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Serologic Testing for Epstein-Barr Virus
Hematologic Manifestations
Gastrointestinal Manifestations
Rheumatologic Manifestations
Neurologic Manifestations
Dermatologic Manifestations
Cardiopulmonary Manifestations
Otorhinolaryngologic Manifestations
Renal Manifestations
Epstein-Barr Virus in Older Patients
Chronic Epstein-Barr Viral Syndrome

Infectious mononucleosis caused by the Epstein-Barr virus (EBV) is a common disease, most commonly noted in children and adolescents. Presentation is age-dependent. Clinical expression is most often seen in adolescents or young adults, whereas subclinical disease occurs frequently in younger children. Older persons may have subtle, primarily constitutional presentations. Recent advances in serologic testing for infectious mononucleosis have demonstrated an enlarging spectrum of disease caused by this virus. For instance, 5% to 10% of patients with typical illness test negatively for heterophil antibodies but have positive EBV-specific test results. The classic syndrome of infectious mononucleosis includes fever, atypical lymphocytosis, lymphadenopathy, pharyngitis, and heterophil positivity in the adolescent and generally poses few clinical difficulties. However, many unusual presentations of EBV-related disease exist that may pose difficult diagnostic problems. These can be seen primarily in young children and adults. The following discussion focuses on atypical manifestations of this disease, summarized in Table 3-1, which also provides an overview of many of the uncommon presentations. An understanding of these syndromes can prevent both unnecessary diagnostic evaluations and the unneeded prescription of medications.

Table 3-1. Unusual manifestations of infectious mononucleosis

Serologic Testing for Epstein-Barr Virus
Because approximately 90% to 95% of cases of infectious mononucleosis can be diagnosed by standard heterophil antibody testing, more specific serologic evaluations are needed infrequently. EBV-specific testing is indicated mainly when infectious mononucleosis is clinically suspected but results of heterophil antibody testing are negative, or when the presentation is atypical and the diagnosis of infectious mononucleosis is suspected. IgM antibodies to viral capsid antigen appear early in the course of disease and persist for only several months. Thus, a positive test result, combined with the presence of IgG and the absence of EBV nuclear antigens, confirms acute disease. IgG antibodies to the same antigen peak early in the course of disease, and therefore it may be difficult to demonstrate a change in titer. Because of lifelong persistence of this antibody, positivity on a single test does not imply acute disease. Antibodies to Epstein-Barr nuclear antigen appear late in the course of infectious mononucleosis and persist indefinitely. This test is most useful as an epidemiologic tool and cannot define acute disease.
Hematologic Manifestations
Up to 3% of patients with infectious mononucleosis manifest hematologic abnormalities that can involve any primary marrow component. In most instances, problems arise during weeks 2 to 4 of illness and thus complicate a more classic presentation. However, occasional patients present with primarily hematologic complaints; more usual components of infectious mononucleosis have either not occurred or have been overlooked. Hemolytic anemia is the most commonly recognized abnormality and is usually caused by the presence of IgM cold agglutinins with anti-i specificity. Hemolysis may be severe and life-threatening and may require administration of corticosteroids. Thrombocytopenia may also be noted but rarely reaches critical levels. However, cases with platelet levels below 1,000/mm3 have been reported, and bleeding complications may occur. In most instances, thrombocytopenia is caused by peripheral destruction of platelets rather than primary marrow hypoproduction, and both corticosteroids and splenectomy have been used therapeutically. Neutropenia and absolute granulocytopenia have been reported. Clinical problems related to this are rare, and counts generally return to normal within 5 to 21 days. However, the absence of granulocytes has occasionally proved fatal. In most cases, bone marrow evaluation reveals maturation arrest, possibly caused by a toxic effect of the virus. Recent investigations of aplastic anemia and agranulocytosis have demonstrated an unexpected, statistically important relationship between a history of infectious mononucleosis at least 1 year previously and the presence of agranulocytosis (but not aplastic anemia). Reasons for this are unclear at the present.
