Epstein-Barr Virus Infection Infectious Mononucleosis

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					Epstein-Barr Virus Infection
(Infectious Mononucleosis)

                  Pranee Sitaposa, M.D.
           Pediatric Infectious Diseases Fellow
 Queen Sirikit National Institute of Child Health
                                    Sep21, 2007
      Epstein-Barr Virus : History
   In 1889, German physician “Pfeiffer”
     – fever
     – lymphadenopathy
     – malaise
     – hepatosplenomegaly
     – abdominal discomfort in adolescents and young
       adults

   In England, “DrÜsenfieber,” or glandular fever

   In the early 1900s
    – numerous case descriptions of illnesses epidemiologically
      and clinically compatible with IM.
        FEIGIN et al. Textbook of Pediatric Infectious Diseases5th ed;2004:1952-1957.
      Epstein-Barr Virus : History
   In 1920, Sprunt and Evans
     – published cases of spontaneously resolving
       acute leukemia associated with blast-like cells
       in the blood

   In 1923, Downey and McKinlay
     – detailed description of the lymphocyte
       morphology.

   In 1932, Paul and Bunnell
     – Identified heterophile antibodies in serum during
       acute IM.

       FEIGIN et al. Textbook of Pediatric Infectious Diseases5th ed;2004:1952-1957.
       Epstein-Barr Virus : History
   In 1958, Dennis Burkitt
     – described 38 cases of “round-cell sarcoma” in children and
       adolescent living in Uganda, Africa. (Lymphoma)

   In 1964, Epstein
     – described the first human tumor virus in a Burkitt
       lymphoma cell line by EM; herpes simplex virus (HSV).
     – human herpesvirus type 4

   In 1968, Henle
     – reported the relationship between acute IM and EBV.

   Yale University
     – showed EBV-transformed B-lymphoblastoid cell lines in
       tissue culture.

         FEIGIN et al. Textbook of Pediatric Infectious Diseases5th ed;2004:1952-1957.
    Virology : Structure and Genome

   The structure of EBV is typical for a member
    of herpesvirus family : Inner core of DNA
    surrounded by a nucleocapsid, tegument,
    and an envelope.

   The entire EBV genome : short and long
    sections of “unique” sequences (Us and UL)
     Molecular Biology : Replication
   To infect cells, EBV uses a cell surface receptor
    (CR2,CD21) found primarily on B lymphocytes and
    nasopharyngeal epithelial cells.

   MHC class II protein functions as a cofactor for this
    virus-receptor interaction.

   After infection of epithelial cells, active replication
    occurs and leads to lysis and death of the cell.
     Molecular Biology : Replication
   Viral capsid antigens (VCAs) are the primary
    structure protiens in viral capsids and are found
    in replicating cells.

   EBV early antigens (EAs) consist of >15 protiens
    codes by genes distributed throughout the
    genome.

   EBV nuclear antigen (EBNA) corresponds to six
    virally encoded protiens found in the nucleus of
    an EBV-infected cell.
Viral capsid antigens (VCAs)
       Molecular Biology : Latency
   Latently infected B cells are the primary reservoir
    of EBV in the body.

   >100 gene products may be expressed during
    active viral replication, only 11 are expressed
    during viral latency.

   In this way, the virus limits cytotoxic T-cell
    recognition of EBV-infected cells.
    Molecular Biology : Transformation

   EBV generally transforms relatively mature B
    lymphocytes secreting a complete immunoglobulin
    product.

   EBV : infect and transform B cells in earlier stages
    of development (e.g. pre-B cells and lymphoid
    precusors lacking immunoglobulin gene
    rearrangement)
Molecular Biology : EBV Subtype
   2 subtypes
        EBV-1 (type A): Western countries
        EBV-2 (type B): less virulence

   In immunocompromised persons : co-infection
    both type 1 and type 2 strains

   No one subtype is responsible for specific
    lymphoproliferative diseases
    (geographic differences)
       Immunopathogenesis : IM
   In a normal host, both cellular and humoral
    immunity develops in response to EBV infection.

