Infect - PowerPoint Presentation

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Infectious mononucleosis: Practical considerations and evidence-informed managementEvelyn Wiener, MDExecutive DirectorStudent Health ServiceUniversity of PennsylvaniaSamuel L. Seward, Jr., MDAssociate Vice President/Medical DirectorColumbia HealthColumbia University

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I have no actual or potential conflict of interest in relation to this educational activity or presentation.2Slide3

ObjectivesReview the pathophysiology of infectious mononucelosis (IM)Describe typical presentation and natural history of (IM)Review atypical presentations of IMReview diagnostic tests Review management of student with IM, including early recognition of serious complications 3Slide4

1st Virus-Cancer Association4Sir Anthony EpsteinYvonne BarrBurt AchongSlide5

Gamma herpesvirusLargeStableDouble-stranded DNACo-evolution with usReplication cycle:Entry into memory B CellLyti

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Latency

Simplified diagram of the structure of EBV.

Reproduced from: http://en.wikipedia.org/wiki/File:Viral_Tegument.svg

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6Main Target = Memory B Cells(up to 20%)CD21 = entry receptor Slide7

Odumade O A et al. Clin. Microbiol. Rev. 2011;24:193-2097Infection is complex immunological phenomenonLatency =programmed hiding from normal immunosurveilance;down-regulation of normal proteinexpression Lytic phase =immunodysregulation;robust CD8 T-cell response Slide8

Natural History of EBV InfectionPrimary EBV infection with containment:Asymptomatic infection (common in children with naturally lower populations of memory B cells)Acute IM (adolescents)Recurrent infection/reactivationPrimary EBV infect

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Chronic active infection

Lymphoproliferative

disorders (e.g., in the setting of XLP or organ transplantation)

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gnancyRelationship between EBV and Chronic Fatigue Syndrome?

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9Chronic 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.Slide10

Risk factors: Physical intimacyDeep kissingRisk Factors

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11w/Ampicillin: 95-100%w/o: 5-15%Adolescents naturally have larger memory B cellpopulationGreater number of B cellsinfected more robust cytokine cascade, etc.and more symptomatic patient Slide12

Diagnosis12Slide13

Diagnostic testsViral cultures CBC w/differential (most common: lymphocytosis)Heterophile antibody EBV titersEBV PCROther viral serologies LFTsRadiography (neck films, U/S)13Slide14

Sensitivity and specificityIn the presence of IM symptoms, a positive heterophile antibody test:has a sensitivity of 85% and a specificity

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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):875Slide15

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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;362:1993-200016Atypical lymphocyte = activated T cell andis an indicator of Ag stimulation and diffuse immune system activation Slide17

17http://www.youtube.com/watch?v=u0ozqFNCHKUSplenomegalySlide18

Imaging18Slide19

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 19Slide20

Differential Diagnosis of Pharyngitis. Reproduced from: Luzuriaga K, Sullivan JL. N Engl J Med 2010;362:1993-200020Slide21

Persistent (sometimes severe) IM-like symptoms w/ :prolonged active viremia (dsDNA and very high anti-EBV Ab titers)Infection of other immune populations (Tcells and NK cells)Fever,adenopathy,hepatosplenomegaly, fatigue, encephalitisMore common in children, JapanLFT and hematologic abnormalities, including signs of hepatic failure~transformation into hemophagocytic lymphohistiocytosis Chronic active infection21Slide22

Lymphoproliferative Disorders1) Hemophagocytic lymphohistiocytosis 2) Lymphomatoid granulomatosis3) X-linked lymphoproliferative disease 4) Post-transplant lymphoproliferative diseaseHallmark: absence of normal T cell response

(Treatment #4: infusion of EBV-specific T cells)

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MalignanciesBurkitt lymphomaEndemic (100% = EBV-related)Sporadic (40%) 2) Nasopharyngeal carcinoma3) Hodgkin lymphoma24Slide25

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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 diseaseHuman Herpesviruses: Biology, Therapy, and Immunoprophylaxis.Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors.Cambridge: Cambridge University Press; 2007.26Slide27

AlnolnSerology of Epstein-Barr virus infectionLevels 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;362:1993-200027Slide28

In most cases is supportive only….Management28Slide29

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. 29Slide30

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

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Cochrane Review: steroids for pharyngitisEndpoint: complete pain resolution (CPR)8 trials: 743 participants (369 adults)ALL patients given Abx + steroids (IM or PO) +/- analgesicsResults: steroids were beneficial:31At 24 hoursLikelihood of Complete Pain Resolution 3x controlRR3.2P value<0.001NNT<4Slide32

Cochrane Review: steroids for IMEndpoint: symptom control7 trials but heterogeneity precluded combined analysis2 trials showed benefit at 12 hours…but benefit not maintainedResults: inconclusive evidence to support Tx32Slide33

Return to schoolNo restrictionsWhen they are ready33Slide34

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35Return 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. Slide36

Prognosis36Vast 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.