1. Infectious Mononucleosis & EBV Infection
Dave Rupar MD
3 April 2012

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

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

4. 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

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

6. 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,

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

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

9. Infectious Mononucleosis
Fever
Pharyngitis
Lymphadenopathy

10. Sumaya and Ench, Pediatrics 1985;75:1003

11. IM: other manifestations
Splenomegaly
Hepatitis
Rash
Anemia
Thrombocytopenia
Encephalitis

12. 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

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

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

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

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

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

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

20. IM: Lab Diagnosis

21. 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

22. 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

23. Heterophile tests vary with age

24. EBV-specific Serology

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

26. 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”

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

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

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

30. 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

31. 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?

32. Complications after IM
Splenic rupture
Airway Obstruction
Fatigue

33. 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

34. 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

35. How to decide?

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

37. 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

38. Complications after IM
Splenic rupture
Airway Obstruction
Fatigue

39. 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

40. Complications after IM
Splenic rupture
Airway Obstruction
Fatigue

41. 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

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

43. “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

44. 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

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

46. 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

47. 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

48. 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

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

50. 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

51. 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

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

53. 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

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

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

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

57. 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