Infectious Mononucleosis & EBV Infection Dave Rupar MD 3 April 2012

EBV- a herpesvirus Large, ds DNA Identified in 1964 from Burkitt’s lymphoma tissue

EBV- a herpesvirus Ubiquitous Problems for normal and immunocompromised hosts Latent infection Transformation of lymphocytes Oncogenic potential

Spread of EBV Spread by oral secretions 4-7 week incubation Only 6% have identifiable contact Viral shedding by: 50-100% IM 25% asymptomatic seropositives 50% renal x-plant

Epidemiology of EBV 50% seroconversion by age 5 College students seroconvert 12%/year By age 25, 95% population is seropositive

A case, courtesy of HWC, MD “I am the man” A 16 year old boy, star of the football team, comes to see you because of sore throat for 5 days with mild fatigue,

I am the man... PE: Fever 102 2+ AC nodes, no rash or jaundice Red throat with marked tonsillar exudate abdomen benign

I am the man... LAB: Rapid strep test negative Monospot positive

Infectious Mononucleosis Fever Pharyngitis Lymphadenopathy

Sumaya and Ench, Pediatrics 1985;75:1003

IM: other manifestations Splenomegaly Hepatitis Rash Anemia Thrombocytopenia Encephalitis

IM: other manifestations Splenomegaly Hepatitis Rash Anemia Thrombocytopenia Myocarditis Encephalitis By PE: 17% By U/S: >95% Average increase in size: 50% Rupture is rare but exciting

IM: other manifestations Splenomegaly Hepatitis Rash Anemia Thrombocytopenia Encephalitis Hepatomegaly 10% Increased transaminases: 80% Rarely severe EBV not a cause of classic hepatitis

IM: other manifestations Splenomegaly Hepatitis Rash Anemia Thrombocytopenia Encephalitis Ampicillin Other antibiotics

IM: other manifestations Splenomegaly Hepatitis Rash Anemia Thrombocytopenia Encephalitis AIHA 0.5-3% Anti-i cold agglutinin Hemophagocytosis

IM: other manifestations Splenomegaly Hepatitis Rash Anemia Thrombocytopenia Encephalitis 1-2 % of encephalitis Clinical picture not well established

IM: Diagnosis Clinical DDx GAS CMV “mono” Acute HIV syndrome Adenovirus Toxoplasmosis Kawasaki disease Malignancy

Activated Cytotoxic T-lymphocytes = IM: Lab Diagnosis Non-specific CBC LFT’s Activated Cytotoxic T-lymphocytes = “ Atypical Lymphs”

IM: Lab Diagnosis

Lab Diagnosis: Heterophile Ab Paul & Bunnell, 1932: Serum from IM patients reacts with sheep blood Monospot uses horse rbc’s IgM polyclonal Ab Does not react with EBV antigens PPV 95% for EBV in patients with consistent illness

Lab Diagnosis: Heterophile Ab False negatives Too early (days-weeks) Too young (<4 yo) Heterophile neg mono: CMV, HIV, hep B, toxo. False positives HPV B19, CMV, other viruses SLE Sarcoid Lymphoma

Heterophile tests vary with age

EBV-specific Serology

EBV-specific Serology Positive VCA IgM Positive VCA IgG, negative EBNA = ? Positive VCA IgG Positive EBNA, negative VCA IgM =? All negative =?

What can you learn from EBV serology? Recent infection - positive VCA IgM & IgG, negative EBNA, variable EA Old infection - positive VCA IgG and EBNA, negative VCA IgM Never infected - all negative Do Not overinterpret- much variation in patterns Beware of “chronic infection” or “reactivation”

Detection of Virus: PCR Primarily a research tool Clinical application in PTLD, severely immunosuppressed patients No standardization for use in mono syndromes

The natural history of mono Rea et al. JABFP 2001;14:234 150 patients with IM, mean age 21+7

Labs quickly return to normal Rea et al. JABFP 2001;14:234 150 patients with IM, mean age 21+7

Back to the case: You know that the most common serious complications are… 1. Airway obstruction 2. Splenic rupture 3. Liver failure 4. Lymphoproliferative disease 5. 1 and 2

I am the man... 6 days after first visit (11days into illness), Dad (an MD) says son is well and wants to play football now At recheck that day, he is well and has nl PE Should you let him play?