   Diagnosis of acute infection : viral capsid and
    nuclear proteins.

   2-7 wks after exposure, up to 20% of circulating B
    lymphocytes become infected during primary EBV
    infection.
        Immunopathogenesis : IM
   In acute stage, proliferating EBV-infected B cells are
    controlled principally by NK cells, CD4 and CD8 cells.

   After T-cell response, number of EBV-infected B cells
    falls dramatically.

   Convalescence : EBNA-3 protein.
        Immunopathogenesis : IM
   Primary EBV infection, like herpesviruses,
    is able to persist in a latent state in a human host
    throughout that person’s lifetime.

   This ability indicates that EBV exerts some influence
    on the immune response to prevent its complete
    eradication.
Infectious Mononucleosis




                 NEJM;343:481-492.
Serum EBV antibodies




           Nelson 17 edition, Textbook of Pediatrics
  Serum Epstein-Barr Virus (EBV)
    Antibodies in EBV Infection
 Infection    VCA   VCA    EA(D)          EBNA
              IgG   IgM

No previous    -     -          -             -
infection
Acute         +     +         +/-             -
infection
Recent        +     +/-       +/-           +/-
infection
Past          +      -        +/-            +
infection
                          AAP. Red book2006;286-288.
          EBV-associated tumors
   In normal hosts, cellular immune
        : adequate for control and sequestration
          of EBV-infected cells.

   In cellular immune deficiency
        : excess EBV-associated B-cell production
          -histologically pleomorphic
          (B-cell lymphoproliferative disease)
          -relatively uniform
          (monomorphic, B-cell lymphomas)
        EBV-associated tumors
   Life-threatening EBV infections
     – strong virus-induced T-cell proliferation
       cause autoaggressive activity producing
       hypogammaglobulinemia or other major organ
       dysfunctions
     – multifactorial :
       mixture of virology
       genetic
       environmental factors
EBV-associated lymphoproliferative diseases

   The most common form of non-Hodgkin lymphoma
    (NHL) is Burkitt lymphoma, which consists of sheets
    of small noncleaved cells that are histologically
    uniform.

   HD tissues : presence of Reed-Sternberg cells
    admixed with lymphocytes and other reactive cells.

   Reed-Sternberg cells are large (15-45 μm),
    multinucleated cells probably derived from
    B or T cells.
EBV-associated lymphoproliferative diseases




  Reed-Sternberg cells
      Other EBV-associated diseases
   The hemophagocytic lymphohistiocytosis (HLH)
    typically include the bone marrow, spleen, liver,
    lymph nodes, skin and brain.

   In BM
         -hypocellularity
         -activated macrophages (histiocytes) are
         egulfing all bone marrow cellular element
    Other EBV-associated diseases
   Three histopathologic categoies of epithelial
    tumors in nasopharynx, most common form is
    the undifferentiated variety, which is associated
    most strongly with EBV.

   Malignant cells consistently contain multiple
    copies of monoclonal EBV DNA within episomes
    and several EBV proteins are expressed.
Epidemiology : Seroprevalence
   In the mid-1960s : detection of antibodies to
       - VCA (long lasting, early in infection)
       - EA (short duration, early in infection)

   EBV-VCA antibodies : 100% in BL patients
                          85% in normal adults

   80-95% of adults have serologic evidence, most
    infections occuring during infancy and children.
    Primary EBV infection : Seroprevalence

   In developing countries
        -80-100% of children becoming infected by 3-6 yrs
         of age
        -clinically silent or mild disease.

   In developed countries
        -occurs later in life, 10-30 years of age
        -induce clinically mononucleosis syndrome
         (U.S.college students : 50-75% associated
         with primary EBV infection)


                       Hickey SM et al. Pediatr Clin North Am. Dec 1997;44(6):1541-56.
        Epidemiology : Incidence
   Population-based studies ; 50-100 : 100,000
    population.

