Infectious mononucleosis



Infectious mononucleosis 

Updated 2013 Feb 28 11:24:00 AM: EFNS/ENS guideline on use of PCR technology for diagnosis of infections of nervous system (National Guideline Clearinghouse 2013 Feb 25) view updateShow more updates

Related Summaries: 

Streptococcal pharyngitis

General Information Description: 

infectious disease caused by Epstein-Barr virus typically presenting with fever, exudative pharyngitis, and lymphadenopathy(1)

Also called:   

mono kissing disease glandular fever

Who is most affected:  

children, adolescents, and young adults(2) no predisposition by gender(3)

Incidence/Prevalence: 

  

> 95% adults worldwide are infected with Epstein-Barr virus (EBV)(3) o half the population in industrialized countries and higher socioeconomic groups have primary EBV infection at age 1-5 years o another large proportion of population has primary EBV infection at age 1020 years 25%-30% of patients < 30 years old with primary EBV infection will become sick with infectious mononucleosis(1) overall incidence of infectious mononucleosis in United States about 500 cases per 100,000 persons/year, with highest incidence at age 15-24 years(3) no seasonal distribution of incidence(3)



mononucleosis may account for 3% of cases of ill travelers with febrile illness o analysis of 17,353 patients diagnosed with specific illnesses at 30 travel clinics after international travel included 3,907 patients presenting with systemic febrile illness o mononucleosis (due to EBV or cytomegalovirus [CMV]) responsible for  3.2% cases overall  7% in Caribbean  6.9% in Central America  7.9% in South America  1% in sub-Saharan Africa  1.7% in South Central Asia  3.2% in Southeast Asia o Reference - N Engl J Med 2006 Jan 12;354(2):119, correction can be found in N Engl J Med 2006 Aug 31;355(9):967, commentary can be found in N Engl J Med 2006 Apr 27;354(17):1851

Causes and Risk Factors Causes: 

Epstein-Barr virus (EBV)(1, 2)

Pathogenesis: 

 

transmission is mainly through infected saliva (3) o often via kissing o less commonly sexual transmission latent infection in circulating memory B lymphocytes provides lifelong viral reservoir(3) low risk of transmission (< 10%) o based on systematic literature review o incubation period 33-49 days, based on moderate evidence (well-designed study with 5-50 subjects) o duration of shedding up to 16 months (median > 5 months), based on moderate evidence (well-designed study with 5-50 subjects) o period of infectiousness at least 2 months, based on limited evidence o serial interval (interval between onset of clinical disease in index case and secondary case) not known (no evidence found) o no recommended exclusion period from school, based on moderate evidence (well-designed study with 5-50 subjects); exclusion will not be fully effective because asymptomatic infections occur and may be involved in transmission; prolonged excretion makes exclusion impractical o Reference - Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184

Possible risk factors:





active sexual history associated with increased rate for Epstein-Barr virus seropositivity o based on study of 1,006 incoming Edinburgh University students o risk factors include being sexually active and larger number of past sexual partners o Reference - J Infect Dis 2002 Sep 15;186(6):731 transmission of Epstein-Barr virus from blood donors to organ transplant recipients has been reported (Blood 1996 Jan 15;87(2):812 PDF)

Complications and Associated Conditions Complications: 

 

 



splenic rupture o splenic ruptures occur in 0.1%-0.2% of cases with highest estimate being 0.5%  rupture can occur spontaneously or be caused by trauma  rupture may result from altered splenic architecture  Reference - Curr Sports Med Rep 2002 Apr;1(2):116 o most reported splenic ruptures have occurred within 3 weeks after diagnosis, but ruptures have occurred as late as 7 weeks after diagnosis(3) o splenic rupture may be difficult to predict because physical exam to detect splenomegaly often unreliable(3) o splenic rupture thought to occur due to sudden increase in portal venous pressure which may be related to Valsalva maneuver or sudden compression from external trauma (Clin J Sport Med 2008 Jul;18(4):309) airway obstruction from tonsillar enlargement (lymphoid hyperplasia) and generalized inflammation (mucosal edema)(3) hematologic complications(2, 3) o thrombocytopenia o aplastic anemia o hemolytic anemia o thrombotic thrombocytopenic purpura (TTP) o hemolytic-uremic syndrome (HUS) o disseminated intravascular coagulation (DIC) acute interstitial nephritis(2) neurologic abnormalities including(2, 3) o cranial nerve palsies (including Bell's palsy) o encephalitis o meningitis o mononeuropathies o seizures o retrobulbar neuritis o Guillain-Barre syndrome o transverse myelitis cardiac complications(2) o cardiac conduction abnormalities





