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Infectious Mononucleosis

(Mono)

By

Kenneth M. Kaye

, MD, Harvard Medical School

Last full review/revision Sep 2021| Content last modified Oct 2021
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Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or months. Severe complications, including airway obstruction, splenic rupture, and neurologic syndromes, occasionally occur. Diagnosis is clinical or with EBV serologic testing. Treatment is supportive.

EBV is a herpesvirus that infects 50% of children before age 5. Over 90% of adults are seropositive for EBV. Its host is humans.

EBV infection is usually asymptomatic.

Pathophysiology of Infectious Mononucleosis

After exposure in the oral cavity, EBV infects B lymphocytes. Morphologically abnormal (atypical) lymphocytes develop, mainly from CD8+ T cells that respond to the infection.

After primary infection, EBV remains within the host, primarily in B lymphocytes, for life and undergoes intermittent asymptomatic shedding from the oropharynx. The virus is detectable in oropharyngeal secretions of 15 to 25% of healthy EBV-seropositive adults. Shedding increases in frequency and titer in immunocompromised patients (eg, organ allograft recipients, HIV-infected people).

EBV has not been recovered from environmental sources and is not very contagious.

Transmission

Transmission may occur via transfusion of blood products but much more frequently occurs via kissing between an uninfected and an EBV-seropositive person who is shedding the virus asymptomatically. Only about 5% of patients acquire EBV from someone who has acute infection.

Early childhood transmission occurs more frequently among lower socioeconomic groups and in crowded conditions.

Associated disorders

Symptoms and Signs of Infectious Mononucleosis

In most young children, primary EBV infection is asymptomatic. Symptoms of infectious mononucleosis develop most often in older children and adults.

The incubation period is about 30 to 50 days. Fatigue can last for months but is usually maximal during the first 2 to 3 weeks.

Most patients have the triad of

  • Fever

  • Pharyngitis

  • Adenopathy

Fever usually peaks in the afternoon or early evening, with a temperature around 39.5° C, although it may reach 40.5° C.

Pharyngitis may be severe, painful, and exudative and may resemble streptococcal pharyngitis.

Adenopathy is usually symmetric and may involve any group of nodes, particularly the anterior and posterior cervical chains. Adenopathy may be the only manifestation.

Other symptoms and signs include

  • Splenomegaly

  • Mild hepatomegaly and hepatic percussion tenderness

  • Periorbital edema and palatal petechiae

  • Less frequently maculopapular eruptions

  • Rarely jaundice

Splenomegaly, which occurs in about 50% of cases, is maximal during the 2nd and 3rd week and usually results in only a barely palpable splenic tip.

Complications

Although recovery is usually complete, complications may be dramatic.

Neurologic complications are rare but may include encephalitis, seizures, Guillain-Barré syndrome, peripheral neuropathy, viral meningitis, myelitis, cranial nerve palsies, and psychosis. Encephalitis may manifest with cerebellar dysfunction, or it may be global and rapidly progressive, similar to herpes simplex encephalitis, but is usually self-limited.

Hematologic complications are usually self-limited. They include

  • Granulocytopenia

  • Thrombocytopenia

  • Hemolytic anemia

Transient mild granulocytopenia or thrombocytopenia occurs in about 50% of patients; severe cases with bacterial infection or bleeding occur less frequently. Hemolytic anemia is often due to anti-i-specific cold-agglutinin antibodies.

Splenic rupture can have severe consequences. It can result from splenic enlargement and capsular swelling, which are maximal 10 to 21 days after presentation. A history of trauma is present only about half of the time. Rupture is usually painful but occasionally causes painless hypotension. For treatment, see Splenic Injury Treatment Splenic injury usually results from blunt abdominal trauma. Patients often have abdominal pain, sometimes radiating to the shoulder, and tenderness. Diagnosis is made by CT or ultrasonography... read more .

Respiratory complications include, rarely, upper airway obstruction due to pharyngeal or paratracheal lymphadenopathy; respiratory complications may respond to corticosteroids.

Hepatic complications include elevated aminotransferase levels (about 2 to 3 times normal, returning to baseline over 3 to 4 weeks); they occur in about 95% of patients. If jaundice or more severe enzyme elevations occur, other causes of hepatitis Causes of Hepatitis Hepatitis is an inflammation of the liver characterized by diffuse or patchy necrosis. Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis... read more should be investigated.

Overwhelming infection with EBV occurs sporadically but may cluster in families, particularly those with X-linked lymphoproliferative syndrome X-linked Lymphoproliferative Syndrome X-linked lymphoproliferative syndrome results from a T-cell and natural killer cell defect and is characterized by an abnormal response to Epstein-Barr virus infection, leading to liver failure... read more . Survivors of overwhelming primary EBV infection are at risk of developing agammaglobulinemia or lymphoma.

Diagnosis of Infectious Mononucleosis

  • Heterophile antibody test

  • Sometimes EBV serologic testing

Infectious mononucleosis should be suspected in patients with typical symptoms and signs. Exudative pharyngitis, anterior cervical lymphadenopathy, and fever may be clinically indistinguishable from those caused by group A beta-hemolytic streptococci Streptococcal Infections Streptococci are gram-positive aerobic organisms that cause many disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and endocarditis. Symptoms vary with the organ... read more Streptococcal Infections . However, posterior cervical or generalized adenopathy or hepatosplenomegaly suggests infectious mononucleosis. Moreover, detection of streptococci in the oropharynx does not exclude infectious mononucleosis.

