Hindawi Publishing Corporation
Clinical and Developmental Immunology
Volume 2013, Article ID 430209, 11 pages
Posttransplant Lymphoproliferative Disease after
Isabel P. Neuringer
Pulmonary and Critical Care Unit, Massachusetts General Hospital, Bullfinch 148, 55 Fruit Street, Boston, MA 02114, USA
Correspondence should be addressed to Isabel P. Neuringer; email@example.com
Received 28 November 2012; Accepted 10 January 2013
Academic Editor: Jan Delabie
Copyright © 2013 Isabel P. Neuringer. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Posttransplant lymphoproliferative disease (PTLD) after lung transplantation occurs due to immunosuppressant therapy which
of EBV may occur within the lung allograft early posttransplantation or later onset which is more likely to be disseminated.
Improvements in monitoring through EBV viral load have provided a means of earlier detection; yet, sensitivity and specificity
of EBV load monitoring after lung transplantation may require further optimization. Once PTLD develops, staging and tissue
diagnosis are essential to appropriate histopathological classification, prognosis, and guidance for therapy. The overall paradigm
to treat PTLD has evolved over the past several years and depends upon assessment of risk such as EBV-na¨ ıve status, clinical
presentation, and stage and sites of disease. In general, clinical practice involves reduction in immunosuppression, anti-CD20
biologic therapy, and/or use of plasma cell inhibition, followed by chemotherapy for refractory PTLD. This paper focuses upon the
immunobiology of EBV and PTLD, as well as the clinical presentation, diagnosis, prognosis, and emerging treatments for PTLD
after lung transplantation.
After lung transplantation, the allograft recipient is typically
prescribed immunosuppressant therapy to inhibit adaptive
immunity and cellular rejection, thus concurrently limiting
innate and antiviral host response. The presence of Epstein
Barr virus (EBV) affects 90% of the world’s population, with
immunity to EBV present in the majority of adults , and
thus the majority of donor organs are EBV positive .
Those who are EBV na¨ ıve at the time of transplant are more
likely to acquire an infection from the donor and progress
through primary EBV infection to viral transformation of
na¨ ıve B cells, resulting in posttransplant lymphoprolifera-
tive disease (PTLD) . Conditions such as plasma cell
hyperplasia and primary EBV infection may be viewed
as manifestations of potential PTLD, while polymorphic
PTLD, monomorphic PTLD, B cell neoplasms, T cell neo-
tic processes as recently reviewed . Due to higher levels
of immunosuppression in thoracic organ transplantation
compared to recipients of other solid organs with the excep-
tion of intestinal transplantation, the rate of PTLD in lung
transplant recipients may range between 5% and 15% [5–10].
In one of the first reports of PTLD after lung transplantation
over 20 years ago, Armitage and colleagues reported an
incidence of 7.9% of PTLD, observing a peak occurrence of
PTLD within the first year and different clinical outcomes
for PTLD occurring after 1 year. Early PTLD responded to
of cases, and carried a mortality of 36%, while late-occurring
disease did not respond to lowered immunosuppression, was
disseminated at presentation, and had a mortality of 70%. In
this early study, the majority of cases of PTLD also followed
primary EBV infection . Reports from lung transplant
centers over a more recent era of 10 years have demonstrated
an incidence of ∼5% [11–13], the reduced rate attributed
surveillance of EBV negative patients. Nevertheless, despite
advances in earlier detection of DNA viremia, after lung
to a combination of factors such as prolonged antiviral
prophylaxis, improved detection assays, and anticipatory
2Clinical and Developmental Immunology
transplant care, and immunomodulatory therapies, the mor-
tality still may approach greater than 50% due to infectious
complications or late-presenting or refractory PTLD. This
paper will discuss current advances in understanding EBV
immunobiology, risk factors for PTLD, clinical presentation,
diagnosis, staging, and therapies.