  





o myocarditis oncologic complications o Hodgkin disease  infectious mononucleosis appears to be associated with increased incidence of Hodgkin disease  based on long-term follow-up of 38,562 infectious mononucleosis patients  1,381 (3.6%) developed cancer  46 (0.1%) developed Hodgkin disease  compared to "expected" incidence of Hodgkin disease, standardized incidence ratio was 2.55 (95% CI 1.87-3.4)  Reference - J Natl Cancer Inst 2000 Sep 20;92(18):1522  infectious mononucleosis-related Epstein-Barr virus (EBV) infection associated with increased risk of developing EBV-positive Hodgkin lymphoma (but not EBV-negative Hodgkin lymphoma)  based on cohorts of 38,555 patients followed by national registry data for up to 30 years  Reference - N Engl J Med 2003 Oct 2;349(14):1324 o Burkitt lymphoma o head and neck cancer - serologic markers for EBV infection associated with 33 times risk for subsequent nasopharyngeal carcinoma in study of 9,699 Taiwanese men (N Engl J Med 2001 Dec 27;345(26):1877) o thymic carcinoma in United States (J Exp Med 1991 Apr 1;173(4):971) oral hairy leukoplakia o nonmalignant hyperplastic lesion of epithelial cells of tongue that occurs in immunocompromised patients o EBV considered to have causative role in oral hairy leukoplakia (Head Neck Pathol 2008 Mar;2(1):19, J Periodontal Res 2006 Aug;41(4):235, Braz Oral Res 2005 Oct-Dec;19(4):317) nonulcerative stromal keratitis (interstitial keratitis) may result from immune response in stroma to EBV (Biosci Rep 2001 Aug;21(4):419) posttransplant lymphoproliferative disease (Pharmacol Res 2011 Jan;63(1):1, Ann Transplant 2010 Jun 28;15(2):40) genital ulceration in case reports and case series o 26 cases of EBV presenting as genital ulceration (Acta Derm Venereol 2006;86(5):439) o case presentation of EBV presenting as genital ulceration (Obstet Gynecol 2007 Jun;109(6):1447, 1461) o EBV infection in 31% in case series of 13 girls aged 11-19 years with nonsexually related acute genital ulcers (Arch Dermatol 2009 Jan;145(1):38) case reports of o bilateral pulmonary artery thrombosis (Cases J 2009 Jan 22;2(1):76) o EBV-associated cholecystitis (Ann Intern Med 2007 Jun 5;146(11):826) o infectious mononucleosis hepatitis in 2 young adults (Korean J Intern Med 2009 Dec;24(4):381 ) X-linked recessive progressive combined variable immunodeficiency (Duncan disease) is rare genetic disease reported to have high rate of death from

lymphoproliferative disease which may be triggered by EBV (Lancet 1975 Apr 26;1(7913):935) Associated conditions: 



concomitant streptococcal pharyngitis reported in patients with infectious mononucleosis, rates range from < 3% to 30% o 30% patients had group A beta-hemolytic streptococcal pharyngitis in study of 500 consecutive patients with infectious mononucleosis ( (2), Prim Care 1975 Jun;2(2):295) o < 3% throat cultures positive for group A beta-hemolytic streptococci in study of throat cultures from 133 patients with infectious mononucleosis, < 3% cultures were positive from 2,881 patients with pharyngitis during same period (Clin Pediatr (Phila) 1976 May;15(5):424) o 4% throat cultures positive for group A beta-hemolytic streptococci at diagnosis in study of 100 consecutive patients with infectious mononucleosis (South Med J 1983 May;76(5):575) o avoid amoxicillin and ampicillin which may cause morbilliform rash in patients with infectious mononucleosis(2) tender points are common and transient with acute infectious mononucleosis, fibromyalgia is not a typical long-term outcome o based on study of 150 subjects diagnosed with acute infectious mononucleosis o at presentation, mean tender point count was 7.5 and 19% subjects met modified criteria for fibromyalgia o at 2 months, mean tender point count was 4.6 and 3% met modified criteria for fibromyalgia o at 6 months, mean tender point count was 3 and 1% met modified criteria for fibromyalgia o Reference - Arch Intern Med 1999 Apr 26;159(8):865



infectious mononucleosis may be associated with development of chronic fatigue syndrome in adolescents o based on prospective cohort study o 301 adolescents aged 12-18 years with infectious mononucleosis were evaluated at 6, 12, and 24 months after diagnosis o chronic fatigue syndrome diagnosis in  13% at 6 months  7% at 12 months  4% at 24 months o Reference - Pediatrics 2009 Jul;124(1):189



infectious mononucleosis associated with subsequent increased risk for developing multiple sclerosis (MS) o based on systematic review o systematic review of 4 cohort studies and 18 case-control studies evaluating association of MS and infectious mononucleosis

o o

o o



data included 19,390 patients with MS and 16,007 controls infectious mononucleosis associated with MS  relative risk 2.17 (95% CI 1.97-2.39) in overall meta-analysis  relative risk 2.33 (95% CI 1.96-2.78) in analysis limited to 4 cohort studies Reference - PLoS One 2010 Sep 1;5(9):e12496 largest cohort study included 25,234 Danish patients with mononucleosis followed for mean 22 years  104 cases of multiple sclerosis observed (0.4%), with standardized incidence ratio 2.27 (95% CI 1.87-2.75) compared to expected number of cases  Reference - Arch Neurol 2007 Jan;64(1):72

no association between history of infectious mononucleosis and risk for invasive breast cancer o based on Nurses' Health Study II with 81,807 women followed from 1989 to 2007 with 2,349 cases of invasive breast cancer o Reference - Cancer Causes Control 2012 Dec;23(12):1893

