Epstein-Barr Virus

ANDREW NOWALK1 and MICHAEL GREEN1

1
University of Pittsburgh School of Medicine, Division of Infectious Diseases,
Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224

ABSTRACT This review covers relevant clinical and laboratory ing and controlling the primary infection. Control of
information relating to Epstein-Barr virus (EBV) infections in EBV proliferation is signaled by a shift from lytic viral
immunocompromised hosts. It describes the epidemiology and
activity (marked by lytic proteins associated with cell
clinical manifestations with a primary focus on disease in solid
organ and stem cell transplant recipients. The review pays
destruction, such as BZLF1 and BRLF1) to a latent
particular attention to diagnostic approaches, including phenotype in an immortalized B lymphocyte pool, which
serologic testing and imaging, with an expanded discussion provides a lifelong source of low-grade reactivation.
on the role of measuring the EBV load in peripheral blood, Development of a serological response, with initial IgM
identifying both strengths and limitations of this assay. and IgG to viral capsid antigen, followed by antibody to
Additional attention is paid to potential additional strategies the EBV nuclear antigen developing months after infec-
of immunologic monitoring that may enhance the performance tion, provides reliable markers for acute and chronic
of EBV load monitoring.
infection in immunocompetent hosts.
Symptoms of EBV infection vary widely based on
EBV INFECTION IN THE the age and immune status of the patient. The majority
IMMUNOCOMPROMISED HOST of infections in younger children are benign and are

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often subclinical (1). In this group, the most common
Background and Clinical Information acute presentation of EBV infection is of a febrile viral
Epstein-Barr virus (EBV), a gamma herpesvirus, is a upper respiratory illness, which is not distinguish-
ubiquitous cause of infection in humans worldwide able from illness associated with other common viral
(1). Evidence of prior infection is present in adults pathogens. Young adults who undergo primary in-
throughout the world, with over 90% showing a sero- fection are more likely to present with classic findings
logic response. Exposure typically occurs early in life, of infectious mononucleosis. This cardinal symptom
with the majority of children in developing countries complex of fever, pharyngitis, adenopathy, hepato-
becoming seropositive by age 5. While onset of infection splenomegaly, and fatigue accompanied by laboratory
is delayed in areas with greater socioeconomic devel- evidence of hepatitis is not absolutely specific to EBV,
opment, adults are almost uniformly positive. EBV is but in young adults between 15 and 24 years of age,
most commonly transmitted by contact with respiratory it represents the virtually pathognomonic findings of
secretions, which promotes access and entry into the
Received: 8 May 2015, Accepted: 8 February 2016,
reticuloendothelial cells of the upper respiratory tree. Published: 24 June 2016
While the primary target cell of EBV is the B lymphocyte, Editors: Randall T. Hayden, St. Jude Children’s Research Hospital,
infection of a wider range of cell types can occur in Memphis, TN; Donna M. Wolk, Geisinger Clinic, Danville, PA;
immunocompromised hosts, particularly in those of Karen C. Carroll, Johns Hopkins University Hospital, Baltimore, MD;
Yi-Wei Tang, Memorial Sloan-Kettering Institute, New York, NY
epithelial lineage. Pharyngeal infection is followed by Citation: Nowalk A, Green M. 2016. Epstein-Barr virus. Microbiol
dissemination of virus throughout the body, with B Spectrum 4(3):DMIH2-0011-2015. doi:10.1128/microbiolspec
lymphocytes as the primary target. The immune re- .DMIH2-0011-2015.
Correspondence: Michael Green, [email protected]
sponse to infection mounts steadily, with expansion of
© 2016 American Society for Microbiology. All rights reserved.
EBV-specific cytolytic T-cell clones eventually recogniz-

