EBV

Structure and classification:  

• EBV, or human herpesvirus 4, is a gamma-1 herpesvirus.
• EBV has a double-stranded DNA genome encased in an icosahedral protein nucleocapsid surrounded by a lipid envelope embedded with viral glycoproteins.
• Herpesviruses also have an amorphous protein layer, the tegument, which lies between the capsid and envelope.
• EBV, like other herpesviruses, is relatively labile in the laboratory.
• EBV may be cultured from oropharyngeal washings or from circulating lymphocytes of 80% to 90% of patients with infectious mononucleosis.

Incubation:

• 2 weeks to 2 months

Transmission:

• direct salivary contact "kissing disease".
• Lower socioeconomic groups have a higher EBV antibody prevalence than more affluent age-matched control groups.
• EBV is a widespread agent that is not particularly contagious and that most cases of infectious mononucleosis are probably contracted by intimate contact between susceptible individuals and asymptomatic shedders of EBV.

Pathogenesis:

• On entering the oral cavity, the oral mucosal cells are infiltrated. EBV binds to its receptor, the CD21 molecule, through an interaction with its major envelope glycoprotein, gp350. CD21 is a 145-kD glycoprotein that is also the receptor for the d region of the third component of complement and is also termed the C3d receptor or CR2. This receptor is demonstrable on B lymphocytes and nasopharyngeal epithelial cells of humans. However, the massive atypical lymphocytosis of infectious mononucleosis is composed primarily of antigen-stimulated CD8 cytotoxic T cells. These lymphocytes probably produce most of the signs and symptoms of infectious mononucleosis through the abundant production of cytokines, including tumor necrosis factor, interleukin-1 (IL-1), and IL-6.
• Direct haematogenous spread result in latent infections in solid organs and bone marrow (hence risk of re-activation in Tx). Atypical lymphocytes are the abnormal B-cells.

Clinical Features:

• EBV induces a broad spectrum of illness in humans. Classic or typical infectious mononucleosis is an acute illness characterized clinically by sore throat, fever, and lymphadenopathy; serologically by the transient appearance of heterophile antibodies; and hematologically by a mononuclear leukocytosis that consists, in part, of atypical lymphocytes. During the acute phase of the illness, lymph nodes throughout the body are moderately enlarged. Individual nodes reveal increased numbers of enlarged, moderately active lymphoid follicles. Germinal centers are also enlarged, with cores containing blast cells, histiocytes, and lymphocytes. Bone marrow aspirate and biopsy specimens are often strikingly normal when compared with the florid changes noted in peripheral blood.
• The age of the patient has a profound influence on the clinical expression of EBV infection. In children, primary EBV infection is often asymptomatic. Young children may be more likely to exhibit rashes, neutropenia, or pneumonia than individuals undergoing primary EBV infection at an older age.
• In the absence of effective immune surveillance, uncontrolled proliferation of EBV-infected B lymphocytes can occur. This disorder is referred to as lymphoproliferative disease and represents the in vivo equivalent of the immortalized B-cell lines seen with EBV infection in vitro. Proliferating B cells in LPD express all EBV latent proteins (latency III), including the EBNA3 proteins that are strong targets for CD8 cytotoxic T cells. Patients with LPD typically present with symptoms similar to those of infectious mononucleosis or with fever and lymphomatous infiltration of lymph nodes, spleen, liver, bone marrow, kidney, lung, CNS, or intestine. The frequency of this disease in solid organ and bone marrow transplant recipients has led to the designation post-transplantation lymphoproliferative disease (PTLD), but it can be seen in any patient receiving high-dose immune suppression or in those with inherited disorders affecting T-cell immunity. Patients with more severe cellular immune impairment, such as those receiving T cell-depleted bone marrow transplants or antithymocyte globulin, are at increased risk for PTLD, as are those who experience primary EBV infection after transplantation. EBV viral load elevations, reflecting an increase in circulating EBV-transformed B cells, may precede the onset of overt LPD. A B-cell lymphoma seen in HIV infected patients, diffuse large cell lymphoma, bears a striking resemblance to PTLD. As with PTLD, it occurs in the setting of profound immunosuppression; those with the lowest CD4 counts for the longest time are at greatest risk. Presentation as primary CNS lymphoma is frequent and essentially all CNS lymphomas are EBV positive, whereas about two thirds of diffuse large cell lymphomas outside the CNS are EBV positive.

Associations:

• EBV is associated with the development of multiple malignancies, including Burkitt's lymphoma, lymphoproliferative disease, Hodgkin's lymphoma, primary central nervous system (CNS) lymphomas in acquired immunodeficiency syndrome (AIDS), and nasopharyngeal carcinoma based on seroepidemiologic data and the detection of EBV genomes in these tumors. 

Investigations:

1. Serology: EBNA IgG (evidence of past infection), VCA IgM (acute infection), VCA IgG (recent infection). Antibody responses to the latency-associated EBV nuclear antigens (EBNA1, EBNA2, EBNA3s, and EBNALP) do not develop until convalescence. The significance of any of these antibody responses to containing EBV infection is not established, but athey appear to prevent experimental EBV infection.
2. Histology/Blood film: Atypical lymphocytes seen in Burkitts and peripheral smear.
3. Paul-Bunnell/Monospot: anti-heterophile antibodies - antigens coated onto latex give an agglutination reaction.(Similar to the Weil-Felix in typhoid).

Treatment:

1. Supportive
2. Anti-viral agents: Phosphonoacetic acid, adenine arabinoside, aciclovir, desciclovir, and ganciclovir inhibit EBV replication in vitro. However, these agents target the viral DNA polymerase, which is expressed only during lytic infection. Because EBV infection is predominantly latent, it is not surprising that these agents are ineffective in treatment of infectious mononucleosis. Further, the clinical symptoms and signs of infectious mononucleosis are largely due to the vigorous immune response directed against EBV. A meta-analysis of five randomized, controlled trials demonstrated no significant benefit of acyclovir in the treatment of infectious mononucleosis. These trials included patients with mild, moderate, and severe mononucleosis. As expected, viral shedding from the oropharynx, where lytic replication commonly occurs, was reduced, but inhibition of shedding was lost 3 weeks after withdrawal of the antiviral agent.
3. Steroids: Corticosteroids have indicated that corticosteroids decrease the period of febrility and hasten the resolution of tonsillopharyngeal symptoms but do not reproducibly affect lymphadenopathy or liver and spleen involvement. Corticosteroids should not generally be used in uncomplicated infectious mononucleosis.
4. PTLD: The mainstay of LPD therapy is reduction of immune suppression. This strategy is logical because LPD most likely results from ineffective immune surveillance of EBV-infected B cells. Reduction of immune suppression leads to regression of tumors in up to 50% of cases. Complications of this approach include organ rejection or graft-versus-host disease (GVHD) in allogeneic stem cell recipients. Surgical resection and radiotherapy are often used in localized LPD and can be combined with reduction of immune suppression with good results. Interferon-α produces antiviral effects and boosts immune function and is used for LPD treatment. It is difficult to assess accurately the efficacy of interferon-α because it is usually combined with other treatment modalities. Antiviral therapy with agents such as acyclovir or ganciclovir is commonly used to treat LPD, with or without immunoglobulin. Rituximab is a monoclonal antibody directed against the CD20 B-cell antigen. Binding of this antibody to B cells results in B-cell death through CTLs and activation of the complement cascade.

AMH