History and Physical History: Chief concern (CC): 



classic triad(1) o pharyngitis (sore throat) o moderate-to-high fever o generalized lymphadenopathy fatigue(2)

Social history (SH): 



ask about(1) o potential exposure to saliva of infected person o ill contacts o sexual history as with any infectious disease, recent travel and animal exposure may be informative for diseases that mimic infectious mononucleosis(1)

Physical: General physical:  

exam may only show nonspecific findings(1) generalized lymphadenopathy typically involving (1) o inguinal region

o o o

axilla posterior auricular nodes posterior cervical nodes

Skin:  

urticarial and maculopapular rashes rare except among patients given beta-lactam antibacterials (of whom most develop rash)(1) jaundice more common in patients > 40 years old(1)

HEENT:   

mild-to-moderate tonsillar enlargement common, often with greyish exudates (1) 25% of patients may have petechiae of palate (1) periorbital edema may occur(3)

Neck: 

lymphadenopathy(1) o typically symmetric o moderately tender o tends to peak during first week of symptoms o less prominent in patients > 40 years old

Abdomen:   

splenomegaly may be palpable in up to 63% of patients(1) physical exam to detect splenomegaly often unreliable (3) hepatomegaly more common in patients > 40 years old(1)

Pelvic: 

painful vulvar ulcers may be present (Curr Infect Dis Rep 2009 Nov;11(6):449, Acta Derm Venereol 2011 Jan;91(1):55 )

Diagnosis Making the diagnosis:  



clinical suspicion if fever, pharyngitis, lymphadenopathy, and malaise (1, 2) findings which make diagnosis likely (high specificity) (1) o positive heterophile antibody (such as Monospot or Monolatex) (2) o differential white blood cell count with either of  lymphocytosis ≥ 50% and atypical lymphocytes ≥ 10%  atypical lymphocytes ≥ 20% serology can be diagnostic when heterophile antibody test is negative

o

o

optimal combination of Epstein-Barr virus (EBV) serologic testing consists of antibody titration of 4 markers  immunoglobulin M (IgM) to viral capsid antigen (VCA)  immunoglobulin G (IgG) to VCA  IgM to early antigen  antibody to Epstein-Barr nuclear antigen (EBNA) findings in primary EBV infection include positive IgM to VCA and early antigen, increasing or high IgG to VCA after 4 weeks, and negative antibody to EBNA

Rule out: 





heterophile antibody-negative conditions with clinical presentation similar to infectious mononucleosis(1) o non-Epstein-Barr virus (EBV) viral etiologies  cytomegalovirus (CMV infection)  human herpesvirus-6 (roseola infantum)  adenovirus (adenoviral pharyngitis)  herpes simplex virus type 1 (herpes labialis)  primary HIV infection o streptococcal pharyngitis o toxoplasmosis systemic disorders with findings (such as atypical lymphocytosis or adenopathy) similar to infectious mononucleosis(1) o connective tissue disorders  sarcoidosis  systemic lupus erythematosus o malignancies  Hodgkin disease  non-Hodgkin lymphoma o infections  Bartonella henselae (cat-scratch disease)  Corynebacterium diphtheriae (diphtheria)  enteroviruses (coxsackievirus A pharyngitis, echoviruses)  Francisella tularensis (oropharyngeal tularemia)  hepatitis A  hepatitis B  Mycobacterium tuberculosis (tuberculosis adenitis)  rubella (German measles) o drug reactions  carbamazepine  minocycline  phenytoin determined causes of mononucleosis-like illnesses in cohort of 40 adults in Japan o EBV in 17 patients o CMV in 11 patients o human herpesvirus-6 in 2 patients

o o o o



parvovirus B19 in 2 patients HIV-1 in 1 patient unknown in 7 patients Reference - Intern Med 2006;45(13):833 PDF pseudo-outbreak linked to laboratory error described in 57 persons in community hospital in Puerto Rico (MMWR Morb Mortal Wkly Rep 1991 Aug 16;40(32):552)

Testing overview:  



heterophile antibody (such as Monospot or Monolatex)(1) if heterophile antibody test negative(1) o complete blood count with differential o Epstein-Barr virus (EBV) serology radiographic modalities may be considered for liver and spleen size in athletes who want to return early to contact sports

Blood tests: Heterophile antibody:    

