Detailed Awareness Campaign On Infectious Mononucleosis (Epstain Barr Viral Infection)

Infectious mononucleosis is the best-known clinical syndrome caused by Epstein-Barr virus (EBV). It is characterized by systemic somatic complaints consisting primarily of fatigue, malaise, fever, sore throat, and generalized lymphadenopathy. Originally described as glandular fever, it derives its name from the mononuclear lymphocytosis with atypical-appearing lymphocytes that accompany the illness. Other less common infections may cause infectious mononucleosis–like illnesses.

ETIOLOGY. 

EBV, a member of the Herpesviridae, causes more than 90% of infectious mononucleosis cases. Approximately 5–10% of infectious mononucleosis–like illnesses are caused by primary infection with cytomegalovirus, Toxoplasma gondii, adenovirus, viral hepatitis, human immunodeficiency virus (HIV), and possibly rubella virus. In the majority of EBV-negative infectious mononucleosis–like illnesses, the exact cause remains unknown.

EPIDEMIOLOGY.

The epidemiology of infectious mononucleosis is related to the epidemiology and age of acquisition of EBV infection. EBV infects up to 95% of the world's population. It is transmitted in oral secretions by close contact such as kissing or exchange of saliva from child to child, such as occurs between children in out-of-home child care. Nonintimate contact, environmental sources, or fomites do not contribute to spread of EBV.

EBV is shed in oral secretions for 6 mo or longer after acute infection and then intermittently for life. Healthy individuals with serologic evidence of past EBV infection excrete virus 10–20% of the time. Immunosuppression may permit reactivation of latent EBV; approximately 60% of seropositive, immunosuppressed patients shed the virus. EBV is also found in the genital tract of women and may possibly be spread by sexual contact.

Infection with EBV in developing countries and among socioeconomically disadvantaged populations of developed countries usually occurs during infancy and early childhood. In central Africa, almost all children are infected by 3 yr of age. Primary infection with EBV during childhood is usually inapparent or indistinguishable from other childhood infections; the clinical syndrome of infectious mononucleosis is practically unknown in undeveloped regions of the world. Among more affluent populations in industrialized countries, infection during childhood is still most common, but approximately one third of cases occur during adolescence and young adulthood. Primary EBV infection in adolescents and adults is manifest in 50% or more of cases by the classic triad of fatigue, pharyngitis, and generalized lymphadenopathy, which constitute the major clinical manifestations of infectious mononucleosis. This syndrome may be seen at all ages but is rarely apparent in children younger than 4 yr, when most EBV infections are asymptomatic, or in adults older than 40 yr, when most individuals have already been infected by EBV. The true incidence of the syndrome of infectious mononucleosis is unknown but is estimated to occur in 20–70 of 100,000 persons per year; in young adults the incidence rises to about 1 in 1,000 persons per year. The prevalence of serologic evidence of past EBV infection increases with age; almost all adults in the United States are seropositive.

PATHOGENESIS.

After acquisition in the oral cavity, EBV initially infects oral epithelial cells; this may contribute to the symptoms of pharyngitis. After intracellular viral replication and cell lysis with release of new virions, virus spreads to contiguous structures such as the salivary glands with eventual viremia and infection of B lymphocytes in the peripheral blood and the entire lymphoreticular system including the liver and spleen. The atypical lymphocytes that are characteristic of infectious mononucleosis are CD8+{plus} T lymphocytes, which exhibit both suppressor and cytotoxic functions that develop in response to the infected B lymphocytes. This relative as well as absolute increase in CD8+{plus} lymphocytes results in a transient reversal of the normal 2:1 CD4+{plus}/CD8+{plus} (helper-suppressor) T-lymphocyte ratio. Many of the clinical manifestations of infectious mononucleosis may result, at least in part, from the host immune response, which is effective in reducing the number of EBV-infected B lymphocytes to less than one per 106 of circulating B lymphocytes.

Epithelial cells of the uterine cervix may become infected by sexual transmission of the virus, although neither local symptoms nor infectious mononucleosis have been described following sexual transmission.

