Epstein-BarrEpstein-Barr Virus (EBV) Virus (EBV)

Erika Guevara, Elly Nagata and Bin YangErika Guevara, Elly Nagata and Bin Yang

Case StudyCase Study

17-year-old high school student17-year-old high school student No prior major illnessesNo prior major illnesses Low grade feverLow grade fever Malaise- several daysMalaise- several days Sore throatSore throat Swollen cervical lymph nodesSwollen cervical lymph nodes Increasing fatigueIncreasing fatigue Discomfort in left upper quadrant of Discomfort in left upper quadrant of

abdomenabdomen Sore throat, lymphadenopathy and Sore throat, lymphadenopathy and

fever resolve over next two weeksfever resolve over next two weeks Full energy level does not return for Full energy level does not return for

another six weeksanother six weeks

HerpesvirusesHerpesviruses Linear genomeLinear genome dsDNA with nicks or gapsdsDNA with nicks or gaps Enveloped Enveloped Icosahedral capsidIcosahedral capsid Infect humansInfect humans Remain latent within hostRemain latent within host cell after primary infection cell after primary infection and may become activated and may become activated

EBV vs. Cytomegalovirus EBV vs. Cytomegalovirus (CMV)(CMV)

CMV InfectionCMV Infection Human Human

herpesvirus type 5herpesvirus type 5 Severe systemic Severe systemic

disease can disease can develop in infantsdevelop in infants

Negative Negative heterophile heterophile antibody test and antibody test and serologyserology

EBV InfectionEBV Infection Human herpesvirus Human herpesvirus

type 4type 4 Usually Usually

asymptomatic in asymptomatic in infantsinfants

Severe pharyngitisSevere pharyngitis

Tests Performed:Tests Performed:

CBC countCBC count Liver function testLiver function test Heterophile antibody testHeterophile antibody test

- differential absorption - differential absorption

- heterophile antibody titers - heterophile antibody titers

- monospot- monospot EBV serologyEBV serology Imaging StudiesImaging Studies

CBC countCBC count 40%-70% of patients have leukocytosis with a 40%-70% of patients have leukocytosis with a

WBC count of 10,000-20,000 cells/mL. 10% of WBC count of 10,000-20,000 cells/mL. 10% of patients will have a WBC count greater than patients will have a WBC count greater than 25,000 cells/mL by the second week.25,000 cells/mL by the second week.

80-90% of patients have lymphocytosis with 80-90% of patients have lymphocytosis with more than 50% lymphocytes. 20-40% of the more than 50% lymphocytes. 20-40% of the lymphocytes are atypical. The illness typically lymphocytes are atypical. The illness typically lasts for 2-6 weeks.lasts for 2-6 weeks.

The atypical lymphocytes appear larger, have The atypical lymphocytes appear larger, have a lower nuclear-to-cytoplasmic ratio, and a lower nuclear-to-cytoplasmic ratio, and have a nucleus that is less dense than that of have a nucleus that is less dense than that of normal lymphocytes.normal lymphocytes.

Liver function testLiver function test

80-100% patients have elevated liver 80-100% patients have elevated liver function test results.function test results.

Alkaline phosphatase, aspartate Alkaline phosphatase, aspartate aminotransferase (AST), and bilirubin aminotransferase (AST), and bilirubin levels peak 5-14 days after onset, and levels peak 5-14 days after onset, and gama-glutamyltransferase (GGT) levels gama-glutamyltransferase (GGT) levels peak at 1-3 weeks after onset.peak at 1-3 weeks after onset.

Lactic acid dehydrogenase (LDH) levels Lactic acid dehydrogenase (LDH) levels are increased in approximately 95% of are increased in approximately 95% of patients.patients.

Most liver function test results return to Most liver function test results return to normal within 3 months.normal within 3 months.

Differential absorption testDifferential absorption test

Bovine RBCs absorb infectious Bovine RBCs absorb infectious mononucleosis heterophile mononucleosis heterophile antibodies, but Guinea pig kidney antibodies, but Guinea pig kidney cells do not.cells do not.

Serum from a patient with infectious Serum from a patient with infectious mononucleosis agglutinates sheep mononucleosis agglutinates sheep RBCs after absorption with guinea RBCs after absorption with guinea pig cells, but no agglutination occurs pig cells, but no agglutination occurs after absorption with bovine RBCs.after absorption with bovine RBCs.

