Infectious Mononucleosis and Other Manifestations of Epstein-Barr Virus Infection

Definition, Etiology, PathogenesisTop

Infectious mononucleosis is a syndrome characterized by fever, pharyngitis/tonsillitis, lymphadenopathy, and peripheral atypical lymphocytosis.

1. Etiologic agents: Ninety percent of cases of typical mononucleosis are caused by the Epstein-Barr virus (EBV)  from the Herpesviridae family. The virus first infects oropharyngeal epithelial cells and B cells. Some of these B cells are transformed into immortal plasma cells and are triggered to produce polyclonal gamma globulins, which are detected as nonspecific heterophile antibodies. The activated B cells, which are visualized as atypical lymphocytes, stimulate proliferation of T cells, leading to the enlargement of the lymph nodes, tonsils, spleen, and liver. After the primary infection, EBV remains latent in B cells and oral epithelial cells; its reactivation may lead to uncontrolled monoclonal lymphoproliferation. The shedding of active EBV virus takes place intermittently thereafter from the asymptomatic host.

There are other pathogens that cause infectious mononucleosis indistinguishable from EBV, the most common of which is cytomegalovirus (CMV; also from the Herpesviridae family), which has been estimated to account for 7% of cases of infectious mononucleosis. Like EBV, CMV infects B lymphocytes, establishing a reservoir of latent virus that persists for life. Other pathogens that are rarer causes of infectious mononucleosis–like symptoms include human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), HIV, and the protozoal pathogen Toxoplasma gondii.

2. Reservoir and transmission: Humans are the only reservoir for EBV. The pathogen is ubiquitous worldwide; almost all adults become seropositive at some point. In industrialized countries, at least half of individuals are infected by early adulthood; age-specific prevalence has been steadily decreasing over the past decades. In lower-income settings, people acquire the infection more rapidly. EBV is spread via direct contact, and transmission is usually mediated through saliva, which contains large amounts of the virus. Transmission is also possible by blood transfusion as well as bone marrow and solid organ transplant.

3. Incubation period: The incubation period for EBV infection is 30 to 50 days.

Clinical FeaturesTop

EBV infection can often be asymptomatic, especially in young children.

1. Infectious mononucleosis, as noted above, refers to a clinical syndrome featuring fever, pharyngitis, lymphadenopathy, and peripheral atypical lymphocytosis. This is often preceded by a prodromal phase of fever, headache, and malaise indistinguishable from that associated with other viral pathogens. This classic syndrome is less often seen in very young children and older adults.

2. Pharyngitis associated with EBV can be accompanied by severe sore throat and fever up to 40 degrees Celsius (this usually resolves within 1-2 weeks, although in exceptional cases may persist longer). Classically, the tonsils are enlarged and covered with a characteristic exudate reminiscent of streptococcal pharyngitis (see Pharyngitis (Tonsillitis)); the pharyngeal mucosa is erythematous, and frequently palatal petechiae and halitosis are detected. Signs may also include edema involving the uvula and/or skin edema around the eyelids, at the nasal root, and above the eyebrows (more frequent in children). EBV infection can present with pharyngitis alone in the absence of other features of infectious mononucleosis.

3. Lymphadenopathy and splenomegaly: Lymph nodes may be significantly enlarged, even >3 cm in diameter, and are elastic, movable, tender, do not form aggregates, and are often surrounded by edema. Lymphadenopathy is the longest-persisting symptom (may be observed for up to 6 months following the acute infection). Children can develop generalized lymphadenopathy, while in adolescents and adults, lymphadenopathy is more often limited to posterior and anterior cervical and submandibular lymph nodes, and generalized lymphadenopathy with the involvement of axillary and inguinal lymph nodes is less frequent. Note that cervical lymphadenopathy, if massive, can cause airway obstruction. Splenomegaly occurs during the second and third week of the infection in 50% of patients and generally resolves after 7 to 10 days.

4. Hepatitis occurs in 20% to 90% of patients. It is usually without jaundice but may be accompanied by hepatomegaly (in 10%-15% of cases). Hepatitis persists for up to 4 weeks.

5. Rash develops in 3% to 15% of patients and can vary in appearance; morbilliform, macular, petechial, scarlatiniform, urticarial, or erythema multiforme rashes occur. A more severe and generalized rash can result after the administration of antibiotics, especially aminopenicillins (ampicillin or amoxicillin), much less frequently cephalosporins or macrolides.

