Epstein-Barr Virus

Etiology

Epstein Barr virus is a herpesvirus with double-stranded DNA enclosed by proteins. The envelope of the virus has glycoproteins, which are important for attachment and entry into the host cells (B cells and epithelial cells). EBV targets B cells by utilizing their molecular machinery to replicate the viral genome. The virus causes B cells to differentiate into memory B cells, which then can move into the circulatory system, or become latent until a trigger causes reactivation.[1]

The transmission of the Epstein Barr virus occurs in several ways, such as deep kissing or food-sharing. Increased levels of viral DNA are found in salivary secretions after the initial infection. Children can be infected after eating food that has already been chewed by an EBV infected individual.[3] The transmission has occurred through stem cell and organ transplantation, as well as blood transfusion.[1][3]

Epidemiology

Nearly 95% of the world’s population of adults have been infected with the Epstein Barr virus.[2] In the United States, children and adolescents between the ages of 6 to 19 years had an EBV prevalence of 66.5%. Children between 6-8 years of age had a prevalence of approximately 54%, while adolescents 18-19 years old had a prevalence of 82.9%. More females than males were infected, but the difference was minimal. Children and adolescents who identified as Mexican-American had a higher prevalence of Epstein Barr virus than non-Hispanic Blacks and Whites. There was a higher prevalence of Epstein Barr virus infection in children and adolescents who had larger households, lower household incomes, lower parental education, and who were born outside the U.S.[4] 

Worldwide prevalence rates of Epstein Barr virus vary. In England, the Epstein Barr virus prevalence rate for children ages 11 to 24 was 74.6%. Younger patients 11 to 14 years old had a lower prevalence rate of Epstein Barr virus when compared to older children. Young adults 22 to 24-year olds had 93% seropositivity.[5] In a study population from Tehran, Iran, the seroprevalence of Epstein Barr virus IgG antibody was 81.4%. Almost 95% of the subjects over 40 years old were seropositive. The prevalence of seropositive subjects increased as age increased, except for in the infant population. Infants had elevated levels of Epstein Barr virus IgG antibodies that decreased as they aged, likely due to loss of maternal antibodies over time.[6] In China, a study showed a prevalence rate of greater than 50% before 3 years of age, and over 90% by ages 8 to 9 years old.[7] 

One study found that the infection rates tend to increase between June and August, most likely due to increased human interaction during the summer months.[8]

History and Physical

Determining if a patient has Epstein Barr virus requires a thorough history and physical. Infection with Epstein Barr virus can cause a variety of symptoms, ranging from asymptomatic to a spectrum of illnesses. In children, infection with Epstein Barr virus can often be asymptomatic or present with vague symptoms.[2] Patients infected with Epstein Barr virus can have systemic manifestations including splenomegaly, lymphadenopathy, headache, malaise, fever, and sore throat.[8] Patients may show symptoms for several months, with fatigue as the most common lingering complaint. In a study done by Rea et al., physical exam findings such as cervical lymphadenopathy and pharyngitis, were seen at six months after the initial infection in about one-quarter of the study group (n=140). Lab abnormalities such as lymphocytosis, with a presence of atypical lymphocytes, are most common. Liver function tests can also be abnormally elevated. In some patients, there was even a decline in functional and emotional status while they were sick that improved throughout the study period.[9]

Evaluation

Determining if a patient has an infection due to Epstein Barr virus is usually most effective through serological testing. Atypical appearing lymphocytosis is most commonly present on peripheral smear.[1] Heterophile antibody tests identify IgM antibodies against EBV. Heterophile antibody testing is a good initial test since it is inexpensive, fast, and has a sensitivity of 63-84% and specificity of 84 to 100%.[2][10] The disadvantages of the heterophile antibody test include the possibility of a negative result in children, since they may not produce heterophile antibodies to EBV. Unfortunately, other disease processes can induce heterophile antibodies, or they may be present for over a year, causing a positive result unrelated to an acute EBV infection.[1][3] Viral capsid antigen (VCA) IgM and IgG can be used to confirm the diagnosis. Elevated levels of VCA IgM antibodies detect an acute infection, while increased VCA IgG antibody levels indicate prior or chronic infection.[1] Patients with EBV who were followed for 6 months showed VCA-IgM antibodies that subsided after a month and VCA-IgG that decreased over time.[9]

Treatment / Management

Epstein Barr virus is treated symptomatically with medications that can reduce fever and pain.[1] Some studies using antiviral medications for EBV treatment did show a decrease in the amount of virus shed in the oral cavity, but there was no improvement in overall symptoms.[2] Corticosteroids are not therapeutic, but they can be beneficial in patients who develop airway compromise or autoimmune complications caused by EBV infection.[1](B3)

Differential Diagnosis

Several other diseases need to be considered as part of the differential diagnosis. Bacterial pharyngitis presents with a sore throat, cervical lymphadenopathy, pharyngeal swelling, and tonsillar exudates. Viral pharyngitis usually includes fatigue, fever, rhinorrhea, or conjunctivitis.[11] Cytomegalovirus (CMV) is another virus in the Herpesviridae family that presents similarly to EBV with a sore throat, fevers, chills, elevated liver function tests, and fatigue. Splenomegaly and lymphadenopathy are less common CMV symptoms.[12] Acute HIV infection is also on the differential. These patients present with fevers, muscle and joint pain, fatigue, headaches, and sometimes with lymphadenopathy and pharyngitis.[13]

Prognosis

Infectious mononucleosis caused by Epstein Barr virus is a self-limiting disease with a relatively good prognosis, as most patients will improve over time.[9] However, there are complications from having EBV infection, which vary in frequency.[1]

Complications

Epstein Barr virus has several associated complications. One dangerous complication is splenic rupture due to infectious mononucleosis. In one case study, splenic rupture occurred 6 days after symptoms of infection. It can be treated conservatively or surgically. Pain control and close monitoring are appropriate conservative management strategies reserved for hemodynamically stable patients. Another non-surgical management option is splenic artery embolization. The surgical option is splenectomy which requires post-operative immunizations, antibiotics, and close follow-up.[14] 

Another complication of infectious mononucleosis from EBV is airway obstruction from tonsillar edema of the pharyngeal tissues. Treatment of airway obstruction includes steroids, tracheotomy, or intubation. Airway obstruction is a rare (1-3.5% of cases) but an important complication of infectious mononucleosis that occurs mostly in children.[2][15][16]

Acute acalculous cholecystitis is a complication that can be treated conservatively with pain medication and antiemetics.[17][18] In some cases, patients elected to have laparoscopic cholecystectomy due to unbearable abdominal pain.[18]

There are many other complications from Epstein Barr virus infection that can occur, such as myocarditis, encephalitis, hemophagocytic lymphohistiocytosis, pancreatitis, and autoimmune hemolytic anemia.[19][20][21][22] EBV has also been implicated in causing lymphomas and nasopharyngeal cancers.[1]