AUTHOR INFORMATION

Section 1 of 11

Authored by Nicholas John Bennett, MBBCh, PhD, Staff Physician, Department of Pediatrics, State University of New York Upstate Medical University

Coauthored by Joseph Domachowske, MD, Associate Professor, Department of Pediatrics, Division of Infectious Diseases, State University of New York-Upstate Medical University; Glenna B Winnie, MD, Division Chief, Allergy, Pulmonology and Sleep Medicine, Department of Pediatrics, Children's National Medical Center, Washington, DC

Nicholas John Bennett, MBBCh, PhD, is a member of the following medical societies: American Academy of Pediatrics

Edited by Rosemary Johann-Liang, MD, Medical Officer, Infectious Diseases and Pediatrics, Division of Special Pathogens and Immunological Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota School of Medicine; Robert W Tolan, Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at St Peter's University Hospital, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; and Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center

Author's Email:	Nicholas John Bennett, MBBCh, PhD
Editor's Email:	Rosemary Johann-Liang, MD

eMedicine Journal, May 23 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 11

Background: Epstein-Barr virus (EBV), or human herpesvirus 4, is a gamma-herpesvirus that infects more than 95% of the world's population. The most common manifestation of primary infection with this organism is acute infectious mononucleosis, a self-limited clinical syndrome that most frequently affects adolescents and young adults. Classic symptoms include sore throat, fever, and lymphadenopathy. Infection with EBV in younger children usually is asymptomatic or mild. However, EBV also is a human tumor virus, the first virus associated with human malignancy. Infection with EBV is associated with lymphoproliferative disorders, especially in immunocompromised hosts, and with a variety of tumors including nasopharyngeal carcinoma and Burkitt lymphoma.

Acute infectious mononucleosis first was described in the late 19th century as acute glandular fever, an illness consisting of lymphadenopathy, fever, hepatosplenomegaly, malaise, and abdominal discomfort in adolescents and young adults. In 1920, Sprunt and associates applied the name infectious mononucleosis to cases of spontaneously resolving acute leukemia associated with blastlike cells in the blood. Downey described the lymphocyte morphology in 1923. In 1932, Paul and Bunnell discovered that serum from symptomatic patients had antibodies that agglutinate the red blood cells (RBCs) of unrelated species, the heterophile antibodies. This allowed enhanced diagnostic accuracy of infectious mononucleosis.

The search for the etiologic agent of infectious mononucleosis was unsuccessful for many years, partly because researchers did not appreciate that most primary infections are asymptomatic and that most adults are seropositive. In 1964, Epstein described the first human tumor virus when he found virus particles in a Burkitt lymphoma cell line. Henle reported the relationship between acute infectious mononucleosis and EBV in 1968. Subsequently, a large prospective study of students at Yale University firmly established EBV as the etiologic agent of infectious mononucleosis.

Pathophysiology: Humans are the only known reservoir of EBV. EBV is present in oropharyngeal secretions and most commonly is transmitted through saliva. After initial inoculation, the virus replicates in nasopharyngeal epithelial cells. Cell lysis is associated with release of virions, with viral spread to contiguous structures, including salivary glands and oropharyngeal lymphoid tissues. Further viral replication results in viremia, with subsequent infection of the lymphoreticular system, including the liver, spleen, and B lymphocytes in peripheral blood. Host immune response to the viral infection includes CD8-positive T lymphocytes with suppressor and cytotoxic functions, the characteristic atypical lymphocytes found in the peripheral blood. The T lymphocytes are cytotoxic to the EBV-infected B cells and eventually reduce the number of EBV-infected B lymphocytes to less than 1 per 106 circulating B cells.

Primary infection with EBV is followed by latent infection, a characteristic of herpesviruses. After acute EBV infection, latently infected lymphocytes and epithelial cells persist and are immortalized. In vivo, this allows perpetuation of infection, while in vitro, immortalized cell lines are established. During latent infection, the virus is present in the lymphocytes and oropharyngeal epithelial cells as episomes in the nucleus. These episomes rarely integrate into the cell genome but do replicate with cell division and are passed to subsequent generations of cells. A low rate of viral reactivation occurs within the population of latently infected cells. Epithelial cells are the primary source of new virus in latently infected individuals, infecting B cells as they circulate through the oropharynx.

Two strains labeled EBV-1 and EBV-2 (also known as type A and type B) exist. Although some differences are present in the genes expressed during latent infection, no apparent differences exist in acute illnesses caused by the 2 strains. Both strains are prevalent throughout the world and can simultaneously infect the same person.

Knowledge of the structure of EBV and which proteins are expressed during different stages of its life cycle is required to understand the laboratory tests used to determine if an individual has primary acute, convalescent, latent, or reactivation infection. A mature infectious viral particle, which may be present in the cytoplasm of an epithelial cell, consists of a nucleoid, a capsid, and an envelope. The nucleoid contains linear double-stranded viral deoxyribonucleic acid (DNA). It is surrounded by the capsid, an icosahedral constructed of capsomers, which are tubular protein subunits. An envelope derived either from the outer membrane or the nuclear membrane of the host cell encloses the capsid and nucleoid, ie, the nucleocapsid. The envelope also contains viral proteins that were constructed and placed in the host cell membrane before viral assembly began.

To initiate cellular infection, a viral particle attaches via its major outer envelope glycoprotein, ie, gp350/220, to the EBV receptor CD21 on a B lymphocyte. The binding site on epithelial cells is not certain but also may be CD21. EBV then is internalized into cytoplasmic vesicles. After fusion of virus envelope with the vesicle membrane, the nucleocapsid is released into the cytoplasm. The nucleocapsid dissolves, the genome is transported to the cell nucleus, and the linear genome then circularizes, forming an episome. The cell then may proceed with either lytic infection with release of infectious virus or latent infection of the host cell. B lymphocytes with latent infection undergo growth transformation.

