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[Case Report]

Presumed Infectious Mononucleosis in a College Basketball Player

Rosemary A. Greenslade, MD, MS

THE PHYSICIAN AND SPORTSMEDICINE - VOL 28 - NO. 6 - JUNE 2021


In Brief: A 20-year-old college basketball player was diagnosed as having acute infectious mononucleosis and was withheld from championship competition. Subsequent clinical, laboratory, and serologic evaluation revealed that he, in fact, had a latent infection with Epstein-Barr virus (EBV), a current viral syndrome, and a false-positive Monospot test. This case demonstrates the need to consider obtaining specific serologic titers for EBV to confirm a diagnosis of infectious mononucleosis and establish eligibility for return to play.

Infectious mononucleosis (IM) is caused by the Epstein-Barr virus (EBV) and most commonly affects young adults ages 15 to 35. The infection rate among previously unexposed college students is about 15% (1,2). Numerous case reports of associated complications including spontaneous or posttraumatic splenic rupture (3) have led to the development of the general guidelines that patients avoid strenuous physical for approximately 3 to 4 weeks after the onset of illness and avoid contact sports until there is no physical or radiographic evidence of splenomegaly.

Though several other diseases produce heterophile antibody and can cause a false-positive Monospot agglutination test (1-6), no previous case reports of this patient's scenario—a false-positive test associated with a latent infection with Epstein-Barr virus (EBV) and a current viral syndrome—could be found in a thorough review of the literature.

This case, presumed to be IM, demonstrates the misconceptions about the serology of the disease that may interfere with or prevent prompt diagnosis and confuse the team physician making return-to-play decisions.

Case Report

History. A 20-year-old, otherwise healthy male Division III basketball player developed flulike symptoms 6 days before the start of a holiday tournament. He was the team's leading scorer, usually contributing 25 to 30 points per game. The team had great hopes of winning the tournament and advancing to conference play.

The patient experienced a sore throat, low-grade fever, swollen glands, and malaise but denied having cough, rhinorrhea, vomiting, or diarrhea. He missed team practices for the first 3 days of his illness, then sought treatment at an urgent care center because his symptoms had not improved. A Monospot heterophile antibody screening test (Meridian Diagnostics, Inc, Cincinnati, approximately $25) was positive, and the patient was told he had acute IM. He was withheld from play by the team's trainer.

The patient verbally reported that he had had IM about 2 years earlier. He said that his Monospot test then was negative, no other tests were done, and he had had the usual symptoms of IM, including fever, pharyngitis, lymphadenopathy, and splenomegaly and was held from contact sports for 1 month. The extent of his splenomegaly was not known.

The morning before the start of the tournament he was feeling much better with no fever or other symptoms. He sought the advice of a friend's father, a surgeon, who ordered several laboratory studies but did not do a physical exam. The patient wished to play in the tournament and, as the team physician, I was called that evening to make the return-to-play decision. Because I was unable to examine him that night and did not have access to the lab results, I withheld him from tournament play based on his symptoms and positive Monospot test. He was instructed to follow up in the training room after the tournament.

Physical exam. He arrived in the training room, not appearing acutely ill, with his somewhat disgruntled coach. Apparently, the patient remained asymptomatic over the weekend and was feeling fully recovered. On examination, he was afebrile, his oropharynx was slightly erythematous with no exudates, and his tonsils were not enlarged. Palpation revealed one enlarged anterior lymph node adjacent to a furuncle on the left side of his neck and no posterior cervical adenopathy. His lungs were clear to auscultation, and he had no rhinorrhea, splenomegaly, or other adenopathy.

His coach was anxious to know if the patient could play in the next game. Though his quick recovery, lack of symptoms and physical findings, and medical history suggested that he did not have IM, he was withheld until the results of the laboratory studies (ordered by the friend's father) were back, which included EBV serology (approximately $270). Because there was no definitive diagnosis and the patient had a potentially life-threatening risk of splenic rupture with acute IM, it was felt that playing posed too great a risk.

An ultrasound to assess spleen size was not obtained because the general guidelines recommend limited physical activity for at least 1 month.

Laboratory studies. Laboratory results received the following day showed a normal complete blood count with no atypical lymphocytosis and normal liver function tests. Immunologic studies showed a positive heterophile screen but an EBV-viral capsid antigen (VCA-Ag) immunoglobulin M (IgM) of less than 1:10, indicating no current infection with EBV. The EBV-VCA Ag immunoglobulin G (IgG) titer was greater than 1:80, and the EBV nuclear antigen (EBNA) titer was greater than 1:10, both indicating previous infection and current immunity (table 1).


