INFECTIOUS MONONUCLEOSIS

General Goal: To know the cause of this disease, the most common modes of transmission and the major manifestations of this disease.

Specific Educational Objectives: The student should be able to:

1. recite the common means of transmission and the major disease manifestations.

2. identify the cell-types in which the virus infects and establishes latency.

3. identify the people groupings that are more likely to get lymphoproliferative diseases.

4. serologically determine if a patient is infected with the virus and what stage of the infection the patient is currently experiencing (acute, chronic, past infections and  reactivation).

Reading: P.R. Murray, K.S. Rosenthal, and M.A. Pfaller. 2009. Medical Microbiology. 6th Edition. pg. 529-534. Mosby Elsevier, Philadephia, PA.

Lecture: Dr. Neal R. Chamberlain

References: 

B.A. Cunha. Oct. 19, 2008, Infectious Mononucleosis, eMedicine.com

http://emedicine.medscape.com/article/222040-overview

OVERVIEW

"Epstein-Barr virus" (EBV or Human Herpes Virus 4; HHV-4).

EPIDEMIOLOGY

About 70% of the people in the U.S. are infected by 30 years of age.

Infectious mononucleosis occurs in young adults 15-25 years of age.

Transmission: EBV is acquired by contact with infected cervical and oral secretions (kissing, sharing drinking glasses, etc.); EBV can be isolated from saliva. EBV can be transmitted via blood transfusions. Several doses are required for infection since EBV is not very contagious. The virus is still present in the saliva for months after the patient recovers. More than 90% of EBV-infected people intermittently shed virus for life even when asymptomatic.

The incubation period is 1-2 months and many patients cannot recall how they may have been exposed to EBV.

EBV infects B lymphocytes and epithelial cells of the oropharynx and results in a lifelong infection of memory B lymphocytes. The diseases caused by EBV occur from an overactive immune response as is seen in infectious mononucleosis or from the lack of immune system control of this viral infection as is seen in lymphoproliferative diseases, lymphoma, and oral hairy leukoplakia.

Infectious Mononucleosis: Disease in patients with infectious mononucleosis is the result of viral replication and host immune responses to EBV viral antigens. EBV is transmitted by repeated contact with body secretions, primarily oropharyngeal secretions. EBV infects the B lymphocytes and the epithelial cells in the oropharyngeal epithelium. EBV invades B cells by means of their CD21 receptor. The infected cells shed EBV virus that can get in the saliva to infect other people and into the bloodstream. During the acute phase of infection, as many as 20% of the circulating B cells will produce EBV antigens, while only 1% will produce EBV antigens during convalescence.

The viremia that results from this viral shedding allows the virus particles to infect B lymphocytes in the lymphatic tissue and the blood. The infection spreads throughout the reticular endothelial system (RES), ie, liver, spleen, and peripheral lymph nodes. EBV infection of B-lymphocytes results in the humoral and cellular response to the virus. B cells that produce complete virions are killed by viral-directed cytolysis, while infected B cells that do not produce complete virions are the target of cytotoxic T cells that are attempting to control their proliferation.

The humoral immune response is the basis for the serological tests used to diagnose EBV infectious mononucleosis. EBV can infect and then activate many different B lymphocytes to proliferate and produce antibody even though the antibody that is made is not specific for EBV antigens (B-cell mitogen). One serological test used in diagnosis of infectious mononucleosis is the heterophile antibody test (Monospot and a rapid ELISA test) in which the B lymphocytes produce IgM to the Paul-Bunnell antigen. The Paul-Bunnell antigen is present on the surface of sheep, horse and bovine red blood cells. The heterophil antibody test is a nonspecific test for infectious mononucleosis and may not be positive in all patients with EBV infections.

B lymphocytes that produce antibodies that react with EBV antigens are also activated and are used in serological tests. These serologic tests are specific for detection of patients with an active or past EBV infection. These tests are more likely to be positive in EBV infected patients than the heterophil antibody tests. Antibodies to EBV antigens VCA (viral capsid antigen) and MA (membrane antigen- not used in serological tests) are produced early on in an EBV infection. Antibody to EA (early antigen) viral antigen is produced later in the infection. After the infection is resolved antibody to EBNA (EBV nuclear antigen) can be detected. EBV is not usually found free in the blood but is present as immune complexes. These complexes are believed to be responsible for arthralgias and urticarial rashes occurring during the acute phase of the disease.