Complications after IM Splenic rupture Airway Obstruction Fatigue

Complications after IM Splenic rupture Fatigue Airway Obstruction Spontaneous rupture 0.1% 40 years at Mayo 8116 IM 5 definite, 4 probable LUQ pain Consider non-op mgmt Mayo Clin Proceed 1992;67:846

How soon can he safely return to sports after his mono? 1. 3 weeks 2. 4 weeks 3. 5 weeks 4. 6 weeks 5. 6 months

How to decide?

Clinical algorithm: Return to play Auwater P. Infectious mononucleosis: Return to play. Clinics in Sports Medicine 2004; 23:485. Thanks, Dr Henin

What about the Athlete? Part Deux “Contact Sports should be avoided until the patient is recovered fully from IM and the spleen is no longer palpable.” 2009 Red Book, p 292

Complications after IM Splenic rupture Airway Obstruction Fatigue

Acute Airway Obstruction Little data Rare (<1%?) More common in young children? Look for stridor, dyspnea Monitor O2 sats Steroids may be helpful in hospitalized patient

Complications after IM Splenic rupture Airway Obstruction Fatigue

Complications after IM Splenic rupture Airway Obstruction Fatigue Generally “2-4 week” duration 1948: 25% persistent illness with fatigue at 3 mo. 2001: 2 mo- 38% not recovered 6 mo- 12% not recovered

Disease Profile in Male and Female Case Patients with Infectious Mononucleosis. Macsween K F et al. Clin Infect Dis. 2010;50:699-706 © 2010 by the Infectious Diseases Society of America

“Chronic Mono”? Fatigue after IM is common Female sex, premorbid personality are risk factors No evidence of ongoing viral replication or organ involvement Prognosis is excellent Encourage activity

Chronic Fatigue Syndrome Fatigue is common in the adolescent/young adult population More common after IM than other infections Much is unexplained “Abnormal” EBV AB no more common in CFS than in general population “Necessary but insufficient”? Don’t blame Lyme, either http://www.cdc.gov/cfs/

Contrast “Chronic Mono” with Severe Chronic Active EBV Infection X-linked Lymphoproliferative Syndrome Virus-Associated Hemophagocytic Syndrome

EBV: treatment Supportive only in most cases Acyclovir, etc. of limited value Widespread belief in value of steroids despite suspicion of increased serious complications Role for prednisone (1 mg/kg) in UAO Hemolytic anemia Myocarditis HPS

Does treatment work? C: Time away from school/work A: Duration of ST 94 patients, mean age 18, with IM. Randomized, DB, PC Acyclovir + prednisone vs placebo. All results NS Tynell et al. J Infect Dis 1996;174:324

EBV: treatment “Although therapy with short-course corticosteroids may have a beneficial effect on acute symptoms, because of potential adverse effects, their use should be considered only for patients with impending airway obstruction, massive splenomegaly, myocarditis, hemolyic anemia or HLH.” Emphasis added. 2009 Red Book, page 292

Don’t forget to fill out your pathogen brackets! The End ? Don’t forget to fill out your pathogen brackets!

SCAEBV >6 months duration Fever Lymphadenopathy HSM Pancytopenia Often fatal High VCA IgG High EA IgG EBV DNA in tissue, blood No HPS Organ involvement BM Lungs Hepatitis Uveitis

Hemophagocytic Syndrome Median age ~18 months Primary (HLH) vs. secondary (VAHPS) EBV one of identified causes High fatality FUO HSM Lymphadenopathy Rash Pneumonia DIC Clin Infect Dis 2003;36:306

Hemophagocytic Syndrome Pancytopenia (>2 cell lines) Elevated LFT’s, LDH Coagulopathy Hyperferritinemia HP in BM, spleen, nodes

IM: Encephalitis CEP: 17 patients with encephalitis due to EBV Median age 11 (1-31) 11 ICU 14 fever 11 seizure 4 coma CSF 7 wbc ((0-2250) Pro 37 (21-139) Glucose normal

XLP Young males Severe, fatal IM May have IAHPS Hypogammaglobulin-emia NHL Genetic Diagnosis Family History

Graph showing correlation of initial fatigue score with the duration of fatigue (P=.023). Macsween K F et al. Clin Infect Dis. 2010;50:699-706 © 2010 by the Infectious Diseases Society of America

EBV- associated malignancies Burkitt’s lymphoma (African children) NP carcinoma CNS lymphoma in AIDS patients Hodgkin’s lymphoma

EBV- a herpesvirus Binds to CD21 receptor (B-lymphocytes) Up to 20% infected acutely Most cleared 50/109 remain latently infected (episome) Express only 10 genes Lifelong reservoir