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Nowalk and Green

EBV. In young solid-organ recipients, the early ac- development. The highest risk profile for PTLD in SOT
quisition of infection is a key determinant of the pre- recipients is for EBV-seronegative recipients of seropos-
dominance of primary EBV infection after transplant itive donors. The low prevalence of EBV infection in
(2) and is associated with an increased risk for more children thus predicts much higher rates of EBV-driven
severe outcomes. malignancies in younger recipients. Rates of PTLD are
While immunocompromised patients may manifest also associated with specific organ types (Table 1), with
typical findings of EBV infection, they are at greater pediatric recipients demonstrating rates of PTLD that
risk for severe complications of disease. Asymptom- are 4- to 10-fold greater than similar organs in adult
atic infection is common in all categories of patient recipients. Lung and intestinal transplants demonstrate
and can occur at any age and in a diverse variety of the highest rates of PTLD in pediatric recipients, with
clinical situations. As described below, the routine estimates of 4% in lungs and 14% incidence in intestinal
use of EBV nucleic acid detection in patients at risk transplantation (8, 9). This association is maintained
has allowed recognition of asymptomatic infection even in high-risk situations associated with chronic EBV
as a frequent event. Even immunocompromised hosts carriage; prior studies of high viral load liver transplant
frequently experience infection in the absence of recipients demonstrated rates of PTLD of 2.7%, versus
clinical symptoms. Smets and colleagues noted that 11% in intestinal transplant recipients (10, 11). Rates of
only 15% of a panel of pediatric liver transplant PTLD and EBV infection vary for HSCT recipients based
recipients developed symptoms with primary infec- on transplant type—allogeneic HSCT rates often run
tion (3). Fever without a source is also a common greater than 10%, while cord blood transplant incidence
disease presentation; therefore, EBV must be consid- is reported as high as 30% (6, 12, 13). In contrast to
ered in the differential diagnosis of immunocompro- these patient groups, patients with primary immunode-
mised patients with unexplained fever. Patients may ficiency present with diverse manifestations of EBV in-
also present with a classic infectious mononucleosis fection. Patients with X-linked lymphoproliferative
syndrome, including hepatitis, adenopathy, and or- disorder present with uncontrolled EBV proliferation,
ganomegaly. which may progress to fulminant hemophagocytic
Of note, disease presentations that are not widely lymphohistiocytosis (14). In contrast, HIV-infected
observed in immune-competent individuals are espe- patients often tolerate EBV infection initially, but later
cially important in a range of hosts with compromised are at higher risk for EBV-driven malignancies such as
immunity. EBV is capable of in vitro and in vivo trans- lymphoma (15). Because of the strong association be-
formation of host cells and associates with specific tween SOT and HSCT and EBV-driven complications,

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tumors (Hodgkin’s and non-Hodgkin’s lymphomas, the remainder of this review will focus on the role of EBV
nasopharyngeal carcinoma, and Burkitt’s lymphoma) in these disorders. While other manifestations of EBV-
in immunocompetent populations (4). This neoplastic driven disease such as encephalitis, pneumonitis, and
potential is intensified in immunocompromised hosts. hepatitis can occur, the impact of posttransplant lym-
The most important manifestation is posttransplant phoproliferative disorder and the challenges of its diag-
lymphoproliferative disorder (PTLD), a complication of nosis are the central theme of our discussion.
both solid organ transplant (SOT) and hematologic stem
cell transplant (HSCT) patients. TABLE 1 Cumulative 1- and 5-year incidence of PTLD in
PTLD is classified by pathologic appearance, ranging pediatric and adult SOT recipients by transplanted organ
from infectious mononucleosis-like lesions, to poly- as reported in the 2010 Organ Procurement and Trans-
morphic collections of EBV-infected B cells, to mono- plantation Network/Scientific Registry of Transplant
morphic collections and frank lymphoma (5). The Recipients (OPTN/SRTR) Annual Report (9)a
development of PTLD is most likely to occur in EBV-
Pediatric Adult
seronegative hosts who experience infection after solid
organ transplant, explaining the higher incidence in Organ 1 year 5 year 1 year 5 year
pediatric recipients. Conversely, development of PTLD Lung/heart–lung 4.0 16% 1.0 1.5%
in HSCT patients is most strongly associated with EBV- Liver 2.1% 4.7% 0.25% 1.1%
Pancreas (isolated) N/A N/A 2.3% 2.3%
infected donors (6, 7). Heart 1.6% 5.7% 0.3% 0.7%
The risks and specific associations of lymphopro- Kidney 1.3% 2.4% <0.2% 0.6%
liferation correlate with the specific categories of im- aData for intestinal transplant recipients not broken down by pediatric versus

mune defects when considering EBV-associated tumor adult and therefore not included.