   Highest incidence rates : 15-19 years.

   No seasonal predilection.

   Higher rate in persons of white race than in other
    ethnic groups.
     Epidemiology : viral shedding
   In 1971, Chang and Golden :
        identified a “leukocyte-transforming agent” in
        oropharyngeal secretions.
   Studies in healthy populations indicating
        1) most children and adults with acute IM shed
           EBV in their oropharynx
        2) 6 – 20% of general population shed EBV in the
           oropharynx
        3) oropharyngeal shedding may be intermittent
           or continuous
        4) high concentrations of EBV in oropharyngeal
       secretions are associated with high concentrations
       of EBV in B lymphocytes in peripheral blood but
       not with concentrations of EBV-specific serum
       antibodies
    Epidemiology : Transmission
   Incubation period : 30 – 50 days.
    (shorter in young children)

   Oral secretion
       : major role but occur slowly

   Blood products,Transplanted organs
        : less commonly than CMV

   Intrauterine
        : infrequently
        : if infected; no adverse fetal outcomes
          and no viral transmission to the fetus.
                                 Fleisher, et al. J. Pediatr.98:16-19, 1981.
    Clinical Syndromes Associated with
               EBV Infection
   Silent, nonspecific infections : in children
     - prolonged low-grade fever + lymphadenopathy
     - cough
     - rhinorrhea
     - pharyngitis

   Infectious mononucleosis (IM)
     - prodrome
        2 – 5 days malaise, fatigue, possibly fever
     - acute phase
        fever (last 4–5 wks), lymphadenopathy (2–4 wks),
    tonsillopharyngitis, splenomegaly, hepatomegaly,
    rash, abdominal pain, eyelid edema 15%
     - resolution phase : organomegaly may persist 1–3 m
           IM : Pathophysiology
   Reservoir of EBV : Humans only.

   EBV founds in the saliva for the first 12-18 months
    after acquisition.

   Viral replication
     – lymphoreticular system
     – liver
     – spleen
     – B lymphocytes in peripheral blood.
           IM : Pathophysiology
   Host immune response to the viral infection
    – atypical lymphocytes.

   After acute EBV infection, latently infected
    lymphocytes and epithelial cells persist and are
    immortalized.

   During latent infection, the virus is present in the
    lymphocytes and oropharyngeal epithelial cells as
    episomes in the nucleus.
           IM : Pathophysiology
   A low rate of viral reactivation occurs within the
    population of latently infected cells.

   Primary source of new virus in latently infection
     – Epithelial cells.

   Virus can be isolated from oral secretions of 20-
    30% of healthy latently infected individuals at
    anytime.
IM : Pathophysiology




               NEJM;343:481-492.
       Infectious Mononucleosis
   In Africa, the virus is associated with endemic
    Burkitt lymphoma.

   NP cacinoma : numerous EBV episomes
     – Most common CA in adult men in southern
       China
     – North American Inuits
     – North African whites.
Infectious Mononucleosis
       Infectious Mononucleosis
   No racial and sexual difference.

   The peak incidence occurs 2 years earlier in females.

   Report in middle-aged and elderly adults
     – heterophile antibody negative.

   Most clinical symptoms are a consequence of T cell
    proliferation and organ infiltration.
       Infectious Mononucleosis
   Acute infectious mononucleosis
     – fatique and malaise 1-2 wks
     – sore throat, pharyngitis
     – retro-orbital headache
     – fever
     – myalgia
     – nausea
     – abdominal pain
     – generalized lymphadenopahy
     – hepatosplenomegaly
       Infectious Mononucleosis
   Pharyngitis is the most consistent physical finding.
     – 1/3 of patients : exudative pharyngitis.

    – 25-60% of patients : petechiae at the junction
      of the hard and soft palates.

