Mononucleosis

See Also

Pathophysiology

Epstein-Barr Virus
1. Human Herpes Virus (Herpesviridae)
2. Infects B Cells (B-Cell Lymphotrophic)
3. Of those infected with EBV, 26-74% will not manifest Infectious Mononucleosis
Transmission
1. Transmission through infected Saliva (e.g. kissing, sharing drinks)
2. Oral secretions transmit for up to 6 months
3. May also be transmitted via genital secretions and sexual intercourse
Incubation
1. Range: 4-8 weeks (may be as short as 2 weeks)
Life long infection
1. Adults (by age 35 years) who have been previously infected and are carriers: 90-95% worldwide

Epidemiology

No seasonal pattern
No gender predisposition
Adolescents and young adults
1. Incidence ages 10 to 19 years: 6-8 per 1,000/year
2. Incidence ages >30 years: <1 case per 1,000/year
3. Incidence ages <10 years: <1 case per 1,000/year
  1. Likely underestimates Incidence
  2. Often these children have subacute presentations
  3. Mononucleosis is rare under age 1 year old (due to passive maternal Immunity)
  4. Mononucleosis in age 1-5 year olds may occur more in developing countries and unsanitary conditions
4. Peak Incidence (highest Incidence ages 15 to 24 years old)
  1. Girls: 14-16 years old
  2. Boys: 16-18 years old
Commonly occurs in congested, confined spaces
1. College Students
2. Military recruits (>0.9% annual Incidence)

Symptoms

Asymptomatic in 90% of cases
Initial prodrome
1. Mild-flu like symptoms for 3-5 days
Classic symptom triad
1. Fever (in >97% of cases)
  1. Persists for 7-10 days
2. Severe Sore Throat
3. Prominent Cervical Lymphadenopathy
  1. Large unilateral Anterior Cervical Lymphadenopathy is common
  2. However, Posterior Cervical Lymphadenopathy is more specific for Mononucleosis (LR+ 3.2)
Other common symptoms
1. Fatigue (93% of cases)
2. Chills
3. Malaise
4. Myalgias
5. Headache (50% of cases)
Less common symptoms
1. Decreased appetite or Anorexia
2. Abdominal discomfort
3. Nausea or Vomiting
4. Rash (esp. age <5 year)

Signs

Common findings
1. Exudative Pharyngitis or exudative Tonsillitis (>97%)
2. Pharyngeal erythema and edema (85%)
3. Prominent Cervical Lymphadenopathy (>97%)
  1. Posterior Cervical Lymphadenopathy (+LR 12) most common
  2. Axillary (+LR 21) and inguinal (+LR 2.9) Lymphadenopathy also common
Other findings
1. Splenomegaly (50 to 75%)
  1. Physical exam is unreliable in detecting Splenomegaly (which occurs in most patients with Mononucleosis)
  2. Present from as early as day 4 of illness (typically day 14) to as late as 8 weeks after onset
2. Palatal Petechiae (50%, +LR 5.8)
3. Periorbital edema (33%)
4. Hepatomegaly (20%)
5. Jaundice (8% of young adults, 26% of those over age 60 years old)

