Epstein-Barr Virus and Mononucleosis
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Epstein-Barr virus
Epstein-Barr virus
Shane C. McAllister, MD, PhD
Shane C. McAllister, MD, PhD
Pediatric Infectious Diseases Fellow
Pediatric Infectious Diseases Fellow
Stony Brook Long Island Children’s Hospital
Stony Brook Long Island Children’s Hospital
Overview
History of EBV and mononucleosis
EBV structure and gene expression
Pathogenesis/Clinical manifestations
Epidemiology
Diagnosis
Treatment
Cases
History of EBV and mononucleosis
INTRODUCTION
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
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
8 herpesviruses known to
infect humans
Strict species specificity
Closely related rodent and
non-human primate strains
used as animal models
Herpesviruses
Large double-stranded
DNA Viruses
≥ 84 different proteins
Maintenance/replication
of genome in host cell
nucleus
Herpesviruses
Life-long latency with
periodic lytic reactivation
Control of infection
requires cellular and
humoral immunity
Kinetic Classes of EBV Genes
Latency
LMP-1, EBNAs
Immediate Early
: initiate lytic cycle
Zta, Rta
Early
: condition the host cell environment and synthesize viral DNA
EA-D
Late
: structural components of capsids/mature virions
gp350
Pathogenesis/Clinical manifestations
DISEASE ASSOCIATIONS
Infectious Mononucleosis
Chronic Infectious Mononucleosis
Burkitt Lymphoma
Nasopharyngeal carcinoma
Hodgkin Lymphoma
Lymphoproliferative disease
X-linked Lymphoproliferative disease
Oral Leukoplakia (AIDS)
PATHOGENESIS
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
PATHOGENESIS
EBV infection triggers an impressive but
self-limited immune response
Infected B-cells are transformed and
secrete a diverse group of antibodies
Heterophile antibodies
Antibodies to specific EBV antigens
Various auto-antibodies
EBV induced polyclonal activation of B-
cells also leads to an increase in serum
immunoglobulins
PATHOGENESIS
Infected B-Lymphocytes induce T-
Lymphocyte proliferation
Manifested as Atypical Lymphocytosis
Proliferation of reactive T-cells and infected
B-cells leads to
Lymphadenopathy
Hepatosplenomegaly
CLINICAL MANIFESTATIONS
SYMPTOM
SYMPTOM
%
%
RANGE (%)
RANGE (%)
SORE THROAT
SORE THROAT
82
82
70 - 88
70 - 88
MALAISE
MALAISE
57
57
43 - 76
43 - 76
HEADACHE
HEADACHE
51
51
37 - 55
37 - 55
ANOREXIA
ANOREXIA
21
21
10 - 27
10 - 27
MYALGIAS
MYALGIAS
20
20
12 - 22
12 - 22
CHILLS
CHILLS
16
16
9 - 18
9 - 18
NAUSEA
NAUSEA
12
12
2 - 17
2 - 17
ABDOMINAL DISCOMFORT
ABDOMINAL DISCOMFORT
9
9
2 - 14
2 - 14
COUGH
COUGH
5
5
5
5
VOMITING
VOMITING
5
5
5
5
ARTHRALGIAS
ARTHRALGIAS
2
2
2
2
CLINICAL MANIFESTATIONS
SIGNS
SIGNS
%
%
RANGE (%)
RANGE (%)
LYMPHADENOPATHY
LYMPHADENOPATHY
94
94
93 - 100
93 - 100
PHARYNGITIS
PHARYNGITIS
84
84
69 - 91
69 - 91
FEVER
FEVER
76
76
63 - 100
63 - 100
SPLENOMEGALY
SPLENOMEGALY
52
52
50 - 63
50 - 63
HEPATOMEGALY
HEPATOMEGALY
12
12
6 - 14
6 - 14
PALATAL ENANTHEM
PALATAL ENANTHEM
11
11
5 - 13
5 - 13
JAUNDICE
JAUNDICE
9
9
4 - 10
4 - 10
RASH
RASH
10
10
0 - 15
0 - 15
PHYSICAL FINDINGS
EXUDATIVE PHARYNGITIS
PHYSICAL FINDINGS
TONSILLAR HYPERTROPHY
EBV – Physical Findings
