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Running Head: EPSTEIN-BARR VIRUS
Melisa Dervisevic
Epstein - Barr virus Written Protocol
SUNY IT
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EPSTEIN-BARR VIRUS
Epstein - Barr virus Written Protocol
Definition of Problem, Pathophysiology, Etiology
Epstein-Barr virus (EBV), also called human herpes virus 4 (HHV-4) is part of the herpes
virus family. The virus was first revealed in 1964 by Michael Epstein and Yvonne Barr during
their research on Burkett’s lymphoma (Grywalska et al, 2013). EBV virions have a doublestranded, linear DNA genome encoding approximately 100 genes surrounded by a protein
capsid. A protein tegument lies between the capsid and the envelope (2013). The EBV genome
convert a series of products interacting with or exhibiting homology to a wide variety of
antiapoptotic molecules, cytokines, and signal transducers, therefore promoting EBV infection,
immortalization, and transformation (Carbone, Gloghini, & Dotti, 2008). There are three types of
latent gene expression in the EBV genome: latency I, latency II, and latency III (2008). In
latency I, there is an Epstein- Barr nuclear antigen I (EBNA-1) and two small noncoding
Epstein-Barr RNAs (EBERs). The gene expression in latency II includes the EBNA-1, the
EBERs, latent membrane protein (LMP)-1, LMP-2A, and LMP-2B. Latency III involves all of
the EBNAs, EBERs, and LMPs (2008).
Most primary EBV infections in healthy individuals are asymptomatic but occasionally
can cause acute infectious mononucleosis, which clears on its own. Once the individual has the
EBV infection, they become lifelong carriers of the virus. EBV then continues latently in the
host within long-life memory B cells. In a normal response, the growth of B cells latently
infected with EBV is controlled by the host immune response, mainly by virus- specific T cells.
However, in some individuals, the virus is implicated in the development of malignancy
(Grywalska et al, 2013). In the immunocompromised hosts, the interaction between EBV
replication, latency, and immune control can be interrupted and induces extended proliferation of
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EBV-infected lymphocytes and their malignant transformation (2013). EBV has been classified
as class I carcinogen and is associated with multiple malignancies and lymphoproliferative
disorders (Grose & Schub, 2013). There is strong evidence that shows association between EBV
and Burkitt’s lymphoma, NK/T-cell lymphoma, nasopharyngeal carcinoma (NPC), Hodgkin’s
lymphoma, and malignant lymphoma (2013). Also there has been some relations between EBV
and gastric carcinoma and breast carcinoma.
Incidence
The incidence of EBV is higher now than it was before because of all the detection tests
and studies being done that show correlation with different disease processes. Many children
become infected with EBV, and these infections are usually mild and cause no symptoms. When
adolescence and young adults get EBV infections, it causes infectious mononucleosis in 35-50%
of the time. Up to 95% of American adults aged 35-40 have been infected with EBV (Zhong,
2012). According to Centers for Disease Control and Prevention (CDC), infants become
susceptible to EBV as soon as maternal antibody protection disappears (2013).
Burkitt’s lymphoma is broken down into three different variants: endemic (affecting
children in equatorial Africa and New Guinea), sporadic (affecting children and young adults
throughout the world), and immunodeficiency related (HIV infection). Based on the different
variants, EBV has been identified in all cases of endemic variant, 15-20% of sporadic variant
cases, and 30-40% of the cases of the immunodeficiency variant (Carbone, Gloghini, & Dotti,
2008). There are different types of Hodgkin’s lymphoma and all have different degrees of EBV
in the tissue. EBV was found in lymphoma tissue in 70% of mixed cellularity (MC) Hodgkin’s
disease, 95% of lymphocyte depleted (LD), and 10-40% of nodular sclerosing (Grywalska et al,
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2013). AIDS-related lymphomas show an EBV infection in 40-90% of all cases (Leruez-Ville et
al, 2012).
