Transcript Infectious Mononucleosis.

Infectious Mononucleosis.
By,
Vaibhav .Kallianpur
•
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 Englishspeaking countries) is an
infectious, widespread
viral disease caused by
the Epstein-Barr virus
(EBV).
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.
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.
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)
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.
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 :
•
80-95% of adults have serologic evidence, most infections
occuring during infancy and children.
85% in normal adults
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)
Infectious Mononucleosis
Transmission
“The Kissing Disease”
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.
:
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.
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.
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.
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 virusreceptor 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)
Infectious Mononucleosis
Serum EBV antibodies
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
+
-
+/-
+
Symptoms.
• Acute infectious mononucleosis
– fatique and malaise 1-2 wks
– sore throat, pharyngitis
– retro-orbital headache
– fever
– myalgia
– nausea
– abdominal pain
– generalized lymphadenopathy
– hepatosplenomegaly
• Pharyngitis is the most consistent physical finding.
– 1/3 of patients : exudative pharyngitis.
– 25-60% of patients : petechiae at the junction
the hard and soft palates.
of
– Tonsillar enlargement can be massive, and occasionally
it causes airway obstruction.
• 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.
• 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.
• 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
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
Lymphadenopathy
Fever
Sore throat or
tonsillopharyngitis
Exudative
tonsillopharyngitis
Splenomegaly
Hepatomegaly
Cough or rhinitis
51
Rash
Abdominal pain or
discomfort
Eyelid edema
Age 4 – 16 yr Adults (range)
94
92
67
95
100
75
93 – 100
63 – 100
70 – 91
45
59
40 – 74
82
63
53
32 – 51
6 – 24
30
5 – 31
15
34
17
17
0
0 – 15
2 – 14
14
14
5 – 34
Infectious Mononucleosis
Infectious Mononucleosis
Exudative pharyngotonsillitis
Infectious Mononucleosis
Cervical lymphadnopathy
Hepatosplenomegaly
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
– 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
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.
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 : Complications
• 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 : 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
• 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.
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.
• 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.
PREVENTION.
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.
•THANK YOU
FOR YOUR
ATTENTION.