" MD Consult - Book Text Reese: Practical Approach to Infectious Diseases, 4th ed., Copyright © 1996 Richard E. Reese and Robert F. Betts

Classic Infectious Mononucleosis

The term infectious mononucleosis was first introduced in 1921 to describe a syndrome characterized by fever, lymphadenopathy, prostration, and a mononuclear lymphocytosis in six previously healthy young adults. Two years later, a more detailed description of the atypical lymphocyte appeared and, in the early 1930s the findings of Paul and Bunnell and others led to the specific heterophil antibody tests now used in the diagnosis of IM. In 1968, Henle and coworkers (1) presented evidence from seroepidemiologic data that EBV was the etiologic agent of heterophil antibody-positive IM.

  1. Etiology. IM is caused by a double-stranded DNA virus of the herpesvirus group called EBV. There is evidence that EBV is the etiologic agent in heterophil-positive IM.
    1. Seroepidemiologic studies revealed that only individuals lacking anti-EBV antibodies developed IM, and the presence of antibody to EBV confers immunity to heterophil-positive IM.
    2. EBV could be demonstrated in cultured B lymphocytes of patients with IM.
  2. Clinical features (2)
    1. Age. Classic IM occurs most commonly in the 15- to 25-year age group. In very young children, the primary infection is either asymptomatic or insidious, producing mild tonsillitis that often is indistinguishable from that caused by other viral agents or group A streptococci. Clinical IM is uncommon in young children. IM also can occur in the elderly, with a clinical presentation different from classic IM (3) . EBV infection in older adults can be severe, with debilitating fever, malaise, and fatigue, but pharyngitis, cervical adenopathy, and splenomegaly may be minimal.
    2. The incubation period for primary EBV infection is approximately 30-45 days. The onset usually is accompanied by a prodromal period that may last 7-14 days; it is characterized by fatigue, generalized malaise, myalgias, and headache. In some cases, the onset may be acute, and the first sign is high fever.
    3. Signs and symptoms. Common symptoms include fever, sore throat, malaise, headache, myalgias, sweats, anorexia, abdominal pain (due to splenic enlargement or associated hepatitis), chest pain, and cough. The onset of symptoms may be insidious. Clinical diagnostic clues that are helpful in distinguishing classic IM at the bedside include:
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      1. Tonsillar enlargement, exudative tonsillitis, and pharyngeal inflammation, which may be indistinguishable from acute pharyngitis caused by group A streptococci or other viruses.
      2. Lymphadenopathy that primarily involves the posterior cervical area, although generalized adenopathy may occur. The lymph nodes are symmetric, discrete, and tender, but are not fixed.
      3. Hepatomegaly, seen in 50% of cases. Abnormal liver function tests are obtained in 80% of cases. Compared with classic viral hepatitis, alkaline phosphatase is elevated and is disproportionately higher than transaminase enzymes. Bilirubin usually is only minimally elevated, and clinical jaundice is rare.
      4. Splenomegaly, seen in approximately 75% of cases. If it is present, care should be taken to avoid traumatic palpation, which may increase the risk of splenic rupture.
      5. Maculopapular rashes, which are present in fewer than 5% of cases. However, if ampicillin is given inadvertently to patients with IM, almost all will develop a drug eruption (see Chap. 27) .
      6. Petechial enanthema on the soft palate, which is common but not specific for IM.
    4. Hematologic abnormalities
      1. Lymphocytes. An important feature of IM is an absolute (>4,500/mm3 ) and relative (>50% of the total WBC count) increase in peripheral mononuclear cells, of which 10-20% are atypical lymphocytes. The atypical lymphocyte (Downey cell) is a large lymphocyte with an abundant cytoplasm, cytoplasmic vacuoles, loose nuclear chromatin, and indentation of the cell membrane by adjacent erythrocytes. Atypical lymphocytes in the peripheral blood are not pathognomonic for IM and can be associated with infection by CMV, adenovirus, rubella, herpes simplex virus, T. gondii, and other viral infections. Studies have shown that the atypical lymphocytes are of thymic origin (T lymphocytes), whereas EBV infects bone marrow-derived lymphocytes (B lymphocytes).
