Transcript Epstein-Barr Virus (Powerpoint presentation)

Epstein-Barr virus
Shane C. McAllister, MD, PhD
Pediatric Infectious Diseases Fellow
Stony Brook Long Island Children’s Hospital
Overview
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History of EBV and mononucleosis
EBV structure and gene expression
Pathogenesis/Clinical manifestations
Epidemiology
Diagnosis
Treatment
Cases
History of EBV and mononucleosis
INTRODUCTION
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Infectious mononucleosis (IM) was first
recognized in1920 however the etiology was
unknown
The heterophile test was discovered to be
diagnostic for Infectious Mononucleosis in
1932
A viral cause of mononucleosis was
suspected in the 1960s when a laboratory
worker became ill while working with Burkitt
lymphoma tissue samples
INTRODUCTION
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In 1968, Epstein-Barr Virus was actually
identified as the cause of Infectious
Mononucleosis
Since the initial discovery, EBV has
been implicated in a wide variety of
both benign and malignant diseases
EBV structure and gene expression
Herpesviruses
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8 herpesviruses known to
infect humans
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Strict species specificity
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Closely related rodent and
non-human primate strains
used as animal models
Herpesviruses
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Large double-stranded
DNA Viruses
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≥ 84 different proteins
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Maintenance/replication
of genome in host cell
nucleus
Herpesviruses
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Life-long latency with
periodic lytic reactivation
Control of infection
requires cellular and
humoral immunity
Kinetic Classes of EBV Genes
 Latency
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LMP-1, EBNAs
 Immediate Early: initiate lytic cycle
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Zta, Rta
 Early: condition the host cell environment and synthesize viral DNA
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EA-D
 Late: structural components of capsids/mature virions
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gp350
Pathogenesis/Clinical manifestations
DISEASE ASSOCIATIONS
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Infectious Mononucleosis
Chronic Infectious Mononucleosis
Burkitt Lymphoma
Nasopharyngeal carcinoma
Hodgkin Lymphoma
Lymphoproliferative disease
X-linked Lymphoproliferative disease
Oral Leukoplakia (AIDS)
PATHOGENESIS
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EBV infection is considered
immunopathologic rather than tissue
destructive
EBV initially infects and replicates in the
oropharyngeal epithelial cells
 B-cells are subsequently infected
 Infected B-cells disseminate throughout the
lymphoreticular system
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PATHOGENESIS
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EBV infection triggers an impressive but
self-limited immune response
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Infected B-cells are transformed and
secrete a diverse group of antibodies
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Heterophile antibodies
Antibodies to specific EBV antigens
Various auto-antibodies
EBV induced polyclonal activation of Bcells also leads to an increase in serum
immunoglobulins
PATHOGENESIS
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Infected B-Lymphocytes induce TLymphocyte proliferation
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Manifested as Atypical Lymphocytosis
Proliferation of reactive T-cells and infected
B-cells leads to
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Lymphadenopathy
Hepatosplenomegaly
CLINICAL MANIFESTATIONS
SYMPTOM
%
RANGE (%)
SORE THROAT
82
70 - 88
MALAISE
HEADACHE
ANOREXIA
MYALGIAS
CHILLS
NAUSEA
ABDOMINAL DISCOMFORT
COUGH
VOMITING
ARTHRALGIAS
57
51
21
20
16
12
9
5
5
2
43 - 76
37 - 55
10 - 27
12 - 22
9 - 18
2 - 17
2 - 14
5
5
2
CLINICAL MANIFESTATIONS
SIGNS
%
RANGE (%)
LYMPHADENOPATHY
94
93 - 100
PHARYNGITIS
FEVER
SPLENOMEGALY
HEPATOMEGALY
PALATAL ENANTHEM
JAUNDICE
RASH
84
76
52
12
11
9
10
69 - 91
63 - 100
50 - 63
6 - 14
5 - 13
4 - 10
0 - 15
PHYSICAL FINDINGS
EXUDATIVE PHARYNGITIS
PHYSICAL FINDINGS
TONSILLAR HYPERTROPHY
EBV – Physical Findings
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Rash and Antibiotics
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Nonspecific maculopapular eruption associated
with administration of Ampicillin/Amoxil (50 –
100%)
 May be associated with other -lactam
antibiotics (40 – 60%)
 Usually develops 7 – 10 days after the first dose
 Does not represent Penicillin allergy
 Mechanism is unclear
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Transient hypersensitivity reaction
Immune complex production
Complications of Primary EBV
ORGAN/SYSTEM
LIVER:
COMPLICATIONS
Abnormal Liver Function Tests (80 – 90%)
Clinical jaundice (5%)
Fulminant hepatitis (rare)
RESPIRATORY:
Airway Obstruction (<5%)
Interstitial Pneumonitis (Rare)
HEMATOLOGIC:
Thrombocytopenia (25-50% Mild/Mod)
Neutropenia (50 – 80% - Mild/Mod)
Pancytopenia (Rare)
Hemolytic Anemia (3%)
Aplastic Anemia (Rare)
Complications of Primary EBV
