Epstein-Barr virus: Difference between revisions
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m (ββ) Β |
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β | == |
+ | ==Background== |
β | === |
+ | ===Microbiology=== |
β | * A gamma-1 [[human herpesvirus|herpesvirus]] |
||
β | * Double-stranded DNA inside an icosahedral protein nucleocapsid surrounded by a lipid envelope with glycoproteins |
||
β | * Two strains (type 1 and 2) are serologically identical, but have unique epitopes |
||
β | * Infection can remain quiescent in B cells for life |
||
+ | *A member of the ''Gammaherpesvirinae'' subfamily within the [[Herpesviridae]] family |
||
β | === Epidemiology === |
||
+ | *Double-stranded DNA inside an icosahedral protein nucleocapsid surrounded by a lipid envelope with glycoproteins |
||
β | * Acquired via oral secretions, e.g. by kissing or sharing of food |
||
+ | *Two strains (type 1 and 2) are serologically identical, but have unique epitopes |
||
β | * Seroprevalence about 90-95% in adults, with about half of 5 year-olds already being seropositive |
||
+ | *Infection can remain quiescent in B cells for life |
||
β | ** Acquired earlier in low-income countries |
||
β | * Highest morbidity is with young adults who develop infectious mononucleosis during primary disease |
||
β | ** Includes barracks and universities |
||
β | === |
+ | ===Epidemiology=== |
β | * Acquired through mucous membrane contact of oral secretions |
||
β | * Immune response primarily with cytotoxic T cells and NK cells |
||
β | ** Atypical lymphocytosis develops from CD8 cells |
||
β | * Early response is against lytic antigens (including VCA and EA), and later response against latent proteins (EBNA1, EBNA2, EBNA3, and EBNALP) |
||
β | * Response also creates IgM antibodies to sheep, horse, and cow RBCs, called '''heterophile antibodies''' |
||
+ | *Acquired via oral secretions, e.g. by kissing or sharing of food |
||
β | == Clinical Presentation == |
||
+ | *Seroprevalence about 90-95% in adults, with about half of 5 year-olds already being seropositive |
||
β | === Childhood === |
||
+ | **Acquired earlier in low-income countries |
||
β | * In childhood, mostly asymptomatic or mild febrile illness |
||
+ | *Highest morbidity is with young adults who develop infectious mononucleosis during primary disease |
||
β | * May develop rashes, neutropenia, or pneumonia |
||
+ | **Includes barracks and universities |
||
β | * Can cause lymphadenopathy |
||
β | * Heterophile antibody may be negative if young; about 80% are positive by 4 years, though |
||
+ | ===Pathophysiology=== |
||
β | === Infectious mononucleosis === |
||
β | * Caused by primary infection, typically in an adolescent or young adult |
||
β | * Incubation period 30 to 50 days, and can have asymptomatic viral shedding for up to a month before symptoms |
||
β | * Causes about 80% of mononucleosis, with the rest being [[CMV]] |
||
β | * Symptoms include a triad of sore throat, fever, and lymphadenopathy (classically posterior cervical chain) |
||
β | ** Often preceded by prodromal symptoms of chils, sweats, anorexia, and malaise |
||
β | ** Can also have retro-orbital headaches, myalgias, and abdominal discomfort |
||
β | ** May have a rash which can take any form, and may have palatal petechiae |
||
β | ** Tonsils are sometimes exudative |
||
β | ** Often has splenomegaly, may have hepatomegaly, and rarely has jaundice |
||
β | * With exposure to [[amoxicillin]], almost all patients develop a diffuse maculopapular rash |
||