      2. Total WBC count usually numbers between 10,000 and 20,000 leukocytes per cubic millimeter by the second or third week of illness. On occasion, the total count may rise to as high as 50,000/mm3 , suggesting a leukemoid reaction. Neutropenia with increased immature cells frequently can be present in the early stages of the illness.
    5. Heterophil antibodies develop in response to primary infection with EBV. They are reactive with antigens of other species, can be present in normal human sera, and are associated with a variety of lymphoproliferative states as well. The heterophil antibody that develops in response to EBV infection is an IgM antibody that reacts with surface antigens of sheep and horse RBCs but not guinea pig kidney cells. Heterophil antibodies unrelated to EBV infection react with guinea pig kidney cells. The differential absorption of heterophil antibodies to guinea pig kidney is the basis of the Paul-Bunnell-Davidsohn test, used to detect heterophil antibodies specific for EBV infectious mononucleosis (see sec. III.B.1).
    6. Nonspecific antibody responses observed during various stages of classic IM include rheumatoid factors, antinuclear factors, antiplatelet antibodies, Salmonella agglutinins, Proteus OX 19 antibodies, cryoglobulins, and cold-reactive antibodies to the i antigen on RBCs.
  3. Diagnosis
    1. Differential diagnosis. A variety of conditions that closely mimic classic EBV-induced IM are now recognized (2) . These IM-like syndromes have as a unifying feature peripheral lymphocytosis with the presence of circulating atypical lymphocytes. In addition, the IM syndromes are characterized by some or all of the following: fever, malaise, pharyngitis, adenopathy, hepatomegaly, and splenomegaly. Unlike classic IM, there is no associated heterophil antibody response. Therefore, these syndromes are also called heterophil-negative IM. Proper differentiation of these conditions is necessary to avoid misdiagnosis of serious illnesses (e.g., lymphoma, leukemia, or viral hepatitis) and to prevent patient anxiety and invasive diagnostic procedures for more benign, self-limited illnesses (e.g., CMV or T. gondii infections). The following is a list of causes of heterophil-negative IM, with some important differentiating features (see discussion under Infectious Mononucleosis-like Syndromes later in the chapter).
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      1. Cytomegalovirus IM uncommonly is accompanied by pharyngitis or adenopathy. Splenomegaly is less prominent than in EBV-induced illness.
      2. T. gondii IM commonly presents with posterior cervical adenopathy only and no pharyngitis; liver function tests can be completely normal even in the presence of hepatomegaly.
      3. Viral hepatitis may be associated with atypical lymphocytes, but the percentage is lower than in classic IM. The transaminase enzymes are elevated and are disproportionately higher than levels of alkaline phosphatase, whereas the reverse is true of EBV and CMV hepatitis.
      4. Leptospirosis has modest pharyngeal symptoms and either a normal differential WBC count or a predominance of polymorphonuclear leukocytes.
      5. Rubella is associated with postauricular and suboccipital adenopathy, a characteristic exanthem, and a shorter course than classic IM.
      6. Lymphoma is associated with nontender, fixed adenopathy.
      7. Leukemia has a characteristic peripheral WBC morphology.
      8. Infectious lymphocytosis is not accompanied by lymphadenopathy or splenomegaly.
      9. Diphenylhydantoin, para-aminosalicylic acid (PAS), and isoniazid drug reactions can be associated with fever and generalized lymphadenopathy.
      10. Acute human immunodeficiency virus (HIV) infection can mimic IM. See Chap. 19 (p. 724).
      11. Miscellaneous causes include adenovirus infections, herpes simplex virus infections, and brucellosis. A severe infectious mononucleosis-like syndrome caused by human herpesvirus 6 infection has recently been reported in one patient (4) .
        The two most common causes of heterophil-negative IM are CMV and T. gondii. Except for EBV-induced illness, an IM syndrome is not the most common clinical presentation for any of the diseases just listed. However, IM syndromes do occur frequently enough to cause diagnostic confusion. CMV and T. gondii are discussed in more detail under Infectious Mononucleosis-like Syndromes.
