Epstein Barr Virus (EBV)

Epidemiology and Etiology:

· Herpesvirus family

· DS DNA

· Infectious mononucleosis:

· Late adolescents / young adults (developed nations, upper socioeconomic classes)

· Childhood (the rest of the world)

· Route of infection:

· Ingestion of saliva

· Close contact

· Infected cells

· B cells

· Epithelial cells (maybe)

· Mechanism of infection:

· Most B cells

· Latent infection in most

· Productive infection with lysis of host cell in a minority

· Cytotoxic T cell and NK cells reaction

· Cause lymphadenopathy and splenomegaly

· EBV persists throughout life in a small population of resting B cells

Common sites:

· Infectious mononucleosis:

· Oropharynx

· tonsils

· Lymph nodes

· Posterior cervical

· Axillary

· groin

· Spleen

· Liver

· Meninges

· Brain

· Lung

· Skin rash

Gross features:

· Infectious mononucleosis:

· Generalized lymphadenopathy

· Splenomegaly (300-500 g)

· Soft and fleshy

· Hyperemic cut surface

· Hepatomegaly (mild to moderate)

· CNS:

· Congestion maybe

· Edema maybe

· Skin rash resembling rubella maybe

Histologic features:

· Infectious mononucleosis:

· Peripheral blood:

· Large, atypical activated T cells in the peripheral blood

· 12 to 16 um in diameter

· Abundant cytoplasm with multiple clear vacuolations and scattered azurophilic granules

· Oval, indented, or folded nucleus

· CD8+ mostly

· Lymph node:

· Expansion of paracortical areas by activated T cells (immunoblasts)

· May be so exuberant that it is difficult to distinguish from malignant lymphomas

· Minor population of EBV-infected B cells in paracortex

· Occasional Reed-Sternberg-like EBV-infected B cell

· Hyperplastic follicles maybe (mild)

· Spleen:

· Similar to lymph node

· Expansion of white pulp follicles and red pulp sinusoids with numerous activated T cells

· Liver:

· Atypical T cells in portal areas and sinusoids

· Scattered isolated cells or parenchymal necrosis filled with lymphocytes maybe

· CNS:

· Perivascular mononuclear infiltrates in the leptomeninges

· Peripheral nerves

· Myelin degeneration maybe

· Destruction of axis cylinders maybe

Immunophenotype:

Marker:	Sensitivity:	Specificity:
CD8 (most atypical lymphocytes)
EBNA2 (proliferating infected B cells)
LMP-1 (proliferating infected B cells)

Molecular features:

· An EBV envelope protein binds to CD21 on B cells

· Receptor for the C3d component of complement

· EBNA1 and EBNA2 genes, and latent membrane protein-1 (LMP-1) are involved in establishment of latency

· EBNA1 plays a role in EBV DNA replication

· EBNA2 and LMP-1 drives B cell activation and proliferation

· LMP-1 binds to TNF receptor-associated factors (TRAFs)

· Activates signaling pathways that mimic B cell activation by CD40

· Causes B cell proliferation

· Not expressed in latently-infected resting B cells

· EBNA2 stimulates transcription of many host cell genes:

· Cyclin D

· Activated B cells secrete antibodies with several specificities

· heterophile anti-sheep red blood cell antibodies are used for diagnosis of infectious mononucleosis (monospot test)

· latently infected resting B cells only express EBNA1 and LMP-2

Other features:

· Infectious mononucleosis

· Fever

· Sore throat

· Peripheral lymphocytosis

· 12,000 – 18,000 cells / uL total WBC count

· > 60% lymphocytes

· Many are large atypical lymphocytes

· Risk of splenic rupture

· Liver function transiently impaired

· May be marked hepatic disfunction

· rarely with liver failure

· Monospot test (see above)

· Specific antibodies for EBV antigens

· Neoplasms, particularly in the immunosuppressed (cellular immunity defects):

· Lymphomas

· Burkitt lymphoma t(8;14)

· Hodgkin

· May be polyclonal in severe acute immunosuppression (ex. BMT)

· Nasopharyngeal carcinoma

· X-linked lymphoprolferation syndrome:

· Defect in gene SH2D1A (SAP) expressed by cytotoxic T cells and NK cells

· No problems until infected by EBV

· Failure to control EBV infection

· Chronic infectious mononucleosis

· Agammaglobulinemia

· B cell lymphoma

· Fatal in ~1/3

References:

· Kumar V, Fausto N, Abbas A. Robbins & Cotran Pathologic Basis of Disease, Seventh Edition. 7th ed. Saunders; 2004.