ORGAN/SYSTEM
SPLEEN:
COMPLICATIONS
Splenic rupture (0.1 – 0.5%)
Splenic Infarction
RENAL:
Hematuria
Interstitial nephritis
Glomerulonephritis
CARDIAC:
Myocarditis
Pericarditis
Arrhythmias
Complications of Primary EBV
ORGAN/SYSTEM
SECONDARY INFECTION:
COMPLICATIONS
Streptococcal pharyngitis
Secondary sepsis due to neutropenia
IMMUNOLOGIC:
Depressed T-cell immunity
NEUROLOGIC:
Encephalitis
Aseptic Meningitis
Guillain-Barre Syndrome
Cranial nerve palsies
Transverse Myelitis
Optic Neuritis
Cerebellar Ataxia
Brachial Plexus Neuropathy
Neurologic Complications
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May be the first or sole manifestation of EBV
mononucleosis
Occurs in 1 – 5% of cases
Prognosis is generally good with 85%
complete recovery
Most frequent cause of death related to
EBV Infectious Mononucleosis
Diagnosis is difficult
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Heterophile is negative
Atypical lymphocytosis is minimal or absent
Neurologic Complications
“Because EBV may present atypically
and has been associated with a
myriad of neurologic diseases, EBV
should be considered in all acute
neurologic illnesses of unknown
etiology in the Pediatric population”
Connelly et al., Pediatr Neurol 1994; 10: 181-184
INFECTIOUS MONO IN CHILDREN
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Compared with adolescents, young
children more commonly had the
following features:
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URI symptoms
Rash
Splenomegaly and/or Hepatomegaly
Higher peak leukocyte counts with fewer
Atypical Lymphocytes
More frequent neutropenia
Epidemiology
EPIDEMIOLOGY
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Antibodies to EBV found in all populations
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Lower socioeconomic groups- higher prevalence
By adulthood, 90 - 95% of most populations
have demonstrable antibodies
In the US, EBV seroconversion occurs before
age 5 years in 50% of the population
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Second wave in the second decade of life
No predilection for male or female
EPIDEMIOLOGY
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In the US - 45.2 cases/100,000/year
The incidence is highest in the 15 - 24
year-old age group
College and military populations have
the highest morbidity
Not a reportable disease
No clear seasonal pattern
Diagnosis
DIFFERENTIAL DIAGNOSIS OF
MONO-LIKE SYNDROME
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Epstein-Barr virus
Cytomegalovirus
Toxoplasma gondii
Adenovirus
Human herpesvirus 6/7
Hepatitis A
Influenza A and B
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Rubella virus
Diphtheria
HIV
Malignancies
DIFFERENTIAL DIAGNOSIS OF
MONO-LIKE SYNDROME
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CMV mononucleosis is most frequently
confused with EBV:
Patients are generally older (Adults)
 Pharyngitis and lymphadenopathy – less
common
 Fever and malaise are the major
manifestations
 Heterophile negative
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Atypical Lymphocytes
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Activated T cells responding to the
EBV-infected B-cells
Features of Atypical Lymphs:
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Larger than mature Lymphocytes
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Have vacuolated basophilic cytoplasm
DIAGNOSIS
ATYPICAL LYMPHOCYTES
Heterophile Antibody Test
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Heterophile antibodies comprise a broad
class of antibody characterized by ability to
agglutinate antigens on RBCs from different
mammalian species
IM heterophile Ab (IgM) does not react with
EBV- specific antigens characterized by its
ability to react with beef, sheep and horse
RBCs
The antigen that stimulates this heterophile
ab is unknown
Heterophile Antibody Test
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Replaced by the monospot slide test
(Antigen-coated beads on a slide)
15% of patients with IM may be initially
heterophile negative and become positive
within 2 – 3 weeks
High false negative rate in children less than
4 years (>50%)
False positive rate - 7%
Remains positive for up to 9 months
Sensitivity and specificity: 85%/97%
MONOSPOT
NEGATIVE
POSITIVE
Sumaya et al., Pediatrics 1985; 75: 1011 - 1019
FALSE – POSITIVE MONOSPOT
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Collagen Vascular diseases
Leukemia/Lymphoma
Malaria
Pancreatic Carcinoma
Viral Hepatitis
Other
EBV SEROLOGY
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The appearance of antibodies induced by
EBV specific antigens correlates with the
phase of replication
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IgM antibody to VCA appears at the onset of
symptoms and typically disappears within 1 – 3
months
IgG antibody to VCA begins to rise shortly after
the onset of symptoms
 Peaks at 2 – 3 months
 Gradually decreases to a steady-state and
persists for life
EBV SEROLOGY
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Antibodies to EA are not always detectable
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IgG to EA begins to rise at the onset of symptoms
Peak concentration occurs at 3 – 4 weeks
Subsequently decreases and disappears
Antibodies to EBNA appear during the
convalescent period and persist for life along
