Infectious mononucleosis

Infectious mononucleosis (IM), also called "mono" or the "kissing disease", is an acute condition caused by the Epstein-Barr virus (EBV). The disease is highly contagious and spreads via bodily secretions, especially saliva. Infection frequently goes unnoticed in children; mainly adolescents and young adults exhibit symptoms. Symptomatic individuals typically first experience fever, malaise, and fatigue, which is later accompanied by acute pharyngitis, tonsillitis, lymphadenopathy, and/or splenomegaly lasting up to a month. IM is also sometimes associated with a measles-like exanthem, especially in individuals who are falsely diagnosed with bacterial tonsillitis and given ampicillin or amoxicillin. To avoid misdiagnosis, suspected cases are confirmed with a heterophile antibody test (monospot test), or in some cases, positive serology. Patients exhibit lymphocytosis, often with atypical T lymphocytes on a peripheral smear. IM is treated symptomatically, as it is usually self-limiting. Although complications are rare, IM is associated with atraumatic splenic rupture due to splenomegaly and multiple malignancies (e.g., Hodgkin's lymphoma, Burkitt lymphoma).

• 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 ^[3]

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen: : Epstein-Barr virus (EBV), also called human herpesvirus 4 (HHV-4)
• Transmission: : Infectious mononucleosis spreads via bodily secretions, especially saliva. Therefore, it is also called kissing disease.

References:^[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).”

• Incubation period: ∼ 6 weeks ^[5]
• Clinical course
  • Symptoms typically occur in adolescents and young adults and last for 2–4 weeks.
  • Young children are often asymptomatic.
• Signs and symptoms
  • 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
  • Possibly hepatomegaly and jaundice
  • Maculopapular rash; (similar to measles): The rash is caused by the infection itself in about 5% of cases but is most commonly associated with the administration of aminopenicillin (e.g., ampicillin, amoxicillin) ^[6][7]

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

In most cases, a maculopapular rash occurs due to empiric administration of aminopenicillins, and not due to EBV infection.

Clinical suspicion of IM is confirmed via antibody testing.

• Monospot test
  • Detects heterophile antibodies produced in response to EBV infection using RBCs from sheep or horses
  • Patient's serum is mixed with a solution of sheep/horse RBC in vitro
    • Positive test: cross-reaction between heterophile antibodies and sheep/horse RBCs → agglutination
    • Negative test
      • No heterophile antibodies present → no cross-reaction → no agglutination
      • In some cases, the test can show negative results if it is performed too soon (i.e. within the first 1–2 weeks after symptom onset) and antibodies have not developed yet.
  • Specificity of ∼ 100%, sensitivity of 85%
• Laboratory analysis: elevated LDH and liver transaminases
• Peripheral smear: : lymphocytosis with > 10% atypical lymphocytes (in some cases, up to 90%)
• Serology: indicated if IM is suspected but monospot testing is negative
  • Anti-viral capsid antigen antibodies (anti-VCA)
    • Anti-VCA IgM: appears early and vanishes ∼ 3 months after infection
    • Anti-VCA IgG: appears after 2–4 weeks and persists for life
  • Anti-EBV nuclear antigen-antibody (anti-EBNA-1) IgG

• Lymph nodes show: ^{[8][9][10][11]}
  • 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 ^[12]
  • Streptococcal pharyngitis, tonsillitis
  • Acute HIV infection
  • CMV infection (CMV mononucleosis)
  • Viral hepatitis
  • Toxoplasmosis
• Diphtheria
• Acute leukemia

Tonsillitis is an important differential diagnosis that is often treated with aminopenicillins (e.g., ampicillin). However, if given to a patient with IM, the patient often develops a macular erythematous rash after 5–9 days.

The differential diagnoses listed here are not exhaustive.

Therapy of IM is mainly symptomatic.

• Avoid physical activity because of the risk of splenic rupture.
  • Patients should avoid strenuous physical activities for at least 21 days after initial symptoms develop. ^[13]
  • Patients should avoid high-contact sports (e.g., football, wrestling) for at least 4 weeks
• Fluids (IV administration if necessary)
• Analgesics/antipyretics (e.g., acetaminophen), viscous lidocaine for throat pain
• Steroids are not recommended for routine use but may be considered in complicated cases.
• Contact persons should avoid direct contact to the patient's bodily fluids (e.g., no sharing of food, drinks, personal items, no kissing)

Immunocompromised patients have a higher risk of developing complications. ^[14]

• Nervous system
  • Guillain-Barré syndrome
  • Meningoencephalitis
  • Cranial nerve disorders (esp. CN VII)
  • Primary CNS lymphoma
  • Multiple sclerosis ^[15]
• Hematological system
  • Hemophagocytic lymphohistiocytosis (HLH): a life-threatening hematologic disorder involving pancytopenia and severe inflammation due to increased activity of cytotoxic T cells and macrophages ^[16]
    • Other secondary causes: malignancy (e.g., colon cancer) ^[17]
    • 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) ^[18]
    • 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.