Heterophile antibody titersHeterophile antibody titers The titer of heterophile antibody is determined The titer of heterophile antibody is determined

with tube dilution. A titer of 1:40 after absorption with tube dilution. A titer of 1:40 after absorption with guinea pig cells is considered positive for with guinea pig cells is considered positive for acute infectious mononucleosis.acute infectious mononucleosis.

60-90% of patients have test results that are 60-90% of patients have test results that are positive for heterophile antibodies in the second or positive for heterophile antibodies in the second or third weeks. Then it begins to decline until less third weeks. Then it begins to decline until less than 1:40 within 2-3 months.than 1:40 within 2-3 months.

As many as 20% of patients still have positive titer As many as 20% of patients still have positive titer resutls within 1-2 years. 75% of patients have resutls within 1-2 years. 75% of patients have positive horse RBC agglutinin findings at 1 year.positive horse RBC agglutinin findings at 1 year.

10-30% of children younger than 2 years and 50-10-30% of children younger than 2 years and 50-75% of children aged 2-4 years develop 75% of children aged 2-4 years develop heterophile antibodies with primary EBV infection.heterophile antibodies with primary EBV infection.

EBV serologyEBV serology

Antibodies to EBV antigens include antibodies to Antibodies to EBV antigens include antibodies to viral capsid antigen (VCA), early antigens (EAs), viral capsid antigen (VCA), early antigens (EAs), and EBNA.and EBNA.

They are measured with enzyme immunoassays, They are measured with enzyme immunoassays, indirect immunofluorescence assays, and indirect immunofluorescence assays, and immunoblot assays.immunoblot assays.

Antibody to the restricted component of early Antibody to the restricted component of early antigens (EA/R) is measurable in children younger antigens (EA/R) is measurable in children younger than 4 years with primary EBV infection or in than 4 years with primary EBV infection or in patients with nonsymptomatic infection.patients with nonsymptomatic infection.

80% of the patients with infectious mononucleosis 80% of the patients with infectious mononucleosis have antibodies to the diffuse-staining component have antibodies to the diffuse-staining component of EA (EA/D).of EA (EA/D).

Patients who are immunocompromised and have Patients who are immunocompromised and have persistent or reactivated EBV infections often have persistent or reactivated EBV infections often have high levels of antibodies to EA/D or EA/R.high levels of antibodies to EA/D or EA/R.

EBV serologyEBV serology

In patients with a more prolonged In patients with a more prolonged symptomatic illness, EA/D may become symptomatic illness, EA/D may become umeasurable, and EA/R results may umeasurable, and EA/R results may become positive.become positive.

The antibody pattern in 3-12 months The antibody pattern in 3-12 months includes positive findings for VCA-IgG and includes positive findings for VCA-IgG and EBNA antibodies, negative VCA-IgM EBNA antibodies, negative VCA-IgM antibodies, and positive EA antibodies.antibodies, and positive EA antibodies.

After 12 months, EA antibodies are not After 12 months, EA antibodies are not present.present.

EBV serologyEBV serology

Kit ComponentsKit ComponentsPeptide-coated paddles, IgM EnzymePeptide-coated paddles, IgM Enzymeconjugate, IgG Enzyme conjugate, conjugate, IgG Enzyme conjugate, Substrate 1, Substrate 2, Substrate Substrate 1, Substrate 2, Substrate mixingmixingvial, Wetting agent /wash solution, vial, Wetting agent /wash solution, Stop Stop solution, Paddle storage bag. Positive solution, Paddle storage bag. Positive and and negative controls available separatly.negative controls available separatly.Indirect immunofluorescence Indirect immunofluorescence assay designed for qualitative assay designed for qualitative and/or semi-quantitative and/or semi-quantitative detection of IgM antibodies to detection of IgM antibodies to Epstein-Barr Virus viral capsid Epstein-Barr Virus viral capsid antigen (EBV-VCA) in human antigen (EBV-VCA) in human serum.serum.

MonospotMonospot

Slide tests use either horse RBCs or bovine Slide tests use either horse RBCs or bovine RBCs.RBCs.

Bovine RBCs are specific for acute Bovine RBCs are specific for acute infectious mononucleosis heterophile infectious mononucleosis heterophile antibodies, while horse RBCs are more antibodies, while horse RBCs are more sensitive.sensitive.

Low sensitivity (63%-84%), with a negative Low sensitivity (63%-84%), with a negative predictive value of more than 10%.predictive value of more than 10%.

Rarely yield false-positive results in Rarely yield false-positive results in patients.patients.

