eMedicine Specialties > Infectious Diseases > Viral Infections

Infectious Mononucleosis

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Updated: Oct 19, 2009

Introduction

Background

Infectious mononucleosis was first described by Sprunt and Evans in the Bulletin of the Johns Hopkins Hospital in 1920.¹ They described the clinical characteristics of Epstein-Barr virus (EBV) infectious mononucleosis. At the time, their article was entitled "Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis)," because the causative organism, EBV, had yet to be described.
 
Since the 1800s, infectious mononucleosis has been recognized as a clinical syndrome consisting of fever, pharyngitis, and adenopathy. The term glandular fever was first used in 1889 by German physicians and was termed Drüsenfieber. The association between infectious mononucleosis and EBV was described in the late 1960s.

Pathophysiology

EBV is transmitted via intimate contact with body secretions, primarily oropharyngeal secretions. EBV infects the B cells in the oropharyngeal epithelium. The organism may also be shed from the uterine cervix, implicating the role of genital transmission in some cases. On rare occasion, EBV is spread via blood transfusion.

Circulating B cells spread the infection throughout the entire reticular endothelial system (RES), ie, liver, spleen, and peripheral lymph nodes. EBV infection of B lymphocytes results in a humoral and cellular response to the virus. The humoral immune response directed against EBV structural proteins is the basis for the test used to diagnose EBV infectious mononucleosis. However, the T-lymphocyte response is essential in the control of EBV infection; natural killer (NK) cells and predominantly CD8⁺ cytotoxic T cells control proliferating B lymphocytes infected with EBV.

The T-lymphocyte cellular response is critical in determining the clinical expression of EBV viral infection. A rapid and efficient T-cell response results in control of the primary EBV infection and lifelong suppression of EBV.

Ineffective T-cell response may result in excessive and uncontrolled B-cell proliferation, resulting in B-lymphocyte malignancies (eg, B-cell lymphomas).

The immune response to EBV infection is fever, which occurs because of cytokine release consequent to B-lymphocyte invasion by EBV. Lymphocytosis observed in the RES is caused by a proliferation of EBV-infected B lymphocytes. Pharyngitis observed in EBV infectious mononucleosis is caused by the proliferation of EBV-infected B lymphocytes in the lymphatic tissue of the oropharynx.

Frequency

United States

EBV infectious mononucleosis is a common cause of viral pharyngitis in patients of all ages, but it is particularly frequent in young adults. In the United States, approximately 50% of the population seroconverts before age 5 years, with much of the rest seroconverting in adolescence or young adulthood. Approximately 12% of susceptible college-aged young adults convert each year, half of whom develop acute infectious mononucleosis.

International

See United States.

Mortality/Morbidity

• Patients with EBV infection who present clinically with infectious mononucleosis invariably experience accompanying fatigue. Fatigue may be profound initially but usually resolves gradually in 3 months. Some patients experience prolonged fatigue and, after initial recovery, enter a state of prolonged fatigue without the features of infectious mononucleosis.
• Mortality and morbidity rates due to uncomplicated primary EBV infectious mononucleosis are low. The rare cases of attributed mortality are usually related to spontaneous splenic rupture. Splenic rupture may be the initial presentation of EBV mononucleosis.
• Most cases of EBV infectious mononucleosis are subclinical, and the only manifestation of EBV infection is a serological response to EBV surface proteins discovered with EBV serological tests. Airway obstruction and central nervous system (CNS) mononucleosis are also responsible for increased morbidity in infectious mononucleosis. Selective immunodeficiency to EBV, which occurs in persons with X-linked lymphoproliferative syndrome, may result in severe, prolonged, or even fatal infectious mononucleosis.
• Hepatic necrosis caused by extensive EBV proliferation in the RES of the liver is the usual cause of death in affected males. EBV is the main cause of malignant B-cell lymphomas in patients receiving organ transplants.
• Most instances of posttransplant lymphoproliferative disorder (PTLD) are associated with EBV. EBV in PTLD is acquired from an EBV-positive donor organ. The likelihood of PTLD is directly proportional to the degree of immunosuppressive drugs administered to the transplant patient.
• Depending on the intensity, rapidity, and completeness of the T-lymphocyte response, malignancy may result if EBV-induced B-lymphocyte proliferation is uncontrolled. Hodgkin disease and non-Hodgkin lymphoma (NHL) may result. Other EBV-related malignancies include oral hairy leukoplakia in patients with HIV infection.
• Leiomyomas and leiomyosarcomas in immunocompromised children, nasopharyngeal carcinoma, and Burkitt lymphoma are among other neoplasms caused by EBV.

Age

Although primarily a disease of young adults, EBV infectious mononucleosis may occur from childhood to old age.

Clinical

History

• Most patients with Epstein-Barr virus (EBV) infectious mononucleosis are asymptomatic and, therefore, have few if any symptoms. Most adults (approximately 90%) show serological evidence of previous EBV infection.
• The incubation period of EBV infectious mononucleosis is 1-2 months. Many patients cannot recall close contact with individuals with pharyngitis. Virtually all patients with EBV infectious mononucleosis report fatigue and prolonged malaise. A sore throat is second only to fatigue and malaise as a presenting symptom.
• Fever is usually present and is low grade, but chills are relatively uncommon. Arthralgias and myalgias occur but are less common than in other viral infectious diseases.
• Nausea and anorexia, without vomiting, are common symptoms.
• Various other symptoms have been described in patients with EBV infectious mononucleosis, including cough, ocular muscle pain, chest pain, and photophobia.
• Importantly, patients without CNS involvement experience no cognitive difficulties. CMV infectious mononucleosis rarely involves the CNS.
• Myalgias, which are uncommon, are rarely (if ever) severe.

