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Infectious mononucleosis:
Practical considerations and
evidence-informed
management
Evelyn Wiener, MD
Executive Director
Student Health Service
University of Pennsylvania
Samuel L. Seward, Jr., MD
Associate Vice President/Medical Director
Columbia Health
Columbia University
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I have no actual or potential conflict of interest in
relation to this educational activity or presentation.
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Objectives
1. Review the pathophysiology of infectious
mononucelosis (IM)
2. Describe typical presentation and natural history of
(IM)
3. Review atypical presentations of IM
4. Review diagnostic tests
5. Review management of student with IM, including
early recognition of serious complications
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1st Virus-Cancer Association
Sir Anthony
Epstein
Yvonne Barr
Burt Achong
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Gamma herpesvirus
Large
Stable
Double-stranded DNA
Co-evolution with us
Replication cycle:
− Entry into memory B Cell
− Lytic replication
− Latency
Simplified diagram of the structure of EBV. Reproduced from:
http://en.wikipedia.org/wiki/File:Viral_Tegument.svg
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Main Target = Memory B Cells
(up to 20%)
CD21 = entry receptor
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Infection is complex immunological phenomenon
Lytic phase =
immunodysregulation;
robust CD8 T-cell response
Odumade O A et al. Clin. Microbiol. Rev. 2011;24:193-209
Latency =
programmed hiding
from normal
immunosurveilance;
down-regulation of
normal protein
expression
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Natural History of EBV Infection
 Primary EBV infection with containment:
1. Asymptomatic infection (common in children with naturally lower populations
of memory B cells)
2. Acute IM (adolescents)
3. Recurrent infection/reactivation
 Primary EBV infection with loss of containment:
1. Chronic active infection
2. Lymphoproliferative disorders (e.g., in the setting of XLP or organ
transplantation)
3. Malignancy
 Relationship between EBV and Chronic Fatigue Syndrome?
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Chronic fatigue syndrome after infectious
mononucleosis in adolescents. Katz BZ, et al.
Pediatrics. 2009;124(1):189.
METHODS: A total of 301 adolescents (12-18 years
of age) with infectious mononucleosis were
identified and screened for non-recovery 6 months
after infectious mononucleosis by using a
telephone screening interview. Non-recovered
adolescents underwent a medical evaluation, with
follow-up screening 12 and 24 months after
infectious mononucleosis. After blind review, final
diagnoses of chronic fatigue syndrome at 6, 12, and
24 months were made by using established
pediatric criteria.
RESULTS: Six, 12, and 24 months after infectious
mononucleosis, 13%, 7%, and 4% of adolescents,
respectively, met the criteria for chronic fatigue
syndrome. All 13 adolescents with chronic fatigue
syndrome 24 months after infectious
mononucleosis were female and, on average, they
reported greater fatigue severity at 12 months.
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Risk Factors
Risk factors:
• Physical intimacy
• Deep kissing
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Adolescents naturally have
larger memory B cell
population
Greater number of B cells
infected
more
robust cytokine cascade, etc.
and more symptomatic patient
w/Ampicillin: 95-100%
w/o: 5-15%
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Diagnosis
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Diagnostic tests
Viral cultures
CBC w/differential (most common: lymphocytosis)
Heterophile antibody
EBV titers
EBV PCR
Other viral serologies
LFTs
Radiography (neck films, U/S)
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Sensitivity and specificity
In the presence of IM symptoms, a positive
heterophile antibody test:
has a sensitivity of 85%
and a specificity of 94%
Source: Brigden ML, et al, Infectious mononucleosis in an outpatient population: diagnostic utility of 2 automated hematology analyzers
and the sensitivity and specificity of Hoagland's criteria in heterophile-positive patients. Arch Pathol Lab Med. 1999;123(10):875
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An Atypical Lymphocyte in a Patient with Infectious Mononucleosis (Wright–Giemsa).