Screening/Risk Factors
There are no current screenings done to test for EBV. The diagnosis is made by
symptoms and laboratory studies. EBV infections are most common in developing countries and
populations of low socioeconomic status (Grywalska et al, 2013). The areas with poor hygiene
practices have also shown to have an increased risk of developing EBV. Gender is not a risk
factor due to males and females both having the same chance of developing the virus. The
geographic location is another risk factor, regions such as central Africa, Papua New Guinea and
Alaska have higher percentages of EBV (2013). The virus can be spread through oral contact,
therefore sharing food, utensils, dishes, or glasses with an infected person is a risk factor. Kissing
an individual that has the virus is another risk factor. There are groups of individuals that are at
risk for developing a serious illness caused by EBV. Those people are organ transplant
recipients, those who are human immunodefiency (HIV) positive, those receiving chemotherapy,
or have other immune system disorder (Grose & Schub, 2013). Those individuals with Duncan’s
disease such as X-linked lymphoproliferative syndrome may also develop a serious illness
because they have weakened immune response (2013).
Clinical Findings
Infectious mononucleosis (IM) is the most common cause of EBV. The clinical
findings of the virus will depend on what illness/disease they have caused and it could be
different with the other diseases such as lymphoma. The classic three symptoms that characterize
IM are fever, pharyngitis, and lymphadenopathy (Marshall & Foxworth, 2012). Cervical lymph
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nodes are enlarged in majority of the cases. Before the patient develops any of these three
symptoms, they usually start with prodrome symptoms that last about a week. The nonspecific
clinical findings are headache, anorexia, malaise, and fatigue. There could be associated signs
and symptoms such as splenomegaly, hepatomegaly, rhinitis, cough, rash, abdominal pain, and
periorbital edema. This presentation usually represents adolescents.
Older adults are less likely to have sore throat and lymphadenopathy instead they have
hepatomegaly and jaundice (Ebell, 2004). When young children get infected with the virus, they
show minimal to no symptoms. If they do have any symptoms it will present as a viral upper
respiratory infection or gastrointestinal illness. IM in many cases could be confused with group
A streptococcal pharyngitis because they both can have palatal petechiae and tonsillar exudates
on the posterior oropharynx. Rash is normally not see with EBV, however a muculopapular rash
can occur in more than 90% of those patients treated with an aminopenicillin antibiotic
(ampicillin, amoxicillin) (Marshall & Foxworth, 2012). In this case the provider might have
treated the patient for group A streptococcal pharyngitis instead of IM.
Differential Diagnosis
When the virus is in the body the individual can present in many different ways. The
provider won’t always have a clear diagnosis from the start and will think about other reasons
why the patient is having the symptoms. The list of differential diagnosis that can come to mind
are:
1. Streptococcal pharyngitis and tonsillitis
2. Diphtheria
3. Blood dyscrasias
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4. Rubella
5. Measles
6. Viral Hepatitis (hepatitis A or B)
7. Cytomegalovirus
8. Toxoplasmosis
9. Acute HIV infection
(Marshall & Foxworth, 2012)
Social/Environmental Considerations
Based on the risk factors, good hand washing and hygiene is important to minimize the
chances of spreading or getting infected with the virus. Every person should avoid close contact
with a person that is infected and symptomatic. Transmission of this virus involves intimate
contact with saliva of an infected person. Transmission of this virus through the air or blood does
not normally occur (Centers for Disease Control and Prevention, 2013). The incubation period is
usually 4-6 weeks. There is no special precautions or isolation procedures required because the
virus is also found frequently in the saliva of healthy people (2013). These people can carry and
spread the virus sporadically throughout their life. They are usually the reservoir for person-toperson transmission. That is the prime reason why transmission of the virus is almost impossible
to prevent.
Laboratory Tests
When symptoms are not enough to make a clear diagnosis, laboratory studies might need
to be done to confirm before treatment is started. The most frequently used and rapid test is the
heterophil antibodies, also known as the monospot test. This test has great specificity because a
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positive result usually indicates infection with EBV, however the sensitivity ranges from 70-90%
(Marshall & Foxworth, 2012). Providers can also use viral capsid antigen of EBV to
differentiate between acute, recent, and past infections. The presence of IgM antibodies to the
viral capsid antigen of EBV happens within the first few weeks of the infection and disappears
after 3 months. The occurrence of IgG antibodies to the viral capsid antigen of EBV is seen early
in the disease but is also stays in the system for life. Antibodies to EBV early antigen (anti-EA)
occur weeks to months after infection and may exist for 6 months to years after the infection
(2012).