2. Immunobiology of EBV and PTLD
due to altered host immunity after transplantation. Initial
EBV infection results in a cellular program aimed at viral
production through ultimately lytic infection of tonsillar
B cells and establishment of a latent infection which is a
life-long one. During type III latency, a period of growth
and survival of infected B cells, genes expressed include
Epstein Barr nuclear antigens (EBNAs 1-3C), latent mem-
brane proteins (LMPs 1-2B), and nuclear RNAs (EBERs).
Subsequently, during type II latency, LMP 1 and LMP 2
provide differentiation within germinal centers, through
CD40, a common pathway for T helper signaling of B cells.
Lastly, during type I latency, no genes are expressed, thus
promote B cell immortalization include EBNA-1, EBNA-
2, EBNA-3A, EBNA-3C, EBNA-LP, and LMP-1. Functions
associated with these proteins include replication of the EBV
genome, upregulation of c-myc, cell cycle checkpoint inhi-
bition, binding of CD40, anti-apoptosis pathways through
Bcl-2, and modulation of intracellular signaling pathways
including NF휅B .
and induction of anti-apoptosis pathways which prevent cell
death by EBV latency proteins. During lytic infection, viral
interleukin-10 (vIL-10), bearing homology to human IL-10,
Host immunity to EBV is inhibited by EBV-derived
cytokines which downregulate cytotoxic T cell responses
reduces IL-12 and 훾-interferon release essential for cytotoxic
essary for monocyte-associated antiviral cytokine produc-
tion. Stimulation of anti-apoptosis results from blockade of
death receptor signals at the cell surface (Fas, TNF-related
apoptosis inducing ligand), Bcl-2 amplification within mito-
T cell activity. Similarly, an EBV-secreted soluble receptor
causes inhibition of colony-stimulating factor-1 (CSF-1) nec-
toxic T cells, primed by prior immunological stimuli, with
specific antigen-specific memory. Mifsud and colleagues
described EBV-specific CD8+ T cells in a longitudinal study
cohort of lung transplant recipients, focusing upon an HLA-
B8 restricted cohort with reactivity directed towards epitope
FLRGRAYGL on the EBV protein EBNA3A. The authors
found the frequency of EBV-specific T cells in immuno-
suppressed lung transplant patients to be 4-5-fold greater
compared to healthy controls. Although ex vivo stimulation
cell. Please see Figure 1 for a diagram of EBV proliferation.
Antiviral responses are predominantly mediated by cyto-
of EBV specific T cells revealed alloreactive responses, 훾-
interferon production was blunted and variable among the
patient’s peripheral T cells tested, compared to healthy
controls, suggesting limited cytotoxic responses in EBV
seropositive lung transplant patients likely persisting after
initial EBV infection . In a pediatric thoracic transplant
CD8+ cells compared to those with undetectable viral loads,
although they showed no difference compared to healthy
high viral loads had significantly lower levels of 훾-interferon
45% rate of progression to PTLD in these patients .
