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InFocus: Part I in a Series

Infectious Mononucleosis: Epidemiology and Pathophysiology

Roberts, James R. MD

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    While researching previous columns on acute pharyngitis, I was quickly reminded that many patients with suspected strep throat, especially adolescents, actually may be suffering from mononucleosis. Clearly the physician cannot clinically differentiate adenovirus from Group A beta hemolytic strep.

    In its early stages, mononucleosis is likewise clinically indistinguishable from strep throat. In fact, mononucleosis looks just like a bad strep infection. Fever, adenopathy, and a sore throat is a much more complex syndrome than initially meets the clinician's eye. Fortunately, most scenarios involving these symptoms are self-limited and relatively benign, and even if one is not academically correct in making a specific diagnosis, almost any conservative intervention is usually quite clinically correct.

    Terminology can be confusing, and it's important to realize that “infectious mononucleosis” is not a specific disease. More correctly, the term merely describes a syndrome that may or may not be caused by the ubiquitous Epstein Barr virus, the organism that most commonly causes generic “mono.” This month's column initiates a discussion of infectious mononucleosis with a focus on epidemiology and pathophysiology. Highlighted is the unexpected incidence of infectious mononucleosis in children and the association with HIV infection. Next month's discussion will attempt to clarify the confusing issue of specific laboratory diagnosis, and the final column will review the more straightforward issues relating to symptoms, treatment options, and complications.

    Infectious Mononucleosis: Complexities of a Common Syndrome Godshall S, Kirchner J Postgrad Med 2000;107:175

    This recent update is well written, straightforward, and easily understood account of some of the clinical issues concerning infectious mononucleosis that should be known to the practicing clinician. It was likely written for primary care specialists, but emergency physicians are frequently members of that group. A more in-depth and decidedly highly academic discussion can be found in Pediatric Clinics of North America by Hickey and Strasburg (1997;44:1541).

    The syndrome of fever, pharyngitis, and lymphadenopathy has been known in the medical literature since the 1800s. It is likely that apparent spontaneous remissions of some suspected leukemias were actually undiagnosed infectious mononucleosis in the early 1900s. In the 1920s, the term infectious mononucleosis came into common use. Ten years later heterophil antibodies were identified by Drs. Paul and Burnell, and 20 years later the Epstein Barr herpes virus was identified as a common cause of the syndrome. It was not until 1968, however, that the Epstein Barr virus was identified as the primary cause of infectious mononucleosis.

    The Epstein Barr virus is omnipresent, and more than 90 percent of adults in the United States show serological evidence of having had prior exposure. Interestingly, in the 1960s, a laboratory technician acquired symptoms of infectious mononucleosis while working with Epstein Barr virus and serologically converted, thereby establishing the link between the virus and the syndrome. More recently, Epstein Barr virus infections have been linked to a prolonged fatigue syndrome, although this is a rather controversial and poorly understood association.

    Importantly, infectious mononucleosis and symptomatic Epstein Barr virus infections are not always exactly the same entities. The infectious mononucleosis symptom complex can be caused by a number of organisms, and even the atypical lymphocytes so commonly seen in the acute Epstein Barr virus mononucleosis are proliferated after exposure to a variety of agents. Although approximately 80 percent of patients with clinical mononucleosis do have acute EBV infection, up to 20 percent have this exact same syndrome cause by a different organism. The second most common cause is probably CMV infection. In short, Epstein Barr-associated infectious mononucleosis is only one variant of the universe of similar infections. Therefore, it is best to think of the term infectious mononucleosis as a clinical syndrome of fever, pharyngitis, and adenopathy, regardless of the specific infecting agent.

    Almost every adult in the world has serological evidence of prior Epstein Barr virus infection, usually acquired during childhood. In the United States approximately 50 percent of asymptomatic 5-year-olds will have serologic evidence of previous Epstein Barr virus exposure, and by the time children reach their first year of college, more than 70 percent have evidence of such exposure. In lower socioeconomic settings, infections become more prevalent at earlier ages. Exposure and serologic evidence of such exposure can occur at an early age, but usually childhood exposure is subclinical and only confirmed by serologic testing years later.