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 Epstein-Barr Virus

Diagnostic Approaches markedly elevated loads in comparison to those with

Serologic testing evidence of EBV infection that do not develop disease.
The diagnosis of EBV infection and disease in immu- The major difficulty in defining the relationship between
nocompromised hosts is more complicated than in im- level of load and the likelihood that EBV disease is
mune-competent individuals, largely due to the fact that present in these patients is that EBV load monitoring has
serologic diagnostic testing is confounded by the not been standardized between laboratories. Thus, while
patient’s potential inability to mount appropriate anti- serial results of EBV load monitoring have been shown to
body responses as well as the frequent presence of pas- be consistent within a single laboratory, substantial
sively acquired antibody from blood products in many variability exists in the results of EBV load measurement
of these patients. Accordingly, while serologic studies between different laboratories (up to a 3.30-log differ-
may be obtained in some immunocompromised hosts ence on the same samples in a recent study (20), limiting
with suspected EBV infection, the resulting interpreta- the ability to extrapolate published single-center data to
tion must take these factors into consideration. Serologic generate reliable EBV viral load thresholds which should
testing for EBV infection should be avoided in patients trigger diagnostic and therapeutic interventions. Ac-
with congenital or acquired antibody deficiencies as well cordingly, individual centers need to review and correlate
as in patients with known exposure to passive antibody results of their EBV load assays to clinically relevant
in the last 6 to 12 months. This approach would include events to determine appropriate thresholds for their
all recipients of solid organ and hematopoietic stem cell patients. Because of inconsistencies in results between
transplants for at least the first 1 to 2 years following labs, patients undergoing serial monitoring should have
transplantation. In accordance with this principle, EBV viral load measurements performed by the same labo-
serologic status should be documented prior to trans- ratory even when they leave their hospital, to assure the
plant on donors and recipients as this information can be reliability of following loads over time. It is hoped that
used in assessing risk and guiding the need for potential the recently released 1st WHO International Standard
preventive interventions. for Epstein-Barr Virus for Nucleic Acid Amplification
Techniques will allow for enhanced standardization
which may overcome some of the current concerns noted
EBV load measurement by above (21).
nucleic acid amplification testing Additional concerns exist with the sensitivity of EBV
Over the last 20 years, the measurement of EBV loads in loads for the diagnosis of EBV infection and disease.
the peripheral blood using nucleic acid amplification Although the majority of patients with proven EBV

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testing (e.g., PCR) has become an essential tool in the disease have been found to have markedly elevated EBV
diagnosis and monitoring of EBV infection and disease in loads in their individual center, a small number of im-
immunocompromised hosts. Measurement of EBV viral munocompromised patients with proven EBV disease
loads is widely recommended to aid in the diagnosis and including PTLD have very low or even negative EBV
management of EBV disease in solid organ recipients loads in the peripheral blood. While most patients de-
(16), stem cell transplant recipients (6), and other im- velop an elevated EBV load prior to onset of symptoms,
munocompromised hosts (17). Quantitative EBV load the EBV load in patients with rapidly progressive disease
measurement has also been proposed as a guide to the (particularly stem cell transplant recipients) may present
initiation of preemptive interventions against the devel- with clinical symptoms so quickly that measurement of
opment of EBV disease (5, 18, 19). Despite this long the load at the onset of clinical symptoms might un-
experience, a number of limitations in the ability to derestimate the likelihood of the presence of EBV disease
interpret results of EBV load measurement in the pe- and PTLD. For such patients, the analytical sensitivity of
ripheral blood continue to exist. The most important EBV load measurement will likely be enhanced by repeat
limitation is that data defining clinically relevant measurement of the EBV load 4 to 7 days later. Addi-
breakpoints and performance specifications of these tionally, some solid organ transplant recipients with
assays applicable to all centers are lacking. This is par- proven EBV disease including PTLD have had persistent
ticularly true in defining a universally applicable level of low or nondetectable EBV loads in the peripheral blood
EBV load that accurately predicts the presence of EBV (2). Some lung transplant recipients with proven EBV
disease including PTLD in solid organ and stem cell disease and low loads or nondetectable loads in the pe-
transplant recipients. In general, populations of immune- ripheral blood had elevated EBV loads in broncho-
compromised hosts with active EBV disease usually have alveolar lavage fluid alone (22).

