EPSTIN BAR VIRUS IN ENT

1. EPSTIEN-BARR VIRUS
BY DR V SANKAR NAIK
M.S ENT PG
NMCH

2. The herpes virus family are ENVELOPED DNA VIRUSES.
They affect humans and animals.
MORPHOLOGY:
Capsid:Icosahedral,composed of 162 capsomeres and enclosing the core
containing the linear ds DNA.
Nucleocapsid is surrounded by lipid envelope derived from the modified host cell
membrane through which the naked virions bud during replication.
Envelope carries spikes about 8nm long.
Tegument:Amorphous structure between envelope and capsid containing several
proteins.
Enveloped virion - 200 nm ; Naked virion - 100 nm.
RESISTANCE:
They are susceptible to fat solvents like alcohol ,ether , chloroform and bile salts.

4. CLASSIFICATION OF HUMAN HERPES VIRUSES:

5. HUMAN HERPESVIRUS TYPE-4

6. EPSTEIN BARR VIRUS
EPIDEMIOLOGY:
The Epstein barr virus is ubiquitous in all human populations .
Infection with Epstein barr virus leads to latency , periodic reactivation and lifelong
persistence.
In the overcrowded developing world,EB virus infection occurs in infancy and
childhood , when it is usually asymptomatic.
In affluent countries , primary infection is often delayed till adolescence and early
adulthood, leading to INFECTIOUS MONONUCLEOSIS.

7. SOURCE OF INFECTION:
Saliva of the infected persons who shed the virus in oropharyngeal secretions for
months following primary infection and intermittently thereafter.
Not highly contagious.
Droplets and aerosols are not efficient in transmitting infection.
Intimate oral contact , as in kissing appears to be predominant mode of
transmission so called as Kissing Disease.

9. PATHOGENICITY:
Virus enters the pharyngeal epithelial cells through CR2 (CD 21) receptors which is
same as for C3d component of complement.
Multiplies locally and invades bloodstream and infects B lymphocytes in which two
types of changes are produced.
In most cases , virus becomes latent inside the lymphocytes , which become
transformed or immortalised so that they become capable of indefinite growth in
vitro.
They are polyclonally activated to produce many kinds of immunoglobulins.
A second type of effect , shown by a few infected B cells is lytic infection with cell
death and release of mature progeny virions.

10. Mononucleosis represents a polyclonal transformation of infected B lymphocytes.
EB virus antigens are expressed on surface of infected B cells.
Atypical lymphocytes seen in blood smear in infectious mononucleosis are T
lymphocytes undergoing blast transformation in response to such neoantigens .
Intermittent reactivation of the latent EB virus leads to clonal proliferation of
infected B cells.
Genetic influence is best illustrated in the X-linked lymphoproliferative (XLP or
Duncan)syndrome associated with extreme susceptibility to EB virus infection

11. INFECTIOUS MONONUCLEOSIS
Acute self limiting illness, usually seen in non immune young adults
following primary infection with the EB virus.
Incubation period:4 to 8 weeks
Symptoms:
Fever
Sore throat
Lymphadenopathy
Presence of abnormal lymphocytes in peripheral blood smears.
Some patients treated with Ampicillin developed maculopapular
rash as a immunocomplex reaction to the drug.

13. Complications:
Hepatitis,Haematological,Neurological,Cardiac and pulmonary conditions and
splenic rupture.
Most cases resolve spontaneously in 2-4 weeks.
In some it leads to more prolonged and lead to a state of mental and physical
fatigue in convalescence.

15. Laboratory diagnosis:
Blood examination
Initial phase : Leucopenia due to drop in the number of polymorphs.
Late phase : Prominent leucocytosis , with appearance of abnormal
mononuclear cells characterised by deeply basophilic vacuolated cytoplasm and
kidney shaped nuclei showing a lattice of fenestrated chromatin.
These atypical mononuclear cells are not virus infected B cells but lymphoblasts
derived from T cells reactive to the virus infection.

