Infectious mononucleosis (IM) is an infectious disease described in 1889 as “glandular fever”. The causative agent, Epstein–Barr virus (EBV), was discovered in 1968 by examining electron micrographs of cultured cells of Burkitt’s lymphoma (BL).
Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a large enveloped virus which replicates in the nuclei of infected cells and has a double-stranded DNA genome.
EBV has two major target tissues in vivo, B lymphocytes and pharyngeal epithelium. In pharyngeal epithelium, which EBV enters by oral route, the infection is predominantly lytic. In B cells, the infection is predominantly nonproductive (latent).
EBV acquired in early childhood usually does not cause symptoms. However, in developed countries the infection is usually acquired only during adolescence or early adulthood years when it is often (in 25-50% of cases) associated with IM.
The clinical symptoms range from mild fever to prolonged debilitating illness. Typically, the disease presents as pharyngitis, lymphadenopathy, and fever. Enlarged spleen and a swollen liver are less common symptoms. Microscopic blood observation reveals lymphocytosis; most lymphocytes have atypical morphology.
Although most persons with IM resolve their symptoms within 2 to 4 weeks, іn more than 90% of adults a latent infection of B lymphocytes develops. EBV reactivation from latency is a common phenomenon even in immunocompetent persons, though it is not correlated to any symptomatic disease.
Despite the generally benign course of IM, severe complications (hepatitis, myocarditis, splenic rupture, neurological complications) could occur in approximately 1% of immunocompetent individuals. In immunocompromised individuals as well as persons with certain diseases, such as X-linked lymphoproliferative syndrome, primary EBV infection is associated with disorders with high rates of mortality such as BL.
Typical symptoms of IM usually appear 4 to 6 weeks after infection.
EBV spreads most commonly through bodily fluids, especially saliva, sporadically also through blood and semen. Humans are the most infectious during acute IM, but the virus could be shed into saliva even during latency. Transmission occurs mainly via household and sexual routes; however, transmission via blood transfusion and organ transplantation was also demonstrated.
Risk groups for IM are adolescents, senior school students, blood transfusion recipients, as well as people with immunodeficiencies (risk group for complications). Up to 50% of adolescents and young adults in developed countries are seronegative and hence at risk of developing IM.
EBV is a genetically stable virus.
EBV is one of the most common human viruses. EBV is found all over the world; virus is able to infect more than 95% of all individuals within the first four decades of life. The current incidence of IM in USA is estimated at approximately 125 000 reported cases/year.
EBV DNA is surrounded by a nucleocapsid; protein tegument is situated between the nucleocapsid and envelope; outer envelope has glycoprotein spikes typical of all herpesviruses. The viral genome encodes around 90 proteins. The most of these proteins (80) are expressed only during EBV lytic cycle.
On the basis of their time of expression, EBV genes are designated early or late. Early genes encode mostly non-structural proteins, the most important among them is viral DNA polymerase. Late genes encode mostly structural viral proteins which are required for successful packaging of the viral DNA and formation of the virion. The viral capsids have several polypeptide components ranging in size from 18 to 155 kDa, with a 155-kDa polypeptide being the major component. The membrane antigen (MA) complex is found on the virion envelope and consists of at least three major EBV glycoproteins: gp350/220 (the most abundant protein), gp110, and gp85.
In contrast, during latent infection only up to 11 EBV genes are expressed. These encode six nuclear antigens and three integral membrane proteins.
The presence of EBV in epithelial and B cells provokes an intense immune response consisting of antibodies to a large variety of virally encoded antigens. During the acute phase of IM, the humoral response is directed toward viral antigens of the lytic cycle, notably membrane antigen complex, several early antigens (p 54 and p138), and VCA. A strong IgM response (the so-called heterophile antibodies) is directed towards a complex glycoprotein structure on the surface of EBV infected cells. As IM patients recover from clinical symptoms, the IgM response reduces significantly while the IgG response in serum plateaus at a reduced level and is maintained throughout the persistent infection.
Antibodies to the proteins of the latent cycle, the most well studied being EBNA-1 IgG antibodies, in contrast, are produced late (several months) after onset of infection and persist lifelong.
The main purpose of the diagnostics of IM is to rule out less common but more serious causes of IM-like symptoms, requiring immediate intervention, such as hepatitis or various leukemic malignancies.
The mainstay in the diagnostics of IM are still clinical symptoms (classic triad-fever, lymphoadenopathy, and pharyngytis) in combination with anamnestic aspects.
The specificity of the “classic triad” is around 90%, since IM-like symptoms may be caused by a variety of other pathogens and malignancies, such as cytomegalovirus, human herpesvirus 6, adenovirus, rubella virus, mumps virus, human immunodeficiency virus, hepatitis A virus, influenza A and B viruses, and Toxoplasma gondii, lymphoma and leukemia. Therefore, EBV infection should be confirmed with a blood antibody test.
It is well known for many years that acute IM is characterized by the appearance of heterophile antibodies (i.e. antibodies to EBV antigen described above) in the serum. This peculiarity is used in the so-called “monospot tests”, detecting agglutination of sheep erythrocytes in the presence of serum of patients with acute-phase IM. This test is now not recommended for general use by the Centers for Disease Prevention and Control, USA, since it produces both false positive and false negative results.
Only three serological parameters are essential for the detection of EBV-specific antibodies in immunocompetent individuals: VCA IgG (marker of disease, present or past), VCA IgM (marker of recent or present disease), and EBNA-1 IgG (marker of past disease).
The most widely used serological methods are immunofluorescence assay (IFA) and enzyme immunoassay (EIA). IFA has always been used as a reference method. However, some investigators found EIA to be more sensitive than IFA.
On the contrary, in immunosuppressed individuals serological assays are not recommended for many reasons, such as dysfunctions in the production of antibodies. To date, only detection of viral load by PCR is an established marker for immunosuppressed patients.
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