Differential diagnosis

  • Quantitative HIV RNA viral load in blood

  • Combination antibody immunoassay and p24 antigen assay

HIV enzyme-linked immunosorbent assay (ELISA)/Western blot is usually negative during the acute infection and thus should not be used alone to diagnose early primary HIV infection. Quantitative HIV RNA and p24 antigen detection are more sensitive for diagnosing acute HIV infection because HIV RNA and p24 antigen are present in blood before HIV antibodies develop.

Pearls & Pitfalls

  • Primary HIV infection can resemble acute EBV infection; patients with risk factors for HIV infection should be tested using quantitative HIV RNA viral load in blood, combination antibody immunoassay, and p24 antigen testing.

Laboratory tests

Laboratory diagnosis usually involves a complete blood count and EBV serologic testing. Lymphocytes that are morphologically atypical account for up to 30% of the white blood cells. Although individual lymphocytes may resemble leukemic lymphocytes, lymphocytes are heterogeneous, which is unlikely in leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more . Atypical lymphocytes may also be present in HIV Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Human Immunodeficiency Virus (HIV) Infection or CMV Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more infection, hepatitis B Hepatitis B, Acute Hepatitis B is caused by a DNA virus that is often parenterally transmitted. It causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Fulminant hepatitis and... read more , influenza B Influenza Influenza is a viral respiratory infection causing fever, coryza, cough, headache, and malaise. Mortality is possible during seasonal epidemics, particularly among high-risk patients (eg, those... read more , rubella Rubella (See also Congenital Rubella.) Rubella is a contagious viral infection that may cause adenopathy, rash, and sometimes constitutional symptoms, which are usually mild and brief. Infection during... read more Rubella , or other viral illnesses, so diagnosis requires serologic testing. However, very high atypical lymphocyte counts are typically seen only in primary EBV and CMV infection.

Two serologic tests are used to diagnose acute EBV infection:

  • Heterophile antibody testing

  • Specific EBV antibody testing

Heterophile antibodies are measured using various agglutination card (monospot) tests. However, heterophile antibodies are present in only 50% of patients < 5 years and in about 80 to 90% of adolescents and adults with infectious mononucleosis. Importantly, the heterophile antibody test may be false-positive in some patients with acute HIV infection. The titer and prevalence of heterophile antibodies rise during the 2nd and 3rd week of illness. Thus, if the diagnosis is suspected and the heterophile antibody test is negative early in clinical illness (in the first week), testing can be repeated approximately 7 days later. Alternatively, EBV antibody testing can be performed..

EBV-specific antibody testing is highly sensitive. The presence of IgM antibodies to the EBV viral capsid antigen (VCA) indicates primary EBV infection (these antibodies disappear within 3 months after infection). IgG VCA (EBV VCA-IgG) also develops early in primary EBV infection, but these antibodies persist for life. EBV nuclear antigen (EBNA-IgG) antibodies develop later (after 2 to 4 months ) in acute EBV infection and also persist for life. If EBV antibody titers are negative or indicate remote infection (ie, positive for IgG antibodies and negative for IgM antibodies), other diagnoses that can present with similar symptoms (eg, acute HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Human Immunodeficiency Virus (HIV) Infection , CMV infection Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more ) should be considered.

Prognosis for Infectious Mononucleosis

Infectious mononucleosis is usually self-limited. Duration of illness varies; the acute phase lasts about 2 weeks. Generally, 20% of patients can return to school or work within 1 week, and 50% within 2 weeks. Fatigue may persist for several more weeks or, in up to 10% of cases, for months.

Death occurs in < 1%, mostly resulting from complications (eg, encephalitis, splenic rupture, airway obstruction).

Treatment of Infectious Mononucleosis

  • Supportive care

  • Corticosteroids possibly helpful for severe disease

Treatment of infectious mononucleosis is supportive. Patients are encouraged to rest during the acute phase but can resume activity when fever, pharyngitis, and malaise abate. To prevent splenic rupture, patients should avoid heavy lifting and contact sports for 1 month after presentation and until splenomegaly (which can be monitored by ultrasonography) resolves.

Although corticosteroids hasten defervescence and relieve pharyngitis, they generally should not be used in uncomplicated disease. Corticosteroids can be helpful for complications such as impending airway obstruction, severe thrombocytopenia, and hemolytic anemia. Although oral or IV acyclovir decreases oropharyngeal shedding of EBV, there is no convincing evidence to warrant its clinical use.

Key Points

  • EBV infection is very common; the virus remains within the host for life and is intermittently and asymptomatically shed from the oropharynx.

  • Only about 5% of patients acquire EBV from someone who has acute infection.

  • Typical manifestations include fatigue (sometimes persisting weeks or months), fever, pharyngitis, splenomegaly, and lymphadenopathy.

  • Uncommon severe complications include encephalitis and other neurologic manifestations, splenic rupture, airway obstruction due to tonsillar enlargement, hemolytic anemia, thrombocytopenia, and jaundice.

  • Do heterophile antibody testing or specific EBV antibody testing.

  • Primary HIV infection can have a clinical presentation similar to acute EBV; therefore, HIV testing is done in patients at risk of HIV infection.

  • Provide supportive care and recommend avoidance of heavy lifting and contact sports; antivirals are not indicated.

  • Consider corticosteroids for complications such as impending airway obstruction, severe thrombocytopenia, and hemolytic anemia.

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