Referat Ebv
Referat Ebv
Referat Ebv
Anne K. Junker
Pediatrics in Review 2005;26;79
DOI: 10.1542/pir.26-3-79
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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
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Pediatrics. All rights reserved. Print ISSN: 0191-9601.
Epstein-Barr Virus
Anne K. Junker, MD*
Objectives After completing this article, readers should be able to:
Introduction
EBV was identified initially in 1964 in tumor tissue from a patient who had African Burkitt
lymphoma (BL), a rapidly growing, usually fatal malignancy of the B lymphocyte. When a
laboratory technician working with this new virus became ill with mononucleosis and
seroconverted to EBV, the link between EBV and mononucleosis became apparent. Soon
thereafter, seroepidemiologic studies revealed that EBV infects virtually all of the world’s
population, usually as a subclinical or trivial illness in childhood. A decade later, reports of
a familial X-linked disorder of fatal infectious mononucleosis highlighted the importance
of immunogenetic factors in the management of EBV infec-
tion. Now, nearly 40 years after its discovery, EBV continues
to captivate clinicians, virologists, oncologists, geneticists,
Abbreviations and immunologists attempting to understand this highly
BL: Burkitt lymphoma successful human pathogen.
BLPD: B-cell lymphoproliferative disease
CAEBV: chronic active EBV infection Epidemiology
CMV: cytomegalovirus EBV is a ubiquitous, worldwide pathogen that is harbored
EBNA: EB nuclear antigen persistently by virtually all adults, regardless of geographic
EBV: Epstein-Barr virus location. After primary infection, the virus latently infects
EBV-HLH: EBV-associated hemophagocytic circulating B cells and is shed silently into saliva and genital
lymphohistiocytosis secretions. The colloquial term “kissing disease” acknowl-
HD: Hodgkin disease edges the oral route by which most people are infected.
HHV: human herpesvirus Spread is associated with close personal contact, so it is not
HSV: herpes simplex virus surprising that the age at first infection varies according to
Ig: immunoglobulin living conditions. Infection occurs at an earlier age in the
IL: interleukin presence of poor hygiene and crowded living conditions;
IM: infectious mononucleosis infection rates in young children are higher in developing
NK: natural killer countries and underprivileged societies. Depending on the
NPC: nasopharyngeal carcinoma population studied, the prevalence of EBV infection during
PCR: polymerase chain reaction childhood ranges from 20% to 80% by age 2 to 3 years. In
VCA: virus capsid antigen industrialized countries that have high standards of living, it
VZV: varicella-zoster virus is more common for primary EBV infection to occur in
XLP: X-linked lymphoproliferative disease adolescence. Infection at this time causes infectious mono-
nucleosis (IM) in 30% to 50% of cases. IM does not show
*Associate Professor, Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British
Columbia and Children’s & Women’s Health Centre of British Columbia, Vancouver, BC, Canada.
consistent seasonal or yearly variation in occurrence and site of persistence and can reactivate, intermittently, with
rarely is associated with temporal clustering of cases. or in the absence of clinical disease. HSV infects the
EBV infection of siblings in families can occur, and adult motor root ganglia, and reactivation can be silent or
household members can show serologic evidence of re- result in “cold sores.” VZV infects dorsal root ganglia,
cent (re)exposure. EBV also can be transmitted by blood and reactivation presents as “shingles.” EBV and CMV
product transfusion and with bone marrow and solid regularly reactivate, but without signs or symptoms of
organ transplantation. Sexual transmission is suggested clinical disease.
by the demonstration of virus in cervical and male genital Unlike the other herpesviruses, it has not been possi-
secretions and in the significantly greater EBV seropreva- ble to identify EBV in clinical specimens by using tradi-
lence among sexually active students. Congenital infec- tional virus diagnostic laboratory techniques. EBV was
tion after primary disease of mothers during pregnancy is identified initially by electron microscopy in BL cells, but
rare, probably because of the very low proportion of only after these tumor cells had been “shocked” by
EBV-naive women. culture as a cell suspension for some time. EBV does not
The two major strains of EBV (EBV type-1 and replicate well in tissue culture systems, does not tend to
-2) differ biologically and in their geographic and ethnic carry out a full lytic cycle, and, thus, is not cytopathic.
prevalences, although they show no clear differences in This feature means that clinical specimens from patients,
associated clinical diseases. Minor genetic variations give even those heavily infected with EBV, are “culture-
rise to distinct EBV isolates or substrains. Healthy indi- negative.” EBV has the ability to infect B lymphocytes.