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Nowalk and Green

Problems also exist with the specificity of EBV assays. confirmed to allow for staging. Magnetic resonance
While it is true that the majority of patients with proven imaging of the brain is paramount if there are any cen-
EBV disease will have a load that exceeds local tral nervous system symptoms such as headache, focal
thresholds for disease, many organ transplant recipients neurologic findings, or visual changes. Some experts
have high viral loads in the absence of clinical disease. advocate routine magnetic resonance imaging or com-
While some of these patients may eventually progress puted tomography of the head in all patients at the time
and develop disease, some patients will not progress of initial imaging, particularly in children, to identify
even when high loads persist over long periods of time asymptomatic lesions (16). Increasing interest has also
(10, 11, 23). While some experts have suggested that use focused on the use of positron emission tomography
of plasma or serum specimens may improve the speci- scanning in the evaluation for EBV disease including
ficity of EBV load assays, comparative data confirming PTLD (28). Experience to date has not defined its exact
this are lacking, and reports of patients having EBV role, including whether all immunocompromised pa-
disease in the presence of a positive whole blood or tients with proven or suspected EBV disease should
PBL assay and negative plasma or serum result have undergo one or serial positron emission tomography
been observed. scan evaluations.
Concerns over specificity highlight a final important
controversy in the measurement of EBV load in the pe- Histopathology
ripheral blood by nucleic acid amplification tests and The definitive diagnosis of EBV disease (including
may be another explanation for why universally appli- PTLD) is made by biopsy of lesions or affected tissue. In
cable clinically relevant breakpoints have not been de- addition to confirming the presence of EBV, results of
fined. Debate over what is the optimal compartment of the biopsy are frequently used to help categorize the EBV
peripheral blood to test has not been fully defined, with disease manifestation, which frequently helps guide
conflicting results for assays using peripheral blood therapeutic approaches in affected patients. The biopsy
lymphocytes, whole blood, or plasma (16, 24–27). Pe- also serves the role of ruling out other opportunistic
ripheral blood lymphocytes (PBL) and peripheral blood infections that might require alternate therapy or be
mononuclear cells contain EBV within infected B cells. present concurrently. Because the bowel can frequently
Conversely, serum and plasma sampling measure the be involved in EBV disease, early endoscopy and
presence of viral DNA, either contained in mature virions colonoscopy should be performed in patients with un-
or as fragments, which are more common in acute in- explained abdominal pain and diarrhea. In addition,
fection or EBV-driven malignancies (24). Whole blood recipients of intestinal transplants may manifest similar

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sampling has also been used to minimize sample prepa- symptoms with rejection or infection with other patho-
ration; EBV load measurements from whole blood cor- gens. Biopsy specimens should be evaluated by a pa-
relate well with PBL/peripheral blood mononuclear cell thologist familiar with EBV disease (including PTLD
levels but not with plasma/serum loads (27). As a con- and other lymphoproliferative processes). For transplant
sequence of these differences in compartments, some recipients, histologic disease should be characterized
experts feel that measurement of EBV load in serum or according to WHO Consensus definitions (29). Specific
plasma may provide greater specificity compared to assays should be performed to characterize the involved
measurements derived from PBL or whole blood samples. cell (T-cell versus B cell) with emphasis on evaluating cell
However, experience at multiple centers suggests a de- markers such as CD20 which may influence therapeutic
crease in sensitivity using this approach (2). A large, options and in situ hybridization for EBV-encoded
comparative trial would be required to fully define the RNA, a marker of EBV-infected cells (30).
performance of testing from different compartments.
Monitoring of EBV Infection
Additional diagnostic modalities Careful attention for resolution of clinical signs,
Radiographic testing symptoms, and aberrant laboratory tests associated with
In addition to measurement of EBV load in peripheral the presence of EBV disease is the most reliable approach
blood, patients with suspected EBV disease should un- to assessing the clinical response of the patient with
dergo radiographic evaluation using computed tomog- symptomatic EBV infection. In addition, many experts
raphy of neck, chest and abdomen to identify lesions not recommend serial measurement of the EBV load to fol-
apparent from symptoms or examination (7, 16). These low clinical response to therapy in those being treated
imaging studies should also be performed when PTLD is for EBV disease. Serial measurement of EBV load after

