Mononucleosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. [3]{{#meta: itemprop="medicalWebPageAudiences" content="patient"}}{{#meta: itemprop="medicalWebPageSpecialities" content="cardiology"}}{{#meta: itemprop="medicalWebPageInfoTypes" content="symptoms,diagnosis,treatment,causes,prognosis,complications"}} Classification Classic::Classification Atypical::

Overview

Mononucleosis Microchapters
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Patient Information
Overview
Pathophysiology
Epidemiology and Demographics
Risk Factors
Causes
Differentiating Mononucleosis from other Diseases
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Mononucleosis On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
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Images
American Roentgen Ray Society Images of Mononucleosis All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Mononucleosis
CDC on Mononucleosis
Mononucleosis in the news
Blogs on Mononucleosis
Directions to Hospitals Treating Mononucleosis
Risk calculators and risk factors for Mononucleosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]

Overview

Epstein-Barr virus, frequently referred to as EBV, is a member of the herpesvirus family and one of the most common human viruses.

Pathophysiology

Epstein-Barr virus, frequently referred to as EBV, is a member of the herpesvirus family that targets oro-pharyngeal epithelium and B cells. Transmission of the EBV through the air or blood does not normally occur. The incubation period, or the time from infection to appearance of symptoms, ranges from 4 to 6 weeks. Persons with infectious mononucleosis may be able to spread the infection to others for a period of weeks. However, no special precautions or isolation procedures are recommended, since the virus is also found frequently in the saliva of healthy people. In fact, many healthy people can carry and spread the virus intermittently for life. These people are usually the primary reservoir for person-to-person transmission. For this reason, transmission of the virus is almost impossible to prevent.

Epidemiology and Demographics

Majority of mononucleosis syndromes are caused by Epstein-Barr virus, and most people become infected with EBV sometime during their lives with an estimated 90%-95% of persons greater than 21 years of age demonstrating antibody to EBV. In the United States, the disease occurs most often among older children and young adults; however, in certain socioeconomically depressed areas the infection affects young children who remain asymptomatic. Additionally, the dormant feature combined with long (4 to 6 week) incubation period of the disease, makes epidemiological control of the disease impractical.

Risk Factors

Majority of the population become infected with EBV at sometime during their lives with an estimated 90%-95% of adults demonstrating seropositivity by 21 years of age. Therefore, even individuals exposed to infected contacts have shown to be previously infected with EBV and hence are not at risk for the manifestation of mononucleosis. However, once infected, the patient carries the virus for the rest of their life with the virus typically residing dormantly in the B lymphocytes. Independent infections of mononucleosis may be contracted multiple times, regardless of whether the patient is already carrying the virus dormantly. Periodic reactivation of the virus may occur, during which time the patient is again infectious, but usually without any symptoms of illness. Therefore, in susceptible hosts under the appropriate environmental stressors, reactivation of the virus occurs to cause vague subclinical symptoms or remain mostly asymptomatic and diagnosed only by a positive serologic response. However, its imperative to note that during this phase the virus can spread to others.

Causes

Epstein-Barr virus is ubiquitous across the globe and the strongest causative agent for the manifestation of infectious mononucleosis. Commonly, a person is first exposed to the virus during or after adolescence. Though once deemed "The Kissing Disease", recent research has shown that transmission of mononucleosis not only occurs from intimate contact with infected saliva, but also from contact with the airborne virus.

For more information on the virus, click here

Differentiating Mononucleosis from other Diseases

Acute mononucleosis, acute cytomegalovirus infection and toxoplasma gondii infection have similar clinical presentations. In addition, since their management is much the same, it is not always helpful, or possible, to distinguish between infectious mononucleosis and cytomegalovirus infection. However, in pregnant women, it is imperative to differentiate mononucleosis from toxoplasmosis as toxo is associated with significant consequences in the fetus. Acute HIV infection can also mimic signs similar to those of infectious mononucleosis, and tests should be performed in pregnant women for the same reason as toxoplasmosis.

Natural History, Complications and Prognosis

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.

Diagnosis

History and Symptoms

Symptoms of infectious mononucleosis are fever, sore throat, and swollen lymph glands. Sometimes, a splenomegaly or hepatomegaly may develop. Heart problems or involvement of the central nervous system occurs only rarely, and infectious mononucleosis is almost never fatal. There are no known associations between active EBV infection and problems during pregnancy, such as miscarriages or birth defects. 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.

