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Infectious Mononucleosis in Active Patients

Definitive Answers to Common Questions

Paul G. Auwaerter, MD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 30 - NO. 11 - NOVEMBER 2021


In Brief: Infectious mononucleosis may account for considerable illness, especially among adolescents and young adults. Although the disorder was well described more than 70 years ago as involving fever, sore throat, and lymphadenopathy, questions often arise about diagnosis and management. Because primary infection with the Epstein-Barr virus (EBV) can lead to diverse disease manifestation and complications, physicians must be well-versed in the disorder's epidemiology and pathophysiology. New information assesses the reliability of heterophil antibody testing and the role of EBV-specific antibody testing, and addresses issues of management, including corticosteroids, antiviral drugs, and restriction from athletic participation. Most athletes can return to sports after a minimum of 4 weeks, provided the spleen is not palpable.

Whatever their clinical practice, most healthcare practitioners must be familiar with infectious mononucleosis (IM). Although teenagers and young adults are most often affected, patients of all ages may contract IM. Often easy to recognize and diagnose by its characteristic triad (fever, sore throat, and lymphadenopathy), this disorder arises from Epstein-Barr virus (EBV) infection and may challenge the most capable diagnostician with its diverse manifestations.

Although many febrile glandular illnesses had been described earlier, the first reliable description of IM dates to 1920.1 Later, the discovery of human heterophil antibodies that could agglutinate sheep red blood cells helped firmly establish IM as a distinct disease,2 but EBV was only definitively identified as the cause of IM in 1968.3

Viral Transmission and Infection

EBV is one of the most successful of viruses, eventually infecting more than 90% of humans. The virus is spread mostly through oral secretions and is intermittently shed within the oropharynx in most seropositive patients.4 Hoagland5 dubbed it the "kissing disease," after this mode of transmission. The virus appears to infect nasopharyngeal epithelial cells and B cells, although which of these is the primary site of infection remains controversial.6 Viral infection of B cells causes subsequent activation of polyclonal antibody production that includes the nonvirally specific heterophil antibodies and, rarely, more clinically relevant antineutrophil, antierythrocyte, antiplatelet, antinuclear, and cryoglobulin antibodies. The virus becomes latent within a subset of infected, EBV-immortalized B cells and becomes a persistent, but generally silent, lifelong infection.

An individual's immune response to EBV is highly variable and appears to determine the degree of symptomatic disease.7 This appears to depend on the proliferation and activation of T cells in response to infection. For unexplained reasons, infection acquired during infancy or childhood is usually asymptomatic or yields nonspecific symptoms. By teenage or young adult years, the percentage of patients with symptoms from acute infection increases to 20% to 70%. Although uncommon, primary EBV infection acquired in middle-aged or older adults can provoke a vigorous immune reaction that often leads to unusually severe, prolonged fever with hepatitislike features.8

The peak incidence of IM in industrialized countries, such as the United States, occurs between the ages of 15 and 24 (300 to 700 per 100,000). Serologic studies of college freshmen suggest that 30% to 50% remain susceptible to infection. Annually, 1% to 3% of students on college campuses develop IM.9 The rate of symptomatic infection decreases 100-fold by age 35 or older (2 to 4 per 100,000).10

In less developed countries with large, closely knit extended families and less rigorous hygiene, infection appears to be universal by age 4, thus making IM unusual, as most infections are subclinical at young ages. However, travelers abroad may encounter this virus for the first time, making EBV a consideration for those returning ill with fever, along with more typical tropical infections such as malaria, dengue fever, and viral hepatitis.

Clinical Features

The typical features of IM include lymphadenopathy, sore throat, and fever, but other complaints may also be present (table 1). IM often begins as a 3- to 5-day prodrome with nonspecific symptoms such as headache, malaise, myalgia, and loss of appetite. Splenomegaly is more common than hepatomegaly. A rash can be seen in 5% to 10% of patients, but its appearance can range from macular to petechial or urticarial, and even occasionally as erythema nodosum. In patients who receive ampicillin or amoxicillin empirically for suspected streptococcal pharyngitis, a diffuse maculopapular rash occurs in 95% to 100% of the patients who ultimately are found to have EBV IM.11 Although the precise reason for such a rash during IM is unknown, in this setting it is virtually diagnostic of primary EBV and does not mean the patient will have a future allergy to penicillin.

TABLE 1. Clinical Features of Infectious Mononucleosis in Patients of Different Ages
FeaturePatients ≤35 Years Old  
(% Expressing)
Patients ≥40 Years Old (%)
(% Expressing)

Lymphadenopathy9447
Pharyngitis8443
Fever7695
Splenomegaly5233
Hepatomegaly1242
Rash1012
Jaundice 927

Reprinted with permission from Auwaerter PG: Infectious mononucleosis in middle age. JAMA 1999;281(5):454-459.