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 Epstein-Barr Virus

transplant has also been used to identify those at risk of CXCL13, and NK cells are of current interest. Future
developing EBV disease (as potential candidates for data will hopefully clarify which, if any, of these can-
preemptive interventions). While there is consensus didate markers might rise to the level of being of clinical
agreement for the role of EBV load monitoring for at value.
least transplant recipients, concerns over the previously
noted limitations with specificity of the assay limit our Prognosis
full understanding of the meaning of results in patients The outcome of EBV infection in immunocompromised
with elevated loads, particularly those that persist over hosts is variable and is influenced by a diverse array of
time in the absence of clinical symptoms. The optimal clinical factors. Estimating risk for infection involves the
frequency for assessing EBV load at specific time points correlation of a number of these individual data points;
post transplant for varying circumstances (e.g., surveil- thus, a simple equation for risk estimation and outcome
lance, follow-up of elevated load, responses to treat- prediction is not feasible. Determining which infections
ment) remains center-specific, and a gold standard is not are more likely to result in clearance and establishment
well defined. of long-lasting immunity and which may progress to
These concerns have prompted interest in adjunctive more serious manifestations such as PTLD requires risk
testing assays which might enhance the performance of stratification through examination of key underlying
the EBV load measurement. Since the development of factors, which helps to rank the available therapeutic
EBV disease in immunocompromised patients represents options. Key factors to consider include:
an imbalance between the host’s immune response and
viral-driven proliferation of immortalized B cells, at- • Primary versus reactivation/secondary infection.
tention has focused on measurement of EBV cytotoxic T Regardless of host or type of immunocompro-
lymphocyte (CTL) response. A provocative study in mised state, primary infection with EBV is associ-
pediatric liver transplant recipients looked concurrently ated with a greater level of risk in hosts with
at EBV loads and EBV CTL activity using ELISPOT; the impaired immunity. The increased rates of PTLD
investigators found a 100% positive predictive value for in pediatric SOT recipients are strongly associated
the development of PTLD in recipients who experienced with the increased rate of seronegativity in pedi-
primary EBV infection without developing a significant atric patients, as noted above. While recurrence
EBV CTL response (31, 32). Not surprisingly, others of EBV viremia may represent a risk for com-
have also noted reduced EBV CTL levels (using com- plications of EBV, the development of T-cell-
mercial measurement of CD3+ T-cell response to PHA) specific immunity in all hosts is associated with

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in PTLD patients when compared to asymptomatic re- clearance of primary infection and is a key factor in
activation of EBV (33). Other investigators character- the protection against EBV progression to more
ized the level of CTL responses (low or high) combined serious disease.
with the presence of undetectable, low, or high EBV • Type of transplant. Previous work in many centers
loads and found that those with persistently high EBV has established a stratification of risk dependent on
loads had a low CTL response on the basis of an “im- the specific transplant type. Among SOT, organs
mune exhaustion” phenotype, which they felt pre- associated with a need for higher baseline levels of
disposed these patients to PTLD (31). immune suppression (intestine, heart and lung) are
The presence of EBV-specific CTLs has most com- associated with correspondingly higher rates of
monly been identified using interferon gamma release progression to PTLD (18). This risk can also in-
assays or ELISPOTs. Additionally, the presence and fluence outcomes even from reactivation, as indi-
functional capabilities of EBV-specific CTLs has also cated by low rates of PTLD development (2.7%) in
been assessed using flow-based (tetramer and multimer) pediatric liver recipients with high viral load car-
assays. While measurement of EBV-specific CTL appears riage versus pediatric heart transplant patients
promising as a clinically helpful adjunct marker, no such with a 40% rate of progression to PTLD (16, 23).
assays are currently FDA-approved for clinical use. Recipients of HSCT are also varied in their risk
A number of additional candidate markers have for EBV infection and progression to PTLD based
been considered as potential adjunct assays to the EBV on the type of transplant (6). Because of the de-
load. While previous candidate markers (e.g., mRNA pendence of EBV risk on donor infection and im-
for LMP2a) have not been successfully validated, munity, recipients of CBT are naturally at higher
newer options including free light chains, sCD30, IL-6, risk due to their developing immune function and