Lytic infection occurs early after primary inoculation. As a result of lytic infection in oral epithelial cells, EBV can be found in the saliva for the first 12-18 months after acquisition. Thereafter, epithelial cells and lymphocytes are latently infected, with a few spontaneously converting, leading to viral replication, host cell lysis and death, and release of mature virions. Thus, virus can be isolated from oral secretions of 20-30% of healthy latently infected individuals at any time.

During latent infection, cell proteins are expressed in 1 of 3 patterns. Type I latency, associated with Burkitt lymphoma, is characterized by expression of only EBV-encoded ribonucleic acids (RNAs), Epstein-Barr early regions (EBERs), and Epstein-Barr nuclear antigen 1 (EBNA1). Type II latency, associated with nasopharyngeal carcinoma, is characterized by expression of 3 latent membrane proteins, LMP1, LMP2A, and LMP2B, plus EBERs and EBNA1. Type III latency is the pattern found in healthy individuals with latent infection. In addition to the EBERs and EBNA1 expressed in type I latency, other nuclear antigens (including EBNA2, EBNA3A, EBNA3B, EBNA3C, and LMP) are expressed in type III latency.

Frequency:

• In the US: EBV is not a reportable infection, and exact frequency of symptomatic primary infection is not known. By age 5 years, approximately 50% of the US population is infected. During childhood, primary infection usually is asymptomatic or associated with mild elevation of liver function tests. EBV infection acquired during adolescence is asymptomatic or associated with the syndrome of acute infectious mononucleosis.

  Incidence of acute infectious mononucleosis was approximately 45 cases per 100,000 population per year in the early 1970s, with the highest incidence in individuals aged 15-24 years. However, changes in economic status may have changed both the age of initial infection and the incidence of infectious mononucleosis since the large epidemiologic studies were completed. In lower socioeconomic groups, EBV infection is more common, occurs at an earlier age, and is less likely to be associated with acute infectious mononucleosis.

  Roommates of students with primary EBV infection develop seroconversion at the same rate as the general population of college students.

  Approximately 90% of the US population is infected with EBV by age 25 years.

  EBV infection does not occur in epidemics, and it is of relatively low transmissibility.

• Internationally: EBV infection occurs with the same frequency and symptomatology in the developed nations of the world as in the United States.

  EBV more frequently is acquired in childhood in underdeveloped nations, and therefore the syndrome of acute infectious mononucleosis is unusual in these nations.

  In Africa, the virus is associated with endemic Burkitt lymphoma.

  High numbers of EBV episomes are found in the cells of undifferentiated or poorly differentiated nasopharyngeal carcinoma. This is the most common tumor in adult men in southern China, and it also occurs frequently in North American Inuits and North African whites.

Mortality/Morbidity:

• Most primary EBV infections are asymptomatic. Death is unusual in the immunocompetent patient with acute infectious mononucleosis, but it may occur due to neurologic complications, upper airway obstruction, or splenic rupture.

• EBV infection is linked with a number of tumors. Endemic Burkitt lymphoma, the most common tumor of childhood in Africa, is associated with EBV and malaria. Infection with Plasmodium falciparum malaria stimulates polyclonal B cell proliferation with EBV infection and impairs T lymphocyte response to EBV, apparently contributing to tumor pathogenesis. In Asia, EBV infection is related to development of nasopharyngeal carcinoma. Most non-Hodgkin lymphomas are associated with EBV, and evidence of the EBV genome is demonstrable in many of these tumors. EBV also is associated with Hodgkin lymphoma, where EBV genome is present in the Reed-Sternberg cell.

• EBV infection in patients who are immunocompromised is associated with several syndromes and proliferative disorders.
  
  
  • Individuals with Duncan syndrome, ie, X-linked lymphoproliferative syndrome, may develop fatal primary EBV infection due to a defect in immune response to EBV. These boys often develop fatal massive hepatitis or a disseminated lymphoproliferative disorder triggered by primary EBV infection. Median age of presentation is 2.5 years, with median survival of 33 days. Survivors of the initial infection develop B-cell lymphoma or hypogammaglobulinemia and usually die by age 10 years.
    
    
  • Other congenital immunodeficiencies are associated with the development of EBV-associated lymphoproliferative disorders. These include ataxia-telangiectasia, Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome, and common variable immunodeficiency.
    
    
  • Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal lymphoproliferative syndrome associated with EBV and monoclonal or polyclonal expansion of B cells. It occurs in patients after organ transplantation, particularly after heart transplants, and usually responds to decreased immune suppression.
    
    
  • EBV-associated lymphomas occur in patients with secondary immunodeficiencies (eg, after cancer chemotherapy). Unfortunately, these tumors do not respond to lessening of immunosuppression.
    
    
  • In patients with AIDS, EBV is associated with hairy leukoplakia, leiomyosarcoma, CNS lymphoma, and with lymphoid interstitial pneumonitis in children.

Race:

• No racial predilection exists.

• Large epidemiologic studies performed in the 1970s revealed that acute infectious mononucleosis was 30 times more likely to occur in whites than in African Americans. However, this correlated with lower social economic status and earlier asymptomatic infection in African Americans and therefore did not reflect a true racial difference.

Sex:

• No sexual predilection exists.

• Incidence of infectious mononucleosis is the same in men and women, although the peak incidence occurs 2 years earlier in females.