    The peak years for developing clinical disease occur between 15 and 25, and the most common place to acquire Epstein Barr virus antibodies and the overt disease is at college

    The peak years for developing the clinical syndrome occur between the ages of 15 and 25. The most common place to acquire Epstein Barr virus antibodies and the overt disease is at college. It is especially associated with dormitory life. After the end of freshman year, almost 15 percent of students have newly acquired exposure to the Epstein Barr virus. In those who seroconvert, about 75 percent will develop mild or severe clinical infectious mononucleosis. The rest remain asymptomatic, and are simply laboratory curiosities. Although older adults sometimes develop the clinical mononucleosis syndrome, they often have atypical presentations and are frequently worked up for a variety of other illnesses, such as hepatitis, collagen diseases, or neoplasms. There is no sexual or seasonal preference for infectious mononucleosis, although for some yet unknown reason it occurs much more often in whites than blacks. This may reflect primary Epstein Barr virus infection at an earlier age and a higher frequency of initial subclinical infection in the African-American population.

    Epstein Barr virus is a DNA herpes virus. It cannot survive for a prolonged period outside a host, which is only humans and a few other primates. Failure to produce infectious mononucleosis in animal models has hampered research efforts. Transmission occurs through exposure to oropharyngeal secretions; therefore, infectious mononucleosis has been often termed the kissing disease. These observations may explain the high prevalence among college students. Epstein Barr virus also can be rarely transmitted via blood products, and it is found in genital and rectal mucosal secretions, raising the possibility of sexual transmission. Actual sexual transmission has not been clarified. Mononucleosis does not occur in epidemics, and the direct intimate oral contact that is required for transmission is probably a reflection of this observation. Only rarely do family members become infected. Epstein Barr virus is not highly contagious, and the main reservoir in humans is the oral pharyngeal or saliva glands and epithelial cells. In short, sharing infected saliva is the most common mode of transmission.

    Once the virus infects oral epithelial cells, it spreads to the B lymphocytes. The virus generally does not produce cytopathic changes in the cells that it infects. These infected lymphocytes circulate through the reticular endothelial system, and trigger a massive but self-limited immunological response to the infection. It is this immunological response that is likely responsible for many of the clinical manifestations of mononucleosis. An acute Epstein Barr virus infection will stimulate the production of a number of antibodies directed against both the virus itself and unrelated antigens. Therefore, the laboratory can measure both specific Epstein Barr antibodies (IgG, IgM, and others) and other nonspecific antigens that react with sheep or horse red blood cells called heteophil antibodies.

    Other unusual antibodies, such as those that bind neutrophils, platelets, and the antibiotic ampicillin, have been reported, and are probably responsible for the mild thrombocytopenia and the curious ampicillin-related rash commonly associated with infectious mononucleosis. Once the Epstein Barr virus is in the body, it remains there for life, usually in a clandestine fashion. It is this lifelong carrier state that has been related to the chronic fatigue syndrome. The “atypical lymphocytes” seen in acute infections are due to acute viral changes produced in T lymphocytes, and they are a classic but not diagnostic laboratory finding.

    The Epstein Barr virus also is associated with a variety of neoplasms, particularly those of the lymph system such as Burkitt's lymphoma, nasopharyngeal tumors, some leukemias, and lymphomas. In fact, many neoplasms also cause an infectious mononucleosis-like syndrome. The exact link and relationship between Epstein Barr virus and neoplasm is unclear. Epstein Barr virus is not thought to be the direct cause of these neoplasms. Other organisms known to cause acute infectious mononucleosis appear in the table. Cytomegalovirus is likely the second leading cause of infectious mononucleosis, and can be transmitted by blood products. CMV has been associated with the post-bypass pump mononucleosis-like syndrome.

    The Epstein Barr virus incubation period is somewhere from 30 to 50 days, and the communicability period commonly lasts up to three months, although it may be more prolonged. Individuals affected with Epstein Barr virus have intermittent or continual shedding of the virus in their saliva for a number of months after they are clinically cured. Titers of Epstein Barr virus virus can be demonstrated in the throat washings of those patients with infectious mononucleosis.

