Mononucleosis

INFECTIOUS DISEASES UPDATE

MONONUCLEOSIS Robert S. Egerman, MD

ELSEVIER

Infectious mononucleosis is a common, usually self-limited infection of early adulthood. The disease is manifested by pharyngitis, adenopathy, and atypical lymphocytosis. The diagnosis is commonly confirmed using the heterophil antibody screen. Specijic antibody testing is occasionally necessary. The diferential diagnosis includes other viral, bacterial, and protozoan infections. Concomitant group A streptococcal infections should be treated. However, ampicillin or amoxicillin should not be used for treatment because these drugs may provoke a difise skin eruption. Immediate complications of mononucleosis include airway obstruction, anemia, thrombocytopenia, and hepatitis. Splem’c enlargement is typical. Splenic rupture must be considered in infected patients presenting witb abdominal pain and requires immediate supportive measures and surgical interven tion. Long-term complications associated with Epstein-Barr virus infection include chro~k Epstein-Barr virus infection, lymphoproliferative disorders, oral hairy leukoplakia, and chronic fatigue syndrome. (Prim Care Update Ob/ Gym 1995;2:152-6)

Infectious mononucleosis is an infection frequently seen in young adults who have the classical presentation of fever, pharyngitis, and cervical adenopathy. The agent responsible for 90% of infectious mononucleosis, Epstein-Barr virus (EBV), is one of seven types of herpes viruses: Herpes simplex types I From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Tennessee.

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and II, varicella, cytomegalovirus (CMV), and the more recently recognized human herpes virus types 6 and 7 (HHV). CMV contributes to 8% of clinically recognized IM. This article will facilitate correct identification of this generally selflimited infection, discuss the lesscommon complications of this disease, and provide a guide to therapy and patient counseling.

Prevalence and Transmission By adulthood, all but 5% of people throughout the world demonstrate antibody to EBV. Fifty percent of children in Western countries experience a predominantly asymptomatic infection by 5 years of age. Otherwise, pediatric infectious mononucleosis can be seen as a flu-like illness and diarrhea. Children from developing countries are infected even before age 5. Over half of adolescents and young adults infected with EBV present with the classic symptoms. Approximately 10% of freshman college students are infected yearly, although peak incidence is age 16 in females and age 18 in males. Transmission occurs from intimate contact with saliva because the virus is shed from the oropharynx. Kissing appears to be the predominant risk factor; however, EBV has been located in the genital tract suggesting sexual spread of the virus.l The virus itself is somewhat frail. Household contacts rarely acquire the infection, reinforcing the necessity of intimate contact with oropharyngeal secretions for transmission to occur. The incubation period is 2 weeks to 2 months.

0 1995 Elsevier

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Pathophysiology EBV is shed from the salivary glands in 15-20% of healthy, previously infected individuals. It is a doublestranded DNA virus of which there are two strains, types A and B. The virus enters epithelial cells of the oropharynx or cervix or B lymphocytes traveling through adjacent lymphoid tissue. The similarity among these cell types is the presence of the CD21 receptor, a locale for binding of the C3d component of complement. Viral envelope glycoprotein binds to this receptor. Infected B lymphocytes stimulate T lymphocyte proliferation, and cytotoxic and suppressor T cells are seen systemically as atypical lymphocytes. Lymphocytes infiltrate the perivascular regions of the liver, the spleen, and the cervical and inguinal lymph nodes. Hepatic enlargement is produced, and commonly, the spleen doubles in size. Other tissues, including the brain and heart, may also be affected. Activated cytotoxic T cells are responsible for controlling the initial infection as well as maintaining viral dormancy by destroying immortalized B lymphocytes infected with EBV. Remarkably, infected B lymphocytes secrete growth factors that promote B cell expansion. Furthermore, a number of viral gene products mediate the behavior of this virus. EBNA-1 promotes latency inside the host cell. The ZEBRA protein evokes viral reproduction, and LMP (latent membrane protein) and EBNA-2 trigger indefinite B cell immunoglobulin production.’ These are the antigens that cytotoxic T cells recognize. During an acute infection, antibody is produced; however, it is

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ineffectual at removing infected cells. Therefore, the virus lies dormant in epithelial and lymphatic tissue where reactivation can occur if cell-mediated immunity is impaired by either organ transplant, congenital lymphoproliferative disease, or human immunode~ciency virus, Very small numbers of immortalizod B cells are able to persist indefinitely in the circulation of even healthy patients. The majority of patients are essentially cured after the acute illness. Rarely, EBV persists as a chronic infection or reactivates in immunocompromised patients.