EBV, like the other herpesviruses, establishes lifelong latent infection after the primary illness. The latent virus is carried in oropharyngeal epithelial cells and systemic B lymphocytes as multiple episomes in the nucleus. The viral episomes replicate with cell division and are distributed to both daughter cells. Viral integration into the cell genome is not typical. Only a few viral proteins, including the EBV-determined nuclear antigens (EBNA), are produced during latency. These proteins are important in maintaining the viral episome during the latent state. Progression to viral replication begins with production of EBV early antigens (EA), proceeds to viral DNA replication, followed by production of viral capsid antigen (VCA), and culminates in cell death and release of mature virions. Reactivation with viral replication occurs at a low rate in populations of latently infected cells and is responsible for intermittent viral shedding in oropharyngeal secretions of infected individuals. Reactivation is apparently asymptomatic and not recognized to be accompanied by distinctive clinical symptoms.

Oncogenesis. EBV was the first human virus to be associated with malignancy and, therefore, was the first virus to be identified as a human tumor virus. EBV infection may result in a spectrum of proliferative disorders ranging from self-limited, usually benign disease such as infectious mononucleosis to aggressive, nonmalignant proliferations such as the virus-associated hemophagocytic syndrome to lymphoid and epithelial cell malignancies. Benign EBV-associated proliferations include oral, hairy leukoplakia, primarily in adults with the acquired immunodeficiency syndrome (AIDS), and lymphoid interstitial pneumonitis, primarily in children with AIDS. Malignant EBV-associated proliferations include nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin disease, and lymphoproliferative disorders and leiomyosarcoma in immunodeficient states including AIDS.

Nasopharyngeal carcinoma occurs worldwide but is 10 times more common in persons in southern China, where it is the most common malignant tumor among adult men. It is also common among whites in North Africa and Inuits in North America. All malignant cells of undifferentiated nasopharyngeal carcinoma contain a high copy number of EBV episomes. Undifferentiated and partially differentiated, nonkeratinizing nasopharyngeal carcinomas have diagnostic and prognostic antibodies to EBV antigens. High levels of immunoglobulin (Ig) A antibody to EA and VCA may be detected in asymptomatic individuals and can be used to follow response to tumor therapy (Table 215–1 Table 215–1). Cells of well-differentiated, keratinizing nasopharyngeal carcinoma contain a low or zero copy number of EBV genomes and have EBV serologic patterns similar to those of the general population.

Endemic (African) Burkitt lymphoma, often found in the jaw, is the most common childhood cancer in equatorial East Africa and New Guinea. The median age of onset is 5 yr. These regions are holoendemic for Plasmodium falciparum malaria and have a high rate of EBV infection early in life. The constant malarial exposure acts as a B-lymphocyte mitogen that contributes to the polyclonal B-lymphocyte proliferation with EBV infection. It also impairs the T-lymphocyte control of EBV-infected B lymphocytes. Approximately 98% of cases of endemic Burkitt lymphoma contain the EBV genome compared with only 20% of nonendemic (sporadic or American) Burkitt lymphoma cases. Individuals with Burkitt lymphoma have unusually and characteristically high levels of antibody to VCA and EA that correlate with the risk of developing tumor.

All cases of Burkitt lymphoma, including those that are EBV negative, are monoclonal and demonstrate chromosomal translocation of the c-myc proto-oncogene to the constant region of the immunoglobulin heavy-chain locus, t(8;14), to the kappa constant light-chain locus, t(2;8), or to the lambda constant light-chain locus, t(8;22). This results in the deregulation and constitutive transcription of the c-myc gene with overproduction of a normal c-myc product that autosuppresses c-myc production on the untranslocated chromosome.

The incidence of Hodgkin disease peaks in childhood in developing countries and in young adulthood in developed countries. Levels of EBV antibodies are consistently elevated preceding development of Hodgkin disease; only a small minority of patients are seronegative for EBV. Infection with EBV appears to increase the risk of Hodgkin disease by a factor of two to four. EBV is associated with more than one half of cases of mixed-cellularity Hodgkin disease and approximately one quarter of cases of the nodular sclerosing subtype and is rarely associated with lymphocyte-predominant Hodgkin disease. Immunohistochemical studies have localized EBV to the Reed-Sternberg cells and their variants, the pathognomonic malignant cells of Hodgkin disease.