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Nowalk and Green

lack of preexisting immunity to EBV. Second al- mortalized B lymphocytes (which does not provide
logenic HSCT also increase risk (23, 25). The na- targets for ganciclovir activity) reduces its importance in
ture of conditioning regimens has influence on risk, therapy. Therapy thus focuses on alternatives, which
as T-cell depletion will limit transfer of immune balance stimulating immune responses to EBV infection
cells critical to the effective defense against EBV and destruction of EBV-infected lymphocyte populations.
infection and monitoring for PTLD development. The primary therapeutic option with all mani-
• Level of immune suppression. While the types festations of EBV infection is the reduction or cessation
of SOT and HSCT correlate with risk of EBV of immune suppression (2, 3, 35). In controlled trials
complications, increased immune suppression in a examining this intervention in SOT patients, up to two-
broad spectrum of recipients can be associated thirds of patients will show a clinical and virologic re-
with PTLD. Increases in baseline immunosup- sponse, with reduction of circulating EBV viremia and in
pressants, such as tacrolimus, constitute a smaller many cases regression of PTLD lesions. This approach is
risk, but addition of corticosteroids for the treat- the first line of therapy for all management of EBV in-
ment of rejection can augment risk. The receipt of fection, but it may not be available in cases of concom-
antilymphocyte therapy is a strong predictor of itant rejection. With recipients of HSCT, ongoing
increased risk with primary or reactivated EBV GVHD, which requires continued immune suppression,
infection (21). Whether polyclonal antithymocyte also may compromise the ability to modulate steroid and
globulin or more targeted biologics such as alem- calcineurin inhibitor regimens.
tuzumab, these broad-spectrum cytolytic therapies Failure of first-line therapy with reduced immune
are often associated with long-lasting suppression suppression leads to the use of second-line therapies,
of cell-mediated immune function and increased which continue to be studied. The use of rituximab for
risk for any EBV infection. Similarly, therapy for direct targeting of EBV-infected B lymphocytes has in-
acute or chronic GVHD in HSCT augments im- creased in frequency in both SOT and HSCT patients (2,
mune suppression and increases risk for PTLD. 12, 36). A recent study of European SOT practices
• Level of specific EBV immunity. Data examining reported that 15% of programs used rituximab as pre-
the specific level of EBV-specific T-cell activity emptive treatment of EBV viremia to prevent PTLD,
suggest that this is an important correlate for the while 50% employed reduction of immune suppression
risk of progression to PTLD. An example is a 2002 (37). Surprisingly, the routine use of rituximab has not
study of pediatric liver transplant recipients, which been accompanied by risk estimation of side effects
such as hypogammaglobulinemia and opportunistic

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demonstrated that the development of PTLD cor-
related both to elevated levels of EBV viremia and infections such as PML (2). This area of research is in
to depletion of EBV-specific cytotoxic T lympho- need of well-designed trials to determine best practices
cyte activity by ELISPOT. Similar data from single for the management of EBV loads, which do not respond
centers have suggested a similar relationship in to reduction of immunosuppression. Progression to
heart transplant patients (23, 34). While limited by higher-grade PTLD lesions, including non-Hodgkin’s
the availability of commercial standardized assays lymphoma, warrants the use of chemotherapy regimens
for the measurement of this activity, this clinical studied for these clinical situations. A recent Children’s
circumstance represents an important future field Oncology Group study of low-dose cyclophosphamide
of study for the improvement of risk assessment with prednisone and rituximab had a 69% response
and prognosis in EBV infection in the immuno- rate, and work continues to delineate the ideal thera-
compromised host. peutic regimens for pediatric and adult populations (38).
A final area of development for therapies includes the
use of adoptive immunotherapy for treatment of EBV
Therapeutic Approaches infection and PTLD. While these strategies have good
While antiviral agents play a key role in the therapy of evidence for their use in HSCT (6), their use in SOT
many infections in immunocompromised hosts, EBV is remains anecdotal (7). While early studies were en-
notable for the limited role that antiviral therapy plays. couraging in the observed responses to adoptive therapy
Lytic virus does express drug targets such as virally (39–41), the slow development and lack of generaliz-
encoded kinases, which are common to other herpes- ability of these therapies has continued to limit their use.
viridae and predict activity for agents such as ganciclovir. It seems clear that further work is warranted in these
However, the important role of EBV-infected and im- cases, as the transfer of effective cellular immunity