    

heterophile antibody tests include Monospot, Monolatex, Mono-Latex, Mono-Lex, Mono-Plus, Cards OS Mono, Clearview IM, and OSOM MonoTest heterophile antibodies develop within first 7 days after onset of symptoms, peak between 2 and 5 weeks, and can be detected at low levels for up to 12 months(1) heterophile antibodies may be falsely negative in up to 25% patients in first week of symptoms(1) heterophile antibody has 71%-90% sensitivity for infectious mononucleosis in adolescents and adults, but only 25%-50% sensitivity for acute Epstein-Barr virus (EBV) infection in children(1) heterophile antibodies have very high specificity for infectious mononucleosis, but positive results have been reported in EBV-negative patients with HIV infection(1) Paul-Bunnell heterophile antibody is heterogeneous group of mostly immunoglobulin M (IgM) produced in response to acute EBV infection (1) Paul-Bunnell antigen appears to be glycoprotein structure on surface of EBVinfected cells(1) "spot" test (such as Monospot) is slide-based test using equine erythrocytes to absorb nonheterophile antibodies from patient serum to improve specificity(1) diagnostic characteristics of heterophile antibody tests in patients with suspected infectious mononucleosis(2) o based on evaluation of 6-9 different tests used in 3 studies o reference standard used was positive heterophile antibody plus Epstein-Barr virus viral capsid antigen (EBV-VCA) antibody pattern consistent with recent infection o heterophile antibody latex agglutination assays had  sensitivity 87% (range 79%-95%)  specificity 91% (range 82%-99%)  positive likelihood ratio 9.7

o

o

o

o

o

 negative likelihood ratio 0.14 heterophile antibody solid-phase immunoassays had  sensitivity 83% (range 71%-95%)  specificity 97% (range 94%-99%)  positive likelihood ratio 28  negative likelihood ratio 0.18 most specific of 9 rapid test kits may be Monolatex and Cards OS Mono  based on testing of 9 rapid test kits against 108 serum samples  sensitivities ranged from 63% to 84%  specificities ranged from 84% to 100%  Monolatex had 76% sensitivity and 98% specificity  Cards OS Mono had 65% sensitivity and 100% specificity  Reference - J Clin Microbiol 1994 Jan;32(1):259 PDF most sensitive of 6 heterophile antibody test kits may be Alexon, Avitex, Clearview, and Cards Mono  based on testing of 6 heterophile antibody kits against 241 serum samples  sensitivities ranged from 81% to 95%  specificities ranged from 98% to 100%  Reference - Clin Diagn Lab Immunol 2000 May;7(3):451 Monolatex, Mono-Latex, Mono-Lex, Mono-Plus, and Clearview IM performed well in evaluation of 6 rapid heterophile antibody test kits against 100 serum samples (Clin Diagn Virol 1996 Oct;7(1):17) OSOM MonoTest had 93% sensitivity and 100% specificity for infectious mononucleosis in cohort of 145 patients > 14 years old with sore throat and negative testing for streptococcal pharyngitis (Eur J Gen Pract 2012 Mar;18(1):15)

Complete blood count: 



findings which make infectious mononucleosis highly likely in patient with typical clinical presentation(2) o ≥ 20% atypical lymphocytes o ≥ 50% lymphocytes with ≥ 10% atypical lymphocytes differential cell count by automated hematology analyzer may predict infectious mononucleosis o based on prospective study of patients with clinically suspected infectious mononucleosis, of whom 181 had positive heterophile antibody o peripheral blood samples analyzed by 2 automated hematology analyzers Diagnostic Characteristics for Positive Heterophile Antibody: Positive Negative Sensitivity Specificity Likelihood Likelihood Ratio Ratio ≥ 10% atypical 75% 92% 9.4 0.27 lymphocytes

Diagnostic Characteristics for Positive Heterophile Antibody: Positive Negative Sensitivity Specificity Likelihood Likelihood Ratio Ratio ≥ 20% atypical 56% 98% 28 0.44 lymphocytes ≥ 40% atypical 26% 100% 50 0.75 lymphocytes ≥ 50% lymphocytes 66% 84% 4.1 0.4 ≥ 50% lymphocytes plus ≥ 10% atypical 61% 95% 12 0.41 lymphocytes Reference - (2), Arch Pathol Lab Med 1999 Oct;123(10):875 ≥ 10% atypical lymphocytes may be highly specific for positive heterophile antibody in adults with sore throat o based on prospective study of 709 patients aged 16-73 years with sore throat o heterophile antibody positive in 15 (2%) patients o ≥ 10% atypical lymphocytes found in 4 (27%) heterophile-positive and no heterophile-negative patients o Reference - Ann Intern Med 1982 Apr;96(4):505 lymphocytosis > 35% total white blood cells may have limited ability to distinguish infectious mononucleosis from bacterial tonsillitis (level 2 [midlevel] evidence) o based on retrospective case-control studies o in study of 120 patients with infectious mononucleosis and 100 patients with bacterial tonsillitis  mean lymphocyte/white cell count rate was 0.54 with infectious mononucleosis and 0.1 with bacterial tonsillitis  lymphocyte/white cell count ratio > 0.35 had 90% sensitivity and 100% specificity for infectious mononucleosis  Reference - Arch Otolaryngol Head Neck Surg 2007 Jan;133(1):61 o in study of 500 patients with positive Monospot and 500 patients with negative Monospot  mean lymphocyte to white blood cell count ratio 0.49 in Monospotpositive and 0.29 in Monospot-negative patients  lymphocyte to white blood cell count ratio > 0.35 had 72% sensitivity and 84% specificity for infectious mononucleosis  Reference - Clin Otolaryngol 2010 Oct;35(5):397, commentary can be found in Clin Otolaryngol 2011 Oct;36(5):515, Clin Otolaryngol 2012 Feb;37(1):80, Clin Otolaryngol 2012 Apr;37(2):162 o