Physical

• Physical findings in infectious mononucleosis should be viewed in terms of frequency distribution and time course after clinical presentation.
• Early signs include fever, lymphadenopathy, pharyngitis, rash, and/or periorbital edema. Relative bradycardia has been described in some patients with EBV mononucleosis, but it is not a constant finding.
• Later physical findings include hepatomegaly, palatal petechiae, jaundice, uvular edema, splenomegaly, and, rarely (1-2%), findings associated with splenic rupture.
• CNS findings associated with EBV mononucleosis are rare but usually occur later in the course of the illness.
• Splenic tenderness may be present in patients with splenomegaly.
• Pulmonary involvement is not a feature of EBV infectious mononucleosis.
• The classic presentation of EBV infectious mononucleosis in children and young adults consists of the triad of fever, pharyngitis, and lymphadenopathy.
• Older adults and elderly patients with EBV infectious mononucleosis often have few signs and symptoms referable to the oropharynx and have little or no adenopathy. Elderly patients with EBV mononucleosis present clinically as having anicteric viral hepatitis.
• Predictably, jaundice develops in less than 10% of young adults with EBV infectious mononucleosis, but jaundice may occur in as many as 30% of affected elderly individuals.
• The pharyngitis due to EBV infectious mononucleosis may be exudative or nonexudative.
  • Exudative pharyngitis is commonly confused with group A streptococcal pharyngitis, which is complicated further by the fact that approximately 30% of patients with EBV infectious mononucleosis have group A streptococcal carriage of the oropharynx. The unwary physician may incorrectly conclude that a throat culture or rapid test positive for group A streptococci in a patient with infectious mononucleosis represents streptococcal pharyngitis.
  • Nonexudative pharyngitis with or without tonsillar enlargement is common in patients with EBV infectious mononucleosis and resembles viral pharyngitis.
  • Patients with either exudative or nonexudative EBV infectious mononucleosis are commonly colonized by group A streptococci.
• Tonsillar enlargement is common, and massive tonsillar enlargement may be observed. The term kissing tonsils is used to describe extreme enlargement of both tonsils in patients with EBV infectious mononucleosis. Extreme tonsillar enlargement may result in airway obstruction.
• Palatal petechiae of the posterior oropharynx distinguish infectious mononucleosis from other causes of viral pharyngitis but do not distinguish it from group A streptococcal pharyngitis, in which palatal petechiae may occur.
• Uvular edema is an uncommon finding in infectious mononucleosis, but, if present, it is a helpful sign in distinguishing EBV infectious mononucleosis from other causes of viral pharyngitis or from group A streptococcal pharyngitis.
• Early in the course of EBV infectious mononucleosis, patients may present with a maculopapular generalized rash. The rash is faint and evanescent and rapidly disappears. It is nonpruritic. This is a marked contrast to patients mistakenly diagnosed with streptococcal pharyngitis who have been administered ampicillin or amoxicillin and then develop a maculopapular rash as a drug reaction. Drug-induced rash is usually pruritic and is prolonged, in contrast to the viral rash of EBV infectious mononucleosis. Patients with EBV infectious mononucleosis who experience drug reactions to beta-lactams are not allergic to these medications. Administration of beta-lactams after resolution of the infection does not result in drug fevers or rashes.
• Splenomegaly is a late finding in EBV infectious mononucleosis. Splenic enlargement returns to normal or near normal usually within 3 weeks after the clinical presentation.
• In rare cases, EBV infectious mononucleosis results in various unusual clinical manifestations, including encephalitis, pancreatitis, acalculous cholecystitis, myocarditis, mesenteric adenitis, myositis, and glomerular nephritis.
• Neurologic syndromes due to EBV infectious mononucleosis include optic neuritis, transverse myelitis, aseptic meningitis, encephalitis, meningoencephalitis, cranial nerve (CN) palsies (particularly CN VII), and Guillain-Barré syndrome.
• Although EBV-induced antibodies to RBC membranes may occur, clinical anemia is uncommon with EBV infectious mononucleosis.
• Leukocytosis, rather than leukopenia, is the rule in infectious mononucleosis.
• Periorbital edema is an uncommon, and therefore fairly specific, physical finding in infectious diseases.
  • Bilateral periorbital edema not associated with generalized edema (eg, nephrotic syndrome) suggests trichinosis, Kawasaki disease, allergic reactions, or bilateral periorbital cellulitis.
  • Unilateral periorbital edema suggests conditions such as thyrotoxicosis, retro-orbital eye tumor, Chagas disease, insect sting, or unilateral conjunctivitis.
  • EBV infectious mononucleosis is characterized by early and transient bilateral upper-lid edema. In contrast to the disorders mentioned above, which are either unilateral or bilateral and involve the periorbital area, with or without the eyelids, the external eye involvement of EBV infectious mononucleosis is characterized by bilateral upper-lid edema. This finding was first described by Hoagland and is referred to as Hoagland sign. Hoagland noted the association of EBV infectious mononucleosis in young military recruits with EBV infectious mononucleosis. Hoagland sign may be detected when patients look in the mirror early in the course of their illness or when the astute physician notices this early in the clinical presentation. Hoagland sign is present for only the first few days of illness and should not be sought later in the course of the infectious process.
• Table 1. Differential Diagnoses of Infectious Mononucleosis

*Normal
^† Serum glutamic-oxaloacetic transaminase
^‡ Serum glutamic-pyruvic transaminase
^§ Immunoglobulin M
^II Viral capsid antigen

Causes

• The only predisposing risk factor for EBV infectious mononucleosis is close contact with an individual infected with EBV.
• EBV commonly persists in oropharyngeal secretions for months after clinical resolution of EBV infectious mononucleosis.
• Patients with congenital immunodeficiencies are predisposed to EBV-induced lymphoproliferative disorders and malignancies.
• Acquired immunodeficiencies due to the effects of immunosuppression (eg, PLDT) or infectious disease-induced immunosuppression (ie, HIV) may predispose to oral hairy leukoplakia or non-Hodgkin lymphoma.
• Burkitt lymphoma has a distribution (ie, in Africa) that is the same as the distribution of malaria. The geographic location predisposes to Burkitt lymphoma in children.

