CAUSES AND SYMPTOMS

The Epstein-Barr virus is one of the eight known types of human herpes viruses and is a member of the gamma subtype in this group. Like many herpes virus species, the Epstein-Barr virus is a double-stranded DNA virus that establishes a lifelong presence in the human body, remaining quiescent for long periods and then inexplicably becoming active. Causally related to mononucleosis, it is also associated with various human cancers, such as Burkitt lymphoma and nasopharyngeal carcinoma, and is considered a carcinogenic virus.

Humans are the only known reservoir of Epstein-Barr virus, which is present in oropharyngeal secretions and is usually transmitted through saliva; transmission of the virus requires intimate contact with the saliva of an infected person, including contact with objects such as shared toothbrushes. Most cases of Epstein-Barr virus transfer occur by sharing food or drinks or kissing. Transmission through the air or blood does not usually occur. Still, transmission through blood, semen, and organ transplants has been reported.

The Centers for Disease Control and Prevention (CDC) estimates that the Epstein-Barr virus has infected 95 percent of adult Americans between thirty-five and forty. Still, it is less prevalent in children and teenagers, a pattern observed in the developed world but not in developing regions such as Africa and Asia. In Africa, for example, most children have been infected by the virus by the age of three. Epstein-Barr virus has also been associated with nasopharyngeal cancers in Asia (especially China) and Burkitt lymphoma in equatorial Africa and Papua New Guinea. In tropical regions, Burkitt lymphoma has been shown to coexist with malaria. In the United States, the Epstein-Barr virus has also been associated with nasopharyngeal cancers in immigrants from Asia. The incidence of Burkitt lymphoma has been increasing. Both Hodgkin and non-Hodgkin lymphomas are found in people whose immune systems have been compromised by drug therapy and disease. Epstein-Barr virus has also been associated with approximately 10 percent of gastric carcinomas.

Chronic fatigue syndrome is a multifaceted illness with many symptoms and a host of varying clinical presentations. Some, though certainly not all, cases of chronic fatigue syndrome show a clear association with chronic Epstein-Barr virus infection. Recently, chronic fatigue syndrome was merged with myalgic encephalomyelitis.

Electron microscopic image of two Epstein Barr Virus virions (viral particles) showing round capsids—protein-encased genetic material—surrounded by the membrane envelope.

Image by Liza Gross, PLoS Biol 3(12) (2005), via Wikimedia Commons.

When the Epstein-Barr virus reaches someone’s mouth, it infects two types of cells in the oropharynx. First, it infects epithelial cells that line the services of the oropharynx. Second, it infects B lymphocytes, the lymphoid cells that create antibodies to fight infections. In epithelial cells, the Epstein-Barr virus undergoes the lytic cycle. Viral deoxyribonucleic acid (DNA) is transcribed during the lytic cycle, and the cellular machinery translates messenger ribonucleic acids (mRNAs). These processes form viral proteins packaged into new viruses that leave the host cell after its destruction. These new viruses subsequently infect neighboring epithelial cells.

When the Epstein-Barr virus reaches the lymphoid tissue in the oropharynx, the tonsils, it infects B lymphocytes. The CD21 receptor on the surface of the B lymphocyte is a molecule used by the Epstein-Barr virus to attach and enter the cell. In the infected B cell, the virus enters the latent phase. While in the latent phase, the virus is present in the B lymphocytes but does not kill them. Infected B cells, however, spread the infection to other lymphoid tissues of the body, including the liver, spleen, and other lymph nodes. Therefore, the immune response against the Epstein-Barr virus limits its spread throughout the lymphoid tissues, stopping its spread. Typically, the immune response against infection creates antibodies and cytotoxic T lymphocytes that neutralize the virus and kill the infected B lymphocytes. The immune response against the Epstein-Barr virus prevents some people from having any symptoms (asymptomatic infection).

Destruction of the oropharyngeal epithelium causes infectious mononucleosis. The most common symptoms of this disease are fever, pharyngitis (inflammation of the throat), and swollen lymph nodes (lymphadenopathy). Throat inflammation results from the destruction of the resident epithelial cells. Swollen lymph nodes result from infected B cells that spread throughout the lymph tissue, causing it to swell. Another common symptom of infectious mononucleosis is fatigue, which can be quite severe and may last several months.

Other possible symptoms include tonsillitis (inflamed tonsils), palatal petechiae (red spots on the palate), enlargement of the liver (hepatomegaly), and enlargement of the spleen (splenomegaly). Palatal petechiae result from damage to the epithelial cells on the palate by the virus. Hepatomegaly and splenomegaly result from the flood of infected B lymphocytes and T-cytotoxic cells to these organs, causing them to swell.

Splenomegaly, though rare, is of particular concern because it is susceptible to rupture. Splenic rupture can result in excessive bleeding and even death.

Another infrequent symptom of infectious mononucleosis is a rash that consists of pink macules or patches that do not itch and appear on the trunk and arms. The presence of a rash causes infectious mononucleosis to be frequently misdiagnosed as a group A streptococcus infection (strep throat). For some unknown reason, patients with infectious mononucleosis who are prescribed antibiotics like amoxicillin can develop an itchy maculopapular rash. This rash is not an allergic reaction since people who recover from infectious mononucleosis can take these antibiotics without incident.