Age:

• EBV infection usually occurs during infancy or childhood and remains latent through life.

• In developed nations, infection may not occur until adolescence or adulthood, and approximately 50% of adolescents who acquire EBV develop the infectious mononucleosis syndrome.

• Acute infectious mononucleosis has been reported in middle-aged and elderly adults, and usually they are heterophile antibody negative.

CLINICAL

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History:

• Acute infectious mononucleosis presents with a history of 1-2 weeks of fatigue and malaise; however, onset may be abrupt.



• Incubation period in adolescents is 30-50 days; it is shorter in young children.



• Symptoms include sore throat, headache, fever, myalgias, nausea, and abdominal pain.



• Sore throat is the most frequent presenting symptom. Gradually worsening over the first week, it may be the most severe sore throat the patient has experienced.



• Headache usually occurs during the first week and may be retro-orbital.



• Left upper quadrant pain may be due to splenic enlargement. Abdominal pain should lead to consideration of splenic rupture.



• Symptoms usually persist for 2-3 weeks, but fatigue often is more prolonged.



• Infants and young children with primary infection usually are asymptomatic.

Physical:

• Infectious mononucleosis is characterized by pharyngitis, generalized lymphadenopathy, and hepatosplenomegaly. Most clinical symptoms are a consequence of T cell proliferation and organ infiltration.



• Pharyngitis is the most consistent physical finding.


• • Pharyngitis is exudative in one third of patients.
  
  
  
  • Petechiae are present at the junction of the hard and soft palates in 25-60% of patients.
  
  
  
  • Tonsillar enlargement can be massive, and occasionally it causes airway obstruction. The enlargement can be associated with dehydration due to difficulty in swallowing.
  
  
  
• Lymphadenopathy is prominent, and most commonly it affects the posterior cervical lymph nodes. Anterior cervical and submandibular nodal involvement is common, and axillary and inguinal nodes also are affected.


• • Enlarged epitrochlear nodes are very suggestive of infectious mononucleosis.
  
  
  
  • Nodal enlargement usually is symmetric.
  
  
  
  • Nodes are mildly tender to palpation and are freely moveable.
  
  
  
• Hepatomegaly frequently is present, but jaundice is rare. Percussion tenderness over the liver is common.



• Splenomegaly is common. The spleen often is palpable 2-3 cm below the left costal margin and may be tender.


• • The spleen enlarges rapidly over the first week of symptoms, usually decreasing in size over the next 7-10 days.
  
  
  
  • The spleen can rupture from relatively minor trauma or even spontaneously.
  
  
  
  • Fever occurs in more than 90% of patients. Temperature peaks in the afternoon, typically at 38-39°C, but it may reach 40°C. Fever resolves over 10-14 days.
  
  
  
  • Despite fever, pulse usually is normal or relatively low, and tachycardia is unusual.
  
  
  
• Maculopapular rash (usually faint, widely scattered, and erythematous) occurs in 3-15% of patients and is more common in young children.


• • Treatment with amoxicillin or ampicillin is associated with rash in approximately 80% of patients. This is often encountered when treating a suspected case of strep throat that is, in fact, primary Epstein-Barr virus (EBV) infection.
  
  
  
  • Circulating immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to ampicillin are demonstrable.
  
  
  
• Eyelid edema may be present, especially in the first week of illness.



• Children younger than 4 years more commonly have splenomegaly or hepatomegaly, rash, and symptoms of an upper respiratory tract infection.

Causes:

• EBV is the etiologic agent in approximately 90% of acute infectious mononucleosis cases.



• Cytomegalovirus (CMV), another herpesvirus is most commonly associated with EBV-negative infectious mononucleosis syndrome.



• Other viruses associated with a similar acute illness include adenovirus; hepatitis A, hepatitis B, or hepatitis C; herpes simplex 1 and herpes simplex 2; human herpesvirus 6; rubella; and primary human immunodeficiency virus in adolescents or young adults.



• Etiology of most EBV-negative infectious mononucleosis cases remains unknown.

DIFFERENTIALS

Section 4 of 11

Hepatitis A
Hepatitis B
Hepatitis C
Herpes Simplex Virus Infection
Herpesvirus 6 Infection
Human Immunodeficiency Virus Infection
Streptococcal Infection, Group A
Toxoplasmosis

Other Problems to be Considered:

Drug reaction to phenytoin or sulfa
Lymphoma
Acute Myelocytic Leukemia
Acute Lymphoblastic Leukemia
Adenovirus
Rubella

WORKUP

Section 5 of 11

Lab Studies:

• Classic criteria: The 3 classic criteria for laboratory confirmation of acute infectious mononucleosis are (1) lymphocytosis, (2) the presence of at least 10% atypical lymphocytes on peripheral smear, and (3) a positive serologic test for Epstein-Barr virus (EBV).



• Complete blood count


• • Leukocytosis with white blood cell (WBC) count of 10,000-20,000 cells per cm³ (10-20 X 10⁹/L) occurs in 40-70% of patients with acute infectious mononucleosis. By the second week of illness, approximately 10% have a WBC count greater than 25,000 per cm³.
  
  
  
  • Approximately 80-90% of patients have lymphocytosis, with greater than 50% lymphocytes. Lymphocytosis is greatest during the second and third weeks of illness and lasts for 2-6 weeks. Usually 20-40% of the lymphocytes are atypical, although not all patients have more than 10% atypical lymphocytes.

    The atypical lymphocytes of 3 Downey types are larger, have a lower nuclear-to-cytoplasmic ratio, and have a less dense nucleus than normal lymphocytes. Most of these atypical lymphocytes are polyclonal-activated CD8 cytotoxic-suppressor T lymphocytes, although CD4 helper T cells and CD11 natural killer cells also are present.