    – Tonsillar enlargement can be massive, and
      occasionally it causes airway obstruction.
       Infectious Mononucleosis
   Lymphadenopathy : 90%
     – symmetrical enlargement.
     – mildly tender to palpation and not fix.
     – posterior cervical lymph nodes.
    – anterior cervical and submandibular nodes.
    – axillary and inguinal nodes.
    – Enlarged epitrochlear nodes are very suggestive
      of infectious mononucleosis.
       Infectious Mononucleosis
   Hepatomegaly : 60%
    – jaundice is rare.
    – Percussion tenderness over the liver is common.

   Splenomegaly : 50%
     – palpable 2-3 cm below the left costal margin
       and may be tender.
     – rapidly over the first week of symptoms, usually
       decreasing in size over the next 7-10 days.
     – spleen can rupture from relatively minor trauma
       or even spontaneously.
       Infectious Mononucleosis
   Maculopapular rash : 15%
    – usually faint, widely scattered, and erythematous
    – occurs in 3-15% of patients and is more common
      in young children.
    – 80% of patients, treatment with amoxicillin or
      ampicillin is associated with rash
    – Circulating immunoglobulin G (IgG) and
      immunoglobulin M (IgM) antibodies to ampicillin are
      demonstrable.
 Infectious Mononucleosis




IM with rash after treatment with amoxicillin or ampicillin
                                             NEJM;343:481-492.
       Infectious Mononucleosis
   Eyelid edema : 15%
     – may be present, especially in the first week

   Children younger than 4 years : more commonly
     – splenomegaly or hepatomegaly
     – rash
     – symptoms of an upper respiratory tract
       infection
        Clinical manifestation of IM
           in children and adults
                                 Frequency (%)
Sign or symptom         Age < 4 yr     Age 4 – 16 yr      Adults (range)

Lymphadenopathy            94                95                93 – 100
Fever                      92               100                63 – 100
Sore throat or             67                75                70 – 91
  tonsillopharyngitis
Exudative                  45                59                40 – 74
  tonsillopharyngitis
Splenomegaly               82                53                32 – 51
Hepatomegaly               63                30                 6 – 24
Cough or rhinitis          51                15                 5 – 31
Rash                       34                17                 0 – 15
Abdominal pain or          17                 0                 2 – 14
 discomfort
Eyelid edema               14                14                  5 – 34

                                     Sumaya, et al. J Infect Dis.131:403-408,1975.
Infectious Mononucleosis




                 NEJM;343:481-492.
Infectious Mononucleosis




    Exudative pharyngotonsillitis
   Infectious Mononucleosis




Cervical lymphadnopathy   Hepatosplenomegaly
    Infectious Mononucleosis : Cause
   EBV 90% of acute IM
   Etiology of most EBV-negative IM : unknown
   Other Herpesviruses :
    – Cytomegalovirus (CMV)
    – herpes simplex 1 and simplex 2
    – human herpesvirus 6
   Other viruses :
    – adenovirus
    – hepatitis A, hepatitis B, or hepatitis C
    – rubella
    – primary human immunodeficiency virus in
       adolescents or young adults.
    Infectious Mononucleosis : Lab
   The 3 classic criteria for laboratory confirmation
       1 lymphocytosis
       2 the presence of at least 10% atypical
          lymphocytes on peripheral smear
       3 a positive serologic test for Epstein-Barr virus
        (EBV).
Infectious Mononucleosis : Lab
   Complete blood count
     – 40-70%, Leukocytosis                  (WBC
       10,000-20,000 cells per cm3)
     – By the second week of illness, approximately
       10% have a WBC count > 25,000 per cm3.
     – 80-90% of patients have lymphocytosis,
       with greater than 50% lymphocytes.
       Lymphocytosis is greatest during 2-3 weeks of
       illness and lasts for 2-6 weeks.
     – 20-40% of the lymphocytes : atypical
       lymphocytes > 10% ; Downey types
     – 25-50%, Mild thrombocytopenia
Infectious Mononucleosis