Another laboratory test that could be done is a CBC with differential that would show an
elevated white blood cell (WBC) count, decreased hematocrit, and decreased platelet count.
Liver function tests should be done to see if the liver enzymes are elevated. Peripheral blood
smears can be used in evaluating if there are any atypical large lymphocytes. If there are any
respiratory symptoms, a chest x-ray should be done to rule out infiltrates or pneumonia. If a
splenic rupture is questionable then an abdominal ultrasound must be done (Grose & Schub,
2013).
Management/Treatment
Non-Pharmacological
The ultimate treatment for IM is supportive care for symptomatic relief and promote
physiologic recovery. Adequate hydration and rest are the two main recommendations.
Encourage patients to do warm saline gargles for sore throat at least three times a day. The
patients should be provided writing material if they difficulty with verbal communication
because of the swelling. Vital signs should be monitored frequently. Humidification and head of
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the bed should be elevated to help patients breathe easier. Patients should be provided assistance
if they need it with hygiene and re-positioning themselves to prevent skin breakdown. All
physiological systems should be assessed especially neurological, lymphatic, and respiratory to
prevent further complications from occurring. Intake and output monitoring is important to
prevent dehydration.
Pharmacological
Pharmacological treatment is not recommended for a patient with IM but can be used to
treat some of the discomfort. Nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen
can be used for fever and myalgias. If the patient has moderate-severe sore throat, they can use
throat lozenges, sprays, or gargle with 2% lidocaine (Xylocaine) solution to relieve pharyngeal
discomfort (Ebell, 2004). Acyclovir (antiviral) can be used early in the course to reduce some of
the symptoms. However according to Ebell, a meta-analysis of five randomized controlled trials
involving 339 patients found that patients who took acyclovir had less oropharygneal shedding at
the end of therapy but it provided no significant or consistent clinical benefit (2004). If the
patient has a secondary bacterial infection such as streptococcal pharyngitis, an antibiotic can be
used. Corticosteroids are not recommended but can be used with severe complications such as
hematologic or neurologic complications or when the airway is compromised (severe
pharyngotonsillitis and oropharyngeal edema). The typical dose of corticosteroids is 1mg/kg/day
(with a maximum dose of 20mg/day) for 7 days. After the 7 days, the dosing should be tapered
before discontinuation. A small, double blinded, randomized trial of 33 confirmed IM children
was done, those who were given dexamethasone orally had less pain at 12 hours but not at
24,48,and 72 hours (Ebell,2004). This finding shows that more doses would be needed and is not
the best treatment.
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Complications
The two most serious complications of IM caused by EBV are airway obstruction and
splenic rupture. Airway obstruction can occur because of palatal and tonsillopharyngeal
hypertrophy. This could be very serious and might require an emergency tracheal insertion for
open airway. Splenic rupture is rare, it occurs in 0.1% of all cases but can be fatal if it does occur
(Marshall & Foxworth, 2012). In a review of 55 athletes with splenic rupture, almost all of the
ruptures occurred in the first three weeks of the illness. In the same group one half of the
ruptures didn’t cause any trauma (Ebell, 2004). The presence of acute abdominal pain that
localizes to the left quadrant and radiating to the left shoulder is a positive Kehrs sign and
indicates splenic rupture. The most common complications of EBV infections are mild
laboratory abnormalities. There could be neutropenia and thrombocytopenia that occurs early in
the infection. Severe autoimmune thrombocytopenia and autoimmune hemolytic anemia are less
common. Many patients have elevated transaminases but most of the time are asymptomatic.
EBV has been found to be a major cause of viral-induced hemophagocytic lymphohistiocytosis
(HLH) and is often associated with fatal IM (2012).
