II. 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 (e.g. kissing, sharing drinks)
    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

III. 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)

IV. Symptoms

  1. Asymptomatic in 90% of cases
  2. Initial prodrome
    1. Mild-flu like symptoms for 3-5 days
  3. Classic symptom triad
    1. Fever (in >97% of cases)
      1. Persists for 7-10 days
    2. Severe Sore Throat
    3. Prominent Cervical Lymphadenopathy
  4. Other common symptoms
    1. Fatigue (93% of cases)
    2. Chills
    3. Malaise
    4. Myalgias
    5. Headache (50% of cases)
  5. Less common symptoms
    1. Decreased appetite or Anorexia
    2. Abdominal discomfort

V. 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 (50 to 75%)
      1. 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)

VI. Labs

  1. Streptococcal Rapid Antigen Test with reflex to Throat Culture
    1. Exclude coexisting Streptococcal Pharyngitis
    2. Concurrent Streptococcal 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. HemeoncLymphocyteAtypia.jpg
    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

VII. Differential Diagnosis

VIII. Diagnosis

IX. 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

X. 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. Males account for 70% of rupture cases
    4. Timing: Days 4-21 from symptom onset (uncommon after 28 days)
    5. Diagnosis with CT Abdomen
    6. May present with Left upper quadrant pain (may radiate into left Shoulder)
    7. May present with significant hemodynamic instability including Hypotension, Syncope or Tachycardia
    8. 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)

XI. 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]

XII. Associated Conditions

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

XIII. 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]

XIV. Resources: Patient Education

XV. 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]

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Related Studies

Ontology: Epstein-Barr Virus (C0014644)

Definition (NCI_CDISC) Any viral organism that can be assigned to the species Human Herpesvirus 4.
Definition (NCI) A species of Herpetoviridae that is responsible for infectious mononucleosis (glandular fever). Discovered in 1964, this virus has been associated with Burkitt's lymphoma in South African children and with nasopharyngeal carcinoma in Asian populations.(On-line Medical Dictionary)
Definition (NCI_NCI-GLOSS) A common virus that remains dormant in most people. It has been associated with certain cancers, including Burkitt's lymphoma, immunoblastic lymphoma, and nasopharyngeal carcinoma.
Definition (CSP) infects B-cells in humans; thought to be the causative agent of infectious mononucleosis and is strongly associated with oral hairy leukoplakia, Burkitt lymphoma, and other malignancies.
Definition (MSH) The type species of LYMPHOCRYPTOVIRUS, subfamily GAMMAHERPESVIRINAE, infecting B-cells in humans. It is thought to be the causative agent of INFECTIOUS MONONUCLEOSIS and is strongly associated with oral hairy leukoplakia (LEUKOPLAKIA, HAIRY;), BURKITT LYMPHOMA; and other malignancies.