   atypical lymphocytes : Downey types
Infectious Mononucleosis : Lab
   Liver function tests
     – 80-100% of patients : elevated LFT
     – Alkaline phosphatase, AST and bilirubin
       peak 5-14 days after onset
     – GGT peaks at 1-3 weeks. Occasionally, GGT
       remains mildly elevated for up to 12 months
     – 95% of patients : elevated LDH
     – most liver function test results are normal by
       3 months.
Infectious Mononucleosis : Lab
   Heterophile antibodies
    – 50% in first week of illness
    – 60-90% in the second or third weeks
    – begins to decline during the fourth or fifth
      week and often is less than 1:40 by 2-3
      months after symptom onset
    – 20% of patients have positive titers 1-2 years
      after acquisition
    – children < 2 years : 10-30%
    – children 2-4 years : 50-75%
Infectious Mononucleosis : Lab
   EBV serology
        EAs (early antigens)
                     : early in the lytic cycle
        VCA (Viral capsid antigen) and membrane
         antigens
                     : late in the lytic cycle
        EBNA (Epstein-Barr nuclear antigen)
                     : latent infection
        Antibodies    to membrane antigens
                      : usually are not measured
Infectious Mononucleosis : Lab
                       component of EA) : 80%
 EA/D (diffuse-staining

 EA/R (restricted component of early antigens)

   – measurable in children younger than 4 years
     with primary EBV infection or in asymptomatic
     infection.
 nasopharyngeal   carcinoma
   – antibodies to EA/R are high in individuals with
     EBV-associated Burkitt lymphoma.
 immunocompromised      patient
   – persistent or reactivated EBV infections often
     have high antibody levels to EA/D or EA/R.
Infectious Mononucleosis : Lab
 – Time course of antibody production
    EA is rising at symptom onset : rise for 3-4
     weeks, then quickly decline to undetectable
     levels by 3-4 months, although low levels
     may be detected intermittently for years.
    VCA-IgM usually is measurable at symptom
     onset, peaks at 2-3 weeks, then declines
     and unmeasurable by 3-4 months.
    VCA-IgG rises shortly after symptom onset,
     peaks at 2-3 months, then drops slightly but
     persists for life.
    EBNA    : convalescence and remain present
     for life.
                 IM Treatment
Medical Care :
 self-limited illness : not require specific therapy.


   Inpatient therapy of medical and surgical
    complications may be required.

   Acyclovir (10 mg/kg/dose IV q8h for 7-10 d)
     – inhibit viral shedding from the oropharynx
     – clincal course is not significantly

   IVIG (400 mg/kg/d IV for 2-5 d)
     – immune thrombocytopenia associated with
                     Andersson J et al. J Infect Dis. Feb 1986;153(2):283-90.
                     Cyran EM et al. Am J Hematol. Oct 1991;38(2):124-9.
                 IM Treatment
Medical Care :
 Short-course corticosteroids
    : prednisolone (1 mg/kg/d, max 60 mg/d for 7 d
      and tapered over another 7 d)
   – Marked tonsillar inflammation with impending
     airway obstruction
   – Massive splenomegaly
   – Myocarditis
   – Hemolytic anemia
   – Hemophagocytic syndrome
   – Seizure and meningitis
Surgical Care :
 Splenic rupture.           AAP. Red book2006;286-288.
                               Nelson. Textbook of Pediatrics17th ed;977-981.
     Infectious Mononucleosis
Activity :
 depends on severity of the patient's symptoms.
 Extreme fatigue : bed rest for 1-2 weeks.
 Malaise may persist for 2-3 months.
 Patients should not participate in contact
  sports or heavy lifting for at least 2-3 weeks
 some authors recommend avoiding activities that
  may cause splenic trauma for 2 months.
             IM : Complication
   Hepatitis : > 90% of patients
    – LFT : < 2-3 times of NUL in the second and third
      weeks of illness
    – 45% of patients : elevated bilirubin, but jaundice
      occurs in only 5%. Mild thrombocytopenia occurs
      in approximately 50% of patients with infectious
      mononucleosis.