Physical Examination

The classic initial presentation of mononucleosis include: fever, lymphadenopathy, pharyngitis, rash and/or periorbital oedema. Occasionally, patients infected with EBV may also display splenomegaly, with subsequent life-threatening complication of splenic rupture and/or hepatomegaly.

Laboratory Findings

In most cases of infectious mononucleosis, the clinical diagnosis can be made from the characteristic triad of fever, pharyngitis, and lymphadenopathy lasting for 1 to 4 weeks.

Other Imaging Findings

Direct and indirect evidence of persistent viral infection long after recovery from acute illness has been found in patients with chronic fatigue syndrome. This is possibly due to the activation of microglia during the acute infection phase in such individuals. Lumbar puncture, EEG, CT scan and/or MRI may help to evaluate such patients with presumable CNS involvement.

Other Diagnostic Studies

Bilateral tender lymphadenopathy, particularly, the posterior posterior cervical lymph nodes are characteristic of mononucleosis. Therefore, lymph node biopsy if done may reveal atypical lymphocytosis.

Treatment

Medical Therapy

Infectious mononucleosis is generally self-limiting and only symptomatic and/or supportive treatments are used. However, severe tonsillar enlargement may cause life-threatening airway obstruction and therefore, close monitoring of such high-risk patients is essential. Glucocorticoids may be indicated in such cases of severe airway obstruction. Acyclovir has been tried as they decrease oropharyngeal viral shedding. Recently, valacyclovir has shown to lower or eliminate the presence of the Epstein-Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms.

Surgery

Infectious mononucleosis is generally self-limiting and only symptomatic and/or supportive therapy may be required. However, in cases of life-threatening splenic rupture which may occur even without trauma, immediate surgery may be life-saving.

Primary Prevention

Majority of mononucleosis syndromes are caused by Epstein-Barr virus, and most people become infected with EBV sometime during their lives with an estimated 90-95% population aged more than 21 years demonstrate antibody to EBV. The transmission of the virus requires intimate contact with the saliva of an infected person and rarely occurs via air or blood. Therefore, the most reasonable way to prevent mono is to avoid close contact with infected saliva.

References

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Pathophysiology

Mononucleosis Microchapters
Home
Patient Information
Overview
Pathophysiology
Epidemiology and Demographics
Risk Factors
Causes
Differentiating Mononucleosis from other Diseases
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Mononucleosis On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Mononucleosis All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Mononucleosis
CDC on Mononucleosis
Mononucleosis in the news
Blogs on Mononucleosis
Directions to Hospitals Treating Mononucleosis
Risk calculators and risk factors for Mononucleosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]

Overview

Epstein-Barr virus, frequently referred to as EBV, is a member of the herpesvirus family that targets oro-pharyngeal epithelium and B cells. Transmission of the EBV through the air or blood does not normally occur. The incubation period, or the time from infection to appearance of symptoms, ranges from 4 to 6 weeks. Persons with infectious mononucleosis may be able to spread the infection to others for a period of weeks. However, no special precautions or isolation procedures are recommended, since the virus is also found frequently in the saliva of healthy people. In fact, many healthy people can carry and spread the virus intermittently for life. These people are usually the primary reservoir for person-to-person transmission. For this reason, transmission of the virus is almost impossible to prevent.

Pathophysiology

• Following intimate contact with infected saliva, the virus infects B cells located in the oropharyngeal epithelium and subsequently spreads to involve the lymph nodes, liver and spleen.

• Mononucleosis was so-named because the count of mononuclear leucocytes (white blood cells with a one-lobed nucleus) rises significantly.

• There are two main types of mononuclear leucocytes: monocytes and lymphocytes.
• Mononuclear leucocytes normally account for about 35% of all white blood cells and in patients infected with mononucleosis, this count can rise to 50-70%.
• In addition, the total white blood count may increase to 10,000-20,000 per cubic millimeter.

• Humoral response: As with many viral infections, such as chicken pox, antibodies to the viral antigens are developed with resultant recovery from acute illness.

• In addition, these antibodies remain in the system for most individuals, creating a lifelong immunity to further infections.
• Also, assessment of these specific antibodies forms the basis to diagnose mononucleosis in patients with atypical presentation or in heterophile negative cases.