Monospot testMonospot testQualitative or semi-quantitative differential slide Qualitative or semi-quantitative differential slide agglutination test for detection of infectious agglutination test for detection of infectious mononucleosis heterophile antibodies in human serum mononucleosis heterophile antibodies in human serum or plasma. The test is based on fresh horse RBC.or plasma. The test is based on fresh horse RBC.

Kit ComponentsKit Components

Guinea Pig Antigen (Reagent I), Guinea Pig Antigen (Reagent I), Beef RBC Beef RBC Antigen (Reagent II), Horse Antigen (Reagent II), Horse RBC (Indicator RBC (Indicator cells), Positive control, cells), Positive control, Negative control, Negative control, Glass Slide, Glass Slide, Microcapillary Pipettes, Rubber Microcapillary Pipettes, Rubber Bulbs, Bulbs, Plastic Pipettes, Wooden ApplicatorsPlastic Pipettes, Wooden Applicators

Imaging StudiesImaging Studies

Not for diagnosing acute infectious Not for diagnosing acute infectious mononucleosis.mononucleosis.

Chest radiography can detect lymph node Chest radiography can detect lymph node enlargement, but should prompt enlargement, but should prompt consideration of other diagnoses.consideration of other diagnoses.

Abdominal CT scanning can reveal splenic Abdominal CT scanning can reveal splenic rupture.rupture.

Ultrasonography, radionuclide scanning or Ultrasonography, radionuclide scanning or the spleen may assist diagnosis.the spleen may assist diagnosis.

DiagnosisDiagnosis Symptoms and age Symptoms and age

of patientof patient Increased Increased

percentage of percentage of atypical atypical mononuclear cellsmononuclear cells

Positive reaction to Positive reaction to “mono spot” test“mono spot” test- Positive for - Positive for heterophile heterophile antibodiesantibodies

Serology results: Serology results: -Positive EA, VCA--Positive EA, VCA-IgM, VCA-IgG, EBNAIgM, VCA-IgG, EBNA

Epstein-Barr VirusEpstein-Barr Virus Also known as Human Also known as Human

Herpesvirus 4Herpesvirus 4 Infectious mononucleosis; Infectious mononucleosis;

hepatitis; retinitis; pneumonia; hepatitis; retinitis; pneumonia; colitis; Burkitt’s lymphoma, colitis; Burkitt’s lymphoma, certain B-cell tumors; certain B-cell tumors; nasopharyngeal carcinomanasopharyngeal carcinoma

EBV remains dormant or latent EBV remains dormant or latent throughout lifetimethroughout lifetime

Affects 95% of the population Affects 95% of the population Only 5% of patients acquire EBV Only 5% of patients acquire EBV

from someone who has an acute from someone who has an acute infectioninfection

More transmission in areas of More transmission in areas of lower socioeconomic groups and lower socioeconomic groups and crowded conditionscrowded conditions

Patients that are Patients that are immunocompromised (organ immunocompromised (organ allograft recipients or HIV-allograft recipients or HIV-infected) are at greater risk.infected) are at greater risk.

Infections do not occur in Infections do not occur in epidemicsepidemics

Infectious MononucleosisInfectious Mononucleosis Transmission:Transmission:

-Intimate contact of oral saliva; usually -Intimate contact of oral saliva; usually between an uninfected person and EBV-between an uninfected person and EBV-seropositive person who is shedding the seropositive person who is shedding the virus asymptomaticallyvirus asymptomatically

-Transfusion of blood products-Transfusion of blood products Widespread; infection apparent chiefly in Widespread; infection apparent chiefly in

young adultsyoung adults

Symptoms:Symptoms: Fatigue- usually lasts 2-3 weeks. Fatigue- usually lasts 2-3 weeks. Splenomegaly- occurs in about 50% Splenomegaly- occurs in about 50%

of cases in 2of cases in 2ndnd-3-3rdrd week and lasts 6- week and lasts 6-8 weeks. This can cause anemia = 8 weeks. This can cause anemia = fatigue.fatigue.

