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

Updated: Apr 21, 2021
Author: Kartika Shetty, MD, FACP; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Epstein-Barr virus (EBV), also known as human herpes virus 4, is a widely disseminated double stranded DNA herpesvirus. It is the causative agent of infectious mononucleosis ("mono" or "glandular fever").

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. 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 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.

Pathophysiology

Epstein-Barr virus (EBV) is transmitted via intimate contact with body secretions, primarily oropharyngeal secretions and to a lesser degree through genital secretions. It infects the B cells in the oropharyngeal epithelium; after acute infection the virus has been detected in oro-pharyngeal secretions for up to 32 weeks[2]  and may persist for decades. On rare occasion, EBV is spread via blood transfusion and organ transplantation.

Epstein-Barr virus 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, but the T-lymphocyte cellular response is critical in determining the clinical expression of EBV infection. Natural killer (NK) cells and predominantly CD8+ cytotoxic T cells control proliferating B lymphocytes infected with EBV.

Ineffective T-cell response may cause 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 reticuloendothelial system (RES) is caused by a proliferation of EBV-infected B lymphocytes and similar proliferation in the lymphatic tissue of the oropharynx causes pharyngitis.

Epidemiology

Epstein-Barr Virus (EBV) is among the most prevalent human viruses in the world.[3]  It is estimated that 90% of the global population is seropositive for EBV,[4]  with developed countries bearing a comparatively lower burden of EBV seroprevalence.[5]  Residents of developed countries also experience primary EBV infection at a later age.[6]  In the United States, the EBV seroprevalence for children and adolescents between the ages of 6-19 is about 66.5%, with female, African-American, and Hispanic populations experiencing significantly higher rates of seropositivity.[5]  Significant seroprevalence differences exist by family income, with children in the lowest income quartile having 81.0% seroprevalence compared with 53.9% in the highest income quartile.[5]  In US institutions characterized by the presence of many young adults, such as universities and the armed forces, the annual incidence for infectious mononucleosis ranges from 11 to 48 cases per 1000 persons.[7]

Prognosis

Mortality/Morbidity

Various complications related toEpstein-Barr virus (EBV), either directly or secondary to unregulated immune response, are described in the literature. Important conditions include the following:

Airway obstruction 

Fatigue

Renal complications

Nervous System complications

Malignancy

Chronic Active EBV (CAEBV)

Lymphoproliferative disorders 

Posttransplantation lymphoproliferative disorders (PTLD)

Splenic Rupture - Splenomegaly is a common presentation among those with infectious mononucleosis, and although splenic rupture is rare, it can be life-threatening. Most spleen ruptures occur after even mild abdominal trauma and are more likely to occur between day 4 and 21 of the illness. Rest and restriction from weight-lifting and contact sports should be implemented at least for the first 4 weeks on onset of symptoms. These patients can present with non-specific abdominal pain, left upper quadrant pain that radiates to the left shoulder, acute drop in Hematocrit, or shock.[8, 9]  Some will require splenectomy and others will require supportive care which is the preferred treatment.[10]  

Airway obstruction - Obstruction of the upper airway due to massive lymphoid hyperplasia and mucosal edema is an uncommon but potentially fatal complication of infectious mononucelosis.

Fatigue - 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.

Renal Complications - Epstein-Barr virus is connected to a variety of renal syndromes, including interstitial nephritis, myositis-associated acute kidney injury, hemolytic uremic syndrome, and jaundice-associated nephropathy.[11]  Although rare, there are documented cases of fatalities resulting from the aforementioned diseases.

Nervous System Disorders- Central nervous system (CNS) mononucleosis is also responsible for increased morbidity in infectious mononucleosis.

