Understanding Epstein-Barr Virus and Infectious Mononucleosis

Miscellaneous Viral Infections of Respiratory Tract

INFECTIOUS MONONUCLEOSIS 2

INFECTIOUS MONONUCLEOSIS Epstein-Barr Virus (EBV) causes infectious mononucleosis - also associated with several human tumors - nasopharyngeal carcinoma, Burkitt s lymphoma, Hodgkin s disease, and B cell lymphoma. 3

Morphology of EBV EBV - member of sub-family of Herpesviridae Possess dsDNA, enveloped with an icosahedral symmetry. EBV expresses three classes of antigens. 1. Latent phase antigens 2. Early antigens 3. Late antigens 4

Pathogenesis EBV is transmitted by oropharyngeal contact through infected salivary secretions. EBV receptors: EBV binds to specific receptors present on B cell (CD21 or CR2) - such receptors also present on pharyngeal epithelial cells. Primary infection occurs in the oropharynx. EBV replicates in epithelial cells or surface B lymphocytes of the pharynx and salivary glands 5

Pathogenesis Infected B cells - immortalized by the virus - large number of variety of immunoglobulins (polyclonal) - many of those are autoantibodies In response to this, the bystander CD8 T lymphocytes - stimulated and appear atypical, feature characteristically seen in infectious mononucleosis 6

Pathogenesis Oncogenicity: Persistent EBV infection induce malignant transformation of infected B cells and epithelial cells by expressing latent EBV antigens - LMP and EBNA 7

Clinical Manifestations - Infectious Mononucleosis Also called kissing disease (transmitted through salivary contact) or glandular disease. Usually affects young adults, not children. Headache, fever, malaise, pharyngitis Cervical lymphadenopathy, hepatosplenomegaly, rashes following ampicillin therapy 8

Clinical Manifestations - Infectious Mononucleosis Atypical lymphocytosis (CD8 T cells) Autoantibodies reactive to sheep RBC antigens (detected by Paul-Bunnell test). 9

Comparison of infectious mononucleosis and mononucleosis-like syndrome Features Features Infectious mononucleosis Infectious mononucleosis Mononucleosis Mononucleosis- -like syndrome like syndrome Agent Epstein-Barr virus (EBV) CMV (20 50%) HHV-6, Toxoplasma, Ehrlichia, HIV Seen Atypical lymphocytosis Seen Clinical symptoms Fever, myalgia, hepatosplenomegaly, exudative pharyngitis, cervical lymphadeno- pathy, rashes following ampicillin therapy Elevated (detected by Paul-Bunnell test) Similar presentation, except that exudative pharyngitis, cervical lymphadenopathy are absent Negative Heterophile antibodies Specific antibodies Antibodies to specific EBV antigens are elevated Antibodies to CMV or other agents may be elevated 10

EBV-associated Malignancies Burkitt s lymphoma Nasopharyngeal carcinoma Hodgkin s lymphoma Non-Hodgkin s lymphoma 11

Other Conditions Associated with EBV Lymphoproliferative disorder: It is seen among immunodeficient patients Oral hairy leukoplakia: Wart-like growth of epithelial cells of the tongue developed in some HIV-infected patients and transplant recipients Chronic fatigue syndrome. 12

Epidemiology Age: Most common in early childhood, with a second peak during late adolescence. Transmission: Intimate and prolonged oral contact - required for effective transmission. Other modes - blood transfusion and following bone marrow transplantation. 13

Epidemiology (Cont..) Source: Asymptomatic seropositive individuals shed the virus in oropharyngeal secretions. Shedding is more in immunocompromised patients 14

Laboratory diagnosis of Epstein-Barr virus infections Antibody detection: Nonspecific heterophile antibody detection: Paul-Bunnell test Differential absorption test Monospot test EBV specific antibody detection ELISA and indirect IF assay detect antibody to viral capsid antigen, EBNA and early antigen. 15

Laboratory diagnosis of Epstein-Barr virus infections (Cont..) Molecular methods: Detects EBV DNA (by PCR) Quantifies EBV DNA (by real-time PCR) detecting genes BamH1W, EBNA1 and LMP Detects EBER RNA (by RT-PCR). EBV antigen: By direct IF assay. 16