    Acute HIV Infection among Patients Tested for Mononucleosis Rosenberg, et al New Engl J Med 1999;340:969

    Up to 50 percent of HIV-infected homosexual men shed the Epstein Barr virus in oropharyngeal secretions. Curiously, however, acute or first time HIV infection can be clinically very similar to Epstein Barr virus mononucleosis, and this is far more common than previously thought. In this sobering study, the authors reported that acute infection with HIV-1 is associated with a self-limited mononucleosis-like illness in the majority of persons. This is characterized by fever, adenopathy, pharyngitis, rash, oral lesions, orthostasis, and GI symptoms — common scenarios in previously healthy individuals.

    Many of these patients seek medical attention only to be told that they have a “virus,” and invariably they initially improve. At this stage, the standard serologic tests for HIV will be negative, even if the process is considered by the clinician. As an example, in the Rosenberg study, the serum of 11 of 563 patients who were initially suspected of having Epstein Barr virus infectious mononucleosis was retrospectively retested as positive for quantitative HIV-1 RNA. Some of these samples had very high levels of viral RNA but negative ELISA for HIV, representing an acute HIV infection. The authors concluded that about one percent of negative Epstein Barr virus heterophile antibody tests performed at their hospital represented acute HIV infection.

    Comment: Most emergency physicians will see a sore throat or two every shift. The degree of clinical testing and the therapeutic options are quite varied, unscientific, and open to intense debate between practical clinicians and theoretical academicians. Simply stated, it matters little what one does on the first visit for the patient with mild symptoms, although many will argue (including myself) that empiric treatment with penicillin is both rational, reasonable, and cost-effective in the very symptomatic patient that has a reasonable chance (>50%) of having a strep throat. Certainly throat cultures, CBC, and other viral tests, such as those looking for mononucleosis, have little and probably no role in the initial evaluation and treatment of most ED patients. We usually diagnose mononucleosis after the family practitioner or one of our colleagues has seen the patient a week or two previously when more classic symptoms develop. In fact, the serological confirmation of Epstein Barr virus mononucleosis is often impossible during the first few days of the illness, and a negative test on the first visit does not prove that the patient does not have some type of mononucleosis.

    Emergency physicians probably don't think about infectious mononucleosis on a daily basis, but those of us who have children in college rapidly become acutely aware of the prevalence of this syndrome, and its ability to wreak havoc during freshman finals. My interest was peaked when my own daughter developed mononucleosis during her freshman year at college, and it took a quick trip back to the textbooks to explain the vagaries of transmission, diagnosis, and therapy to my inquisitive wife. We still haven't found the fraternity stud who gave our poor, innocent daughter this terrible disease, but we are certain that she did not catch it from the toilet seat. This, however, is the most common story, and less than 10 percent of infected college students can cite previous contact with another known case of infectious mononucleosis. The prolonged carrier state in the absence of symptoms certainly makes this a difficult disease for the school health department to track. Most discouraging news is that the Epstein Barr virus can persist rarely in the oropharynx of asymptomatic patients with infectious mononucleosis for up to 18 months after clinical recovery.

    Of course, the parents of the roommate of the mono student always want to know the risk of transmission from merely sharing a dormitory room with the carrier. Fortunately, assuming no direct sharing of saliva, the roommate of a student with clinical infectious mononucleosis or a recent seroconversion will not seroconvert any more frequently than the susceptible general college population. However, up to 12 percent of susceptible college freshmen will undergo seroconversion yearly. Most cases are subclinical.

    Although CMV and other strains of the herpes virus can cause direct tissue destruction, the clinical manifestation of Epstein Barr virus mononucleosis are believed to be largely immunopathologic in origin. It is this impressive but self-limited immune response that is responsible for most of the symptomatology. The spectrum of Epstein Barr virus infection includes asymptomatic carriers, nonspecific febrile illnesses, and overt infectious mononucleosis with or without complications. Epstein Barr virus also has been associated with neoplastic transformation of some cells, such as nasophyringial carcinomas and lymphomas. The role of Epstein Barr virus in causing chronic fatigue syndrome has been a topic of controversy for some time. I find this syndrome extremely confusing, but would note that currently the CDC does not consider testing for Epstein Barr virus infections to be useful in the work-up of patients with chronic fatigue, although this is challenged by some health professionals. A chronic symptomatic low grade Epstein Barr virus infection has been suggested, but this is also essentially unproven.