   Platelet count : nadir approximately 1 week after
    symptom onset (100,000-140,000/cm3. ), then
    gradually improves over the next 3-4 weeks. Mild
    thrombocytopenia occurs in approximately 50% of
    patients with infectious mononucleosis.
            IM : Complications
   Hemolytic anemia
    – 0.5-3%, associated with cold-reactive
      antibodies, anti-I antibodies, and with
      autoantibodies to triphosphate isomerase
    – mild and is most significant during the second
      and third weeks of symptoms.

   Upper airway obstruction
     – 0.1-1%, due to hypertrophy of tonsils and other
       lymph nodes of Waldeyer ring
     – treatment with corticosteroids may be beneficial
            IM : Complications
   Splenic rupture : 0.1-0.2%
     – Spontaneous or history of some antecedent
       trauma.
     – occur during the second and third weeks.
     – mild-to-severe abdominal pain below the left
       costal margin, sometimes with radiation to the
       left shoulder and supraclavicular area.
     – Massive bleeding : Shock
            IM : Complications
   Hematologic complications
    – hemophagocytic syndrome.
    – Immune thrombocytopenic purpura occurs and
      may evolve to aplastic anemia.
    – accelerate hemolytic anemia in congenital
      spherocytosis or hereditary elliptocytosis.
    – Disseminated intravascular coagulation
      associated with hepatic necrosis has occurred.
             IM : Complications
   Neurologic complications : < 1%
     – during the first 2 weeks.
     – negative for the heterophile antibody.
     – Severe (fatal), complete recovery
     – aseptic meningitis, acute viral encephalitis, coma,
       meningitis, and meningoencephalopathy.
     – Hypoglossal nerve palsy, Bell palsy, hearing loss,
       brachial plexus neuropathy, multiple cranial nerve
       palsies, Guillain-Barré syndrome, autonomic
       neuropathy, gastrointestinal dysfunction
       secondary to selective cholinergic dysautonomia,
       acute cerebellar ataxia, transverse myelitis.
            IM : Complications
   Cardiac and pulmonary complications
    – rare
    – chronic interstitial pneumonitis.
    – myocarditis and pericarditis.
            IM : Complications
   Autoimmune complications
    – Autoimmune diseases and Reye syndrome
      have been associated with EBV infection.
    – Infectious mononucleosis stimulates
      production of many antibodies not directed
      against EBV. These include autoantibodies, anti-
      I antibodies, cold hemolysins, antinuclear
      antibodies, rheumatoid factors, cryoglobulins,
      and circulating immune complexes. These
      antibodies may precipitate autoimmune
      syndromes.
             IM : Complications
   Miscellaneous complications
    – Renal disorders : immune deposit nephritis,
      renal failure, paroxysmal nocturnal
      hemoglobinuria.
    – After cardiac bypass or transfusion, an infectious
      mononucleosis–like syndrome : primary CMV
      infection > EBV.
    – A syndrome of chronic fatigue, myalgias, sore
      throat, and mild cognitive dysfunction occurring
      primarily in young adult females initially was
      attributed to EBV. Current data suggest that EBV
      is not the etiologic agent.
                  IM : Prognosis
   Immunocompetent : full recovery in several months.
   The common hematologic and hepatic complications
    resolve in 2-3 months.
   Neurologic complications
     – Children : resolve quickly
     – Adults : neurological deficits
   All individuals develop latent infection
     – asymptomatic.
                    IM : Prevention
   Isolation is not required : low transmission.
   Avoid contact with saliva.
   Do not kiss children on the mouth.
   Maintain clean conditions : day care, avoid sharing
    toys.
   EBV can be transmitted by blood transfusion and by
    bone marrow transplantation.
   Vaccine development is proceeding, although the
    role of a vaccine is unclear.




       FEIGIN et al. Textbook of Pediatric Infectious Diseases5th ed;2004:1952-1957.
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