Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono) Differential Diagnoses

Updated: Sep 20, 2018
  • Author: Burke A Cunha, MD; Chief Editor: Michael Stuart Bronze, MD  more...
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Diagnostic Considerations

See Table 1.


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 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.


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.


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 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.


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 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.


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 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.