Mononucleosis

Infectious mononucleosis (IM), also known as “the kissing disease,” is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Diagnosis is clinical and confirmed through heterophile antibody testing or specific serologic antibody testing. There is currently no specific antiviral therapy available for this condition.

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Introduction

Definition

Infectious mononucleosis (IM) is a viral infectious disease caused by the Epstein-Barr virus (EBV) and is characterized by a triad of fever, tonsillar pharyngitis, and lymphadenopathy.  

Synonyms

  • Mononucleosis infectiosa
  • Pfeiffer’s disease or Pfeiffer‘s glandular fever
  • “Mono” or “kissing disease”

Epidemiology

  • 90%–95% lifetime prevalence worldwide
  • Occurs more frequently in spring and autumn
  • Children and adolescents aged 15–19 years are the most commonly affected 
  • A common cause of viral pharyngitis, especially among young adults in the United States
  • Clinical infection is 30 times higher in Caucasians than African Americans in the United States

Etiology

EBV belongs to the group of human herpesviruses (HHV-4).

Pathophysiology

Pathogenicity

EBV has an exceptionally high species specificity:

  • Replicates almost exclusively in human epithelial cells of the oropharynx and in B lymphocytes
  • Has not been recovered in the environment, suggesting that its major reservoir is humans

Transmission

  • The disease is mainly transmitted via contact with body secretions, primarily oropharyngeal secretions
    • Smear infection (direct contact infection): especially common in children by parents, playmates, etc.
    • Indirect infection: by touching contaminated objects 
    • Contact infection: especially in adolescents by infected saliva during kissing and sharing beverages; kissing appears to be a more important route than coitus
    • Rarely spreads through blood transfusions and organ transplantation due to the use of highly sensitive nucleic acid amplification testing (NAAT) of donor tissue
    • Vertical transmission of EBV appears to be exceptional.
  • The virus spreads throughout the body from the oropharynx and infects CD21-positive epithelia in the nasopharynx and B lymphocytes, which infiltrate other lymphoid tissue throughout the lymphoreticular system of the entire body. 
  • There is an immortalization of B lymphocytes and a strong increase in EBV levels. 
  • In primary infection, only a small number of viral proteins are likely to be expressed. This results in a mild immune response and lack of clinical symptoms.
  • Oral shedding of EBV usually persists for six months after the onset of illness and can be intermittently shed for decades.
EBV infection cycle

The Epstein-Barr virus can infect both B cells and oropharyngeal epithelial cells. EBV enters B cells by binding to the cellular receptor CD21, allowing fusion of the viral envelope with the cell membrane. The lytic cycle results in the production of infectious virions in both B cells and oropharyngeal epithelial cells. In B cells, lytic replication normally only takes place after reactivation from latency, whereas in oropharyngeal epithelial cells the lytic replication often directly follows viral entry. During lytic replication, viral DNA polymerase is responsible for synthesizing the viral genome. This contrasts with latency, in which host-cell DNA polymerase copies the viral genome. However, latency does not result in the production of virions, since only a portion of EBV’s genes are expressed.

Image by Lecturio.

Clinical Presentation

  • Incubation period: 4–8 weeks
  • Prodromal stage: usually asymptomatic (especially in children < 10 years, of whom only 10% are symptomatic) but can include malaise, headache, and low-grade fever
  • Symptoms present in adolescents and adults and last 2–4 weeks.

Classic triad of symptoms

  1. Fever
  2. Tonsillitis (swollen and erythematous tonsils that may be covered in exudate)
  3. Cervical lymphadenopathy
    • Most common in the posterior cervical and posterior auricular chains

Additional symptoms

  • Headache 
  • General malaise to persistent and severe fatigue
  • Petechiae present at the junction between the hard and soft palates
  • Fetor ex-ore (“halitosis”): foul-smelling breath
  • Hepato-, spleno-, or hepatosplenomegaly
    • May present with abdominal pain and/or jaundice
  • Generalized lymph node swelling (tender, firm, mobile nodes)
  • Maculopapular rash (similar to measles, present in approximately 5% of cases)

Hoagland syndrome: the maximum manifestation of infectious mononucleosis

  • Impaired nasal breathing
  • Periorbital edema
  • Swollen upper eyelids
  • Symptoms of chronic mononucleosis

Neurologic syndromes: can occur 2–4 weeks after initial symptom onset

  • Guillain-Barré syndrome
  • Facial and other cranial nerve palsies
  • Aseptic inflammation of the brain, meninges, and/or central and peripheral nerves