Failure to control EBV infection may result from host immunologic deficits. The prototype is the X-linked lymphoproliferative syndrome (Duncan syndrome), an X chromosome–linked recessive disorder of the immune system associated with severe, persistent, and sometimes fatal EBV infection. Approximately two thirds of these male patients die of disseminated and fulminating lymphoproliferation involving multiple organs at the time of primary EBV infection. Surviving patients acquire hypogammaglobulinemia, B-cell lymphoma, or both. Most patients die by 10 yr.

A number of other congenital and acquired immunodeficiency syndromes are associated with an increased incidence of EBV-associated B-lymphocyte lymphoma, particularly central nervous system lymphoma. The incidence of lymphoproliferative syndromes parallels the degree of immunosuppression. A decline in T-cell function evidently permits EBV to escape from immune surveillance. Congenital immunodeficiencies predisposing to EBV-associated lymphoproliferations include the X-linked lymphoproliferative syndrome, common-variable immunodeficiency, ataxia-telangiectasia, Wiskott-Aldrich syndrome, and Ché-iak-Higashi syndrome. Individuals with acquired immunodeficiencies resulting from anticancer chemotherapy, immunosuppression after solid organ or bone marrow transplantation, or HIV infection have a significantly increased risk of EBV-associated lymphoproliferations. The lymphomas may be focal or diffuse, and they are usually histologically polyclonal but may become monoclonal. Their growth is not reversed on cessation of immunosuppression.

EBV has been linked with a multitude of other tumors; the strongest association of EBV is to primary central nervous system lymphoma and carcinoma of the salivary glands. Other tumors include T-lymphocyte lymphoma, lethal midline granuloma (a T-cell lymphoma), angioimmunoblastic lymphadenopathy–like lymphoma, thymomas and thymic carcinomas derived from thymic epithelial cells, supraglottic laryngeal carcinomas, lymphoepithelial tumors of the respiratory tract and gastrointestinal tract, leiomyosarcoma, and gastric adenocarcinoma. The precise contribution of EBV to these various malignancies is not well defined.

CLINICAL MANIFESTATIONS.

The incubation period of infectious mononucleosis in adolescents is 30–50 days. In children it may be shorter. The majority of cases of primary EBV infection in infants and young children are clinically silent. In older patients, the onset of illness is usually insidious and vague. Patients may complain of malaise, fatigue, fever, headache, sore throat, nausea, abdominal pain, and myalgia. This prodromal period may last 1–2 wk. The complaints of sore throat and fever gradually increase until patients seek medical care. Splenic enlargement may be rapid enough to cause left upper quadrant abdominal discomfort and tenderness, which may be the presenting complaint.

The physical examination is characterized by generalized lymphadenopathy (90% of cases), splenomegaly (50% of cases), and hepatomegaly (10% of cases). Lymphadenopathy occurs most commonly in the anterior and posterior cervical nodes, and submandibular lymph nodes and less commonly in the axillary and inguinal lymph nodes. Epitrochlear lymphadenopathy is particularly suggestive of infectious mononucleosis. Symptomatic hepatitis or jaundice is uncommon. Splenomegaly to 2–3 cm below the costal margin is typical; massive enlargement is uncommon.

The sore throat is often accompanied by moderate to severe pharyngitis with marked tonsillar enlargement, occasionally with exudates.

 

Fig. Tonsillitis with membrane formation in infectious mononucleosis.

Tonsillitis in infectious mononucleosis

chiae at the junction of the hard and soft palate are frequently seen. The pharyngitis resembles that caused by streptococcal infection. Other clinical findings may include rashes and edema of the eyelids. Rashes are usually maculopapular and have been reported in 3–15% of patients. Eighty per cent of patients with infectious mononucleosis will experience a rash if treated with ampicillin or amoxicillin; the reason for this phenomenon is unknown.

COMPLICATIONS.

Very few patients with infectious mononucleosis experience complications. The most feared complication is splenic rupture, which occurs most frequently during the 2nd week of the disease. A 0.2% rate has been reported in adults; the rate in children is unknown but is probably much lower. Rupture is commonly related to trauma, which often may be mild. Swelling of the tonsils and oropharyngeal lymphoid tissue may be substantial and cause airway impairment manifest by stridor and interference with breathing. Airway impairment may be treated by administration of corticosteroids; respiratory distress with incipient or actual airway occlusion should be managed by maintaining the airway with intubation in an intensive care setting.

