An 18 year old freshman college student presents to the health center complaining of sore throat and fever for 3 days. She also states that she has been feeling tired for the past week. On physical exam, she is tired and subdued but not toxic in appearance with a temperature of 38 degrees C. Her tonsils are enlarged and erythematous. She has enlarged posterior cervical lymph nodes bilaterally, which are mildly tender to palpation. She has no supraclavicular, axillary, or inguinal lymphadenopathy. Her spleen tip is palpable below the left costal margin. A throat swab is obtained to test for group A streptococcal antigen, which is negative. Laboratory testing reveals a mild leukocytosis with the presence of atypical lymphocytes. A Monospot test is positive. She declines a course of corticosteroid therapy. Her symptoms improve in a week.
The Epstein-Barr virus (EBV) causes a broad spectrum of disease in humans with several clinical syndromes. Perhaps the best known is the one illustrated in the case above, the syndrome of infectious mononucleosis. This is an acute illness that results from primary infection with the virus. It is characterized by the triad of sore throat, fever, and lymphadenopathy. The name is derived from the mononuclear lymphocytosis with atypical appearing lymphocytes that accompany the illness.
The EBV virus is ubiquitous, infecting more than 95% of the world's population. Its clinical manifestations depend on the age when the infection is first acquired. Most infections occur during infancy or early childhood. These are often asymptomatic or indistinguishable from other childhood illnesses. Among affluent communities, however, primary infection may be delayed until adolescence or young adulthood. This is when the classic syndrome of infectious mononucleosis often manifests. Almost all adults over age forty have been infected with EBV and show serologic evidence of prior infection.
The EBV virus is a member of the herpes virus family. EBV is also known as human herpes virus-4 or HHV-4. Like other herpes viruses, it establishes a lifelong latent infection. The virus is transmitted in oral secretions and is acquired from close contact such as kissing or exchange of saliva between children. It initially infects epithelial cells in the oropharynx, where viral replication occurs and lysis of the epithelial cell results in release of new virions into the circulation. The virus then infects B lymphocytes in the peripheral blood and the reticuloendothelial system, including the liver, spleen, and lymph nodes. It is in these cells where the virus establishes latency, via formation of a viral episome. The host mounts a cell-mediated immune response to control the number of proliferating infected B lymphocytes. The atypical lymphocytes seen in infectious mononucleosis are activated CD8 T-cells, which exhibit suppressor and cytotoxic functions in response to the infected B cells. Infection is thus controlled but not abolished. Reactivation may occur intermittently with viral shedding in oral secretions of affected individuals.
The incubation period of infectious mononucleosis is 30-50 days. The onset of symptoms is often insidious, with a prodrome of malaise, headache, fatigue, fever, sore throat, anorexia, and myalgia. Patients seek medical attention with worsening sore throat and fever. On physical exam, the most common finding is lymphadenopathy, which is present in 90% of cases. It often occurs in the cervical region, particularly the posterior cervical chain, but may also be generalized with involvement of submandibular, epitrochlear, axillary, and inguinal lymph nodes. Lymph nodes are not spontaneously painful but may be mildly tender to palpation. Fever and pharyngitis occur in most patients. Pharyngitis may be moderate to severe with tonsillar enlargement and exudate. Abdominal exam may reveal splenomegaly in 60% and hepatomegaly in 10%. Patients treated with ampicillin/amoxicillin for presumed bacterial infection characteristically develop a maculopapular rash, which may be useful in diagnosis, but it is also an annoying adverse effect that often results in an inappropriate diagnosis of penicillin allergy.
The diagnosis of infectious mononucleosis may be made by clinical history, physical exam, and typical laboratory findings. Greater than 90% of patients will have leukocytosis, with white blood cell counts ranging from 10,000 to 20,000. Atypical lymphocytes usually account for 20-40% of the total number. These cells appear larger, with eccentrically placed nuclei and a larger amount of cytoplasm compared to typical lymphocytes. Mild elevation of liver enzymes occurs in 50%.