Differential Diagnoses

Other Problems to Be Considered

See Table 1.

Fever

Fever is rarely the sole manifestation of Epstein-Barr virus (EBV) infectious mononucleosis. Because most patients with EBV infectious mononucleosis usually have fever, pharyngitis, and lymphadenopathy, the differential diagnoses are those of an infectious mononucleosis–like illness, which include infectious mononucleosis due to cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), acute HIV disease, toxoplasmosis, and anicteric viral hepatitis.

These infectious diseases, which have presentations similar to those of infectious mononucleosis, have also been termed heterophile-negative infectious mononucleosis because the heterophile test and EBV serology findings are negative in these patients. In rare cases, EBV infection has been reported as a cause of fever of unknown origin (FUO).

Fevers due to EBV infectious mononucleosis may reach 103-104°F but are usually less than 102°F. Relative bradycardia is a rare finding in patients with EBV mononucleosis and suggests myocardial involvement (eg, myocarditis). Persistent fever or a recrudescence of fever after clinical recovery should suggest an alternate diagnosis.

Pharyngitis

Pharyngitis is one of the cardinal manifestations of EBV infectious mononucleosis. Exudative pharyngitis may resemble streptococcal pharyngitis. Patients with EBV mononucleosis may present with a pseudomembrane resembling Corynebacterium haemolyticum or Corynebacterium diphtheriae. However, these infections do not have the associated findings that comprise the infectious mononucleosis syndrome and should present no diagnostic difficulties.

Palatal petechiae are most commonly found in association with EBV infectious mononucleosis but may also be observed in group A streptococcal pharyngitis. In patients with pharyngitis, palatal petechiae may also be a sign of a granulocytosis caused by aplastic anemia or a lymphoreticular malignancy involving the bone marrow (eg, acute leukemias or lymphomas).

Uvular edema is an important and fairly specific finding in individuals with EBV infectious mononucleosis. The causes of heterophile-negative infectious mononucleosis and group A streptococcal pharyngitis are not accompanied by uvular edema. Although uncommon, uvular edema has important diagnostic significance when present. Patients with a C1q deficiency may present with uvular edema; however, these patients have no evidence of pharyngitis, fever, or adenopathy and should not be confused with patients with EBV infectious mononucleosis.

The posterior oropharynx in patients with EBV infectious mononucleosis is uniformly erythematous. This is in contrast to the discreet pretonsillar purplish discoloration observed in chronic fatigue syndrome (CFS) that has been termed "crimson crescents." Crimson crescents, a possible marker of CFS, occur in the absence of surrounding posterior pharyngeal erythema. Patients with CFS do not present predominantly with pharyngitis.

Patients with heterophile-negative infectious mononucleosis have minimal or mild nonexudative pharyngitis. Palatal petechiae and uvular edema are usually absent, and exudative pharyngitis is not a feature of these infectious diseases.

Lymphadenopathy

Any or all chains may be enlarged in individuals with EBV infectious mononucleosis. Lymphadenopathy is always bilateral and symmetrical in all patients, including those presenting with generalized adenopathy. Bilateral posterior cervical adenopathy is most highly suggestive of EBV infectious mononucleosis.

Some of the causes of heterophile-negative infectious mononucleosis may manifest as bilateral posterior cervical adenopathy (eg, rubella), but other signs and symptoms serve to differentiate these patients from those with EBV infectious mononucleosis. Patients with rubella have other associated findings, including the distribution and progression of the rash and occipital or preauricular adenopathy; usually, they do not have generalized adenopathy, and liver involvement is not a feature of rubella infections.

Acquired toxoplasmosis in adults has minimal pharyngeal or hepatic involvement, but adenopathy may be prominent. In contrast to EBV infectious mononucleosis, generalized adenopathy is not a feature of toxoplasmosis. Highly characteristic of toxoplasmosis is asymmetrical lymphadenopathy limited to an isolated lymph node group. Patients with toxoplasmosis have little or no fever, fatigue, or pharyngitis, which helps differentiate toxoplasmosis-induced infectious mononucleosis from EBV-induced infectious mononucleosis.

Patients with HHV-6 infection may have a presentation that is identical to that of infectious mononucleosis, but fatigue is usually less prominent. Isolated posterior cervical adenopathy may also occur with in HHV-6 infectious mononucleosis.

Patients with HIV infection with acute seroconversion may present with a mononucleosislike illness with a maculopapular rash, mild pharyngitis, and lymphadenopathy. The adenopathy in HIV may be localized or generalized, but splenomegaly is not a feature of uncomplicated early HIV infection. Adenopathy localized to a lymph node group in a patient with HIV infection should suggest a lymphoma rather than a primary manifestation of acute HIV infection.

Anicteric hepatitis is rarely, if ever, accompanied by localized or generalized adenopathy. The finding of bilateral posterior cervical adenopathy argues against the diagnosis of anicteric hepatitis in a patient with otherwise unexplained fatigue.