Neurologic complications are rare but can occur. These are encephalitis, meningitis,
Guillain-Barre syndrome, cranial nerve palsies, and transverse myelitis. Cardiac complications
are also rare but EBV can cause pericarditis and myocarditis. Even though it’s very uncommon,
EBV can cause malignancies such as Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin
disease, T-cell lymphoma, and gastric carcinoma (2012).
Follow-up
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Since EBV can cause many different complications, the patients should be monitored
closely during the first 2-3 weeks after the onset of symptoms. Then continue following the
patient until the symptoms subside completely. The patient should be closely monitored for
physical and laboratory evidence of splenic rupture, severe hemolytic anemia, thrombocytopenia
purpura, and encephalitis.
Counseling/Education
Education is very important in a patient who has IM caused by EBV in order to prevent
worsening symptoms or complications. You want to instruct the patient to avoid any contact
sports, heavy lifting, and excess exertion until spleen and live have returned to normal size. It
usually takes 3-4 weeks. It is difficult to depend on the physical exam alone in determining if the
patient has splenomegaly. In one study, an ultrasound detected splenomegaly in all affected
individuals with IM compared with 17% found by palpation only (Marshall & Foxworth, 2012).
The individual needs to eliminate alcohol and any other exposure to hepatotoxic drugs until liver
function tests are back to normal. They need to avoid oral (kissing) and physical contact with
others for several weeks during the active infection. Patients need to be educated on the
complications that could occur with IM and to call if they develop any new or worsening
signs/symptoms.
Consultation/Referral
Other specialist might need to be involved in the care of the patient with IM caused by
EBV if severe complications occur. A list of potential consults are:
1. Surgeon ( splenic rupture)
2. Ears, nose, throat (ENT) specialist ( airway obstruction)
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3. Hematologist ( anemia or thrombocytopenia)
4. Neurologist (Encephalitis)
5. Cardiologist (Pericarditis)
(Domino, 2010)
Literature Review
The majority of the articles were obtained from CINAHL databases. Some articles were
found at Medline plus, SAGE journals, and google scholar. It was difficult finding 25 peer
reviewed studies because there were too many case studies and descriptive articles. The key
terms used were Epstein - Barr virus, EBV, EBV diseases, EBV treatment, EBV education,
and EBV complications. A librarian helped out by guiding me in the right direction and
showing me how to search key terms suggested by the database. Most of the articles were
found using CINAHL’s suggested terms. The limitations that were used were the year from
2008-2013, English language, peer reviewed, journal articles, and full text. This helped
narrow the search down to the articles that were most helpful. EBV can cause many different
diseases or complications to the patient. After the 25 articles were obtained, I narrowed it
down to the most common themes and used the information from there to develop the
Appendix table.
The state of the science in most of the articles for EBV were related to infectious
mononucleosis as the most popular one but it also had different malignancies that were
related to EBV. The ones most commonly mentioned are lymphoma, childhood leukemia,
laryngeal carcinoma, breast cancer, multiple myeloma, nasopharyngeal carcinoma, and
Hodgkin’s. There were no specific guidelines that were mentioned, just the different
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correlations that were made between EBV and other medical illnesses. The major credible
authorities for the topic were department of cancer, pathology and microbiology, surgery,
hematology and research, and biomedical imaging. The similarities that were often include
the age group they used, population, where information was obtained from, and the positive
correlations between EBV and cancers. The differences are the different malignancies that
were mentioned in each article. I think this created the gaps in the studies. There were way
too many different diseases that were mentioned and small studies that were done. The
largest population size that was used was 108 and smallest was 10. Cancer was the common
theme in majority of the articles. There were a few studies that were done on the pediatric
population but the age group most often seen was 30’s-50’s. There some that were done on
men only and others that were done on female only. Refer to appendix for more information
on the different articles.