In addition to immunological exhaustion demonstrated by
these EBV-specific T cells, a subsequent study of pediatric
thoracic transplant recipients with PTLD by Wiesmayr and
coworkers also identified impaired NK cell responses, as
evidenced by decreased expression of NKp46 and NKG2D
and increasedPD-1 expression, thuslimitingTcell responses
. Taken together, these studies provide significant insight
into pathogenic mechanisms which amplify EBV-infected B
cell immortalization, constrain maximal host immunity, and
controls. Examination of 훾-interferon production as related
with depletion and reflecting a possible mechanism for the
to level of EBV viral load showed that those children with
3. Clinical Presentation of PTLD after
3.1. Risk Factors. Identifiable risk factors for PTLD in lung
and solid organ transplantation may be related to multi-
ple factors unique to the type of organ transplanted, as
the rate of PTLD increases from the lowest in kidney,
intermediate for pancreas, liver, heart, and lung, to highest
in small intestine transplantation . Early presentation
within the first year after lung transplantation is associated
with primary EBV infection in a seronegative, na¨ ıve patient
[6, 21, 22] and pediatric thoracic transplant recipients [23,
24], underlying cystic fibrosis diagnosis likely due to EBV
rejection frequency , and use of induction therapy at
time of transplant [4, 25, 26]. In general, later onset PTLD
was associated with extent of exposure to higher levels of
immunosuppression, older recipient age, and male gender
. Individual lung transplant centers have also reported
PTLD which was not associated with pretransplant EBV
serological status or occurred more frequently in recipients
who were EBV positive before transplant. These centers
identified PTLD predominantly in older patients with an
underlying diagnosis of COPD, as well as equally distributed
between those with COPD, IPF, Eisenmengers, and alpha-1
antitrypsin deficiency [9, 11]. Immunosuppressant regimens
to patients receiving cyclosporin and mycophenolate mofetil
. To date, few studies in the lung transplant literature
have cited clear PTLD risk with distinct immunosuppressant
regimens, other than overall immunosuppressant load and
use of induction therapy. Lastly, Wheless and coworkers
Clinical and Developmental Immunology3
B cell lymphoproliferation
(a) Viral infection
(b) Genetic alterations
cells, PDCs, (2), net increase in IL-10, release of 훼-interferon and 훾-interferon, and stimulation of cytotoxic T lymphocytes and NK cells (3),
and B cell lymphoproliferation (4). From .
identified an association between HLA-A3 allele either of
in lung transplant recipients .
3.2. Monitoring EBV Viral Load. Early means of testing for
primary EBV infection and the immunological program
associated with current or past infection relied upon sero-
logical sampling and an understanding of the phases of
EBV infection. Sequentially, IgM antibodies to EBV viral
capsid and early antigen rise and fall within the first month,
followed by antibodies to EBNA and the sustained IgG
antibody response to viral capsid antigen . Monitoring
of the EBV DNA load by quantitative PCR has replaced
serological testing, although variability exists for techniques
for DNA extraction, optimal targeted sequence, and ranges
of detection by commercial assays and custom-designed
upon initial assessment of EBV status before transplant and
serial testing aimed at assessing trends in viral load, rather
than a single, on-time value. There have been few studies
addressing the sensitivity and specificity of EBV viral load
testing in lung transplantation, and given the limited num-
bers of patients, they have yielded variable results. In a study
of 13 cases of PTLD after lung transplantation, 5 of which
occurred during the recent era of viral load monitoring, EBV
viral load levels at the time of detection were significantly
higher in those who were seronegative before transplant. The
1 patient who was seropositive before transplant exhibited
an elevated EBV viral load when diagnosed with PTLD.
The 4 patients who were seronegative before transplant all
had detectable levels, but only 2/4 patients’ were elevated,
expressed in lung transplant patients (group 1) and those
undergoing evaluation for PTLD (group 2). In group 1, a
minority had positive EBV viral load detected in plasma, and
conferring a sensitivity of 50% and specificity of 22% .
Tsai and colleagues examined a panel of EBV proteins
∼40% had intracellular EBV. In group 2, of whom ∼50 had
Testing for LMP-1, EBER-1, and EBNA-1 together conferred a
sensitivity of 92% and specificity of 72%, with plasma EBNA
PCR yielding the greatest sensitivity (77%) and specificity
PTLD, approximately 90% had detectable EBV by PCR and
thus demonstrated high sensitivity for EBV-positive PTLD.
3.3. Clinical Presentation. Recognition of predisposing risk
factors for PTLD and the routine testing of EBV viral
load after lung transplantation have contributed towards
earlier diagnosis and have likely altered overall mortality.
The clinical presentation of PTLD may also depend upon
time from transplantation to diagnosis of PTLD, with ear-
lier disease occurring within the first year more likely to
present within the thorax including allograft parenchyma
or mediastinal lymph nodes [6, 9, 11–13, 34]. After the first
gastrointestinal tract is a common site of PTLD due to the
include cervical lymph nodes , central nervous system
including epidural mass with spinal cord compression ,
bone marrow , and paranasal sinuses .