A further source of morbidity in the context of this disease is research that points to a link between EBV and the development of multiple sclerosis (MS). Epstein-Barr virus seroprevalence is higher among people with MS, symptomatic EBV infection (IM) is more prevalent among people with MS and higher anti-EBV antibody titers are associated with an increased risk for MS.[12]  Epstein-Barr virus infection appears to be a necessary but not sufficient requirement for developing MS. Multiple sclerosis is overwhelmingly likely to be the result of multiple environmental risk modifiers.

Presentation

Age

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

 

Presentation

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 4-6 weeks. 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. Fevers due to EBV infectious mononucleosis may reach 103-104°F but are usually less than 102°F.  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.

Causes

The only predisposing risk factor for Epstein-Barr virus (EBV) infectious mononucleosis is close contact with an individual infected with EBV. Epstein-Barr virus 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.

 

Physical Examination

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.
  • Splenic tenderness may be present in patients with splenomegaly. Splenomegaly is a late finding in EBV infectious mononucleosis. Generalized adenopathy with prominent splenomegaly should suggest EBV infectious mononucleosis. Splenic enlargement returns to normal or near normal usually within 3 weeks after the clinical presentation. 
  • 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.
  • 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.
  • 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.
  • 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. Palatal petechiae may also be a sign of agranulocytosis caused by aplastic anemia or a lymphoreticular malignancy involving the bone marrow (eg, acute leukemias or lymphomas).
  • 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.
  • 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.
  • 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 drug-induced rash which is usually pruritic and is prolonged. 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. Rash has also been seen with azithromycin, levofloxacin, piperacillin-tazobactam, and cephalexin.
  • 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.
  • In rare cases, EBV infectious mononucleosis results in various unusual clinical manifestations, including encephalitis, pancreatitis, acalculous cholecystitis, myocarditis, mesenteric adenitis, myositis, and glomerular nephritis.
  • Central nervous system (CNS) findings associated with EBV mononucleosis are rare but usually occur later in the course of the illness. 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.
  • 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.
    • Epstein-Barr virus infectious mononucleosis is characterized by early and transient bilateral upper-lid edema. This finding was first described by RJ 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 [13]  is usually present for only the first few days of illness.

Complications

 

 

Other clinical manifestations

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. 

Malignancy

After resolution of the acute viral syndrome, EBV persists as memory T cells in the blood of all virus carriers where it exists as a latent, asymptomatic infection.[14]  Malignancy may occur in patients with latent EBV infections if EBV-induced B-lymphocyte proliferation becomes uncontrolled.[15]  Malignancies associated with EBV include nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and Leiomyomas and leiomyosarcomas in immunocompromised children - all major contributors to the disease burden of EBV.[16]

Selective immunodeficiency to EBV, which occurs in persons with X-linked lymphoproliferative syndrome, may result in severe, prolonged, or even fatal infectious mononucleosis.

Epstein-Barr virus infection is associated with certain malignancies that are described briefly as follows:

Burkitt's Lymphoma (BL) is a highly aggressive B cell neoplasm characterized by the translocation and deregulation of the MYC gene on chromosome 8. Three distinct clinical forms of BL are recognized: endemic, sporadic, and immunodeficiency-associated forms.[17]  It is the most common childhood malignancy in equatorial Africa and Papua New Guinea and is characteristically localized to the jaw. The role of EBV infection in the development of BL is poorly understood. Epstein-Barr virus infection in BL displays a latent infection phenotype, characterized by the lack of expression of the EBV transforming proteins LMP-1 and EBNA-2. Chronic EBV infection appears to play a role in virtually all cases of endemic (African) BL[18]  and a minority of sporadic and immunodeficiency-associated BL.[19]  Antibodies to early antigen restricted (EA-R) are only occasionally detected in patients with infectious mononucleosis, but are often found at elevated titers in patients with African BL or chronic active EBV infection.