As with many viral infections the T lymphocyte response is essential in the control of EBV infection. The activation of these T lymphocytes causes significant T lymphocyte proliferation. So many T lymphocytes are produced that cervical lymph nodes, the spleen and the liver can swell. These activated T lymphocytes become so numerous in the peripheral blood that they can account for 10-80% of the total white blood cell count. This lymphocytosis contains many of these activated T lymphocytes that are atypical in appearance and have been called Downey cells. It is the Downey cells that cause the atypical lymphocytosis seeing in infectious mononucleosis.

Even after disappearance of circulating Downey cells and recovery from illness, EBV can be recovered from oropharyngeal washings 12-18 months later. During resolution of the EBV infection the virus establishes itself in memory B lymphocytes. Infection with this virus is lifelong. If these memory B cells are activated they can then produce EBV virions and the person may shed the virus asymptomatically.

EBV induced Lymphoproliferative Diseases: People that lack T cell immunity are more likely to develop life-threatening polyclonal leukemia-like B lymphocyte proliferative disease and lymphoma following EBV infection rather than infectious mononucleosis. Transplant recipients receiving immunosuppressive therapy are more likely to develop posttransplant lymphoproliferative disease when infected with EBV or after reactivation of latent EBV virus. Similar diseases can be seen in AIDS patients. One unusual manifestation of EBV infection or reactivation in AIDS patients is hairy oral leukoplakia. Hairy oral leukoplakia is a productive infection of the epithelial cells causing lesions on the tongue and mouth. EBV infection contributes to endemic lymphoma of the B lymphoctyes in children living in malaria endemic regions of Africa. These children get African Burkitt lymphoma. It is yet to be determined how malarial infection and EBV interact to cause the lymphoma. In Asia EBV infection is associated with nasopharyngeal carcinoma in children and adults that is of epithelial cell origin.

Heterophile Antibody-Positive Infectious Mononucleosis:

Prodrome: headache, malaise, and fatigue occur for 4-5 days following the invasion of B cells by EBV. Most infections in young children are asymptomatic. Symptoms are more pronounced in previously uninfected young adults.

Usually a triad of symptoms: fever, pharyngitis, and lymphadenopathy

Acute disease: 

• Fever - adults 101-102°F; Children may not have fever
• Cervical lymphadenopathy
• severe sore throat- diffuse pharyngeal inflammation- tonsillar swelling can be severe. Can be exudative or nonexudative.
• diffuse pharyngeal inflammation
• edema-can sometimes see bilateral upper eyelid edema early in illness (palpebral edema).
• Early in the illness a faint evanescent non-pruritic maculopapular rash may appear.
• petechiae on hard and soft palates (30% of symptomatic patients)
• Besides the anterior and posterior cervical lymph nodes, axillary, epitrochlear, mediastinal, and mesenteric nodes may also be infected.
• Splenomegaly - 50% of cases with acute mononucleosis.
• Severe abdominal pain in this disease is very rare.
• Hepatomegaly (occurs in about 10% of patients). Altered liver function tests for several weeks.
• Increased serum transaminase and lactic acid dehydrogenase.
• Jaundice develops in only about 5% of the cases.

Chronic Disease
EBV can cause cyclical recurrent disease in some people. These patients experience chronic tiredness, low-grade fever, headaches, and sore throat. This disease is different from chronic fatigue syndrome.

EBV Induced Lymphoproliferative Diseases

1. People lacking T-cell immunity are most likely to suffer life-threatening polyclonal leukemia-like B-cell proliferative disease and lymphoma rather than infectious mononucleosis when infected by EBV.
2. X-linked lymphoproliferative disease= is a life threatening disease seen in people infected with EBV that have congenital deficiencies of T-cell function .
3. Posttransplant lymphoproliferative disease is seen in transplant recipients undergoing immunosuppressive therapy after exposure to the virus or reactivation of the virus.
4. Similar lymphoproliferative diseases are seen in AIDS patients after exposure to EBV or reactivation of a previous infection.
5. Burkitt's lymphoma
6. Hodgkin's lymphomas= a large precentage of these lymphomas contain EBV DNA sequences.
7. Nasopharyngeal carcinoma= endemic in China. Tumors are from epithelial cells.

