The spectrum of diseases caused by EBV includes both non-malignant and malignant conditions. Table 1 enlists the diseases with the respective host immune status and viral markers.

Table1. EBV associated diseases

 Infectious mononucleosis (IM): Primary EBV infection in adolescents and young adults usually results in infectious mononucleosis (IM). However, it can also be seen in developing countries and also in other age groups. Incubation period is 4–6 weeks. Fever, sore throat and cervical lymphadenopathy are the three most common manifestations of infectious mononucleosis and considered as the clinical triad. Tonsilar exudates and posterior cervical lymphadenopathy can be there. The less common manifestations are splenomegaly, hepatomegaly, periorbital edema and rash. Complications, which occur rarely in IM, include upper airway obstruction due to enlarged tonsils, autoimmune hemolytic anemia, granulocytopenia, thrombocytopenia, aplastic anemia, myocarditis, hepatitis, splenic rupture, palatal rash and neurologic complications such as Guillain Barré syndrome, encephalitis, and meningitis.

Most of the IM patients show leukocytosis with increase T cells and atypical lymphocytes but not increase in B cells. Atypical lymphocytes are predominantly activated T lymphocytes with a large amount of cytoplasm with vacuoles. There can be polyclonal B cell activation leading to increase in level of immunoglobulin and heterophile antibodies. Serum alkaline phosphatase and serum transaminase level are raised. There occur activation and proliferation of T lymphocytes in response to the EBV infected B cells. Most of the symptoms of IM are attributed to these CD8 T cell expansion and production of cytokines by them and not due to lytic infection of B cell.

Diagnosis of IM: Diagnosis of IM is confirmed by detection of IM specific heterophile antibody or EBV specific IgM antibody.

EBV specific antibody: IgM antibody to EBV virus capsid antigen (EBV VCA IgM) appears during acute infection and persists for only 2–3 months, indicating acute or recent infection. During the early part of the illness, EBV VCA IgM may be present in absence of EBV VCA IgG.

EBV VCA IgG antibody, though detectable during the acute infection, persists for years. Therefore, positive EBV VCA IgG positivity in absence of IgM to EBV VCA indicates past infection. Figure 1 depicts the schematic representation of kinetics of EBV antibodies in relation to symptoms.

Fig1. Schematic diagram showing antibody kinetics during primary EBV infection VCA: Viral capsid antigen, EA: Early antigen

Antibody to EBNA-1 appears during convalescence period, so positivity of this antibody during acute illness rules out acute infection, whereas seroconversion to EBNA antibody is an indicator of acute infection.

Heterophile antibody: Heterophile antibody against sheep/mammal agglutinin is produced in EBV associated infectious mononucleosis (Table 2). These antibodies are IgM in nature and present during acute infection in >95% of IM patients.

Tbale2. Salient features of infectious mononucleosis

Heterophile antibody is detected by presumptive or differential agglutination test.

Presumptive test is known as Paul-Bunnell test: This test measures the titer of agglutinin against sheep RBC in patient’s serum. Antibody titer >1:224 is considered as positive for IM. However, because of the non-specificity of the test, the test may be positive in other conditions such as serum sickness, and even in healthy individuals.

Differential agglutination test or Paul Bunnell-Davidsohn test: This test is employed to remove the Forssman antibodies and differentiates it from IM specific heterophil antibodies.

This test is based on the principle that anti sheep agglutinins of IM are not absorbed by guinea pig kidney (GPK) powder but absorbed completely by beef RBC. Patient’s serum is tested for sheep agglutinin as per the presumptive test and in addition another two rows of serum dilution are tested which have been pre-absorbed separately with guinea pig kidney powder and beef RBC.

In case of true IM specific heterophile anti body:

• Agglutination titer in serum pre-absorbed with GPK should either be same as that of presumptive test or if less, the decrease in titer should not be > 3 tubes than presumptive test.

• Agglutination titer in serum pre-absorbed with beef RBC should decrease and the decrease should be >4 tubes than that of presumptive test.