  
  
  
  • Mild thrombocytopenia occurs in 25-50% of patients.
  
  
  
• Liver function tests


• • Most (ie, 80-100%) patients with acute infectious mononucleosis have elevated liver function test results.

  • Alkaline phosphatase, aspartate aminotransferase (AST), and bilirubin peak 5-14 days after onset, and gamma-glutamyltransferase (GGT) peaks at 1-3 weeks.

  • Lactic (acid) dehydrogenase (LDH) is increased in approximately 95% of patients.

  • Occasionally, GGT remains mildly elevated for up to 12 months, but most liver function test results are normal by 3 months.
  
  
  
• Heterophile antibody test


• • EBV infection stimulates polyclonal secretion of antibodies by infected B cells, including transient production of heterophile antibodies. These are antibodies that agglutinate cells from other species and are not directed against EBV. The Paul-Bunnell test for heterophile antibodies is based on the fact that serum from patients with acute mononucleosis contains antibodies that agglutinate sheep RBCs in a tube dilution assay, while such antibodies are absent from or present in a low titer in serum from healthy persons.
  
  
  
  • Differential absorption
    • Antibodies other than those produced during acute infectious mononucleosis can agglutinate sheep RBCs. Such antibodies include those formed in serum sickness, during drug reactions, and naturally occurring antibodies to the Forssman antigen.

    • Differential absorption permits identification of the antibody type. Bovine RBCs absorb infectious mononucleosis heterophile antibodies from serum, but not Forssman antibodies. Guinea pig kidney cells absorb Forssman antibodies, leaving the infectious mononucleosis heterophile antibodies. Antibodies formed in serum sickness absorb to both guinea pig kidney cells and to bovine RBCs. Thus, in terms of absorbing infectious mononucleosis heterophile antibodies, clinicians use the saying, "cow can, pig can't."

    • Serum from a patient with infectious mononucleosis agglutinates sheep RBCs after absorption with guinea pig cells, but no agglutination occurs after absorption with bovine RBCs.
  
  
  
  • Heterophile antibody titers
    • The titer of Paul-Bunnell—heterophile antibody is determined by tube dilution. Depending on the dilution system, a titer of 1:40 or 1:28 after absorption with guinea pig cells is considered positive for acute infectious mononucleosis.

    • Titer level does not correlate with severity of clinical illness.
  
  
  
  • Monospot
    • Rapid slide agglutination tests, including Monospot assays, have been developed to measure acute infectious mononucleosis heterophile antibodies in a rapid qualitative fashion. Slide tests use either horse RBCs or bovine RBCs. Horse RBCs are more sensitive than sheep RBCs or bovine RBCs and can be treated with formalin to extend the shelf life of the test. Bovine RBCs are specific for acute infectious mononucleosis heterophile antibodies and thus do not require differential absorption.

    • All commercial kits for rapid diagnosis of acute infectious mononucleosis heterophile antibodies have low sensitivity (63-84%), with a negative predictive value of more than 10%.

    • Spot tests have rare false-positive results in patients with lymphoma or hepatitis.
  
  
  
  • Frequency of positive heterophile antibodies
    • Heterophile antibodies are measurable in approximately 50% of patients in the first week of illness, and 60-90% of patients have positive test results for heterophile antibodies in the second or third weeks. The titer begins to decline during the fourth or fifth week and often is less than 1:40 by 2-3 months after symptom onset.

    • As many as 20% of patients have positive titers 1-2 years after acquisition. Also, because horse RBC agglutinins are more sensitive than sheep RBCs, 75% of patients have positive horse RBC agglutinins at 1 year.

    • Only 10-30% of children younger than 2 years and 50-75% of children aged 2-4 years develop heterophile antibodies with primary EBV infection.
  
  
  
• EBV serology


• • Infection with EBV is characterized by development of the specific antibodies to antigenic components of the virus. These antigens appear at different stages of infection and differ in lytic versus latent infection.
  
  
  
  • Antibodies to EBV antigens measured for clinical purposes are those to viral capsid antigen (VCA), early antigens (EAs), and Epstein-Barr nuclear antigen (EBNA).
    • EAs are expressed early in the lytic cycle, while VCA and membrane antigens are structural viral proteins expressed late in the lytic cycle.

    • EBNA is expressed in cells that are latently infected.

    • Antibodies to membrane antigens usually are not measured, but their presence correlates with viral neutralizing activity.

    • Antibodies to these proteins are measured by enzyme immunoassays, indirect immunofluorescence assays, and immunoblot assays.
  
  
  
  • With early infection, EAs are expressed in cells in the lytic cycle. These antigens are nonstructural EBV proteins, which are classified into 2 groups based on cell distribution and stability with methanol treatment.
    • The restricted component of early antigens (EA/R) is found in the cytoplasm of infected cells and is methanol sensitive. Antibody to EA/R most often is measurable in children younger than 4 years with primary EBV infection or in nonsymptomatic infection.

    • Approximately 80% of patients with infectious mononucleosis have antibodies to the diffuse-staining component of EA (EA/D).

    • EA/D antibodies are elevated in patients with nasopharyngeal carcinoma, and antibodies to EA/R are high in individuals with EBV-associated Burkitt lymphoma. Patients who are immunocompromised and have persistent or reactivated EBV infections often have high antibody levels to EA/D or EA/R.
  
  
  
  • Time course of antibody production
    • In early primary EBV infection, oropharyngeal epithelial cells are lytically infected, and the above antigens are expressed. Antibodies are measurable at the onset of clinical symptoms or even slightly before.