4Clinical and Developmental Immunology
Clinical symptoms of PTLD relate to the systemic effects
ness, fever and sweats, fatigue, sinus pain, cough, headache,
intestinal pain, and neurological deficits. Examination of
patients with PTLD may reveal enlarged lymph nodes or
nodules, tonsillar prominence, hepatosplenomegaly, intesti-
nal obstruction, and neurologic deficits.
3.4. Laboratory Testing. Since PTLD presents with systemic
manifestations, laboratory testing may provide additional
insight into localization of PTLD. Testing of complete CBC,
chemistries, liver function tests, LDH, uric acid, and hemoc-
cult positivity may reveal systemic anemia, involvement of
the reticuloendothelial system of the liver and spleen, tumor
lysis from rapid cell growth and turnover, and GI bleeding
from neoplastic lesions. Concurrent viral infection furthers
host immunosuppression and may be a cofactor in PTLD
tumor growth. Thus, assessment of quantitative CMV viral
load should be routinely performed. EBV serology is an
insensitive and nonspecific test for PTLD due to altered
host antibody responses and may be difficult to interpret
as well after transfusion of red blood cell or plasma prod-
ucts. Quantitative measurement of EBV viral load used for
surveillance monitoring and indication of systemic disease
may be limited by insensitivity and lack of specificity but,
nevertheless, remain consistent within individual laboratory
testing . Michelson and coworkers analyzed bronchoalve-
for quantitative PCR for EBV and found values 50 times
higher in patients with PTLD. BAL proved to be highly
sensitive in detecting 3/3 cases of PTLD compared to testing
of peripheral blood .
3.5. Radiology and Imaging of PTLD. Since PTLD is likely
to present within the thorax, chest X-ray (CXR) may reveal
parenchymal lesions, infiltrates, and nodules, followed by
CT scan of the chest, abdomen, and pelvis, to assess lym-
phadenopathy. Concurrent imaging of the head and neck
may be performed given PTLD predilection for the CNS and
cervical lymph nodes. In recipients of solid organ transplant,
pulmonary nodules as noted on CXR and CT scanning in
EBV seronegative patients and lung transplant recipients
proved to be associated with PTLD (odds ratios 21.7 and
36.6, resp.) . Fluoro-2-deoxy-D-glucose (FDG-PET) has
become essential for accurate staging of extranodal and
extrathoracic sites of disease, as reported by Marom and
colleagues . In a retrospective analysis of lung transplant
patients who had developed PTLD, 4 patients were identified
pulmonary nodules noted on chest CT >5mm in diameter
attenuation lesions on CT in the liver and areas of bowel
thickening. FDG-PET also detected areas not noted on CT
scanning, such as abdominal and axillary lymph nodes. In
as well. FDG-PET has been proven superior to CT or PET
were identified by FDG-PET. A paracardiac lymph node
and pleural thickening were FDG-PET avid, as were low-
solid organ transplantation [41, 42].
In terms of localization of PTLD, intrathoracic location
is present in >70% of lung transplant recipients [6, 9, 11–
pulmonary nodule was most frequently found. Additional
abnormalities included numerous nodules, infiltrates, and
13, 34], and radiological findings provided the first sign of
disease. In 50% of cases of intrathoracic PTLD, a single
was associated with a better overall prognosis, as 8/9 patients
20% of lung transplant recipients, most often occurring in
the distal small bowel, and may reveal bowel wall thickening
or mass lesions [44, 45]. Involvement of the liver with
discrete nodularity  and CNS mass lesions have also been
noted on imaging . Complete staging may therefore
be accomplished by full body imaging, assessment of bone
marrow, and CNS.
with intrathoracic PTLD were alive 1 year after diagnosis
. Radiographically, GI involvement has been detected in
after Lung Transplantation. Current standard diagnosis of
PTLD requires a tissue diagnosis, evaluation of histopatho-
logical morphology, immunophenotype, presence of clonal-
ity, and testing of tissue for EBV using in situ hybridization
for EBER. Categories of PTLD as categorized by the WHO
classification of tumors of hematopoietic and lymphoid
tissues list early lesions, polymorphic PTLD, monomorphic
PTLD including B and T cell tumors, and classical Hodgkins
disease. Early lesions are considered benign and include
infectious mononucleosis-like and plasmacytic hyperplasia.