16. Serology-
Paul Bunnell test:
It is a standard diagnostic procedure In infectious mononucleosis.
Heterophile antibodies agglutinate sheep erythrocytes.
Infectious mononucleosis antibodies can be differentiated by absorption tests.
Inactivated serum(56 degree celcius for 30 mins)in doubling dilutions is mixed with
equal volumes of a 1% suspension of sheep erythrocytes.
After incubation at 37 degrees for 4 hrs the tubes are examined for agglutination.
An agglutination titre of 100 or more is suggestive of infectious mononucleosis.

17. Differential agglutination test:
For confirmation, differential absorption of agglutinins with guinea pig kidney and
ox red cells is necessary.
Forsmann antibody induced by injection of horse serum is removed by treatment
with guinea pig kidney and ox red cells.
Normally occuring agglutinins are removed by guinea pig kidney, but not ox red
cells.
Infectious mononucleosis antibody is removed by ox red cells but not guinea pig
kidney.

18. Immunofluorescences and ELISA-
a)IgM antibody to VCA(viral capsid antigen) appears soon after primary infection
and disappears in 1-2 weeks.
Reliable indication of primary infection.
b)IgG antiVCA persists throughout life and indicates past or recent infection.
C)New appearance of antibody to EB nuclear antigen(EBNA) is also a useful marker
for primary infection.

19. EBV associated malignancies

20. EBV associated malignancies include:
• Nasopharyngeal carcinoma
• Burkitt ’s lymphoma
• Lymphomas in immunodeficiency like infection with HIV
• Varying degree of association : non Hodgkin lymphoma .Hodgkin disease
• Possible association : gastric adenocarcinoma , breast carcinoma
• Genetic : x – linked lymphoproliferative syndrome

21. NASOPHARYNGEAL CARCINOMA
Genetic and environmental factors are said to be important in
nasopharyngeal carcinomas.
Nasopharyngeal carcinoma is more common in CHINA.
Burning of incense or wood (polycyclic hydrocarbon),use of preserved
salted fish(nitrosamines) along with vitamin C deficient diet(Vit C blocks
nirosification of amines and is thus protective)-may be other factors
operative in CHINA.
It is uncommon in India.

23. AETIOLOGY:
Exact aetiology is not known.Factors responsible are:
1.Genetic-Chinese have higher genetic susceptibility.
2.Viral-EB virus.
EBV have two important antigens-viral capsid antigen and early antigen.
IgA antibodies of EA are highly specific for nasopharyngeal cancers but have
sensitivity of only 70-80%.While IgA antibodies VCA are more sensitive but not
specific.
IgA antibodies against VCA and EA should be done for screening of patients for
nasopharyngeal carcinoma.
3.Environmental-Air pollution , smoking of tobacco and opium , nitrosamines from
dry salted fish , smoke from burning of incense and wood.

24. Classification based on histopathology:

25. SPREAD:
Local spread:
Anterior- blockage of choana and nasal cavity
Inferior-oropharynx, hypopharynx
Lateral - parapharyngeal space and infratemporal fossa through sinus of Morgagni
Upward- intracranial structures
Foramen lacerum and foramen ovale- direct spread to middle cranial fossa
6th cranial nerve is first to involve.
Spreads to jugular foramen, hypoglossal canal or sympathetic chain.
Lymphatic spread:
Retropharyngeal and parapharyngeal lymph nodes
Hematogenous : bone , liver , lungs .

26. Clinical Features:
Age: involve adult age groups.
Sex:Males are 3 times more prone than females.
Symptoms-
a)Nasal : Nasal obstruction ( unilateral) , Nasal discharge, Epistaxis.
b)Otologic : Due to obstruction of eustachian tube there is conductive hearing loss,
serous or suppurative otitis media.Tinnitus and dizziness may occur.
c)Ophthalmoneurologic : Squint and diplopia due to involvement of CN VI
ophthalmoplegia(CN III,IV and VI),facial pain and reduced corneal reflex(invasion of
CN V through foramen lacerum) may occur.
Tumors directly invade the orbit leading to exophthalmos or blindness.
Involvement of IX,X and XI cranial nerves occur constituting Jugular foramen
syndrome.CN XII may be invovled due to extension of growth to hypoglossal canal.
Horner syndrome occurs due to involvement of sympathetic chain.

