified from the donor,
and treatment is usually extended to a therapeutic
course of 10 to 14 days. In the absence of proven or
suspected infection in the donor, perioperative prophy-
laxis is usually limited to the first 48 hours after trans-
plant.
Considerations regarding long-term prophylaxis
against infections occurring beyond the perioperative
period include the risk and severity of infection as well
as the toxicity, cost, and efficacy of a given prophylactic
strategy. Nystatin is recommended for all pediatric
transplant recipients in an effort to prevent oropharyn-
geal candidiasis. Trimethoprim/sulfamethoxazole is
used to prevent PCP. Although some centers recom-
mend using trimethoprim/sulfamethoxazole for only
the first 6 months following LTx, anecdotal experience
with patients presenting with PCP long after transplan-
tation and the relative safety of this agent have led us to
recommend its use indefinitely following LTx in chil-
dren.
The frequency and severity of CMV infection in trans-
plant recipients have prompted consideration of pro-
phylactic strategies. Potential roles exist for intrave-
nous and oral ganciclovir85-87 and oral valganciclovir.88
Currently, we recommend the use of intravenous gan-
ciclovir for younger pediatric LTx recipients. However,
oral valganciclovir is a reasonable alternative for ado-
lescents. Upon completion of pharmacokinetic studies
for dosing oral valganciclovir suspension in children
 T.H.E. CORNER 1395

TABLE 1. Suggested Accelerated Schedule for the Vaccination of Solid Organ Transplant Candidates

Minimum Review and Update

Age of Minimum Interval Determination of Vaccine Status of
Vaccine Vaccination Between Doses Serologic Status Household Contacts
DTaP 6 weeks First and second, 4 weeks Not routinely recommended Yes
Second and third, 4 weeks
Third and fourth, 6 months
Fourth and fifth, 6 months
Hepatitis A 6 months First and second, 4 weeks Pre- and post-transplant Consider
Hepatitis B Birth First and second, 4 weeks Pre- and post-transplant Yes
Second and third, 8 weeks
HiB 6 weeks First and second, 4 weeks Not routinely recommended No
Second and third, 4 weeks
Third and fourth, 8 weeks
Influenza 6 months First and second, 4 weeks Not routinely recommended Yes
MPV 2 years Not routinely recommended No
MMR 6 months First and second, 4 weeks Pre- and post-transplant Yes
PCV7 6 weeks First and second, 4 weeks Not routinely recommended No
Second and third, 4 weeks
Third and fourth, 8 weeks
PPV23 2 years Not routinely recommended No
Varicella 6 months First and second, 4 weeks Pre- and post-transplant Yes

NOTE: This table was adapted from Campbell and Herold.93

Abbreviations: DTaP, diphtheria, tetanus, and acellular pertussis vaccine; HiB, Haemophilus influenzae type B vaccine; MMR,
measles, mumps, and rubella vaccine; MPV, meningococcal polysaccharide vaccine; PCV7, 7-valent pneumococcal conjugate
vaccine; PPV23, pneumococcal polysaccharide vaccine.

