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Infectious Mononucleosis (IM)

Brief facts

• Discovery

  Infectious mononucleosis (also known as glandular fever or mono) was named by Sprunt and Evans in 1920 to describe a syndrome that resembled an acute infectious disease accompanied by atypical large peripheral blood lymphocytes (atypical lymphocytosis). These atypical lymphocytes, also referred as Downey cells, are activated CD8+ T lymphocytes, most of which are thought to be responding to EBV-infected B cells. Epstein-Barr virus (EBV) as a causative agent was first identified in 1968, which was 4 years after Anthony Epstein and his PhD student Yvonne Barr found the virus in cultured cells derived from Burkitt's lymphoma.

• Epidemiology

  Highest rates of incidence are in persons 10 to 24 years of age with no consistent seasonal peak. Primary infection often occurs in adolescence when new social contacts are being made. Infection at this time causes IM in 30-60% of cases. The severity of primary EBV infection in adults increases with age, and patients older than 40 years are especially prone to serious illness.

• Transmission

  Transmission occurs primarily via saliva (kissing, toy sharing, etc.).

• Incubation period

  The incubation period is 4 to 8 weeks.

• Duration

  In the majority of individuals, the disease is self-limiting with median duration 16 days (ranging 2-6 weeks), which is much longer than duration of most acute viral illnesses. Recovery is gradual, and may take months. Viral loads in oral cells and saliva remain elevated for many months. Detectable virus in the blood is eliminated by 7^th week of illness in almost every patient.

• Laboratory test

  In 1932, Paul and Bunnell discovered that heterophile antibodies, specifically sheep cell agglutinins, were elevated during infectious mononucleosis but not during many other diseases and thus can be used for diagnosis. Today, heterophile antibodies form basis for the Monospot Rapid Agglutination test. Although they are relatively specific, heterophile antibody tests are somewhat insensitive, particularly in the first weeks of illness.

• Immune response

  Primary EBV infection induces both humoral and cellular immune responses that control but not eliminate the infection. Antibodies are generated to both latent and lytic antigens, the latter are directed against the virus receptor on the viral envelope, glycoprotein 350 (g350), blocking virus binding to CR2 (complement receptor type 2) on B cells and thereby limiting viral spread and prevent reinfection. CD8-positive (CD8+) cytotoxic T-cell responses are key to controlling primary infection. These cells are present in the blood and tissues in very high numbers. Typically lymphocytosis of up to 15x10⁹/L (normal is 1-4x10⁹/L) is seen, with over 60% of cells being CD8+ cells with activated phenotype. These cells probably give rise to most of the symptoms and signs of IM as a result of massive production of cytokines, including lymphotoxin, tumor necrosis factor-α (TNFα), interleukin (IL)-1β and IL-6.

• Persistent infection

  Despite vigorous immune response directed against both latent and lytic viral antigens, EBV persists for life following primary infection. In each individual viral load remains fairly constant over time at around 5-500 virus infected cells in every 10x10⁶ circulating B-cells. These cells carry the virus in latent form, and there is low level of continuous or intermittent production of infectious virus into saliva.

• Lytic cycle

  In excess of 80 EBV proteins are expressed during lytic viral replication. Activation of lytic cycle from latency is initiated by expression of two immediate-early proteins encoded by BZLF1 and BRLF1 genes. Their Zta and Rta protein products are transcription factors which activate a cascade of viral gene transcription, starting with several early genes after about 2 hours, followed by delayed early and late genes from about 4 hours onward. Maximum expression of late proteins, including structural viral capsid antigens (VCA) and envelope glycoproteins, is achieved within about 12 hours after Zta and Rta expression. Although viral release can be detected within 24 hours, cells in lytic cycle can actually survive in vitro for several days before dying. Parent virus produces 10-100 progeny per cell. Consequently, there is considerable opportunity for the host organism for mounting immune responses to lytic cycle proteins. Serum IgA antibodies to VCA are reliable indicators of the EBV carrier status of healthy infected individuals.

• Treatment

  The mainstay of treatment for infectious mononucleosis is supportive care, including adequate hydration, nonsteroidal anti-inflammatory drugs or acetaminophen, and throat lozenges or sprays.

• Chronic Active EBV (CAEBV)

  First described in the late 1940s, chronic active EBV is due to inadequate control of viral replication. The disease is characterized by chronic infectious mononucleosis-like symptoms (fever, lymphoadenopathy, and hepatosplenomegaly), with illness lasting for more than 6 months. EBV-specific antibody titers are abnormal in CAEBV, and viral loads are elevated. Further complications can include pancytopenia, hypergammaglobulinemia, and B- or T-cell malignant lymphoma or lymphoproliferation. Various treatment strategies have been attempted, including antiviral drugs, chemotherapy, immunomodulation, cell therapy using EBV-specific cytotoxic T lymphocytes (CTLs), and hematopoietic stem cell transplantation. While the hematopoietic stem cell transplantation has seen some success, there remains no clear consensus as to optimal treatment regimen.

• X-linked lymphoproliferative disease (XLP)

  Patients with XLP are unable to control primary EBV infection. Such patients have a mutation in Src-homology-2-domain-containing protein (SH2D1A or SAP) that regulates signal transduction by 2B4 as well as by SLAM (signaling lymphocyte activation molecule). In the absence of functional SH2D1A, 2B4 inhibits rather than activates Natural Killer (NK) cells and they become unable to kill EBV-transformed cells.

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Prevalence of symptoms and laboratory abnormalities

Based on Odumade OA, Hogquist KA, Balfour HH Jr. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev. 2011 Jan;24(1):193-209.

Differential diagnosis

Based on Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Physician. 2004 Oct 1;70(7):1279-87.

Potential complications

• Acute interstitial nephritis (inflammation of spaces between the kidney tubules)
• Hemolytic anemia
• Myocarditis and cardiac conduction abnormalities
• Neurologic abnormalities
• Cranial nerve palsies
• Encephalitis
• Meningitis
• Mononeuropathies (damage to a single nerve or a nerve group outside the brain and spinal cord)
• Retrobulbar neuritis (inflammation of optic nerve)
• Thrombocytopenia
• Upper airway obstruction
• Splenic rupture

References

• Tembhare P, Ramani M, Syed K, Gupta AD. Immunophenotypic profile in acute infectious mononucleosis mimicking malignant lymphoproliferative disorder: a case report and review of literature. Indian J Hematol Blood Transfus. 2010 Sep;26(3):118-21.

  

  Peripheral blood smear showing atypical lymphocytes (Downy cells). Leishman stain 100×

• "Infectious Mononucleosis"[Majr]
• CDC: Epstein-Barr Virus and Infectious Mononucleosis