Infectious mononucleosis

Infectious mononucleosis, also called mono or the kissing disease, is an acute condition most commonly caused by the Epstein-Barr virus (EBV). The disease is highly contagious and spreads via bodily secretions, especially saliva. Infection is often asymptomatic in young children, but adolescents and young adults usually develop symptoms. Symptomatic cases typically last for 2–4 weeks and manifest with fever, malaise, fatigue, acute pharyngitis, tonsillitis, lymphadenopathy, and/or splenomegaly. Infectious mononucleosis is also sometimes associated with a measles-like maculopapular rash, especially in individuals prescribed beta-lactam antibiotics (e.g., ampicillin, amoxicillin). There is no standardized diagnostic approach to infectious mononucleosis. EBV serology confirms the diagnosis, but staged testing using supportive studies is often performed as an alternative because it is lower cost and more accessible. Infectious mononucleosis is usually self-limiting and is typically treated conservatively. Physical activity (e.g., contact sports) should be limited to lower the risk of splenic rupture. Malignancy (e.g., Hodgkin lymphoma, Burkitt lymphoma) is a rare complication.

• General: Approx. 90–95% of adults are EBV-seropositive worldwide. ^[1]
• Peak incidence: (of symptomatic disease): 15–24 years of age ^[2]
• Incidence: 5/1000 per year ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Pathogens: ^[3]
  • Most common: EBV
  • Approximately 10% of cases are caused by cytomegalovirus (CMV).
• Transmission: spreads via bodily secretions, especially saliva ^[3]
• Incubation period: ∼ 6 weeks ^[4]

EBV infects B lymphocytes in mucosal epithelium (e.g., oropharynx, cervix) via the CD21 receptor; → infected B lymphocytes induce a humoral (B-cell) as well as a cellular (T-cell) immune response → an increased concentration of atypical lymphocytes in the bloodstream, which are CD8+ cytotoxic T cells that fight infected B lymphocytes

“You must Be (B lymphocytes) 21 (CD21) to drink in a BAR (Epstein-BARr virus).”

• Clinical course ^[3][5][6]
  • Symptoms most commonly occur in adolescents and young adults and last for 2–4 weeks.
  • Young children are often asymptomatic.
• Signs and symptoms ^[3][5][6]
  • Splenomegaly, fever, fatigue, malaise
  • Pharyngitis and/or tonsillitis; (reddened, enlarged tonsils covered in pus), palatal petechiae
  • Bilateral cervical lymphadenopathy (especially posterior) that may become generalized and can, in severe cases, lead to airway obstruction
  • Abdominal pain
  • Possible hepatomegaly and jaundice
  • Maculopapular rash (similar appearance to measles)
    • ∼ 5–15% caused by the infection itself ^[7]
    • Most commonly caused by antibiotic use (e.g., aminopenicillins) ^[7]

Splenomegaly can lead to a potentially life-threatening splenic rupture.

In most cases, a maculopapular rash is caused by empiric administration of antibiotics rather than EBV infection. ^[7]

There is no standardized diagnostic approach to infectious mononucleosis.

General principles ^[3][6][8]

• Infectious mononucleosis can be diagnosed clinically, but laboratory studies are usually performed. ^[3][6][8][9]
• EBV serology is the most reliable way to diagnose infection but is usually slow and expensive.
• Staged testing is often performed as an alternative: ^[3]
  • Order supportive laboratory studies (e.g., CBC, monospot test).
  • Initiate management if findings suggest infectious mononucleosis.
  • Request EBV serology if findings are inconclusive.
• Additional studies (i.e., diagnostics for CMV, HIV testing) are performed if: ^[3][8][10]
  • Patient is pregnant.
  • EBV serology is inconclusive.
  • Manifestation is atypical.
  • Patient is immunocompromised.
• If concurrent bacterial tonsillitis is suspected, consider diagnostics for acute tonsillitis. ^[3][11]

Confirmatory laboratory studies

EBV serology ^[3][6][9]

EBV serology is the most reliable laboratory study to diagnose infectious mononucleosis.

• Antiviral capsid antigen antibodies (anti-VCA) for EBV
  • Anti-VCA IgM alone is sufficient to diagnose acute infection.
  • Anti-VCA IgG titers peak 2 weeks after symptom onset and may persist for life.
• EBV nuclear antigen antibodies are detectable ≥ 6 weeks after symptom onset and may persist for life.

The presence of anti-VCA IgG without anti-VCA IgM indicates past infection. ^[6]

Nucleic acid amplification test (NAAT)

• Not routinely used ^[8]
• Consider NAAT for immunocompromised patients or in complex cases. ^[6]

Supportive laboratory studies

The following studies have low specificity but can support the diagnosis in patients with clinical features of infectious mononucleosis. ^[6]

• CBC with differential ^[3]
  • Findings suggestive of infectious mononucleosis include:
    • Absolute lymphocyte count > 4 x 10⁹/L ^[8]
    • > 50% lymphocytes
    • > 10% atypical lymphocytes
  • Anemia and/or thrombocytopenia may also be present (see “Complications of infectious mononucleosis”).
• Liver chemistries: Mild elevation of aminotransferase is a common but nonspecific finding. ^[3][6]
• Monospot (heterophile antibody) test: a latex agglutination rapid test that uses red blood cells from horses to detect heterophile antibodies against EBV ; ^[3][12][13]
  • False negatives are more likely in:
    • Adults tested within 1 week of symptom onset
    • Children < 5 years of age
  • False positives are more likely in patients with previous infection, HIV, autoimmune disease, and viral hepatitis.

