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Infectious Mononucleosis

Ensuring a Safe Return to Sport

John M. MacKnight, MD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 30 - NO.1 - JANUARY 2002


In Brief: Among the unique clinical properties of infectious mononucleosis are prolonged and often debilitating fatigue, a high incidence of spleen enlargement and fragility, and a resultant risk for spleen rupture. Sports medicine practitioners are charged both with the recognition and management of such clinical features as well as the safe and timely return of the athlete to participation. Safeguarding against splenic injury and attempting to minimize the duration of symptomatic illness are the major factors that guide decisions about disqualification from sport and the eventual resumption of training and competition.

Infectious mononucleosis (IM) is an acute medical condition commonly encountered in the care of active adolescents and young adults. Although IM is self-limited and rarely requires more than symptomatic management, it poses a consistent challenge for the treating physician with regard to safe return of the athlete to competitive sports. The presence of splenomegaly, the risk for spleen rupture, and the time to resolution of active illness are the primary factors governing return-to-play decisions, but a spectrum of other clinical features must also be considered to safeguard the health of the patient.

Establishing a management protocol based on current data about the natural history of IM is the key to the timely and safe return to participation.

Clinical Presentation and Testing

First described over a half century ago, IM is a self-limited lymphoproliferative illness. Classically, IM results from infection with Epstein-Barr virus (EBV), a DNA herpes virus that typically enters the body via oropharyngeal secretions (thus giving rise to Hoagland's designation as the "kissing disease" [1]) and infects B lymphocytes.

Course of illness. After an incubation period of 30 to 50 days, an intense T-cell-mediated response develops and coincides with the onset of clinical illness.

Initially, patients experience a 3- to 5-day prodrome of headache, malaise, myalgias, and anorexia that is then followed by prominent fatigue, exudative pharyngitis and tonsillar enlargement, fever, headache, and posterior cervical lymphadenopathy. Splenomegaly develops in more than 50% of patients. Other clinical features may include hepatomegaly, jaundice, periorbital edema, soft palatal petechiae, generalized adenopathy, rubella-like rash, and a 30% co-incidence of streptococcal pharyngitis. The heart, lungs, lower gastrointestinal (GI) tract, and joints are rarely involved.

After the prodromal period, acute symptoms generally last 5 to 15 days. Although it is variable, the total time to recovery is 4 to 6 weeks; rarely, a patient may experience symptoms for 12 or more weeks. The number of days from onset of symptoms to the time of diagnosis has been shown to be a statistically significant predictor of the duration of illness (2). For patients with an abrupt onset of symptoms and a rapid diagnosis, the recovery period may be quite short (10 days). Prominent GI symptoms at diagnosis may imply a prolonged convalescence; no other symptoms have been shown to have any predictive significance.

Complications. Fortunately, most IM patients have an uneventful clinical course, but serious complications have been noted in up to 5% of patients (3). A wide variety of complications has been described in IM (table 1) (2). Among the most dramatic immune-mediated complications are splenomegaly and airway obstruction. The latter can arise from hypertrophy and edema of Waldeyer's ring in the oropharynx. Further complicating IM is the latency of EBV in infected patients, thus creating the possibility, particularly for those resuming vigorous physical activity, of clinical relapse or overall prolongation of the acute illness.


TABLE 1. Complications of Infectious Mononucleosis


Dermatologic
Dermatitis
Erythema multiforme
Urticaria

Cardiac
Electrocardiographic changes
Pericarditis

Gastrointestinal
Hepatitis/splenomegaly
Malabsorption
Reye's syndrome

Hematologic
Aplastic anemia
Hemolytic anemia
Thrombocytopenia

Immunologic
Lymphoma

Neurologic
Bell's palsy
Encephalitis
Guillain-Barré syndrome
Seizures
Transverse myelitis

Ophthalmologic
Choroiditis
Conjunctivitis, keratitis, uveitis, or episcleritis
Eyelid or periorbital edema
Retinitis
Oculoglandular syndrome
Ophthalmoplegia

Psychiatric
Psychosis

Pulmonary
Adult respiratory distress syndrome
Airway edema
Interstitial pneumonitis
Pneumonia