Hodgkin lymphoma (HL) can be divided into classical HL (cHL) and nodular lymphocyte predominant HL. Though NLPHL is rarely EBV-positive, the link with EBV is fairly well established. The precise mechanisms by which EBV contributes to HL pathogenesis are uncertain, but EBV gene products may replace one of the genetic alterations that are required for the development of HL.[15]  Epstein-Barr virus-infected tumor cells express a subset of EBV genes, some of which are suspected as contributing to aberrant signaling, suppression of apoptosis, and immune evasion by Hodgkin/Reed-Sternberg (HRS) cells.[20]

Nasopharyngeal carcinoma - is one of the most common cancers in southern China. Epstein-Barr virus (EBV) latency is universally associated with the undifferentiated subtype of nasopharyngeal carcinoma.[21]  Furthermore, the association of EBV with nasopharyngeal carcinoma is consistently seen in both low- and high-incidence areas.[22]  Levels of EA-D antibodies are elevated in patients with nasopharyngeal carcinoma. IgA antibodies to EBV antigens have proved useful for the identification of patients with nasopharyngeal carcinoma and of persons at high risk for the disease. EBV DNA detected in cell-free plasma in patients with NPC has been noted to be a prognostic marker of residual disease post-therapy and predictor of disease-free and overall survival.[21]

Diffuse Large B-cell lymphoma - Epstein-Barr virus–positive diffuse large B-cell lymphoma (EBV-positive DLBCL) was entered as a provisional entry in WHO classification system in 2008,[23]  which was later revised to include “not otherwise specified” (NOS). This is a subtype of B cell lymphoma demonstrating numerous large EBV+ B cells and that often involves extranodal sites in apparent immunocompetent patients. Epstein-Barr virus-positive DLBCL accounts for 8% to 15% of DLBCL in the Asian population and approximately < 5% in the western population.[23]  The prognosis of EBV+ DLBCL is poor, with a median survival of 2 years. 

Leiomyosarcoma – Epstein-Barr virus-associated smooth muscle tumors are rare with a high incidence in immunocompromised patients such as HIV.[24]  There may be multiple smooth muscle tumors, often found in uncommon locations such as the central nervous system (CNS), lung, pericardium, pleura, spleen, adrenal gland, lymph node, and orbit. High levels of EBV genomes have been found in tumor tissue.[25]  AIDS-associated leiomyosarcomas behave in an aggressive fashion and frequently recur despite therapy, resulting in poor survival.[26]

Non-Hodgkin’s lymphoma (NHL) - Individuals infected with HIV and EBV also tend to have higher incidence of NHL. The significant immune system defects in HIV, especially cytotoxic lymphocytes controlling EBV induced proliferation, appear to play a role.

Chronic Active EBV (CAEBV)

Another contributor to EBV-related morbidity is Chronic Active Epstein-Barr virus (CAEBV). The revised World Health Organization (WHO) classification defined CAEBV as a chronic, active EBV infection of T- and NK-cell types.[27]  This is a disease of exclusion. Chronic Active Epstein-Barr virus is characterized by persistent inflammatory symptoms such as fever, lymphadenopathy, liver dysfunction, mononucleosis-like symptoms for more than 3 months, elevated EBV DNA PCR in peripheral blood, infiltration of tissues by EBV positive lymphocytes, and skin lesions hydroa vacciniforme.[12]

Posttransplantation lymphoproliferative disorders:

Posttransplantation lymphoproliferative disorders encompass a wide spectrum of disease, and most frequently present as diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma.[27]  Epstein-Barr virus is the most common cause, and the condition is seen in EBV-negative recipients who develop primary EBV infection, usually from a graft from an EBV-positive donor. More than 90% of PTLD cases are associated with re-activation of latent EBV in the setting of post-transplant pharmacologic immunosuppression; despite advances, prognosis for affected patients remains poor.[28]

 

DDx

Diagnostic Considerations

EBV-negative Mononucleosis

Approximately 10 percent of mononucleosis-type cases are not caused by EBV. CMV, HIV, Toxoplasma, human herpesvirus type 6 (HHV-6), hepatitis B and HHV-7 present similarly to EBV induced IM and should be considered in a heterophile-negative mononucleosis-like syndrome.