Concepts Virus (T005)
MSH D004854
SnomedCT 186753009, 40168006
LNC LP14383-1
English Burkitt Herpesvirus, Burkitt Lymphoma Virus, Burkitt's Lymphoma Virus, Burkitts Lymphoma Virus, E B Virus, E-B Virus, E-B Viruses, EBV, Herpesvirus, Burkitt, Infectious Mononucleosis Virus, Infectious Mononucleosis Viruses, Mononucleosis Virus, Infectious, Mononucleosis Viruses, Infectious, Herpesvirus 4 (gamma), Human, Herpesvirus 4, Human, Human Herpesvirus 4, HHV-4, Lymphoma Virus, Burkitt, HERPESVIRUS HUMAN 04, HUMAN HERPESVIRUS 04, HERPESVIRUS 4 GAMMA HUMAN, HHV 4, INFECT MONONUCLEOSIS VIRUS, human herpesvirus 4 group, Burkitt's lymphoma virus, EB virus, herpesvirus 4, human, mononucleosis infectious virus, epstein barr virus, epstein-barr virus, e-b virus, epstein barr virus (EBV), eb virus, e b virus, Lymphocryptovirus, Epstein-Barr Virus, HUMAN HERPESVIRUS 4, Epstein Barr virus, Epstein-Barr virus EBV, Human herpesvirus type 4, Epstein-Barr virus, Human herpesvirus 4, EBV - Epstein-Barr virus, Human (gamma) herpes virus 4, Human herpesvirus 4 (organism), Epstein Barr Virus, Virus-Epstein-Barr
French Virus du lymphome de Burkitt, Virus Epstein-Barr, Human herpesvirus 4, Virus de la mononucléose infectieuse, EBV (Epstein-Barr Virus), HHV-4 (Human HerpesVirus 4), Burkitt's lymphoma virus, Infectious mononucleosis virus, Herpèsvirus humain de type 4
Swedish Herpesvirus 4, humant
Czech EBV, virus Epsteinův-Barrové, lidský herpesvirus 4, virus Epsteina a Barrové
Portuguese Herpesvirus Humano Tipo 4, Herpesvirus Humano 4, EBV, Herpesvirus de Burkitt, Vírus da Mononucleose Infecciosa, Vírus do Linfoma de Burkitt, Vírus E-B, Vírus Epstein-Barr
Spanish Herpesvirus Humano Tipo 4, Herpesvirus Humano 4, virus de Epstein - Barr - EBV, virus herpes humano tipo 4 (organismo), virus Epstein - Barr, virus del herpes humano tipo 4, virus herpes humano tipo 4, virus Epstein - Barr - EBV, virus del herpes humano (gamma) tipo 4, virus herpes humano (gamma) tipo 4, virus de Epstein - Barr, virus del herpes humano tipo 4 (organismo), EBV, Herpesvirus de Burkitt, Virus de Epstein-Barr, Virus de la Mononucleosis Infecciosa, Virus del Linfoma de Burkitt, Virus E-B
Finnish Ihmisen herpesvirus 4
Italian Herpesvirus 4 (gamma) umano, Linfoma virus di Burkitt, Virus dell'infezione della mononucleosi, Virus E-B, Herpesvirus di Burkitt, Virus di Epstein-Barr, HHV-4, EBV, Herpesvirus 4 umano
Japanese Epstein-Barrウイルス, バーキット・ヘルペスウイルス, Burkittヘルペスウイルス, Burkittリンパ腫ウイルス, EBウイルス, ヒトヘルペスウイルス4(ガンマ), ヒトヘルペスウイルス4, ヒトヘルペスウイルス4型, ヘルペスウイルス4型-ヒト, 伝染性単核症ウイルス, 感染性単核症ウイルス, Epstein Barrウイルス, エプスタイン-バーウイルス, バーキットリンパ腫ウイルス, ヘルペスウイルス4-ヒト
German HUMAN HERPESVIRUS 04, HERPESVIRUS HUMANES 04, Burkitt-Herpesvirus, Burkitt-Lymphom-Virus, Burkitt-Lymphoma-Virus, E-B-Virus, EBV, Epstein-Barr-Virus, Herpesvirus 4, humanes, Humanes Herpesvirus 4, Infektiöse Mononukleose-Virus
Polish Wirusy EB, Wirusy Epsteina-Barr, Wirusy chłoniaka Burkitta, Wirusy mononukleozy zakaźnej, Wirus herpes człowieka typu 4, Herpeswirus 4 ludzki
Dutch Burkitt's lymfoomvirus, EB-virus, EBV, Epstein-Barr-virus, Burkitt-herpesvirus, Burkitt-lymphomavirus, Herpesvirus-4, humaan, Humaan herpesvirus 4, Mononucleosis-infectiosavirus, Virus 4, humaan herpes-, Ziekte-van-Pfeiffer-virus