    Infectious Mononucleosis in Young Children Schaller RJ, Counselman FL Am J Emerg Med 1995;13:438

    This is a brief report of a young child with acute infectious mononucleosis. It describes a typical case in a 2-year-old, and highlights the clinical presentation of this syndrome in children. The child in this case presented to the ED with asymptomatic cervical lymphadenopathy, was afebrile, and had no other associated symptoms. Large, soft, nontender posterior cervical adenopathy was the only finding, and initially the diagnosis was not suspected. In a few days the child developed fever, an exudative tonsillitis, and a leukocytosis. The monospot test was positive, and a benign clinical course ensued. The authors note that the consulting pediatrician was “surprised” that the EP would look for this disease in a 2-year-old. I was likewise surprised.

    The authors note that Epstein Barr virus can occur even during the first year of life, but the presentation in young children often differs from that of teenagers. Most often the young child has URI-like symptoms, and is often thought to have a cold, otitis media, or gastroenteritis. Importantly, atypical lymphocytes are often absent, and the heterophil antibody test is often negative in children younger than 4 years, but Epstein Barr virus serology will be conclusive.

    Comment: Most cases of infectious mononucleosis in children are subclinical, and overt infectious mononucleosis usually only comes to medical attention when it occurs in the teenage years. However, after reading this article, I wonder how many children I have seen with minor viral-sounding illnesses that actually had infectious mononucleosis. Sumaya and Ench (Pediatrics 1985;75:1003) were able to identify Epstein Barr virus infectious mononucleosis in an amazing 113 children, and most of the younger children appeared to have only a typical URI or symptoms of recurrent strep throat. About 25 percent of the children had a nonspecific rash, usually those “little red dots” that we frequently ascribe to a “viral examthum.” Those cases of exudative tonsillitis that are thought to be adenovirus because the strep tests are negative or because the child does not rapidly respond to penicillin just might be infectious mononucleosis. One clinical tip-off might be that the cervical adenopathy is invariably posterior, not only anterior, with infectious mononucleosis. The next time you prescribe ampicillin for that fabricated otitis, and the child gets clinically better but returns with little red bumps, don't be so quick to diagnose a penicillin allergy — it could be mono.

    One particular aspect of infectious mononucleosis in children should be highlighted. Because the airway in children is small and the tonsillilar swelling so prominent with infectious mononucleosis, airway occlusion is a consideration in the infant and small child with known infectious mononucleosis. Wohl and Isaacson (Ear Nose Throat J 1995;74:630) describe 11 of 36 children with infectious mononucleosis who had consultation for potential airway obstruction with infectious mononucleosis. I have not seen such a case, but the panpharyngeal and transglottic edema seen with infectious mononucleosis in children may necessitate intervention for airway compromise.

    Several authors have reported the coexistence of infectious mononucleosis and peritonsillar abscess (Ir Med J 1999;92:278). One wonders how many cases of sterile pus obtained from a peritonsillar abscess were actually infectious mononucleosis, not just the result of those presumed fastidious anaerobes that once again escaped detection by the lab.

    I am certain that many cases of infectious mononucleosis, especially in children, simply slip through the cracks. This observation may explain why so many adults have serologic evidence of infectious mononucleosis yet never have a typical history of the disease. The disease in childhood is mild, and the classic clinical findings so often seen in adolescents are lacking. In addition, laboratory tests can be misleading or even negative even when the sagacious clinician thinks about the disease. Atypical lymphocytes elude the lab tech, and heterophil antibody testing, in particular, is of little value in children under age 2.

    I am not sure what to do with this pediatric information other than to add it to the long list of diseases frequently missed, never considered, or misdiagnosed in the ED. Widespread Epstein Barr virus serologic testing is not the answer, but perhaps this investigation can be implemented when the cold just does not go away, or the adenopathy, especially the posterior cervical chain, seems a bit too swollen.

