Epstein-Barr Virus

Infectious mononucleosis

• Caused by Epstein-Barr virus (EBV). • Characterized by: fatigue, malaise, fever, sore throat, and

generalized lymphadenopathy. • Was called glandular fever: Because it has mononuclear lymphocytosis with

atypical- lymphocytes.

Other infections may cause infectious mononucleosis-like illnesses

ETIOLOGY

• EBV, a member of the γ-herpesviruses, causes >90% of cases of infectious mononucleosis.

• Two distinct types of EBV: - type 1 (type A): more prevalent worldwide - type 2 (type B): more common in Africa • Both types lead to persistent, lifelong, latent infection.• Dual infections with both types have been documented

among immunocompromised persons.

Infectious mononucleosis-like illnesses

5–10% of are caused by: - CMV -Toxoplasma gondii - adenovirus - viral hepatitis - HIV - rubella virus.

• Causes of majority of mononucleosis-like illnesses still unknown.

EPIDEMIOLOGY

• EBV infects >95% of the world's population. • Transmitted by: 1. sexual intercourse 2. through oral secretions. 3. In children by exchange of saliva • Not transmitted by: - Nonintimate contact - fomites.

• EBV is shed in oral secretions consistently for >6 mo after acute infection and then intermittently for life.

• 20–30% excrete virus at any particular time.

• 60–90% in infected immunosuppressed patients.

• Immunosuppression help reactivation of latent EBV

• Also found in male and female genital secretions.

• Infection with EBV occurs during infancy and early childhood.

• 1ry infection in children usually inapparent.

• in >50% adolescents and adults:

classic triad:

- fatigue

- pharyngitis

- generalized lymphadenopathy.

INCIDENCE:

• Estimated: up to 70/100,000 persons/yr.

• in young adults:1/1,000 persons/yr.

• Almost all adults in USA are seropositive.

PATHOGENESIS

• Infection of the oral epithelial cells cause pharyngitis • viral replication and cell lysis.

• spreads to near structures as the salivary glands

• viremia and infection of B lymphocytes and the lymphoreticular system, including the liver and spleen.

• Characteristic atypical lymphocytes are CD8+ T lymphocytes.

• Transient reversal of the normal 2 : 1

CD4+/CD8+(helper:suppressorT-lymphocytes)

• This causes cytokine release which causes many of the clinical manifestations.

• Sexual transmission infects the epithelial cells of the uterine cervix.

• EBV is consistently found intracellularly in smooth muscle cells of leiomyosarcomas of immunocompromised persons.

• EBV has lifelong latent infection after the primary illness.

• The latent virus found in oropharyngeal epithelial cells and in memory B lymphocytes.

ONCOGENESIS

• EBV was the 1st human virus to be associated with malignancy.

• Spectrum of EBV infection:

- self-limited infectious mononucleosi

- nonmalignant proliferations

- malignancies in lymphoid and epithelial cell.

ONCOGENESIS-2

• Benign EBV-associated proliferations include: - Oral hairy leukoplakia, primarily in adults with AIDS - Lymphoid interstitial pneumonitis, in children with AIDS. • Malignant EBV-associated proliferations include: - nasopharyngeal carcinoma - Burkitt lymphoma - Hodgkin disease - lymphoproliferative disorders, and - leiomyosarcoma in immunodeficient including AIDS.

Nasopharyngeal carcinoma

• It is worldwide • 10 times more common in southern China,

where it is the most common malignant tumor among adult men.

• Patients present with: - cervical lymphadenopathy - eustachian tube blockage - nasal obstruction with epistaxis.

Nasopharyngeal carcinoma-cont

• Patients have elevated EBV antibody titers that are both diagnostic and prognostic.

Nasopharyngeal carcinoma-cont

• Diagnosis: - CT and MRI - Biopsy from lymph nodes or masses - Surgery is important for staging and diagnosis.

