by EB Virus · Cited by 2 — Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a member of the herpes virus family. It is one of the most common human viruses.

1. Epstein-Barr virus

2. o Epstein-Barr virus (EBV), is a
member of the herpesvirus family
and one of the most common human
viruses.
o The virus occurs worldwide, and
most people become infected with
EBV sometime during their lives.

3. o Infants become susceptible to
EBV as soon as maternal
antibody protection disappears.
o Many children become infected
with EBV, and these infections
usually cause no symptoms or
are indistinguishable from the
other mild, brief illnesses of
childhood.

4. When infection with EBV occurs
during adolescence or young
adulthood, it causes infectious
mononucleosis 35% to 50% of the
time.

5. The virus infects oral epithelium
where a productive infection takes
place and B-cells, where infection is
non-productive.

6. The virus is shed in the throat
during the illness and for up to a
year after infection.
After the initial infection, the virus
tends to become dormant for a
prolonged period and can later
reactivate and be shed from the
throat again.

7. The virus is spread by
person-to-person contact, via
saliva through intimate
contact (kissing) and in young
children through transfer of
saliva.

8. In rare instances, the virus
has been transmitted by blood
transfusion or
transplacentally.

9. There are no known associations
between active EBV infection and
problems during pregnancy, such as
miscarriages or birth defects.

10. Although the symptoms of infectious
mononucleosis usually resolve in 1 or
2 months, EBV remains dormant or
latent in a few cells in the throat and
blood for the rest of the person's life.

11. Periodically, the virus can
reactivate and is commonly
found in the saliva of infected
persons.
This reactivation usually occurs
without symptoms of illness.

12. Epstein Barr Virus is also
associated with:
 Nasopharyngeal carcinoma,
 Burkitts lymphoma,
 Hodgkin's Disease,
 B cell lymphoma.


13. Epstein-Barr Viral Infection

14. EBV infected B-lymphocytes express a
variety of “new” antigens encoded by
the virus. Infection with EBV results in
expression of:
1. Viral Capsid Antigen (VCA)
2. Early Antigen (EA)
3. Nuclear Antigen (NA)
Each antigen expression has
corresponding antibody responses.

15. Epstein-Barr Virus (VCA)
Viral capsid antigen (VCA) is produced by
infected B cells and can be found in the
cytoplasm.
 Anti-VCA IgM is usually detectable early
in the course of infection, 4 to 7 days
after onset of signs and symptoms, but it
is low in concentration and disappears
within 2 to 4 months.

16. Epstein-Barr Virus (EA)
Early antigen (EA) is a complex of two
components, early antigen-diffuse (EA-D),
which is found in both the nucleus and
cytoplasm of the B cells, and early antigen-
restricted (EA-R), which is usually found as
a mass only in the cytoplasm.

17. Anti-EA-D of the IgG type is highly
indicative of acute infection, but it is
not detectable in 10% to 20% of
patients with IM.
EA-D disappears in about 3 months;
however, a rise in titer is
demonstrated during reactivation of a
latent EBV infection.

18. Anti-EA-R IgG is not usually found in
young adults during the acute phase.
Anti-EA-R IgG appears transiently in
the later convalescent phase.
In general, anti-EA-D and anti-EA-R
IgG are not consistent indicators of
the disease stage.

19. Epstein-Barr Virus (EBNA)
Epstein-Barr nuclear antigen (EBNA) is found
in the nucleus of all EBV-infected cells.
Although the synthesis of NA precedes EA
synthesis during the infection of B cells, EBV-
NA does not become available for antibody
stimulation until after the incubation period of
Infectious Mono, when activated T
lymphocytes destroy the EBV genome-
carrying B cells.

20. As a result, antibodies to NA are
absent or barely detectable
during acute IM.

21. Anti-EBNA IgG does not appear until a
patient has entered the convalescent period.
EBV-NA antibodies are almost always
present in sera containing IgG antibodies to
VCA of EBV unless the patient is in the early
acute phase of IM.
Patients with severe immunologic defects or
immunosuppressive disease may not have
EBV-NA antibodies, even if antibodies to VCA
are present.

22. Epstein-Barr Virus (EBNA)
Under normal conditions, antibody titers to NA
gradually increase through convalescence and
reach a plateau between 3 and 12 months
postinfection.
The antibody titer remains at a moderate,
measurable level indefinitely because of the
persistent viral carrier state established following
primary EBV infection.

23. Test results of antibodies to EBV-
NA should be evaluated in
relationship to patient symptoms,
clinical history, and antibody
response patterns to EBV-VCA and
EA to establish a diagnosis.

24. Signs and Symptoms of
Infectious Mononucleosis

25. Mononucleosis is characterized by fever,
sore throat, fatigue, malaise, and loss of
appetite.
Patients generally have swelling of the
lymph nodes in the neck and often have
an enlarged spleen.
No treatment, other than rest, is needed in
the vast majority of cases and there is no
vaccine available to prevent IM.