CMV mononucleosis is the heterophile-negative cause of infectious mononucleosis that is most likely to be confused with EBV infectious mononucleosis. CMV infectious mononucleosis may be indistinguishable in clinical presentation from EBV but is usually not accompanied by posterior cervical adenopathy. Nonexudative pharyngitis is minimal or absent, and splenomegaly is less common than in EBV infectious mononucleosis. CMV infectious mononucleosis is characterized by its prolonged course and prominent liver involvement. Serum transaminases may persistently remain mildly to moderately elevated for prolonged periods. In patients presenting with infectious mononucleosis that has persisted for 6-12 months after a mononucleosislike illness, the condition is most likely due to CMV infectious mononucleosis.

Pseudolymphoma

Patients receiving certain drugs, particularly phenytoin (Dilantin), may present with a mononucleosislike illness. Such patients usually present with fever and generalized adenopathy without pharyngitis or liver involvement. The finding of isolated groups of lymph node enlargement (eg, posterior cervical adenopathy) argues against the diagnosis of drug-induced pseudolymphoma.

Atypical lymphocytes may be present in patients with drug fevers and pseudolymphomas, but the percentage of atypical lymphocytes is less than 10%, in contrast to EBV-induced infectious mononucleosis. Pseudolymphoma may be confused with lymphomas but may be differentiated readily based on a lack of eosinophils or basophils, which may be present in the peripheral smear of patients with lymphoma, or the finding of abnormal lymphocytes in the peripheral smear versus the atypical lymphocytes of pseudolymphoma and viral infections, which are reactive and atypical but not abnormal.

Anicteric hepatitis

Patients with anicteric hepatitis present with anorexia, malaise, and fatigue. Pharyngitis may occur, but it is mild and nonexudative. Generalized adenopathy and splenomegaly may occur with anicteric hepatitis, but this occurs much more infrequently than with EBV infectious mononucleosis. Anicteric hepatitis is most likely to be confused with EBV infectious mononucleosis in elderly individuals who present with hepatitis. Positive findings on hepatitis serology and negative findings on heterophile/EBV serology differentiate these two infectious diseases.

Splenomegaly

Splenomegaly may be classified according to the degree of splenic enlargement and whether it occurs alone or as part of generalized lymph node involvement. Although, in rare cases, splenic rupture is the initial clinical manifestation of EBV infectious mononucleosis, the splenomegaly of EBV infectious mononucleosis is usually accompanied by localized or generalized adenopathy. In the absence of splenic rupture, patients with EBV infectious mononucleosis do not present with isolated splenomegaly in the absence of other findings. The many systemic disorders that manifest as splenomegaly in the absence of lymphadenopathy, eg, brucellosis, lymphoma, and subacute bacterial endocarditis (SBE), are readily differentiated from EBV infectious mononucleosis with splenic enlargement.

Generalized adenopathy may occur with many infectious and noninfectious diseases, most commonly group A streptococcal infections, systemic lupus erythematosus (SLE), and sarcoidosis. Because the spleen is part of the RES, most cases of generalized adenopathy are accompanied by splenomegaly. However, most disorders with presentations that predominantly involve generalized adenopathy rarely involve splenomegaly, and, when present, the splenic enlargement is not prominent (eg, generalized adenopathy is common in SLE, but splenomegaly is uncommon). Generalized adenopathy with prominent splenomegaly should suggest EBV infectious mononucleosis. A diagnosis of EBV infectious mononucleosis in the absence of bilateral posterior cervical adenopathy with or without generalized adenopathy or splenomegaly should raise suspicion of the diagnosis.

Leukocytosis

Most patients with EBV infectious mononucleosis have a mildly to moderately increased peripheral WBC count, usually in the range of 12-20,000 cells/µL. Leukocytosis is a nonspecific finding in medicine in general and in infectious disease in particular. Leukocytosis has importance in ruling out some other causes of heterophile-negative infectious mononucleosis. Leukopenia, rather than leukocytosis, is expected in patients with CMV, rubella, HHV-6, acute HIV, and anicteric hepatitis-related infectious mononucleosis. Patients with toxoplasmosis and pseudolymphoma usually have a normal rather than an elevated peripheral WBC count.

Lymphocytosis

Lymphocytosis is one of the classic hematological abnormalities associated with EBV infectious mononucleosis. Relative lymphocytosis (>60%) plus atypical lymphocytosis (>10%) are the characteristic findings of EBV infectious mononucleosis. The causes of heterophile-negative infectious mononucleosis rarely, if ever, have a relative lymphocytosis in excess of 60%. However, in contrast, atypical lymphocytosis is a common feature of any agent responsible for heterophile-negative infectious mononucleosis. The important differential diagnostic point is that the atypical lymphocytosis of EBV infectious mononucleosis is not simply equal to or greater than 10% but is frequently equal to or greater than 30%. An important point is that EBV infectious mononucleosis is more likely to be the cause of atypical lymphocytosis in patients with infectious mononucleosis with greater degrees of atypical lymphocytosis.

Thrombocytopenia

Mild transient thrombocytopenia is not uncommon in EBV infectious mononucleosis. Severe or persistent thrombocytopenia should suggest an alternate diagnosis, eg, acute HIV or other viral infectious diseases. Thrombocytosis is not a feature of EBV infectious mononucleosis, and its presence should suggest an alternate diagnosis, eg, malignancy due to lymphoma in adults or, in children, Kawasaki disease.

Increased serum transaminases

An early, transient, mild increase in serum transaminases is characteristic of EBV infectious mononucleosis. High elevation of the serum transaminases should suggest viral or drug-induced hepatitis. The mild elevations of serum transaminases that occur in infectious mononucleosis are useful diagnostic tests before the heterophile becomes positive. Mild-to-moderate elevations of the serum transaminases that persist over months in a patient with a mononucleosislike illness should suggest CMV rather than EBV infectious mononucleosis.

