Infectious mononucleosis: Practical considerations and

evidence-informed management

Evelyn Wiener, MDExecutive Director

Student Health ServiceUniversity of Pennsylvania

Samuel L. Seward, Jr., MDAssociate Vice President/Medical Director

Columbia HealthColumbia University

1

I have no actual or potential conflict of interest in relation to this educational activity or presentation.

2

Objectives

1. Review the pathophysiology of infectious mononucelosis (IM)

2. Describe typical presentation and natural history of (IM)

3. Review atypical presentations of IM4. Review diagnostic tests 5. Review management of student with IM, including

early recognition of serious complications

3

1st Virus-Cancer Association

4

Sir Anthony Epstein

Yvonne Barr

Burt Achong

• 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

5

6

Main Target = Memory B Cells(up to 20%)CD21 = entry receptor

Odumade O A et al. Clin. Microbiol. Rev. 2011;24:193-209 7

Infection is complex immunological phenomenon

Latency =programmed hiding from normal immunosurveilance;down-regulation of normal proteinexpression

Lytic phase =immunodysregulation;robust CD8 T-cell response

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 infection2. Lymphoproliferative disorders (e.g., in the setting of XLP or organ

transplantation)3. Malignancy

Relationship between EBV and Chronic Fatigue Syndrome?

8

9

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.

Risk factors:• Physical intimacy• Deep kissing

Risk Factors

10

11

w/Ampicillin: 95-100%w/o: 5-15%

Adolescents naturally have larger memory B cellpopulation

Greater number of B cellsinfected more robust cytokine cascade, etc.and more symptomatic patient

Diagnosis

12

Diagnostic tests

Viral cultures

CBC w/differential (most common: lymphocytosis)

Heterophile antibody

EBV titersEBV PCR

Other viral serologies

LFTsRadiography (neck films, U/S)

13

Sensitivity and specificity

In the presence of IM symptoms, a positive heterophile antibody test:

has a sensitivity of 85%

and a specificity of 94%

14

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

15

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

16

Atypical lymphocyte = activated T cell andis an indicator of Ag stimulation and diffuse immune system activation

17

http://www.youtube.com/watch?v=u0ozqFNCHKU

Splenomegaly

Imaging

18

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:

CMVHIV ToxoplasmosisHuman herpesvirus type 6 (HHV-6)Hepatitis B ?HHV-7

19

Differential Diagnosis of Pharyngitis. Reproduced from: Luzuriaga K, Sullivan JL. N Engl J Med 2010;362:1993-2000

20

• 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

Chronic active infection

21

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)

22

23

Malignancies

1) Burkitt lymphoma• Endemic (100% = EBV-related)• Sporadic (40%)

2) Nasopharyngeal carcinoma

3) Hodgkin lymphoma

24

25

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 diseaseHuman Herpesviruses: Biology, Therapy, and Immunoprophylaxis.Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors.Cambridge: Cambridge University Press; 2007.

26

Alnoln

Serology of Epstein-Barr virus infection

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

27

In most cases is supportive only….

Management

28

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. Short-term suppression of oral viral shedding was shown, but significant clinical benefit was not.

29

Date of download: 5/14/2014Copyright © 2014 American Medical

Association. All rights reserved.

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

The overwhelming majority of patients given corticosteroids received them for indications other than the classically accepted airway concerns and idiopathic thrombocytopenic purpura (ITP).

Figure Legend:

30

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:

31

At 24 hours

Likelihood of Complete Pain Resolution

3x control

RR 3.2

P value <0.001

NNT <4

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

32

Return to school

No restrictions

When they are ready

33

34

35

Return to Play After Infectious MononucleosisJonathan 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.

Prognosis

36

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.