Reproduced from: Luzuriaga K, Sullivan JL. N Engl J Med 2010;362:1993-2000
Atypical lymphocyte = activated T cell and
is an indicator of Ag stimulation and
diffuse immune system activation
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Splenomegaly
http://www.youtube.com/watch?v=u0ozqFNCHKU
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Imaging
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Heterophile-negative IM
Approximately 10 percent of mono-like cases are not caused by
EBV. Other infectious agents that produce a similar clinical
syndrome include:
CMV
HIV
Toxoplasmosis
Human herpesvirus type 6 (HHV-6)
Hepatitis B
?HHV-7
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Differential Diagnosis of Pharyngitis. Reproduced from: Luzuriaga K, Sullivan JL. N Engl J Med 2010;362:19932000
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Chronic active infection
• Persistent (sometimes severe) IM-like
symptoms w/ :
o prolonged active viremia (dsDNA and very
high anti-EBV Ab titers)
o Infection of other immune populations
(Tcells and NK cells)
• Fever,adenopathy, hepatosplenomegaly,
fatigue, encephalitis
• More common in children, Japan
• LFT and hematologic abnormalities, including
signs of hepatic failure
• ~transformation into hemophagocytic
lymphohistiocytosis
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Lymphoproliferative Disorders
1) Hemophagocytic lymphohistiocytosis
2) Lymphomatoid granulomatosis
3) X-linked lymphoproliferative disease
4) Post-transplant lymphoproliferative disease
Hallmark: absence of normal T cell response
(Treatment #4: infusion of EBV-specific T cells)
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Malignancies
1) Burkitt lymphoma
• Endemic (100% = EBV-related)
• Sporadic (40%)
2) Nasopharyngeal carcinoma
3) Hodgkin lymphoma
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Age-specific distribution of EBV antibody positive individuals in four populations.
Reproduced from de The et al., 1975; Henle and Henle, 1967; Melbye et al., 1984.
From: Chapter 53, The epidemiology of EBV and its association with malignant disease
Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.
Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors.
Cambridge: Cambridge University Press; 2007.
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Serology of Epstein-Barr virus infection
Alnoln
Levels of Antibodies Specific to Epstein–Barr Virus (EBV) during Infectious Mononucleosis and Convalescence. EBNA denotes
EBV nuclear antigen, and VCA viral capsid antigens. Reproduced from: Luzuriaga K, Sullivan JL. N Engl J Med
2010;362:1993-2000
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Management
In most cases is supportive only….
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Acyclovir?
Acyclovir = a nucleoside analogue that inhibits permissive EBV infection
through inhibition of EBV DNA-polymerase but has no effect on latent
infection or ability to cure the infection.
Tx of acute EBV infections with intravenous and oral formulations has been studied. Shortterm suppression of oral viral shedding was shown, but significant clinical benefit was not.
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From: Infectious Mononucleosis and Corticosteroids: Management Practices and Outcomes
Arch Otolaryngol Head Neck Surg. 2005;131(10):900-904. doi:10.1001/archotol.131.10.900
Figure Legend:
The overwhelming majority of patients given corticosteroids received them for indications other than the classically accepted airway
concerns and idiopathic thrombocytopenic purpura (ITP).
Date of download: 5/14/2014
Copyright © 2014 American Medical Association.
All rights reserved.
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Cochrane Review: steroids for
pharyngitis
Endpoint: complete pain resolution (CPR)
8 trials: 743 participants (369 adults)
ALL patients given Abx + steroids (IM or PO) +/- analgesics
Results: steroids were beneficial:
At 24 hours
Likelihood of
Complete Pain
Resolution
3x control
RR
3.2
P value
<0.001
NNT
<4
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Cochrane Review: steroids for IM
Endpoint: symptom control
7 trials but heterogeneity precluded combined analysis
2 trials showed benefit at 12 hours…but benefit not maintained
Results: inconclusive evidence to support Tx
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Return to school
No restrictions
When they are ready
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Return to Play After Infectious Mononucleosis
Jonathan A. Becker, MD et al, Sports Health, 2014.
Evidence Acquisition: PubMed and MEDLINE
database search through December 2012 by
searching for epidemiology, diagnosis, clinical
manifestations, management, and the role of the
spleen in infectious mononucleosis.
Results: Infectious mononucleosis is commonly
encountered in young athletes. Its disease pattern
is variable. Supportive care is the cornerstone, with
little role for medications such as corticosteroids.
Exercise does not appear to place the young athlete
at risk for chronic fatigue, but determining who is at
risk for persistent symptoms is a challenge.
Conclusion: Return-to-play decisions for the athlete
with infectious mononucleosis need to be
individualized because of the variable disease
course and lack of evidence-based guidelines.
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Prognosis
Vast majority of individuals with primary EBV
infection recover uneventfully and develop durable
immunity controlling the latent virus. Most acute
symptoms resolve in one to two weeks, although
fatigue and poor functional status can persist for
months.
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