Serology:



when heterophile antibody test is negative, optimal combination of EpsteinBarr virus (EBV) serologic testing consists of antibody titration of 4 markers o IgM to viral capsid antigen (VCA)  appears early in infection  disappears within 4-6 weeks o immunoglobulin G (IgG) to VCA  appears in acute phase  peaks at 2-4 weeks after onset  declines slightly then persists for life o IgM to early antigen  appears in acute phase  generally falls to undetectable levels after 3-6 months  may be sign of active infection in many people, but 20% of healthy people may have this antibody for years o antibody to Epstein-Barr nuclear antigen (EBNA)  for EBNA antibodies using immunofluorescent tests  not seen in acute phase  slowly appears 2-4 months after onset  some EBNA enzyme immunoassays may detect antibody within few weeks of onset  persists for life o Reference - CDC Epstein-Barr Virus and Infectious Mononucleosis Disease Information 2006 May 16 Epstein-Barr Virus-specific Antibody Titer Patterns(3): 0-3 Months 3-12 Months Antigen > 1 Year (Past) (Acute) (Recent) Heterophile antigen Positive Positive Negative IgM > 160, IgG > IgM < 160, IgG > IgM not detectable, IgG VCA 60 160 > 40 NA Not detectable < 10 > 40 Diffuse early > 40 < 40 < 40 antigen Restricted early < 10 < 10 < 10 antigen Abbreviations: IgG, immunoglobulin G; IgM, immunoglobulin M; NA, nuclear antigen; VCA, viral capsid antigens.



prolonged clinical syndromes not usually caused by EBV o although EBV antibody tests may suggest reactivated infection  results do not necessarily indicate that medical condition is caused

by EBV infection  some persons with no symptoms have antibodies to EBV early antigen for years after initial EBV infection o chronic infection not usually present



o

reliable laboratory evidence for continued active EBV infection rarely found in patients who have been ill for > 4 months  when illness lasts > 6 months, investigate for other causes of chronic illness or chronic fatigue syndrome Reference - CDC Epstein-Barr Virus and Infectious Mononucleosis Disease Information

Epstein-Barr virus (EBV) genome testing: 



testing EBV genome in peripheral blood mononuclear cells may aid diagnosis in infants who are negative for anti-EBV antibodies during acute phase (level 2 [mid-level] evidence) o based on retrospective chart review o records from 104 Japanese children aged 2 months to 13 years with EBVinfectious mononucleosis were reviewed o 20% of infants were negative for all anti-EBV antibodies and required repeat serologic testing o anti-VCA IgM positive rate during acute illness  25% in infants  80% in children > 4 years old o 3 patients with infectious mononucleosis were found to be EBV genome positive but seronegative during acute phase o follow-up serological tests confirmed anti-VCA IgG seroconversion and definitive diagnosis at later stage in disease o Reference - Pediatr Int 2010 Aug;52(4):536 review on laboratory assays for EBV-related disease can be found in J Mol Diagn 2008 Jul;10(4):279

Imaging studies: 

radiographic modalities for liver and spleen size may be considered for athletes wishing early return to contact sports, but not well studied (Clin J Sport Med 2005 Nov;15(6):410)

Treatment Treatment overview:  

hydration and pain relief as needed corticosteroids o recommended for life-threatening complications such as acute upper airway obstruction (grade C recommendation [lacking direct evidence]) o corticosteroids not routinely recommended (grade B recommendation [inconsistent or limited evidence]) but might relieve sore throat over 12-36 hours in patients with infectious mononucleosis (level 2 [mid-level] evidence) o insufficient evidence that corticosteroids improve other symptoms







acyclovir not routinely recommended (grade B recommendation [inconsistent or limited evidence]) as not shown to have clinical benefit (level 2 [mid-level] evidence) but may reduce oropharyngeal viral shedding (level 3 [lacking direct] evidence) activity restriction to prevent splenic rupture (grade C recommendation [lacking direct evidence]) o avoid strenuous physical activity for 1 month after symptom onset o avoid contact sports as long as splenomegaly is present exclusion from school not recommended for infection control (UK expert Grade B, Level II/III)

