Infectious Mononucleosis

Infectious Mononucleosis (IM) is a common childhood/adolescent illness. It is most commonly caused by the Epstein-Barr Virus (EBV). Classic physical findings include fever, splenomegaly, pharyngitis, and lymphadenopathy. Treatment for infectious mononucleosis is generally supportive. 

Etiology

  • Ninety percent of cases of infectious mononucleosis are caused by the Epstein-Barr virus. 
  • Two major strains of EBV exist; EBV type-1 and EBV type-2. They differ biologically and in their geographic distribution, but cause the same clinical symptoms. 
  • Other causes of mononuleosis-like syndromes include CMV, Toxoplasmosis, Adenoviruses, Hepatitis A, and HIV.

Epidemiology

  • The Epstein-Barr Virus is ubiquitous. EBV is harbored persistently by virtually all adults, regardless of their geographic location.  
  • After the primary infection, the virus latently infects circulating B-cells and is shed in saliva and genital secretions. Most people acquire the infection via the oral route, but it can also be acquired through sexual contact, blood products, and bone marrow and solid organ transplants.
  • Spread of EBV is associated with close personal contact.
  • Living conditions inpact the age at which a child first contracts the virus.
    -Infection occurs earlier in children who live in the presence of poor hygiene and crowded living conditions.  
    -The prevalence of EBV infection ranges between 20-80% in children aged 2-3 years old worldwide.  
    -In the industrialized world, the primary EBV infection usually occurs during the teen years. 

Pathophysiology

  • The Epstein-Barr Virus is a gamma-type herpes virus; herpesviruses are large DNA viruses that code for more than 100 proteins. 
  • EBV has the ability to infect B lymphocytes. During the initial infection, the virus activates B-cells and induces rapid expansion of the infected cell population. 
  • When active and replicating, the EBV virus can spread and infect tissues. In this state, is also vulnerable to detection and destruction by NK cells and cytotoxic T-cells.
  • When latent, the virus rests in peripheral blood B-cells and expresses few proteins, making it virtually invisible to the host's immune system. 
  • During the acute infection, antibodies develop to lytic cycle proteins, including membrane antigen, virus capsid antigen (VCA) and other early antigens. 
  • EBV infection occurs at least 30 days prior to the development of symptoms.  Little is known about the pathophysiology of early EBV infection. 
  • Host response accounts for many of the clinical findings of IM.  The course of the illness parallels the lymphoproliferative phase, during which there is an increase in the number of CD8+ cytotoxic T-cells directed against early viral proteins. 
  • The T-cell response leads to the classic clinical findings of IM: lymphadenopathy, heptaosplenomegaly, and the absolute and atypical lymphocytosis.  Fever and fatigue result from the release of massive amounts of cytokines from these T-cells. 
  • Symptoms improve as EBV DNA levels in serum fall and the T-cell counts normalize. 

Clinical Presentation

  • In young children, EBV infection is often indistinguishable from other viral illnesses.  
  • Adolescents and adults usually manifest the classic signs and symptoms of IM: 
    -Fever: usually present for 1-3 weeks, ranging from 37.5-40.5 C
    -Tonsillopharyngitis: ranges from mild erythema to a very painful throat with thick, whitish exudate and swollen tonsils
    -Hepatosplenomegaly: may be associated with LLQ or LUQ abdominal pain
    -Fatigue: usually present for 8 weeks
    -Lymphadenopathy: cervical nodes are most often involved, but generalized LAD can occur; nodes tend to tender, firm and discrete
    -Rash: 3-15% of patients (not treated with penicillins, see "Ampicillin rash" below) develop a rash, which varies widely from patient-to-patient and has been described as described as petechial, macular, scarlatinoform, urticarial, vesicular, or erythema multiforme.

Diagnosis

  • Infectious mononucleosis is diagnosed based on the presence of typical signs and symptoms as well as a positive "monospot" test. The classic hematologic criteria, an absolute (>50%) and atypical (>10%) lymphocytosis, may be used when a monospot is not available. 
  • Documenting the presence of heterophile antibodies via the monospot test confirms an acute EBV infection. No further diagnositic tests are warranted. 
    -If initially negative, the heterophile antibody test may turn positive after 2-3 weeks.  Many patients with IM initially have a negative monospot test. 
    -Very young children will not produce heterophile antibodies, but modern tests are able to detect these antibodies in children as young as 4 years old.
    -The monospot may remain positive for up to 9 months after the intial infection. 
  • Patients with suspected EBV infection and a repeatedly negative monospot test may require further testing:
    -IgM to the viral capsid antigen (VCA): becomes positive when symptoms present and disappears after 4-8 weeks, indicating acute infection.
    -A PCR test for EBV DNA exists; this test is sensitive and specific for primary infection.