Labs

Streptococcal Rapid Antigen Test with reflex to Throat Culture
1. Exclude coexisting Streptococcal Pharyngitis
2. Concurrent Streptococcal Pharyngitis Incidence: 4-30%
3. If positive, avoid Amoxicillin due to rash
Complete Blood Count with differential
1. Absolute Lymphocyte Count >4000 mm3
  1. Absolute Lymphocyte Count <4000 makes the Mononucleosis diagnosis unlikely
2. Lymphocyte predominance: >50% of total White Blood Cell Count
3. Lymphocyte atypia >10%
  1. Very specific to EBV
  2. No further tests needed if Lymphocyte atypia present
4. Efficacy: Combination of >50% Lymphocytes and >10% Atypical lymphocytes
  1. Test Sensitivity: 75%
  2. Test Specificity: 92%
5. Other findings (see complications below)
  1. Hemolytic Anemia
  2. Mild Thrombocytopenia
    1. Platelet Count 100,000 to 150,000/mm3
  3. Neutropenia
    1. Neutrophil Count <1000/mm3
Liver Function Tests
1. Increased liver transaminases in 80% of Mononucleosis cases
Heterophil Antibody Test (Monospot Test)
1. Decreased Test Sensitivity in age <12 years old (esp. age <5 years) and in early infection (<1 week)
2. False Positive tests do occur related to alternative diagnoses (see Monospot Test)
3. Remains positive for up to one year after initial EBV infection
Epstein-Barr Virus Antibody
1. Expensive and typically a send-out lab
2. Consider in cases of high suspicion, negative Monospot test and results would change management
3. Where VCA is Viral Capsid Antigen, EBNA is EBV-Associated nuclear Antigen (Test Sensitivity 97%, Specificity 94%)
  1. Acute phase antibodies
    1. xIgM VCA (positive from early infection to 4 to 6 weeks)
  2. Convalescent Antibody
    1. xIgG VCA (positive starting at 2 weeks after onset and persists for life)
  3. Recovered State
    1. xIgG VCA
    2. xIgG EBNA (positive starting at 6 to 8 weeks after infection)

Differential Diagnosis

See Mononucleosis Differential Diagnosis

Diagnosis

See Mononucleosis Diagnostic Approach

Management

Symptomatic
1. See Pharyngitis Symptomatic Treatment
2. Relative rest (Pace activity for the day)
3. Non-caffeinated fluids for adequate hydration
4. Analgesics (NSAIDs or Acetaminophen)
5. Avoid Aspirin
  1. Risk of Reye Syndrome
  2. Risk of worsening Thrombocytopenia
  3. Increased risk of Splenic Rupture
Avoid strenuous Exercise or Contact Sport
1. Risk of Splenic Rupture
2. Return to play guidelines
  1. Return to play should be gradual
  2. Avoid splenic Ultrasound as a prognostic indicator for early return
  3. Three weeks: Moderate training allowed
    1. No Splenomegaly (not palpable or painful)
    2. No fever
    3. Liver Function Tests Normal
    4. Asymptomatic
  4. Four weeks: strenuous activity allowed
    1. Contact Sport participation may resume (if Splenomegaly has resolved)
Severe odynophagia or Airway compromise
1. Oral Prednisone 30-50 mg orally daily tapered over 10-14 days or
2. Dexamethasone 0.3 mg/kg (up to 10 mg IV or oral)
  1. May require repeat doseing
Antibiotics
1. Only indicated for coexisting Streptococcal Pharyngitis (4% of cases)
2. Maculopapular rash develops in 90% of EBV patients on Antibiotics (esp. with Amoxicillin)
Other ineffective agents
1. No benefit with Acyclovir
2. No benefit with Ranitidine

Complications
Most common

Splenic Rupture
1. Spontaneous rupture in >50-80% of cases (remainder are Traumatic)
  1. Rinderknecht (2012) Pediatr Emer Care 28(12): 1377-9 [PubMed]
2. Occurs in 0.5 to 1% of cases
3. Mortality up to 9%
4. Males account for 70% of rupture cases
5. Timing: Days 4-21 from symptom onset (uncommon after 28 days, case reports up to 8 weeks)
6. Diagnosis with CT Abdomen
7. May present with Left upper quadrant pain (may radiate into left Shoulder)
8. May present with significant hemodynamic instability including Hypotension, Syncope or Tachycardia
9. Nonoperative management unless hemodynamically unstable
Airway Obstruction
1. Overall some sense of airway obstruction occurs in up to 25% of cases
2. Significant airway obstruction occurs in 0.5 to 1% of cases (especially age <6 years old)
3. Severe, life-threatening obstruction may occur with Stridor, Dyspnea, Tachypnea and Cyanosis
  1. Typically responds to Corticosteroids (see above)
  2. Rarely intervention may be needed (Endotracheal Intubation, Tracheostomy, Tonsillectomy)