Although 70% to 80% of adolescents and young adults have the triad, usually one of the three cardinal findings forms the basis of the presenting complaint. Moreover, some patients do not have the complete triad of classic IM but present with a cluster of symptoms that make up one of three distinct forms: pharyngeal, glandular, or febrile.

Pharyngeal form. Pharyngitis is the most frequent presenting complaint, necessitating differentiation from other causes of tonsillar inflammation, such as another virus infection (including acute HIV infection), or bacterial infections with streptococci, Arcanobacterium, or mycoplasma. The sore throat may be severe with enlargement of tonsils because of edema and lymphoid hyperplasia. An exudative pharyngitis may be seen in more than 50% of patients and can rarely lead to obstruction of the airway.12 Patients may appear toxic with high fever. These "pharyngeal" patients often seek medical attention promptly, and laboratory testing usually leads to ready determination of the cause, although IM and group A streptococcal pharyngitis may occur simultaneously in 7% to 30% of patients.

Glandular form. Patients with this form often have some fever and malaise but do not feel overly ill; instead, they are disturbed by significant lymph node enlargement. IM-related lymphadenopathy is characteristically found in both posterior cervical chains but can include anterior chains or generalized lymph node enlargement. Both the patient and physician are more typically concerned with distinguishing between lymphoma and HIV infection, although toxoplasmosis and cytomegalovirus (CMV) infections must also be considered. Appropriate early laboratory testing usually abrogates the need for biopsy.

Febrile form. Some patients present because of prolonged fever or a flulike illness of more than 2 weeks' duration. These patients tend to have more gastrointestinal complaints such as anorexia, nausea, vomiting, and diarrhea. Findings of pharyngitis and lymphadenopathy may be delayed or remain absent. In these scenarios, IM is often not incorporated into the differential diagnosis for evaluating fevers of unknown origin. Such patients are often older than age 35 (see table 1), and physicians may neglect considering primary EBV infection as a cause. Initial laboratory tests may show a hepatitis-like picture, and differential diagnosis often centers on the causes of viral hepatitis. Besides hepatitis A, B, and C, other causes of this kind of illness should include consideration of CMV, rubella, adenovirus, toxoplasmosis, and typhoid fever.

Atypical manifestations. Perhaps the most challenging clinical presentations are atypical of IM (table 2). The characteristic findings of IM generally are not prominent or appear later in the illness, giving little indication of the probable diagnosis. For example, the neurologic findings may either be the sole manifestation of primary EBV infection or occur several weeks after well-recognized IM. Although serious neurologic disease occurs in less than 0.5% of patients, some series report a 5.5% to 7.3% prevalence in hospitalized patients. Neurologic complications are the leading cause of death from acute EBV infection.13

TABLE 2. Atypical Presentations of Infectious Mononucleosis
Type of PresentationEstimated Frequency (%)

Neurologic
Meningoencephalitis
Aseptic meningitis
Acute cerebellar ataxia
Seizures
Transverse myelitis
Guillain-Barré syndrome
Mononeuritis multiplex
Cranial nerve palsies
  (especially Bell's palsy)
Brachial plexus mononeuropathy
Optic neuritis
Acute psychosis
1-2 (composite)
Rare*
Rare
Rare
Rare
Rare
Rare
Rare
Rare

Rare
Rare
Rare
Cardiac
Myocarditis
Pericardititis

Rare
Rare
Respiratory
Interstitial pneumonia
Pleurisy

Rare
Rare
Hematologic
Autoimmune hemolytic anemia
Granulocytopenia (<500/mm3)
Thrombocytopenia
Disseminated intravascular coagulation
Pancytopenia
3
0.5
Rare
Very rare†
Rare
Hepatic
Hepatic necrosis or fulminant liver failure
Reye's syndrome

Very rare
Very rare
Other
Orchitis
Glomerulonephritis

Rare
Very rare
*Rare is less than 0.5%.
†Very rare is fewer than than 10 case reports.

Autoimmune hemolytic anemia is the most common hematologic abnormality and may occur in up to 3% of patients, although usually only after the symptomatic phase of illness has ended.9 Cardiac, renal, hepatic, and other severe complications have all been described more than occasionally. Primary EBV can be responsible for myriad clinical problems, and only by maintaining a keen awareness of the potential spectrum of EBV-related illnesses will the clinician be able to order appropriate tests.

