Etiology
Epstein-Barr virus (EBV), also known as human herpes virus 4, is the etiologic agent in approximately 80% to 90% of IM cases.[1][2] In remaining EBV-negative cases, mononucleosis syndrome may be caused by human herpes virus 6 (9%), cytomegalovirus (5% to 7%), herpes simplex virus-1 (6%), and rarely by Streptococcus pyogenes, Toxoplasma gondii, HIV-1, adenovirus, as well as Corynebacterium diptheriae, Francisella tularensis, hepatitis A and B viruses, rubella, or enteroviruses. This syndrome may also be caused by connective tissue disorders, malignancies, and drug reactions.[21][6][22] The etiology of many EBV-negative IM cases often remains unknown.[21]
EBV is most commonly transmitted through saliva, hence the name ''kissing'' disease. In one study, all patients with EBV-caused IM shed virus from the oropharynx for 6 months after the disease onset.[23] In a prospective study, 22 out of 24 healthy individuals with past history of EBV infection shed virus in saliva for 15 months.[24] There is also evidence of sexual transmission of EBV.[25][26] It has been shown that in young women, the risk of EBV seroconversion increases with increasing number of sexual partners.[27] In one study the risk of acquiring EBV was lower among university students who always used a condom than among those who had sexual intercourse without one.[25] As there are significantly lower levels of EBV in genital secretions compared to saliva, sexual intercourse is probably not the most important route of transmission.[26] However, both saliva and genital secretions are considered inefficient means of transmission. Rare instances of EBV transmission from blood products, organ transplantation, and intrauterine transmission have been reported. The risk of acquiring EBV infection from a blood transfusion is extremely low. Humans, and possibly primates, are the only known reservoir of EBV. Identifying clear risk factors is impossible due to the high prevalence of infection (over 90% of humans are infected by the time they are adults).
Pathophysiology
EBV has lytic and latent lifecycles. The early primary infection (lytic) probably occurs in the oropharyngeal B cells when EBV directly accesses these cells via the tonsillar crypts. Circulating B cells then spread infection to liver, spleen, and peripheral lymph nodes, prompting humoral and cellular immune responses to the virus.[3] Antibodies produced in response to infection are directed against EBV structural proteins, such as viral capsid antigens, early antigens, and EBV nuclear antigen; these antibodies are used for the serologic diagnosis of EBV infection. A rapid cellular response by T cells is crucial for suppression of the primary EBV infection and determines the clinical expression of EBV infection. Symptomatic primary infection with EBV is usually followed by a latent stage. The latent infection is established by self-replicating extrachromosomal nucleic acid, the episomes. In latency, EBV immortalizes infected lymphocytes; that is, it causes normal human lymphocytes with a limited life span in vitro to form continuous cell lines. In a healthy EBV-seropositive adult, approximately 0.005% of circulating B cells are infected with EBV.[28] It is likely that in latency there are low levels of ongoing viral replication and infection of B cells in the tonsillar and lymphoid tissues controlled by the residual populations of EBV-specific T cells. An observational study in patients with asymptomatic primary infection suggests that symptoms may arise from a hyperactivated immune response rather than viral infection itself.[29]
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