Fluid and electrolytes: 

hydration as needed

Activity: 





patients with infectious mononucleosis should avoid contact or collision sports while symptomatic and for at least 4 weeks after onset of symptoms (grade C recommendation [lacking direct evidence])(2) all mononucleosis patients should avoid strenuous physical activity for 1 month after symptom onset (grade C recommendation [lacking direct evidence]) o no clinical or laboratory factors reliably predict risk of splenic rupture o most splenic ruptures occur within 4 weeks of symptom onset o Reference - J Fam Pract 2005 Jun;54(6):547 avoid contact sports as long as splenomegaly is present o based on literature reviews finding little supporting evidence o detection of splenomegaly may require abdominal x-ray, ultrasound, or computed tomography but use of imaging studies is controversial o evidence-based review supports these recommendations but finds no strong evidence to guide timing of return to athletic participation, recommendations based on case reports and case series of splenic rupture (Arch Fam Med 2000 Nov-Dec;9(10):1122 ) o no strong evidence to support use of single parameter to predict safe return to sports participation  current consensus supports gradual return to competition 1 month after diagnosis if afebrile, well-hydrated, and asymptomatic without palpable liver or spleen  these conditions do not guarantee spleen has returned to normal  radiographic modalities for liver and spleen size may be considered for athletes wishing to return to sports earlier, but not well studied  Reference - Clin J Sport Med 2005 Nov;15(6):410

Medications: Corticosteroids:







recommendations regarding steroids in infectious mononucleosis o not recommended for routine treatment (grade B recommendation [inconsistent or limited evidence]), but may be helpful for respiratory compromise or severe pharyngeal edema in infectious mononucleosis (grade C recommendation [lacking direct evidence]) (Am Fam Physician 2004 Oct 1;70(7):1279 ) o prednisone 60-80 mg once daily for 5-7 days, then tapered over 14 days, recommended for life-threatening complications including upper airway obstruction, severe thrombocytopenia, and severe hemolytic anemia (grade C recommendation [lacking direct evidence]) (Am Fam Physician 1994 Mar;49(4):879) corticosteroids might relieve sore throat over 12-36 hours in patients with infectious mononucleosis (level 2 [mid-level] evidence), but insufficient evidence that corticosteroids improve most other symptoms o based on Cochrane review limited by heterogeneity o systematic review of 7 randomized trials evaluating steroids for symptom control in 366 patients with documented infectious mononucleosis o no meta-analyses performed due to heterogeneity of outcomes o significant differences in relief of sore throat at 12 hours with 1 dose comparing steroids vs. placebo reported in  60% vs. 26% in 1 trial with 39 patients (p = 0.038, NNT 3)  64% vs. 8% in 1 trial with 24 patients (p = 0.012, NNT 2) o nonsignificant differences in relief of sore throat with steroids vs. placebo reported at  24 hours in 1 trial with 40 patients (55% vs. 30%, p = 0.11)  36 hours in 1 trial with 24 patients (73% vs. 31%, p = 0.048) o 2 trials had conflicting results for return to normal activities comparing steroids vs. placebo  70% vs. 31% at 1 week in 1 trial with 36 patients (p = 0.025, NNT 3)  60% vs. 41% at 1 week in 1 trial with 32 patients (not significant)  80% vs. 81% at 4 weeks in 1 trial with 32 patients (not significant) o no significant differences found in single trials in  relief of sore throat at 48, 60, or 70 hours, or 1 week (39 patients)  relief of sore throat at 2 or 4 weeks (35 patients)  fatigue at 1 or 4 weeks (44 patients)  anorexia at 1 or 4 weeks (29 patients)  swallowing at 1 or 4 weeks (32 patients)  pharyngeal secretions at 1 or 4 weeks (37 patients) o severe complications from steroid therapy reported in 1 trial included  1 case of acute onset of diabetes mellitus with acidosis  1 case of peritonsillar cellulitis o Reference - Cochrane Database Syst Rev 2011 Apr 13;(3):CD004402 systemic corticosteroids may not reduce disease complications, rates of hospital admission, or length of hospital stay (level 2 [mid-level] evidence) o based on retrospective chart review o records of 206 patients with infectious mononucleosis between 1998 and 2003 were analyzed

o

o

o

o

o 

64 patients (31.1%) required inpatient admission for severe and persistent symptoms including  dehydration  fever  concern for airway obstruction  other systemic complications systemic corticosteroids used in 44.7% of patients  8% for airway concerns  92% for other indications  poor oral intake  severe dysphagia or odynophagia  persistent symptoms  repeat visits  unknown reasons corticosteroids not positively associated with any clinical characteristic used to diagnose infectious mononucleosis including  fever  decreased oral intake  tonsillar hypertrophy  duration of symptoms no significant differences comparing corticosteroids vs. no corticosteroids in  incidence of disease complications  rates of hospital admission  length of hospital stay Reference - Arch Otolaryngol Head Neck Surg 2005 Oct;131(10):900

see also Steroids for pharyngitis

Other symptomatic treatment: 



medications for symptomatic relief include (2) o nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for fever and myalgias o for pharyngitis  throat lozenges or spray  gargling with lidocaine 2% (Xylocaine) antihistamines not recommended for routine treatment of infectious mononucleosis (grade B recommendation [inconsistent or limited evidence])(2)