Gastrointestinal Manifestations
Subclinical elevations of hepatic enzymes occur in at least 50% of patients with infectious mononucleosis and can be considered part of the normal course of this illness. Severe jaundice that may be associated with icteric hepatitis can be the presenting complaint. Recent anecdotal reports demonstrate cases that have progressed to fulminant hepatic failure. Other cases of jaundice with clinically milder disease probably represent a combination of hemolysis and hepatitis. Maximum levels of serum bilirubin reported have been 38.5 mg/dL. Prompt response to corticosteroids was noted. Clinical and laboratory manifestations mimicking viral hepatitis may also denote this disease, making other viral diseases the major diagnostic considerations. Cases of acute hepatitis secondary to EBV infection are usually associated with complete recovery. Cases progressing to chronicity have been documented. Hepatitis caused by EBV should be suspected when alternative diagnoses have been ruled out.
Splenomegaly occurs regularly in uncomplicated infectious mononucleosis and rarely poses clinical problems. Rupture of this organ is well documented and represents the most common cause of death from EBV infection. Rupture most often occurs during weeks 2 and 3 and may be the primary manifestation of infectious mononucleosis. Abdominal pain may herald this complication and probably represents the presence of subcapsular hematoma. Rupture secondary to bleeding may also be a consequence of severe thrombocytopenia but more commonly is associated with trauma. Initial presentation of rupture may be hypovolemic shock, but abdominal pain and a more subacute course are the rule. If rupture is suspected, emergent splenectomy is generally recommended.
Patients with significant splenomegaly should be cautioned about injury.
Rheumatologic Manifestations
Vague arthralgias and myalgias may be noted during the course of uncomplicated infectious mononucleosis but rarely are of clinical significance. True arthritis is rare, but at least one review demonstrated polyarthritis in up to 50% of patients studied. Disease was always self-limited.
Neurologic Manifestations
Neurologic dysfunction may be noted either as a primary manifestation of EBV disease or as a complication of classic infectious mononucleosis. Common syndromes include (a) aseptic meningitis, (b) Guillain-Barré syndrome, (c) transverse myelitis, (d) Bell’s palsy, (e) cerebellar meningoencephalitis, and (f) other focal cranial nerve palsies. In general, patients who present with manifestations such as these and have no other diagnosis should be evaluated for infectious mononucleosis. Recent retrospective investigations of EBV disease in children also demonstrate the clinical presentations of combative behavior, seizures, and severe headache. Clinical manifestations of these may be noted at any time during the course of EBV infection. In up to 7% of cases of EBV-related infection, a neurologic syndrome may either herald or be the sole sign of disease. More often, however, central nervous system manifestations occur in conjunction with more characteristic forms of disease, but clinical documentation may prove elusive. Historically, most authorities have felt that complete neurologic recovery could be anticipated. However, recent investigations in children suggest that approximately 40% may demonstrate neurologic sequelae at long-term follow-up. These include global impairment, autistic behavior, and limb paresis.
Aseptic meningitis is the most common central nervous system abnormality associated with infectious mononucleosis and has been reported in up to 25% of patients. Often, the patient is free of central nervous system-related complaints. Lymphocytic pleocytosis with normal cerebrospinal fluid glucose levels is most commonly noted, and atypical lymphocytes may be seen.
In a prospective investigation designed to assess the role of EBV in neurologic diseases, 7 of 24 persons with Guillain-Barré syndrome and 3 of 16 with Bell’s palsy demonstrated serologic evidence of acute infection with EBV. This study also demonstrated that many of these persons had no other evidence of infectious mononucleosis and that several had negative results on heterophil agglutination tests.
A number of investigations have depicted the role of EBV as a cause of meningoencephalitis and have documented its capacity to cause primarily an acute cerebellar syndrome. More global forms of encephalitis may also be noted, and seizures have been described. In some instances, routine heterophil agglutination test results have been negative, with atypical lymphocytes present at nondiagnostic levels.