26. The most important and most
characteristic symptom of IM is a sore
throat.
This usually develops a few days after
the onset of the illness, increases in
severity during the first week, and then
rapidly subsides during the next five to
seven days.
In many young adults sore throat is the
first indication of sickness and in some
it is the only major symptom throughout
the entire illness.

27. Tongue and palate of patient with infectious
mononucleosis.

28. A conjunctival hemorrhage of the right eye of this
patient with infectious mononucleosis.

29. Although anorexia may persist for as long
as there is fever, its intensity and duration
are more directly related to the severity of
sore throat and dysphagia.
Gross tonsillar and pharyngeal edema may
cause virtually complete pharyngeal
obstruction with harsh-sounding breathing
and complete inability to swallow either
food or fluids.
In some patients the soreness of the throat
is so severe that swallowing water becomes
extremely painful.

30. The headaches of early IM are often retro-
orbital in location but have no characteristic
features.
They may be moderately severe for one or
two days but usually they are mild and rarely
last for more than three or four days.
Ocular symptoms may be in the form of
photophobia, and ocular muscle aching .

31. Lymphadenopathy, is sometimes
accidentally discovered or detected
during self-examination following the
development of systemic symptoms.
In about 3 percent of all cases of IM,
the gross cervical lymphadenopathy
imparts a “bull neck” appearance.

32. Enlargement of lymph nodes
usually begins two or three days
after the onset of the first
symptoms and, by the end of the
week, palpable lymphadenopathy
is present in 70-80 percent of all
patients.

33. Jaundice is a moderately important
symptom of infectious mono as 8-10
percent of patients eventually become
visibly jaundiced.
In most instances, however, it is not
noticed since it consists of only a
transient icteric tint to the sclera and
mucous membranes, lasting for a few
days.

34. Complications
Most cases of IM are self-limited.
Deaths are very rare and most often
are due to central nervous system
(CNS) complications, splenic rupture,
upper airway obstruction, or bacterial
superinfection.

35. Pathogenesis & Immunity
The infection first occurs in the
oropharynx (epithelium/ lymphoid
tissue) and then spreads to the blood,
where it infects B lymphocytes.
Cytotoxic T lymphocytes react against
the infected B cells. The T cells are the
"atypical lymphs" seen in the blood
smear.

36. EBV remains latent within B
lymphocytes. A few copies of EBV
DNA are integrated into the cell
genome; many copies of circular
EBV DNA are found in the
cytoplasm.

37.  The immune response to EBV infection
consists first of IgM antibody to the VCA.
 IgG antibody to the VCA follows and
persists for life.
 The IgM response is therefore useful for
diagnosing acute infection, whereas the
IgG response is best for revealing prior
infection.
 Lifetime immunity against second
episodes of infectious mononucleosis is
based on antibody to the viral membrane
antigen.

38.  In addition to the EBV specific
antibodies, nonspecific heterophil
antibodies are found.
 The term "heterophil" refers to
antibodies that are detected by tests
using antigens different from the
antigens that induced them.

39. The heterophil antibodies formed in
infectious mononucleosis agglutinate
sheep or horse red blood cells in the
laboratory. (Cross-reacting Forssman
antibodies in human serum are
removed by adsorption with guinea pig
kidney extract prior to agglutination.)

40.  Note that these antibodies do not react
with any component of EBV. It seems
likely that EBV infection modifies a cell
membrane constituent such that it be-
comes antigenic and induces the
heterophil antibody. Heterophil
antibodies usually disappear within 6
months after recovery.

41. Clinical Manifestations of
Infectious Mono

42. Examination of the blood usually shows
an increase in the white blood cells, due
to the appearance of many atypical
lymphocytes in the blood.
Blood serum in IM often contains
heterophil antibody that agglutinates, or
clumps, the red blood cells of sheep.

43. Heterophil antibodies are antibodies that
are stimulated by one antigen and react
with an entirely unrelated surface
antigen present on cells from different
mammalian species.

44. Heterophil antibody titers rise during the
first two or three weeks with half or more
developing a significant titer during the
first week of illness.
The level of antibody gradually declines
and usually disappears in eight to twelve
weeks following the onset.

45. Elevated titers sometimes linger for
four to six months up to a year or more.
Heterophil antibody most commonly
used in the serological diagnosis of IM
is an IgM antibody which agglutinates
sheep red blood cells.

46. The diagnosis of EBV infection is
summarized as follows:
Susceptibility:
If antibodies to the viral capsid antigen are
not detected, the patient is susceptible to
EBV infection.

47. Primary Infection:
Primary EBV infection is indicated if
IgM antibody to the viral capsid
antigen is present and antibody to
EBV nuclear antigen, or EBNA, is
absent.