• Cellular response:

• Is required to control the proliferation of infected B cells.
• This in turn, helps to terminate active EBV infection and also suppress future infections with EBV.
• Ineffective cellular response results in excessive proliferation of B cells with resultant EBV-associated malignancies such as Burkitt's lymphoma and nasopharyngeal carcinoma.

Transmission

• Transmission of EBV requires intimate contact with the saliva of an infected person.

• Typically, the disease is transmitted from asymptomatic individuals through blood or saliva (hence the kissing disease), or by sharing a drink, or sharing eating utensils. The disease is far less contagious than is commonly thought. In rare cases, a person may have a high resistance to infection.

• Modes of transmission include:

• Saliva

• Epstein-Barr virus (EBV) shed for up to 18 months after primary infection
• Intermittent viral shedding thereafter in asymptomatic sero-positive patients
• Increased viral shedding in immunocompromised patients

• Blood transfusion is rare.

• Individuals in close living arrangements nearly always pass the infection onto each other, although symptoms may not present for months or even years.

Electron Microscopy

Two Epstein-Barr virions

Microscopic Pathology

Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission. © PEIR, University of Alabama at Birmingham, Department of Pathology

• 
  BONE MARROW: INFECTION-ASSOCIATED HEMOPHAGOCYTIC SYNDROME A bone marrow aspirate smear from a child with infection-associated hemophagocytic syndrome secondary to an Epstein-Barr virus infection. On this field there are several large histiocytes. Phagocytosis of nucleated red blood cells, neutrophils, and platelets is evident. The histiocytes have the appearance of reactive cells and should be readily distinguishable from neoplastic histiocytes. (Wright-Giemsa stain)
• 
  LOWER RESPIRATORY TRACT: (Supplement) AIL/LYG CD20 staining (for B cells) in the viable tissue shows positive staining of scattered large lymphoid cells (C) which were also the cells that were positive for Epstein-Barr virus by in situ hybridization
• 
  LOWER RESPIRATORY TRACT: (Supplement) AIL/LYG CD20 staining (for B cells) in the viable tissue shows positive staining of scattered large lymphoid cells (C) which were also the cells that were positive for Epstein-Barr virus by in situ hybridization

• 
  LYMPH NODES-SPLEEN: EPSTEIN-BARR VIRUS-ASSOCIATED INFECTIOUS MONONUCLEOSIS A heterogeneous population is present, including cells mimicking Hodgkin cells. However, the spectrum of cell types and the extensive apoptosis present would not be found in Hodgkin's disease.
• 
  LYMPH NODES-SPLEEN: METASTATIC NASOPHARYNGEAL CARCINOMA IN LYMPH NODE PRESENTING AS METASTATIC CARCINOMA OF UNKNOWN PRIMARY Nuclear labeling of the carcinoma cells for Epstein-Barr virus-encoded RNA strongly suggests that the primary is nasopharyngeal.
• 
  BONE MARROW: REACTIVE (ATYPICAL) LYMPHOCYTES This blood smear is from a 19-year-old male college student with infectious mononucleosis. The two reactive (atypical) lymphocytes are large, with abundant cytoplasm and coarse nuclear chromatin, and lack a nucleolus. Cytoplasmic basophilia is radial in distribution and accentuated at the cell margin. In contrast, lymphoblasts are generally smaller, have less cytoplasm with uniform basophilia and more dispersed nuclear chromatin, and may contain a nucleolus. (Wright-Giemsa stain)

• 
  LYMPH NODE: INFECTIOUS MONONUCLEOSIS, LYMPH NODE
• 
  BLOOD: INFECTIOUS MONONUCLEOSIS; PERIPHERAL BLOOD
• 
  EYE AND OCULAR ADNEXA: BURKITT LYMPHOMA Bilateral involvement.
• 
  EYE AND OCULAR ADNEXA: BURKITT LYMPHOMA Lymphoblastic tumor with numerous mitotic figures.

