Epstein-Barr Virus Case File

Epstein-Barr Virus Case File

Eugene C.Toy, MD, Cynthia Debord, PHD, Audrey Wanger, PHD, Gilbert Castro, PHD, James D. Kettering, PHD, Donald Briscoe, MD

CASE 26

A 17-year-old female is brought to the physician’s office for evaluation of a sore throat and fever. Her symptoms started approximately 1 week ago and have been worsening. She has been extremely fatigued and has spent most of the last 3 days in bed. She denies any ill contacts. She has no significant medical history, takes no medications, and has no allergies. On examination, she is tired and ill appearing. Her temperature is 38.5°C (101.3°F). Examination of her pharynx shows her tonsils to be markedly enlarged, almost touching in the midline. They are erythematous and covered with white exudates. She has prominent cervical adenopathy, which is mildly tender. A cardiovascular examination is normal, and her abdomen is soft, nontender, and without palpable organomegaly. A rapid streptococcal antigen test in the office is negative. You send a throat culture and decide to start amoxicillin for strep pharyngitis, assuming that the office test was a false-negative. Two days later, you get a call from her mother stating that she has had an allergic reaction to the amoxicillin, and she now has a red rash from head to toe.

◆ What is the most likely diagnosis of this patient?

◆ What is the most likely cause of her infection?

◆ In what human cells can this virus replicate? In what cells can it cause latent infection?

ANSWERS TO CASE 26: EPSTEIN-BARR VIRUS

Summary: A 17-year-old female with fever, exudative pharyngitis, and adenopathy develops a prominent macular-papular rash after ampicillin is instituted.

◆ Most likely diagnosis: Infectious mononucleosis.

◆ Most likely etiology: Epstein-Barr virus (EBV).

◆ In the human cells this virus can replicate, and in the cells it can cause latent infection: EBV preferentially replicates in epithelial cells and B cells, and is known to cause latent infections in B cells.

CLINICAL CORRELATION

Epstein-Barr virus (EBV) is a member of the human herpesvirus family, and more specifically a member of the Gammaherpesvirinae subfamily. Humans are the only known natural host for these viruses. EBV infections are most commonly known for causing infectious mononucleosis in adolescents and young adults, and it is often referred to as the “kissing disease.” Viral transmission occurs via repeated close intimate contact or through the sharing of items contaminated with saliva, because virus is intermittently shed in the saliva of most seropositive individuals. Secondary attack rates with family and household contacts tend to be low because 90–95 percent of adults have previously been exposed to EBV. Most primary infections are asymptomatic, whereas symptomatic infections are marked with fever, fatigue, pharyngitis, tender lymphadenitis, and possible hepatosplenopathy. Infections with these symptoms can be mistakenly diagnosed as streptococcal pharyngitis, and the resulting inappropriate treatment with amoxicillin can produce an allergic rash.

APPROACH TO SUSPECTED EBV INFECTION

Objectives

1. Be aware of the genomic and other characteristics of EBV.
2. Be able to describe the clinical disease caused by EBV, mode of transmission, and strategies for treatment.

Definitions

Lymphocytosis: A larger than normal number of T lymphocytes.

Atypical lymphocytes: Enlarged T lymphocytes, also referred to as “Downey cells,” with eccentric nuclei and a vacuolated cytoplasm.

Heterophile antibodies: Nonspecific antibodies, including an IgM antibody, that recognizes the Paul-Bunnell antigen on sheep, horse, and bovine erythrocytes.

DISCUSSION

Characteristics of EBV That Impact Transmission Similar to other members of the Herpesviridae (Table 26-1), EBV is an enveloped virus with a double-stranded linear DNA genome that is approximately 172 kb in size and encodes more than 70 viral proteins. The DNA core is surrounded by an icosadeltahedral nucleocapsid, with a protein tegument located between the capsid and viral envelope, containing viral enzymes and proteins necessary for replication. The outer membrane of EBV contains virally encoded glycoprotein spikes, important for host cell attachment to human B cells and epithelial cells of the oro- and nasopharynx via the receptor for the C3d component of the complement system. As an enveloped virus, EBV is easily disrupted by acids, detergents, and desiccation and, thus, is effectively transmitted via intimate contact and saliva.

There are two infectious subtypes of EBV, EBV-1, and EBV-2, which are closely related except for differences in their nuclear antigens. The various EBV antigens are expressed in different phases of productive viral replication or in latent infection and can be used in diagnoses. Early EBV antigens, such as early antigens (EAs) and nuclear antigens (NAs), are nonstructural proteins expressed at the onset of lytic viral infection and are followed by the expression of late viral antigens, including the structural components of the viral capsid (VCA) and membrane (MA). Latent phase antigens are expressed in latently infected B cells and include Epstein-Barr nuclear antigens (EBNAs), latent proteins (LPs), and latent membrane proteins (LMPs).

Table 26-1

PROPERTIES OF HERPES VIRUSES

EBV was first discovered in association with African Burkitt lymphoma, a common malignancy of young children in sub-Saharan Africa. The highest occurrence of Burkitt lymphoma appears to occur in regions with high incidence of malaria, indicating malaria as a possible disease cofactor. Other EBV-related diseases include nasopharyngeal carcinoma and, in immunocompromised patient populations, B-cell lymphomas, interstitial lymphocytic pneumonia, and hairy leukoplakia of the tongue.