Renal
Glomerulonephritis
Mild hematuria
Mild proteinuria
Nephrotic syndrome

Rheumatologic
Monoarticular arthritis


Laboratory evaluation and testing. Laboratory evaluation generally reveals modest leukocytosis (10,000 to 20,000/mm3) during the first week of illness, although leukopenia may be seen early in the course. The white blood cell differential shows an absolute lymphocytosis (50% or more of total white blood cell count) with many "atypical lymphocytes," so-called because of their cytoplasmic vacuolation; oval, kidney-shaped, or slightly lobulated nuclei; and highly variable size and staining characteristics. Atypical lymphocytes generally account for 10% to 20% of the total leukocyte count. Mild thrombocytopenia may be seen in 50% of patients, and fully 85% of infected individuals develop a two- to threefold elevation in hepatic transaminases by the second and third weeks of clinical illness (2-4).

Testing to confirm EBV infection can be a diagnostic challenge. The most widely employed assays are highly sensitive heterophile antibody absorption tests (eg, the Monospot test). Heterophile antibodies, however, are present in only 60% of patients by the second week of clinical illness; thus, the Monospot test should be repeated later in the clinical course if the diagnosis remains in doubt. Even with an acute EBV infection, 10% to 15% of patients will have a false-negative test (5). A further complication is that cytomegalovirus, adenovirus, and Toxoplasma gondii, among others, may cause IM-like syndromes that may be clinically indistinguishable from classic IM and may result in heterophile antibody cross-reactivity. Among these patients, 5% to 15% will also have false-positive Monospot test results (6).

A battery of antibody assays for EBV-specific antigens is available when a definitive diagnosis remains in question or to address the possibility of a false-positive Monospot test. EBV capsid antigen immunoglobulin (IgM) titer is the most accurate and useful tool for the diagnosis of acute primary infection.

Epidemiology

IM most commonly affects patients between the ages of 15 and 25, with a peak incidence 2 years earlier in females than males (age 16 vs age 18) (2). Men and women are affected equally, but the incidence is 12 to 30 times higher in whites than in African-Americans (5). Each year, clinical IM develops in 1% to 3% of college students (7-10), and the overall prevalence is 45 per 100,000 in the general population (7,8).

Transmission. Only 6% of patients relate a history of exposure to a known case (7,8), and college roommates of infected patients appear to be at no increased risk (9,10). Viral shedding in saliva is found in 90% of IM patients in the first week of illness and may persist for many months (2). In fact, 60% to 80% of normal, asymptomatic, EBV-seropositive patients have been shown to shed virus intermittently (2), but the relationship between the frequency and quantity of viral shedding and infectivity is not clear.

IM among athletes. At present, there are no data to suggest that highly trained athletes are more or less susceptible to IM. Some sports medicine physicians have, however, noted an "almost epidemic occurrence [of IM] in athletes who have been trained excessively, and [occurring] where particular coaches are known for their strenuous training programs" (11). Additional epidemiologic studies are necessary to clarify these anecdotal observations. By virtue of their baseline level of health and fitness, athletes do appear to experience a milder course of illness than the general population (12). Unfortunately, the current data suggest that although athletes may recover more quickly, they often are unable to compete at preillness levels for as long as 3 months (5).

Ascertaining Clinical Progression

Once IM has been diagnosed, the ongoing role of the physician is threefold: appropriate disqualification of the athlete from sport, vigilance for complications, and a sound plan for a safe return to play.

The most important task for the treating physician is to ascertain whether the athlete has progressed clinically to the point of having no significant participation-associated risk. Based on the natural history and behavior of IM, that risk is most closely correlated with spleen status and the likelihood of clinical decline from a relapse of symptoms.

Risk of Splenic Rupture

For athletes in general, and particularly those in contact or collision sports, the single most important complication to be considered is splenic rupture. It accounts for the greatest risk for both morbidity and mortality in IM patients (13).

Present in 50% to 100% of patients with acute IM (14), splenomegaly results from lymphocytic infiltration of the red and white pulp, with subsequent involvement of blood vessel walls and the spleen capsule. As the trabecular structure of the spleen becomes increasingly diffuse and distorted, the spleen becomes fragile and may rupture even without trauma. This fragility seems to exist both early and late in the course of spleen involvement, even at times when the patient's overall spleen size may not be sufficient to be clinically apparent (3).