Epstein-Barr virus has been shown to take advantage of those with weakened immune systems; Burkitt lymphoma, a non-Hodgkin lymphoma (NHL), is found in organ transplant patients undergoing immunosuppression therapy, as well as those living with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) who are immunocompromised by their disease. Because Burkitt lymphoma typically occurs in tropical climates where malaria is endemic, it is believed that the immune systems of those with malaria are altered, resulting in tumor production. The Epstein-Barr virus is also associated with nasopharyngeal carcinoma, prevalent in those of Chinese and Southeast Asian ancestry. Environmental/occupational exposure to pesticides and organic solvents shows no significant positive association with Epstein-Barr virus and related cancers.

Simplified diagram of the structure of EBV.

Image via Wikimedia Commons. [Public domain.]

Epstein-Barr virus is among the most ubiquitous viruses. It occurs in nearly all regions of the world. Most people become infected with Epstein-Barr virus sometime during their lifetimes. In the United States, as soon as maternal antibodies dissipate, infants become vulnerable to Epstein-Barr virus infection. In adolescents, infection with the Epstein-Barr virus results in infectious mononucleosis in 35 to 50 percent of cases. Although the symptoms of infectious mononucleosis usually dissipate within weeks to several months, the Epstein-Barr virus lies dormant in a few cells in the throat and blood for the remainder of the person’s life. The virus may reactivate from time to time and is often present in the saliva, suppressing the immune system by causing repeated mutations in B cells, which may proliferate unabated, resulting in tumors.

Epstein-Barr virus establishes a lifelong latent infection in the body’s immune system that may later result in the emergence of lymphoma or carcinoma. Latently infected B lymphocytes are usually killed by T-cytotoxic cells. Sometimes, however, cytotoxic T cells cannot kill all the infected B cells. These leftover, infected B lymphocytes experience an extended latency period. They express viral genes that cause increased B-lymphocyte proliferation. Increased latency in B lymphocytes increases the risk of developing B-cell cancers or lymphomas. The leading B-cell cancers linked to Epstein-Barr virus are Hodgkin lymphoma and non-Hodgkin lymphoma, especially Burkitt lymphoma and primary central nervous system lymphoma.

The initial symptoms of Burkitt lymphoma may include a swollen lymph node in the upper body or abdomen. If the tumor is found in the chest, breathing difficulties may ensue. Itching, weight loss, fever, and fatigue may be present in other patients. Burkitt lymphoma commonly results in a large tumor mass in the jawbone. Adults with AIDS often develop tumors in various parts of the body. Symptoms of nasopharyngeal cancer may include a lump in the neck or nose, numbness on the side of the face, headaches, ear pain, and difficulty speaking or breathing.

Epstein-Barr virus-infected epithelial cells can sometimes enter the latent phase and express viral genes that increase their proliferation. In such cases, a cancer of the upper part of the throat called “nasopharyngeal carcinoma” results.

In individuals with poorly functioning immune systems, such as those with human immunodeficiency virus (HIV), cytotoxic T cells cannot destroy all the infected B cells. Consequently, B-cell cancer development in such individuals is more likely. Individuals with HIV exposed to Epstein-Barr virus may develop a white plaque on the lateral side of the tongue that resists things scraped off. This condition is called “oral hairy leukoplakia.”

TREATMENT AND THERAPY

Infectious mononucleosis is typically suspected based on clinical signs and symptoms such as fever, sore throat, swollen cervical lymph nodes, and fatigue. The posterior cervical lymph nodes in the back of the neck are commonly swollen during Epstein-Barr virus infections because those lymph nodes drain the tonsils where the B lymphocytes are initially infected.

Peripheral blood smears reveal the presence of atypical lymphocytes, most of which are enlarged cytotoxic T lymphocytes. Infected B lymphocytes make unusual antibodies known as “heterophile antibodies.” These heterophile or other loving antibodies bind antigens from other animal species. They bind antigens on sheep and horse red blood cells, causing those red blood cells to clump or agglutinate. A so-called Monospot test detects the presence of heterophile antibodies. A positive Monospot test is definitive for Epstein-Barr virus infection. Unfortunately, false negatives of the Monospot test may occur. Early in the infection, heterophile antibodies may not yet have been produced in high enough quantities to be detected. Likewise, in children under four, their B cells do not produce heterophile antibodies.

PERSPECTIVE AND PROSPECTS

In the latter part of the nineteenth century and the early part of the twentieth century, the medical community in the United States and Europe began to report on a novel syndrome consisting of fever, sore throat, and swollen glands that were later termed mononucleosis and were later found to be causally related to Epstein-Barr virus. Epstein-Barr virus was discovered in the 1960s from a biopsy of a tumor associated with Burkitt lymphoma and was the first virus directly linked to human cancer; in 1964, Michael Epstein and Yvonne Barr isolated virus particles from cell lines derived from Burkitt lymphoma, hence the name, Epstein-Barr virus. Subsequently, the Epstein-Barr virus was found to be the leading viral cause of cancer in humans, having an etiological role in Burkitt lymphoma and other B-cell lymphomas and nasopharyngeal carcinoma.

Epstein-Barr virus also shows a tight association with multiple sclerosis. An extensive survey of military personnel covering over ten years of data showed that those who had a previous Epstein-Barr virus infection had a 32 times greater risk of developing multiple sclerosis. How Epstein-Barr virus might induce multiple sclerosis remains uncertain.