The main disadvantage of heterophil antibody test is false negative in children as majority of children do not mount heterophil antibody during primary infection.

EBV DNA assay: EBV DNA in blood is detected by PCR or real-time PCR. The detection of EBV DNA is recommended in patients with atypical clinical features or in children with negative heterophil antibody. The major recommendation for EBV DNAemia or quantitation is required for monitoring of therapy in EBV associated malignancies including PTLD.

The average EBV viral load in blood in various conditions:

• Healthy individuals with latent EBV: <1000 copies/mL of whole blood

 • Immunocompetent with symptomatic EBV infection: 5000 copies/mL of whole blood

• Transplant recipients: 5000–50,000 copies/mL of whole blood.

Burkitt lymphoma: Burkitt lymphoma (BL) is a high grade malignant B cell tumor. Endemic BL is seen in African children, where malaria is holoendemic. It is manifested as a tumor of jaw. More than 90% of these tumors are associated with EBV. Sporadic BLs are seen in America and Europe. These are mostly present as abdominal tumor and around 20% are associated with EBV. In AIDS patients, 40% BLs are EBV associated.

It is thought that malaria impairs the T cell control, leading to proliferation of EBV infected B cell. This in turn increases the EBV viral load. In BL, there occur chromosomal translocations involving 8:14, 8:22 or 8:2. This leads to dysregulation of c-myc oncogene which gets overexpressed. This in turn inhibits the immunological recognition of EBV proteins by various mechanisms leading to virus proliferation.

Thus BL can be diagnosed by detection of EBV VCA antibody in patients’ serum and EBV antigen and EBV DNA in BL tumor tissue (Table 3).

Table3. Evidences of EBV as causative agent of BL

Nasopharyngeal carcinoma: Nearly 100% anaplastic or undifferentiated type of nasopharyngeal carcinoma (NPC) are EBV positive. Anaplastic NPC is common in South East Asia more so in Southern China.

EBV associated diagnostic, screening and prognostic markers are given in Table 4.

Table4. EBV associated markers in nasopharyngeal carcinoma (NPC)

Lymphoproliferative disease: EBV associated lymphoproliferative disease can occur in patients with congenital or acquired immunodeficiency. 1–5% recipients of various trans plants; solid organ or bone marrow, develop EBV associated lymphoproliferative disease during the post-transplant period. Recipients of solid organ transplant are at higher risk of developing post transplant lymphoproliferative disorder (PTLD) than hematopoietic stem cell transplant (HSCT) recipients.

The risk of developing post-transplant lymphoproliferative disease (PTLD) increases with:

• HLA mismatch bone marrow.

 • Primary EBV infection

• Cytomegalovirus infection

 • TNF-a promoter polymorphism

Due to the impaired T cell immunity, these patients are unable to control the EBV infected B cell proliferation.

Majority of patients present with infectious mononucleosis like symptoms with fever and local or disseminated lymphoproliferation. Lesions are often extranodal involving liver, lungs, gastrointestinal tract, kidney and central nervous system. Increased level of IL-6, TNF-a and B cell growth factor is usually found in blood of PTLD patients.

PTLD is associated with high EBV viral load, expression of viral proteins (LMP-1, LMP-2, EBNA-1, EBNA-2 and BZLF). Estimation of EBV DNA load is recommended in patients with symptoms suggestive of PTLD or in high risk patients. Detection of high viral DNA in blood is used as a marker or predictor for diagnosis of PTLD and also for post-treatment follow-up. EBV DNA load along with EBV specific CD8 T cell acts as a better predictive marker than EBV DNA alone.

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مواضيع ذات صلة

EBV Life Cycle

Epstein–Barr virus

Treatment of Cytomegalovirus

Diagnosis of Cytomegalovirus

Clinical Manifestations of Cytomegalovirus

The Viral Genome

Human Immunodeficiency Virus

Viral Pathogenesis

VIRUSES

Human Cytomegalovirus

Influenza Virus Infections in Humans

Varicella-Zoster Virus