Ontology: Infectious Mononucleosis (C0021345)

Definition (MEDLINEPLUS)

Infectious mononucleosis, or "mono", is an infection usually caused by the Epstein-Barr virus. The virus spreads through saliva, which is why it's sometimes called "kissing disease." Mono occurs most often in teens and young adults. However, you can get it at any age. Symptoms of mono include

  • Fever
  • Sore throat
  • Swollen lymph glands

Sometimes you may also have a swollen spleen. Serious problems are rare.

A blood test can show if you have mono. Most people get better in two to four weeks. However, you may feel tired for a few months afterward. Treatment focuses on helping symptoms and includes medicines for pain and fever, warm salt water gargles and plenty of rest and fluids.

Definition (MSHCZE) Infekční onemocnění způsobené herpetickým virem EBV, méně často CMV. Postihuje především mladší jedince a přenáší se přímým kontaktem (virus se vylučuje do slin a je možné jej přenést líbáním – „nemoc z líbání“). Inkubační doba je průměrně okolo 2 týdnů, ale i kratší či delší. Nejč. se projevuje horečkou, zduřením mízních uzlin, angínou, někdy bývají lehce postižena i játra, vzácněji další orgány. Proliferace B lymfocytů vede k infiltraci lymfatických orgánů (splenomegalie, lymfadenopatie). (cit. Velký lékařský slovník online, 2013 http://lekarske.slovniky.cz/ )
Definition (MSH) A common, acute infection usually caused by the Epstein-Barr virus (HERPESVIRUS 4, HUMAN). There is an increase in mononuclear white blood cells and other atypical lymphocytes, generalized lymphadenopathy, splenomegaly, and occasionally hepatomegaly with hepatitis.
Definition (CSP) acute disease characterized by fever and swollen lymph nodes and an abnormal increase of mononuclear leucocytes or monocytes in the bloodstream; not highly contagious; some believe it can be transmitted by kissing.
Concepts Disease or Syndrome (T047)
MSH D007244
ICD9 075
ICD10 B27 , B27.0, B27.9
SnomedCT 186667007, 26851006, 154359004, 186670006, 187460007, 314131007, 271558008, 186668002
English Glandular Fever, Mononucleosis, Infectious, mononucleosis, Fever, Glandular, INFECTIOUS MONONUCLEOSIS, Infectious mononucleosis, unspecified, Infectous mononuclosis,unsp, [X]Infectious mononucleosis, unspecified, [X]Infectous mononuclosis,unsp, INFECT MONONUCLEOSIS, MONONUCLEOSIS INFECT, infectious mononucleosis, infectious mononucleosis (diagnosis), Infectious Mononucleosis, Mononculeosis infectious, Mononucleosis infectious, monocytic angina, Infectious Mononucleosis [Disease/Finding], glandular fever, pfeiffer's disease, gammaherpesviral mononucleosis (diagnosis), Kissing disease, Mono, Infectious mononucleosis (& Pfeiffer's disease), Infectious mononucleosis (& Pfeiffer's disease) (disorder), Pfeiffer's disease (disorder), [X]Infectious mononucleosis, unspecified (disorder), Mononucleosis, Pfeiffer's disease, Glandular fever, Infectious mononucleosis, Gammaherpesviral mononucleosis, Monocytic angina, GF - Glandular fever, IM - Infectious mononucleosis, Infective mononucleosis, IM - Infective mononucleosis, Gammaherpesviral mononucleosis (disorder), Infectious mononucleosis (disorder), Epstein-Barr; mononucleosis infectiosa, Filatow, disease; kissing, gammaherpesviral; mononucleosis infectiosa, kissing disease, kissing; disease, monocytic; angina, mononucleosis, infectious; Epstein-Barr, mononucleosis, infectious; gammaherpesviral, mononucleosis, infectious, angina; monocytic, Infectious mononucleosis (disorder) [Ambiguous]
Dutch mononculeosis infectiosa, mononucleosis infectiosa, klierkoorts, Epstein-Barr; mononucleosis infectiosa, angina; monocytotica, disease; kissing, gamma-herpesvirus; mononucleosis infectiosa, kissing; disease, monocytotica; angina, mononucleosis infectiosa; Epstein-Barr, mononucleosis infectiosa; gamma-herpesvirus, Mononucleosis door gamma-Herpesvirus, Mononucleosis infectiosa, niet gespecificeerd, infectieuze mononucleose, Mononucleosis infectiosa, Pfeiffer-klierkoorts, Ziekte van Pfeiffer
French Fièvre glandulaire, Mononucléose infectieuse, Maladie du baiser, MNI (MonoNucléose Infectieuse)
German Druesenfieber, Mononucleosis infectiosa, Infektioese Mononukleose, nicht naeher bezeichnet, Infektioese Mononukleose, Mononukleose durch Gamma-Herpesviren, infektioese Mononukleose, Monozytenangina, Drüsenfieber, Infektiöse Mononukleose, Pfeiffer-Drüsenfieber, Pfeiffersches Drüsenfieber
Spanish Fiebre glandular, enfermedad de Pfeiffer, enfermedad de Pfeiffer (trastorno), [X]mononucleosis infecciosa, no especificada, [X]mononucleosis infecciosa, no especificada (trastorno), mononucleosis gammaherpesviral, angina monocítica, fiebre glandular, mononucleosis infecciosa (concepto no activo), mononucleosis infecciosa (trastorno), mononucleosis infecciosa, mononucleosis por herpesvirus del grupo gamma (trastorno), mononucleosis por herpesvirus del grupo gamma, mononucleosis por virus herpes del grupo gamma, Mononucleosis infecciosa, Fiebre Glandular, Mononucleosis Infecciosa
Swedish Körtelfeber
Japanese センネツ, デンセンセイタンカクショウ, 感染性単核細胞症, パイフェル病, 伝染性単核球症, 伝染性単核症, 伝染性単核細胞増多症, 伝染性単核細胞症, 伝染性単球増加, 伝染性単球増加症, 感染性単核症, 感染性単球増加, 感染性単球増加症, 流行性腺熱, 腺熱
Czech infekční mononukleóza, Infekční mononukleóza, Pfeifferova nemoc, monocytická angina, žlázová horečka
Finnish Mononukleoosi
Korean 감마헤르페스바이러스성 단핵구증, 상세불명의 감염성 단핵구증, 감염성 단핵구증
Italian Febbre ghiandolare, Febbre ghiandolare di Pfeiffer, Mononucleosi infettiva
Polish Mononukleoza zakaźna
Hungarian mononucleosis infectiosa, Mononculeosis, fertőző, Mononucleosis, fertőző, Pfeifer-féle mirigyláz
Norwegian Mononukleose, Kyssesyke, Kjertelfeber
Portuguese Mononucleose infecciosa, Febre Glandular, Mononucleose Infecciosa

Ontology: Mononucleosis syndrome (C0272210)

Concepts Disease or Syndrome (T047)
SnomedCT 16944002
Italian Sindrome mononucleosica
Japanese 単核細胞症症候群, タンカクサイボウショウショウコウグン
Czech Syndrom mononukleózy
English mononucleosis syndrome, syndrome mononucleosis, Mononucleosis syndrome, Mononucleosis syndrome (disorder), Mononucleosis syndrome, NOS
Hungarian mononucleosis syndroma
Spanish síndrome de mononucleosis (trastorno), síndrome de mononucleosis, Síndrome de mononucleosis
Portuguese Síndrome de mononucleose
Dutch mononucleosesyndroom
French Syndrome mononucléosique
German Mononukleose