Polymorphic PTLD demonstrates mature lymphocytes and
polyclonal or monoclonal B cells for the majority, while
B cell neoplasms may include diffuse large B cell lym-
phoma (DLBCL), Burkitt’s lymphoma, plasma cell myeloma,
and plasmacytoma-like lesion, while T cell neoplasms may
include peripheral T cell lymphoma and hepatosplenic
T cell lymphoma . The two most commonly found
histopathologies of PTLD after lung transplantation have
been monomorphic diffuse large B cell lymphoma (DLBCL)
[11, 12, 48, 49] and polymorphic B cell lymphoma [3, 9], with
phic characteristic of later onset .
Recent consensus statements conclude that classification
according to WHO categories describes histopathological
features alone and therefore requires a complement of
additional studies to characterize immunohistochemistry,
testing for CD20 positivity, clonality, and in situ studies
clinical context such local or disseminated disease [4, 50].
Glotz and colleagues have also recommended addition of a
prognostic index, such as the International Prognostic Index
. The International Prognostic Index (IPI) is composed
into different survival outcomes based upon the number of
negative prognostic factors. These factors include age >60,
stage of tumor (grade III/IV disease), performance status,
Clinical and Developmental Immunology5
(LDH). A low or intermediate risk group would therefore
have age <60, stage I or II, lymphoma located within the
In addition to histopathology and ancillary testing to
provide insight into subsequent focused therapy, advances
in molecular and genetic analyses define additional features
of PTLD. As reviewed by Ibrahim and colleagues, distinct
genetic rearrangement, amplification, and somatic hypermu-
tation involving point mutations of the immunoglobulin (Ig)
variable region are associated with BCL6, BCL2, p53, and
PAX5 genes in PTLD. Gain or loss of chromosomal material
12q, 17p, and 18q.
Deletions of 4q, 17q, and Xp are unique to PTLD as
contrasted to lymphomas in immunocompetent patients.
which is hypothesized to play a role in immune surveillance
avoidance may reflect genetic alterations in immunosup-
suppressor genes, apoptotic pathways, and genes involved
in cell cycle regulation can be identified in PTLD. Such
genes found to be hypermethylated include death-associated
protein kinase (DAP-k) which plays a role in apoptosis, O6-
methylguanine-DNA methyltransferase (MGMT), a DNA
repair gene, P73, a tumor suppressor gene, P16, a cell cycle
inhibitor, and SHP1 gene, a cell cycle regulator .
lymph nodes, intact functionality, and normal serum LDH
3.7. Prognosis. In general, poor performance status, wide-
spread disease, CNS involvement, monoclonality, and T-,
outcome . Early PTLD as opposed to later onset PTLD
may be more amenable to reduced immunosuppression.
A retrospective review of all cases of PTLD at the Mayo
Clinic (Rochester) further noted that there were differences
a relatively late time point after transplant. The investigators
found that positive EBV in situ hybridization status, CD20-
positive status, and involvement of the organ that was trans-
not find differences in outcomes between PTLD presented
early compared to later . Paranjothi and colleagues from
confirmed the majority of PTLDs localized within the thorax
during the first year after lung transplantation and that
subsequent survival was better in those patients exhibiting
extra-thoracic disease .