with anti-VCA IgG
Past infection:
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No anti-VCA IgM (Potential for false-positives)
No anti-EA IgG
DIAGNOSIS
Interpretation of EBV Serology
INFECTION
ANTI-VCA-IgM ANTI-VCA-IgG ANTI-EA
NONE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE
ACUTE
POSITIVE
POSITIVE
POS/NEG
NEGATIVE
RECENT
POS/NEG
POSITIVE
POS/NEG
POS/NEG
PAST
NEGATIVE
POSITIVE
NEGATIVE
POSITIVE
ANTI-EBNA
EBV SEROLOGY
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Effective lab diagnosis can be made
on single acute phase serum sample
Antibody response appears rapidly
(onset of symptoms)
Acute and Convalescent phase serum
will not demonstrate a significant
change in antibody titer
EBV SEROLOGY
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Literature supports the general
concern that there is considerable
variation in the performance of
serological test kits for EBV and other
infectious agents
VCA-IgM
Cross-reactivity occurs
 Especially with other herpesviruses (CMV)
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EBV - DIAGNOSIS
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The ability of EBV to maintain lifelong
latency with low levels of replication
and viral shedding results in enduring
antigen exposure and continued
humoral immune response
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Variation of EBV antibody titers may be
due to reactivation of latent virus due to
infection with another virus and
development of cross-reactive antibodies
EBV - DIAGNOSIS
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Important to be aware of nuances of
serologic testing as well as viral
detection for latent viruses such as EBV
Must be cautious with utilization of
serologic testing/DNA detection as the
sole means for establishing causal
relationship between illness and EBV
infection
Treatment
TREATMENT
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Supportive care
Avoid contact sports
Corticosteroids for selective complications
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Airway obstruction
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Massive splenomegaly
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Myocarditis
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Hemolytic Anemia/ITP
Acyclovir – No clearly documented benefit
ANTIVIRAL TREATMENT
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5 randomized clinical trials conducted to
evaluate treatment of Infectious
Mononucleosis with Acyclovir (339 patients)
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Studies showed no statistically significant benefit
or clinical effectiveness
Met-analysis also showed no significance
No evidence that therapy shortens duration of
symptoms or prevents complications
Prognosis and Outcome
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The majority of cases are
uncomplicated resolving in 1 – 2
months
Minority of patients experience
persistent fatigue for up to 6 months
Although EBV remains latent lifelong in
a few cells in throat and blood, not
thought to be clinically significant
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Periodically the virus can reactivate (virus
isolated in saliva)
Cases
Case 1
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5 year old female with acute febrile illness
including URI symptoms and sore throat
Physical exam significant for exudative tonsillitis
and cervical adenopathy
Rapid GAS test negative but patient started on
Amoxil pending culture.
Patient developed diffuse rash on second day of
antibiotic treatment.
Culture negative
Interpretation of EBV Serology
INFECTION
ANTI-VCA-IgM ANTI-VCA-IgG ANTI-EA
NONE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE
ACUTE
POSITIVE
POSITIVE
POS/NEG
NEGATIVE
RECENT
POS/NEG
POSITIVE
POS/NEG
POS/NEG
PAST
NEGATIVE
POSITIVE
NEGATIVE
POSITIVE
ANTI-EBNA
Case 2
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15 year old female with acute febrile illness of 6
days duration including sore throat, malaise,
fatigue, and swollen glands
Physical exam significant for no tonsillar tissue,
positive cervical adenopathy, no HSM
Lab work demonstrated:
elevated WBC with lymphocyte predominance
 Heterophile antibody positive, VCA IgM positive;
VCA IgG, EAD IgG, and EBNA IgG negative
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DIAGNOSIS
Interpretation of EBV Serology
INFECTION
ANTI-VCA-IgM ANTI-VCA-IgG ANTI-EA
NONE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE
ACUTE
POSITIVE
POSITIVE
POS/NEG
NEGATIVE
RECENT
POS/NEG
POSITIVE
POS/NEG
POS/NEG
PAST
NEGATIVE
POSITIVE
NEGATIVE
POSITIVE
ANTI-EBNA
Case 3
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17 year old male diagnosed with mono one year
ago presents with continued fatigue. He sleeps 7
to 8 hours a night and is a long distance runner
Physical exam is normal
Lab work demonstrated:
Normal CBC
 Heterophile antibody, VCA IgM, and EAD IgG
negative; VCA IgG and EBNA IgG positive
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DIAGNOSIS
Interpretation of EBV Serology
INFECTION
ANTI-VCA-IgM ANTI-VCA-IgG ANTI-EA
NONE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE
ACUTE
POSITIVE
POSITIVE
POS/NEG
NEGATIVE
RECENT
POS/NEG
POSITIVE
POS/NEG
POS/NEG
PAST
NEGATIVE
POSITIVE
NEGATIVE
POSITIVE
ANTI-EBNA
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