β | * May have transient heterophile antibodies, as well as [[atypical lymphocytosis]] |
||
β | * Resolves over 2 to 3 weeks, with fevers lasting up to 14 days, and fatigue lasting months |
||
+ | *Acquired through mucous membrane contact of oral secretions |
||
β | === Complications === |
||
+ | *Immune response primarily with cytotoxic T cells and NK cells |
||
β | * Linked to a number of '''malignancies''', including Burkitt lymphoma, nasopharyngeal carcinoma, and lymphoproliferative disorders |
||
+ | **Atypical lymphocytosis develops from CD8 cells |
||
β | * '''Neurologic''' complications include meningitis, encephalitis, Guillain-BarrΓ© syndromes, optic neuritis, retrobulber neuritis, cranial nerve palsies, mononeuritis multiplex, brachial plexus neuropathy, seizures, subacute sclerosing panencephalitis, transverse, myelitis, psychosis, demyelination, and hemiplegia |
||
+ | *Early response is against lytic antigens (including VCA and EA), and later response against latent proteins (EBNA1, EBNA2, EBNA3, and EBNALP) |
||
+ | *Response also creates IgM antibodies to sheep, horse, and cow RBCs, called '''heterophile antibodies''' |
||
+ | ==Clinical Manifestations== |
||
β | === Chronic infection === |
||
+ | ===Childhood=== |
||
β | * Classically in Japan and east Asia, possibly South America |
||
β | * Progressive disease related to infection of NK cells rather than B cells |
||
+ | *In childhood, mostly asymptomatic or mild febrile illness |
||
β | === EBV-associated malignancies === |
||
+ | *May develop rashes, neutropenia, or pneumonia |
||
+ | *Can cause lymphadenopathy |
||
+ | *Heterophile antibody may be negative if young; about 80% are positive by 4 years, though |
||
+ | |||
+ | ===Infectious Mononucleosis=== |
||
+ | |||
+ | *Caused by primary infection, typically in an adolescent or young adult |
||
+ | *EBV causes about 80% of mononucleosis, with the rest being [[CMV]] |
||
+ | *Incubation period [[Usual incubation period::30 to 50 days]], and can have asymptomatic viral shedding for up to a month before symptoms |
||
+ | *Symptoms include a triad of sore throat, fever, and lymphadenopathy (classically posterior cervical chain) |
||
+ | **Often preceded by prodromal symptoms of chils, sweats, anorexia, and malaise |
||
+ | **Can also have retro-orbital headaches, myalgias, and abdominal discomfort |
||
+ | **May have a rash which can take any form, and may have palatal petechiae |
||
+ | **Tonsils are sometimes exudative |
||
+ | **Often has splenomegaly, may have hepatomegaly, and rarely has jaundice |
||
+ | *With exposure to [[amoxicillin]], almost all patients develop a diffuse maculopapular rash |
||
+ | *May have transient heterophile antibodies (see Diagnosis, below), as well as [[Causes::atypical lymphocytosis]] |
||
+ | *Resolves over 2 to 3 weeks, with fevers lasting up to 14 days, and fatigue lasting months |
||
+ | |||
+ | ===Complications=== |
||
+ | |||
+ | *Linked to a number of '''malignancies''', including Burkitt lymphoma, nasopharyngeal carcinoma, and lymphoproliferative disorders |
||
+ | *'''Neurologic''' complications include meningitis, encephalitis, Guillain-BarrΓ© syndromes, optic neuritis, retrobulber neuritis, cranial nerve palsies, mononeuritis multiplex, brachial plexus neuropathy, seizures, subacute sclerosing panencephalitis, transverse, myelitis, psychosis, demyelination, and hemiplegia |
||
+ | |||
+ | ===Chronic Active EBV Disease=== |
||
+ | |||
+ | *See also [[Chronic active Epstein-Barr virus disease]] |
||
+ | *Classically in Japan and east Asia, possibly South America |
||