Approximately half of all infections and nearly all recurrences are asymptomatic. Typically, during the 3-5 day prodrome, the patient has headaches and malaise. A more symptomatic period follows, lasting l-3 weeks, with fever, sore throat, lethargy, and possible upper respiratory symptoms. Myalgias and nausea also may occur. Elevated temperature (90% of symptomatic patients), exudative pharyngitis (80%) and adenopathy (90-1000/o) are the most-common manifestations of infectious mononucleosis. Adenopathy is usually cervical, affecting both anterior and posterior chains; palpable inguinal lymph nodes also may be present. Adenopathy usually precedes other signs by a few days. ~plenomegaly is present in up to 50% of patients. Because the spleen can rupture, percussion rather than deep palpation should be employed while examining the spleen. Pharyngotonsillitis due to anaerobic bacteria in the oral flora is another common finding. The pharyngitis may persist for 2 weeks before resolution occurs. Petechiae found at the base of the hard palate also may be present.3 In a minority of patients, various cutaneous findVolume

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Figure 1. Two characteristic atypical lymphocytes are shown in the same field as

a normal lymphocyte. Note the increased size of the nucleolus, irregularly shaped nucleus, and vacuolated cytoplasm. (Courtesy of Ann Bell, M.S.S.H. (ASCP), Division of Hematology-Oncology, University of Tennessee,Memphis.)

ings have been noted such as a macular rash involving the trunk, urticaria, and even genital ulcers. Periorbital edema has been reported in 50% of patients.

Differential Diagnosis The triad of fever, adenopathy, and the presence of atypical lymphocytes in the peripheral smear is suggestive of infectious mononucleosis; however, other organisms must be considered. CMV, HIV, toxoplasma gondii, and HHV 6 can present similarly. Isolated tonsillopharyngitis also may be due to adenovirus, rubella, mumps, rubeola, HSV, Neisseria gonorrhoeae, or group A streptococcal infection. CMV and toxoplasmosis generally do not produce an exudative pharyngitis.* HHV 6 is the etiologic agent of roseola infantum or sixth disease, a common viral exanthem

of infancy. Most people acquire antibody to this virus by age 3; however, reactivation can occur in immunocompromised patients. In addition to adenopathy and fever, HHV 6 can produce hepatitis, lymphoproliferative disorders, and chronic fatigue syndrome.

Diagnosis Patients with mononucleosis usually have a total white blood cell count in the range of lO,OOO-20,000 cells/~L. Lymphocytes typically account for 50% of the total number of white blood cells. Atypical lymphocytes may constitute between 10% and 50% of the lymphocyte count, the majority being activated T lymphocytes (Figure 1). Atypical lymphocytes are not required for the diagnosis of infectious mononucleosis. In some patients, mild neutropenia and thrombocytopenia may 153

EGERMAN be evident. The altered white cell differential may take several weeks to resolve, EBV may cause hepatitis. Transaminase elevations, approximately four times above control levels, are common. However, hyperbilirubinemia is less frequent. The mainstay of diagnosis is serologic testing. Heterophil antibody, a nonspecific IgM antibody reacting with mammalian cell surface antigen, is produced in 8090% of adults, The majority of young children with mononucleosis do not produce this antibody. Either specially prepared horse red cells or latex particles are mixed with the patient’s plasma or serum; when the heterophil antibody is present agglutination of the red blood cells occurs. The specificity of the heterophil antibody is approximately 98%; thus, the vast majority of positive screens represent EBV infections. Once a positive test is obtained, no further serology is necessary. Although most rapid slide tests are positive within 1 week, there may be a 2-3 week delay between the onset of symptoms and seroconversion. Once present, these antibodies can persist for months after the infection. Unfortunately, this nonspecific antibody can be present in a variety of other infections such as hepatitis A, toxoplasmosis, adenovirus, parvovirus, and CMV infection. Rheumatoid arthritis may produce a false positive test as well. The Mono-Test (Wampole Laboratories, Cranbury, NJ) is one of several rapid tests; a kit for 40 samples costs approximately $82. If infectious mononucleosis is suspected and the heterophil antibody screen is negative, a more sensitive test for IgM and IgG antibody directed at Epstein-Barr viral capsid antigen (VCA) should be ordered. IgM VCA is the first antibody to be made after EBV infection (within the first week to month) and generally persists for a few months.