    Table 1. Differential Diagnoses of Infectious Mononucleosis (Open Table in a new window)

Clinical Parameters

Epstein-Barr Virus

Cyto-megalovirus

Toxoplasmosis

Viral Hepatitis

Symptoms

Fatigue

+++

+

+/-

+

Malaise

++

+

-

+

Mild sore throat

+

+

+/-

+/-

Early maculopapular rash

±

-

-

+/-

Signs

Early bilateral upper eyelid edema

±

-

-

-

Unilateral localized adenopathy

-

-

+

-

Bilateral posterior cervical adenopathy

+

+

-

+/-

Tender hepatomegaly

+/-

+/-

-

+

Splenomegaly

+

+/-

+/-

-

Laboratory abnormalities

WBC count

N*/-

N/-

N

¯

Elevated SGOT†/SGPT‡

++

+

+/-

+++

Atypical lymphocytes (≥ 10%)

+

+

-

-

Thrombocytopenia

+/-

+/-

-

+/-

Elevated IgM§ CMV titer

-

+

-

-

Elevated IgM EBV VCAII titer

+

-

-

-

Elevated IgM toxoplasmosis titer

-

-

+

-

Positive hepatitis (eg, A, B, D) test

-

-

-

+

*Normal

† Serum glutamic-oxaloacetic transaminase

‡ Serum glutamic-pyruvic transaminase

§ Immunoglobulin M

II Viral capsid antigen

 

 

Workup

Approach Considerations

Epstein-Barr virus should be suspected when an adolescent or young adult complains of sore throat, fever, and malaise, with lymphadenopathy and pharyngitis on physical exam. The presence of lymphocytosis and increased circulating atypical lymphocytes supports the diagnosis of EBV infection; however, the diagnosis should be confirmed with a heterophile antibody test or through EBV-specific antibodies. Confirmatory testing is helpful to inform patients with infecitous mononucleosis of risks such as splenic rupture and airway obstruction. Once a reactive heterophile antibody is present, it is not necessary to test for specific antibodies to EBV. Specific antibody testing may be necessary to identify the cause of an illness in an individual who does not have a typical case of infectious mononucleosis or has other illnesses that can be cause by EBV. Timeline should be considered when ordering tests.

Laboratory Studies

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

  • 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 antibodies

Since heterophile antibodies typically return quicker than EBV specific antibodies, it is the test of choice in most clinical settings to determine if an individual has infectious mononucleosis. Reactive heterophile antibodies in a patient with the typical symptoms are diagnostic of EBV and further testing for specific antibodies to EBV is not necessary. Studies have shown that the Monospot test can lead to false negative and false positive results. 

One must consider that the heterophile antibody test results may be negative early in the course of EBV infectious mononucleosis. Positivity increases during the first 6 weeks of the illness. In patients with a compatible syndrome and negative heterophile antibodies, the test can be repeated if the patient is early in their clinical course.[29]  Another consideration is that heterophile antibody tests are often negative in infants and children younger than 4 years; thus, EBV-specific serologies are generally favored for diagnosing acute EBV infection in young children.[30]  Although rare, false-positive heterophile tests have been reported in those with leukemia, lymphoma, pancreatic cancer, systemic lupus erythematosus, toxoplasmosis, HIV infection, and rubella.[31]  

Patients who remain heterophile negative after 6 weeks with a mononucleosis illness should be considered as having heterophile-negative infectious mononucleosis.