Dermatologic Manifestations
Skin disorders in infectious mononucleosis are noted in fewer than 5% of patients. A severe maculopapular eruption with hemorrhage may be noted in 60% to 80% of patients with infectious mononucleosis who receive ampicillin or amoxicillin. This response is toxic rather than allergic and does not contraindicate the future use of these agents. A single case of solitary penile ulcer has been reported with infectious mononucleosis, but the relationship is uncertain.
Cardiopulmonary Manifestations
Symptomatic cardiac disease with infectious mononucleosis is unusual. However, both myocarditis and pericarditis have been demonstrated, usually in association with more classic presentations of the disease. The most commonly observed cardiac disturbance is nonspecific ST-T wave changes on electrocardiogram, noted in up to 6% of persons. Deaths are unusual.
Chronic interstitial pulmonary infiltrates associated with fever have been recently described in two patients following recovery from acute infectious mononucleosis. Both persons demonstrated continued viral replication and had a clinical response to acyclovir.
Otorhinolaryngologic Manifestations
Ear, nose, and throat complaints in infectious mononucleosis are well documented. In one series of patients hospitalized with this disease, 55% had such problems. Findings included airway obstruction, peritonsillar abscess, sinusitis, and periorbital cellulitis. The latter two were more likely to have been secondary to bacterial complications than to EBV infection itself. Tonsillopharyngitis is commonly seen in classic infectious mononucleosis and must be differentiated from numerous other causes of this syndrome. A recent retrospective investigation of infectious mononucleosis in children demonstrated that approximately 50% of 60 patients with infectious mononucleosis complicated by tonsillopharyngitis had severe airway obstruction. Three required surgical intervention, and the remainder responded to systemic corticosteroids.
A common presentation of mononucleosis is tonsillopharyngitis, treated with ampicillin or amoxicillin, with resultant severe rash. Dramatic illness with dysphagia and “touching tonsils” should make the clinician consider streptococcal pharyngitis, even if the diagnosis of infectious mononucleosis has been confirmed. Most cases of airway obstruction are related to hypertrophy of the tissue comprising Waldeyer’s ring. The cause of such obstruction was thought to be EBV-induced. If this and other ear, nose, and throat complications occur, a bacterial process should always be ruled out by suitable laboratory studies.
Renal Manifestations
Involvement of the kidneys with infectious mononucleosis has been reported infrequently, and infectious mononucleosis generally has not been associated with symptomatic renal disease. A recent investigation reviewed 27 cases of infectious mononucleosis with symptomatic renal involvement and reported a case that resulted in oliguric renal failure requiring hemodialysis. Interstitial nephritis was seen on renal biopsy specimens. Recovery was associated with the use of corticosteroids and acyclovir.
Epstein-Barr Virus in Older Patients
Although cases of infectious mononucleosis in adults over 30 years of age have historically been felt to comprise less than 3% of cases, recent investigations suggest that this is an underestimate. Infectious mononucleosis may be overlooked in older persons because of its historic association with younger people and the higher likelihood of atypical presentation. Disease in older persons is well described and may be acquired either parenterally (e.g., blood transfusions) or by less obvious means. Fever and fatigability may be the sole clinical manifestations. Splenomegaly, lymphadenopathy, and pharyngitis occur much less frequently than in younger persons. The time course of disease in older persons may be more prolonged, perhaps related to a higher degree of hepatic dysfunction. Fever may be substantially more prolonged (13 days in adults vs. 7 days in adolescents), and peak WBC counts may be lower (6,600/mm3 in adults vs. 11,000/mm3 in adolescents). Usually, typical serologic manifestations and atypical lymphocytosis are noted, although the latter may be demonstrable only on serial testing. Infectious mononucleosis in patients over 40 years of age should be suspected when individuals present with fever and malaise even if other classic features are absent.