Expedient Diagnosis

For most patients, the diagnosis of IM is suggested by the constellation of symptoms and findings. IM should rank high in the differential diagnosis of an acute febrile illness occurring in adolescents and young adults, especially with illnesses lasting more than the usual 5 to 7 days of common viral infections.12

Hematologic tests. Supportive evidence may be obtained from hematology or chemistry laboratory tests. By the second week of illness, more than 70% of patients with IM will have absolute lymphocytosis, with values peaking no later than the third week.5 Total white blood cell counts usually range between 12,000 to 18,000 cells/mm3 but may occasionally rise to more than 30,000 cells/mm3.

The white blood cell differential typically consists of more than 60% lymphocytes. Atypical lymphocytes usually account for 10% to 30% of this total and are a characteristic, but nonspecific, feature of IM. They can be present in patients who have other acute viral illnesses such as rubella, roseola, viral hepatitis, CMV, and acute HIV infection and in those who experience drug reactions. Atypical lymphocytes reflect activation and clonal expansion of T cells directed against EBV, rather than EBV-infected B-lymphocytes as was originally believed.14,15 Most laboratories have no trouble distinguishing polymorphic atypical lymphocytes from the more ominous, uniform leukemic white blood cells.

Liver function tests may be elevated, most frequently with a mild transaminitis observed in as many as 80% of patients with IM. Hyperbilirubinemia (greater than 2 mg/dL) affects less than 9% of children and adolescents but may occur in more than 30% of patients older than age 40. Jaundice occurs less often. Any abnormality of liver function may help raise suspicion of IM in patients with severe pharyngitis.16

Heterophil antibody tests. With a compatible clinical picture, a case of IM may be confirmed by the demonstration of heterophil antibodies, which recognize cells from a different species. Heterophil antibodies originally described in IM were human immunoglobulin (Ig) M class antibodies that caused sheep erythrocytes to agglutinate. These antibodies do not recognize viral epitopes but rather arise from the immunologic chaos provoked by EBV infection of B lymphocytes.

Heterophil antibodies may appear within the first week after onset of clinical symptoms and generally have their peak titer between weeks 2 and 5, but they may persist at low levels for up to 1 year. Rapid latex agglutination tests such as the Monospot have replaced the more cumbersome Paul-Bunnell-Davidsohn test in most laboratories. These newer tests have sensitivities of 70% to 92% and specificities of 96% to 100%.17 False-positive results are rare and may occur in patients with lymphoma, autoimmune disease, or hepatitis.

Physicians should order a Monospot test to confirm a diagnosis, although the test may be negative, especially during the first week of illness. Repeat testing during the second and subsequent weeks often will be positive.

However, up to 10% of patients with primary EBV infection may not have detectable heterophil antibodies. These so-called heterophil-negative (Monospot- negative) cases of IM prove to be the most diagnostically challenging. The clinician is faced with deciding if this is still a case of EBV infection or if there is an alternative explanation. The differential diagnosis of heterophil-negative illness includes toxoplasmosis and viral infections such as CMV, viral hepatitis, rubella, and acute HIV infection. Infections due to causes other than EBV are more properly termed mononucleosis-like syndromes, since IM is reserved for illness caused by EBV infection only.

Additional antibody tests. The physician who suspects IM but has a heterophil-negative patient should then order tests for EBV-specific antibodies. Since EBV-infected patients have had virus incubating for an average of 5 to 7 weeks before the onset of symptoms, most patients will have these antibodies at presentation. The most informative antibodies are those directed against the viral capsid antigen (VCA). Presence of VCA IgM and VCA IgG usually confirms the diagnosis of IM; however, because EBV can transiently reactivate, VCA IgM can sometimes be detected even years after the initial infection, especially as a consequence of intense immune activation of any cause.

Many laboratories offer an EBV panel that also includes VCA antibodies and a determination of EBV nuclear antigen (EBNA) antibodies. EBNA antibodies tend to appear much later—6 to 12 weeks after initial symptoms—therefore, finding these antibodies early in an illness excludes a diagnosis of primary EBV infection.18 IM patients who are heterophil-negative in the first month of illness should thus be VCA IgM positive, VCA IgG positive, and EBNA negative. Often, these EBV panels include determinations of the EBV early antigen (EA) antibodies. EA antibodies represent an unreliable tool for diagnosing IM, but they are greatly elevated in EBV-related malignancies such as nasopharyngeal carcinoma.

Effective Management

Common therapies. In nearly all patients, IM is self-limited. Many patients are ill for less than 1 week, although fatigue tends to be a common lingering symptom. Bed rest is not required, and individuals may perform nonstrenuous activities as tolerated. Most individuals have completely recuperated within 1 month. Often, physicians can be most helpful in guiding supportive therapy. For example, they can recommend acetaminophen for analgesia rather than aspirin, since aspirin can contribute to the rare but serious complications of IM-related splenic rupture or thrombocytopenia.

