EBV and Infectious Mononucleosis — Clinical Triad, Atypical Lymphocytes, Serology and Complications

Infectious mononucleosis (IM), also called glandular fever, is a clinical syndrome of fever, tonsillar pharyngitis and lymphadenopathy. It is most often caused by Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV-4). About 90% of IM cases are caused by EBV; the rest are mononucleosis-like illnesses from other agents.

EBV is one of the most widespread human viruses: more than 95% of adults carry antibodies from a past infection. Infection in early childhood is usually silent or mild; symptomatic IM is typical of adolescents and young adults, which is why the disease is classically linked to college students.

• Spread: mainly through saliva — kissing, sharing utensils or water bottles; also sexual contact, and rarely blood transfusion or transplantation.
• Incubation: long — symptoms start roughly 4 to 8 weeks after exposure (32–49 days in one estimate).
• Target cells: the virus replicates in oropharyngeal epithelium, then infects B lymphocytes in lymphoid tissue.
• Immune response: strong activation of CD4+ and CD8+ T cells causes lymphoid hyperplasia — lymphadenopathy, tonsillitis and hepatosplenomegaly.
• Latency: EBV persists for life in memory B cells and reactivates periodically, shedding again in saliva. Shedding continues for 6 to 18 months after the illness.

The classic triad is sore throat, lymphadenopathy and fever. In one series of 500 confirmed cases over 98% had sore throat, lymphadenopathy, fever and tonsillar enlargement, but in another series of 150 patients the full triad was much less common (sore throat 74%, lymphadenopathy 57%, fever 45%). Marked fatigue is almost universal and can outlast the other symptoms.

Age changes the picture. Children under 5 years more often have rash, palpable splenomegaly and upper respiratory symptoms. Patients older than 30 years have more severe disease, with more frequent hepatic, splenic, neurological and haematological complications.

The acute phase usually settles in 1 to 2 weeks, and most patients recover within 2 to 3 weeks, but fatigue can persist for months — occasionally 6 months or longer.

The complete blood count typically shows leukocytosis with lymphocytosis and atypical lymphocytes. Atypical, or reactive, lymphocytes — 'Downey cells' — are large cells with a lobed or indented nucleus and abundant, visible bluish cytoplasm that often appears to wrap around neighbouring red cells.

One systematic review found that lymphocytosis above 50% combined with atypical lymphocytes above 10% had a sensitivity of 99% for infectious mononucleosis. Atypical lymphocytes are not specific, however — CMV, acute HIV, toxoplasmosis and drug reactions can produce them too. The disease takes its name from these 'mononuclear' cells.

EBV infection makes the body produce heterophile antibodies — IgM antibodies that agglutinate red cells of other species. The original Paul-Bunnell test was an agglutination test of this kind; the modern Monospot is a latex agglutination test using horse (equine) erythrocytes. Clumping means a positive result.

Because of these limits, the CDC does not recommend the Monospot for general use: at best it suggests a typical case of IM but does not confirm EBV infection. A patient with a mononucleosis picture and a negative heterophile test should have EBV-specific antibody testing, and acute HIV should be excluded.

EBV-specific antibody testing is more accurate than the Monospot, with a sensitivity of about 97% and a specificity of about 94%. The panel measures antibodies to three antigens, each with a different time course.

• Susceptible (never infected): no antibody to VCA.
• Primary (recent) infection: VCA IgM positive, EBNA antibody negative — or a high or rising VCA IgG with no EBNA antibody after at least 4 weeks of illness.
• Past infection: antibodies to both VCA and EBNA — the usual adult pattern, since over 90% of adults have been infected.

IM is self-limiting and treatment is supportive: rest, fluids, and paracetamol or NSAIDs for fever and sore throat. Antivirals such as acyclovir have no established role — they reduce oral shedding but do not improve symptoms. Routine corticosteroids are not recommended; they are reserved for complications such as threatened airway obstruction from massive tonsillar and nodal enlargement, or autoimmune complications.

Antibiotics are not indicated. If a patient with IM is given amoxicillin or ampicillin (usually because the illness is mistaken for streptococcal tonsillitis), a generalised maculopapular rash appears in up to 30%. It is thought to reflect a transient hypersensitivity to penicillin derivatives during the infection, not a lifelong penicillin allergy.

Splenic rupture is rare — about 0.1% to 0.2% of cases — but potentially fatal. Most ruptures happen within the first 21 days after symptom onset, when the spleen is enlarged and fragile, and it can follow trivial trauma. Management of a rupture is usually splenectomy.

• Upper airway obstruction from massive tonsils and nodes — rare (1–3.5%), mostly in children.
• Haematological: autoimmune haemolytic anaemia, pancytopenia, haemophagocytic lymphohistiocytosis.
• Neurological and cardiac: encephalitis, myocarditis.
• Others: hepatitis, acalculous cholecystitis, pancreatitis, haemolytic uraemic syndrome, uveitis and episcleritis, erythema multiforme.
• Long term: EBV-associated malignancy and an association with autoimmune disease such as multiple sclerosis.

EBV is an oncogenic virus. It is linked with tumours of lymphoid origin (Burkitt lymphoma, Hodgkin lymphoma) and epithelial origin (nasopharyngeal and gastric carcinoma). Infectious mononucleosis itself increases the later risk of Hodgkin lymphoma.

For the head-and-neck side of this association — undifferentiated nasopharyngeal carcinoma, its presentation and EBV markers — see nasopharyngeal tumours: JNA and carcinoma.