    2. Serologic diagnosis. Clinical suspicion of EBV-induced IM can be confirmed serologically in the majority of cases.
      1. Heterophil antibody that agglutinates sheep or horse RBCs develops as a nonspecific serologic response to EBV infection. After the onset of IM, heterophil antibodies are detectable at variable levels, depending on the duration of illness: 40% by week 1, 60% by week 2, and 80-90% by week 3. Titers remain elevated for 3-6 months, and this elevation usually implies acute disease; however, a titer occasionally can remain elevated for as long as 1 year. Common laboratory tests used to detect heterophil antibodies include the following:
        1. Tests designed to measure heterophil antibodies have been adapted for purposes of rapid diagnosis. These so-called slide or spot tests have virtually replaced the more traditional tests due to their ease of use. They are highly sensitive for the detection of EBV-induced IM. However, repeat testing (e.g., at weekly intervals) may be necessary in some patients because only 60% of individuals will have heterophil antibodies by the second week of the illness. See sec. I.
        2. The spot tests are available from more than 25 different manufacturers. An early prototype test was the Monospot. Some of the more widely used tests now are Mono-Test and Mono-Latex (Wampole Diagnostics, Cranbury, NJ), Access Color Slide II (Seradyn, Inc., Indianapolis, IN), Monosticon (Organon Teknika Corp., Durham, NC), and ImmunoCard Mono (Meridian Diagnostics, Inc., Cincinnati, OH). As initially formulated, spot tests detected agglutinins to formalized horse RBCs after an absorption step with guinea pig or horse kidney to eliminate cross-reactions with Forssman and serum sickness antibodies (Monosticon). Newer tests use bovine red cell membranes attached to latex particles (Mono-Latex), specially treated horse RBCs (Mono-Test), or solid-phase enzyme-linked immunosorbent assay (ELISA; ImmunoCard Mono) to eliminate the absorption step while maintaining a high degree of specificity.
        3. The false negative rate of these rapid tests is 10-15%, and false negative results are more frequent among children (the test is usually negative in
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          children younger than 5 years). For these patients, EBV-specific serologic testing is needed (5) .
        4. False positive spot tests generally are considered uncommon but have been described with rubella, hepatitis, other viral infections, and lymphoma.
        5. The duration of a positive spot test after acute IM is not well described but appears to be in the range of 3-6 months, although the test may occasionally be positive for up to 1 year.
      2. EBV antibody seroconversion for diagnosis of classic IM is most useful in those adults (approximately 10%) with EBV-induced IM who do not develop heterophil antibodies or who do not have a positive Monospot test. EBV antibody titers may also be necessary for confirming infection in young children, who rarely have a positive heterophil response, or in a patient of any age with an atypical mononucleosis-like illness.
        1. Infected B lymphocytes produce several virus-specific antigens: viral capsid antigen (VCA), early antigen (EA), and Epstein-Barr nuclear antigen (EBNA). Assay of the antibody response to these antigens can be used to differentiate recent from remote EBV infection and to diagnose classic IM in the absence of a heterophil response (2) .
          (1) IgG antibody to viral capsid antigen (VCA-IgG) is present in active, recent, and past infections and persists for life. A single elevated titer of VCA-IgG does not, by itself, confirm a diagnosis of acute EBV illness but indicates only that infection with EBV has occurred sometime in the past.
          (2) IgM antibody to viral capsid antigen (VCA-IgM) is present in primary EBV infection and usually disappears within 1-2 months.
          (3) Antibody to early antigen may be detected in up to 70% of patients with acute IM. This antibody resolves after the patient recovers from the infection.
          (4) Antibody to Epstein-Barr nuclear antigen appears within 3-4 weeks of the onset of IM and persists for life. The appearance of EBNA in persons who previously had antibody to VCA (see sec. B.2.a.(1)) is strong evidence for recent EBV infection.
        2. EBV-specific antibody studies should be reserved for the diagnosis of heterophil-negative or atypical primary EBV infection. Acute or recent infection is probable if all four of the following serologic criteria are present: (1) VCA-IgM; (2) high titers ( 1:320) of VCA-IgG; (3) anti-EA ( 1:10); and (4) absence of antibody to EBNA. Serum should be obtained during convalescence (e.g., at 6-8 weeks) to demonstrate disappearance of VCA-IgM and appearance of anti-EBNA as further confirmation of recent EBV infection.
  4. Complications. Although most patients have a benign clinical course with EBV-induced IM, complications occasionally occur.