    • Although not always measurable, antibody to EA is rising at symptom onset. EA/D is observed more frequently, although EA/R is present more often in asymptomatic infection or in children younger than 4 years. Levels of antibody to EA rise for 3-4 weeks, then usually quickly decline to undetectable levels by 3-4 months, although low levels may be detected intermittently for years. However, in patients with a more prolonged symptomatic illness, EA/D may become unmeasurable, and EA/R may become positive.

    • VCA-IgM usually is measurable at symptom onset, peaks at 2-3 weeks, then declines and becomes unmeasurable by 3-4 months. VCA-IgG rises shortly after symptom onset, peaks at 2-3 months, then drops slightly but persists for life. Antibodies to EBNA appear during convalescence and remain present for life.
  
  
  
• Interpretation of EBV serology: Primary acute EBV infection is associated with VCA-IgM, VCA-IgG, and absent EBNA antibodies.


• • Antibody pattern in recent infection (3-12 mo) includes positive VCA-IgG and EBNA antibodies, negative VCA-IgM antibodies, and usually positive EA antibodies.

  • After 12 months, the pattern is the same as recent infection, except EA antibodies are not present.
  
  
  

Imaging Studies:

• No specific imaging studies are indicated for making the diagnosis of acute infectious mononucleosis.



• Chest radiograph (CXR) shows mediastinal adenopathy in fewer than 1% of patients. Mediastinal lymph node enlargement should prompt consideration of other diagnoses.



• Abdominal CT scan is the preferred imaging modality to assess for splenic rupture but can be performed only in patients who are hemodynamically stable. Ultrasonography or radionuclide scanning of the spleen also may assist in ascertaining the diagnosis.



• Lateral neck films are occasionally helpful to document tonsillar hypertrophy and exclude epiglottis or retropharyngeal abscess in a patient with upper airway obstruction or stridor.



• Imaging studies for PTLD: In PTLD, CXR may reveal nodular lesions. Chest CT scan with contrast may show the characteristic peripheral nodules, and abdominal CT scan with contrast can define the extent of intra-abdominal lesions.

Other Tests:

• Quantitative polymerase chain reaction (PCR) can measure EBV DNA in plasma during acute infectious mononucleosis. Levels decline during convalescence and are rarely measurable in latently infected individuals. However, EBV DNA in serum may be detectable by PCR with reactivation of infection, such as in PTLD.



• Epstein-Barr early region (EBER) probe can identify the EBV messenger RNA in the nuclei of EBV-infected lymphoid cells by in situ hybridization.

During acute mononucleosis, lymph nodes are increased in size, with enlarged germinal centers and lymphoid follicles. Perifollicular areas of the tonsils contain many infected B lymphocytes, which express EBV-specific antigens, including LMP1, EBNA1, and EBNA2.

The spleen is larger with lymphocytic infiltration of the capsule and trabeculae. Pleomorphic blast cells are present in the hyperplastic red pulp. Vascular congestion is coupled with focal and subcapsular hemorrhages.

Histologic changes in the liver usually are minimal with mild swelling in hepatic sites and bile ducts and lymphocytic portal infiltration.

In fatal infectious mononucleosis, degenerative changes are observed in the neurons of the CNS. Neuronal degeneration, perivascular cuffing, and astrocytic hyperplasia may be present.

PTLD is characterized by homogeneous lymphocytic proliferation with an immunoblastic component. Lesions may efface lymphoid organ architecture or develop ectopically in nonlymphoid organs. The EBV-infected cells in PTLD express EBER.

TREATMENT

Section 6 of 11

Medical Care:

• Infectious mononucleosis is a self-limited illness that usually does not require specific therapy.



• Because of low transmissibility of Epstein-Barr virus, isolation is not indicated.



• Most affected individuals can be evaluated and treated as outpatients. Inpatient therapy of medical and surgical complications may be required.

Surgical Care:

• Splenic rupture is an acute abdominal emergency that usually requires surgical intervention.


• • Rupture may occur with trauma as minor as palpation, and sometimes it is the presenting complaint.
  
  
  
  • Diagnosis can be confirmed by imaging procedures or by peritoneal lavage in an unstable patient.
  
  
  
  • Splenectomy usually is required.
  
  
  
  • Occasionally, observation and supportive measures are adequate treatment for a hemodynamically stable patient.
  
  
  
  • Although partial splenectomy or suturing the capsular tear has been advocated to preserve splenic function, the acute changes that led to rupture militate against the success of this approach.
  
  
  

Consultations:

• Surgical consultation should be sought when the patient has abdominal pain or evidence of shock.



• Consultation with the appropriate subspecialist is indicated for management of significant complications.

Diet:

• No dietary modifications are required.

Activity:

• Acceptable activity level during the acute illness depends on severity of the patient's symptoms.



• Extreme fatigue may require bed rest for 1-2 weeks.



• Malaise may persist for 2-3 months, and activity can increase as tolerated.



• Patients should not participate in contact sports or heavy lifting for at least 2-3 weeks, although some authors recommend avoiding activities that may cause splenic trauma for 2 months.

MEDICATION

Section 7 of 11

Acute infectious mononucleosis is treated symptomatically. NSAIDs are used to treat fever and discomfort. Corticosteroids do not significantly alter the course of infectious mononucleosis. Although they ameliorate symptoms, do not use corticosteroids in the treatment of uncomplicated disease. They are used in the presence of significant upper airway obstruction due to tonsillar or lymph node hypertrophy and in severe thrombocytopenia or hemolytic anemia.