A review (15) of published reports of splenic rupture in IM indicates that the spleen was not palpable on initial evaluation in more than half the cases. Capsular and trabecular changes are seen most prominently during days 4 to 21 of clinical illness (16,17), and, thus, the risk for splenic rupture is highest in the second and third weeks of illness (18). For athletes, it is this clinical feature that mandates an absolute minimum disqualification period of 21 days.

Pathologic studies of spleen rupture indicate that all spleens that rupture are enlarged (16,17), on average two- to threefold. (Recall that the normal spleen obeys the "rule of odds": 1 X 3 X 5 in. in size, weighing 7 oz [about 200 g], and lying between ribs 9 and 11 (19).) No correlation has been found between either the clinical severity of IM or laboratory abnormalities and risk for rupture (20), so every IM patient must be considered at risk, and care providers must be vigilant for evidence of spleen activity.

Warning signs and rupture prevalence. Splenic rupture is heralded by the onset of left upper-quadrant pain that may radiate to the top of the left shoulder (Kehr's sign), is increased with deep inspiration, and may be followed by signs and symptoms of shock and hypovolemia. Fortunately, IM-associated splenic rupture has been relatively rare; in the English language medical literature, only 64 cases were reported from 1941 to 1981 (21). American College Health Association data from 1976 reported only 22 cases of traumatic spleen rupture in athletes from more than 50 responding collegiate institutions over an average of 13.5 practice-years (22). More recent data have shown that despite our best efforts to accurately diagnose and disqualify affected individuals, approximately 80% of IM-associated traumatic splenic injuries still occur in young men participating in contact sports (21,23). Alarmingly, in many of these individuals the presenting feature of their IM was splenic rupture.

Evaluation methods. Although relied upon heavily for decision-making about return to athletic participation, the clinical evaluation of the spleen is difficult at best, with a great deal of inter- and intra-examiner variability. This is further confounded by the fact that 3% of healthy college students have palpable spleens (24).

The limitations of the physical exam are well demonstrated by the ultrasound study of Dommerby et al (14) of 29 patients with known IM. All of the patients had enlarged spleens by ultrasound (mean enlargement, 50% to 60%); however, splenomegaly was appreciated by physical exam in only 17%! Consequently, many athletes who appear to have normal spleens in clinical exams do indeed have hyperplastic spleens, which can subsequently be injured.

Although authorities differ on whether a formal imaging study is required before allowing an athlete to return to play, it is clear that ultrasonography has become the standard means for efficiently and accurately assessing spleen size. When a question about the status of an athlete's spleen exists, especially in light of the alarming data about injury, the treating physician should not hesitate to use ultrasonography to ensure that spleen size is normal. For concerns about acute splenic trauma with resultant hemorrhage in these patients, abdominal computed tomography (CT) is the test of choice and should be performed as soon as possible.

Dommerby et al (14) also assessed many laboratory parameters in conjunction with spleen activity and found no correlation between the size or changes in the size of the liver and spleen when compared with absolute changes in blood enzyme values such as lactate dehydrogenase (LDH) and hepatic transaminases (asparagine transaminase [AST], and alanine transaminase). LDH and AST were, however, elevated during the same times as spleen and liver enlargement and followed parallel curves to resolution at about 28 days. Thus, determinations of LDH and AST may be useful, at a minimum, in noninvasively determining the continued presence of IM-associated spleen and liver involvement.

Role for corticosteroids? Much has been made of the potential role for corticosteroid therapy for significant splenomegaly. Although corticosteroids reduce fever and rapidly resolve pharyngeal inflammation in acute IM, no definitive data exist to show that corticosteroids reduce splenomegaly or the risk of rupture (2). Therefore, the routine use of corticosteroids in uncomplicated IM is not recommended.

Clinical Relapse

The other major factor that must be considered when contemplating return to play is whether the athlete's viral syndrome has resolved sufficiently to prevent immediate relapse of the symptomatic aspects of the illness. Although EBV can become latent in humans, current data do not support the notion that patients truly have a "chronic" EBV infection (19). Rather, the fear is that too rapid a resumption of vigorous physical activity may exacerbate the patient's delicate immunologic status and lead to a "relapse" of symptoms such as disabling fatigue, lymphadenopathy, and splenomegaly.

