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Infectious Mononucleosis: Recognizing the Condition, 'Reactivating' the Patient

E. Randy Eichner, MD


In Brief: A two-step infection by the Epstein-Barr virus accounts for the characteristic features of infectious mononucleosis (IM). New serologic tests for viral antigens exist, but a rapid kit test for heterophil antibody usually suffices to confirm the diagnosis. General management is supportive only. Splenic rupture is very rare, almost never fatal if diagnosed early, and, in most cases, is probably best treated by splenectomy. Athletes tend to recover from IM faster than nonathletes. When the spleen returns to normal size, the athlete can return to contact sports, though it may take 3 to 6 months for an elite athlete to regain top form.

Infectious mononucleosis (IM) can pose headaches for physicians who treat young athletes and other physically active young people. The condition, whose prevalence peaks in about the same age range as athletic activity, is sometimes difficult to diagnose. Further, the risk of splenic rupture may complicate decisions about when athletes may safely return to play, especially in view of the lack of consensus on that issue.

Two-Stage Pathogenesis

IM is caused by the Epstein-Barr virus (EBV). EBV is a herpesvirus that, like other herpesviruses (herpes simplex, varicella-zoster, cytomegalovirus), imparts a two-step pathogenesis. First, EBV infects epithelial cells and propagates, causing cytolysis and shedding progeny. The progeny then invade a secondary cell type, where they remain latent and so establish a persistent infection.

Specifically, EBV infects oropharyngeal epithelial cells, causing pharyngitis and releasing infectious viruses that invade B lymphocytes in the area. In vitro EBV immortalizes B lymphocytes it infects: The white cells multiply indefinitely. In a related action that produces characteristic clinical and laboratory features of IM, in vivo EBV triggers many clones of B lymphocytes to proliferate wildly (1,2).

Mature EBV is rarely replicated by B lymphocytes. Indeed, if mature virus is made, the lymphocyte dies. Infected lymphocytes, however, do express virally encoded EBV nuclear antigens and latent membrane proteins that become targets for the host's primary immune response to IM.

The primary immune response comprises natural killer cells and CD4+ suppressor T lymphocytes that attack the above targets. Later on, a secondary immune response consists of HLA-restricted CD8+ cytotoxic T lymphocytes specific for EBV. This secondary response, which normally persists for life, controls the EBV-induced proliferation of infected B cells.

Disease of the Young

The earlier in life EBV infection occurs, the milder the illness. In the United States, full-blown IM, the triad of clinical features (fever, malaise, pharyngitis, and lymphadenopathy), laboratory features (lymphocytosis with atypical lymphocytes), and serologic features (heterophil antibodies), is seen mainly in adolescents (1,3).

Viral transmission is thought to be mainly salivary exchange in one way or another. In adolescents, this is thought to be by intimate kissing, although, in theory, sharing toothbrushes or cups could transmit virus. In practice, however, IM travels between lovers, not between classmates, roommates, or teammates: Quarantine is unwarranted. Viral shedding in saliva occurs in 90% of IM patients in the first week of full-blown illness and intermittently for many months thereafter; individuals remain contagious during this period.

The incubation period is 30 to 50 days, making it difficult to pinpoint contacts. Peak incidence by age is 2 years earlier in females (age 16) than in males (age 18). The attack rate in college is as high as 3% per year. IM is rare after age 40 (1,3,4).

Clinical and Laboratory Features

Classically, a 3- to 5-day prodrome (malaise, fatigue, headache, anorexia, and myalgia) leads into a 1- to 2-week syndrome of moderate to high fever (often with sweats and even chills), sore throat (often with incapacitating exudative tonsillopharyngitis), and tender, symmetrical lymphadenopathy (classically posterior cervical but often also anterior cervical or generalized). Splenomegaly is palpable by week 2 of illness in 50% to 75% of cases. Hepatomegaly is less common; jaundice is seen in up to 10% of patients. Petechiae on the posterior palate are suggestive but not pathognomonic. Swollen eyelids are common. About 10% of patients develop a rubellalike or maculopapular rash (90% if ampicillin is given).

Clinically evident involvement of the lungs, lower gastrointestinal tract, or joints is rare. Thus, IM rarely accounts for prominent cough, generalized abdominal pain, diarrhea, or arthritis (1).

Two potential complications especially relevant to sports medicine are upper airway obstruction (from pharyngeal edema and swollen tonsils) and splenic rupture. These will be considered below. Other complications, all uncommon or rare, are listed in table 1.

Table 1. Uncommon or Rare Complications of Infectious Mononucleosis

Interstitial pneumonitis

Autoimmune hemolytic anemia
Immune granulocytopenia or thrombocytopenia

Cholestatic jaundice (severe hepatitis)
Massive hepatic necrosis and failure

Cranial nerve palsies
Guillain-Barré syndrome
Transverse myelitis

The complete blood count in an IM patient typically reveals (1) modest leukocytosis (white blood cell count 10,000 to 20,000 per mm3); (2) absolute lymphocytosis (more than 4,500 lymphocytes per mm3 and more than 50% lymphocytes in the differential); and (3) atypical lymphocytosis (atypical lymphocytes more than 10% of total leukocytes or more than 1,000 per mm3).