Erythrocyte sedimentation rate

Erythrocyte sedimentation rate (ESR) elevations occur in virtually all patients early in the course of EBV infectious mononucleosis. Similar to the early and mild elevations of the serum transaminases that occur in EBV infectious mononucleosis, an elevated ESR can be a useful diagnostic test early in the course of the disease in patients presenting with pharyngitis. While the ESR is elevated in patients with EBV as well as with other causes of viral pharyngitis, it is not elevated in patients with group A streptococcal pharyngitis. In patients with pharyngitis, elevations of the ESR are most useful in differentiating EBV infectious mononucleosis from group A streptococcal pharyngitis early in the course of the disease before the heterophile or the antistreptolysin-O (ASO) titers increase.

Maculopapular rash

Maculopapular rash may be caused by a large variety of infectious and noninfectious agents. Maculopapular rashes associated with pruritus are not caused by infectious agents. Nonpruritic maculopapular rashes may be caused by a wide variety of infectious and noninfectious disorders. The differential diagnoses of rash and fever depend largely on the distribution of the rash. Unfortunately, maculopapular rashes are generalized, offering little opportunity to narrow differential diagnostic possibilities. Therefore, the best approach to the differential diagnoses of maculopapular rashes must depend on their clinical behavior, rate of progression and/or recession, and associated nondermatologic features.

The rash of EBV infectious mononucleosis occurs in the first few days and is transient, mild, and evanescent. The early rash of EBV infectious mononucleosis is easily missed by patients and physicians. The causes of heterophile-negative infectious mononucleosis are usually unaccompanied by a rash, except for acute HIV infection, which has a rash indistinguishable from EBV primary infection.

Rubella is the least likely exanthem to be confused with EBV mononucleosis; the rash persists longer and is not accompanied by the other features that are characteristic of infectious mononucleosis, eg, prominent pharyngitis. Patients with measles have conjunctival injection, coryza, and a rash that is maculopapular but blotchy and progresses from the head downward, differentiating it from the rash of EBV. A rash caused by contact dermatitis or drug-induced maculopapular rashes are pruritic, differentiating them easily from the rash of EBV. Erythrodermas with an initial presentation of maculopapular rashes caused by systemic disorders are usually persistent (eg, Sézary syndrome), in contrast to the evanescent mild rash of EBV infectious mononucleosis.

Periorbital edema

Periorbital edema is caused by various agents. Periorbital edema is an uncommon, and therefore fairly specific, physical finding in infectious diseases. Bilateral periorbital edema not associated with generalized edema, eg, nephrotic syndrome, should suggest trichinosis, Kawasaki disease, allergic reactions, or bilateral periorbital cellulitis. Unilateral periorbital edema suggests conditions such as thyrotoxicosis, retro-orbital eye tumor, Chagas disease, insect sting, and unilateral conjunctivitis. EBV infectious mononucleosis is characterized by early and transient bilateral upper-lid edema.

In contrast to the disorders mentioned above, which are either unilateral or bilateral and involve the periorbital area, with or without the eyelids, the external eye involvement of EBV infectious mononucleosis is characterized by bilateral upper-lid edema. This finding first was described by Hoagland and is referred to as Hoagland sign (see Physical). In contrast, infectious mononucleosis is characterized by palpebral edema rather than periorbital edema.

Splenic rupture

Splenic rupture is a rare complication of EBV infectious mononucleosis. Splenic rupture may be the presenting sign of EBV primary infection.

Meningoencephalitis

Meningoencephalitis is a very rare manifestation of EBV infectious mononucleosis. Patients who have unusual neurologic manifestations (eg, scalp tenderness, optic neuritis) usually have other features of EBV infectious mononucleosis, which should suggest the cause of the patient's neurologic symptoms. Neurologic manifestations as the sole indication of EBV infectious mononucleosis are rare. The diagnosis of EBV infectious mononucleosis is a syndromic diagnosis, which is based on the association of fever, pharyngitis, and lymphadenopathy in conjunction with the characteristic hematologic abnormalities of EBV infectious mononucleosis. The clinician should look for associated features of infectious mononucleosis to rule in or rule out the possibility in patients with otherwise unexplained mental status changes.

Chronic fatigue

Profound initial fatigue and malaise is a feature of EBV infectious mononucleosis. Fatigue has extensive differential diagnoses because many systemic disorders are accompanied by fatigue. The cause of fatigue in the patient with EBV infectious mononucleosis is suggested by the constellation of signs, symptoms, and laboratory abnormalities that suggest the diagnosis. In the absence of such findings, other causes of fatigue should be sought.

Many infectious agents, including EBV infectious mononucleosis, are known to initiate a state of chronic fatigue. Appreciate that EBV may trigger chronic fatigue, but it does not cause chronic fatigue. The fatigue of EBV infection usually resolves within 3 months and uncommonly lasts for longer than 6 months. Patients with CFS have otherwise unexplained fatigue for a duration equal to or greater than 1 year (for a full discussion on CFS, see Chronic Fatigue Syndrome). In summary, acute, but not chronic, fatigue is a feature of EBV infectious mononucleosis.

Chronic infectious mononucleosis is rare and occurs in those with immunologic abnormalities. Such patients present with fever, lymphadenopathy, persistently elevated serum transaminases, and pancytopenia. Eye or neurologic abnormalities may also be present. Importantly, patients with CFS have none of these findings. Patients with acute EBV infection do not have pancytopenia, and their clinical presentation rapidly resolves. Chronic infectious mononucleosis is a diagnosis that should be made rarely and carefully. Commonly, patients and physicians equate increased EBV immunoglobulin G (IgG) VCA antibody titers with chronic infectious mononucleosis or CFS because more than 90% of the population has increased EBV IgG VCA antibodies. The associated findings of fatigue are coincidental and are not related causally.