Chronic Epstein-Barr Viral Syndrome
The role of EBV in patients suffering from chronic fatigue remains controversial. Although data have surfaced concerning the presence of chronic fatigue syndrome and its relationship to EBV infection, most recent studies fail to provide support for a relationship. Therapeutic trials with antiviral medications such as acyclovir have been unrewarding. Treatment remains primarily supportive.
The mainstay of management of infectious mononucleosis is supportive care coupled with careful observation for the occasional bacterial complication, primarily streptococcal pharyngitis. The role of corticosteroids remains controversial, and these agents are not indicated for the usual case. However, these agents, generally administered as 60 to 80 mg of prednisone daily for short periods, may be beneficial for the occasional patient with severe tonsillopharyngeal complications of EBV infection. A recent investigation suggests that this may preclude the need for surgical intervention. Rebound may occasionally be noted. Secondary infection with Streptococcus pyogenes must be ruled out. Corticosteroids are also occasionally utilized for severe thrombocytopenia. Acyclovir has been studied, with mixed results. Most patients did not demonstrate clinical or laboratory improvement when treated with this agent in comparison with those treated with placebo. A double-blinded, placebo-controlled trial of acyclovir plus prednisolone versus placebo demonstrated that EBV shedding was significantly reduced in the drug group, but that no clinical variables were favorably influenced. As noted above, a recent case of acute oliguric renal failure was successfully treated with acyclovir plus corticosteroids.
A recent double-blinded, placebo-controlled trial of ranitidine compared with placebo demonstrated only that liver enzymes returned to baseline more quickly in the drug-treated group (p = .03). No other variables were influenced in a statistically significant manner. (R.B.B.)
Andersson J, et al. Effect of acyclovir on infectious mononucleosis; a double-blind, placebo-controlled study. J Infect Dis 1986;153:283–290.
Thirty-one patients with infectious mononucleosis of short duration were randomized to receive acyclovir or placebo. Therapy reversibly inhibited oropharyngeal viral shedding but generally had no effect on individual symptoms or laboratory parameters. However, the authors conclude that cumulatively, patients who received acyclovir fared better. Acyclovir is not indicated for the usual patient with this disease; other studies may uncover a subset of severely ill patients who may benefit.
Carter J, Edson RS, Kennedy CC. Infectious mononucleosis in the older patient. Mayo Clin Proc 1978;53:146–150.
In an early report of six patients over the age of 60 years with infectious mononucleosis, presentation was often primarily constitutional, without exudative pharyngitis. An awareness of the subtle presentation may disallow unnecessary diagnostic studies.

Cheeseman S. Infectious mononucleosis. Semin Hematol 1988;25:261–268.
This excellent recent overview of the classic syndrome of infectious mononucleosis also contains brief discussions of issues related to diagnosis and treatment.
Comachowske JB, et al. Acute manifestations and neurologic sequelae of Epstein-Barr virus encephalitis in children. Pediatr Infect Dis J 1997;16:871–875.
This retrospective analysis of 11 cases of infectious mononucleosis-associated encephalitis demonstrates the diversity of clinical presentations that may occur. Classic accompanying features are infrequently observed. Long-term sequelae are noted in about 40% of cases.
Farley DR, et al. Spontaneous rupture of the spleen due to infectious mononucleosis. Mayo Clin Proc 1992;67:846–853.
This report reinforces the possibility of spontaneous nontraumatic splenic rupture as a life-threatening complication of infectious mononucleosis. Presentation is often one of acute abdominal pain, and emergent splenectomy remains the treatment of choice.

Ghosh A, et al. Infectious mononucleosis hepatitis: report of two patients. Indian J Gastroenterol 1997;16:113–114.
Two patients in whom icteric hepatitis was associated with infectious mononucleosis are presented. One case was complicated by fulminant hepatic failure, and the patient died. Infectious mononucleosis-associated hepatitis should be suspected if other causes have been ruled out.
