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, G.S. Kobayashi and M.A. Pfaller, MEDICAL MICROBIOLOGY, 3^rd Edition. p. 430-434.

Lecture: Dr. Neal R. Chamberlain

References: 

B.A. Cunha. July 6, 2004, Infectious Mononucleosis, eMedicine.com

http://www.emedicine.com/med/topic1499.htm

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.

Disease is the result of viral replication and host immune responses to viral antigens. EBV is transmitted by repeated contact with body secretions, primarily oropharyngeal secretions. EBV infects the B cells in the oropharyngeal epithelium. The infected B cells spread the infection throughout the reticular endothelial system (RES), ie, liver, spleen, and peripheral lymph nodes. EBV infection of B-lymphocytes results in the humoral (B-cell mitogen) and cellular response to the virus. The humoral immune response is the basis for the tests (Monospot and EBV specific tests) used to diagnose EBV infectious mononucleosis. As with many viral infections the T-lymphocyte response is essential in the control of EBV infection; natural killer (NK) cells and predominantly CD8⁺ cytotoxic T cells control proliferating B-lymphocytes infected with EBV.

Portal: EBV infects and multiplies in the epithelial cells of the oropharynx.

Dissemination: 30-50 d (adults) or 10-14 d (in children) later, EBV can be isolated from saliva, blood and lymphatics.

B cell invasion: EBV invades B cells by means of their CD21 receptor, and 18-24 hours later EBV antigens are detectable within the lymphocyte nucleus. During the acute phase, as many as 20% of the circulating B cells will show EBV antigens, while only 1% will show them during convalescence.

Immune complexes: The virus usually is not 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.

B cell mitogen: The EBV infection initiates B cell proliferation and immortalization without the role of T helper cells; EBV can be thought of as a B cell mitogen.

B cell killing: 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. These EBV-infected B cells are recognized through their expression of a lymphocyte-determined antigen.

Lymphocytosis associated with infectious mononucleosis is caused by an increase in the number of circulating activated T cells; also called Downey cells because of their atypical presence in peripheral blood.

Carrier state: Even after disappearance of circulating Downey cells and recovery from illness, EBV can be recovered from oropharyngeal washings 12-18 months later. Infection with this virus is lifelong.

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).