Chronic mononucleosis: rare, due to persistent viral replication

  • Chronic or recurrent fever
  • Fatigue
  • Weight loss
  • Lymphadenopathy
  • Cytopenia
  • Interstitial pneumonia
  • Hepatitis
Infectious Mononucleosis

Pharyngitis demonstrating exudative tonsillitis and an enlarged uvula in an adolescent patient 5 days after the onset of infectious mononucleosis

Image: “Infectious mononucleosis” by University of Minnesota Medical School, Minneapolis, MN, USA. License: CC BY 4.0

Diagnosis

Diagnosis is based on clinical symptoms noted above with confirmatory testing.

  • Laboratory:
    • Absolute and relative lymphocytic leukocytosis (> 4,500/ml and > 50% of leukocytes) with > 10% atypical large reactive CD8+ T cells (“atypical lymphocytes”)
    • Mild anemia, neutropenia, and thrombocytopenia
    • ↑ Blood sedimentation rate
    • ↑ C-reactive protein
    • Mild ↑ transaminases, alkaline phosphatase, and total bilirubin
  • Mononuclear spot, monospot, or heterophile antibody test:
    • Detects heterophile antibodies produced in response to EBV infection
    • Has a sensitivity of 85% and specificity of 100%
    • Further testing is not necessary if reactive
  • Serology:
    • Detects antibodies against EBV 
    • Positive immunoglobulin G represents a past infection
    • Positive immunoglobulin M represents a current infection
  • Histopathology of lymph nodes:
    • The picture of polymorphic hyperplasia of the pulp is typical.
    • Propagation in lymph nodes and fast growth of blast cells/necrosis are present in the histological sample.

Summary

If IM is suspected from history and physical examination, order a WBC count with differential and a heterophile test.

  • + heterophile: no further testing, confirmed diagnosis of IM
  • – heterophile: suggests cytomegalovirus (CMV) as a possible cause, but definitive diagnosis for EBV is serologic testing for EBV viral capsid antigen via EBV antibody testing
Classic triad of IM

Diagnostic algorithm for infectious mononucleosis

Image by Lecturio.

Management

There is currently no specific antiviral therapy available, so treatment is supportive.

  • Symptomatic treatment includes: 
    • Rest from physical activity for 3 (non-contact sports) to 4 (contact sports) weeks after onset of initial symptoms to avoid splenic rupture
    • Antipyretics
    • Analgesics (e.g., acetaminophen)
    • Nonsteroidal anti-inflammatory drugs
  • Administration of penicillin and aminopenicillins can trigger exanthema formation.

Prognosis

  • In normal cases, a favorable resolution is common and durable immunity is developed.
  • In patients with cellular immunodeficiencies and post-transplant patients, more severe courses may occur. 
  • Chronic infections are extremely rare.
  • Dormancy of virus in B cells → increased risk for recurrence and B-cell lymphoma in immunodeficient patients (e.g., HIV patients)
Amoxicillin rash

Amoxicillin rash in patients with infectious mononucleosis

Image: “Amoxicillin rash in a patient with infectious mononucleosis (patient 4)” by Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary. License: CC BY 4.0

Complications

Bacterial superinfection
Many patients develop secondary streptococcal pharyngitis.

Cardiac

  • Myocarditis: inflammatory disease of the heart muscle, which mostly arises due to infection with cardiotropic viruses, especially infection with coxsackievirus
  • Arrhythmias (bradyarrhythmias and tachyarrhythmias): disturbances in heart rhythm that affect the pumping efficiency of the heart muscle
  • Pericarditis: inflammation of the pericardium resulting from infection, autoimmune disease, radiation, surgery, or myocardial infarction

Dermatologic

  • Ampicillin-associated rash
  • Oral hairy leukoplakia: triggered by EBV; results in white patches on the tongue that may have a hairy appearance

Hematologic

  • Hemolytic anemia: type of anemia caused by premature destruction of RBCs. There is increased clearance by the spleen (extravascular hemolytic anemia) or damage caused by a narrowed vascular lumen (intravascular hemolytic anemia).
  • Thrombocytopenia: The normal range for platelet count is 150–400 X10⁹/L; thrombocytopenia is a platelet count of less than 150 X10⁹/L.
  • Neutropenia: an abnormally low concentration of neutrophils (a type of WBC) in the blood
  • Aplastic anemia: dysfunction of the hematopoietic cells ending in bone marrow failure. Patients usually present with pancytopenia.