Treatment:• Radiation therapy is effective for control of the

primary tumor and regional nodal metastases.• Chemotherapy is effective but not always curative.Prognosis: good if the tumor is localized.

Endemic (African) Burkitt lymphoma

• Often in the jaw• The most common childhood cancer in equatorial East Africa• The median age at onset is 5 yr. • These regions are endemic for Plasmodium falciparum

malaria and have a high rate of EBV infection early in life. • Malarial exposure acts as a B-lymphocyte mitogen

increasing the risk of Burkitt lymphoma. • Approximately 98% of cases of endemic Burkitt lymphoma

contain the EBV genome.

1Other Malignancies-

• Infection with EBV also increase the risk for Hodgkin disease.

• EBV is find in the Reed-Sternberg cells which are pathognomonic malignant cells of Hodgkin disease.

• Duncan syndrome: (X-linked lymphoproliferative syndrome): is associated with severe, persistent, and fatal EBV infection .

• Many Immunodeficiency syndromes are associated with an increased incidence of EBV-associated B-lymphocyte lymphoma include:

- X-linked lymphoproliferative syndrome, - common-variable immunodeficiency, - ataxia-telangiectasia, - Wiskott-Aldrich syndrome, and - Chédiak-Higashi syndrome.

- T-lymphocyte lymphomas (including lethal midline) - angio-immunoblastic lymphadenopathy-like lymphoma - thymomas and thymic carcinomas - supraglottic laryngeal carcinomas - lympho-epithelial tumors of the respiratory tract and GIT. - gastric adenocarcinoma.

2Other Malignancies-

CLINICAL MANIFESTATIONSof EBV infection

• The incubation period: 30–50 days. • 1ry infection in infants and young children is silent. • In older patients: insidious and vague onset.

Prodromal symptoms: last 1–2 wk. • Malaise• fatigue• Fever & headache• sore throat, nausea, abdominal pain• myalgia.

• Splenic enlargement :may cause left upper abdominal discomfort and tenderness

Physical examination• generalized lymphadenopathy (90% of cases), • splenomegaly (50% of cases), • hepatomegaly (10% of cases).

• Lymphadenopathy :

Common in: - anterior and posterior cervical

- submandibular

less common in: axillary and inguinal.

Epitrochlear lymphadenopathy is suggestive of infectious mononucleosis.

• elevated liver enzymes are common. • Splenomegaly to 2–3 cm below the costal

margin is typical; massive enlargement is uncommon.

• The sore throat is often accompanied by moderate to severe pharyngitis with marked tonsillar enlargement, occasionally with exudates .

• Petechiae at junction of the hard and soft palate• Others: rashes and edma of the eyelids .

• Maculopapular in 3–15% of patients • Up to 80% of patients have “ampicillin rash” if treated

with ampicillin or amoxicillin. • This vasculitic rash is immune mediated and resolves

without specific treatment. • Gianotti-Crosti syndrome: a symmetrical rash on the

cheeks with multiple erythematous papules, which may coalesce into plaques, and persists for 15–50 days.

DIAGNOSIS

• clinical symptoms• atypical lymphocytosis• heterophile antibody or specific EBV antibodies.• Culture of EBV requires 4–6 wk. • The cultures are observed for 6 wk for signs of cell

transformation: - proliferation and rapid growth - mitotic figures: large vacuoles, granular morphology,

and cell aggregation.

Differential Diagnosis

• Cytomegalovirus-adenovirus-viral hepatitis-HIV- rubella. • Streptococcal pharyngitis: not associated with

hepatosplenomegaly. - If failure of streptococcal pharyngitis to improve within

48–72 hr you suspect infectious mononucleosis.

• In patients with extremely high or low white blood cell counts, moderate thrombocytopenia, and even hemolytic anemia.

You do: bone marrow examination and hematologic consultation to exclude the possibility of leukemia.

LABORATORY TESTS

• leukocytosis of 10,000–20,000 cells/mm3: In >90% of cases ⅔ are lymphocytes 20–40% atypical lymphocytes

• The atypical lymphocytes are large, with larger eccentric and folded nuclei with a lower nuclear-to-cytoplasm ratio.

