Mononucleosis (Mono)

Among the unique clinical properties of infections 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-Bart 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”) 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. 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.[ A wide variety of complications has been described in IM.[ 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.

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.

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. 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.

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). Men and women are affected equally, but the incidence is 12 to 30 times higher in whites than in African-Americans. 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.

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

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 gaining programs.” 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. Unfortunately, the current data suggest that although athletes may recover more quickly, they often are unable to compete at pre-illness levels for as long as 3 months.

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.

Present in 50% to 100% of patients with acute IM, 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 rapture 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.

A review of published reports of splenic rapture 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, and, thus, the risk for splenic rupture is highest in the second and third weeks of illness.[ 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,on average two- to threefold. (Recall that the normal spleen obeys the “rule of odds”: 1 × 3 × 5 in. in size, weighing 7 oz [about 200 g], and lying between ribs 9 and 11.) No correlation has been found between either the clinical severity of IM or laboratory abnormalities and risk for rupture, 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.[ 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. 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. Alarmingly, in many of these individuals the presenting feature of their IM was splenic rupture.

Last updated Jan 4/07