viduals can be coinfected with more than one distinct Rather than damaging the cells, EBV activates B cells and
EBV isolate. Infection with a new strain may provide the induces rapid expansion of the infected cell population
basis for some cases of recurrent IM because initial by increasing cell numbers and extending cell survival. In
infection with one EBV strain does not preclude subse- years past, before the advent of molecular diagnostic
quent superinfection. tools, the presence of EBV was implied when filtered
clinical specimens, applied to cultures of (EBV-naı̈ve)
The Biology of EBV Infection cord blood lymphocytes, led to transformation of these
EBV is a gamma-type herpesvirus and shares the special cells into permanently growing, “immortalized” cell
characteristics of lymphotropism and neoplastic associa- lines. EBV has been a valuable tool for immunology
tion with other members in this group, which includes studies of B lymphocyte function in vitro because the
the most recently identified Kaposi sarcoma-associated virus is a potent stimulator of antibody production. Per-
virus, human herpesvirus 8 (HHV8). The herpesviruses manently growing B-lymphocyte cell lines, developed by
are large, complex DNA viruses that code approximately in vitro EBV infection of patient B cells, have provided a
100 proteins. These pathogens have coevolved with their sustainable source of material for metabolic and genetic
hosts over millions of years, and both parties have devel- studies.
oped highly sophisticated strategies for survival.
Probably no other virus group has such an impact on The Virus Life Cycle
the pediatric population. Members include herpes sim- The current belief is that the B lymphocyte provides all
plex (HSV) 1 and 2; varicella-zoster virus (VZV), the the conditions necessary for EBV to maintain its life
cause of chickenpox and “shingles”; cytomegalovirus cycle. A balanced, generally benign, virus-host relation-
(CMV), currently the most common cause of congenital ship has evolved, making it beneficial for both virus and
infection; and herpesviruses 6 and 7, causes of exanthema host for EBV to adopt a strictly latent state in blood. If
subitum (roseola infantum). The infectiousness of EBV active and replicating, EBV can spread and infect tissues,
and its propensity to infect children at a young age with but it also is vulnerable to rapid detection and elimina-
mild disease are features in common with these other tion by cytotoxic T cells and natural killer (NK) cells.
pathogens. CMV can cause a mononucleosis syndrome, Residing in resting peripheral blood B cells, EBV remains
but most children suffer only trivial respiratory infec- virtually invisible to the immune system by expressing
tions. Primary HSV infection is common in childhood very few virus proteins. For years after acute EBV infec-
and subclinical in 85% of cases. HHV6 is a well- tion, latently infected B cells in peripheral blood are
recognized cause of nonspecific febrile illness in toddlers. present at a frequency that ranges from 1 to 60/106 B
After primary infection, it is usual for all of these cells (⬃10 mL of blood). Each cell carries approximately
viruses to establish a permanent, lifelong infection of two to five copies of an intact circular (latent, episomal)
their human host. Each virus has a preferred cell type and viral genome. Healthy individuals infected with EBV
shed infectious EBV silently, sometimes continuously, kines, which include lymphotoxin, tumor necrosis factor-
into saliva and genital secretions. The source of this virus alpha, interleukin (IL)-1beta, and IL-6. Disease features
is believed to be B cells that have become activated and resolve as EBV DNA levels in serum fall and T-cell
circulated to the mucosal epithelium. Mucosal shedding numbers normalize. The reason for this exaggerated
facilitates viral spread to susceptible individuals and pos- T-cell response that focuses on a few immunodominant
sibly plays a role in bolstering local defenses against epitopes of the virus lytic cycle is not clear, but this
infection with new EBV strains. response distinguishes IM from asymptomatic primary
EBV infection in which homeostatic T-cell numbers and
The Host Immune Response diversity are maintained. In both circumstances, systemic
The patterns of antibody responses to EBV antigens were EBV DNA levels are high, but there is an intriguing
delineated soon after their discovery. Antibodies develop speculation that EBV establishes a different form of
during acute infection to lytic cycle proteins, including infection and pattern of gene expression in these two
membrane antigen, virus capsid antigen (VCA), and conditions. EBV DNA detected in IM could derive from
early antigens, and appear during convalescence to the virus replication and cell lysis; the DNA in asymptomatic
latency-associated virus nuclear antigens (EBNA). Anti- primary infection could derive from B cells driven to
bodies have little role in control of established EBV proliferate by the virus.