References

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Epidemiology and Demographics

Mononucleosis Microchapters
Home
Patient Information
Overview
Pathophysiology
Epidemiology and Demographics
Risk Factors
Causes
Differentiating Mononucleosis from other Diseases
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Mononucleosis On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Mononucleosis All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Mononucleosis
CDC on Mononucleosis
Mononucleosis in the news
Blogs on Mononucleosis
Directions to Hospitals Treating Mononucleosis
Risk calculators and risk factors for Mononucleosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6]

Overview

Majority of mononucleosis syndromes are caused by Epstein-Barr virus, and most people become infected with EBV sometime during their lives with an estimated 90%-95% of persons greater than 21 years of age demonstrating antibody to EBV. In the United States, the disease occurs most often among older children and young adults; however, in certain socioeconomically depressed areas the infection affects young children who remain asymptomatic. Additionally, the dormant feature combined with long (4 to 6 week) incubation period of the disease, makes epidemiological control of the disease impractical.

Epidemiology and Demographics

Age

• In the United States, as many as 95% of adults between 35 and 40 years of age have been infected with approximately 50% of the population seroconverts during early childhood.

• Infants become susceptible to EBV as soon as maternal antibody protection which is present at birth starts to disappears.

• Children if infected with EBV usually remain asymptomatic and hence are indistinguishable from the other mild, brief illnesses of childhood. However, when the infection occurs during adolescence or young adulthood, it causes acute infectious mononucleosis 35% to 50% of the time.

Outbreaks

• True outbreaks of infectious mononucleosis are extremely rare.

• A substantial number of pseudo-outbreaks have been reported and linked to laboratory error.

References

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Risk Factors

Mononucleosis Microchapters
Home
Patient Information
Overview
Pathophysiology
Epidemiology and Demographics
Risk Factors
Causes
Differentiating Mononucleosis from other Diseases
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Mononucleosis On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Mononucleosis All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Mononucleosis
CDC on Mononucleosis
Mononucleosis in the news
Blogs on Mononucleosis
Directions to Hospitals Treating Mononucleosis
Risk calculators and risk factors for Mononucleosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [7]

Overview

A majority of the population is infected with EBV at sometime during their lives with an estimated 90%-95% of adults demonstrating seropositivity by 21 years of age. Therefore, even individuals exposed to infected contacts have shown to be previously infected with EBV and hence are not at risk for the manifestation of mononucleosis. However, once infected, the patient carries the virus for the rest of their life with the virus typically residing dormantly in the B lymphocytes. Independent infections of mononucleosis may be contracted multiple times, regardless of whether the patient is already carrying the virus dormantly. Periodic reactivation of the virus may occur, during which time the patient is again infectious, but usually without any symptoms of illness. Therefore, in susceptible hosts under the appropriate environmental stressors, reactivation of the virus occurs to cause vague subclinical symptoms or remain mostly asymptomatic and diagnosed only by a positive serologic response. However, its imperative to note that during this phase the virus can spread to others.

Risk Factors

By Epidemiology

• It is predominantly found in under-developed countries, and almost everyone is exposed to the ebstein barr virus by 18 months of age. Therefore, even individuals exposed to infected contacts are not at risk for the manifestation of the disease. Additionally, antibody to the virus is almost universally positive.

• In the United States, roughly half of five-year-olds have been infected and up to 95% of adults between 35 and 40 years of age.

By Age

• Infants become susceptible to EBV as soon as maternal antibody protection which is present at birth starts to disappears.

• Children if infected with EBV usually remain asymptomatic and hence are indistinguishable from the other mild, brief illnesses of childhood. However, when the infection occurs during adolescence or young adulthood, it causes acute infectious mononucleosis 35% to 50% of the time.

• Among adults, increased risk of acquiring mononucleosis is observed among:

• Adolescents and young adults
• Patients who have intimate contact with the saliva of an infected person
• Contact with the airborne virus

By Immune System Status

• Any condition that weakens the immune system is a predisposing factor for the development of mononucleosis secondary to EBV infection. Such states include:

• Diabetes
• Following solid organ transplant
• Chemotherapy
• HIV

By Genetic Susceptibility

• A recent twin study done to assess the genetic susceptibility to infectious mononucleosis demonstrated results compatible with a heritable contribution to the risk of acquiring mononucleosis.

References

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Causes

Mononucleosis Microchapters
Home
Patient Information
Overview
Pathophysiology
Epidemiology and Demographics
Risk Factors
Causes
Differentiating Mononucleosis from other Diseases
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Mononucleosis On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Mononucleosis All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Mononucleosis
CDC on Mononucleosis
Mononucleosis in the news
Blogs on Mononucleosis
Directions to Hospitals Treating Mononucleosis
Risk calculators and risk factors for Mononucleosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [8]

Overview

Epstein-Barr virus is ubiquitous across the globe and the strongest causative agent for the manifestation of infectious mononucleosis. Commonly, a person is first exposed to the virus during or after adolescence. Though once deemed "The Kissing Disease", recent research has shown that transmission of mononucleosis not only occurs from intimate contact with infected saliva, but also from contact with the airborne virus.