Workup

Laboratory Studies

• Epstein-Barr virus (EBV) infection induces specific antibodies to EBV and various unrelated non-EBV heterophile antibodies (see Image 1). These heterophile antibodies react to antigens from animal RBCs.
  
  

  

  Infectious mononucleosis. Antibody response to Epstein-Barr virus. Adapted with permission from Johnson DH, Cunha BA. Epstein-Barr virus serology. Infect Dis Pract. 1995;19:26-27.

  
  
  • Sheep RBCs agglutinate in the presence of heterophile antibodies and are the basis for the Paul-Bunnell test.
  • Agglutination of horse RBCs on exposure to heterophile antibodies is the basis of the Monospot test.
• Heterophile test antibodies are sensitive and specific for EBV heterophile antibodies, they are present in peak levels 2-6 weeks after primary EBV infection, and they may remain positive in low levels for up to a year.
• The latex agglutination assay, which is the basis of the Monospot test using horse RBCs, is highly specific. Sensitivity is 85%, and specificity is 100%.
• The heterophile antibody test (eg, the Monospot test) results may be negative early in the course of EBV infectious mononucleosis. Positivity increases during the first 6 weeks of the illness. Patients who remain heterophile negative after 6 weeks with a mononucleosis illness should be considered as having heterophile-negative infectious mononucleosis.
  • Patients with heterophile infectious mononucleosis should be tested for EBV-specific antibodies before definitively diagnosing heterophile-negative infectious mononucleosis.
  • Patients with heterophile- or Monospot-negative infectious mononucleosis should be tested serologically as are patients who present with a mononucleosislike illness who are negative for heterophile antibodies. The heterophile test is less useful in children younger than 2 years, in whom the results are frequently negative.
  • Although virtual 100% specificity exists with the Monospot test, rarely, other disorders have been reported that may produce a false-positive Monospot test result. These causes of false-positive Monospot test results include toxoplasmosis, rubella, lymphoma, and certain malignancies, particularly leukemias and/or lymphomas.
• Testing for EBV-specific antibodies is as follows:
  • EBV induces a serological response to the various parts of the Epstein-Barr viral particle. IgM and IgG antibodies directed against the VCA of EBV are useful in confirming the diagnosis of EBV and in differentiating acute and/or recent infection from previous infection. EBV IgM VCA titers decrease in most patients after 3-6 months but may persist in low titer for up to 1 year. EBV IgG VCA antibodies rise later than the IgM VCA antibodies but remain elevated with variable titers for life.
  • False-positive VCA antibody titer results may occur on the basis of cross-reactivity with other herpes viruses, eg, CMV, or with unrelated organisms, eg, Toxoplasma gondii.
• Other antigens indicating EBV infection are less useful diagnostically and include early antigen (EA), which is present early in EBV infectious mononucleosis. EBV nuclear antigen (EBNA) appears after 1-2 months and persists throughout life. The presence of elevated EBNA titers has the same significance as elevated IgG VCA titers. The presence of these antibodies suggests previous exposure to the antigen (past infection) and excludes EBV infection acquired in the previous year.
• As with heterophile antibody responses, specific EBV antibodies may not be present in children younger than 2 years.
• Nonspecific tests are as follows:
  • Patients with infectious mononucleosis in the differential diagnoses should have a CBC count with differential and an evaluation of the erythrocyte sedimentation rate (ESR). The CBC count is more useful in ruling out other diagnoses that may mimic infectious mononucleosis than in providing any specific diagnostic information. Because leukocytosis is the rule in infectious mononucleosis, the presence of a normal or decreased WBC count should suggest an alternative diagnosis. Lymphocytosis accompanies infectious mononucleosis, increases during the first few weeks of illness, and then gradually returns to normal. The appearance, peak, and disappearance of atypical lymphocytes follow the same time course as lymphocytosis. Patients with fever, pharyngitis, and lymphadenopathy are likely to have EBV infectious mononucleosis if the relative atypical lymphocyte count is equal to or greater than 20%.
  • Atypical lymphocytes should be differentiated from abnormal lymphocytes. Abnormal lymphocytes are associated with lymphoreticular malignancies, whereas atypical lymphocytes are associated with various viral and noninfectious diseases, as well as drug reactions. Atypical lymphocytes are each different in their morphology as observed on the peripheral smear, whereas abnormal lymphocytes are monotonous in their sameness, which readily permits differentiation on the peripheral smear.
  • Because anemia is so rare with EBV infectious mononucleosis, patients with anemia should undergo workup for another cause of their anemia.
  • Thrombocytopenia not uncommonly accompanies EBV infectious mononucleosis, but it may be present in various other viral illnesses, including in patients with heterophile-negative infectious mononucleosis.
  • An ESR is most useful in differentiating group A streptococcal pharyngitis from EBV infectious mononucleosis. The sedimentation rate is elevated in most patients with EBV infectious mononucleosis, but it is not elevated in group A streptococcal pharyngitis. However, an elevated ESR does not differentiate EBV from the other heterophile-negative causes of infectious mononucleosis, nor does it differentiate infectious mononucleosis from malignancies.
  • Because the liver is uniformly involved in EBV infectious mononucleosis, mild elevation of the serum transaminases is a constant finding in early EBV infectious mononucleosis. Mild increases in the serum transaminases are also a feature of the infectious agents responsible for heterophile-negative infectious mononucleosis. High elevation of the serum transaminases should suggest viral hepatitis. The serum alkaline phosphatase and gamma-glutamyl transpeptidase (GGTP) levels are not usually elevated in individuals with EBV infectious mononucleosis.
• Specific tests are as follows:
  • Heterophile antibody tests
    • Patients with infectious mononucleosis should first be tested with a heterophile antibody test. The most commonly used is the latex agglutination assay using horse RBCs, and it is marketed as the Monospot test. Enzyme-linked immunosorbent assay (ELISA) rapid diagnostic tests are also available, which are based on the detection of heterophile antibodies. Physicians should remember that heterophile antibody responses require 1-2 weeks to become positive. In a group of patients with EBV mononucleosis, the number of patients becoming positive increases to a maximum 6 weeks after the onset of the illness.
    • If results are initially negative, a Monospot test should be ordered weekly for 6 weeks in patients with suspected EBV infectious mononucleosis. If the Monospot test remains persistently negative after 6 weeks of weekly serial testing, then a specific EBV serological test should be ordered. Before patients with an infectious mononucleosis–like syndrome are labeled as having heterophile-negative infectious mononucleosis, specific EBV serological tests should be obtained, and the results should be negative (see below).
    • Major antibodies - Heterophile (Paul-Bunnell), EBV antigens, cold agglutinins (anti-1), smooth muscle antibodies (SMA)
    • Minor antibodies - Rheumatoid factor (RF), antinuclear antibodies (ANA), antimitochondrial antibodies, antireticulin antibodies, antimicrosomal antibodies, anti–intermediate filaments (IMF), lymphocytotoxin, Wasserman reagin
    • The Monospot test has high sensitivity and specificity, eg, 85% and nearly 100%, respectively. Rarely, Monospot test results may be falsely positive, particularly in patients with CMV or rubella but also in patients with SLE and rheumatoid arthritis. Potential false-positive reactions may occur in those with HIV infection or herpes simplex virus (HSV). If a false-positive Monospot test result is suspected, then specific testing using an EBV-based antibodies serological test is indicated. A false-negative Monospot test result may occur if testing is performed too early in the course of the illness or in very young children (<2 y) and occasionally in elderly patients.
  • Specific EBV antibody tests
    • Specific EBV antibody testing is more time-consuming and expensive than the Monospot test. EBV serological tests should be obtained in patients with a mononucleosislike illness and a negative finding on the Monospot test. As with the heterophile test, the EBV antibody response may be falsely negative early in the course of the infection. False negativity may also occur in young children (<2 y).
    • The antibody response to specific EBV serological testing consists of measuring the antibody response to surface and core EBV viral proteins. For clinical purposes, the most useful EBV-specific antibodies are the VCAs and the EBNA. Both VCA and EBNA antibodies are usually reported as IgM or IgG antibodies. Acute infection is diagnosed in patients who have an increased EBV IgM VCA titer. Later in the course of infection, the increase in IgM VCA antibodies may be accompanied by an increase in IgG VCA antibodies and an increase in IgG EBNA antibodies. Many laboratories report EBNA titers only, which usually measure the IgG EBNA.
    • Increased IgG VCA and/or increased IgG EBNA titers indicate past exposure to EBV, which may have been subclinical or clinical. Increased IgG VCA titers are not synonymous with chronic infectious mononucleosis, and these titers are not diagnostic of CFS. Following acute infection, the increase in IgM titers peaks after 4-8 weeks and usually remain positive for as long as 1 year. The Monospot heterophile antibodies follow the same time course as the IgM VCA titers.
    • Rarely, cross-reactivity occurs between VCA antibodies to EBV and those to CMV or toxoplasmosis. False-positive cross-reactivity to specific EBV antibodies is extremely rare. Such patients have high elevations of IgM CMV or toxoplasmosis titers, which helps to differentiate between the primary infectious agent and the serological cross-reactivity resulting in a false-positive test result.
    • Patients with heterophile-negative infectious mononucleosis, eg, those with persistently negative Monospot test results for 6 weeks and those with a negative EBV-specific test result, should be tested serologically for the infectious agents that cause heterophile-negative infectious mononucleosis (eg, HIV, HHV-6, toxoplasmosis, CMV, rubella, anicteric viral hepatitis).