A few (less than 5%) of these atypical lymphocytes (or Downey cells) are EBV-transformed B lymphocytes; most (more than 95%) are "counterattacking" T lymphocytes (5).

Mild and transient neutropenia and thrombocytopenia are common, but severe cytopenias are rare. A recent report (6) of five college-aged patients details the course and therapy of severe immune thrombocytopenia in IM. Clinically important immune hemolytic anemia is also rare in IM.

Chemical evidence of mild hepatitis is seen in up to 90% of patients. Serum aminotransferases (transaminases), alkaline phosphatase, and lactate dehydrogenase can double or triple (peaking in weeks 2 to 3 of illness), but serum bilirubin is generally only mildly elevated. Severe hepatitis is rare.

Serologic Confirmation

The diagnosis of IM is suggested by the characteristic clinical and laboratory features and confirmed by serologic testing. The most practical serologic test—that used most widely in office and clinical laboratories—is a rapid slide or card test for IM-related immunoglobulin-M (IgM) heterophil antibody (HA), so named because it reacts with red cells (and other tissues) from other species.

These tests (commercial kits) are based on visually gauging the agglutination (or not) of latex particles coated with antigens from foreign (equine or bovine) red cells after differential absorption of the patient's serum. They are miniature, convenient, speedy versions of the classic absorbed-HA test of Paul, Bunnell, and Davidsohn.

In a study of six different brands, all kits performed well, with general agreement among them, few false-negatives (in comparison with the classic test), and generally low false-positive rates (0% to 4% among five kits). The one kit with a high false-positive rate (19%) gave the most reactions classified as weak; if these were read as negative, the false-positive rate would be low (7).

In general use, however, these kits have limitations. Interobserver variation occurs in interpretation. HA is apparently not produced in up to 15% of adults with IM (leading to false-negative tests) and in an even higher percentage of children. Also, infections that could be confused with IM (cytomegalovirus, adenovirus, hepatitis A, toxoplasmosis) can sometimes produce HA and false-positive tests.

Consequently, other serologic tests exist. Tests that identify IgM specific for EBV capsid antigen can confirm acute EBV infection, but are done in referral laboratories. A rapid, enzyme-linked immunosorbent assay (ELISA) that detects antibodies to EBV nuclear antigen has been marketed to diagnose HA-negative IM. Even the ELISA test, however, like the above kit tests, is neither 100% sensitive nor 100% specific (8,9).

What to do? If, early in suspected IM, a kit test for HA is negative, repeat it in 1 week. If the repeat test is also negative, yet the clinical and laboratory features still suggest IM, the physician can stand on clinical acumen or can refer serum to test for IgM to EBV capsid antigen and/or IgM to cytomegalovirus or other viruses that may mimic IM.

Look-Alike Illnesses

In adolescents and young adults, the illness that best mimics IM is cytomegalovirus infection. In my experience, the latter tends to be characterized by milder pharyngitis and more severe hepatitis. Probably, many cases of "HA-negative IM" in young athletes are cytomegalovirus infection.

Severe pharyngitis from group A, beta-hemolytic streptococci (GABHS) can mimic some features of IM. GABHS pharyngitis is confirmed by rapid antigen detection and throat culture. IM and GABHS can occur simultaneously: 5% to 30% of IM patients have GABHS on throat culture. The GABHS may not always be pathogenic, but it seems prudent to prescribe penicillin (not ampicillin) or erythromycin when GABHS is cultured.

Less convincing look-alikes listed in the differential diagnosis of IM are mycoplasma, adenovirus, or human immunodeficiency virus infection; and rubella, toxoplasmosis, typhoid fever, and diphtheria. Arcanobacterium (Corynebacterium) haemolyticum can also cause exudative pharyngitis and rash in adolescents (3).

Although fatigue is a prominent feature of IM, there is no credible evidence that EBV infection or "chronic IM" plays any role in chronic fatigue syndrome; testing EBV serology is no longer recommended in the work-up of the chronically fatigued patient (10).

Are Athletes Special?

There is no reason to believe that athletes or active people are either more or less vulnerable to IM than are their nonathletic peers. As reviewed before (1), however, the degree of clinical illness and the rate of recovery correlate with personality, and one study (11) of IM suggests that athletes recover faster than other students. Some cases of IM in athletes are so mild (or some athletes so stoic) that loss of athletic stamina is apparently the paramount feature (12).

General Management

No specific therapy exists for IM, but general support helps: rest and fluids; acetaminophen or aspirin for fever and aches; lozenges, salt-water gargles, or viscous lidocaine hydrochloride for sore throat.

Most patients feel much better by the end of the first week; there is no need for strict or prolonged bed rest, which only ensures deconditioning and slow recovery. Convalescence is gradual; fatigue may wax and wane. Afternoon naps help. Most patients are well in 4 to 6 weeks, but the elite athlete may not regain top form for 3 to 6 months.