6 ASMscience.org/MicrobiolSpectrum
 Epstein-Barr Virus

would likely play a key role in combination with other Resources and Services Administration, Healthcare Systems Bureau,
therapies in the effective treatment of EBV com- Division of Transplantation. Am J Transplant 12(Supplement 1):1–156.
10. Lau AH, Soltys K, Sindhi RK, Bond G, Mazariegos GV, Green M.
plications.
2010. Chronic high Epstein-Barr viral load carriage in pediatric small
bowel transplant recipients. Pediatr Transplant 14:549–553.
Summary/Conclusion 11. Green M, Soltys K, Rowe DT, Webber SA, Mazareigos G. 2009.
Chronic high Epstein-Barr viral load carriage in pediatric liver transplant
EBV is associated with a range of clinical disease in the recipients. Pediatr Transplant 13:319–323.
immunocompromised patient. Clinical syndromes vary 12. García-Cadenas I, Castillo N, Martino R, Barba P, Esquirol A, Novelli
from localized, benign manifestations (e.g., EBV hepa- S, Orti G, Garrido A, Saavedra S, Moreno C, Granell M, Briones J, Brunet
titis) to PTLD including true lymphoma. The diagnosis S, Navarro F, Ruiz I, Rabella N, Valcárcel D, Sierra J. 2015. Impact of
Epstein Barr virus-related complications after high-risk allo-SCT in the era
of EBV disease in this population is challenging, but of pre-emptive rituximab. Bone Marrow Transplant 50:579–584.
measurement of EBV viral load has improved the de- 13. Pinana JL, Sanz J, Esquirol A, Martino R, Picardi A, Barbas P, Parody
tection and management of these syndromes. However, R, Gayoso J, Montesinos P, Guidi S, Terol MJ, Moscard F, Solano C,
the lack of a common standard for EBV measurement as Arcese W, Sanz MA, Sierra J, Sanz G. On behalf of GETH GITMO
Groups. 2015. Umbilical cord blood transplantation in adults with
well as secondary markers which enhance the specificity advanced hodgkin’s disease: high incidence of post-transplant lympho-
of EBV loads remain a challenge. Because of this, biopsy proliferative disease. Eur J Haematol 96:128–135.
and histologic evaluation remains the gold standard for 14. Chandrakasan S, Filipovich AH. 2013. Hemophagocytic lympho-
defining EBV-associated disease in the immunocom- histiocytosis: advances in pathophysiology, diagnosis, and treatment.
J Pediatr 163:1253–1259.
promised patient. Future directions include comparative
15. Pinzone MR, Berretta M, Cacopardo B, Nunnari G. 2015. Epstein-
studies of EBV loads in different disease states utilizing Barr virus- and Kaposi sarcoma-associated herpesvirus-related malig-
the WHO standard and the incorporation of validated nancies in the setting of human immunodeficiency virus infection. Semin
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of EBV disease. 16. Allen U, Preiksaitis J, AST Infectious Diseases Community of Practice.
2009. Epstein-Barr virus and posttransplant lymphoproliferative disorder
in solid organ transplant recipients. Am J Transplant 9(Suppl 4):S87–S96.
ACKNOWLEDGMENTS
17. Loechelt BJ, et al. 2014. Screening and monitoring for infectious
We declare a conflict of interest. Dr. Green is a consultant for complications when immunosuppressive agents are studied in the treat-
Bristol Myers Squibb and Chimerix. Work does not relate to this ment of autoimmune disorders. J Pediatric Infect Dis Soc.
chapter. Dr. Nowalk declares no conflict of interest.
18. Worth A, Conyers R, Cohen J, Jagani M, Chiesa R, Rao K, Goulden
N, Veys P, Amrolia PJ. 2011. Pre-emptive rituximab based on viraemia
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