infection. Much work has been done to define the spe-
cific features of immunity that protect against infection, Complications of EBV Infection
which is important for vaccine development. The lack of Complications occur in about 20% of patients recently
a permissive virus culture system and difficulty in han- infected with EBV; essentially no body system is free
dling T lymphocytes in vitro have delayed analysis of from potential harm. The respiratory, neurologic, and
EBV-directed cellular immune responses, despite their hematologic systems are involved most frequently. Air-
obvious importance in managing EBV infection. Individ- way obstruction resulting from the virus-induced B-cell
uals who have congenital or acquired cellular immuno- proliferation and reactive T-cell expansion can be life-
deficiency disorders suffer more complications, even threatening and is the most common reason for hospital
death, with primary EBV infection and are less able to admission.
maintain the virus in a latent state. In the absence of Neurologic complications occur in about 5% of pa-
effective cellular immunity, EBV promotes activation tients. EBV has been implicated in virtually every form of
and proliferation of its host B cell, leading to infection-related neurologic disorder. Quantitative poly-
B-lymphoproliferative disorders and risk for malignant merase chain reaction (PCR) and detection of EBV lytic
transformation. cycle messenger RNA (mRNA) in cerebrospinal fluid
indicates that direct EBV infection of the central nervous
Pathogenesis and Pathophysiology system is one mechanism of neuropathology.
Based on epidemiologic studies and because it is usual for EBV is renowned for its intriguing ability to activate B
patients who develop IM to have peak VCA- lymphocytes to produce antibodies. During acute IM,
immunoglobulin (Ig)G levels at presentation, it is be- about 1/5,000 (0.02%) peripheral blood B cells are
lieved that EBV infection occurs at least 30 days prior to infected with EBV, which is associated with the transient
the appearance of IM signs and symptoms. There is a appearance of unusual antibodies, including heterophile
paucity of information about the events of early infection (which forms the basis of the rapid “mono” tests), Was-
and an increasing suspicion that IM represents an even- serman, rheumatoid factor-like, cold agglutinins of anti-i
tually contained, but not normal, lymphoproliferative specificity, and antinuclear antibodies. Autoreactive anti-
disorder. Host reactions account for the clinical manifes- bodies cause some of the more frequent hematologic
tations of IM. The course of IM closely parallels the complications, including immune hemolytic anemia or
lymphoproliferative phase, in which there is a massive immune thrombocytopenia. About 10% of preschool-
increase in the number of activated cytotoxic CD8⫹ T age children develop neutropenia that is characterized by
cells directed primarily against EBV lytic cycle proteins. fewer than 0.5⫻109 cells. It has been proposed that the
This T-cellular response accounts for the traditional he- heterophile antibody, which nonspecifically agglutinates
matologic criteria of IM (absolute and atypical lympho- red blood cells of other species, is an autoantibody that
cytosis) and the characteristic signs of lymphadenopathy, recognizes an antigen expressed on the human fetal
hepatomegaly, and splenomegaly. Fever and fatigue re- erythrocyte. This abnormal antibody, a sign of B-cell
sult from a massive T cell-induced production of cyto- activation, can be present up to 1 year after acute infec-
tion; a longer duration of detectable antibody correlates hypersensitive to the drug without subsequent docu-
with the greater geometric mean titer found in acute sera. mentation by appropriate skin test and challenge studies.
Generally, increased levels of Ig increase the propensity Consistent with EBV-induced B-cell activation, patients
for immune complexes to be formed, which may account who have IM can show a transient rise in benzyl-
for other disease-associated features such as rash, myal- penicilloyl-specific IgM antibodies that purportedly
gia, and arthralgia. cause the reaction.
As with many circumstances in medicine, it is not provement of symptoms, physical signs, or scores on the
always possible to be assured completely that a particular Beck Depression Inventory. The antiviral agent acyclovir
patient’s problems are due to acute primary EBV infec- [9-(2-hydroxyethoxymethyl) guanine] inhibits the repli-
tion. Other pathogens are capable of inducing an intense cation of linear EBV DNA through inhibition of the virus
lymphoproliferative response and, in doing so, cause a DNA polymerase. Acyclovir treatment abrogates oral
mononucleosis syndrome. Other infections and inflam- EBV shedding, but it does not affect levels of (circular,
matory conditions can be associated with B-lymphocyte latent) EBV-infected B cells. Because the symptoms and
activation, resulting in heterophile antibody and other signs of IM relate to the intense T-cell response, it is not
abnormal antibody production. The detection of EBV in surprising that there is no evidence for orally adminis-
secretions or tissues through sensitive molecular tech- tered acyclovir affecting the course of IM.
niques is not restricted to acute infection.