A number of drugs inhibit Epstein-Barr virus (EBV) replication in vitro. Nonetheless, antiviral agents are of no benefit in uncomplicated infectious mononucleosis. However, antiviral agents are used in the treatment of interstitial pneumonitis, X-linked lymphoproliferative syndrome, PTLD, and other lymphoproliferative disorders. Intravenous immunoglobulin may be considered to modulate immune function in the presence of disease complications due to autoantibodies.
New therapies, including the use of interferon alpha and the infusion of donor T cells or EBV-specific cytotoxic T cells, are being studied.

Drug Category: Glucocorticoids -- Corticosteroids are potent anti-inflammatory drugs that also modify the immune response. They are used to decrease the size of tonsils and upper airway lymph nodes in the presence of airway compromise and possible upper airway obstruction. They may be useful to treat severe thrombocytopenia or hemolytic anemia. Whether prednisone should be used for myocarditis, pericarditis, or CNS system involvement is unclear.

Drug Name	Prednisone (Deltasone, Liquid Prep, Meticorten, Orasone, Prednicen-M, Sterapred) -- May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Adult Dose	60-80 mg/d PO divided bid for 5-7 d; taper over 1-2 wk
Pediatric Dose	1 mg/kg/d PO divided bid, not to exceed 60-80 mg; administer for 5-7 d, then taper over 1-2 wk
Contraindications	Systemic fungal infections; varicella; vaccination with live or live-attenuated vaccines
Interactions	Immune response to vaccinations may be impaired; phenytoin, rifampin, or drugs that induce hepatic enzymes can decrease serum concentration
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Associated with multiple adverse reactions, including fluid and electrolyte disturbances and musculoskeletal abnormalities including muscle weakness, steroid myopathy, and osteoporosis; GI adverse effects include peptic ulcer disease, pancreatitis, and an increase in LFTs; steroid use has been associated with increased intracranial pressure, seizures, headache, growth suppression, adrenal cortical suppression, menstrual irregularities, hyperglycemia, negative nitrogen balance, glaucoma, and cataracts

Drug Category: Antiviral drugs -- A number of drugs inhibit EBV replication in vitro. These include acyclovir, desciclovir, ganciclovir, interferon-alfa, interferon-gamma, adenine arabinoside, and phosphonoacetic acid. Placebo-controlled clinical trials have been conducted for infectious mononucleosis only with acyclovir, which inhibits viral shedding from the oropharynx. However, clinical course is not affected significantly in uncomplicated infectious mononucleosis.

Drug Name	Acyclovir (Zovirax) -- Strains of HSV1 are most sensitive, followed by HSV2. Also sensitive to other herpesviruses, including, in descending order, varicella zoster, EBV, and CMV.
Adult Dose	800 mg PO 5 times/d for 10 d 10 mg/kg/dose IV q8h for 7-10 d
Pediatric Dose	>24 months: 800 mg PO 5 times/d for 10 d, not to exceed 80 mg/kg/d in 5 divided doses; 10 mg/kg/dose IV q8h for 7-10 d
Contraindications	Documented hypersensitivity
Interactions	Neurotoxicity can occur when combined with zidovudine; probenecid decreases renal clearance of acyclovir; use with cyclosporine increases risk of nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution with other nephrotoxic drugs or in those with preexisting renal disease; maintain adequate urine output for the first 2 h after IV infusion; use carefully in patients with renal, hepatic, or electrolyte disturbances and in patients with hypoxemia or underlying neurologic abnormalities

Drug Category: Immunoglobulins -- Intravenous immunoglobulin is used to modulate immune function in the presence of autoantibodies. It has been used successfully in the treatment of immune thrombocytopenia associated with infectious mononucleosis.

Drug Name	Intravenous immunoglobulin (Gamimune N, Gammagard S/D, Gammar-P, Polygam) -- Neutralizes circulating myelin antibodies through antiidiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).
Adult Dose	400 mg/kg/d IV for 2-5 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; IgA deficiency
Interactions	May interfere with antibody response to live virus vaccines
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hypersensitivity reactions may occur; initiating at rate of administration may increase risk of hypotension; risk of anaphylaxis is greater in IgA-deficient individuals (procure low-titer IgA product if essential)

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Patients with uncomplicated infectious mononucleosis rarely require inpatient therapy.



• Hospitalization is warranted in the presence of splenic rupture, airway compromise, dehydration, significant thrombocytopenia or hemolytic anemia, and neurologic or other major complications.

Further Outpatient Care:

• If diagnosis is firmly established, only supportive care is required in the absence of significant complications.

In/Out Patient Meds:

• Nonspecific treatment includes saline gargles and acetaminophen or ibuprofen for sore throat, fever, and myalgia. Constipation may be treated with a laxative.



• Corticosteroids decrease the duration of febrile illness and constitutional symptoms, but their routine use for treatment of a virus known to be related to tumor development is discouraged.



• Acyclovir has no demonstrable benefit for treatment of uncomplicated infectious mononucleosis in placebo-controlled trials.



• Various therapies are used for complications of Epstein-Barr virus (EBV) infection, although only a few have been studied in controlled trials.


• • Corticosteroids are used for treatment of severe airway obstruction due to tonsillar enlargement, hemolytic anemia, and severe thrombocytopenia.
  
  
  
  • Interferon-alfa decreases shedding of EBV in renal transplant recipients.
  
  
  
  • Acyclovir and desciclovir can reverse EBV-associated hairy leukoplakia in patients with human immunodeficiency virus (HIV). Acyclovir has been used for treatment of interstitial pneumonitis, X-linked lymphoproliferative syndrome, and lymphoproliferative disorders. PTLD has been treated with ganciclovir and CytoGam.
  