Whether PTLD results from donor or recipient origin
may also play a role in prognosis, as Olagne and colleagues
documented in a large cohort of kidney transplant patients,
noting survival of 68% at 5 years in PTLD of recipient
origin, compared to 85% survival in PTLD of donor origin,
although this did not attain statistical significance . The
majority of PTLDs result from transformation of recipient
lymphocytes and are thus of recipient origin ; however,
or associated lymphoid tissue during transplantation .
There is limited data on percentages of PTLD of recipient
or donor origin in the majority of studies involving lung
transplantation yet is likely to play a role in outcomes and
management of host immunosuppression.
cite a mortality figure of 30%–60% due to PTLD [5, 6, 9, 10,
12, 48]. A recent individual center report of 32 patients with
PTLD from the University of Minnesota Lung Transplant
9/32 from PTLD, and 4/32 from other causes not associated
transplanted between the years 2000 and 2011 had better
survival than those transplanted between the years 1990 and
1999 . Taken together, these data confirm that PTLD still
remains a significant cause of morbidity and mortality after
lung transplantation. Please refer to Table 1 for a summary of
key clinical findings, histopathology, and treatment of PTLD
in lung transplant patients at individual transplant centers.
program cited an overall mortality of 75%, including 11/32
with PTLD . Another recent report from the University
of Pennsylvania Lung Transplant center found that patients
due to infection associated with PTLD and chemotherapy,
3.8. Prevention and Monitoring of EBV Viral Load. Essential
including identification of high-risk EBV-na¨ ıve patients and
routine surveillance for EBV viral load, antiviral prophylaxis,
and reduction in immunosuppression in appropriate high-
risk patients who have seroconverted their EBV status and
have detectable and/or rising EBV quantitative PCR. Prior
to transplantation at the time of evaluation, patients at risk
for primary EBV or CMV infection should be identified,
and appropriate serological testing should be performed.
After transplantation, patients whose immunosuppression
is being escalated, or who have received T cell depleting
therapies, should be monitored as well. Antiviral prophylaxis
is routinely given after lung transplantation, primarily for
HSV and CMV, but likely has added chemoprophylaxis
for EBV. Malouf and colleagues described a significantly
diminished rate of PTLD in lung transplant recipients after
elimination of induction therapy and institution of viral
prophylaxis in EBV seronegative patients, decreasing from
4.2% to 0.76% . Ganciclovir was shown to be superior
to acyclovir for reducing the odds of developing PTLD in
a renal transplant population, as prophylactic antiviral use
was associated with up to 83% reduction in the risk of PTLD
. The addition of intravenous immunoglobulin (IVIg) to
to the use of ganciclovir alone . Current practices of
prolonged CMV prophylaxis after lung transplantation 
may cause an unintended but beneficial effect upon reducing
EBV seroconversion during the early, highest period of
immunosuppression after transplant.
Although limited data exists in lung transplantation
regarding the prophylactic reduction of immunosuppression
in patients with presumptive PTLD, studies have shown that
under unique circumstances, immunosuppression may be
6Clinical and Developmental Immunology
Monitor EBV levels
Consider rituximabReduce immunosuppression
Signs or symptoms of PTLD
Continue to monitor
for EBV DNA
Biopsy if possible
± Surgery or radiation
Bortezomib, EBV-specific CTLs
Algorithm for monitoring, diagnosis, and treatment of PTLD
after lung transplantation
EBV na¨ ïve
High-grade extensive disease
Figure 2: This algorithm proposes routine surveillance of high-risk patients to enable diagnosis at an early stage. Starting with EBV viral
load monitoring, patients who manifest elevated levels with symptoms would progress to imaging studies and biopsy of enlarged lymph
nodes or nodules. Identification of CD20 lesion positivity, cytogenetics, immunostaining for LMP and EBER, and assessment of monoclonal
or polyclonal proliferation can focus further therapy. In localized disease, reduction of immunosuppression or surgery may be sufficient to
control disease, while rituximab may be given concurrently. High-grade extensive disease may require chemotherapy, bortezomib, or EBV-
specific cytotoxic T lymphocytes if available. From .