The lag in antibody production is similar to that seen with the heterophi1 antibody. IgG VCA is made subsequently, followed by antibodies to early antigen (EA). Early antigen is named because it is seen before DNA synthesis of EBV DNA. Finally, antibody to Epstein-Barr nuclear antigen (EBNA) is made rather late in the course of the infection Rapid tests using an enzyme linked immunosorbent assay (ELISA) are available for determination of some of the more specific antibodies to EBV. In comparison to office testing for heterophil antibodies, these are more expensive, cumbersome, and better left to reference laboratories.

amazement When infectious mononucleosis is suspected, a rapid screen should be performed as well as a complete blood count. If the rapid test is negative and the infection is of recent onset, the heterophil test should be repeated in 1 week. If the heterophil test remains negative, as it will in 10% of adults, specific antibodies for EBV, particularly anti-EBV VCA and EBNA (IgM and IgG), should be sought. In addition, alternative causes for the infection including HIV, toxoplasmosis, rubella, and CMV should be sought. Because infectious mononucleosis is generally a self-limited disease, with recovery occurring within 4 weeks, reassurance can be given. The evaluation of the rare patient with chronic or recurrent EBV is discussed below. If the patient has an exudative pharyngitis, a culture should be sent for group A streptococcus. Neither acyclovir nor penicillin shorten the duration of the pharyngitis. In fact, ampicillin or amoxicillin may evoke a pruritic, morbilliform rash in some patients infected with EBV. Given anaerobic colonization of tonsillar crypts, ni-

troimidazoles such as metronidazole have shown some clinical benefit in shortening the disease, although they are not widely recommended. A course of metronidazole (2.50 mg every 8 hours for 5 days] may be of benefit when the pharyngitis is severe or persists longer than 5 days. For the 30% of patients co-infected with group A streptococci, either oral penicillin or erythromy~in ~250-500 mg every 6 hours for 10 days for either antibiotic) should be given to prevent renal or cardiac complications4 During the acute infection, acetaminophen and increased fluid intake are all that is required. Patients should be instructed to avoid aspirin because of an increased potential for bleeding and subcapsular splenic rupture. Activity should be limited to light work with no excessive physical exertion. Contact sports should be avoided for at least 4 weeks or until splenomegaly has resolved. Sonography of the spleen to exclude splenomegaly is indicated if the patient desires to return to physical conditioning exercises before this time. Steroids are indicated for airway obstruction, hemolytic anemia, or thrombocytopenia.5 The initial oral dose of prednisone should be 40-60 mglday for 5 days, then tapering over the following week. Patients should be hospitalized for a compromised airway. Rarely is tonsillectomy needed to relieve lifethreatening airway obstruction, Routine steroid use is not recommended because of concerns about suppressing cell-mediated immunity, which is important for controlling this generally self-limited disease. Work is in progress toward the development of an EBV vaccine.’

Complications As mentioned, the airway can become obstructed from hypertrophied lymphoid tissue in the oroPrim

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pharynx in approximately l/100 cases of infectious mononucleosis. Even rarer are neurologic sequelae such as Bell’s palsy, Guillain-Barre syndrome, encephalitis, cerebellar ataxia, transverse myelitis, and peripheral neuropathy. Collectively, these neurologic sequelae occur in approximately 11250 cases of infectious mononucleosis. Nasopharyngeal carcinoma, one of the most frequent tumors in regions of China, is attributed to chronic EBV infection within the epithelium. In East Africa, EBV is the causative agent of Burkitt’s lymphoma. The mechanism of this lymphoid expansion is thought to occur from a translocation of the c-myc gene of chromosome 8 to chromosome 14 causing a monoclonal B cell proliferation.’ A number of other lymphoproliferative disorders also are associated with EBV including both Hodgkin’s and nonHodgkin’s lymphomas and T cell lymphomas. In addition, thymic and salivary gland carcinoma may be related to EBV infection. Oral hairy leukoplakia is a nonmalignant infection of the superficial epithelial cells found predominantly on the lateral aspect of the tongue. It is seen mostly in immunocompromised

patients.

Oral

hairy leukoplakia appears as raised 5 mm to 3 cm white papillations on the tongue surface. Spontaneous resolution is possible; however, the infection

responds

to acyclovir.

Dis-

continuance of the antiviral therapy often results in reactivation of the lesions.

Chronic infectious mononucleosis may occur as a protracted infection with the clinical presentation of fatigue,

myalgias,

weakness,

and

possible adenopathy. Focusing on career or family responsibilities may be difficult. Affected patients usually have persistently high titers of anti-EA (1'.1:640) and anti-VCA IgG (21:5,120) with no anti-EBNA production.7 Other findings that maybe consistent with chronic EBV Vninmc

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Table 1. Summary of the CDC Criteria for Chronic Fatigue Syndrome* Major symptoms (both must be present) Fatigue for 6 months causing a 50% activity reduction No other medical or psychiatric disorder identified Minor symptoms (8 symptoms or 6 symptoms and 2 signs must be present) Mild fever Sore throat Weakness Postexercise fatigue M yalgias Arthralgias Adenopathy (cervical or axillary) Headaches Sleep alterations Neuropsychologic symptoms Abrupt onset Signs Low-grade fever (37.6-38.6 C oral) Pharvngitis Palpible adenopathy CDC, Centers for Disease Control