  
  
  • Immune thrombocytopenia has been treated with intravenous immunoglobulin.
  
  
  
  • Whether corticosteroids are beneficial or harmful in encephalitis, pericarditis, and myocarditis is unclear.
  
  
  
  • Combination therapy with corticosteroids and acyclovir has been reported, with varying outcomes.
  
  
  

Transfer:

• Transfer to a tertiary care center may be necessary for treatment of significant complications.

Deterrence/Prevention:

• Isolation is not required. EBV is of low transmissibility and cannot be recovered from environmental surfaces or fomites.



• Avoid contact with saliva.


• • EBV is present in throat washings of individuals with acute infectious mononucleosis. Virus can be cultured from the oropharynx for up to 18 months. It can be recovered from the oropharynx of 10-20% of healthy adults.
  
  
  
  • EBV infection usually is acquired through contact between a susceptible individual and the saliva of an asymptomatic individual who is shedding EBV. In young children, saliva is spread by drooling and hand-to-mouth behaviors. In adolescents, infected saliva may be transferred by kissing, hence the label "kissing disease."
  
  
  
• Do not kiss children on the mouth.



• Maintain clean conditions, especially when young children are present (eg, in day care), and avoid having children share toys.



• EBV can be transmitted by blood transfusion and by bone marrow transplantation. However, because the organism is so common, presently no procedures are in place to prevent this.



• Vaccine development is proceeding, although the role of a vaccine is unclear.

Complications:

• Hepatitis occurs in more than 90% of patients with infectious mononucleosis.
  • Liver function test results are mildly elevated but usually are no more than 2-3 times normal. Bilirubin is elevated in approximately 45% of patients, but jaundice occurs in only 5%.

  • Liver abnormalities are most pronounced in the second and third weeks of illness.



• Mild thrombocytopenia occurs in approximately 50% of patients with infectious mononucleosis.
  • Platelet count usually is 100,000-140,000/cm³. Platelet count usually reaches its nadir approximately 1 week after symptom onset, then gradually improves over the next 3-4 weeks.

  • Thrombocytopenia may be caused by the production of antiplatelet antibodies and peripheral destruction, especially in the enlarged spleen.



• Hemolytic anemia occurs in 0.5-3% of patients with infectious mononucleosis.
  • Hemolytic anemia has been associated with cold-reactive antibodies, anti-I antibodies, and with autoantibodies to triphosphate isomerase.

  • Hemolysis usually is mild and is most significant during the second and third weeks of symptoms.



• Upper airway obstruction due to hypertrophy of tonsils and other lymph nodes of Waldeyer ring occurs in 0.1-1% of patients.
  • Treatment with corticosteroids may be beneficial.

  • Patients with severe tonsillar and lymph node enlargement with impending airway obstruction may require intubation or tracheostomy.

  • Patients requiring hospitalization may have concurrent streptococcal pharyngitis. Two thirds of patients admitted with infectious mononucleosis with upper airway obstruction and dehydration have alpha-hemolytic Streptococcus infection, usually due to group C streptococci.



• Splenic rupture occurs in 0.1-0.2% of patients with infectious mononucleosis.
  • Rupture may be spontaneous, although often the patient has a history of some antecedent trauma.

  • Rupture is most likely to occur during the second and third weeks of clinical symptoms.

  • Patients can present with mild-to-severe abdominal pain below the left costal margin, sometimes with radiation to the left shoulder and supraclavicular area. Massive bleeding may be accompanied by peritoneal irritation and shifting dullness. Shock may be the only presenting symptom.

  • Because bradycardia is usual in infectious mononucleosis, tachycardia with pulse higher than 100 is an important sign.

  • Neutrophilia, instead of lymphocytosis, can occur.

  • Surgical intervention usually is required.



• Hematologic complications are as follows:
  • EBV has been implicated in hemophagocytic syndrome.

  • Immune thrombocytopenic purpura occurs and may evolve to aplastic anemia. Aplastic anemia and neutropenia sometimes are associated with antineutrophil antibodies.

  • EBV infection may accelerate hemolytic anemia in congenital spherocytosis or hereditary elliptocytosis.

  • Disseminated intravascular coagulation associated with hepatic necrosis has occurred.



• Neurologic complications are as follows:
  • Neurologic complications occur in less than 1% of EBV infections and usually develop during the first 2 weeks of EBV infection. In some patients, especially children, the neurologic symptoms are the only clinical manifestation of infectious mononucleosis. Patients often are negative for the heterophile antibody. However, these complications often are severe. Complete recovery is the rule, but fatalities do occur.

  • Primary EBV infection has been associated with aseptic meningitis, acute viral encephalitis, coma, meningitis, and meningoencephalopathy. Hypoglossal nerve palsy, Bell palsy, hearing loss, brachial plexus neuropathy, and multiple cranial nerve palsies have been described. Guillain-Barré syndrome, autonomic neuropathy, gastrointestinal dysfunction secondary to selective cholinergic dysautonomia, acute cerebellar ataxia, and transverse myelitis have been reported. Metamorphopsia, ie, Alice in Wonderland syndrome, has been described.



• Cardiac and pulmonary complications are as follows:
  • Pulmonary complications are extremely rare, although upper airway obstruction due to lymphoid hypertrophy is relatively common. Chronic interstitial pneumonitis and pleural effusion have been associated with EBV infection.

  • Cardiac abnormalities that can occur with EBV infection include myocarditis and pericarditis.



• Autoimmune complications are as follows:
  • Autoimmune diseases and Reye syndrome have been associated with EBV infection.