+ | *Progressive disease related to infection of NK or T cells rather than B cells |
||
+ | *Poor prognosis, with patients dying of progressive [[pancytopenia]], hypogammaglobulinemia, or NK/T cell nasal lymphoma within a few years |
||
+ | |||
+ | ===Oral Hairy Leukoplakia=== |
||
+ | |||
+ | ===EBV-Associated Malignancies=== |
||
{| class="wikitable" |
{| class="wikitable" |
||
β | ! |
+ | !Disease!!EBV!!Risk factors |
|- |
|- |
||
β | | |
+ | |Lymphoproliferative disease||90%||Transplantation patients and immunosuppression |
|- |
|- |
||
β | | |
+ | |Primary CNS lymphoma||100%||HIV with low CD4 and immunosuppression |
|- |
|- |
||
β | | |
+ | |Hodgkin lymphoma||50%||Children and young adults |
|- |
|- |
||
β | | |
+ | |Nasopharyngeal carcinoma||100%||Southern Chinese, Inuit |
|- |
|- |
||
β | | |
+ | |Gastric cancer||4 to 100%||Unknown |
|- |
|- |
||
β | | |
+ | |Endemic Burkitt lymphoma||95%||African children |
|- |
|- |
||
β | | |
+ | |Sporadic Burkitt lymphoma||20%||HIV independent of CD4 |
|} |
|} |
||
β | == |
+ | ==Diagnosis== |
β | === |
+ | ===Point-of-Care Testing=== |
β | * '''Monospot''' latex agglutination looking for '''heterophile antibodies''' |
||
β | ** 80% sensitive and 99% specific |
||
β | ** Less sensitive in young children |
||
β | ** False positive with acute HIV seroconversion |
||
+ | *'''Monospot''' latex agglutination looking for '''heterophile antibodies''' |
||
β | === Serology === |
||
+ | **50% sensitive in the first week of illness, but up to 80-95% sensitive by the third week, and 98-100% specific, overall |
||
β | * '''Anti-VCA''' (viral capsid antigens): most useful |
||
+ | **Less sensitive (10-50%) in young children (<4 years; lowest in those less than 2 years), with much lower negative predictive power |
||
β | ** Anti-VCA IgM: appears by presentation and disappears within 4 to 6 weeks; most useful with acute and convalescent |
||
+ | **Peak 2 to 5 weeks after symptom onset then usually decline quickly, but can persist for up to 6 to 12 months |
||
β | ** Anti-VCA IgG: appears in acute phase, peaks at 2 to 4 weeks, then declines but remains positive for life |
||
+ | **False positives are rare but can happen with rheumatoid disease, [[SLE]], [[leukemia]], [[lymphoma]], and other infections including [[malaria]], [[HIV]], [[CMV]], [[rubella]], [[viral hepatitis]] and [[tularemia]], and after administration of [[anti-thymocyte globulin]] |
||
β | * '''Anti-EA''' (early antigen) IgG: appears in acute phase and falls to undetectable within 3 to 6 months (but may persist for years) |
||
β | ** Least useful test |
||
β | * '''Anti-EBNA''' (EBV nuclear antigen): negative during acute phase converts after 2 to 4 months and stays positive for life |
||
+ | ===Serology=== |
||
β | ==== Immunocompetent hosts ==== |
||
+ | |||
+ | *Reviewed in [[CiteRef::de paschale2012se]] |
||
+ | *'''Anti-VCA''' (viral capsid antigens): most useful |
||
+ | **Anti-VCA IgM: appears by presentation and disappears within 4 to 6 weeks; most useful with acute and convalescent |
||
+ | **Anti-VCA IgG: appears in acute phase, peaks at 2 to 4 weeks, then declines but remains positive for life |
||
+ | *'''Anti-EA''' (early antigen) IgG: appears in acute phase and falls to undetectable within 3 to 6 months (but may persist for years) |
||
+ | **Least useful test |
||
+ | *'''Anti-EBNA''' (EBV nuclear antigen): negative during acute phase converts after 2 to 4 months and stays positive for life |
||
+ | |||
+ | ====Immunocompetent Hosts==== |
||
{| class="wikitable" |
{| class="wikitable" |
||
β | !align="center" |