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Questions
1. How is the EBV transmitted?
a. Fecal-oral route
b. Blood/bodily fluids
c. Saliva or close oral contact ( EBV cells live in the mouth and spread by saliva)
d. Not contagious
2. What is the most common cause of EBV?
a. Hodgkin's
b. Infectious mononucleosis (EBV shown to cause most frequently)
c. Burkitt’s Lymphoma
d. Breast carcinoma
3. The highest incidence of EBV is between what age group?
a. 15-24 ( college students most at risk)
b. 40-60
c. 10-20
d. 6-8
4. Which individual is at most risk for getting EBV?
a. 12 month old that just started walking
b. 40 y.o that works at the hospital
c. 20 y.o in college ( most at risk because they share drinks, utensils, and risky behavior)
d. 10 y.o that plays three different sports
5. What is the most common clinical finding in Infectious mononucleosis?
a. RLQ pain and fever
b. Nausea/vomiting, increased WBC’s, abdominal pain
c. Jaundice and increased LFT’s
d. Fever, pharyngitis, and lymphadenopathy ( the classic triad of symptoms for Mono)
6. Discharge teaching should include?
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a. Appropriate follow-up
b. Teaching on EBV and how to prevent complications
c. Avoid physical contact
d. All of the above ( teaching should include ways to prevent splenic rupture)
7. What is the major reason you want the pt. to avoid physical contact?
a. So they don’t spread the infection to other teammates
b. They need their rest
c. Prevent dehydration
d. Prevent splenic rupture (one of major complications of Mono)
8. What would the CBC look like with a pt. with mono?
a. Elevated WBC’s, decreased Hct and platelets
b. Hct and Hgb decreased
c. Normal
d. WBC’s increased
9. The best treatment for Mono is?
a. Antibiotics
b. Antivirals
c. Oral or IV hydration and rest (supportive therapy best treatment)
d. Analgesics
10. Why might a person with mono need a surgical consult?
a. Possible tonsillectomy
b. Just to establish care
c. Possible spleenectomy ( if the person ruptures the spleen)
d. Not necessary
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Appendix A
Study
Focus
Dohno et al Evaluate the
(2010)
rate of VCAIgM and/or
VCA-IgG
negative
Japanese
patients
during the
acute phase of
IM
Subjects
N= 104
Japanese
children
with
EBV-IM
Population
Department
of Pediatrics
at Kochi
Medical
School
Hospital
from 19882003
Age
2month
s-13
years
LeruezVille et al
(2012)
Investigate
whether the
risk of
developing
lymphoma
was increased
when blood
EBV DNA
load was high
in previous
years
N= 43
cases of
AIDSrelated
lympho
ma
(ARL)
diagnose
d
between
19882007
French
Agence
Nationale
de
Rechercher
sur le SIDA
(ANRS)
PRIMO and
SEROCO
HEMOCO
No age
group
identifi
ed
Koh et al
(2012)
Evaluate the
potential roles
of age,
gender, stage,
and subtype
in the effect of
EBV on
overall,
diseasespecific, and
N= 159
patients
with
Hodgkin
’s
Lympho
ma (HL)
Patients
diagnosed at
Asan
Medical
Center,
Seoul,
Korea
4-77
years
old.
Male=
94
Female
s=
65
The
median
Method
EBV
genome in
peripheral
blood
mononuclea
r cells was
measured.
Serology
was based
on lab
immunefluorescence
assay
Two case
controls
matched for
the cohort
and CD4
cell count in
the year of
ARL. EBV
DNA was
measured in
PBMC’s
and serum
samples
Clinical
information
was
obtained via
medical
records
Finding
Anti VCAIgM was
positive rate
in acute
phase was
only 25% in
fants but
80% in
patients
>4years of
age
High levels
of EBV
DNA in
PBMCs
collected a
median of
10 months
before
diagnosis
were
associated
with
increased
risk of
system B
lymphoma
Tumor cell
EBV was +
in 34.5%
EBV + HL
was
associated
with age of
>25, male
gender, B
symptoms,
advanced
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event free
survival
Wu et al,
(2013)
Sehgal et
al, (2010)
Rota et al,
(2010)
age was
35.5
Demonstrate
that a
substantial
percentage of
the immune
thrombocytop
enia cases are
associated
with EBV and
CMV
Investigate the
association of
EBV in
childhood
leukemia
N= 42
patients
at
Sichuan
Universit
y
Patients
clinically
diagnosed
with ITP
and
received a
lap
splenectom
y 20082012
N=29
25 patients
consecuti with acute
ve
lymphocytic
patients
leukemia
(ALL) and
4 with
Hodgkin’s
Determine the
serum levels
of cytokines
in EBV DNA
positive
patients with
laryngeal
carcinoma
N=10
patients
Biopsy
tested
positive for
laryngeal
CA and
tumor tissue
positive for
EBV
age stage,
high risk
IPS, tx with
chemo
Averag Retrospectiv Nine
e= 36
e report on
(21.4%) and
42 ITP pts
eight (19%)
Male=1 and 20
ITP pts had
0
healthy
a positive
Female control
EBV and
= 32
cases
CMV
2-14
years
old.