EBV can cause lytic infections of epithelial cells and latent infection or immortalization of B cells. The lytic infection of epithelial and B cells promotes virus shedding into the saliva of the host, allowing for viral transmission to other hosts and spread within the host. In B cells, EBV promotes cell growth and prevents apoptosis. The proliferating B cells produce an IgM antibody to the Paul- Bunnell antigen, called a heterophile antibody, which serves as a diagnostic indicator of infectious mononucleosis. In this stage of infection, antibody is produced against several EBV antigens, and a T-cell response is mounted. This response contributes to the symptoms and signs of mononucleosis, such as lymphadenopathy, splenomegaly, and atypical lymphocytosis. Latent infection of B cells may occur after the resolution of the acute infection, with periodic reactivation and shedding of the virus in the saliva for months, years, or even lifetime. Persons with inadequate T cell immunity may not be able to suppress EBV infection and may progress to lymphoproliferative disease, B-cell lymphomas, or Hodgkin disease. Nasopharyngeal carcinoma, seen primarily in Asian and Aleutian populations, is thought to be associated with EBV infection in conjunction with some other genetic or environmental component.

Diagnosis

EBV-related infectious mononucleosis is clinically recognized by high fever,

malaise, lymphadenopathy, pharyngitis, and occasional hepatosplenomegaly.

Young children, who have a less active immune response, tend to have milder or

subclinical infections. Symptoms from infection can last for days to weeks and

then tend to resolve slowly on their own. Some of the rarer, but serious, complications

of EBV infection include laryngeal obstruction, meningitis, encephalitis,

hemolytic anemia, thrombocytopenia, and splenic rupture. A macular papular

rash often erupts when amoxicillin is taken by an EBV infected patients.

Definitive diagnosis of EBV infections involves the finding of lymphocytosis

with the presence of atypical lymphocytes, heterophile-positive antibodies,

and antibody to EBV antigens. Atypical lymphocytes appear with the

onset of infection, whereas a positive heterophile antibody response can be

detected approximately 1 week after the onset of symptoms and remain present for several months. The Monospot test and ELISA (enzyme-linked immunosorbent

assay) are widely used for detection of heterophile antibody.

Treatment and Prevention

Currently, there is no effective treatment for EBV infection, nor is a viral vaccine available. However, because EBV infections in children tend to be less severe, and the immunity developed is lifelong, it is speculated by some clinicians that early exposure to EBV may be a means of preventing more severe infections and symptomatic disease.

COMPREHENSION QUESTIONS

[26.1] Which of the following statement regarding the serologic diagnosis of infectious mononucleosis is correct?

A. A heterophile antibody is formed that reacts with the membrane protein of EBV.

B. A heterophile antibody is formed that agglutinates sheep or horse red blood cells.

C. A heterophile antigen occurs that cross-reacts with atypical lymphocytes.

D. A heterophile antigen occurs following infection with both EBV and CMV.

[26.2] A transplant patient taking high levels of immunosuppressive drugs becomes infected with EBV and develops a lymphoma. The dosage of immunosuppressive drugs given to the patient is subsequently decreased, and the tumor regresses. Which of the following properties of EBV infection is related to the patient’s tumor development?

A. Immortalization of B cells

B. Increased white blood cell count

C. Presence of atypical lymphocytes

D. Production of heterophile antibodies

[26.3] A 21-year-old man visits the student health center suffering from a sore throat, swollen glands, fatigue, and a temperature of 39.4°C (103°F). Examination of the patient’s peripheral blood smear shows 10 percent atypical lymphocytes, an elevated white blood cell count, and a positive heterophile antibody test. The patient asks for antimicrobial therapy. Which of the following statements would best dictate the clinician’s response?

A. α-Interferon is helpful in EBV infections but has multiple side effects.

B. Ribavirin is effective in patients over 60 years.

C. Attenuated-viral vaccine has been developed but not effective in this case because the infection has already occurred.

D. There is no effective treatment.

Answers

[26.1] B. A nonspecific heterophile agglutination test (Monospot test) is commercially available and can be used to diagnose EBV infectious mononucleosis within a week to months of infection. Infectious mononucleosis-like infection caused by CMV is heterophile negative.

[26.2] A. Aggressive monoclonal B-cell lymphomas can develop in patients with reduced T-cell function. The immortalization of B cells in the absence of functional T cell immunity can give rise to lymphoproliferative disease such as Hodgkin lymphoma, Burkitt lymphoma, and nasopharyngeal carcinoma.

[26.3] D. Currently, there are no effective treatments or vaccines available for EBV infection. Ribavirin is useful in treating respiratory syncytial virusrelated and hepatitis C virus-related infections, while α-interferon has been used in treating the following viral infections: condyloma acuminatum, chronic hepatitis B and C, and Kaposi sarcoma.

MICROBIOLOGY PEARLS ❖ EBV-related infectious mononucleosis is heterophile antibodypositive. ❖ Clinical manifestations are fever, malaise, lymphadenopathy, pharyngitis, with presence of lymphocytosis and atypical lymphocytes. ❖ No current treatment or vaccines are available.

REFERENCES

Cohen JL. Epstein-Barr virus infection. N Engl J Med 2000;343:481–92. 

Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology, 5th ed. St. Louis, MO: Mosby, 2005:553–8. 

Ryan JR, Ray CG. Sherris Medical Microbiology, 4th ed. New York: McGraw-Hill, 2004:567–73.

HomeMicrobiology Case FileEpstein-Barr Virus Case File