+ | ! align="center" |VCA-IgM |
β | !align="center" |
+ | ! align="center" |VCA-IgG |
β | !align="center" |
+ | ! align="center" |EBNA-IgG |
β | ! |
+ | !Interpretation |
|- |
|- |
||
β | |align="center" |
+ | | rowspan="4" align="center" |β |
β | |align="center" |
+ | | rowspan="2" align="center" |β |
β | |align="center" |
+ | | align="center" |β |
β | | |
+ | |Susceptible |
|- |
|- |
||
β | |align="center"| |
+ | | align="center" | + |
+ | |Past infection or non-specific |
||
β | |align="center"| β |
||
β | |align="center"| + |
||
β | | Past infection or non-specific |
||
|- |
|- |
||
β | |align="center"| |
+ | | rowspan="2" align="center" | + |
β | |align="center" |
+ | | align="center" |β |
+ | |Acute or past infection |
||
β | |align="center"| β |
||
β | | Acute or past infection |
||
|- |
|- |
||
β | |align="center"| |
+ | | align="center" | + |
+ | |Past infection |
||
β | |align="center"| + |
||
β | |align="center"| + |
||
β | | Past infection |
||
|- |
|- |
||
β | |align="center"| + |
+ | | rowspan="4" align="center" | + |
β | |align="center" |
+ | | rowspan="2" align="center" |β |
β | |align="center" |
+ | | align="center" |β |
β | | |
+ | |Acute infection or non-specific |
|- |
|- |
||
β | |align="center"| + |
+ | | align="center" | + |
+ | |Uninterpretable |
||
β | |align="center"| β |
||
β | |align="center"| + |
||
β | | Uninterpretable |
||
|- |
|- |
||
β | |align="center"| + |
+ | | rowspan="2" align="center" | + |
β | |align="center" |
+ | | align="center" |β |
+ | |Acute infection |
||
β | |align="center"| β |
||
β | | Acute infection |
||
|- |
|- |
||
β | |align="center"| + |
+ | | align="center" | + |
+ | |Late primary infection or reactivation |
||
β | |align="center"| + |
||
β | |align="center"| + |
||
β | | Late primary infection or reactivation |
||
|} |
|} |
||
β | ==== |
+ | ====EBV-Associated Diseases==== |
{| class="wikitable" |
{| class="wikitable" |
||
β | ! |
+ | !Disease |
β | !align="center" |
+ | ! align="center" |VCA-IgM |
β | !align="center" |
+ | ! align="center" |VCA-IgG |
β | !align="center" |
+ | ! align="center" |VCA-IgA |
β | !align="center" |
+ | ! align="center" |EA(D)-IgG |
β | !align="center" |
+ | ! align="center" |EA(R)-IgG |
β | !align="center" |
+ | ! align="center" |EA-IgA |
β | !align="center" |
+ | ! align="center" |EBNA-IgG |
|- |
|- |
||
β | | |
+ | |Chronic active infection |
β | |align="center" |
+ | | align="center" |Β± |
β | |align="center"| ++ |
+ | | align="center" | ++ |
β | |align="center" |
+ | | align="center" |Β± |
β | |align="center"| + |
+ | | align="center" | + |
β | |align="center"| ++ |
+ | | align="center" | ++ |
β | |align="center" |
+ | | align="center" |β |
β | |align="center" |
+ | | align="center" |Β± |
|- |
|- |
||
β | | |
+ | |Burkitt lymphoma |
β | |align="center" |
+ | | align="center" |β |
β | |align="center"| ++ |
+ | | align="center" | ++ |
β | |align="center" |
+ | | align="center" |β |
β | |align="center" |
+ | | align="center" |Β± |
β | |align="center"| ++ |
+ | | align="center" | ++ |
β | |align="center" |
+ | | align="center" |β |
β | |align="center"| + |
+ | | align="center" | + |
|- |
|- |
||
β | | |
+ | |ENT carcinoma |
β | |align="center" |
+ | | align="center" |β |
β | |align="center"| ++ |
+ | | align="center" | ++ |
β | |align="center"| + |
+ | | align="center" | + |
β | |align="center"| ++ |
+ | | align="center" | ++ |
β | |align="center" |
+ | | align="center" |Β± |
β | |align="center"| + |
+ | | align="center" | + |
β | |align="center"| + |
+ | | align="center" | + |
|- |
|- |
||
β | | |
+ | |Hodgkin lymphoma |