Acyclovir:  

acyclovir not recommended for routine treatment of infectious mononucleosis (grade B recommendation [inconsistent or limited evidence])(2) acyclovir not shown to have clinical benefit (level 2 [mid-level] evidence) but may reduce oropharyngeal viral shedding (level 3 [lacking direct] evidence) o based on systematic review without assessment of allocation concealment

o



systematic review of 5 randomized trials with 339 patients treated with acyclovir for acute infectious mononucleosis o acyclovir IV given in 2 trials (which included patients with more severe disease) and orally in 3 trials o trend toward clinical effectiveness with acyclovir, but no statistically significant results achieved o decreased rate of oropharyngeal Epstein-Barr virus (EBV) shedding at end of therapy with acyclovir vs. placebo (odds ratio 6.62, 95% CI 3.56-12.29, p < 0.0001) o Reference - Scand J Infect Dis 1999;31(6):543 acyclovir plus prednisolone not shown to have clinical benefit for infectious mononucleosis (level 2 [mid-level] evidence) but inhibits oropharyngeal viral shedding (level 3 [lacking direct] evidence) o based on randomized trial with unclear randomization o 94 patients with infectious mononucleosis and symptoms ≤ 7 days were randomized to acyclovir 800 mg 5 times daily plus prednisolone vs. placebo for 10 days o prednisolone dosed at 0.7 mg/kg for first 4 days, then reduced by 0.1 mg/kg each day for another 6 days o no significant differences between groups in  duration of illness  sore throat  weight loss  absence from school or work o oropharyngeal EBV shedding significantly inhibited during treatment (p = 0.02) in analysis of 34 patients o Reference - J Infect Dis 1996 Aug;174(2):324

Valacyclovir: 

valacyclovir might reduce severity of infectious mononucleosis with primary EBV infection (level 2 [mid-level] evidence) o based on small randomized trial without intention-to-treat analysis and without blinding o 28 university students ≥ 18 years old presenting within 7 days of onset of infectious mononucleosis were randomized to valacyclovir 1 g orally every 8 hours for 14 days vs. no antiviral drug o 7 patients excluded due to absence of confirmation of primary EBV infection, 1 patient excluded due to missing data, 20 patients analyzed o comparing valacyclovir vs. no antiviral drug  median severity of illness score (0-5 scale) at baseline 4 vs. 3.5  median severity of illness score at 15 days 1 vs. 2 (p = 0.049)  valacyclovir associated with reduction in EBV excretion in oral fluid o Reference - J Clin Virol 2007 May;39(1):16

Antibiotics:



avoid amoxicillin and ampicillin which may cause morbilliform rash in patients with infectious mononucleosis(2)

Surgery and procedures: 



splenectomy o procedure of choice for spontaneous splenic rupture with hemodynamic instability o option for spontaneous splenic rupture with hemodynamic stability o alternative for spontaneous splenic rupture with hemodynamic stability is nonoperative management  based on case report of 16-year-old boy and review of 23 published cases  8 patients failed conservative management and required splenectomy o Reference - Pediatrics 2007 Aug;120(2):e432 case reports o splenectomy for spontaneous splenic rupture described in case report (Lancet 2007 Dec 15;370(9604):2068) o splenic artery embolization for traumatic splenic rupture in 15-year-old girl described in case report (Am Surg 2008 Feb;74(2):149)

Other management: 



case reports of nonoperative management of spontaneous splenic rupture o arteriography with or without embolization as alternative to surgery (Am Surg 2006 May;72(5):401) o splenic preservation with intensive care unit admission, serial computed tomography scans, and activity limitation in 16-year-old boy (Pediatrics 2007 Aug;120(2):e432 ) management of upper airway obstruction described in 3 case reports (Eur J Emerg Med 2007 Feb;14(1):41, Arch Pediatr 2001 Sep;8(9):952)

Prognosis  

most patients recover without sequelae and resume usual activities within 2-3 months(3) infectious mononucleosis may lead to persistent fatigue, likelihood varies across studies, poor physical functioning predicts delayed recovery o systematic review of 14 cohort studies (2 randomized trials, 1 quasirandomized trial, 7 prospective studies, 4 retrospective studies) of patients with uncomplicated infectious mononucleosis followed for at least 6 weeks o follow-up ranged from 2 months to 2 years, 5 studies with < 80% follow-up were excluded o compared to patients with upper respiratory infection in 1 prospective study, infectious mononucleosis more likely to be followed by fatigue (40% vs.

15%), hypersomnia (22% vs. 2%), and chronic fatigue syndrome (9%-22% vs. 0%-6%)