EBV-associated infectious mononucleosis is associated with the transient production of heterophil antibodies. These are IgM antibodies from the patient's serum that cause agglutination of red cells from sheep or horse serum. The most widely used test is the Monospot (trademark), a qualitative rapid slide test which detects horse red cell agglutination (i.e., the modern equivalent of the heterophil antibody). The sensitivity and specificity of this test is greater than 95% for diagnosing EBV-associated infectious mononucleosis. Children with symptomatic primary EBV infection are often heterophil negative. Ten percent of EBV-associated infectious mononucleosis may be heterophil- negative. Certain organisms may cause an infectious mononucleosis-like syndrome but are not associated with formation of heterophil antibodies, such as cytomegalovirus, T. gondii, adenovirus, viral hepatitis, HIV, and rubella.
The host also produces antibodies specific to the EBV virus. These are unnecessary for the diagnosis of infectious mononucleosis when the Monospot test is positive. These may be useful to clarify the diagnosis of heterophil-negative cases, or for atypical EBV infections when the Monospot test is often negative. Multiple EBV-specific antibody tests are available, including tests for viral capsid antigen (VCA), early antigen (EA), and EBV nuclear antigen (EBNA). The presence of IgM antibodies against viral capsid antigen signifies acute infection, while the presence of IgG antibodies signifies recent or past infection.
Infectious mononucleosis usually resolves in 2-3 weeks, although malaise may persist for weeks to months. Treatment is primarily supportive, with rest during the acute stage of illness and symptomatic care. Contact sports should be avoided while splenomegaly is present due to the risk of splenic rupture, although the incidence of this is low at less than 0.5%. Treatment with acyclovir or corticosteroids has not been proven to be of benefit in uncomplicated cases. Corticosteroids may be considered for severe complications of EBV infection, which are rare. Complications may include marked tonsillar inflammation with impending airway obstruction, massive splenomegaly, myocarditis, autoimmune hemolytic anemia, aplastic anemia, thrombocytopenia, neutropenia, hemophagocytic syndrome, meningitis, and encephalitis. EBV infection has been identified as a possible causative agent for chronic fatigue syndrome, but there is no strong evidence to support this.
EBV has been linked with benign and malignant proliferative disorders, particularly in patients with immunodeficiencies such as HIV, transplant recipients, severe combined immune deficiency, or Wiskott-Aldrich syndrome. The absence of an intact cell-mediated immunity in these patients allows the uncontrolled proliferation of EBV-infected B lymphocytes. Examples of benign disorders include oral hairy leukoplakia, which occurs primarily in adults with HIV and presents with raised, white lesions on the tongue, and lymphoid interstitial pneumonitis, which occurs primarily in children with HIV and is characterized by the presence of diffuse interstitial pulmonary infiltrates. Examples of malignant disorders that have been associated with EBV include nasopharyngeal carcinoma, the most prevalent cancer among adult males in southern China, and African Burkitt lymphoma, the most common childhood cancer in equatorial east Africa. Genetic and environmental factors may play a role in the increased incidence of these diseases in these areas. EBV has also been associated with lymphoma in immunosuppressed patients.
1. A 16 year old male presents with sore throat, fever, and cervical lymphadenopathy. A throat culture is done which is positive for group A streptococcus. Treatment is initiated with penicillin. He returns two days later with worsened symptoms, despite taking the medicine. Which of the following is the most appropriate step to do next?
. . . . . a. Switch to azithromycin.
. . . . . b. Obtain a CBC and Monospot.
. . . . . c. Check anti-VCA, anti-EA, and anti-EBNA titers against EBV.
. . . . . d. Assume the patient has infectious mononucleosis and start acyclovir and prednisone.
2. Which of the following is FALSE regarding EBV infection in young children?
. . . . . a. Primary infection is usually asymptomatic.