Many uncommon and unusual conditions have been reported to be associated with EBV infectious mononucleosis. Neurologic involvement may be serious with ataxia and seizures. Perceptual distortions of space and size, referred to as the Alice in Wonderland syndrome, may be a presenting symptom. There may be meningitis with nuchal rigidity and mononuclear cells in the cerebrospinal fluid, facial nerve palsy, transverse myelitis, and encephalitis. Guillain-Barré syndrome or Reye syndrome may follow acute illness. Hemolytic anemia, often with a positive Coombs test and with cold agglutinins specific for red cell antigen i, may occur late in the illness. Aplastic anemia is a rare complication that usually presents 1 mo after the onset of illness. The prognosis for eventual recovery is good, although substantial supportive treatment is necessary during the acute stages. Myocarditis or interstitial pneumonia may occur, both resolving in 3–4 wk. Other rare complications include pancreatitis, parotitis, and orchitis.

DIAGNOSIS.

The diagnosis of infectious mononucleosis implies primary EBV infection. A presumptive diagnosis may be made by the presence of typical clinical symptoms with atypical lymphocytosis in the peripheral blood. The diagnosis is confirmed by serologic testing.

Differential Diagnosis.

Infectious mononucleosis–like illnesses may be caused by primary infection with cytomegalovirus, T. gondii, adenovirus, viral hepatitis, HIV, or possibly rubella virus. Cytomegalovirus infection is a particularly common cause in adults. Streptococcal pharyngitis may cause sore throat and cervical lymphadenopathy indistinguishable from that of infectious mononucleosis but is not associated with hepatosplenomegaly. Approximately 5% of cases of EBV-associated infectious mononucleosis have positive throat cultures for group A b-hemolytic streptococci; this represents pharyngeal streptococcal carriage. Failure of a patient with streptococcal pharyngitis to improve within 48–72 hr should evoke suspicion of infectious mononucleosis. The most serious problem in the diagnosis of acute illness arises in the occasional patients with low white cell counts, moderate thrombocytopenia, and even hemolytic anemia. In these patients, bone marrow examination and hematologic consultation are warranted to exclude the possibility of leukemia.

Routine Laboratory Tests. In more than 90% of cases, there is leukocytosis of 10,000–20,000 cells/mm3, of which at least two thirds are lymphocytes; atypical lymphocytes usually account for 20–40% of the total number. The atypical cells are mature T lymphocytes that have been antigenically activated. Compared with regular lymphocytes microscopically, atypical lymphocytes are larger overall, with larger, eccentrically placed indented and folded nuclei with a lower nuclear-cytoplasm ratio. Although atypical lymphocytosis may be seen with many of the infections usually causing lymphocytosis, the highest degree of atypical lymphocytes is classically seen with EBV infection. Other syndromes associated with atypical lymphocytosis include acquired cytomegalovirus infection (as contrasted to congenital cytomegalovirus infection), toxoplasmosis, viral hepatitis, rubella, roseola, mumps, tuberculosis, typhoid, mycoplasma infection, malaria, as well as some drug reactions. Mild thrombocytopenia to 50,000–200,000 platelets/mm3 occurs in more than 50% of patients, but only rarely are values low enough to cause purpura. Mild elevation of hepatic transaminases occurs in approximately 50% of uncomplicated cases but is usually asymptomatic without jaundice.

Heterophile Antibody Test. Heterophile antibodies agglutinate cells from species different from those in the source serum. The transient heterophile antibodies seen in infectious mononucleosis, also known as Paul-Bunnell antibodies, are IgM antibodies detected by the Paul-Bunnell–Davidsohn test for sheep red cell agglutination. The heterophile antibodies of infectious mononucleosis agglutinate sheep or, for greater sensitivity, horse red cells but not guinea pig kidney cells. This adsorption property differentiates this response from the heterophile response found in patients with serum sickness, rheumatic diseases, and some normal individuals. Titers greater than 1:28 or 1:40 (depending on the dilution system used) after absorption with guinea pig cells are considered positive.