• the highest degree of atypical lymphocytes is classically seen with

EBV infection.

• Mild thrombocytopenia rarely associated with purpura. • Mild elevation of hepatic transaminases without jaundice.

• Other syndromes with atypical lymphocytosis : - cytomegalovirus infection - toxoplasmosis - viral hepatitis - rubella - roseola - mumps - tuberculosis - typhoid - Mycoplasma - malaria, - Some drug reactions.

HETEROPHILE ANTIBODY TEST

• known as Paul-Bunnell antibodies, are IgM antibodies detected by the Paul-Bunnell-Davidsohn test for sheep red cell agglutination.

• Titers of >1 : 28 or >1 : 40, depending on the

dilution system used, after absorption with guinea pig cells are considered positive.

response to viral capsid antigen (VCA) is divided because of the significant differences noted according to age of the patient.

SPECIFIC EBV ANTIBODIES

TREATMENT • no specific treatment

• Acyclovir in high doses of acyclovir, with or without corticosteroids: - decreases viral replication and oropharyngeal shedding

- not reduce the severity or duration of symptoms.

• Rest and symptomatic treatments are the mainstays of management. • Bed rest is necessary only when the patient has debilitating fatigue.

• Blunt abdominal trauma may predispose to splenic rupture: advise not to participate in contact sports during the 1st 2–3 wk of

illness.

• Short courses of corticosteroids (<2 wk) may be helpful for complications. Indications only if complications:

- airway obstruction - thrombocytopenia with hemorrhaging - autoimmune hemolytic anemia - seizures, and meningitis. • A recommended dosage is prednisone 1 mg/kg/day

(maximum 60 mg/day) or equivalent for 7 days and tapered over another 7 days.

COMPLICATIONS

• Subcapsular splenic hemorrhage or splenic rupture: - during the 2nd week of the disease - rate of <0.5% of cases in adults; much lower in children. • Rupture is commonly related to trauma, which often may

be mild, and is rarely fatal. • Airway obstruction: - due to swelling of tonsils and oropharyngeal lymphoid

tissue - manifests as drooling, stridor, and difficult breathing. - give steroids, may need intubation for 24 hours.

COMPLICATIONS-2

Nurological:• Headache• seizures and ataxia• Alice in Wonderland syndrome (metamorphopsia):

Perceptual distortions of sizes, shapes, and spatial relationships.

• There may be meningitis with nuchal rigidity and mononuclear cells in the CSF, facial nerve palsy, transverse myelitis, and encephalitis.

• Guillain-Barré syndrome or Reye syndrome may follow acute illness.

• Hemolytic anemia, often with a positive Coombs test result and with cold agglutinins specific for red cell antigen i, occurs in 3% of cases.

• The onset is typically in the 1st 2 wk of illness and lasts for <1 mo.• Aplastic anemia is a rare complication that usually presents 3–4 wk

after the onset of illness, usually with recovery in 4–8 days, but some cases do require bone marrow transplantation.

• Mild thrombocytopenia and neutropenia are common, but severe thrombocytopenia (<20,000 platelets/μL) or severe neutropenia (<1,000 neutrophils/μL) are rare.

• Myocarditis or interstitial pneumonia may occur, both resolving in 3–4 wk. Other rare complications include pancreatitis, parotitis, and orchitis.

COMPLICATIONS-3

PROGNOSIS • The prognosis for complete recovery is excellent if no

complications ensue during the acute illness.

• The major symptoms typically last 2–4 wk, followed by gradual recovery.

• Second infections with a different type of EBV (type 1 or type 2) have been demonstrated in immunocompromised persons.

• Prolonged and debilitating fatigue, malaise, and some disability that may wax and wane for several weeks to 6 mo are common complaints even in otherwise unremarkable cases.

• Occasional persistence of fatigue for a few years after infectious mononucleosis is well recognized.