For more information on the virus, click here

Causes

Epstein-Barr Virus

• Epstein-Barr virus is ubiquitous across the globe and the strongest causative agent for the manifestation of infectious mononucleosis. Commonly, a person is first exposed to the virus during or after adolescence.

• Once the acute symptoms of an initial infection disappear, they often do not return. But once infected, the patient carries the virus for the rest of their life. The virus typically lives dormantly in B lymphocytes. Independent infections of mononucleosis may be contracted multiple times, regardless of whether the patient is already carrying the virus dormantly.

• Periodically, the virus can reactivate, during which time the patient is again infectious, but usually without any symptoms of illness. Usually, a patient has few, if any, further symptoms or problems from the latent B lymphocyte infection. However, in susceptible hosts under the appropriate environmental stressors, reactivation of the virus is observed and known to cause vague subclinical symptoms or remain mostly asymptomatic and is diagnosed by positive serologic response. Additionally, its imperative to note that during this phase the virus can spread to others.

• Similar such reactivation or chronic sub-clinical viral activity in susceptible hosts may trigger multiple host autoimmune diseases and cancers secondary to EBV's predilection to B lymphocytes (the primary antibody-producing cell of the immune system) and its ability to alter both lymphocyte proliferation and lymphocyte antibody production.

Burkitt's Lymphoma

• Burkitt's lymphoma is a type of Non-Hodgkin's lymphoma and is most common in the equatorial Africa.
• It is co-existent with the presence of malaria. Malarial infection is shown to reduce the immune surveillance of EBV immortalized B cells; thereby, allowing their proliferation which in turn increases the chance of a mutation to occur. Repeated such mutations lead to the escape of B cells from cell-cycle control and furthermore allow the cells to proliferate unchecked, resulting in the formation of Burkitt's lymphoma.
• Commonly affects the jaw bone, forming a huge tumor mass.
• Responds quickly to chemotherapy treatment, namely cyclophosphamide, but recurrence is common.

Nasopharyngeal Carcinoma

• Nasopharyngeal carcinoma is a cancer found in the upper respiratory tract, most commonly in the nasopharynx, and is linked to the EBV virus.
• Occurs secondary to both genetic and environmental factors
• Predominantly prevalent in Southern China and Africa. It is much more common in people of Chinese ancestry (genetic), but is also linked to the Chinese diet of a high amount of smoked fish, which contain nitrosamines, well known carcinogens (environmental).

Chronic Fatigue Syndrome

• In the late 1980s and early 1990s, EBV became the favored explanation for chronic fatigue syndrome. It was noted that people with chronic exhaustion had EBV, although it was also noted EBV was present in almost everyone.

• In a four year study, the Centers for Disease Control and Prevention found that the virus did not adhere to Koch's Postulates and therefore had no definitive association between CFS and EBV but it is still being studied by researchers.

• Majority of the chronic post-infectious fatigue state 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.

References

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Differential Diagnosis

Mononucleosis Microchapters
Home
Patient Information
Overview
Pathophysiology
Epidemiology and Demographics
Risk Factors
Causes
Differentiating Mononucleosis from other Diseases
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Mononucleosis On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Mononucleosis All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Mononucleosis
CDC on Mononucleosis
Mononucleosis in the news
Blogs on Mononucleosis
Directions to Hospitals Treating Mononucleosis
Risk calculators and risk factors for Mononucleosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [9]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [10]

Overview

Acute mononucleosis, acute cytomegalovirus infection and toxoplasma gondii infection have similar clinical presentations. In addition, since their management is much the same, it is not always helpful, or possible, to distinguish between infectious mononucleosis and cytomegalovirus infection. However, in pregnant women, it is imperative to differentiate mononucleosis from toxoplasmosis as toxo is associated with significant consequences in the fetus. Acute HIV infection can also mimic signs similar to those of infectious mononucleosis, and tests should be performed in pregnant women for the same reason as toxoplasmosis.