after transplantation, this will likely also be a reason-
able alternative to intravenous treatment for younger
children. Serial monitoring of the CMV viral load in the
blood to inform the use of preemptive antiviral therapy
has been proposed as an alternative to these chemopro-
phylactic strategies.36 Although this strategy has
gained acceptance at some centers, experience in pedi-
atric LTx recipients remains limited. Finally, the use of
viral load monitoring after completion of chemoprophy-
laxis is gaining increasing acceptance.
The growing recognition of the importance of EBV
infections in pediatric organ transplant recipients has
led to an interest in the prevention of EBV infections
and PTLD. A number of strategies are currently being
explored (eg, immunoprophylaxis, monitoring, and pre-
emptive therapy)57,89,90; the efficacy of these ap-
proaches has not been established. The use of viral load
monitoring to inform preemptive reductions in immu-
nosuppression appears to be the most promising of
these strategies.45,89,90
Immunizations in Liver Transplant Recipients
Recommendations for the use of immunizations for or-
gan transplant candidates and recipients were included
in the 2004 American Society for Transplantation
Guidelines.91 Central to these recommendations was
that the immunization history should be reviewed early
in the transplant evaluation process and that a strategy
to update and follow immunizations should be created
and regularly reviewed during the pretransplant wait-
ing period. This is particularly relevant for pediatric LTx
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
recipients, who are frequently young when they are
transplanted and consequently have not completed
their primary vaccination series. Furthermore, immu-
nizations are sometimes delayed and often overlooked
while these children are waiting for transplantation be-
cause of their medical conditions. Despite their under-
lying illnesses, vaccine responses are likely to be better
in the transplant candidate compared to the transplant
recipient.92 Because of the young age of some candi-
dates, the initiation of some of the vaccine series may
need to be earlier and intervals between vaccines doses
may need to be shorter than what is routinely recom-
mended.93 A summary of vaccine recommendations is
provided in Table 1.
Live Vaccines
Special consideration must be given to live vaccines. In
general, live viral vaccines are not administered after
transplantation, although several small clinical trials
evaluating the measles, mumps, and rubella vaccine
(MMR) and varicella vaccine have demonstrated prom-
ising safety profiles.94-96 Thus, the ideal time to give
these live vaccines is clearly prior to transplantation.
MMR can be administered as early as 6 months of age.
If children have not received their transplantation by 12
to 15 months of age, revaccination with MMR should
occur. A second dose of MMR is recommended for the
small percentage of individuals who do not respond to
the first dose. The minimum interval between doses
should be 1 month. Optimally, MMR should be admin-
istered a minimum of 3 to 4 weeks prior to transplan-
tation. Varicella vaccine is approved for children ⱖ 12
1396 HALASA AND GREEN
months of age. However, at least 1 transplant center
has published its approach of giving this vaccine to
transplant candidates who are as young as 6 months of
age.93 It is now recommended that 2 doses of varicella
should be administered. The interval between dose 1
and dose 2 can be 1 month. Like MMR, varicella vaccine
should be administered a minimum of 3 to 4 weeks
prior to transplantation.
Two additional live viral vaccines are now routinely
available for children. RotaTeq, a human-bovine reas-
sortant live-attenuated rotavirus vaccine, is licensed for
children between the ages of 6 and 32 weeks. Currently,
there are insufficient data regarding the efficacy and
safety in immunocompromised children, including
transplant recipients. Accordingly, although it is not
specifically contraindicated,97 the ideal time to admin-
ister this vaccine is prior to transplantation.
In addition, rotavirus vaccine should not be admin-
istered to infants with acute, moderate-to-severe gas-
troenteritis until the condition improves.98 Infants with
mild acute gastroenteritis can be vaccinated particu-
larly if the delay in vaccination might be substantial
and might make the child ineligible to receive the vac-
cine (eg, ⬎13 weeks old before vaccination is initiated).
Primary care providers should consider the potential
risks and benefits of administering rotavirus vaccine to
infants with preexisting chronic gastrointestinal dis-
ease. Infants with preexisting chronic gastrointestinal
conditions who are not undergoing immunosuppres-
sive therapy should benefit from rotavirus vaccine vac-
cination, and the benefits outweigh the theoretical
risks. However, the safety and efficacy of rotavirus vac-
cine have not been established for infants with these
preexisting conditions (eg, congenital malabsorption
syndromes, Hirschsprung’s disease, short-gut syn-
drome, and persistent vomiting of unknown cause).
A live-attenuated, trivalent, cold-adapted influenza
vaccine has been licensed for use in healthy individuals
2 to 49 years of age. However, this vaccine is not rec-
ommended for individuals with medical illnesses that
put them at a high risk for influenza, including organ
transplants recipients.
Inactivated Vaccines
Theoretically, there is no contraindication for adminis-
tering inactivated vaccines to transplant recipients. If
vaccines are to be administered post-transplant, they
should be given at a time when the recipient’s immu-
nosuppressive regimen is both stable and at a relatively
low level. In general, this is typically somewhere be-
tween 6 and 12 months after the transplant. With the
exception of influenza vaccine, the use of T cell deplet-
ing induction immunotherapy (eg, Thymoglobulin®)
should prompt consideration of delaying initiation of
vaccinations until the completion of the first posttrans-
plant year.
Hepatitis A is currently recommended for the routine
vaccination of children older than 1 year in the United
States. Two doses should be given at least 6 months
apart.99 There are 2 formulations approved for chil-
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
dren, Vaqta® and Havrix®, and these formulation doses
differ from those of adults. Vaqta® can be administered
to persons 12 months to 18 years old, and they should
receive 25 units per dose in a 2-dose schedule, whereas
persons older than 18 years should receive 50 units per
dose in a 2-dose schedule. Havrix® can be administered
to persons 12 months to 18 years old at 720 ELISA
units per dose in a 2-dose schedule, whereas persons
older than 18 years should receive 1440 ELISA units
per dose in a 2-dose schedule.
Hepatitis B is universally recommended for all infants
in a 3-dose schedule commencing at birth.100 The sec-
ond dose should be administered at 1 to 2 months of
age. The final dose should be administered no earlier
than 24 weeks. If combination vaccines are adminis-
tered, it is acceptable to receive 4 doses of hepatitis B.
For those children who have not received the hepatitis
B vaccine, a 3-dose series is recommended. A 2-dose
series of Recombivax HB® is licensed for children 11 to
15 years old.
Vaccination of Contacts
Another form of protection for transplant recipients is
vaccinating their close contacts. The immunization of
contacts with killed vaccines does not pose a risk to the
transplant recipient. Additionally, with the exception of
oral polio, the receipt of live vaccines is not contraindi-
cated for household contact of transplant recipients.
This includes both varicella vaccine and MMR.
Healthcare workers who are in contact with these
children should be up to date on their vaccinations. At
a minimum, healthcare workers should receive the
yearly influenza vaccine, the full 3-dose series of the
hepatitis B vaccine, the MMR and varicella vaccines,
and a single dose of the tetanus, diphtheria, and per-
tussis vaccine according to the current guidelines.101
Immunization with influenza and pertussis vaccines is
also recommended for household contacts in order to
prevent transmission to these vulnerable children.
SUMMARY
Infections remain an important problem following LTx
in children. Knowledge of the type, timing, and predis-
posing risk factors for these infectious complications
allows for their timely and appropriate diagnosis and
management. The use of vaccines before and after
transplantation can help to minimize the risk of infec-
tion in these children.
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