Fever- peaks in afternoonFever- peaks in afternoon Pharyngitis- may be severe and Pharyngitis- may be severe and

painful painful Lymphadenopathy- usually Lymphadenopathy- usually

symmetric, involves group of nodes; symmetric, involves group of nodes; may be the only manisfestationmay be the only manisfestation

Cardiac, jaundice, periorbital Cardiac, jaundice, periorbital edema, palatal enanthema, edema, palatal enanthema, maculopapular eruptions, CNS maculopapular eruptions, CNS problems (rare)problems (rare)

Complications: neurological, Complications: neurological, hematologic, splenic rupture, hematologic, splenic rupture, respiratory, and hepatic respiratory, and hepatic

Incubation period is about 30-50 Incubation period is about 30-50 daysdays

Asymptomatic in young childrenAsymptomatic in young children Not fatalNot fatal

Palatal petechiae, erosions and a greyish exudate Palatal petechiae, erosions and a greyish exudate in a patient with infectious mononucleosis.in a patient with infectious mononucleosis.

Treatment:Treatment:

No specific treatmentNo specific treatment RestRest No specific antiviral drugNo specific antiviral drug Corticosteroids can be used for Corticosteroids can be used for

swelling of pharyngitis, airway swelling of pharyngitis, airway obstruction, severe obstruction, severe thrombocytopenia, and hemolytic thrombocytopenia, and hemolytic anemia.anemia.

References:References:1. Bennett, N. (2007, July 9). eMedicine from WebMD. Retrieved October 31, 2007, from 1. Bennett, N. (2007, July 9). eMedicine from WebMD. Retrieved October 31, 2007, from

http://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htm

2. Canada.com. Retrieved November 14, 2007, from http://bodyandhealth.canada.com/condition2. Canada.com. Retrieved November 14, 2007, from http://bodyandhealth.canada.com/condition

_info_popup.asp?channel_id=1020&disease_id=75&section_name=_info_popup.asp?channel_id=1020&disease_id=75&section_name=channel_ condition_infochannel_ condition_info

4. Common Viral Infections. Retrieved November 15, 2007, from 4. Common Viral Infections. Retrieved November 15, 2007, from

http://www.link.med.ed.ac.uk/RIDU/Viral.htmhttp://www.link.med.ed.ac.uk/RIDU/Viral.htm

5. eMedicineHealth. Retrieved November 14, 2007, from5. eMedicineHealth. Retrieved November 14, 2007, from

http://www.emedicinehealth.com/swollen_lymph_glands/page2_em.htmhttp://www.emedicinehealth.com/swollen_lymph_glands/page2_em.htm

6. Lab Tests Online. Retrieved October 30, 2007, from6. Lab Tests Online. Retrieved October 30, 2007, from

http://www.labtestsonline.org/understanding/analytes/mono/multiprint/htmlhttp://www.labtestsonline.org/understanding/analytes/mono/multiprint/html

7. Mayo Clinic Staff. (2006, November 10). Mayo Clinic.com. Retrieved November 14, 2007, 7. Mayo Clinic Staff. (2006, November 10). Mayo Clinic.com. Retrieved November 14, 2007,

from from http://www.mayoclinic.com/health/enlarged-spleen/DS00871http://www.mayoclinic.com/health/enlarged-spleen/DS00871

8. MedlinePlus. Retrieved October 30, 2007 from8. MedlinePlus. Retrieved October 30, 2007 from

http://www.nlm.nih.gov/medlineplus/print/ecy/article/003513.htmhttp://www.nlm.nih.gov/medlineplus/print/ecy/article/003513.htm

9. MedlinePlus. Retrieved November 13, 2007 from9. MedlinePlus. Retrieved November 13, 2007 from

http://www.nlm.nih.gov/medlineplus/ency/article/000591.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000591.htm

10. MedlinePlus. Retrieved November 15, 2007 from10. MedlinePlus. Retrieved November 15, 2007 from

http://www.nlm.nih.gov/medlineplus/ency/article/003276.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/003276.htm

11. National Center for Infectious Diseases. Retrieved October 30, 2007, from11. National Center for Infectious Diseases. Retrieved October 30, 2007, from

http://www.cdc.gov/ncidoc/diseases/ebv/htmhttp://www.cdc.gov/ncidoc/diseases/ebv/htm

12. The Merck Manuals Online Medical Library. Retrieved October 31, 2007, from12. The Merck Manuals Online Medical Library. Retrieved October 31, 2007, from

http://www.merck.com/mmhe/print/sec17/ch198/ch198g.htmhttp://www.merck.com/mmhe/print/sec17/ch198/ch198g.htm

13. Smith, C.H. (1956, June). Infectious Mononucleosis. The American Journal of Nursing, 56 13. Smith, C.H. (1956, June). Infectious Mononucleosis. The American Journal of Nursing, 56 (6). Retrieved November 14, 2007, from (6). Retrieved November 14, 2007, from http://www.jstor.orghttp://www.jstor.org