Differentiating Mononucleosis from Other Diseases

The table below summarizes the findings that differentiate Mononucleosis from other conditions that cause fever, fatigue, abdominal pain and diarrhea:

Disease	Findings
Ebola	Presents with fever, chills vomiting, diarrhea, generalized pain or malaise, and sometimes internal and external bleeding, that follow an incubation period of 2-21 days.
Typhoid fever	Presents with fever, headache, rash, gastrointestinal symptoms, with lymphadenopathy, relative bradycardia, cough and leucopenia and sometimes sore throat. Blood and stool culture can confirm the presence of the causative bacteria.
Malaria	Presents with acute fever, headache and sometimes diarrhea (children). A blood smears must be examined for malaria parasites. The presence of parasites does not exclude a concurrent viral infection. An antimalarial should be prescribed as an empiric therapy.
Lassa fever	Disease onset is usually gradual, with fever, sore throat, cough, pharyngitis, and facial edema in the later stages. Inflammation and exudation of the pharynx and conjunctiva are common.
Yellow fever and other Flaviviridae	Present with hemorrhagic complications. Epidemiological investigation may reveal a pattern of disease transmission by an insect vector. Virus isolation and serological investigation serves to distinguish these viruses. Confirmed history of previous yellow fever vaccination will rule out yellow fever.
Shigellosis & other bacterial enteric infections	Presents with diarrhea, possibly bloody, accompanied by fever, nausea, and sometimes toxemia, vomiting, cramps, and tenesmus. Stools contain blood and mucous in a typical case. A search for possible sites of bacterial infection, together with cultures and blood smears, should be made. Presence of leucocytosis distinguishes bacterial infections from viral infections.
Leukemia	Cancer of the blood or bone marrow and is characterized by an abnormal proliferation (production by multiplication) of blood cells, usually white blood cells (leukocytes). It is part of the broad group of diseases called hematological neoplasms.
Tonsillitis	Tonsillitis is characterized by signs of red, swollen tonsils which may have a purulent exudative coating of white patches (i.e. pus). In addition, there may be enlarged and tender neck cervical lymph nodes.
Pharyngitis	Typically characterized by sore throat, but commonly accompanied by fever, headache, joint pain and muscle aches, skin rashes, swollen lymph nodes in the neck, diphtheria and common cold.
Adenovirus infections	Commonly presents by a cold syndrome, pneumonia, croup and bronchitis.
Influenza	Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation but fever is also common early in the infection, with body temperatures as high as 39 °C (approximately 103 °F). Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worst in their backs and legs. Common symptoms of the flu such as fever, headaches, and fatigue come from the huge amounts of proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from influenza-infected cells. In contrast to the rhinovirus that causes the common cold, influenza does cause tissue damage, so symptoms are not entirely due to the inflammatory response.
Others	Leptospirosis, rheumatic fever, typhus, and mononucleosis can produce signs and symptoms that may be confused with Ebola in the early stages of infection.

The table below summarizes the findings that differentiate the rash in Mononucleosis from other conditions, such as:

