EBV Infection

In healthy individuals, infection with EBV induces a strong cellular and humoral immune response that restrains the outgrowth of EBV-infected B cells.
- Although antibodies to the viral membrane proteins neutralize virus infectivity, the cellular immune response is essential for controlling virus-infected cells during both lytic and latent phases.
- CD8+ cytotoxic T lymphocytes represent the major cell type responsible for controlling primary infection. Activated CTL, the majority of which are reactive to EBV lytic proteins, account for up to 50% of the large atypical lymphocytes visible in the blood of individuals with acute IM.
Despite the vigorous EBV-specific T-cell response, virus-infected B cells are never completely eradicated, even in immunocompetent individuals. Accordingly, approximately 1 in 10000 to 100000 memory B cells remain infected throughout the life of the host. Under normal circumstances, this frequency of EBV-infected B cells is stable with an estimated total body load of 10^4 to 10^7 (mean 0.5 ×10^6) EBV-positive memory B cells.

Type I latency is observed in Burkitt lymphoma and a portion of EBV-positive gastric carcinomas.
Type II latency is observed in NPC and other EBV-positive lymphomas, such as T-cell or NK-cell NHL, the Reed-Sternberg cells of HL and some EBV-associated gastric adenocarcinoma.
Type III latency is observed in immunodeficient patients with EBV-induced lymphoproliferation, such as those with HIV-associated NHL or PTLD, as well as in in vitro immortalized B cells (lymphoblastoid cell lines) or naturally infected normal resting B cells.

Small nonpolyadenylated viral RNAs termed EBERs 1 and 2 and the BamHI-A rightward transcripts (BARTS) are expressed in all forms of latency.
The EBERs are the most abundant viral RNAs in latently infected cells. They enhance the oncogenic phenotype of EBV-transformed cells but are nonessential for EBV-mediated transformation.

Infectious Mononucleosis

<aside> 💡 Clinical triad: fever, pharyngitis, and adenopathy.

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Clinical Presentation

The incubation period of IM is estimated to be 30 to 50 days.
IM occurs in adolescents and young adults, where 75% of individuals between the age of 17 and 25 years develop typical manifestations.
- IM is sufficiently uncommon in people older than 30 to 40 years that special care is needed when making the diagnosis. Nevertheless, well-documented cases in patients older than 40 years have been reported.
- IM usually occurs only once; however, recurrences have been reported, and exacerbations of unresolved infection or transition to a chronic course may also occur.
Early, asymptomatic primary EBV infection occurs in individuals from lower socioeconomic groups and in third world countries. In higher socioeconomic groups in industrialized countries, the age of primary infection is often delayed until the second decade of life and clinically apparent IM is more prevalent.
Primary EBV infection in infants and young children is either asymptomatic or accompanied by mild, nonspecific symptoms and signs such as fever, upper respiratory tract infection, pharyngitis with or without tonsillitis, and cervical lymphadenopathy. In contrast, approximately 50% of adolescents and young adults present with the clinical picture of IM.
Infection is often acquired following contact with EBV-containing saliva. In recognition of this mode of transmission, IM is commonly referred to as the “kissing disease.” Other modes of acquiring the virus include transplantation of organs or hematopoietic cells containing EBV-infected B cells.
The disease is characterized by a lymphocytosis caused by clonal expansions of T cells reacting against B lymphocytes infected with EBV.
- A moderate rise in white cell count (e.g. 10000–20000/μL) with an absolute lymphocytosis is usual.
- Large numbers of atypical lymphocytes are seen in the peripheral blood film.
  - These T cells are variable in appearance but most have nuclear and cytoplasmic features similar to those seen during reactive lymphocyte transformation. They are irregular, have slightly larger nuclei, a more open chromatin and abundant cytoplasm. Some cells may appear blastoid.
- The greatest number of atypical lymphocytes are usually found between the seventh and tenth day of the illness.

A self-limiting disease of adolescents that presents with prodrome of fatigue, myalgia lasting 1-2 weeks followed by fever, pharyngitis, exudative tonsilitis, adenopathy, splenomegaly, hepatomegaly and skin ****rash.
- Bilateral cervical lymphadenopathy is present in 75% of cases. Symmetrical generalized lymphadenopathy occurs in 50% of cases.
- Skin manifestations include a faint, morbilliform rash reminiscent of rubella (after ampicillin) and less commonly erythema multiforme and erythema nodosum.
Approximately 5% of patients are jaundiced.
Severe headache and eye signs (e.g. photophobia, conjunctivitis and periorbital oedema) are not uncommon.
- Neurologic complications develop usually during the first 2 weeks of IM and may be the only manifestation of IM.
- The spectrum includes encephalitis, meningitis, Guillain-Barré syndrome, acute transverse myelitis, and peripheral neuritis. Patients with neurologic complications have an excellent outcome.

Complications such as protracted fever, jaundice, pleural effusion, and Guillain-Barré syndrome often dominate the clinical picture in older patients.
Autoimmune hemolytic anemia occurs in approximately 3% of patients with IM. It presents in the first 2 weeks of the illness, and the majority of patients recover within 1 to 2 months. Patients usually have a positive direct Coombs test. Most common anti-i antibodies are present; however, anti-I, anti-N, and Donath-Landsteiner antibodies have also been reported. In addition to hemolysis, IM-associated anemia can be caused by erythroblastopenia.
Mild thrombocytopenia (50000 to 150000/μL) is a common finding in patients with IM. It usually occurs within the first 2 weeks of presentation and resolves within 2 months.