Epstein-Barr virus-specific antibodies

These may be considered in patients with suspected infectious mononucleosis who have a negative heterophile test. Specific EBV testing should be obtained in those with prolonged illness or patients who do not fit the classical diagnostic criteria. IgM and IgG antibodies directed against viral capsid antigen has high sensitivity and specificity.[32]

Viral capsid antigen (VCA) – Anti-VCA IgM and anti-VCA IgG antibodies directed against EBV viral capsid antigen are present at the onset of infection. Anti-VCA IgM appears early and usually disappears within 4 to 6 weeks. Anti-VCA IgG appears in the acute phase of the infection and peaks at 2 to 4 weeks and will remain for life.[32]  Although anti-VCA IgM is highly suggestive of acute EBV infection, other herpes viruses (eg, cytomegalovirus) can induce IgM antibodies to cell lines that express EBV antigens.

EBV Nuclear antigen (EBNA) – This is a protein expressed only when the virus begins to establish latency. It begins to appear 6 - 12 weeks after the onset of initial symptoms and persists throughout life. Its presence early in the disease course of an illness excludes acute EBV infection. 

Early antigen (EA) – Anti-EA IgG appears during the acute phase and falls to undetectable levels after 3 to 6 months.[32]  The presence of anti-EA IgG anti-D antibodies is consistent with recent infection, but their absence does not exclude acute illness. 

EBV DNA Quantification with PCR is usually used in the management of transplant recipients who develop lymphoproliferative disorders related to EBV infection. 

Table 2. EBV Serologic Responses in EBV-Associated Diseases (Open Table in a new window)

EBV Diseases

EBV Antibody Responses

Anti-VCA

Anti-EA

IgM

Monospot/

Heterophile

IgM

IgG

Diffuse EA

Restricted EA

Anti-EBNA

Acute EBV mononucleosis

+

+

+

+

-

-

Past EBV infection

-

-

+

-

-

+

Chronic active EBV infection

-

-

+++

+

+

+

Burkitt lymphoma

-

-

+++

+/-

+

+

Nasopharyngeal carcinoma

-

-

+++

+

+/-

+

 

Additional general laboratory studies

Complete blood cell count 

The complete blood cell (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 similar appearing, which readily permits differentiation on the peripheral smear.
  • Leukopenia, rather than leukocytosis, is expected in patients with cytomegalovirus (CMV), rubella, HHV-6, acute HIV, and anicteric hepatitis-related infectious mononucleosis.
  • 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.

Erythrocyte sedimentation rate

An erythrocyte sedimentation rate (ESR) is 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 in group A streptococcal pharyngitis. An elevated ESR does not differentiate EBV from the other heterophile-negative causes of infectious mononucleosis.

A liver function test (LFT) is abnormal in >90% of cases. Serum levels of aminotransferases and alkaline phosphatase are usually mildly elevated. The serum concentration of bilirubin is elevated in ~40% of cases. 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. 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.

Group A Streptococci co-testing

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 rapid streptococcal test cannot be used to differentiate colonization from infection either. 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, in contrast to the patients with colonization, show an intense polymorphonuclear cellular response with cellular debris and fibrous fragments indicating acute infection.

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

Closely monitor patients with extreme tonsillar enlargement for airway obstruction. Steroids are indicated for impending or established airway obstruction in individuals with Epstein-Barr virus (EBV) infectious mononucleosis.

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 advised to refrain from active physical activity for 3 weeks.

 

Medication

Medication Summary

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, but 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.

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

 

Follow-up

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.

Further Inpatient Care

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

Deterrence/Prevention

Avoid close contact with body fluid secretions, particularly saliva.

Complications

Extreme enlargement of the tonsils may result in airway obstruction.

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 eMedicineHealth's Bacterial and Viral Infections Center and Back, Ribs, Neck, and Head Center. Also, see eMedicineHealth's patient education articles Mononucleosis and Chronic Fatigue Syndrome.

 

Questions & Answers

Overview

When was Epstein-Barr virus (EBV) infectious mononucleosis (mono) first described and how was it characterized?

How is Epstein-Barr virus (EBV) transmitted (the virus that causes infectious mononucleosis [mono])?

What is the pathophysiology of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

What is the role of the T-lymphocyte cellular response in determining the clinical expression of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How does the physiologic response to the Epstein-Barr virus (EBV) cause the symptoms of infectious mononucleosis (mono)?