Rash and Antibiotics
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
Transient hypersensitivity reaction
Immune complex production
Complications of Primary EBV
ORGAN/SYSTEM
COMPLICATIONS
LIVER:
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
COMPLICATIONS
SPLEEN:
Splenic rupture (0.1 – 0.5%)
Splenic Infarction
RENAL:
Hematuria
Interstitial nephritis
Glomerulonephritis
CARDIAC:
Myocarditis
Pericarditis
Arrhythmias
Complications of Primary EBV
ORGAN/SYSTEM
COMPLICATIONS
SECONDARY INFECTION:
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
2
May be the first or sole manifestation of EBV
mononucleosis
2
Occurs in 1 – 5% of cases
2
Prognosis is generally good with 85%
complete recovery
2
Most frequent cause of death related to
EBV Infectious Mononucleosis
2
Diagnosis is difficult
2
Heterophile is negative
2
Atypical lymphocytosis is minimal or absent
Neurologic Complications
Neurologic Complications
“Because EBV may present atypically
“Because EBV may present atypically
and has been associated with a
and has been associated with a
myriad of neurologic diseases, EBV
myriad of neurologic diseases, EBV
should be considered in all acute
should be considered in all acute
neurologic illnesses of unknown
neurologic illnesses of unknown
etiology in the Pediatric population”
etiology in the Pediatric population”
Connelly et al., Pediatr Neurol 1994; 10: 181-184
Connelly et al., Pediatr Neurol 1994; 10: 181-184
INFECTIOUS MONO IN CHILDREN
Compared with adolescents, young
children more commonly had the
following features:
URI symptoms
Rash
Splenomegaly and/or Hepatomegaly
Higher peak leukocyte counts with fewer
Atypical Lymphocytes
More frequent neutropenia
Epidemiology
EPIDEMIOLOGY
Antibodies to EBV found in all populations
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
Second wave in the second decade of life
No predilection for male or female
EPIDEMIOLOGY
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
Epstein-Barr virus
Cytomegalovirus
Toxoplasma gondii
Adenovirus
Human herpesvirus 6/7
Hepatitis A
Influenza A and B
Rubella virus
Diphtheria
HIV
Malignancies
DIFFERENTIAL DIAGNOSIS OF
MONO-LIKE SYNDROME
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
Atypical Lymphocytes
Activated T cells responding to the
EBV-infected B-cells
Features of Atypical Lymphs:
Larger than mature Lymphocytes
Have vacuolated basophilic cytoplasm
DIAGNOSIS
ATYPICAL LYMPHOCYTES
Heterophile Antibody Test
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
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
Collagen Vascular diseases
Leukemia/Lymphoma
Malaria
Pancreatic Carcinoma
Viral Hepatitis
Other
EBV SEROLOGY
The appearance of antibodies induced by
EBV specific antigens correlates with the
phase of replication
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
Antibodies to EA are not always detectable
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:
No anti-VCA IgM (Potential for false-positives)
No anti-EA IgG
DIAGNOSIS
Interpretation of EBV Serology
INFECTION
INFECTION
ANTI-VCA-IgM
ANTI-VCA-IgM
ANTI-VCA-IgG
ANTI-VCA-IgG
ANTI-EA ANTI-EBNA
ANTI-EA ANTI-EBNA
NONE