Complications
Other

Cardiopulmonary
1. Pneumonitis
2. Pericarditis
3. Viral Myocarditis
  1. May present with Chest Pain and ischemic EKG changes
Neurologic complications (1-5% of cases)
1. Encephalitis
  1. May present with Altered Level of Consciousness, combative behavior or Seizure
  2. Encephalitis complications may persist longterm in up to 40% of cases
2. Viral Meningitis
3. Guillain-Barre Syndrome
4. Bell's Palsy
5. Retrobulbar neuritis
6. Syndrome of Inappropriate Antidiuretic Hormone (SIADH)
7. Multiple Sclerosis (EBV postulated as one possible causative factor)
  1. Pohl (2009) J Neurol Sci 286(1-2): 62-4 [PubMed]
Malignancy
1. Lymphoproliferative Disease and malignant transformation risk factors
  1. HIV Infection
  2. Immunodeficiency (e.g. X-linked lymphoproliferative disease)
  3. Transplant recipients (mortality approaches 50%)
2. Burkitt Lymphoma
3. Nasopharyngeal Cancer
4. Hodgkin Disease
Hematologic
1. Hemolytic Anemia (3%)
2. Hemophagocytic Lymphohistiocystosis
3. Thrombocytopenia
  1. Presents between weeks 3 to 5 from symptom onset and resolves by week 6
  2. Mild Thrombocytopenia (Platelet Count 100-150k/mm3) in 25-50% of Mononucleosis cases
  3. Severe Thrombocytopenia (Platelet Count <20k/mm3) occurs rarely and resolves spontaneously
4. Neutropenia (3%)
  1. Neutrophils <1000/mm3, may persist for up to 2 weeks
Head and neck
1. Peritonsillar Abscess (0.2%)
2. Viral Sialoadenitis (especially Parotid Gland)
Other
1. Acute Interstitial Nephritis
2. Severe Hepatitis
3. Autoimmune Disorders (e.g. Systemic Lupus Erythematosus, Rheumatoid Arthritis)
4. Fulminant Epstein Barr Virus Infection
  1. Immunocompromised state
  2. X-Linked Lymphoproliferative Syndrome (associated with a 96% mortality rate)
    1. Seemayer (1995) Pediatr Res 38(4): 471-8 [PubMed]

Associated Conditions

Streptococcal Pharyngitis carriage accompanies Mononucleosis in up to 30% of cases
Chronic Fatigue Syndrome (possibly same viral agent)

Course

Acute illness phase typically resolves within 1-2 weeks
Athletes require 3-6 months to return to prior fitness
Fatigue or Hypersomnia persists 6 months in 9-22%
Fatigue present
1. Initial: 77%
2. Month 1: 28%
3. Month 2: 21%
4. Month 6: 13%
Hypersomnia present
1. Initial: 45%
2. Month 1: 18%
3. Month 2: 14%
4. Month 6: 9%
Arthralgias present
1. Initial: 23%
2. Month 1: 15%
3. Month 2: 6%
4. Month 6: 9%
References
1. Rea (2001) J Am Board Fam Pract 14:234-42 [PubMed]

Resources
Patient Education

AAFP Family Doctor Patient Education Handout
1. http://www.familydoctor.org/handouts/077.html

References

Gantz in Noble (2001) Primary Care, p. 267-71
Katz in Gershon (2004) Krugman's ID, p. 143-55
Peoples (2014) Crit Dec in Emerg Med 28(3): 11-6
Ebell (2004) Am Fam Physician 70(7):1279-87 [PubMed]
Luzuriaga (2010) N Engl J Med 362(21):1993-2000 [PubMed]
Sylvester (2023) Am Fam Physician 107(1): 71-8 [PubMed]
Womack (2015) Am Fam Physician 91(6): 372-6 [PubMed]