epstein-barr virus epstein-barr virus shane c. mcallister, md, phd shane c. mcallister, md, phd...
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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
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 strainsused 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 % RANGE (%)
SORE THROAT 82 70 - 88MALAISE 57 43 - 76HEADACHE 51 37 - 55ANOREXIA 21 10 - 27MYALGIAS 20 12 - 22CHILLS 16 9 - 18NAUSEA 12 2 - 17ABDOMINAL DISCOMFORT 9 2 - 14COUGH 5 5VOMITING 5 5ARTHRALGIAS 2 2
CLINICAL MANIFESTATIONS
SIGNS % RANGE (%)
LYMPHADENOPATHY 94 93 - 100PHARYNGITIS 84 69 - 91FEVER 76 63 - 100SPLENOMEGALY 52 50 - 63HEPATOMEGALY 12 6 - 14PALATAL ENANTHEM 11 5 - 13JAUNDICE 9 4 - 10RASH 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 COMPLICATIONSLIVER: 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 COMPLICATIONSSPLEEN: Splenic rupture (0.1 – 0.5%)
Splenic Infarction
RENAL: HematuriaInterstitial nephritisGlomerulonephritis
CARDIAC: MyocarditisPericarditisArrhythmias
Complications of Primary EBV
ORGAN/SYSTEM COMPLICATIONSSECONDARY INFECTION: Streptococcal pharyngitis
Secondary sepsis due to neutropenia
IMMUNOLOGIC: Depressed T-cell immunity
NEUROLOGIC: EncephalitisAseptic MeningitisGuillain-Barre SyndromeCranial nerve palsiesTransverse MyelitisOptic NeuritisCerebellar AtaxiaBrachial 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
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 Malignancie
s
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 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
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 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
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 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
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 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
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