β | |align="center" |
+ | | align="center" |β |
β | |align="center"| ++ |
+ | | align="center" | ++ |
β | |align="center" |
+ | | align="center" |β |
β | |align="center"| + |
+ | | align="center" | + |
β | |align="center" |
+ | | align="center" |β |
β | |align="center" |
+ | | align="center" |β |
β | |align="center"| + |
+ | | align="center" | + |
|- |
|- |
||
β | | |
+ | |Reactivation |
β | |align="center" |
+ | | align="center" |Β± |
β | |align="center"| ++ |
+ | | align="center" | ++ |
β | |align="center" |
+ | | align="center" |Β± |
β | |align="center"| + |
+ | | align="center" | + |
β | |align="center" |
+ | | align="center" |Β± |
β | |align="center" |
+ | | align="center" |Β± |
β | |align="center" |
+ | | align="center" |Β± |
|} |
|} |
||
β | === |
+ | ===PCR=== |
+ | |||
+ | *Useful for diagnosis of: |
||
+ | **Rare, [[chronic active Epstein-Barr virus disease]] |
||
+ | **Early [[post-transplant lymphoproliferative disease]] |
||
+ | **[[Nasopharyngeal carcinoma]] |
||
+ | *As well as monitoring response to treatment |
||
[[Category:Herpesviridae]] |
[[Category:Herpesviridae]] |
Latest revision as of 16:20, 7 June 2023
Background
Microbiology
- A member of the Gammaherpesvirinae subfamily within the Herpesviridae family
- Double-stranded DNA inside an icosahedral protein nucleocapsid surrounded by a lipid envelope with glycoproteins
- Two strains (type 1 and 2) are serologically identical, but have unique epitopes
- Infection can remain quiescent in B cells for life
Epidemiology
- Acquired via oral secretions, e.g. by kissing or sharing of food
- Seroprevalence about 90-95% in adults, with about half of 5 year-olds already being seropositive
- Acquired earlier in low-income countries
- Highest morbidity is with young adults who develop infectious mononucleosis during primary disease
- Includes barracks and universities
Pathophysiology
- Acquired through mucous membrane contact of oral secretions
- Immune response primarily with cytotoxic T cells and NK cells
- Atypical lymphocytosis develops from CD8 cells
- Early response is against lytic antigens (including VCA and EA), and later response against latent proteins (EBNA1, EBNA2, EBNA3, and EBNALP)
- Response also creates IgM antibodies to sheep, horse, and cow RBCs, called heterophile antibodies
Clinical Manifestations
Childhood
- In childhood, mostly asymptomatic or mild febrile illness
- May develop rashes, neutropenia, or pneumonia
- Can cause lymphadenopathy
- Heterophile antibody may be negative if young; about 80% are positive by 4 years, though
Infectious Mononucleosis
- Caused by primary infection, typically in an adolescent or young adult
- EBV causes about 80% of mononucleosis, with the rest being CMV
- Incubation period 30 to 50 days, and can have asymptomatic viral shedding for up to a month before symptoms
- Symptoms include a triad of sore throat, fever, and lymphadenopathy (classically posterior cervical chain)
- Often preceded by prodromal symptoms of chils, sweats, anorexia, and malaise
- Can also have retro-orbital headaches, myalgias, and abdominal discomfort
- May have a rash which can take any form, and may have palatal petechiae
- Tonsils are sometimes exudative
- Often has splenomegaly, may have hepatomegaly, and rarely has jaundice
- With exposure to amoxicillin, almost all patients develop a diffuse maculopapular rash
- May have transient heterophile antibodies (see Diagnosis, below), as well as atypical lymphocytosis
- Resolves over 2 to 3 weeks, with fevers lasting up to 14 days, and fatigue lasting months
Complications