  • Infectious mononucleosis stimulates production of many antibodies not directed against EBV. These include autoantibodies, anti-I antibodies, cold hemolysins, antinuclear antibodies, rheumatoid factors, cryoglobulins, and circulating immune complexes. These antibodies may precipitate autoimmune syndromes.



• Miscellaneous complications are as follows:
  • Renal disorders associated with EBV infection include immune deposit nephritis, renal failure, and paroxysmal nocturnal hemoglobinuria.

  • After cardiac bypass or transfusion, an infectious mononucleosis–like syndrome has been described. EBV may cause this, but it more commonly is associated with primary cytomegalovirus CMV infection.

  • A syndrome of chronic fatigue, myalgias, sore throat, and mild cognitive dysfunction occurring primarily in young adult females initially was attributed to EBV. Current data suggest that EBV is not the etiologic agent.

Prognosis:

• Immunocompetent individuals with acute infectious mononucleosis have a good prognosis with full recovery expected within several months.



• The common hematologic and hepatic complications resolve in 2-3 months.



• Neurologic complications usually resolve quickly in children. Adults are more likely to be left with neurologic deficits.



• All individuals develop latent infection, which usually remains asymptomatic.

Patient Education:

• Educate patient and family about risk of splenic rupture and the need to refrain from contact sports for 2 months.



• Inform patient and family about usual course of symptoms with acute mononucleosis.



• For excellent patient education resources, visit eMedicine’s Bacterial and Viral Infections Center. Also, see eMedicine’s patient education article Mononucleosis.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to recognize splenic rupture



• Failure to recognize impending airway obstruction



• Acute mononucleosis has been known to cause false-positive enzyme-linked immunoassay (ELISA) findings for HIV. Because the syndrome of mononucleosis is similar to the seroconversion illness of HIV, and Epstein-Barr virus may be acquired through intimate contact (kissing), care should be taken not to label a patient as HIV positive without confirmatory testing, especially in the absence of a high-risk exposure.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A 17-year-old adolescent has a 1-week history of fever, sore throat, lymphadenopathy, and fatigue. The Monospot test result is negative. Which pattern of anti–Epstein-Barr virus antibody titers is most likely in this patient with acute mononucleosis infection?

A: Positive viral capsid antigen–immunoglobulin G (VCA-IgG), negative VCA-immunoglobulin M (VCA-IgM), positive Epstein-Barr nuclear antigen (EBNA) antibodies, negative early antigen (EA) antibodies
B: Positive VCA-IgG, negative VCA-IgM, positive EBNA antibodies, positive EA antibodies
C: Negative VCA-IgG, positive VCA-IgM, positive EBNA antibodies, negative EA antibodies
D: Positive VCA-IgG, positive VCA-IgM, negative EBNA antibodies, negative EA antibodies
E: Negative VCA-IgG, negative VCA-IgM, negative EBNA antibodies, positive EA antibodies

The correct answer is D: VCA-IgG and VCA-IgM are present during acute infection, but EBNA antibodies do not appear until convalescence. EA antibodies are present in some patients with acute or recent infection but disappear during latent infection.

CME Question 2: Which of the following tumors or lymphoproliferative disorders are associated with Epstein-Barr virus (EBV)?

A: Posttransplant lymphoproliferative disorder (PTLD), endemic Burkitt lymphoma, lymphoid interstitial pneumonitis
B: Nasopharyngeal carcinoma, Hodgkin lymphoma, central nervous system lymphoma
C: Hairy leukoplakia, leiomyosarcoma, central nervous system lymphoma
D: Endemic Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma
E: All of the above

The correct answer is E: All of the listed tumors or lymphoproliferative disorders are associated with EBV. PTLD is a potentially fatal lymphoproliferative syndrome associated with EBV and monoclonal or polyclonal expansion of B cells. Endemic Burkitt lymphoma, the most common tumor of childhood in Africa, is associated with EBV and malaria. High numbers of EBV episomes are found in the cells of undifferentiated or poorly differentiated nasopharyngeal carcinoma, which is the most common tumor in adult men in southern China and also occurs frequently in North American Inuits and North African whites. EBV also is associated with Hodgkin lymphoma, where EBV genome is present in the Reed-Sternberg cell. In patients with AIDS, EBV is associated with hairy leukoplakia, leiomyosarcoma, CNS lymphoma, and with lymphoid interstitial pneumonitis in children.

Pearl Question 1 (T/F): Alpha-hemolytic Streptococcus organisms commonly are isolated from the throat cultures of patients hospitalized with acute infectious mononucleosis.

The correct answer is True: Two thirds of patients admitted with infectious mononucleosis with upper airway obstruction and dehydration have alpha-hemolytic Streptococcus infection, usually due to group C Streptococcus.

Pearl Question 2 (T/F): Splenic rupture can occur spontaneously in a patient with infectious mononucleosis.

The correct answer is True: Splenic rupture can present with no history of trauma and may be the presenting complaint.

Pearl Question 3 (T/F): Tachycardia is a frequent sign in infectious mononucleosis.

The correct answer is False: Relative bradycardia is usual. Pulse rate higher than 100 (or the age-specific equivalent) should prompt consideration of splenic rupture with hypovolemia.

Pearl Question 4 (T/F): Most children younger than 4 years with acute Epstein-Barr virus (EBV) infection have a positive heterophile antibody test (Monospot) result.

The correct answer is False: Approximately 70-90% of children younger than 2 years and 25-50% of children aged 2-4 years do not develop heterophile antibodies with primary EBV infection.

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Section 11 of 11

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