Halevy J, Ash S. Infectious mononucleosis in hospitalized patients over forty years of age. Am J Med Sci 1988;295:122.
This investigation compares the clinical presentation of infectious mononucleosis in patients over the age of 40 years with that of a similar number of adolescents. The older persons were more likely to run a prolonged febrile course and have lower total WBC counts, and splenomegaly, lymphadenopathy, and pharyngitis were less likely to develop in these patients.
Kirov SM, Marsden KA, Wongwanich S. Seroepidemiological study of infectious mononucleosis in older patients. J Clin Microbiol 1989;27:356–358.
This Australian report documents a higher likelihood of noted infectious mononucleosis in older patients than is generally considered.
Levy M, et al. Risk of agranulocytosis and aplastic anemia in relation to history of infectious mononucleosis: a report from the International Agranulocytosis and Aplastic Anemia Study. Ann Hematol 1993;67:187–190.
A retrospective analysis of patients with either agranulocytosis or aplastic anemia was performed. Among those with agranulocytosis, 4% had a history of prior infectious mononucleosis. This was significantly different from controls. No association with aplastic anemia was identified.
Madigan NP, et al. Intense jaundice in infectious mononucleosis. Mayo Clin Proc 1973;48:857–862.
This represents a clinical report of the association of severe jaundice with infectious mononucleosis. Hemolysis plus hepatitis is the likely explanation. The presence of jaundice does not rule out infectious mononucleosis as the source of the problem.
Mayer HB, et al. Epstein-Barr virus-induced infectious mononucleosis complicated by acute renal failure: case report and review. Clin Infect Dis 1996;22:1009–1018.
A case of acute oliguric renal failure associated with Epstein-Barr virus is presented, and the related literature is reviewed. Twenty-seven cases of symptomatic renal disease have been published. Disease is generally self-limited. Severe cases appear to respond to treatment that includes corticosteroids and acyclovir.
Schooley RT, Dolin R. Epstein-Barr virus (infectious mononucleosis). In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and practice of infectious diseases, 3rd ed. New York: Churchill Livingstone, 1990:1172–1184.
This chapter summarizes much information on the presentation and complications of infectious mononucleosis and provides a reasonable presentation of the entire clinical and virologic picture of the disease.
Silverstein A, Steinberg G, Nathanson M. Nervous system involvement in infectious mononucleosis. Arch Neurol 1972;26:353–358.
This investigation reports on 15 patients with documented infectious mononucleosis whose initial clinical presentation or heralding feature was neurologic. In six of these, the neurologic finding was the sole manifestation of illness. Findings included severe headache, seizures, paresis, cranial nerve palsies, and radiculopathy.
Snyderman NL. Otorhinolaryngologic presentations of infectious mononucleosis. Pediatr Clin North Am 1981;28:1011–1016.
This review focuses on ear, nose, and throat presentations of infectious mononucleosis. In many instances, the process may represent complications rather than the EBV infection itself.
Straus SE, et al. Epstein-Barr virus infections: biology, pathogenesis, and management. Ann Intern Med 1993;118:45–58.
This National Institutes of Health conference represents an excellent overview of many issues related to infection with EBV. It provides information concerning EBV serology, clinical manifestations, and molecular biology. Regarding management, the authors reinforce the need for supportive care and hedge on the role of corticosteroids. These agents may be of benefit for persons with severe tonsillopharyngeal symptoms caused by EBV, however.
Tynell E, et al. Acyclovir and prednisolone treatment of acute infectious mononucleosis: a multi-center, double-blind, placebo-controlled study. J Infect Dis 1996;174:324–331.
In a randomized placebo-controlled study of acute infectious mononucleosis, acyclovir plus prednisolone was used in the therapy arm. Ninety-four patients were identified. Therapy resulted in no clinical benefit but did inhibit oropharyngeal EBV replication. No effect was noted on later cellular immunity.


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