48. A rising or high IgG antibody to
the viral capsid antigen and
negative antibody to EBNA after at
least 4 weeks of illness is also
strongly suggestive of primary
infection.
In addition, 80% of patients with
active EBV infection produce
antibody to early antigen.

49. Past Infection
If antibodies to both the viral capsid
antigen and EBNA are present, then past
infection (from 4 to 6 months to years
earlier) is indicated.
Since 95% of adults have been infected
with EBV, most adults will show
antibodies to EBV from infection years
earlier.
High or elevated antibody levels may be
present for years and are not diagnostic
of recent infection.

50. Reactivation
In the presence of antibodies to EBNA, an
elevation of antibodies to early antigen
suggests reactivation. However, when EBV
antibody to the early antigen test is
present, this result does not automatically
indicate that a patient's current medical
condition is caused by EBV.

51. A number of healthy people
with no symptoms have
antibodies to the EBV early
antigen for years after their
initial EBV infection. Many
times reactivation occurs
subclinically.

52. Chronic EBV Infection
Reliable laboratory evidence for
continued active EBV infection is very
seldom found in patients who have
been ill for more than 4 months.
When the illness lasts more than 6
months, it should be investigated to
see if other causes of chronic illness
or CFS are present.

53. EBV is only a minor problem for
immunocompetent persons, but it can
become a major one for
immunologically compromised
patients
After primary exposure a person is
considered to be immune and
generally no longer susceptible to
overt reinfection.

54. Treatment
Unlike herpes simplex virus, there are no
drugs available to treat Epstein-Barr
virus. This may reflect the absence of a
thymidine kinase encoded by this virus
(drugs such as acyclovir that are active
against herpes simplex are activated by
the viral thymidine kinase). A vaccine is
being developed.

55. EBV is also associated with
several human tumors, including
Nasopharyngeal carcinoma,
Burkitt’s lymphoma, Hodgkin’s
disease, and (in patients with
immunodeficiencies) B cell
lymphoma.

56. Burkitt's lymphoma
The association between Epstein-Barr
virus and Burkitt's lymphoma has
long been established. This is a
tumor of the jaw and face found in
children.

58. The tumor cells show evidence of
EBV DNA and tumor antigens and
patients show a much higher level of
anti-EBV antibodies than other
members of the population.

59. Biopsy tissue shows large
multinucleated cells .
Further evidence that implicates EBV
in Burkitt's lymphoma is the
observation that EBV can transform B
lymphocytes in culture and can
produce B cell lymphomas in
primates.

60. Burkitt's lymphoma histological stain. Notice the large multinucleated
cells

61. This lymphoma is endemic in
equatorial Africa but only occurs rarely
elsewhere.
Why this is so is unclear but there is
probably a genetic reason possibly
involving an association with malaria.
Persons who are resistant to malaria
appear to be susceptible to
progression to the lymphoma.

62. Nasopharyngeal cancer
This disease, which occurs in a number of
areas (south China, Alaska, Tunisia, east
Africa), is also associated with EBV.
There may be a genetic predisposition to
the development of EBV cancers in these
populations or there may be an
environmental cofactor involved.

63. The disease is a tumor of the
epithelium of the upper
respiratory tract and the cells
contain EBV DNA.
The titer of anti-EBV antibodies
alter as the tumor progresses.

64. Oral hairy leukoplakia:
This EBV-associated disease results
in lesions in the mouth and has
increased in frequency recently as it
is an opportunistic infection of HIV-
infected patients

65. Oral hairy leukoplakia of tongue in AIDS

66. Human herpes virus 6

67. Primary infection: Ubiquitous and most
children infected by age 2.Causes roseola,
or Exanthem subitum characterized by
fever for 2-3 days, followed 48 hours later
by a maculopapular rash.
Tropism: Infects T-cells. It also infects cells
of the central nervous system and possibly
other cells too.

68. Latency: Remains latent for life.
Consequences of latency are unclear,
although it can be pathogenic in
immunocompromised individuals
(persons with AIDS, allograft recipients),
in whom it can cause pneumonitis.
It is also a cause of bone marrow failure in
bone marrow transplant recipients.

69. Treatment: Gancyclovir since it is a beta
herpes virus.

70. HUMAN HERPESVIRUS 7 (HHV-7):
Closely related to HHV-6, with similar
properties. Ubiquitous and most
children infected by age 3 (slightly later
than HHV-6).
May cause some cases of roseola, and
can reactivate HHV-6.
Infects T-cells also, and remains latent
for life.

71. HUMAN HERPESVIRUS 8 (HHV-8):
First detected in 1994 in Kaposi’s sarcoma
(KS) cells; subsequently isolated and
sequenced within 3 years. Appears to the
causative agent of KS, and has also been
linked to some B cell tumors found in
persons with AIDS.
Tropism: The virus is tropic for B-cells and
possibly for other cells too.

73. AIDS-associated Kaposi sarcoma