Treatment

  • Treatment is generally supportive.
  • Bedrest may be recommended as necessary, but there is no evidence that bedrest will hasten recovery or reduce complications. 
  • Contact sports (football, soccer, lacrosse, etc) and activities that could lead to rupture of the spleen (such as bike riding, gymnastics) must be avoided until the spleen is no longer palpable. 
  • Steroids rarely have a role in the treatment of IM, but may be required in the event of impending airway obstruction or severe thrombocytopenia. Treating moderately ill patients with steroids has not been linked to improved outcomes. 
  • Treatment with acyclovir does not affect the course of uncomplicated IM. 
  • With the exception of contact sports, the patient can return to their activities (school, work, and extracurriculars) when they feel ready.  Mononucleosis often occurs when teenagers are involved in important activities.  Let them participate if they feel up to it. 

Complications

  • Most individuals with IM recover completely after an uneventful course. Complications do occur, however, and some are significant. 
  • Ampicillin rash: Treatment with antibiotics (especially Ampicillin and Amoxicillin) has been linked to the development of rash in patients with IM. The rash varies, and has been described as petechial, macular, scarlatinoform, urticarial, and vesicular.  While originally believed to occur in nearly 100% of older IM patients treated with ampicillin, recent students of patients treated with amoxicillin suggest that the incidence of post-antibiotics rash is actually much lower. 
  • Prolonged fatigue and malaise: EBV was once thought to be linked to chronic fatigue syndrome, but more recent studies do not support this association.  Even so, some patients (<5%) do experience prolonged fatigue and malaise that may last for 3-4 months (in some cases, as long as 6 months).  
  • Airway obstruction secondary to lymphoid tissue proliferation is the most common reason for hospital admission in patients with IM. Treatment with steroids and respiratory support may be required in these cases. 
  • Splenic rupture occurs in 0.1% of cases of IM.  Interestingly, splenic rupture is not usually associated with significant abdominal trauma.
  • Neurologic complications occur in 5% of patients with IM. EBV has been implicated in almost every infection-related neurologic disorder. 
  • Hematologic complications in otherwise healthy patients include immune hemolytic anemia and immune thrombocytopenia. 
  • X-linked lymphoproliferative disease (XLP) patients may suffer significant complications (even death) from EBV infection.
  • EBV-Associated Hemophagocytic Lymphohistiocytosis (EBV-HLH) and Chronic Active EBV Infection (CAEBV) may result when EBV infiltrates into immune cells other than B cells (the etiology of these disorders remains unclear). Both disorders present with prolonged (>6 months) IM symptoms and can be fatal. 
  • B-cell Lymphoproliferative Disease (BLPD) occurs in about 10% of transplant recipients; risk is highest for those who experience an initial EBV infection while immunosuppressed-- thus, the incidence is highest in younger children.  The donor organ or marrow may be the source of infection. 
  • Burkitt Lymphoma (BL) is the most common tumor in young children in equatorial Africa; EBV is present in over 96% of these cases.  Severe EBV infection in the first few months of life increases the risk of BL. 
  • All undifferentiated Nasopharyngeal Carcinoma is associated with EBV.  Forms of Hodgkin Disease, T-Cell Lymphomas and Gastric Carcinomas have also been linked to EBV. The role the virus plays in the development of these types of cancers remains unclear. 

References

  1. John P and Ray CG. Infectious Mononucleosis. Pediatrics in Review. 1998; 19:276-279.
  2. Junker A. Epstein-Barr VirusPediatrics in Review. 2005; 26(79). 
  3. Luzuriaga K and Sullivan J. Infectious Mononucleosis. New England Journal of Medicine. 2010; 362(21). 
  4. Marshall BC and Foxworth MK.  EB Virus Associatied Infectious Mononucleosis. Contemporary Pediatrics. October 2012, pp 52-65. 
  5. Rimsza ME and Kirk GM. Common Medical Problems of the College StudentPediatric Clinics of North America. 2005; 52(1): 9-24. 
  6. Roy M. et al. Dexamethasone for the Treatment of Sore Throat in Childrn With Suspected Infectious Mononucleosis. Archives of Pediatric and Adolescent Medicine. 2004; 158.  
  7. Sella et al. Incidence of Rash After Amoxicillin Treatment in Children with Infectious Mononucleosis. Pediatrics. 2013; 131 e1424. 

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