In general, resolution of clinical illness corresponds with the production of antibodies. Relapse of symptoms may then stem from inadequate EBV IgG production and the failure to produce a "protective" antibody response. Subsequent illness, the physical stresses of vigorous training, suboptimal nutrition, or sleep deprivation may create an environment favorable to a return of significant EBV-mediated symptoms. Clinically identifiable "recurrence" or "reactivation" of latent EBV after prior resolution is rare, even in immunocompromised patients. Although there are no infallible means to prevent such relapses, strict adherence to an absolute period of disqualification (see below) is an essential part of appropriate athlete management.

Clearance for Resumption of Activity

The recommendations for returning the athlete recovering from IM to participation have changed dramatically since the risk of athletic participation was discovered. What was once a 6-month period of disqualification from sport (15) has evolved to restricting participation for only a few weeks.

Return-to-play criteria (table 2) are now based on our understanding of IM, consideration for risk of splenic rupture, and the negative effect that premature resumption of play may have on the patient's overall clinical status (5,22). Because the clinical course of IM is quite variable, these criteria may need to be tailored to the individual patient, but the minimum 21-day disqualification period from sport and training activities should always be applied.


TABLE 2. Return-to-Play Criteria for Athletes Who Have Infectious Mononucleosis


Completion of 21-day minimum disqualification period from onset of clinical illness (or diagnosis)

No subjective complaints; fatigue largely resolved and athlete motivated to return to athletics

Improvement of strength (it may take several months to return to premononucleosis levels)

Pharyngitis and lymphadenopathy resolved

Afebrile state

Laboratory studies normal (CBC, AST, ALT, LDH, sedimentation rate, bilirubin <3 mg/dL, urinalysis)

Liver enzymes have peaked and returned to baseline levels

No splenomegaly by physical examination or ultrasound

No hepatomegaly by physical examination

Any or all complications completely resolved


CBC = complete blood count; AST = asparagine aminotransferase; ALT = alanine aminotransferase; LDH = lactate dehydrogenase


Disqualification time is measured from the onset of clinical illness. If a discrete onset date of illness cannot be established (which may be difficult due to baseline fatigue from training), the athlete is absolutely disqualified for 3 weeks from the time of diagnosis. Taken together, these criteria provide a basic framework to ensure a minimum standard for the resumption of activity without undue risk (see "Validation of IM Return-to-Play Guidelines," below).

After the 3-week disqualification period, the athlete may begin a graded return to low impact and noncontact training (maximum of 50% intensity and duration of usual training level) for the following week if there is: (1) subjective improvement in the level of fatigue (regularly performing academic responsibilities, near-normal number of overnight sleep hours, rare or no daytime naps); (2) absence of spontaneous abdominal pain or palpable abdominal tenderness; (3) absence of splenomegaly; and (4) resolution of any previously noted hematologic or hepatic laboratory abnormalities. At 4 weeks, if athletes continue to improve in overall status without any of these four complicating features, they are cleared for full return to participation, even for contact sports.

The Current View

The cornerstones of safely returning an athlete to participation are determining with reasonable clinical certainty the point at which an athlete has no evidence of active spleen involvement and has clinical resolution of generalized viral syndrome. Other care centers choose to establish their confidence in these findings differently. It is crucial that each clinician develop a set of standards based on current data and apply it methodically and consistently, particularly in sports with a high likelihood of contact and collision. A high level of suspicion in making the diagnosis of IM and a strict practice of vigilance of the recovering IM patient, using the criteria presented, should ensure a safe and productive return to athletic participation.