    Next month, I will tackle the rather confusing issue of the laboratory diagnosis of infectious mononucleosis and also concentrate on the clinical syndrome, complications, and potential treatments.

    Epidemiology and Transmission of Infectious Mononucleosis

    • ▪ More than 90 percent of adults worldwide show serologic evidence of Epstein Barr virus infection.
    • ▪ Most common time to develop clinical infectious mononucleosis: Freshman year in college.
    • ▪ Incubation period for infectious mononucleosis: four to eight weeks.
    • ▪ Oropharyngeal lymph tissue serves as Epstein Barr virus repository.
    • ▪ Mode of transmission: Almost entirely via orpharyngeal secretions.
    • ▪ Most common age group for symptomatic infectious mononucleosis: 15 to 25 years.
    • ▪ Clinical course: Self-limited at two to six weeks.
    • ▪ Can shed and transmit virus for up to three months.
    • ▪ Persistent virus shedding has been reported for up to 18 months.

    Source: James R. Roberts, MD, February 2001.

    Chronology of Infectious Mononucleosis

    1880s: Syndrome described, termed “glandular fever.”

    1920s: The term “infectious mononucleosis” first used and atypical lymphocytes described.

    1932: Heterophil (Paul-Bunnell) antibody discovered; relationship not appreciated.

    1950: Epstein Barr virus identified, relationship not known.

    1968: Epstein Barr virus associated with the syndrome.

    Source: James R. Roberts, MD, February 2001.

    Biologic Causes of the Infectious Mononucleosis Syndrome

    • ▪ Epstein Barr virus (about 80%)
    • ▪ Cytomegalovirus (second leading cause)
    • ▪ Human herpesvirus 6
    • ▪ HIV virus (about 1% of cases of clinically suspected infectious mononucleosis)
    • ▪ Adenovirus
    • Toxoplasma gondii
    • ▪ Corynebacterium diphtheria
    • ▪ Hepatitis A virus
    • ▪ Influenza virus A and B
    • ▪ Rubella virus
    • Coxiella burnetti

    Source: Postgrad Med 2000;107(7):175.

    Characteristics of Infectious Mononucleosis in Children

    • ▪ Mild cases of infectious mononucleosis probably not uncommon in the first four years of life.
    • ▪ May be seen in infants.
    • ▪ Presentation can be atypical, disease often not considered.
    • ▪ Rashes, unexplained adenopathy, recurrent pharyngitis, “failure to thrive,” prolonged URI symptoms are most common.
    • ▪ Atypical lymphocytes less often seen.
    • ▪ Heterophil test often negative before age 2.
    • ▪ Inflammation of airways can lead to obstruction.

    Source: James R. Roberts, MD, February 2001.

    Clinical Manifestations of Infectious Mononucleosis

    Most Common

    • ▪ Lymphadenopathy (>95%): Usually anterior and especially posterior cervical
    • ▪ Fever (>95%): May be low or high grade
    • ▪ Tonsillitis/Pharyngitis (75–85%): May be exudative, often severe and common symptoms prompt ED evaluation


    • ▪ Malaise (50%): Can last two to six weeks
    • ▪ Headache (30–50%)

    Less Common

    • ▪ Splenomegaly (almost 100% if studied by ultrasound, about 50 to 60% detected clinically)
    • ▪ Hepatomegaly (up to 30%): Elevated liver enzymes very commonly present
    • ▪ Eyelid edema (15–35%): A peculiar subtle finding, but should prompt suspicion
    • ▪ Petechia (up to 20%): Often on the palate. Thrombocytopenia may be one cause
    • ▪ Jaundice (less than 10%): Hepatitis often misdiagnosed initially
    • ▪ Rash (3–10%): Common, characteristically after treatment with ampicillin. Rash can be urticarial, petechiae, or nacular/papular
    • ▪ Abdominal pain (less than 15%): May be due to hepatosplenomegaly
    • ▪ Cough, other URI symptoms (less than 15%, and of little clinical value in diagnosing)

    Note: Young children and older adults have more atypical presentations.

    Source: James R. Roberts, MD, February 2001.

    © 2001 Lippincott Williams & Wilkins, Inc.