How common is Epstein-Barr virus (EBV) infectious mononucleosis (mono) in the US?

How is fatigue characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Which characteristics or complications of the virus are associated with severe illness or death?

What are the age-related demographics of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Presentation

Do all people with Epstein-Barr virus (EBV) infectious mononucleosis (mono) have symptoms?

What is the incubation period of Epstein-Barr virus (EBV) infectious mononucleosis (mono) and what are the common presenting symptoms?

Which symptoms are associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

What is the predisposing risk factor associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Where in the body does Epstein-Barr virus (EBV) persist in infectious mononucleosis (mono)?

Which comorbidities are associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono) in patients with congenital immunodeficiencies?

Which comorbidities are associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono) in patients with acquired immunodeficiencies?

Which physical findings are associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

DDX

What is the presentation of pharyngitis in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Which conditions in addition to Epstein-Barr virus (EBV) infectious mononucleosis (mono) are associated with palatal petechiae?

What does uvular edema indicate in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How is lymphadenopathy distinguished from Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How is a finding of leukocytosis used to confirm or exclude Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How is lymphocytosis characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How is thrombocytopenia characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How are serum transaminases characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono), and which mononucleosislike illnesses may be indicated by other findings?

How is the erythrocyte sedimentation rate (ESR) measurement used in the diagnosis of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How is the rash associated with Epstein-Barr virus (EBV) infectious mononucleosis (mono) characterized?

How is the external eye involvement of Epstein-Barr virus (EBV) infectious mononucleosis (mono) characterized, and what other findings of the periorbital area suggest a different diagnosis?

How common is splenic rupture in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

What are the diagnostic considerations for meningoencephalitis in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

What is the role of fatigue in the diagnosis of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How is fatigue characterized in Epstein-Barr virus (EBV) infectious mononucleosis (mono) and what does chronic fatigue suggest?

What is is chronic infectious mononucleosis (mono) and how is it differentiated from chronic fatigue syndrome (CFS)?

Workup

Which antibodies does an Epstein-Barr virus (EBV) mononucleosis (mono) infection induce?

What is the sensitivity and specificity of the heterophile antibody test in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How is the heterophile antibody test used to differentiate heterophile-negative infectious mononucleosis (mono) and Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How is testing for Epstein-Barr virus (EBV)-specific antibodies used in the workup of infectious mononucleosis (mono)?

Which nonspecific tests are included in the workup for Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Which lab studies are specific for Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Which other tests may be indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

When are imaging studies indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

When is an EEG indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

When is a bone marrow or lymph node biopsy indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

When is a lumbar puncture indicated in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

What do histologic findings demonstrate in the workup of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Treatment

How are patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono) monitored and when are steroids used for treatment?

When is surgery indicated in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Which consultations may be necessary in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

What type of diet is appropriate in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

What level of activity is encouraged in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Medications

Is antiviral therapy available in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Is antiviral therapy available for immunocompromised patients with Epstein-Barr virus (EBV) lymphoproliferative disease?

When are corticosteroids indicated in the treatment of Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How is group A streptococcal (GAS) infection treated in patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

Follow-up

How are patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono) monitored?

What do patients need to know about fatigue and Epstein-Barr virus (EBV) infectious mononucleosis (mono) titers?

What does extreme tonsillar enlargement indicate in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

How can patients avoid contracting Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

What are complications associated with infectious mononucleosis (mono)?

What is the prognosis of splenic rupture in Epstein-Barr virus (EBV) infectious mononucleosis (mono)?

What do patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono) need to know about physical activity restrictions?

How can patients with Epstein-Barr virus (EBV) infectious mononucleosis (mono) prevent spreading the disease to others?

What patient education resources are available for Epstein-Barr virus (EBV) infectious mononucleosis (mono)?