The presence of atypical lymphocytes . During acute EBV disease, lymphocyte numbers elevate to 50-60% of the total leukocytes in the peripheral blood (a count of 20,000-50,000), of which 10% are atypical lymphocytes (95 percent are T-lymphocytes the rest are B-lymphocytes), or Downey cells. The presence of atypical lymphocytes is probably the earliest indication of EBV infection, but is not specific for EBV infection. These atypical lymphocytes can be seen in patients with hepatitis, CMV, rubella, roseola, and other lymphoproliferative disorders.

Modest leukocytosis is seen. An elevated erythrocyte sedimentation rate (ESR) is also frequently reported.

Detection of heterophile antibodies. IgM (mostly) is produced that does not cross-react with EBV-specific antibodies, but do recognize antigenic determinants on sheep, horse, and beef erythrocytes, but not guinea pig erythrocytes. To remove other EBV-unrelated cross-reacting antibody, patient serum is absorbed with guinea pig kidney homogenate before testing for heterophile antibody. The EBV heterophile antibody titers are highest during the first four weeks of disease, and can be demonstrated after the first week in some patients, while not until the 3rd or 4th week in others.

Monospot test (Paul-Bunnell heterophile test): false positive heterophile antibody tests may be seen with rubella, malaria, serum hepatitis, systemic lupus erythematosus, leukemia, or pancreatic cancer. False negative reactions occur in 10% of adults and 50% of children.

Antibody titers can be used to determine a patient’s response to specific EBV antigens.

EBNA= EBV nuclear antigen, first antigen to appear HOWEVER antibodies to EBNA develop late in infection.
EA= Early antigen, EA-R= appears before EA-D when EBV infects a cell, anti-EA-D is usually seen in mononucleosis.
VCA= Viral Capsid Antigen (a late antigen); Anti-VCA IgM is transient, anti-VCA IgG is persistant.

• Anti-VCA (viral capsid Ag) - develops early in infection; IgM, 1-2 month duration; IgG, lifelong duration.
• Anti-EBNA (nuclear Ag) - develops after 3-6 weeks, lifelong duration.
• Presence of anti-VCA, but NOT anti-EBNA: recent infection.
• Presence of both anti-VCA and anti-EBNA: past infection.

Most infectious mononucleosis cases are mild or moderate in severity. Acute illness lasts 2-3 weeks and patients recover in 4-6 weeks.

Supportive therapy, including bed rest and aspirin (adults only (over 18 years of age); since children given aspirin following viral infections can develop Reye Syndrome) or analgesics (acetaminophen), is the primary form of treatment during acute infectious mononucleosis.

Systemic Acyclovir stops EBV replication, but relief is temporary since replication resumes when drug therapy is discontinued. Treatment does not shorten the course of the infection.

Major complications occur in 1-5% of the cases. Most common complications are lymphocytic meningitis, encephalitis, encephalomyelitis, polyneuritis, and mononeuritis.

The Guillain-Barré syndrome is a condition that can lead to respiratory paralysis and death.

Splenic rupture can occur, but is rare (0.1%).

Severe tonsillitis may lead to airway obstruction if a tracheotomy is not performed.

A rash may appear if the patient has been treated with ampicillin or amoxicillin.

Atraumatic and traumatic splenic ruptures have both been observed. Patients who participate in contact/collision/high-risk sports should not participate in the sport for at least 3-4 weeks following onset of the illness. Although controversial some also suggest radiological confirmation that the spleen is no longer enlarged before allowing an athlete to participate in a high-risk, contact or collision sports (K.E. Burroughs. 2000. Athletes Resuming Activity After Infectious Mononucleosis. Arch Fam Med. 2000;9:1122-1123).