6. Other nonspecific symptoms associated with infectious mononucleosis: Headache (typically retro-orbital), abdominal pain, nausea and vomiting. During the period of convalescence, asthenia, malaise, fatigue, exhaustion, and impaired concentration occur. Fatigue resolves more slowly than other symptoms associated with infectious mononucleosis and can be found in 10% to 15% of patients at 6 months.

7. EBV-associated lymphoproliferative disorder affects immunocompromised individuals, particularly patients with AIDS and transplant recipients; the clinical spectrum can be quite variable, ranging from the development of masses (enlargement of the lymph nodes and other lymphatic organs) to the development of lymphomas.

8. EBV-associated hematologic disorders: EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection are rare types of EBV infection associated with proliferation of T cells or natural killer (NK) cells. The pathogeneses of these conditions are different, but both can be associated with persistent fever, lymphadenopathy, splenomegaly, hepatitis, and cytopenias; chronic active EBV infection (CAEBV) also presents with interstitial pneumonia, uveitis, and the dermatosis hydroa vacciniforme.

9. Other infectious syndromes: EBV can also be a rare cause of meningoencephalitis (especially in pediatric populations), transverse myelitis, cranial nerve palsies, Guillain-Barré syndrome, glomerulonephritis, myocarditis, pancreatitis, and mesenteric adenitis.

DiagnosisTop

Diagnostic Tests

1. Complete blood count: In 98% of cases of infectious mononucleosis, moderate leukocytosis (up to 20×109/L) with a significant proportion of lymphocytes (>50% of all white blood cells or lymphocytes >4.5×109/L) is observed. “Atypical lymphocytosis” is defined as having ≥10% of lymphocytes on blood smear with atypical features (loosely arranged chromatin, eccentric nucleus).

2. Serology:

1) Specific anti-EBV antibodies are most helpful in determining whether an infection with EBV has occurred. As EBV is a ubiquitous pathogen, serologies are often positive; the timing of positivity and negativity for the antigens listed below enable the determination of whether infection was acquired within days, weeks, or months.

a) IgM antibodies against viral capsid antigen (anti-VCA IgM) appear first and are detectable in 95% of patients with a primary infection. The titers increase rapidly within a few days of the acute phase onset and decrease to zero after 2 to 3 months. Anti-VCA IgG appear within a few days of EBV infection and persist for life. Anti-VCA antibodies are highly sensitive and specific for EBV infection.

b) Antibodies against the early antigen (EA) develop later than anti-VCA IgG (within 2 weeks, peaking at 3-4 weeks) after the development of clinical symptoms and persist for 3 to 6 months; however, up to 30% of individuals may not have detectable anti-EA.

c) Antibodies against Epstein-Barr nuclear antigen (EBNA) appear in the later phases of the disease, within weeks (3-6) of acute infection. These persist for life.

2) Nonspecific heterophile antibodies (mainly IgM; Paul-Bunnell-Davidsohn reaction, rapid agglutination tests, monospot test) may be helpful in the diagnostic workup if specific serologic tests are not available; this testing is often readily available. The antibodies appear at the end of the second week of the disease (in 80%-90% of adult patients) and persist for ≥3 to 6 months. A positive result is usually conclusive (specificity, ~90%), although false negatives are common in early infection. The sensitivity of heterophile antibodies is dramatically reduced in children aged <5 years.

3. Detection of EBV DNA (polymerase chain reaction [PCR]; specimens: serum, blood [lymphocytes], tissues): Useful in immunocompromised patients (who lack specific antibodies) or in tracking EBV infection in patients with cancer, after transplant, with lymphoproliferative disorders, and with chronic active EBV infection. There is little benefit to the routine use of EBV PCR in immunocompetent patients, as the diagnosis of EBV infection is readily made by the use of serologic testing.