. . . . . b. Heterophil antibodies are usually positive.
. . . . . c. Immunocompromised patients are at risk for lymphocytic interstitial pneumonitis
. . . . . d. Complications are less common than in adults.
3. Which syndrome has NOT been found to be associated with EBV?
. . . . . a. Nasopharyngeal carcinoma
. . . . . b. Oral hairy leukoplakia
. . . . . c. Aplastic anemia
. . . . . d. Kaposi's sarcoma
4. An 18 year old female presents with malaise, fever, sore throat, and lymphadenopathy. Her CBC reveals atypical lymphocytosis, but her Monospot test is negative. Which of the following statements is TRUE?
. . . . . a. The Monospot test is not a highly sensitive test.
. . . . . b. Her symptoms may be due to primary infection by cytomegalovirus (CMV).
. . . . . c. There is no role for EBV-specific antibodies in making the diagnosis.
. . . . . d. The atypical lymphocytes represent circulating infected B lymphocytes.
5. Which of the following statements about EBV infection is TRUE?
. . . . . a. The syndrome of infectious mononucleosis results from primary infection with the virus.
. . . . . b. Infection usually occurs via contact with the blood of an affected person.
. . . . . c. About 25% of older adults show serologic evidence of prior infection.
. . . . . d. Splenic rupture is a frequent complication in EBV-associated infectious mononucleosis.
1. Cohen JL. Epstein-Barr Virus Infection. New Engl J Med 2000;343:481-492.
2. Schooley R. Epstein Barr Virus Infection. In: Mandell GL (ed). Principles and Practice of Infectious Diseases, 5th ed. 2000, Orlando: Churchill Livingstone, pp. 1603-1608.
3. Jenson HB. Acute complications of Epstein-Barr virus infectious mononucleosis. Curr Opin Pediatr 2000;243:263-268.
4. Jenson HB. Epstein-Barr Virus. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 977-981.
Answers to questions
1. The answer is b. In this case, the group A streptococcus probably represents colonization rather than the etiology of the patient's symptoms. Infectious mononucleosis may have a similar presentation to streptococcal pharyngitis, and must be considered if a patient is not responding clinically to treatment with antibiotics. Diagnosis may be made with a Monospot test as well as the presence of atypical lymphocytes on CBC. EBV titers are not usually needed in diagnosis, but may be considered if the Monospot is negative and EBV infection is to be ruled out. Treatment with acyclovir or corticosteroids has not been proven to be of clinical benefit in uncomplicated cases of infectious mononucleosis.
2. The answer is b. Primary EBV infection occurs more commonly in childhood and is often asymptomatic. In children who do develop symptomatic EBV infection, heterophil antibodies are more often negative. Lymphocytic interstitial pneumonitis may occur in children with HIV. Complications occur less commonly in children than in adults.
3. The answer is d. The first three have all been found to be associated with EBV infection. Kaposi's sarcoma is associated with a different human herpes virus, referred to as human herpes virus-8 or HHV-8.
4. The answer is b. The Monospot test is a highly sensitive test, although ten percent of EBV-associated infectious mononucleosis may be negative. There are also a number of organisms that may cause an infectious mononucleosis-like syndrome but are not associated with formation of heterophil antibodies. The most common cause of a heterophil-negative infectious mononucleosis-like syndrome is CMV, which this patient likely has. Obtaining antibody titers specific against EBV and CMV may clarify the diagnosis. The atypical lymphocytes that may be seen with either EBV or CMV infection represent activated T lymphocytes, which proliferate in response to infected B lymphocytes.
5. The answer is a. The syndrome of infectious mononucleosis results from primary infection with EBV, particularly when it is delayed until adolescence or young adulthood. It is usually transmitted through close contact with oral secretions of an infected individual. The virus is ubiquitous, and almost all adults over age 40 show serologic evidence of prior infection. Splenic rupture is a rare complication of EBV-associated infectious mononucleosis.