NONE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE NEGATIVE
NEGATIVE NEGATIVE
ACUTE
ACUTE
POSITIVE
POSITIVE
POSITIVE
POSITIVE
POS/NEG NEGATIVE
POS/NEG NEGATIVE
RECENT
RECENT
POS/NEG POSITIVE
POS/NEG POSITIVE
POS/NEG POS/NEG
POS/NEG POS/NEG
PAST
PAST
NEGATIVE
NEGATIVE
POSITIVE
POSITIVE
NEGATIVE POSITIVE
NEGATIVE POSITIVE
EBV SEROLOGY
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
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)
EBV - DIAGNOSIS
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
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
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
Supportive care
Avoid contact sports
Corticosteroids for selective complications
Airway obstruction
Massive splenomegaly
Myocarditis
Hemolytic Anemia/ITP
Acyclovir – No clearly documented benefit
ANTIVIRAL TREATMENT
5 randomized clinical trials conducted to
evaluate treatment of Infectious
Mononucleosis with Acyclovir (339 patients)
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
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
Periodically the virus can reactivate (virus
isolated in saliva)
Cases
Case 1
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
INFECTION
ANTI-VCA-IgM
ANTI-VCA-IgM
ANTI-VCA-IgG
ANTI-VCA-IgG
ANTI-EA ANTI-EBNA
ANTI-EA ANTI-EBNA
NONE
NONE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE NEGATIVE
NEGATIVE NEGATIVE
ACUTE
ACUTE
POSITIVE
POSITIVE
POSITIVE
POSITIVE
POS/NEG NEGATIVE
POS/NEG NEGATIVE
RECENT
RECENT
POS/NEG POSITIVE
POS/NEG POSITIVE
POS/NEG POS/NEG
POS/NEG POS/NEG
PAST
PAST
NEGATIVE
NEGATIVE
POSITIVE
POSITIVE
NEGATIVE POSITIVE
NEGATIVE POSITIVE
Case 2
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
DIAGNOSIS
Interpretation of EBV Serology
INFECTION
INFECTION
ANTI-VCA-IgM
ANTI-VCA-IgM
ANTI-VCA-IgG
ANTI-VCA-IgG
ANTI-EA ANTI-EBNA
ANTI-EA ANTI-EBNA
NONE
NONE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE NEGATIVE
NEGATIVE NEGATIVE
ACUTE
ACUTE
POSITIVE
POSITIVE
POSITIVE
POSITIVE
POS/NEG NEGATIVE
POS/NEG NEGATIVE
RECENT
RECENT
POS/NEG POSITIVE
POS/NEG POSITIVE
POS/NEG POS/NEG
POS/NEG POS/NEG
PAST
PAST
NEGATIVE
NEGATIVE
POSITIVE
POSITIVE
NEGATIVE POSITIVE
NEGATIVE POSITIVE
Case 3
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
DIAGNOSIS
Interpretation of EBV Serology
INFECTION
INFECTION
ANTI-VCA-IgM
ANTI-VCA-IgM
ANTI-VCA-IgG
ANTI-VCA-IgG
ANTI-EA ANTI-EBNA
ANTI-EA ANTI-EBNA
NONE
NONE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE
NEGATIVE NEGATIVE
NEGATIVE NEGATIVE
ACUTE
ACUTE
POSITIVE
POSITIVE
POSITIVE
POSITIVE
POS/NEG NEGATIVE
POS/NEG NEGATIVE
RECENT
RECENT
POS/NEG POSITIVE
POS/NEG POSITIVE
POS/NEG POS/NEG
POS/NEG POS/NEG
PAST
PAST
NEGATIVE
NEGATIVE
POSITIVE
POSITIVE
NEGATIVE POSITIVE
NEGATIVE POSITIVE
THANK YOU !
Discover the history, structure, gene expression, pathogenesis, clinical manifestations, epidemiology, diagnosis, and treatment of Epstein-Barr virus (EBV) and mononucleosis. Learn about the identification of EBV as the cause of infectious mononucleosis in 1968, its association with various diseases, and the unique aspects of herpesviruses. Explore the kinetic classes of EBV genes and the lifelong latency of herpesviruses.