reduced safely without risk for acute or chronic allograft
dysfunction. Bakker and colleagues followed EBV viral loads
in a cohort of lung transplant patients on average 4 years
posttransplant, and reduced immunosuppression after find-
ing evidence of EBV reactivation, with no acute rejection,
acceleration of BOS, or poorer survival. The authors hypoth-
esized that EBV viral loads in this setting late after transplant
indicated the net state of immunosuppression . Although
current practice involves reduction in immunosuppression
in the face of a rising EBV viral load and suspicion of
acute rejection and BOS when PTLD occurs within the first
year after lung transplantation, and immunosuppression is
3.9. Treatment. The overall approach to treatment of PTLD
will vary according to the individual risk, clinical presenta-
tion, and stage and sites of disease, as depicted in Figure 2.
In general, treatment starts with reduction of immunosup-
pression, antiviral therapy if early in pathogenesis, anti-
CD20 (monoclonal B cell inhibitor), and chemotherapy
with CHOP for more widely disseminated disease. For
early presenting EBV-positive PTLD, immunosuppression
is reduced specifically by elimination of the cell cycle
inhibitor/antimetabolite, decreasing calcineurin inhibition
(CNI) and lowering corticosteroid dosing. Practices from
immunosuppression, antiviral therapy, surgical intervention
for large masses and/or abdominal perforation, rituximab,
and lastly chemotherapy for refractory or late-staged cancers
[5, 6, 8–13]. For localized or bulky disease within the chest,
as well as colonic obstruction, surgery may play a role in
debulking disease or averting colonic perforation. Rituximab
B cell tumor cells and has been proposed as a first-line agent
against PTLD. This murine/human monoclonal antibody
blocks steps in cell cycle progression and differentiation,
through complement and antibody-mediated cytotoxicity.
After Cook and coworkers cited a 66% response rate to
organ transplantation . Knoop and coworkers achieved
clinical remission in 66% of lung transplant patients with
PTLD after 4 courses, with a median survival subsequently
of 34 months . Oertel and colleagues achieved 52%
remission in recipients of solid organ transplant including
lung, who had developed PTLD, and noted a survival
of 37 months after PTLD . Similar results have been
reported from other centers, with clinical remission rates
Clinical and Developmental Immunology7
Table 1: Summary of outcomes of lung transplant patients with PTLD from US and European lung transplant centers.
Time to Dx PTLD
Sites of presentation
Armitage et al.
Lung, mediastinum, GI tract
RI, surgical resection,
36% mortality <1 year,
70% mortality >1 year
Aris et al.
Mediastinal mass, tonsil
enlargement, lung nodules,
bowel obstruction, skin nodules
Polymorphic B cell
hyperplasia and lymphoma,
RI, surgical excision of
mediastinal mass, CH
Average survival ∼11 months
Wigle et al.
Lung, mediastinum, abdomen
1 year survival rate of 58%
Paranjothi et al.
Lung, mediastinal lymph nodes,
liver, testicle, GI tract, bone
marrow, skin, ovary
RI, surgical resection,
Median survival 1.0 ± 1.5 years
Ramalingam et al.
Lung, small bowel, colon, skin
interferon, CH, XRT
5/8 patients died of
complications from PTLD
Reams et al.
Lung, small bowel, liver,
periaortic adenopathy, tongue,
polymorphic lymphoma, T
RI, rituximab, surgical
resection, CH, XRT
5/10 survival over 1992–2002
Tsai et al.
RI, rituximab, surgical
resection, CH, XRT
Median survival 12 months
Knoop et al.
Lung, mediastinum, cervical
nodes, liver, bone marrow
4/6 complete remission with
relapse free survival of 34
Baldanti et al.
RI, rituximab, CH
4/5 have died
Wudhikarn et al.
Lung, GI tract, intraabdominal
lymph nodes, CNS, bone marrow
RI, rituximab, surgical
resection, CH, XRT
Median survival 10 months
Kremer et al.
