Infectious Mononucleosis.

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Infectious Mononucleosis.

• 
  By,
• 
  Vaibhav .Kallianpur

2

• Infectious Mononucleosis (IM also known as EBV
  infectious mononucleosis or glandular fever or
  Pfeiffer's disease or Filatov's disease and
  sometimes colloquially as the kissing disease
  from its oral transmission or simply as mono in
  North America and as glandular fever in other
  English-speaking countries) is an infectious,
  widespread viral disease caused by the
  Epstein-Barr virus (EBV).

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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.

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VIROLOGY.

• Epstein Barr Virus (EBV)
• Herpes Family (linear DNA virus HHV4)
• Surrounded by nucleocapsid and glycoprotein
  envelope
• Also associated with nasopharyngeal carcinoma,
  Burkitts lymphoma, Hodgkins Disease, B cell
  lymphoma.

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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)

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Epidemiology Incidence

• Population-based studies 90 of population have
  been infected or have antibodies to the virus.
• Highest incidence rates 15-19 years.
• No seasonal predilection.
• Higher rate in persons of white race than in
  other ethnic groups.

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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 85 in normal adults
• 80-95 of adults have serologic evidence, most
  infections occuring during infancy and children.

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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)

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Infectious MononucleosisTransmission
The Kissing Disease
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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.

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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.

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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.

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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.

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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.

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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 gt15 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.

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Viral capsid antigens (VCAs)
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Molecular Biology Latency

• Latently infected B cells are the primary
  reservoir of EBV in the body.
• gt100 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.

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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)

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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)

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Infectious Mononucleosis
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Serum EBV antibodies
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Serum Epstein-Barr Virus (EBV) Antibodies in EBV
Infection
Infection VCA IgG VCA IgM EA(D) EBNA
No previous infection - - - -
Acute infection Recent infection /- /- /- - /-
Past infection - /-
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Symptoms.

• Acute infectious mononucleosis
• fatique and malaise 1-2 wks
• sore throat, pharyngitis
• retro-orbital headache
• fever
• myalgia
• nausea
• abdominal pain
• generalized lymphadenopathy
• hepatosplenomegaly

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• 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.

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• 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.

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• 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.

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• 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.

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Infectious Mononucleosis
IM with rash after treatment with amoxicillin or
ampicillin
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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

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Clinical manifestation of IM
in children and adults

• Frequency ()
• Sign or symptom Age lt 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

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Infectious Mononucleosis
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Infectious Mononucleosis
Exudative pharyngotonsillitis
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Infectious Mononucleosis
Hepatosplenomegaly
Cervical lymphadnopathy
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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).

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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 gt 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 gt 10 Downey types
• 25-50, Mild thrombocytopenia

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Infectious Mononucleosis
atypical lymphocytes Downey types
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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.

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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 140 by 2-3 months after
  symptom onset
• 20 of patients have positive titers 1-2 years
  after acquisition
• children lt 2 years 10-30
• children 2-4 years 50-75

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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

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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.

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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

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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.

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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.

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IM Complications

• Hepatitis gt 90 of patients
• LFT lt 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 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.

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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

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• 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
• 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.

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IM Complications

• Neurologic complications lt 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.
• Cardiac and pulmonary complications
• rare
• chronic interstitial pneumonitis.
• myocarditis and pericarditis.

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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.

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IM Complications

• Miscellaneous complications
• Renal disorders immune deposit nephritis, renal
  failure, paroxysmal nocturnal hemoglobinuria.
• After cardiac bypass or transfusion, an
  infectious mononucleosislike syndrome primary
  CMV infection gt 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.

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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.

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PREVENTION.
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Prevention

• Isolation is not required low transmission.
• Avoid contact with saliva.
• Avoid kissing when in acute phase.
• Maintain clean conditions avoid sharing toys
  among children in day care.
• Vaccine development is proceeding, although the
  role of a vaccine is unclear.

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• THANK YOU FOR YOUR ATTENTION.