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Presentation Transcript
Epstein-Barr virus Shane C. McAllister, MD, PhD Pediatric Infectious Diseases Fellow Stony Brook Long Island Children s Hospital
Overview History of EBV and mononucleosis EBV structure and gene expression Pathogenesis/Clinical manifestations Epidemiology Diagnosis Treatment Cases
INTRODUCTION 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 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
Herpesviruses 8 herpesviruses known to infect humans Strict species specificity Closely related rodent and non-human primate strains used as animal models
Herpesviruses Large double-stranded DNA Viruses 84 different proteins Maintenance/replication of genome in host cell nucleus
Herpesviruses Life-long latency with periodic lytic reactivation Control of infection requires cellular and humoral immunity
Kinetic Classes of EBV Genes Latency LMP-1, EBNAs Immediate Early: initiate lytic cycle Zta, Rta Early: condition the host cell environment and synthesize viral DNA EA-D Late: structural components of capsids/mature virions gp350
DISEASE ASSOCIATIONS Infectious Mononucleosis Chronic Infectious Mononucleosis Burkitt Lymphoma Nasopharyngeal carcinoma Hodgkin Lymphoma Lymphoproliferative disease X-linked Lymphoproliferative disease Oral Leukoplakia (AIDS)
PATHOGENESIS 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
PATHOGENESIS EBV infection triggers an impressive but self-limited immune response Infected B-cells are transformed and secrete a diverse group of antibodies Heterophile antibodies Antibodies to specific EBV antigens Various auto-antibodies EBV induced polyclonal activation of B- cells also leads to an increase in serum immunoglobulins
PATHOGENESIS Infected B-Lymphocytes induce T- Lymphocyte proliferation Manifested as Atypical Lymphocytosis Proliferation of reactive T-cells and infected B-cells leads to Lymphadenopathy Hepatosplenomegaly
CLINICAL MANIFESTATIONS SYMPTOM % RANGE (%) SORE THROAT MALAISE HEADACHE ANOREXIA MYALGIAS CHILLS NAUSEA ABDOMINAL DISCOMFORT COUGH VOMITING ARTHRALGIAS 82 57 51 21 20 16 12 9 5 5 2 5 2 70 - 88 43 - 76 37 - 55 10 - 27 12 - 22 9 - 18 2 - 17 2 - 14 5
CLINICAL MANIFESTATIONS SIGNS LYMPHADENOPATHY PHARYNGITIS FEVER SPLENOMEGALY HEPATOMEGALY PALATAL ENANTHEM JAUNDICE RASH % 94 84 76 52 12 11 9 10 RANGE (%) 93 - 100 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 Rash and Antibiotics 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 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 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 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 Compared with adolescents, young children more commonly had the following features: URI symptoms Rash Splenomegaly and/or Hepatomegaly Higher peak leukocyte counts with fewer Atypical Lymphocytes More frequent neutropenia
EPIDEMIOLOGY Antibodies to EBV found in all populations 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 Second wave in the second decade of life No predilection for male or female
EPIDEMIOLOGY 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
DIFFERENTIAL DIAGNOSIS OF MONO-LIKE SYNDROME Rubella virus Diphtheria HIV Malignancies Epstein-Barr virus Cytomegalovirus Toxoplasma gondii Adenovirus Human herpesvirus 6/7 Hepatitis A Influenza A and B
DIFFERENTIAL DIAGNOSIS OF MONO-LIKE SYNDROME 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
Atypical Lymphocytes Activated T cells responding to the EBV-infected B-cells Features of Atypical Lymphs: Larger than mature Lymphocytes Have vacuolated basophilic cytoplasm
DIAGNOSIS ATYPICAL LYMPHOCYTES
Heterophile Antibody Test 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 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
FALSE POSITIVE MONOSPOT Collagen Vascular diseases Leukemia/Lymphoma Malaria Pancreatic Carcinoma Viral Hepatitis Other
EBV SEROLOGY The appearance of antibodies induced by EBV specific antigens correlates with the phase of replication 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 Antibodies to EA are not always detectable 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: No anti-VCA IgM (Potential for false-positives) No anti-EA IgG
Interpretation of EBV Serology INFECTION ANTI-VCA-IgM ANTI-VCA-IgG ANTI-EA ANTI-EBNA NONE NEGATIVE NEGATIVE NEGATIVE NEGATIVE ACUTE POSITIVE POSITIVE POS/NEG NEGATIVE RECENT POS/NEG POSITIVE POS/NEG POS/NEG PAST NEGATIVE POSITIVE NEGATIVE POSITIVE
EBV SEROLOGY 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 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)
EBV - DIAGNOSIS 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 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 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 Supportive care Avoid contact sports Corticosteroids for selective complications Airway obstruction Massive splenomegaly Myocarditis Hemolytic Anemia/ITP Acyclovir No clearly documented benefit
ANTIVIRAL TREATMENT 5 randomized clinical trials conducted to evaluate treatment of Infectious Mononucleosis with Acyclovir (339 patients) 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