References

  1. Hoagland RJ: Infectious Mononucleosis. New York City, Grune & Stratton, 1967
  2. Chetham MM, Roberts KB: Infectious mononucleosis in adolescents. Pediatr Ann 1991;20(4):206-213
  3. Murray BJ: Medical complications of infectious mononucleosis. Am Fam Physician 1984;30(5):195-199
  4. Gelb D, West M, Zimmerman HJ: Serum enzymes in disease. IX: analysis of factors responsible for elevated values in infectious mononucleosis. Am J Med 1962;33:249-261
  5. Sevier TL: Infectious disease in athletes. Med Clin North Am 1994;78(2):389-412
  6. Bailey RE: Diagnosis and treatment of infectious mononucleosis. Am Fam Physician 1994;49(4):879-888
  7. Heath CW Jr, Brodsky AL, Potolsky AI: Infectious mononucleosis in a general population. Am J Epidemiol 1972;95(1):46-52
  8. Brodsky AL, Heath CW Jr: Infectious mononucleosis: epidemiologic patterns at United States colleges and universities. Am J Epidemiol 1972;96(2):87-93
  9. Sawyer RN, Evans AS, Niederman JC, et al: Prospective studies of a group of Yale University freshmen. I: occurrence of infectious mononucleosis. J Infect Dis 1971;123(3):263-270
  10. Hallee TJ, Evans AS, Niederman JC, et al: Infectious mononucleosis at the United States Military Academy: a prospective study of a single class over four years. Yale J Biol Med 1974;47(3):182-195
  11. Sheehan GA: Infectious mononucleosis in athletes, letter. JAMA 1972;220(6):864
  12. Dalrymple W: Infectious mononucleosis and athletic participation. J Am Coll Health Assoc 1966;14(4):257-259
  13. Asgari MM, Begos DG: Spontaneous splenic rupture in infectious mononucleosis: a review. Yale J Biol Med 1997;70(2):175-182
  14. Dommerby H, Stangerup SE, Stangerup M, et al: Hepatosplenomegaly in infectious mononucleosis, assessed by ultrasonic scanning. J Laryngol Otol 1986;100(5):573-579
  15. Rutkow IM: Rupture of the spleen in infectious mononucleosis: a critical review. Arch Surg 1978;113(6):718-720
  16. York WH: Spontaneous rupture of the spleen: report of a case secondary to infectious mononucleosis. JAMA 1962;179(2):170-171
  17. Srivastava KP, Quinlan EC, Casey TV: Spontaneous rupture of the spleen secondary to infectious mononucleosis. Int Surg 1972:57(2):171-173
  18. Chin TD: Diagnosis of infectious mononucleosis. South Med J 1976;69(5):654-658
  19. Farley DR, Zietlow SP, Bannon MP, et al: Spontaneous rupture of the spleen due to infectious mononucleosis. Mayo Clin Proc 1992;67(9):846-853
  20. Maki DG, Reich RM: Infectious mononucleosis in the athlete: diagnosis, complications, and management. Am J Sports Med 1982;10(3):162-173
  21. Lovaas M: Ruptured spleen in a boxer with infectious mononucleosis. Minn Med 1981;64(8):461-462
  22. Frelinger DP: The ruptured spleen in college athletes: a preliminary report. J Am Coll Health Assoc 1978;26(4):217
  23. Peters RM, Gordon LA: Nonsurgical treatment of splenic hemorrhage in an adult with infectious mononucleosis: case report and review. Am J Med 1986;80(1):123-125
  24. McIntyre OR, Ebaugh FG Jr: Palpable spleens in college freshmen. Ann Intern Med 1967;66(2):301-306


Validation of IM Return-to-Play Guidelines

In our recent experience at the University of Virginia, 45 athletes were diagnosed with infectious mononucleosis (IM) during the 1999-2000 academic year. Each of these athletes either tested positive for IM (heterophile antibody test) or were clinically diagnosed based on a constellation of prolonged fatigue, pharyngitis, atypical lymphocytosis, and, most prominent, left upper-quadrant tenderness and/or frank splenomegaly. We used the management algorithm described in the accompanying text, and all the athletes were able to resume athletic participation safely, most at 4 weeks. No athlete experienced any splenic complication. Three athletes experienced clinical "relapses" up to 6 months after returning to full participation. We did not have an absolute disqualification time for these relapses, choosing rather to return the athlete to participation when the clinical criteria were again satisfied. Each of these athletes subsequently did well.


Dr MacKnight is an assistant professor of clinical internal medicine and orthopedic surgery and primary care team physician at the University of Virginia in Charlottesville. Address correspondence to John M. MacKnight, MD, University of Virginia Health System, University Physicians Clinic, Jefferson Park Ave at Lee St, Box 800-671, Charlottesville, VA 22908; e-mail to [email protected].


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