Treatment of Epstein-Barr virus infections Supportive measures - analgesics for treatment of infectious mononucleosis Acyclovir - treatment of oral hairy leukoplakia - reduces EBV shedding from the oropharynx - no effect on the immortalized B cells - not effective for infectious mononucleosis and other malignancies Antibody to CD20 (rituximab) - effective in some cases. 17

ADENOVIRUS INFECTIONS 18

ADENOVIRUS INFECTIONS Adenoviruses - non-enveloped DNA virus. Icosahedral symmetry with fiber proteins projecting from each vertex - space vehicle shaped appearance 19

Clinical Manifestations Adenoviruses infect and replicate in the epithelial cells of the respiratory tract, eye, gastrointestinal tract, urinary bladder and liver. 1/3rd of the serotypes can cause human diseases, type 1 7 are the most common types worldwide. 20

Clinical Manifestations (Cont..) Respiratory diseases - most common manifestation Upper respiratory tract infection in children - serotypes 1,2 and 5. In adolescents - serotypes 3, 4 and 7 Pneumonia: Types 3, 7, and 21 Acute respiratory disease syndrome - type 4, 7 and occasionally type 3. 21

Clinical Manifestations (Cont..) Ocular Infections- Pharyngoconjunctival fever (swimming pool conjunctivitis) -serotypes 3 and 7 Epidemic keratoconjunctivitis or shipyard eye occurs mainly in adults and is highly contagious, caused by types 8, 19, and 37 22

Clinical Manifestations (Cont..) Infantile gastroenteritis Serotype 40 and 41 Acute hemorrhagic cystitis in children, serotypes 11 and 21 Immunocompromised patients - higher risk of developing serious pneumonia. Transplant recipients may develop pneumonia, hepatitis, nephritis, colitis, encephalitis, and hemorrhagic cystitis. 23

Laboratory Diagnosis Specimens - throat swab, conjunctival swab, stool or urine Virus isolation: Primary human embryonic kidney cell line and A 549 cell line Viral growth can be detected by: Characteristic cytopathic effect: Rounding and grape-like clustering of swollen cells Antigen detection by direct-IF test. 24

Laboratory Diagnosis (Cont..) Serotyping Direct fluorescence antibody test -fluorescent tagged anti-hexon antibody. Fastidious enteric serotypes - type 40 & 41 from stool - detected by electron microscopy or antigen detection by ELISA. 25

Laboratory Diagnosis (Cont..) Molecular methods: PCR - targeting group-specific conserved hexon or fiber genes. Multiplex PCR & Real-time PCR - monitor viral load. Serum antibody detection - ELISA 26

Treatment and Control Symptomatic treatment , only in severe cases of pneumonia cidofovir is recommended. General preventive measures are: Effective hand washing Sodium hypochlorite to disinfect environmental surfaces Chlorination of swimming pools and waste water Strict asepsis during eye examinations. 27

Adenoviruses used for Gene Therapy Replication defective adenoviruses can also be used as livevirus vectors for the delivery of vaccine antigens and for gene therapy; e.g. trials on adenovirus vectored M. tuberculosis (using 85A antigen) , HIV and COVID- 19 vaccines. 28

RHINOVIRUS INFECTION (COMMON COLD ) 29

RHINOVIRUS INFECTION (COMMON COLD ) Rhinoviruses - most common cause of common cold. Belong to Picornaviridae family, which also include enteroviruses. Use host cell intercellular adhesion molecule-1 (ICAM-1) as receptor More than 100 antigenic types have been identified 30

RHINOVIRUS INFECTION (COMMON COLD ) (Cont..) They are similar to enteroviruses in structure and properties except that: Acid-labile (unstable below pH 6) Transmitted by respiratory route. 31

RHINOVIRUS INFECTION (COMMON COLD ) (Cont..) Clinical features: Incubation period - 2 4 days Common cold syndrome Primary disease in adults rhinosinusitis , sneezing, nasal obstruction, nasal discharge, and sore throat, but no fever 32

RHINOVIRUS INFECTION (COMMON COLD ) (Cont..) Secondary bacterial infection otitis media, sinusitis, bronchitis, or pneumonitis, especially in children. 33

RHINOVIRUS INFECTION (COMMON COLD) (Cont..) Relapse: Average adult gets 1 2 attacks each year Laboratory diagnosis: Rhinoviruses can be grown in human diploid cell lines -WI-38 and MRC-5 cell lines. Most strains grow better at 33 C (nasopharynx temperature) but not 37 C Treatment is supportive (i.e. symptomatic treatment). 34