Stool softeners or laxatives may be useful if patients take narcotics or have constipation. These measures help avoid intra-abdominal straining that can precipitate splenic rupture. Reassurance to patients and their families can assuage concerns that often arise when a teen or young adult contracts IM.

Other therapies. Since acyclovir can inhibit EBV replication and viral shedding, several trials have examined its role in IM. Unfortunately, acyclovir appears to have no significant impact, which may not be surprising since most of the symptoms probably represent the host's immune response to the virus.19,20

Many practitioners have long employed corticosteroids to ameliorate severe constitutional symptoms and to shorten the duration of fever and sore throat. Corticosteroid therapy is controversial for routine use because it has been associated with complications such as avascular necrosis.21 A trial22 using prednisolone therapy combined with acyclovir failed to find any benefit in uncomplicated infection. Corticosteroids, though, are necessary for managing severe airway obstruction, profound thrombocytopenia or hemolytic anemia, disseminated intravascular coagulopathy, and myocarditis.

Complications. IM complications (table 3) account for virtually all of the rare fatalities reported.9 All patients who have pharyngitis should have a throat culture to determine whether concomitant group A ß-hemolytic infection exists. If the culture is positive, treatment with penicillin or erythromycin should be considered because ampicillin or amoxicillin usually causes a rash in patients who have IM.

TABLE 3. Most Common Complications of Infectious Mononucleosis
Complication Frequency (%)

Group A ß-hemolytic streptococcal pharyngitis7-30
Upper-airway obstruction0.1-1.0
Splenic rupture0.1-0.2
Rash after exposure to amoxicillin or ampicillin90-100

Adapted from Maki and Reich.9

If pharyngitis is severe enough to threaten airway obstruction, corticosteroid therapy should be instituted; doses range from 40 to 80 mg of prednisone or the equivalent. Airway management should include consideration of nasotracheal intubation or tracheostomy for any patient severely compromised or who does not promptly respond to corticosteroids. Rarely, persisting asymmetric tonsillar enlargement may indicate a peritonsillar abscess that requires culture and drainage.

IM does not generally cause significant abdominal pain; thus, the presence of such pain signals possible, splenic rupture. Although heaviness or fullness of the left upper quadrant is often due merely to rapid enlargement of the spleen, severe left upper quadrant pain or pain also radiating to the left shoulder (Kehr's sign, from diaphragmatic irritation by blood) may indicate splenic rupture. More than half of the cases of IM-related splenic rupture had no obvious inciting trauma.23 Abdominal ultrasonography or computed tomography (CT) can often quickly indicate whether rupture is present, although if severe hemodynamic instability is present, then peritoneal lavage suffices to confirm.

Many early studies of this most feared complication of IM recommended splenectomy in all cases of rupture.24,25 However, a growing consensus suggests that many cases of splenic rupture, especially those due to subcapsular hematoma, may be managed conservatively if bleeding is not profuse (defined by some as requiring less than 2 units of transfused blood).26,27 Some physicians have advocated percutaneous drainage in some cases as an alternative to surgery.28 Salvaging the spleen avoids the potential for long-term complications of asplenia, such as severe sepsis arising from encapsulated bacteria.

Commonly Asked Questions

When is it safe to resume sports after IM? One of the most vexing questions faced by physicians is when to allow an athlete to resume training or competition, especially in a contact sport. Most healthcare providers base the decision to return on resolution of any objective symptoms as well as on the athlete's sense of well-being.9 When athletes resume training, it is prudent to start at 50% of normal levels for the first few days, and athletes should "listen to their bodies" and increase activities as tolerated.23 Highly trained athletes may not attain preillness levels of fitness for up to 3 or more months. Some studies have suggested that the course of IM is less severe in college athletes compared with nonathlete college students.9

Following the diagnosis or suspicion of IM, all athletic training and competition should be curtailed because of the risk of splenic rupture. Published recommendations for cessation of sporting activities have varied tremendously, with suggestions ranging from 3 weeks to 6 months following resolution of EBV symptoms.29 No studies exist to point out prospective risk, but a retrospective study30 of spontaneous splenic rupture suggested that a third or more of athletes had been previously diagnosed with IM before rupture occurred. Although splenic enlargement is an obvious risk factor for this complication, palpation is not a sensitive measure of splenomegaly. The sensitivity of detecting splenomegaly by palpation ranges from 28% to 100%, with very large spleens the easiest to find.31 There also appears to be no correlation between the clinical severity of IM or laboratory findings and the susceptibility to splenic rupture.