PIR Quiz
Quiz also available online at www.pedsinreview.org.
1. A 4-year-old boy is brought to your office because of fever, runny nose, and irritability for the last week.
Physical examination reveals an axillary temperature of 101.3°F (38.5°C), respiratory rate of 28 breaths/
min, and heart rate of 110 beats/min. The child is alert and has no neck stiffness. There is pharyngeal
erythema and enlarged posterior cervical lymph nodes that are moderately tender. The spleen is palpable
2 cm below the costal margin. A complete blood count shows a hemoglobin of 11 g/dL (110 g/L) and a
white blood cell count of 14ⴛ103/mcL (14ⴛ109/L), with 38% polymorphonuclear leukocytes, 60%
lymphocytes, and 2% eosinophils. A peripheral blood smear shows several atypical lymphocytes. Of the
following, the most accurate statement regarding this patient’s heterophile antibody response is that:
A. A positive heterophile antibody test obviates the need for further testing for Epstein-Barr virus (EBV)
infection.
B. Children younger than 4 years of age are more likely to produce heterophile antibodies than are those
who are older.
C. Heterophile antibody is species-specific.
D. Heterophile antibody offers protection against reinfection with EBV.
E. Heterophile antibody response is more likely to occur in patients who have EBV-associated
hemophagocytic lymphohistiocytosis than an infectious mononucleosis presentation.
(continued)
2. During a routine health supervision visit, the mother of a 14-year-old girl tells you that one of her
daughter’s soccer teammates has been diagnosed as having infectious mononucleosis. She is concerned
about her daughter catching the illness. Of the following, the most appropriate advice is that:
A. Her daughter should avoid playing soccer for 2 weeks to be sure no one else on the team develops
manifestations of infectious mononucleosis.
B. Her daughter should receive an intramuscular gamma globulin injection.
C. Infectious mononucleosis, also called a “kissing disease,” is transmitted most often between individuals
of opposite sexes.
D. She should not worry about her daughter catching the illness.
E. The teammate who has infectious mononucleosis should be isolated for 2 weeks.
3. A 6-year-old girl presents with fever, sore throat, and malaise of 1 week’s duration. Physical examination reveals
bilateral posterior cervical lymph nodes that are firm, discrete, and tender. The pharynx is erythematous, with
thick gray-white exudates. The complete blood count shows a hemoglobin of 12 g/dL (120 g/L) and white blood
cell count of 12.4x103/mcL (12.4x109/L), with 28% polymorphonuclear lymphocytes, 64% lymphocytes, and 8%
monocytes. Multiple atypical lymphocytes are seen on the peripheral smear. The heterophile antibody test is
positive. Of the following, a true statement regarding EBV infection is that:
A. A positive throat culture for EBV is highly sensitive for establishing the diagnosis.
B. Ampicillin rash in a child who has infectious mononucleosis is a reflection of lifelong hypersensitivity
and contraindicates the use of ampicillin in future.
C. Atypical lymphocytosis represents activation of B cells responsible for antibody response.
D. The EB nuclear antigen antibody titer peaks at presentation of infectious mononucleosis.
E. The primary host defense mechanism is through cytotoxic T cells and natural killer cells.
4. An 8-year-old boy presents with fever and sore throat, weakness, and loss of appetite for 6 days. Physical
examination reveals four to six cervical lymph nodes bilaterally that are approximately 2 to 3 cm in
diameter, firm, and somewhat tender. The pharynx is erythematous and has grayish exudates. A grade 2/6
systolic murmur is audible over the left sternal border. The spleen is palpable 4 cm below the left costal
margin. A complete blood count shows a hemoglobin of 10 g/dL (100 g/L) and white blood cell count of
14x103/mcL (14x109/L), with 24% polymorphonuclear lymphocytes, 66% lymphocytes, and 10%
monocytes. The platelet count is 110x103/mcL (110x109/L). Multiple atypical lymphocytes are seen on
peripheral smear. A rapid heterophile antibody test is positive. Over the next week, the boy improves and
feels much better. His mother wants to know when he can participate in soccer. Of the following, your best
answer is that he can start participating when:
A. He feels well.
B. His hemoglobin rises above 13 g/dL (130 g/L).
C. His murmur no longer is audible.
D. His platelet count increases above 150x103/mcL (150x109/L).
E. His spleen no longer is palpable.
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