27. Trotter’s triad:
Conductive deafness
Ipsilateral temporoparietal neuralgia(involvement of CN V)
Palatal paralysis(involvement of CN X)
d)Cervical node metastases:Seen in 75% cases of first seen cases.
e)Distant metastasis : Bone , lung , liver

28. DIAGNOSIS:
1.Endoscopic evaluation
2.Imaging studies-
CT –scan : nasopharynx and neck
Extent of tumor
Neck node involment
X ray/CT chest for secondaries , CT abdomen or ultrasound abdomen for liver
secondaries .
Mri scan – gives better soft tissue delination
PET scan.
3.Biopsy
4.Audiogram

29. TREATMENT:
CHEMORADIATION
Cisplatin and 5-fluorouracil
Radiotherapy
Surgery has a limited role

30. BURKITT ’s LYMPHOMA
It is a high grade , B cell , non Hodgkin’s lymphoma.
Fastest doubling time among human tumors .
Often presents with extranodal involvement or as leukemia .
Three variants:Endemic,Sporadic,Immunodeficiency associated BL.
Endemic form mainly seen in tropical Africa and New Guinea.
EPSTEIN BARR VIRUS plays an important aetiological role.
Most common in children.
Nearly 80% cases have a translocation of c-myc from Chromosome 8 to the
immunoglobulin(Ig) heavy chain region on Chromosome 14[t(8;14)].

32. Clinical Features:
ENDEMIC FORM-
Most common in young children(4-7 yrs) with frequent involvement of jaw,
periorbital area and kidneys.Some may develop sudden paraplegia.
SPORADIC FORM-
Presents mainly with abdominal tumors.
1/4th has ileocaecal disease and present with either a right lower quadrant mass or
pain from intussusception.
Some cases are classified as Burkitt’s leukemia and are characterised by extensive
marrow infiltration(>25% blasts),with possible bone pain as a presenting feature.
IMMUNODEFICIENCY FORM-
Associated with HIV infection and usually occurs with CD4 counts above
200/cumm.
It again presents with abdominal involvement.

33. Mandible and Maxillary bone involvement leads to deformity , loosening of teeth
and extrusion of the eye with loss of vision.
Abdominal involvement presents as tumors due to bilateral involvement of
kidneys , adrenals , ovaries , bowel and lymph nodes.
Other sites of involvement are CNS , long bones,Salivary glands ,
thyroid, testes , heart , breast and bone marrow.
CNS involvement common in adults.

34. INVESTIGATIONS:
Histological examination-
Presence of monotonous infiltrates of medium sized blastic lymphoid cells that
show round nuclei with clumped chromatin with multiple,centrally located
nucleoli.
These are B-cell lineage(CD20+ and CD79a+).
The rate of proliferation and rate of death are high,with the dead cells being taken
up by pale histiocytic cells within the tumor that punctate the low-power view
giving a STARRY SKY APPEARANCE.
Chromosome analysis-
For translocation of 8;14 or some cases 2/8;8/22.
Antibodies to EB viral capsid antigen may be detected.

36. TREATMENT:
Adequate hydration to prevent Tumour lysis syndrome.
High intensity , brief duration chemotherapy is highly effective.
Regimens include:
CHOP(Cyclophosphamide, Hydroxydoxorubicin , vincristine , prednisolone)
RITUXIMAB PLUS
EPOCH(Etoposide,prednisolone,vincristine,cyclophosphamide,hydroxydoxorubicin)
Prophylactic intrathecal methotrexate and hydrocortisone for meningeal
prophylaxis.