- Linked to a number of malignancies, including Burkitt lymphoma, nasopharyngeal carcinoma, and lymphoproliferative disorders
- Neurologic complications include meningitis, encephalitis, Guillain-BarrΓ© syndromes, optic neuritis, retrobulber neuritis, cranial nerve palsies, mononeuritis multiplex, brachial plexus neuropathy, seizures, subacute sclerosing panencephalitis, transverse, myelitis, psychosis, demyelination, and hemiplegia
Chronic Active EBV Disease
- See also Chronic active Epstein-Barr virus disease
- Classically in Japan and east Asia, possibly South America
- Progressive disease related to infection of NK or T cells rather than B cells
- Poor prognosis, with patients dying of progressive pancytopenia, hypogammaglobulinemia, or NK/T cell nasal lymphoma within a few years
Oral Hairy Leukoplakia
EBV-Associated Malignancies
Disease | EBV | Risk factors |
---|---|---|
Lymphoproliferative disease | 90% | Transplantation patients and immunosuppression |
Primary CNS lymphoma | 100% | HIV with low CD4 and immunosuppression |
Hodgkin lymphoma | 50% | Children and young adults |
Nasopharyngeal carcinoma | 100% | Southern Chinese, Inuit |
Gastric cancer | 4 to 100% | Unknown |
Endemic Burkitt lymphoma | 95% | African children |
Sporadic Burkitt lymphoma | 20% | HIV independent of CD4 |
Diagnosis
Point-of-Care Testing
- Monospot latex agglutination looking for heterophile antibodies
- 50% sensitive in the first week of illness, but up to 80-95% sensitive by the third week, and 98-100% specific, overall
- Less sensitive (10-50%) in young children (<4 years; lowest in those less than 2 years), with much lower negative predictive power
- Peak 2 to 5 weeks after symptom onset then usually decline quickly, but can persist for up to 6 to 12 months
- False positives are rare but can happen with rheumatoid disease, SLE, leukemia, lymphoma, and other infections including malaria, HIV, CMV, rubella, viral hepatitis and tularemia, and after administration of anti-thymocyte globulin
Serology
- Reviewed in 1
- Anti-VCA (viral capsid antigens): most useful
- Anti-VCA IgM: appears by presentation and disappears within 4 to 6 weeks; most useful with acute and convalescent
- Anti-VCA IgG: appears in acute phase, peaks at 2 to 4 weeks, then declines but remains positive for life
- Anti-EA (early antigen) IgG: appears in acute phase and falls to undetectable within 3 to 6 months (but may persist for years)
- Least useful test
- Anti-EBNA (EBV nuclear antigen): negative during acute phase converts after 2 to 4 months and stays positive for life
Immunocompetent Hosts
VCA-IgM | VCA-IgG | EBNA-IgG | Interpretation |
---|---|---|---|
β | β | β | Susceptible |
+ | Past infection or non-specific | ||
+ | β | Acute or past infection | |
+ | Past infection | ||
+ | β | β | Acute infection or non-specific |
+ | Uninterpretable | ||
+ | β | Acute infection | |
+ | Late primary infection or reactivation |
EBV-Associated Diseases
Disease | VCA-IgM | VCA-IgG | VCA-IgA | EA(D)-IgG | EA(R)-IgG | EA-IgA | EBNA-IgG |
---|---|---|---|---|---|---|---|
Chronic active infection | Β± | ++ | Β± | + | ++ | β | Β± |
Burkitt lymphoma | β | ++ | β | Β± | ++ | β | + |
ENT carcinoma | β | ++ | + | ++ | Β± | + | + |
Hodgkin lymphoma | β | ++ | β | + | β | β | + |
Reactivation | Β± | ++ | Β± | + | Β± | Β± | Β± |
PCR
- Useful for diagnosis of:
- As well as monitoring response to treatment
References
- ^ Massimo De Paschale. Serological diagnosis of Epstein-Barr virus infection: Problems and solutions. World Journal of Virology. 2012;1(1):31. doi:10.5501/wjv.v1.i1.31.