Imaging ^[3][8]

• Imaging is not routinely recommended.
• Ultrasonography shows splenomegaly in almost all patients and is therefore unnecessary. ^[8]
• CT abdomen with contrast is recommended for patients with clinical features of splenic rupture.

In patients with infectious mononucleosis, lymph node biopsy findings typically show: ^{[14][15][16][17]}

• Reactive follicular hyperplasia due to increased activation of B lymphocytes
• Paracortical expansion through numerous, large immunoblasts (B cells and T cells), later expanding throughout the entire node
• Atypical Reed-Sternberg-like cells may be observed, which is why the disease is sometimes mistaken for Hodgkin disease.

• Mononucleosis-like syndromes ^[18]
  • Streptococcal pharyngitis, tonsillitis
  • Acute HIV infection
  • Viral hepatitis
  • Toxoplasmosis
• Diphtheria
• Acute leukemia
• Chronic fatigue syndrome

Tonsillitis is an important differential diagnosis that is often treated with aminopenicillins (e.g., ampicillin). However, if given to a patient with infectious mononucleosis, the patient often develops a maculopapular rash after 2–10 days. ^[7][8]

In patients with fatigue lasting > 6 months, in whom EBV was not confirmed, consider alternative diagnoses (e.g., chronic fatigue syndrome). ^[9]

The differential diagnoses listed here are not exhaustive.

Approach ^[3][6]

• Treat infectious mononucleosis based on the underlying cause:
  • EBV: supportive treatment only ^[6]
  • CMV: Consider adding antiviral therapy (see “Treatment of CMV”).
• Educate patients on:
  • How to prevent infectious mononucleosis transmission
  • Symptoms of serious complications of infectious mononucleosis
  • Limiting the following physical activities to reduce fatigue and the risk of splenic rupture ^[8]
    • Strenuous activity for at least 21 days ^[3][6][19]
    • Contact sports (e.g., football, wrestling) for at least 4 weeks ^{[3][6][8][19]}
  • Avoiding hepatotoxic substances, e.g., alcohol ^[3]
• Manage patient expectations:
  • Fatigue is common and can last ≥ 6 months. ^[6]
  • Athletes may require 3–6 months to return to prior fitness levels. ^[6]

Supportive treatment ^[3][6]

• Sore throat
  • Treatment of acute tonsillitis, e.g.:
    • Analgesia
    • Treatment of dehydration
  • Antibiotics are not usually required. ^[3]
    • Indicated only in confirmed bacterial coinfection (e.g., with group A Streptococcus)
    • Avoid aminopenicillins and consider alternatives (see “Recommended antibiotic regimens for acute GAS pharyngitis”).
• Fever: antipyretics
• Short courses of corticosteroids, e.g., prednisone (off-label) , can be used in complicated cases, e.g.: ^[6]
  • Tonsillar hypertrophy causing impending airway obstruction
  • Massive splenomegaly
  • Myocarditis
  • Hemolytic anemia
  • Severe thrombocytopenia
  • Hemophagocytic lymphohistiocytosis

Immunocompromised patients have a higher risk of developing complications. ^[20]

• Nervous system
  • Guillain-Barré syndrome
  • Meningoencephalitis
  • Cranial nerve disorders (especially CN VII)
  • Primary CNS lymphoma
  • Multiple sclerosis ^[21]
• Hematologic system
  • Hemophagocytic lymphohistiocytosis (HLH): a life-threatening hematologic disorder involving pancytopenia and severe inflammation due to increased activity of cytotoxic T cells and macrophages ^[22]
    • Other secondary causes: malignancy (e.g., colon cancer) ^[23]
    • Clinical features: fever, hepatosplenomegaly, weight loss
    • Laboratory findings: pancytopenia, ↑ serum ferritin, cholestasis
    • Bone marrow biopsy: phagocytosis of hematopoietic cells
  • Autoimmune hemolytic anemia, thrombocytopenia
  • TTP, HUS
  • DIC
• Other organ systems
  • Upper airway obstruction due to oropharyngeal inflammation and enlarged lymph nodes
  • Splenic rupture
  • Oral hairy leukoplakia (typically in HIV patients)
  • Acute renal failure
  • Pericarditis/myocarditis
  • Pneumonia
  • Otitis media
• Associated malignancies
  • Burkitt lymphoma (BL), a non-Hodgkin lymphoma
    • Associated with EBV infection (EBNA-1 antigen) ^[24]
    • Endemic BL
      • Occurs mainly in Africa
      • Typically affects the jaw and facial bones
    • Sporadic BL: manifests with abdominal masses or bone marrow involvement
    • Immunodeficiency-related BL: similar to sporadic BL (typically in HIV patients)
  • Hodgkin lymphoma
  • Nasopharyngeal carcinoma (common in Asian adult population)
  • Post-transplant lymphoproliferative disorder: a group of aggressive and rapidly progressive complications of solid organ transplantation and allogeneic hematopoietic stem cell transplantation
    • Associated with EBV reactivation in patients with severe immunosuppression (e.g., post-transplantation medications)
    • Clinical features: fever, weight loss, fatigue, lymphadenopathy, hepatosplenomegaly
    • Commonly progresses to B-cell lymphoma: poor prognosis
    • Treatment: reduce immunosuppressive therapy

We list the most important complications. The selection is not exhaustive.

• There is no vaccine to prevent transmission of infectious mononucleosis. ^[25]
• Prevent transmission by avoiding exposure (e.g., kissing, sharing cutlery, water bottles, and/or personal items) to individuals who have suspected or confirmed infection. ^[3]