Mononucleosis natural history

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Fatalities from mononucleosis are extremely rare in developed nations. However, chronic sub-clinical infection may persist secondary to the dormant virus within the B cells. Reactivation of the virus may occur in susceptible hosts under the appropriate environmental stressors. Similar such reactivation or chronic sub-clinical viral activity in susceptible hosts may trigger multiple host autoimmune diseases and cancers secondary to virus predilection to B lymphocytes and its ability to alter both lymphocyte proliferation and lymphocyte antibody production.

Natural History

Acute Infection

  • Following the invasion of B cells by EBV there is a resultant acute elevation of cytokines which forms the background for the initial manifestation of disease which lasts for a week or two.


  • Usually, the longer the infected person remains symptomatic, the more the infection weakens the person's immune system, and hence the longer time is required to recover.

Dormant Infection

  • After an initial prodrome, the fatigue of mononucleosis often lasts from 1-2 months.
  • The virus can remain dormant in the B cells indefinitely after symptoms have disappeared, and resurface at a later date.
  • Many people exposed to the virus do not show symptoms of the disease, but remain carriers of the disease. This is especially true in children, in whom infection seldom causes more than a very mild cold which often goes undiagnosed.
  • This dormant feature combined with long (4 to 6 week) incubation period of the disease, makes epidemiological control of the disease impractical.


  • Approximately 6% of patients with prior infection have reported relapse.
  • Cyclical reactivation of the virus, although rare in healthy people, is often a sign of immunological abnormalities in the small subset of organic disease patients in which the virus is active or reactivated.
  • In case of a weak immune system, there is a possibility of EBV reactivation; consistent with the evidence of immune activation observed in patients with chronic fatigue syndrome.

Chronic Infection

  • This confusion seems to lie in the nature of the link (note: any association does not prove or disprove causality) and possible misapprehension as to the syndromic nature of CFS. Also, some of this confusion may be attributed to the use of a new, broadened revision of the CFS research criteria, which has been criticised as overly inclusive.
  • However, current studies suggest that there is an association between infectious mononucleosis and CFS. [1] Additionally, chronic fatigue states appear to occur in 10% of those who contract mononucleosis.[2]
  • While chronic fatigue may rather be a common side effect of infectious mononucleosis, it should be noted that CFS is more than chronic fatigue, requiring at least four other symptoms, and a number of findings have been published which are not typical of EBV infection, although some complications may be shared. Additionally some CFS patients do not even describe fatigue as their worst problem.
  • Majority of chronic post-infectious fatigue states appear not to be caused by a chronic viral infection, but be triggered by the acute infection.
  • Direct and indirect evidence of persistent viral infection has been found in CFS, for example in muscle and via detection of an unusually low molecular weight RNase L enzyme, although the commonality and significance of such findings is disputed.
  • Hickie et al, contend that mononucleosis appears to cause a hit and run injury to the brain in the early stages of the acute phase, thereby causing the chronic fatigue state. This would explain why in mononucleosis, fatigue very often lingers for months after the Epstein Barr Virus has been controlled by the immune system.
  • However, it has also been noted in several (although altogether rare) cases that the only "symptom" displayed by a mononucleosis sufferer is elevated moods and higher energy levels, virtually the opposite of CFS and comparable to hypomania.
  • Just how infectious mononucleosis changes the brain and causes fatigue (or lack thereof) in certain individuals remains to be seen. Such a mechanism may include activation of microglia in the brain of some individuals during the acute infection, thereby causing a slowly dissipating fatigue.


  • Death in persons with weakened immune systems
  • Hemolytic anemia
  • Hepatitis with jaundice (more common in patients older than 35)
  • Inflammation of the testicles (orchitis)
  • Neurological complications (rare), including:


  • Although the symptoms of infectious mononucleosis usually resolve in 1 or 2 months, EBV remains dormant or latent in a few cells in the throat and blood for the rest of the person's life. Periodically, the virus can reactivate and is commonly found in the saliva of infected persons. This reactivation usually occurs without symptoms of illness.
  • EBV also establishes a lifelong dormant infection in some cells of the body's immune system. A late event in a very few carriers of this virus is the emergence of Burkitt's lymphoma and nasopharyngeal carcinoma, two rare cancers that are not normally found in the United States. EBV appears to play an important role in these malignancies, but is probably not the sole cause of disease.
  • Symptoms related to infectious mononucleosis caused by EBV infection seldom last for more than 4 months. When such an illness lasts more than 6 months, it is frequently called chronic EBV infection. However, valid laboratory evidence for continued active EBV infection is seldom found in these patients. The illness should be investigated further to determine if it meets the criteria for chronic fatigue syndrome. This process includes ruling out other causes of chronic illness or fatigue.


  1. Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study BMJ. 2006 Sep 16;333(7568):575
  2. Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006 Sep 16;333(7568):575

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