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. 
- Peak incidence: (of symptomatic disease): 15–24 years of age 
- Incidence: 5/1000 per year 
Epidemiological data refers to the US, unless otherwise specified.
- Pathogen: Epstein-Barr virus (EBV), also called human herpesvirus 4 (HHV-4)
- Transmission: : Infectious mononucleosis is highly contagious and spreads via bodily secretions, especially saliva. Therefore, it is also called kissing disease.
- 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
- Incubation period: ∼ 6 weeks 
- 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) 
Clinical suspicion of IM is confirmed via antibody testing.
- 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
- 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
|Serology||Past infection||Primary infection|
Lymph nodes show: 
- 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 
- 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. 
- 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)
- Steroids are not recommended for routine use but may be considered in complicated cases.
Immunocompromised patients have a higher risk of developing complications. 
- Nervous system
- Hemophagocytic lymphohistiocytosis (HLH): a life-threatening hematologic disorder involving pancytopenia and severe inflammation due to increased activity of cytotoxic T cells and macrophages 
- Autoimmune hemolytic anemia, thrombocytopenia
- TTP, HUS
- Other organ systems
- Burkitt lymphoma (BL), a non-Hodgkin lymphoma
- Hodgkin lymphoma
- Nasopharyngeal carcinoma (common in Asian adult population)
- Post-transplant lymphoproliferative disorder: EBV reactivation in patients with severe immunosuppression (e.g., post-transplantation)
We list the most important complications. The selection is not exhaustive.