Table 2. EBV Serologic Responses in EBV-Associated Diseases

• Other tests are as follows:
  • Patients with suspected infectious mononucleosis should not have their throats cultured for group A streptococci because the carriage rate is approximately 30% in these patients. The mere recovery of group A streptococci from the oropharynx does not signify the cause of the patient's pharyngitis; it does not differentiate colonization from infection. In such patients, a Gram stain of the oropharynx is used to differentiate patients who have pharyngitis with positive cultures for group A streptococci from those colonized with group A streptococci.
  • Patients with EBV infectious mononucleosis or other causes of viral pharyngitis and group A streptococcal colonization have little or no white cell response on the Gram stain of the pharynx. Patients with group A streptococcal pharyngitis also have a positive finding on throat culture, but, in contrast to the patients with colonization, they show an intense polymorphonuclear cellular response with cellular debris and fibrous fragments indicating acute infection. The rapid streptococcal test cannot be used to differentiate colonization from infection any more than throat cultures.
  • Patients with presumed CNS involvement with EBV infectious mononucleosis should undergo serological tests for other causes of viral encephalitis appropriate to the patient's exposure history.

Imaging Studies

• Patients with presumed CNS involvement with EBV infectious mononucleosis should undergo a CT scan and/or MRI to rule out other causes of encephalitis.

Other Tests

• Patients with presumed CNS involvement with EBV infectious mononucleosis should also undergo an EEG to rule out other causes of encephalitis.

Procedures

• Rarely, if ever, is a bone marrow biopsy or lymph node biopsy needed in patients with EBV infectious mononucleosis. In the diagnosis of EBV infectious mononucleosis, the assessment of lymph node enlargement can be made confidently based on specific EBV antibody testing, and surgery is almost never necessary.
• Patients with presumed CNS involvement with EBV infectious mononucleosis should also undergo a lumbar puncture to rule out other causes of encephalitis.