Hepatic

  • Reye’s syndrome: a rare disorder which results in brain and liver damage that happens at any age, but mainly affects children
  • Mild viral hepatitis: infection that causes liver inflammation and damage,
  • Fulminant hepatic necrosis: more common in males and the most common cause of death in affected males

Splenic

  • Splenomegaly
  • Ruptured spleen: occurs in < 0.5% of cases; more common in males. Presents with abrupt abdominal pain, referred shoulder pain, and hemodynamic compromise, and requires immediate surgery. Avoiding contact sports and heavy lifting can reduce risk.

Respiratory

  • Airway obstruction and difficulty breathing due to swollen tonsils (treat with steroids)
  • Interstitial pneumonitis
  • Pneumonia

Immunologic and Oncologic

  • Decreased cell-mediated immunity
  • Lymphoproliferative syndromes
  • Burkitt’s and non-Hodgkin’s lymphomas: associated with EBV infection. Endemic Burkitt’s lymphoma occurs mainly in Africa; the condition typically affects the jaw and facial bones. Sporadic Burkitt’s lymphoma presents with abdominal masses or bone marrow involvement.
  • Hodgkin’s lymphomas: cancer that originates from lymphocytes manifesting as non-painful enlarged lymph nodes in the neck, under the arm, or in the groin

Neurologic

  • Encephalitis: inflammation of the brain, most commonly caused by a viral infection
  • Guillain-Barré syndrome: an auto-immune disorder that manifests as weakness and tingling in the extremities
  • Bell’s palsy: weakness or paralysis of the facial muscles on one side of the face
  • Psychosis: false beliefs (delusions) and seeing or hearing things that others do not see or hear (hallucinations)
  • Optic neuritis: inflammation of the optic nerves
  • Transverse myelitis: inflammation which extends horizontally across the spinal cord, believed to be immune-mediated and triggered by infection; associated with signs and symptoms of motor, sensory, and/or autonomic dysfunction
  • Meningoencephalitis: late-stage manifestation of tick-borne rickettsial diseases, such as Rocky Mountain spotted fever and human monocytotropic ehrlichiosis, caused by Ehrlichia chaffeensis
  • Cranial nerve palsies: decrease or complete loss in function of 1 or more cranial nerves. The etiology may be congenital or acquired.
  • Primary central nervous system lymphoma

Renal

  • Glomerulonephritis: inflammation of glomeruli that can be acute or chronic
  • Interstitial nephritis: spaces between tubules in kidneys become inflamed, reducing the kidneys’ filtration abilities

Clinical Relevance

The following conditions are differential diagnoses for infectious mononucleosis:

  • CMV infection: a double-stranded DNA virus that is spread by secretions such as saliva, urine, and blood. Infection with CMV is usually asymptomatic in immunocompetent hosts but causes severe disease in immunocompromised patients.
  • HIV infection is caused by a single-stranded RNA virus of the Retroviridae family and is transmitted through the exchange of body fluids such as semen and blood. HIV infection causes a deterioration of the immune system, beginning with constitutional symptoms (lymphadenopathy) and advancing into AIDS-defining illnesses (opportunistic infections).
  • Streptococcal infection: gram-positive bacteria known for their characteristic chain-like growth; can cause endocarditis, meningitis, bacterial pink eye, and necrotizing fasciitis
  • Toxoplasmosis: an infectious disease caused by Toxoplasma gondii, which is an obligate intracellular parasite that lives in the feline gut (definite host). Humans can become infected through the consumption of raw meat or food contaminated by cat feces. 
  • Parainfluenza viruses: enveloped RNA viruses that can cause upper and lower respiratory infections and croup, usually presenting as sudden myalgia/arthralgia with fever and tonsillitis
  • Diphtheria: a serious bacterial infection caused by Corynebacterium diphtheriae that affects the mucous membranes in the nose and throat, resulting in sore throat, fever, swollen glands, and weakness
  • Acute necrotizing ulcerative gingivitis: a common, non-contagious infection of the gums with sudden onset. Presents as painful, bleeding gums and ulceration of interdental papillae, with the development of necrosis and a dirty-gray pseudomembrane
  • Listeriosis: an infectious disease caused by the gram-positive bacterium Listeria monocytogenes. Transmitted via contaminated food (especially raw milk), it presents asymptomatically, as a mild flu-like illness or febrile gastroenteritis.

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