Averag
e was
6.5
All
were
male
Averag
e age
54.6
EBV studies
using
sensitive
polymerase
chain
reaction
followed by
hybridizatio
n for
presence of
Bam H1-W
region of
EBV
genome and
detection of
anti Z EBV
replication
activator
The PCR
for EBV
was + in
8/25
patients of
ALL,
Western
blot test
using anti
Zebra
antibodies
was + in
5/25, and
32% of
children
with ALL
had
evidence of
active EBV
replication
Serum
No
cytokine
difference
levels were between
determined serum
by enzyme- levels of
linked
interleukin
immunosorb 1B, 2, 6,
ent assay
and 12.
Serum
levels of
interleukin
10 and B1
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Aguayo et
al, (2011)
Analyze the
presence of
HPV and
EBV in breast
cancer
N= 55
Agborsang
aya et al,
(2011)
Evaluate the
association
between
serum
antibodies
indicating
EBV infection
or reactivation
and risk of
pregnancyassociated
breast cancer
(PABC)
N=108
density
sampled
PABC
casecontrols
that were
previousl
y used
Investigate
whether there
are
differences
between two
groups of
Multiple
myeloma
(MM) and
control group
for presence
of EBV DNA
N=60
patients
(30 MM
and 30
control
group)
Sadeghian
et al,
(2011)
Breast
cancer
patients of
different
hospitals
from
Santiago of
Chile
Case and
controls
were used
from a
linkage of
the Finnish
Maternity
Cohort
(FMC) in
Finland
<65=
34
patients
>65=12
patients
60 formalinfixed
paraffin
embedded
bone
marrow
biopsies in
pathology
lab, Ghaem,
Iran
Averag
e age
control
group =
40-80
Averag
e age=
34.4
All
females
Averag
e age in
MM
58-66
Histological
classificatio
n was made
using the
guidelines
of the Japan
Cancer
Society
Nested casecontrol that
looked at
vitamin D
and
antibodies
to EBV for
PABC
Casecontrol
study was
done.
Several
sections
were cut
from each
paraffin
blocks, and
then DNA
was
extracted by
non-heating
extraction
method.
were higher
in EBV
DNA
+laryngeal
CA
HPV-16
was
detected in
4/46 BCs
(8.7%) and
EBV 3/46
(6.5%) BCs
Immunologi
cal markers
of EBV
reactivation
status
among
individuals
with
sufficient
vit D levels
were
consistently
associated
with
increased
risk of the
disease
DNA of
EBV was
detected in
10 patients
of case
control (5
males and 5
females)
and 3
subjects (2
males and 1
female) of
control
group
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Ferrari et
al, (2012)
Evaluate EBV
DNA levels
before
treatment and
during followup of Western
pts with locoregionally
advanced
nasopharynge
al carcinoma
(NPCs)
N= 36
consecuti
ve
patients
Patients
treated with
induction
chemothera
py followed
by
chemoradiat
ion
29-58
All
Italian
men
PCR was
carried out
for detection
of EBV
genome and
analyzed by
electrophore
sis
Prospective
study, EBV
copy
numbers
were
determined
after DNA
extraction
using realtime
quantitative
polymerase
chain
reaction
The study
confirmed
that patients
from a
Western
country
affected by
locoregionally
NPCs have
high plasma
EPV DNA
levels at
diagnosis.
All but one
patient has
a plasma
EBV DNA
concentratio
n of >350
copies/ml
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