Histologic Findings

Oropharyngeal epithelium demonstrates an intense lymphoproliferative response in the cells of the oropharynx. The lymph node and spleen show lymphocytic infiltration primarily in the periphery of a lymph node.

Treatment

Medical Care

Surgical Care

Surgery is necessary for spontaneous splenic rupture, which occurs in rare patients with EBV infectious mononucleosis and may be the initial manifestation of the condition.

Consultations

• Consult an infectious disease specialist in all but the most straightforward cases of EBV infectious mononucleosis.
• Consulting a hematologist may be necessary if unusual hematologic manifestations of EBV infectious mononucleosis are present (eg, in anemia to determine the cause of the patient's anemia).
• Consulting a neurologist is advised for patients with potential CNS involvement.
• Consultation with a cardiologist is advised for the rare patients with EBV infectious mononucleosis who have presumed myocarditis.
• Consult a gastroenterologist for patients with EBV-induced acalculous cholecystitis or if anicteric hepatitis is in the differential diagnoses.

Diet

Normal diet is appropriate.

Activity

Patients with acute EBV mononucleosis should be encouraged to rest as much as possible and to refrain from active physical activity for 3 weeks.

Medication

No effective antiviral therapy is available for Epstein-Barr virus (EBV) infectious mononucleosis in immunocompetent persons. Acyclovir and ganciclovir may reduce EBV shedding but are ineffective clinically.

Treatment of immunocompromised patients with EBV lymphoproliferative disease is controversial. Acyclovir has not been proven to be beneficial.

Short courses of corticosteroids are indicated for EBV infectious mononucleosis with hemolytic anemia, thrombocytopenia, CNS involvement, or extreme tonsillar enlargement. However, corticosteroids are not indicated for uncomplicated EBV infectious mononucleosis. Corticosteroids should be considered in those with impending airway obstruction.

Patients with EBV infectious mononucleosis who have positive throat cultures for group A streptococci should not be treated because this represents colonization rather than infection (see Workup).

Treatment of group A streptococcal oropharyngeal colonization in patients with EBV infectious mononucleosis may result in a maculopapular rash.

Follow-up

Further Inpatient Care

• Patients with extreme tonsillar enlargement may require extended care if intubation is required.

Further Outpatient Care

• Monitor patients to be sure that the infection is improving over time. Serial CBC counts should document the increase in lymphocytes as well as atypical lymphocytes, and this may be monitored on a weekly basis until these values normalize.
• Patients with positive heterophile tests should not be monitored with serial testing because the heterophile test may remain positive for as much as 1 year after infection.
• Serial specific Epstein-Barr virus (EBV) antibody testing is usually not necessary in patients with acute infection. Caution patients that increased IgG, VCA, and EBNA levels persist for life. Also, inform patients that titers vary and that IgG titers have no relationship to disease activity or to how the patient feels.
• Patients should be advised that fatigue may take some time to resolve, and some patients may develop a state of chronic fatigue that is induced, but not caused by, EBV infectious mononucleosis.

Deterrence/Prevention

• Avoid close contact with body fluid secretions, particularly saliva.

Complications

• Extreme enlargement of the tonsils may result in airway obstruction (see Medical Care).
• Encephalitis and myocarditis are rare complications.
• Splenic rupture is a rare, but potentially lethal, complication of EBV infectious mononucleosis.
• Rare patients with EBV infectious mononucleosis develop lymphoma.

Prognosis

• If splenic rupture is recognized and expeditiously treated surgically, the prognosis is good.
• Patients with EBV infectious mononucleosis who become asplenic as the result of splenic rupture and/or surgical removal should be treated as other patients with asplenia.

Patient Education

• Counsel patients to refrain from strenuous physical activity for the first 3 weeks of illness.
• Patients should avoid exposing other people to their body secretions because EBV remains viable in patients with EBV infectious mononucleosis for months after the initial infection.
• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center and Back, Ribs, Neck, and Head Center. Also, see eMedicine's patient education articles Mononucleosis and Chronic Fatigue Syndrome.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize splenic rupture is a complication of infectious mononucleosis, particularly in patients in whom splenic rupture is the initial clinical manifestation of Epstein-Barr virus (EBV) infectious mononucleosis.

Multimedia

Media file 1: Infectious mononucleosis. Antibody response to Epstein-Barr virus. Adapted with permission from Johnson DH, Cunha BA. Epstein-Barr virus serology. Infect Dis Pract. 1995;19:26-27.

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Keywords

infectious mononucleosis, mono, glandular fever, infectious mono, Drüsenfieber, Epstein-Barr virus, EBV, viral pharyngitis, acute infectious mononucleosis, EBV infectious mononucleosis, EBV mononucleosis, heterophile-negative infectious mononucleosis, adenopathy, spontaneous splenic rupture, malaise, hepatic necrosis, malignant B-cell lymphomas, posttransplant lymphoproliferative disorder, PTLD, Hodgkin disease, non-Hodgkin lymphoma, NHL, oral hairy leukoplakia, leiomyomas, leiomyosarcomas, nasopharyngeal carcinoma, Burkitt lymphoma, anicteric viral hepatitis, exudative pharyngitis, Hoagland sign

Contributor Information and Disclosures

Author

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Medical Editor

Charles S Levy, MD, Associate Professor, Department of Medicine, Section of Infectious Disease, George Washington University School of Medicine
Charles S Levy, MD is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America, and Medical Society of the District of Columbia
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John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center
John W King, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Association of Subspecialty Professors, Infectious Diseases Society of America, and Sigma Xi
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CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
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Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center
Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, Association of Professors of Medicine, Association of Program Directors in Internal Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, and Southern Society for Clinical Investigation
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