Mononucleosis

Aka: Mononucleosis, Acute Mononucleosis Syndrome, Epstein-Barr Virus, Epstein Barr Virus, EBV-Induced Mononucleosis, EBV, Infectious Mononucleosis, Epstein-Barr Virus Infection, Human Herpesvirus 4

1. See Also
   1. Mononucleosis-Like Syndrome
   2. Heterophil Antibody Test (Monospot Test)
   3. Epstein-Barr Virus Antibody
2. Pathophysiology
   1. 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
   2. Transmission
      1. Transmission through infected Saliva (kissing)
      2. Oral secretions transmit for up to 6 months
   3. Incubation
      1. Range: 4-8 weeks (may be as short as 2 weeks)
   4. Life long infection
      1. Adults (by age 35 years) who have been previously infected and are carriers: 90-95% worldwide
3. Epidemiology
   1. No seasonal pattern
   2. No gender predisposition
   3. 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
   4. Commonly occurs in congested, confined spaces
      1. College Students
      2. Military recruits (>0.9% annual Incidence)
4. Symptoms
   1. Initial prodrome
      1. Mild-flu like symptoms for 3-5 days
   2. Classic symptom triad
      1. Fever (in >97% of cases)
         1. Persists for 7-10 days
      2. Severe Sore Throat
      3. Prominent Cervical Lymphadenopathy
   3. Other common symptoms
      1. Fatigue (93% of cases)
      2. Chills
      3. Malaise
      4. Myalgias
      5. Headache (50% of cases)
   4. Less common symptoms
      1. Decreased appetite or Anorexia
      2. Abdominal discomfort
5. Signs
   1. 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
   2. Other findings
      1. Splenomegaly (75%)
      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)
6. Labs
   1. Streptococcal Rapid Antigen Test with reflex to Throat Culture
      1. Exclude coexisting Streptococcal Pharyngitis
      2. Concurrent Strep PharyngitisIncidence: 4-30%
      3. If positive, avoid Amoxicillin due to rash
   2. 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
         3. 
      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
   3. Liver Function Tests
      1. Abnormal in 80% of Mononucleosis cases
   4. Heterophil Antibody Test (Monospot Test)
      1. Decreased Test Sensitivity in age <12 years old and in early infection (<1 week)
      2. False positive tests do occur related to alternative diagnoses (see Monospot Test)
   5. 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. Acute phase antibodies: xEA, xIgM VCA
      4. Convalescent Antibody: xIgG VCA
      5. Recovered State: xIgG VCA, xEBNA
7. Differential Diagnosis
   1. See Mononucleosis Differential Diagnosis
8. Diagnosis
   1. See Mononucleosis Diagnostic Approach
9. Management
   1. 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
   2. Avoid strenuous Exercise or Contact Sport
      1. Risk of Splenic Rupture
      2. Return to play guidelines
         1. Three weeks: Moderate training allowed
            1. No Splenomegaly (not palpable or painful)
            2. No fever
            3. Liver Function Tests Normal
            4. Asymptomatic
         2. Four weeks: strenuous activity allowed
            1. Contact Sport participation may resume (if Splenomegaly has resolved)
   3. 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
   4. 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)
   5. Other ineffective agents
      1. No benefit with Acyclovir
      2. No benefit with Ranitidine
10. Complications: Most common
    1. Splenic Rupture
       1. Spontaneous rupture in >50% 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. Timing: Days 4-21 from symptom onset (uncommon after 28 days)
       4. Diagnosis with CT Abdomen
       5. May present with Left upper quadrant pain (may radiate into left Shoulder)
       6. May present with significant hemodynamic instability including Hypotension, Syncope or Tachycardia
       7. Nonoperative management unless hemodynamically unstable
    2. 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 <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)
11. Complications: Other
    1. Cardiopulmonary
       1. Pneumonitis
       2. Pericarditis
       3. Viral Myocarditis
          1. May present with Chest Pain and ischemic EKG changes
    2. 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]
    3. Malignancy
       1. Burkitt Lymphoma
       2. Nasopharyngeal Cancer
       3. Hodgkin Disease
    4. Hematologic
       1. Hemolytic Anemia (3%)
       2. 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
       3. Neutropenia (3%)
          1. Neutrophils <1000/mm3, may persist for up to 2 weeks
    5. Head and neck
       1. Peritonsillar Abscess (0.2%)
       2. Viral Sialoadenitis (especially Parotid Gland)
    6. Other
       1. Acute Interstitial Nephritis
       2. 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]
12. Associated Conditions
    1. Streptococcal Pharyngitis carriage accompanies Mononucleosis in up to 30% of cases
    2. Chronic Fatigue Syndrome (possibly same viral agent)
13. Course
    1. Acute illness phase typically resolves within 1-2 weeks
    2. Athletes require 3-6 months to return to prior fitness
    3. Fatigue or Hypersomnia persists 6 months in 9-22%
    4. Fatigue present
       1. Initial: 77%
       2. Month 1: 28%
       3. Month 2: 21%
       4. Month 6: 13%
    5. Hypersomnia present
       1. Initial: 45%
       2. Month 1: 18%
       3. Month 2: 14%
       4. Month 6: 9%
    6. Arthralgias present
       1. Initial: 23%
       2. Month 1: 15%
       3. Month 2: 6%
       4. Month 6: 9%
    7. References
       1. Rea (2001) J Am Board Fam Pract 14:234-42 [PubMed]
14. Resources: Patient Education
    1. AAFP Family Doctor Patient Education Handout
       1. http://www.familydoctor.org/handouts/077.html
15. References
    1. Gantz in Noble (2001) Primary Care, p. 267-71
    2. Katz in Gershon (2004) Krugman's ID, p. 143-55
    3. Peoples (2014) Crit Dec in Emerg Med 28(3): 11-6
    4. Ebell (2004) Am Fam Physician 70(7):1279-87 [PubMed]
    5. Luzuriaga (2010) N Engl J Med 362(21):1993-2000 [PubMed]
    6. Womack (2015) Am Fam Physician 91(6): 372-6 [PubMed]