Antibiotics and corticosteroids are indicated only for complications. Table 2 lists possible indications for corticosteroid therapy; most of these are based on anecdotal reports, not controlled studies.

Table 2. Possible Indications for Corticosteroids in Infectious Mononucleosis*

Impending upper-airway obstruction (best accepted indication)
Immune cytopenias
Neurologic complications
Severe hepatitis
Extreme fever, pharyngitis, malaise (most controversial indication)
*Most of these possible indications are based on anecdotal reports rather than controlled studies.

The putative value of corticosteroids in uncomplicated IM to shorten the duration of fever and disability was not borne out by the only well-controlled study (1). Prescribing corticosteroids to improve liver chemistries may be a "biochemical whitewash" that may not speed—and may even slow—the healing of hepatitis (3).

Upper-airway obstruction. The best case for using corticosteroids is impending airway obstruction from tonsillopharyngitis. Corticosteroids can sharply reduce edema and hyperplasia of the tonsils, relieving obstruction and respiratory distress. Surgical intervention (tonsillectomy or tracheostomy) may be averted by timely corticosteroid therapy. Occasionally, however, despite corticosteroid therapy, emergency tonsillectomy is necessary because of continued respiratory distress or uncontrolled bleeding from the tonsils (13,14).

Splenic rupture. The rate of splenic rupture in IM patients is said to be about 1 in 1,000: In a recent 40-year Mayo Clinic review of 8,116 patients, 9 suffered a proved or likely splenic rupture (15). Yet considering how common IM is and how seldom this complication is reported, either most cases go unreported or the incidence is well under 1 in 1,000. Splenic rupture can also occur in cytomegalovirus infection, hepatitis A, and other viral infections (16).

Splenic rupture on the athletic field is rarer yet and fortunately is rarely fatal nowadays. Most cases occur during everyday activities, most of which may involve Valsalva maneuvers: lifting, walking, coughing, vomiting, defecating, or getting into or out of bed. The rare fatalities result from late diagnosis (17).

Splenic rupture usually occurs between weeks 2 and 4 of illness, when the splenic capsule is heavily infiltrated with lymphocytes, but it can occur as early as 3 days or as late as 2 months. Telltale features are abdominal pain (otherwise rare in IM); a palpable, tender left-upper-quadrant mass; and sometimes pain referred to the left shoulder (Kehr's sign).

Diagnosis is best confirmed by computed tomography or ultrasonography. For an unstable patient, however, peritoneal lavage can confirm bleeding, or the patient can go straight to emergency splenectomy (15).

Management of splenic rupture is still debated. The case is made for conservative therapy (support and scrutiny) of selected hemodynamically stable patients (18,19), but most reviewers still favor splenectomy in most cases (15,17,20,21).

Return to Play

The timing of a patient's return to participation can be the most difficult decision the team physician faces. Controversy abounds; patients must be considered individually; and few physicians (or review authors) have had enough personal experience with the rare complication of splenic rupture to be considered authorities (18). Recent recommendations for return to contact sports range from 3 weeks (21) to 3 months (17).

Most reviewers agree that it is reasonable to exclude vigorous sports until the spleen has returned to normal size and location (remember the "rule of odds": the normal spleen is about 1 x 3 x 5 in. in size, weighs about 7 oz, and lies under ribs 9 to 11). In many cases, probably the clinical examination can suffice to determine whether the spleen has receded and is again protected by the rib cage.

Football players, however, tend to be large, and physicians today tend to be uncomfortable deciding spleen size on clinical examination alone. So ultrasonography is often used—and often recommended (17,21,22)—to decide whether the spleen is again normal.

To help make judgments about return to play, the duration of the major features of IM (figure 1: not shown) has been reviewed (1), and a timetable of criteria for return to activity has been offered (22). A practical guide is this: If the athlete feels well—and liver chemistries are normal—he or she can resume easy training (jogging, swimming, or cycling) 3 to 4 weeks after the onset of illness. If the training goes well and the spleen returns to normal size, the athlete can resume contact sports (perhaps wearing a flak jacket at first) in 5 to 6 weeks from onset of illness.

Avoid the Rush

Splenic rupture, the most feared complication of IM in the sports context, is rare and is more likely to happen off the athletic field than on it. Nonetheless, athletic patients should not be allowed to rush back into participation. Their return should be gradual, and they should avoid contact sports until it is clear that splenomegaly has resolved.


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Dr Eichner is a professor of medicine in the Hematology/Oncology Section of the Department of Medicine at the University of Oklahoma Health Sciences Center, Oklahoma City. He is an editorial board member of The Physician and Sportsmedicine and a fellow of the American College of Sports Medicine. Address correspondence to E. Randy Eichner, MD, Hematology/Oncology Section, Dept of Medicine, University of Oklahoma Health Sciences Center, Box 26901, Oklahoma City, OK 73190.