o



prolonged illness (mostly fatigue) reported in 1.5%-56% across studies  in 1 large prospective study 40% had fatigue at 6 months and 9%22% had chronic fatigue syndrome  in 1 large prospective study 12% did not recover at 6 months  in 1 retrospective study fatigue in 56% at 6 months and 16% at 11 months  in 1 retrospective study only 1.5% had persistent fatigue at 2 months o drug therapy (acyclovir with or without prednisolone) did not reduce chronic symptoms in randomized trials o bed rest associated with delayed recovery o poor physical functioning (lengthy convalescence and being less fit or active) predicted chronic ill health o Reference - Br J Gen Pract 2002 Oct;52(483):844 PDF, commentary can be found in Evidence-Based Medicine 2003 May-Jun;8(3):92 most patients improve within 1 month but fatigue and adenopathy often persist o prospective series of 150 patients with acute illness serologically confirmed as Epstein-Barr virus infection o initially 74% had sore throat, 77% had fatigue, 77% had cervical adenopathy o other common (> 30%) features included fever, sleeping too much, painful nodes, headache, pharyngitis, moderate absolute and atypical lymphocytosis, and mildly elevated transaminase levels o splenomegaly only present in 8% o most abnormalities returned to normal by 1 month in most patients o fatigue persisted in 28% at 1 month, 21% at 2 months, and 13% at 6 months o cervical adenopathy persisted in 55% at 1 month, 39% at 2 months, and 29% at 6 months o pharyngitis persisted in 47% at 1 month, 21% at 2 months, and 25% at 6 months o Reference - J Am Board Fam Pract 2001 Jul-Aug;14(4):234 PDF



postinfective fatigue syndrome reported following viral and bacterial infections o prospective cohort of 250 patients in rural Australia followed for 12 months after acute infection o infections were confirmed due to Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), Ross River virus (epidemic polyarthritis), or unconfirmed o rate of postinfective fatigue syndrome was 35% at 6 weeks, 27% at 3 months, 12% at 6 months, and 9% at 12 months o rates did not vary with infectious agent, demographic factors, or psychiatric factors o rates increased with increasing baseline symptom severity o Reference - BMJ 2006 Sep 16;333(7568):575



prognosis may depend on psychosocial factors and physical fitness o prospective study of 250 primary care patients with infectious mononucleosis or ordinary upper respiratory tract infections followed for 6 months after onset

o



in patients without comorbid psychiatric disorders  an empirically defined fatigue syndrome 6 months after onset was most reliably predicted by positive Monospot test (odds ratio 2.1) and lower physical fitness  fatigue syndrome at 2 months associated with cervical lymphadenopathy and initial bed rest o mood disorders were predicted by premorbid psychiatric history, emotional personality score, and social adversity o Reference - Lancet 2001 Dec 8;358(9297):1946 splenomegaly common in athletes with acute infectious mononucleosis o based on cohort of 20 university athletes with infectious mononucleosis o maximum splenic length increased by mean 33.6% from baseline on ultrasound o splenomegaly resolved within 4-6 weeks of symptom onset in most cases o Reference - Br J Sports Med 2008 Dec;42(12):974

Prevention and Screening Prevention: 



exclusion from school not recommended for infection control (UK expert Grade B, Level II/III) o exclusion will not be fully effective because asymptomatic infections occur and may be involved in transmission o prolonged viral excretion makes exclusion impractical o see Causes and Risk Factors section for information on risk of transmission based on systematic literature review o Reference - Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184 recombinant gp350 vaccine might reduce incidence of infectious mononucleosis but not asymptomatic Epstein-Barr virus (EBV) infection in healthy young adults (level 2 [mid-level] evidence) o based on randomized trial without adequate statistical power o 181 EBV-seronegative, healthy patients aged 16-25 years randomized to gp350 vaccine vs. placebo and followed for 18 months o comparing gp350 vaccine vs. placebo  definite infectious mononucleosis in 2.2% vs. 8.8% (p = 0.03 in intention-to-treat analysis, p = 0.06 in per-protocol analysis)  asymptomatic EBV infection in 9.9% vs. 12.1% (not significant) o Reference - J Infect Dis 2007 Dec 15;196(12):1749 , editorial can be found in J Infect Dis 2007 Dec 15;196(12):1724 o DynaMed commentary -- gp350 vaccine in clinical development as of October 25, 2012

Guidelines and Resources

Guidelines: United States guidelines: 

Cincinnati Children's Hospital Medical Center (CCHMC) evidence-based clinical guideline on management of Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) in solid organ transplant can be found at CCHMC 2012 Jan PDF or at National Guideline Clearinghouse 2012 Nov 12:38418

United Kingdom guidelines: 

expert guideline on exclusion policies for control of communicable disease in schools and preschools can be found in Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184

European guidelines: 

European Federation of Neurological Societies/European Neurological Society (EFNS/ENS) guideline on use of PCR technology for diagnosis of infections of nervous system can be found in Eur J Neurol 2012 Oct;19(10):1278 or at National Guideline Clearinghouse 2013 Feb 25:38476

Review articles:       

review can be found at CDC National Center for Infectious Diseases review of mononucleosis and Epstein-Barr virus infection can be found in Virus Adaptation and Treatment 2012 Mar;(4);23 PDF review can be found in Postgrad Med 2000 Jun;107(7):175 review of mononucleosis and athletic participation can be found in Clin J Sport Med 2008 Jul;18(4):309 review of use of corticosteroids in treating infectious diseases can be found in Arch Intern Med 2008 May 26;168(10):1034 review of EBV infection can be found in N Engl J Med 2000 Aug 17;343(7):481 case presentation of 29-year-old woman with fever and abdominal pain can be found in N Engl J Med 2010 Sep 23;363(13):1266