and Prevention

infection include hematologic abnormalities (thrombocytopenia or leukopenia), hepatosplenomegaly, hepatitis, nephritis, and pneumonitis. Chronic fatigue syndrome (CFS) is a disorder defined by the Centers for Disease Control and Prevention as lethargy and fatigue lasting at least 6 months causing a 50% reduction in daily activity.8 Other medical conditions need to be excluded before the diagnosis is made (Table 1). In the recent past, CFS has been attributed to a number of infectious agents including EBV, HHV 6, Borrelia burgdorferi (the cause of Lyme disease), and enteroviral and retroviral infection. Because of the high prevalence of EBV antibody in the population as a whole, the association between EBV and CFS is uncertain. Perhaps as many as 1520% of all patients with CFS demonstrate elevated antibody levels suggesting an abnormal immune response to EBV. Literature surrounding CFS summarily describe this as a heterogeneous disorder. Understandably, the evaluation of the patient with CFS should be extensive, including hematologic and blood chemistry profiles, thyroid stimulating hormone, antinuclear antibody, erythrocyte sedi-

mentation rate, and tuberculin skin testing.g A complete neurologic examination is warranted as is a psychological survey. Ordering EBV serology on patients with CFS is probably not worthwhile and should be avoided in the primary office setting. ELISA testing should be performed for HIV in all patients and for Borrelia burgdorferi infection if indicated. Splenic rupture is an uncommon, yet potentially catastrophic, complication of infectious mononucleosis, occurring in l/l,000 patients. Contrary to classic teaching, splenic rupture is seen in females and can occur at any age.*’ The spleen may not reach its maximal volume until 2-4 weeks after symptoms are recognized. Most cases present during the first 2-3 weeks of the illness. Half of all splenic ruptures occur spontaneously, without antecedent trauma. The diagnosis of splenic rupture should be suspected in patients with left upper quadrant pain or tenderness, particularly in those with left shoulder pain (Kehr’s sign) caused by diaphragmatic irritation from blood. Isolated cases of asymptomatic splenic rupture have been reported; however, they are unusual. Although a radiograph of the chest or abdomen may reveal a me155

EGERMAN dially displaced stomach bubble or opacification in the left upper quadrant, ultrasonography or computed axial tomography will be more inf0rmative.l’ Tachycardia and orthostatic blood pressure changes also should alert the clinician to potential intraabdominal hemorrhage requiring prompt intravascular fluid replacement, red blood cell cross match, and immediate surgical consultation. If a symptomatic patient with an enlarged spleen is managed conservatively, she should be followed in an intensive care unit. Pregnant women do not have increased susceptibility to EBV infection There is some suggestion that the altered immune condition of pregnancy might promote recurrences; however, current opinion is that fetal infection is unlikely and is not associated with structural fetal anomaliesll

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References Durbin WA, Sullivan JL. EpsteinBarr virus infection. Pediatr Rev 1994;15(2):63-8. Schuster V, Kreth HW. Epstein-Barr virus infection and associated diseases in children. I. Pathogenesis, epidemiology and clinical aspects. EurJ Pediatr 1992;151:718-25. Troffater KF Jr. Epstein-Bar virus infections including infectious mononucleosis, ch 101. In: Gleicher N, Gall SA, Sibai BM, Elkayam U, Galbraith RM, Sarto GE (eds). Principles and practice of medical therapy in pregnancy, 2nd ed. Norwalk (CT): Appleton & Lange, 1992: 664-9. Straus SE, Cohen JI, Tosato G, Meier J. Epstein-Barr virus infections: biology, pathogenesis, and management. Ann Intern Med 1993;118: 45-68. Shooley RT. Epstein-Barr virus infections, including infectious mononucleosis. In: Isselbocher K, Braunwald E, Wilson JD, Martin JB, Favei AS, Kesper DL (eds). Harrison’s principles of internal medi-

tine, 13th ed. New York: McGrawHill Inc., 1994:796-3. 6. Morgan AJ. Epstein-Barr virus vaccines Vaccine 1992;10:563-71. 7. Straus SE. The chronic mononucleosis syndrome. J Infect Dis 1988; 157:405-12. a. Holmes GP. Defining the chronic fatigue syndrome. Rev Infect Dis ~99l:l3~suppll):s53-5. 9\ * Stoner BP, Corey GR. Chronic fatigue syndrome: a practical a preach N C Med J 1992;53(6):26!-i 70. ‘ 10. Farley DR, Zietlow SP, Bannon MP, Farnell MB. Spontaneous rupture of the spleen due to infectious mononucleosis. Mayo Clin Proc 1992;67: 846-53. 11. Arvin A, Maldonado Y. Other viral infections of the fetus and newborn. In: Remington JS, Klein JO (edsf: Infectious diseases of the fetus and newborn infant, 4th ed. Philadelphia [WB Saunders, 1995:746-8. Address correspondence and reprint requests to Robert Egerman, MD, 853 Jefferson, Suite El&', Memphis, TN38303.

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