Patients and physicians can take some comfort in the knowledge that splenic rupture appears almost always to occur within 2 to 21 days after the onset of IM, and documented occurrences after the fourth week are rare.25 Because no definitive or prospective studies have been done on return-to-play guidelines, only consensus is available to guide resumption of athletic activities. Several authors9,32 have recommended resumption of all sport activities except for strenuous contact sports no sooner than 21 days after illness onset. For strenuous contact sports that may carry a higher risk of splenic injury (eg, football, gymnastics, rugby, hockey, lacrosse, wrestling, diving, and basketball), athletes should wait a minimum of 4 weeks after onset, provided the spleen is not palpable.9,32

This 4-week recommendation has become common, although some authors33 have recommended that athletes be allowed to resume activity only after the spleen has returned to normal size (and is therefore protected by the rib cage), as judged by CT or ultrasound. Imaging may be useful to confirm resolution of splenomegaly, especially in the athlete who has an equivocal physical examination at 4 weeks, or one who seeks to return to sport sooner than 4 weeks.34

How often is fatigue or depression related to earlier bouts of IM? Although fatigue and depression are part of the common lore, very little data exist on their prevalence and duration. Most individuals have completely recuperated within 1 month of illness onset. One of the most carefully devised studies on the subject35 concluded that transient psychological distress was common during acute IM, but greater distress 2 months after the onset of illness correlated more with poor social functioning before diagnosis, a finding that suggests that depressive or anxious tendencies may have been preexisting. Some students may require excusal from exams or even a leave of absence to recover physical and cognitive functioning. This is an exception rather than a rule.

Chronic fatigue in children and adolescents generally has a shorter course and more optimistic outcome than in adults.36 There are little data pertaining to post-IM fatigue; however, many clinicians adapt recommendations on fibromyalgia and chronic fatigue syndrome that suggest low-impact aerobic conditioning, or consideration of antidepressants or stimulants, such as methylphenidate hydrochloride.37

Should I order EBV-specific serology tests for my patients who report chronic fatigue? EBV infection has been proposed as an explanation for the chronic fatigue syndrome since the 120210s. In an otherwise immunocompetent individual, VCA and EBNA IgG antibodies persist throughout life and denote prior infection with EBV. Since up to 90% of people in the United States eventually will be EBV infected and seropositive, the likelihood that a patient with fatigue has positive EBV titers is high. Current data neither support nor completely disprove an association between chronic fatigue and EBV, and therefore testing is not advised.

How often is IM transmitted from an infected roommate? Although the virus is widespread in populations, the rate of transmissibility is low without intimate contact, making epidemics rare. For example, seroconversion in susceptible roommates of students with IM is no more frequent than it is in the general college population.38 In one study,10 less than 6% of patients with IM cited a known exposure, so most people are likely infected following contact with saliva from people asymptomatically shedding the virus. Prudent behavior includes avoiding exposure to saliva, such as sharing utensils or glassware with someone who has primary EBV infection.

The Current Consensus

Primary infection with EBV varies from an asymptomatic to a severe illness that generally only becomes troublesome after childhood. Although usually involving a characteristic triad of symptoms (fever, sore throat, and lymphadenopathy), IM can produce a challenging array of clinical illness, including neurologic and hematologic problems. Demonstration of heterophil antibodies in a compatible clinical picture confirms the diagnosis. Approximately 10% of patients may lack such antibodies, requiring consideration of either a heterophil-negative IM or alternative causes. These patients will then require EBV-specific serology (VCA IgM, VCA IgG, and EBNA IgG), along with consideration of other causes of mononucleosislike illnesses such as CMV, viral hepatitis, HIV, and drug reactions.

Because IM is usually self-limited, supportive measures and reassurance of recovery remain the most helpful advice for patients. Corticosteroids are reserved for severe and life-threatening complications. Antiviral therapies such as acyclovir have not proven useful. For athletes, training should not resume earlier than 3 weeks after onset because of the risk of provoking splenic rupture. In strenuous contact sports, nonparticipation should be extended to a 4-week minimum, as long as an enlarged spleen is not found by either physical examination or imaging.

References

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Dr Auwaerter is an assistant professor in the divisions of general internal medicine and infectious diseases at the Johns Hopkins University School of Medicine in Baltimore. Address correspondence to Paul G. Auwaerter, MD, 10753 Falls Rd, Suite 325, Lutherville, MD 21093; e-mail to [email protected].

Disclosure information: Dr Auwaerter discloses no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.


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