TABLE 1. Significant Laboratory Results* in a Basketball Player With Suspected Infectious Mononucleosis
Parameter Value Normal Value

EBV-VCA Ag, IgG > 1:80 < 1:80

EBV-antigen-EBNA > 1:10 < 1:10

EBV-VCA Ag, IgM < 1:10 < 1:10

Heterophile screen positive

*All other lab values were within normal limits (Bilirubin [direct and total], AST [SGOT], alkaline phosphatase, ALT [SGPT], albumin, hematocrit, hemoglobin, platelet count, red blood cells, mean corpuscular volume, red blood cell distribution width, white blood cell, lymphocytes, eosinophils, basophils, polymorphonuclear leukocytes, monocytes).

EBV = Epstein-Barr virus; VCA = viral capsid antigen; Ag = antigen; Ig = immunoglobulin; EBNA = Epstein-Barr nuclear antigen


No other serologic studies were ordered.

Diagnosis. An acute viral infection was most likely.

Treatment and follow-up. Because the patient did not have acute IM and was no longer ill, he needed no treatment or follow-up. He was cleared for practice, though the team's hopes of qualifying for the regionals and sectionals were crushed.

Clinical and Lab Features of Mono

The clinical presentation of IM has been described as a classic triad of fever, pharyngitis, and lymphadenopathy accompanied by an enlarged spleen or liver. The disease rarely produces a prominent cough, abdominal pain, diarrhea, arthralgia, rhinorrhea, or chest pain. These symptoms should alert the clinician to consider an alternative diagnosis (1-3).

Laboratory studies typically reveal modest leukocytosis, absolute lymphocytosis (greater than 50%), and atypical lymphocytosis (greater than 10% of total leukocytes). Mild and transient neutropenia and thrombocytopenia are common, as is mild hepatitis with double or triple the normal levels of serum aminotransferases, alkaline phosphatase, and lactate dehydrogenase. Serum bilirubin is generally only mildly elevated. Because these studies were all normal in this patient, his initial diagnosis was questioned.

Several infections have a clinical presentation similar to IM, including group A ß-hemolytic streptococci and corynebacteria, both of which cause exudative pharyngitis and rash. Cytomegalovirus infection, the illness that most closely mimics IM, can produce splenomegaly, hepatomegaly, and atypical lymphocytosis. Other viruses (adenovirus, rubella, rubeola, hepatitis A and B, and HIV) and toxoplasmosis can also be included in the differential diagnosis (1-3,6,7). This patient most likely had a viral infection.

Serology Issues

EBV is a ubiquitous herpes virus that invades oropharyngeal epithelial cells and B lymphocytes. Infected lymphocytes secrete immunoglobulins including nonspecific, transient heterophile antibodies and specific, virally encoded EBV antigens (IgM, IgG, and EBNA).

The appearance of an antibody correlates with the phase of viral replication during which the antigens are elaborated. IgM antibody to VCA appears with the onset of symptoms and disappears within 1 to 3 months. IgG to VCA rises at or shortly after the onset of symptoms, peaks at 2 to 3 months, then slowly declines until a steady state concentration is reached that persists for life and serves as a marker for immunity. During latency, EBV-infected host cells express an EBNA. Antibodies to the EBNA appear during convalescence and persist for life (figure 1: not shown).

The absence of detectable EBNA antibodies and the presence of the IgM antibody to VCA is consistent with acute primary infection. It is prudent to simultaneously obtain an IgG antibody to VCA because false-positive IgM measurements can occur if rheumatoid factor is present (3,4). With past infection, there is no detectable IgM, whereas IgG and EBNA titers are present, as in this patient.

Heterophile antibodies react with antigens from unrelated species and are not specifically targeted against EBV. These antibodies belong to the IgM class and are transient, appearing in 60% to 70% of patients in the first week of clinical illness and 80% to 90% by the third to fourth week. In most patients they disappear within 3 months of symptom onset, but, on rare occasions, they can persist for up to 12 months (3). Failure to produce heterophile antibody (false-negative rapid agglutination kit test) occurs in 10% to 20% of adult patients (1,4), which may explain why this patient had a false-negative Monospot result for the probable primary EBV infection 2 years earlier. This false-negative rate is even higher in children (4).