Lung, GI tract, nasopharynx,
skin, CNS, kidney, liver
RI, rituximab, CH, XRT
Median survival 18.5 months
∗This study examined 6/17 lung transplant patients with PTLD who received rituximab as a first-line therapy.
RI: reduced immunosuppression; CH: chemotherapy, XRT: radiation therapy.
of ∼60% [64–66]. Nevertheless, long-term survival may
period of therapy have yet to be determined. Common
side-effects reported include immediate hypersensitivity to
the infusion, nausea, vomiting, fever and chills, systemic
effects of tumor degradation, neutropenia, and profound B
lymphocyte depletion with increased susceptibility for CMV
reactivation. Another therapy targeting B cell lymphoma
cells is a compound called bortezomib, a boron-based drug
which causes proteosome inhibition. A clinical trial using
bortezomib for EBV-positive PTLD in conjunction with
rituximab is underway and may prove to be more effective
than rituximab alone (ClinicalTrials.gov, no. NCT01058239).
inated disease, clinical progression on rituximab, or non-
B cell PTLD. Regimens used by individual lung transplant
centers include a combination of the following chemother-
apeutic agents: cyclophosphamide, adriamycin, vincristine,
etoposide, and prednisone [5, 6, 8–13]. In a clinical trial of
rituximab followed by chemotherapy for PTLD (Clinical-
Trials.gov, no. NCT01458548), 60% of solid organ patients
had clinical remission and extended survival on average
of 6.6 years . Complications of systemic chemotherapy
are well documented and include nausea, vomiting, anemia,
neutropenia, lung injury, infections, and sepsis .
Promising therapies are emerging in the treatment of
PTLD, such as EBV-specific cytotoxic T cell therapy, which
as yet is still in experimental phase. Cytotoxic T lymphocytes
(CTLs) from healthy, EBV-experienced donors are adop-
tively transferred in order to better respond to EBV-positive
tumor cells in immunosuppressed solid organ transplant
patients. Optimally, HLA-matched allo-CTLs provide better
results and may be stored in a frozen bank after being
obtained from donors. This therapy was applied to solid
organ transplant patients with advanced PTLD in a phase
Clinical and Developmental Immunology
still be impacted, studies are difficult to interpret due to
uncontrolled treatment protocols, and timing and dosing
II clinical trial and resulted in ∼80% survival at 6 months
who had failed reduced immunosuppression, rituximab, and
chemotherapy received allo-CTLs with epitope specificity
to EBNA1, however, succumbed to respiratory failure. The
investigators identified tumor infiltration by the allo-CTLs,
thus demonstrating appropriate engagement of target cells,
but inadequatecontroloftheadoptiveresponse . Further
optimization of allo-CTL therapy in terms of dosing, epitope
specificity, HLA match, and recipient functional status may
help apply this therapy to the clinical arena.
Lastly, patients who survive PTLD and have chronic lung
to drug toxicity, may be considerd for retransplantation. In
a review of solid organ transplant recipients who survived
PTLD and underwent retransplant, time from PTLD to
retransplant was greater than 1 year in 75% of patients, with
[68, 69]. In a study of 3 patients who received allo-CTLs,
a lung transplant patient with monomorphic B cell PTLD
followup of 776 ± 249 days .
As collective experience grows with management of
PTLD after lung transplantation, optimal care, monitor-
ing of high-risk recipients, and treatment continue to be
refined. Additional monitoring tools may include soluble
CD30 which has been associated with lymphoproliferative
disorders  and quantification of circulating antibody free
light chains associated with B cell dysfunction prior to and
during PTLD . Expansion of EBNA1-specific CD4+ T
cells may improve the feasibilityof adoptive immunotherapy,
ultimately for autologous use . Thus, despite continued
challenges in managing PTLD, significant progress has been
made in risk stratification of lung transplant recipients,
monitoring and earlier diagnosis of PTLD, and biologi-
cally directed cell-specific therapies, which will continue to
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