    1. Hematologic complications
      1. Hemolytic anemia of the Coombs -positive type occurs in 1-3% of cases and is mediated by IgM cold-agglutinin antibodies directed at the RBC i antigen.
      2. Thrombocytopenia is not uncommon, but associated purpura is rare.
      3. Granulocytopenia occasionally progresses to agranulocytosis.
    2. Hepatitis with clinical jaundice is uncommon.
    3. Splenic rupture occurs in approximately 0.2% of cases. This may be the initial complaint, or it may occur after multiple palpations (which should be avoided).
    4. Neurologic syndromes reported in association with classic IM are Landry-Guillain-Barre syndrome, meningitis, encephalitis, mononeuritis, cerebellar dysfunction, and transverse myelitis. Cerebrospinal fluid (CSF) pleocytosis may be more common than has been recognized clinically.
    5. Miscellaneous complications include myositis, myopericarditis, pneumonitis (5A) , pancreatitis, and postanginal sepsis resulting from phlebitis of the jugular veins (6) .
  5. Therapy. No therapy is indicated for the vast majority of cases of classic IM, but several antiviral agents currently show promise (see sec. D). Antibiotics have no effect on uncomplicated cases, and the indiscriminate use of ampicillin may lead to the unnecessary complication of a maculopapular rash.
    1. Throat cultures for group A beta-hemolytic streptococci should be obtained (positive in approximately 25% of patients with IM in some series). If they are positive, appropriate treatment is indicated.
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    2. Salicylates or other analgesics usually are adequate to control fever, headaches, and sore throat in the acute phase.
    3. Corticosteroids are employed in the management of certain complications, but their value is uncertain. A short course of prednisone, starting with 40-60 mg/day, can be administered for 7-10 days. Once there is a good clinical response, the dose can be rapidly tapered. Corticosteroids are indicated in:
      1. Severe toxic exudative tonsillitis, pharyngeal edema, or laryngeal edema when there is impending or early airway obstruction.
      2. Acute hemolytic anemia and severe thrombocytopenia.
      3. Neurologic complications.
      4. Myocarditis and pericarditis.
        Occasionally, in a patient with marked toxicity and a prolonged course, steroids will be employed to abbreviate the course of the disease. In these situations, the diagnosis must be clear so that the corticosteroids do not mask some other disease presenting like IM (e.g., leukemia or lymphoma). The authors generally try to avoid corticosteroids in this setting and try to use analgesics and salicylates unless one of the listed purported indications for steroids also exists.
    4. Specific antiviral chemotherapy for EBV infection is not currently available. Although phosphonoacetic acid, acyclovir, and interferons all inhibit EBV in vitro, none of these agents has shown consistent clinical benefit to date (7) (8) . (See Chap. 26 for a more detailed discussion of antiviral agents.)
    5. Transmission and implications for isolation. Since EBV is found in oropharyngeal secretions, kissing is one of the presumed mechanisms of transmission. In the hospital or home, no specific isolation precautions are required other than careful handling of oral secretions. The demonstration of cell-free virus shedding from the human uterine cervix may indicate that sexual transmission of EBV infection is possible (9) .
  6. Prognosis
    1. Duration of EBV-induced IM symptoms usually is 2-4 weeks, but 3% of patients may have disease lasting longer than 1 month.
    2. Long-term sequelae are unusual in uncomplicated illness, but neurologic complications may persist with varying degrees of severity.
    3. Reinfection does not occur because the primary EBV infection confers lifelong immunity.
  7. Chronic EBV infection. After acute primary EBV infection, the virus persists in a latent state in B lymphocytes and salivary glands. Reactivation of EBV can result in a rare, severe illness, characterized by both cellular and humoral immune defects and histologic evidence of major organ involvement: lymphadenopathy, splenomegaly, hypoplasia of bone marrow presenting as cytopenia (anemia, thrombocytopenia, or leukopenia), chronic persistent hepatitis, interstitial pneumonitis, malabsorption due to lymphocyte infiltration of the small intestine, and uveitis (10) (11) . Patients with this illness have a unique serologic response to EBV, with very high titers of VCA-IgG (> 1:5,120), high titers of early antigen (> 1:640), and low titers of EBNA (< 1:2).


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