Other infections such as cytomegalovirus, adenovirus, parvovirus, toxoplasmosis, leptospirosis, hepatitis A, mumps, malaria, and rubella can also produce heterophile cross-reactive antibodies (1-5), contributing to a false-positive rapid agglutination kit test rate of 5% to 15% (1). One study (8) of six commercially available qualitative heterophile agglutination tests demonstrated that five had a low false-positive rate of 0% to 4%. The sixth test, with a false-positive rate of 19%, reported the most reactions that were classified as weak.

These tests are prone to interpretation bias, and quality control during testing is difficult. Frequently, weakly positive results are interpreted as positive (9). Heterophile antibody titer can also rise in response to common viral infections in a patient who has had mononucleosis within the last 2 years (4), as was probably the case in this patient.

For these reasons, other techniques (immunofluorescence, enzyme-linked immunosorbent assay, Western blot) that measure EBV-specific antibodies can be helpful, especially if the kit test result is questioned. Though more expensive and more time-consuming, such confirmatory testing can definitively establish a diagnosis of IM, determine the phase of EBV infection, and aid the team physician in return-to-play decisions, as in the case of this basketball player.

In retrospect, it would have been helpful but costly to have included serologic studies for cytomegalovirus, hepatitis A, and possibly toxoplasmosis and leptospirosis. Though unlikely in a college student, mumps and rubella titers could also have been ordered.

Return-to-Play Issues

Returning a player with IM to sport is controversial, and cases must often be considered individually. Most clinicians agree that it is reasonable to exclude vigorous sports until the spleen has returned to normal size and location under the rib cage. Physicians today tend to be uncomfortable judging spleen size on physical exam alone and often use ultrasonography.

Rupture occurs in 1 to 2 of every 1,000 cases, most frequently between days 4 and 21 of acute illness. It may occur spontaneously. Some clinicians limit activity for more than 1 month until there is no evidence of splenomegaly on physical and radiologic examination (1-3). Splenic rupture can also occur in cytomegalovirus infection, hepatitis A, and other viral infections (2).

A practical guide often cited in the literature (1-3) is if the athlete feels well, and liver chemistries are normal, he or she can resume easy noncontact training (eg, jogging, swimming, cycling) 3 to 4 weeks after the onset of symptoms. If training goes well and the spleen has returned to normal size, the athlete can resume contact sports (possibly wearing a flak jacket) in 5 to 6 weeks.

In this case, establishing a definitive diagnosis with EBV serology was the most expedient way to return this basketball player to play, especially because his IM diagnosis was in question. If his EBV serology had been consistent with acute primary infection, the above guidelines would have been followed.

References

  1. Bailey RE: Diagnosis and treatment of infectious mononucleosis. Am Fam Physician 1994;49(4):879-888
  2. Eichner ER: Infectious mononucleosis: recognizing the condition, 'reactivating' the patient. Phys Sportsmed 1996;24(4):49-54
  3. Hickey SM, Strasburger VC: What every pediatrician should know about infectious mononucleosis in adolescents. Pediatr Clin North Am 1997;44(6):1541-1556
  4. Gray JJ, Caldwell J, Sillis M: The rapid serologic diagnosis of infectious mononucleosis. J Infect 1992;25(1):39-46
  5. Wallach JB: Epstein-Barr virus infections, in Wallach JB: Interpretation of Diagnostic Tests: A Synopsis of Laboratory Medicine, ed 5. Boston, Little, Brown, 1992, pp 323-326
  6. Pseudo-outbreak of infectious mononucleosis: Puerto Rico, 1990. MMWR 1991;40(32):552-555
  7. Waterbury L, Zieve PD: Selected illnesses affecting lymphocytes, in Barker LR, Burton JR, Zieve PD (eds): Principles of Ambulatory Medicine, ed 4. Baltimore, Williams & Wilkins, 1995, pp 624-629
  8. Feorino PM, Dye LA, Humphrey DD: Comparison of diagnostic tests for infectious mononucleosis. J Am Coll Health Assoc 1971;19(3):190-193
  9. Uldall A, Jensen BS, Henrichsen J: Kits for the diagnosis of infectious mononucleosis compared with the Paul-Bunnell test. J Clin Chem Clin Biochem 1990;28(6):423-425

The author wishes to thank Robert J. Johnson, MD, and the staff at the Family Medicine Center at Hennepin County Medical Center in Minneapolis for their support in preparing this manuscript.

Dr Greenslade is a primary care sports medicine physician in private practice in Durango, Colorado. Address correspondence to Rosemary Greenslade, MD, MS, 2323 Forest Ave, Durango, CO 81301; e-mail to [email protected].


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