The sheep red cell agglutination test is likely to be positive for several months after infectious mononucleosis; the horse red cell agglutination test may be positive for as long as 2 yr. The most widely used method is the qualitative, rapid slide test using horse erythrocytes. It detects heterophile antibody in 90% of cases of EBV-associated infectious mononucleosis in older children and adults but in only up to 50% of cases in children younger than 4 yr because they typically develop a lower titer. Approximately 5–10% of cases of infectious mononucleosis are not caused by EBV and are not uniformly associated with a heterophile antibody response. The false-positive rate is less than 10%, usually resulting from erroneous interpretation. If the heterophile test is negative and an EBV infection is suspected, EBV-specific antibody testing is indicated.

Specific EBV Antibodies. EBV-specific antibody testing is useful to confirm acute EBV infection, especially in heterophile-negative cases, or to confirm past infection and determine susceptibility to future infection. Several distinct EBV antigen systems have been characterized for diagnostic purposes.

 The EBNA, EA, and VCA antigen systems are most useful for diagnostic purposes. The acute phase of infectious mononucleosis is characterized by rapid IgM and IgG antibody responses to VCA in all cases and an IgG response to EA in most cases. The IgM response to VCA is transient but can be detected for at least 4 wk and occasionally up to 3 mo. The laboratory must take steps to remove rheumatoid factor, which may cause a false-positive IgM VCA result. The IgG response to VCA usually peaks late in the acute phase, declines slightly over the next several weeks to months, and then persists at a relatively stable level for life.

Anti-EA antibodies are usually detectable for several months but may persist or be detected intermittently at low levels for many years. Antibodies to the diffuse-staining component of EA, EA-D, are found transiently in 80% of patients during the acute phase of infectious mononucleosis and reach high titers in patients with nasopharyngeal carcinoma. Antibodies to the cytoplasmic-restricted component of EA, EA-R, emerge transiently in the convalescence from infectious mononucleosis and often attain high titers in patients with EBV-associated Burkitt lymphoma, which in the terminal stage of the disease may be exceeded by antibodies to EA-D. High levels of antibodies to EA-D or EA-R may be found also in immunocompromised patients with persistent EBV infections and active EBV replication. Anti-EBNA antibodies are the last to develop in infectious mononucleosis and gradually appear 3–4 mo after the onset of illness and remain at low levels for life. Absence of anti-EBNA when other antibodies are present implies recent infection, while the presence of anti-EBNA implies infection occurring more than 3–4 mo previously. The wide range of individual antibody responses and the various laboratory methods used can occasionally make interpretation of an antibody profile difficult. The detection of IgM antibody to VCA is the most valuable and specific serologic test for the diagnosis of acute EBV infection and is generally sufficient to confirm the diagnosis.

TREATMENT.

There is no specific treatment for infectious mononucleosis. Therapy with high doses of intravenous acyclovir decreases viral replication and oropharyngeal shedding during the period of administration but does not affect the severity of symptoms or the eventual clinical course. Rest and symptomatic therapy are the mainstays of management. Bed rest is necessary only when the patient has debilitating fatigue. As soon as there is definite symptomatic improvement, the patient should be allowed to begin resuming normal activities. Because blunt abdominal trauma may predispose patients to splenic rupture, it is customary and prudent to advise withdrawal from contact sports and strenuous athletic activities during the first 2–3 wk of illness or while splenomegaly is present.

Short courses of corticosteroids (less than 2 wk) may be helpful for complications of infectious mononucleosis, but their use has not been evaluated critically. Some appropriate indications include incipient airway obstruction, thrombocytopenia with hemorrhaging, autoimmune hemolytic anemia, and seizures and meningitis. A recommended dosage is prednisone 1 mg/kg/24 hr (maximum 60 mg/24 hr) or equivalent for 7 days and tapered over another 7 days. There are no controlled data to show efficacy of corticosteroids in any of these conditions. In view of the potential and unknown hazards of immunosuppression for a virus infection with oncogenic complications, corticosteroids should not be used in usual cases of infectious mononucleosis.

PROGNOSIS. The prognosis for complete recovery is excellent if no complications ensue during the acute illness. The major symptoms typically last 2–4 wk followed by gradual recovery. Second attacks of infectious mononucleosis caused by EBV have not been documented. Fatigue, malaise, and some disability that may wax and wane for several weeks to a few months are common complaints even in otherwise unremarkable cases. Occasional persistence of fatigue for a few years after infectious mononucleosis is well recognized. At present, there is no specific evidence linking EBV infection to chronic fatigue syndrome (see Chapter 661).