Differential Diagnosis

As noted above, infectious mononucleosis–like illness not attributable to EBV can be due to CMV, HHV-6, HHV-7, HIV, and toxoplasmosis. Pharyngitis can be caused by respiratory viruses (eg, influenza, parainfluenza, rhinovirus, enterovirus), although these do not typically cause exudative pharyngitis, which is commonly due to group A streptococcus and very rarely due to diphtheria. Hepatitis associated with EBV is similar to that resulting from other viruses (eg, CMV, adenovirus, enterovirus) and toxic ingestions. Lymphadenopathy and splenomegaly can also be seen with infections such as enteric (typhoid) fever, brucellosis, bartonellosis, as well as in a number of other infections, rheumatologic diseases, and immunologic disorders.

TreatmentTop

Antiviral Treatment

Ganciclovir is active against EBV but has no role in the treatment of any EBV-associated infections in immunocompetent individuals. It is sometimes used for active EBV infections in severely immunosuppressed patients; however, the evidence base for this practice is scant, and this should only be undertaken in consultation with an expert in infectious diseases.

Other Treatment Modalities

1. General recommendations: The mainstay of treatment is supportive. Acetaminophen (INN paracetamol) or nonsteroidal anti-inflammatory drugs can be used for pain. The vast majority of patients do not require hospitalization or IV therapy to maintain adequate fluid status.

2. Glucocorticoid therapy should not be routinely prescribed to patients with infectious mononucleosis, given the results of a meta-analysis that did not find any significant benefit >12 hours after their administration.Evidence 1Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity and imprecision. Rezk E, Nofal YH, Hamzeh A, Aboujaib MF, AlKheder MA, Al Hammad MF. Steroids for symptom control in infectious mononucleosis. Cochrane Database Syst Rev. 2015 Nov 8;(11):CD004402. doi: 10.1002/14651858.CD004402.pub3. Review. PMID: 26558642. A more recent meta-analysis, including many more patients with pharyngitis in higher-quality trials, showed a significant increase in the rate of resolution of throat pain at 24 hours after treatment with glucocorticoids, but individuals with infectious mononucleosis were specifically excluded.

Treatment with glucocorticoids should generally be reserved for those with severe lymphadenopathy and impeding airway obstruction in an effort to avoid the necessity of operative intervention, though no randomized trials have evaluated this practice.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the lack of available experimental data. Ganzel TM, Goldman JL, Padhya TA. Otolaryngologic clinical patterns in pediatric infectious mononucleosis. Am J Otolaryngol. 1996 Nov-Dec;17(6):397-400. PMID: 8944299. Isolated case reports have documented the use of glucocorticoids for severe persistent fever, neutropenia, thrombocytopenia, or hemophagocytic lymphohistiocytosis following EBV infection.

3. Minimization of immunosuppression, administration of rituximab, and use of EBV-specific cytotoxic lymphocytes are advocated for the treatment of posttransplant EBV-associated lymphoproliferative disorders; treatment of this condition should only be done in consultation with specialists in hematology-oncology.

ComplicationsTop

Complications of infectious mononucleosis are rare but potentially severe and include:

1) Splenic rupture, mainly subcapsular (0.5% of patients), may occur during the second or third week of the disease, is preceded by severe abdominal pain, and may require surgery. It is suggested that athletes refrain from contact sports for 4 weeks and sports where chest/abdominal trauma is possible for 3 weeks,Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of evidence lowered due to the lack of experimental data. Becker JA, Smith JA. Return to play after infectious mononucleosis. Sports Health. 2014 May;6(3):232-8. doi: 10.1177/1941738114521984. PMID: 24790693; PMCID: PMC4000473. simply due to the fact that splenic rupture is less likely >21 days after the onset of symptoms.

2) Malignancy: A very rare late complication; EBV infection is associated with Hodgkin lymphoma, Burkitt lymphoma, T-cell or NK-cell leukemia, nasal-type extranodal NK/T-cell lymphoma, lymphoproliferative disorders associated with immune deficiency, and nasopharyngeal cancer.

PrognosisTop

The prognosis of infectious mononucleosis is good in the vast majority of patients. The disease resolves spontaneously, although some symptoms may persist for several months. In patients who develop very rare hematologic and neurologic complications, the prognosis is unfavorable. Deaths related to infectious mononucleosis are rare and usually result from unrecognized splenic rupture, secondary bacterial infections, or myocarditis.

PreventionTop

Individuals with a recent history of confirmed EBV infection or disease reminiscent of infectious mononucleosis should not donate blood or organs for transplant. No vaccine is available.