Epstein – Barr Virus Disease

EPSTEIN – BARR VIRUS DISEASE

Investigators discovered EBV in the course of their studies to determine the cause of Burkitt’s lymphoma. Serologic studies later found that the virus was the cause of infectious mononucleosis. The greatest interest in EBV hinges on its role in malignant disease, including Burkitt’s lymphoma, nasopharyngeal carcinoma, and lymphoproliferative disease of the immunocompromised.

EPIDEMIOLOGY

EBV can be cultured from saliva of 10 to 20% of healthy adults and is intermittently re-covered from most seropositive individuals. It is of low contagiousness, and most cases of infectious mononucleosis are contracted after repeated contact between susceptible per-sons and those asymptomatically shedding the virus. Secondary attack rates of infectious mononucleosis are low ( < 10%), because most family or household contacts already have antibody to the agent (worldwide 90–95% of adults are seropositive). Infectious mononu-cleosis has also been transmitted by blood transfusions; most transfusion-associated mononucleosis syndromes, however, are attributable to CMV. In more highly developed countries and in individuals of higher socioeconomic status, EBV infection tends to be ac-quired later in life than in individuals from developing countries of lower socioeconomic status. When primary infection with EBV is delayed until the second decade of life or later, it is accompanied by symptoms of infectious mononucleosis in about 50% of cases.

At present, there appears to be many fewer variations of genomic strains among EBV isolates than other herpesviruses.

PATHOGENESIS

Although EBV initially infects epithelial cells, the hallmark of EBV disease is subsequent infection of B lymphocytes and polyclonal B lymphocyte activation with benign prolifer-ation. The virus enters B lymphocytes by means of envelope glycoprotein binding to a surface receptor CD21, which is the receptor for the C36 component of complement; 18 to 24 hours later, EBV nuclear antigens are detectable within the nucleus of infected cells. Expression of the viral genome, which encodes at least two viral proteins, is associated with immortalization and proliferation of the cell. The EBV-infected B lymphocytes are polyclonally activated to produce immunoglobulin and express a lymphocyte-determined membrane antigen that is the target of host cellular immune responses to EBV-infected B lymphocytes. During the acute phase of infectious mononucleosis, up to 20% of circulat-ing B lymphocytes demonstrate EBV antigens. After infection subsides, EBV can be iso-lated from only about 1% of such cells.

EBV has been associated with several lymphoproliferative diseases, including African Burkitt’s lymphoma, nasopharyngeal carcinoma, and lymphomas in immunocompromised patients. The factors that render the EBV infections oncogenic in these cases are obscure. The distribution of EBV infections in Africa has suggested an infectious cofactor, such as malaria, which may cause immunosuppression and predispose to EBV-related malignancy. In nasopharyngeal carcinoma, environmental carcinogens may create the precancerous le-sion although genetic factors may also be operative. In vivo, EBV-associated lymphomas have been shown to be of both monoclonal and polyclonal origin. Chromosomal transloca-tions in B cells are characteristic of Burkitt’s lymphoma and involve specific breaks in chromosomes. These translocations lead to expression of oncogenes that may contribute to clonal activation and ultimately to malignancy. Some breakdown in immune surveillance also appears to play a role in the development of malignancy, because immunosuppressed patients are more prone to develop EBV associated B-cell lymphomas.

IMMUNITY

Virus-induced infectious mononucleosis is associated with circulating antibodies against specific viral antigens, as well as against unrelated antigens found in sheep, horse, and some beef red blood cells. The latter, referred to as heterophile antibodies, are a heteroge-neous group of predominantly IgM antibodies long known to correlate with episodes of infectious mononucleosis, and are commonly used as diagnostic tests for the disease. They do not cross-react with antibodies specific for EBV, and there is not good correla- tion between the heterophile antibody titer and the severity of illness. Cutaneous anergyand decreased cellular immune responses to mitogens and antigens are seen early in the course  of  mononucleosis.  The  “atypical”  lymphocytosis  associated  with  infectious mononucleosis  is  caused  by  an  increase  in  the  number  of  circulating T  cells,  which appear to be activated cells developed in response to the virus-infected B lymphocytes. With recovery from illness, the atypical lymphocytosis gradually resolves, and cell-mediated immune functions return to preinfection levels, although memory T cells maintain the ca-pacity to limit proliferation of EBV-infected B cells. In rare cases, the initial EBV-induced proliferation of B cells is not contained, and EBV lymphoproliferative disease ensues. This syndrome is most often seen in immunocompromised organ transplant recipients.