Disease	Findings
[[Insect bite]]	In an insect bite, the insect injects formic acid, which can cause an immediate skin reaction often resulting in a rash and swelling in the injured area, often with formation of vesicles.
Kawasaki disease	Commonly presents with high and persistent fever, red mucous membranes in mouth, "strawberry tongue", swollen lymph nodes and skin rash in early disease, with peeling off of the skin of the hands, feet and genital area.
Measles	Commonly presents with high fever, coryza and conjunctivitis, with observation of oral mucosal lesions (Koplik's spots), followed by widespread skin rash.
Monkeypox	Presentation is similar to smallpox, although it is often a milder form, with fever, headache, myalgia, back pain, swollen lymph nodes, a general feeling of discomfort, and exhaustion. Within 1 to 3 days (sometimes longer) after the appearance of fever, the patient develops a papular rash, often first on the face. The lesions usually develop through several stages before crusting and falling off.
Rubella	Commonly presents with a facial rash which then spreads to the trunk and limbs, fading after 3 days, low grade fever, swollen glands, joint pains, headache and conjunctivitis. The rash disappears after a few days with no staining or peeling of the skin. Forchheimer's sign occurs in 20% of cases, and is characterized by small, red papules on the area of the soft palate.
Atypical measles	Symptoms commonly begin about 7-14 days after infection and present as fever, cough, coryza and conjunctivitis. Observation of Koplik's spots is also a characteristic finding in measles.
Coxsackievirus	The most commonly caused disease is the Coxsackie A disease, presenting as hand, foot and mouth disease. It may be asymptomatic or cause mild symptoms, or it may produce fever and painful blisters in the mouth (herpangina), on the palms and fingers of the hand, or on the soles of the feet. There can also be blisters in the throat or above the tonsils. Adults can also be affected. The rash, which can appear several days after high temperature and painful sore throat, can be itchy and painful, especially on the hands/fingers and bottom of feet.
Acne	Typical of teenagers, usually appears on the face and upper neck, but the chest, back and shoulders may have acne as well. The upper arms can also have acne, but lesions found there are often keratosis pilaris, not acne. The typical acne lesions are comedones and inflammatory papules, pustules, and nodules. Some of the large nodules were previously called "cysts"
Syphilis	Commonly presents with generalized systemic symptoms such as malaise, fatigue, headache and fever. Skin eruptions may be subtle and asymptomatic. It is classically described as 1) non-pruritic bilateral symmetrical mucocutaneous rash; 2) non-tender regional lymphadenopathy; 3) condylomata lata; and 4) patchy alopecia.
Molluscum contagiosum	Lesions are commonly flesh-colored, dome-shaped, and pearly in appearance. They are often 1-5 millimeters in diameter, with a dimpled center. Generally not painful, but they may itch or become irritated. Picking or scratching the lesions may lead to further infection or scarring. In about 10% of the cases, eczema develops around the lesions. They may occasionally be complicated by secondary bacterial infections.
Mononucleosis	Common symptoms include low-grade fever without chills, sore throat, white patches on tonsils and back of the throat, muscle weakness and sometime extreme fatigue, tender lymphadenopathy, petechial hemorrhage and skin rash.
Toxic erythema	Common rash in infants, with clustered and vesicular appearance.
Rat-bite fever	Commonly presents with fever, chills, open sore at the site of the bite and rash, which may show red or purple plaques.
Parvovirus B19	The rash of fifth disease is typically described as "slapped cheeks," with erythema across the cheeks and sparing the nasolabial folds, forehead, and mouth.
Cytomegalovirus	Common symptoms include sore throat, swollen lymph nodes, fever, headache, fatigue, weakness, muscle pain and loss of appetite.
Scarlet fever	Commonly includes fever, punctate red macules on the hard and soft palate and uvula (Forchheimer's spots), bright red tongue with a "strawberry" appearance, sore throat and headache and lymphadenopathy.
Rocky Mountain spotted fever	Symptoms may include maculopapular rash, petechial rash, abdominal pain and joint pain.
Stevens-Johnson syndrome	Symptoms may include fever, sore throat and fatigue. Commonly presents ulcers and other lesions in the mucous membranes, almost always in the mouth and lips but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children. A rash of round lesions about an inch across, may arise on the face, trunk, arms and legs, and soles of the feet, but usually not on the scalp.
Varicella-zoster virus	Commonly starts as a painful rash on one side of the face or body. The rash forms blisters that typically scab over in 7-10 days and clears up within 2-4 weeks.
Chickenpox	Commonly starts with conjunctival and catarrhal symptoms and then characteristic spots appearing in two or three waves, mainly on the body and head, rather than the hands, becoming itchy raw pox (small open sores which heal mostly without scarring). Touching the fluid from a chickenpox blister can also spread the disease.
Meningococcemia	Commonly presents with rash, petechiae, headache, confusion, and stiff neck, high fever, mental status changes, nausea and vomiting.
Rickettsialpox	First symptom is commonly a bump formed by a mite-bite, eventually resulting in a black, crusty scab. Many of the symptoms are flu-like including fever, chills, weakness and muscle pain but the most distinctive symptom is the rash that breaks out, spanning the person's entire body.
Meningitis	Commonly presents with headache, nuchal rigidity, fever, petechiae and altered mental status.
Impetigo	Commonly presents with pimple-like lesions surrounded by erythematous skin. Lesions are pustules, filled with pus, which then break down over 4-6 days and form a thick crust. It's often associated with insect bites, cuts, and other forms of trauma to the skin.

Pharyngitis vs EBV

• EBV infection may cause either exudative or non-exudative pharyngitis and both of which is colonized by streptococcus pyogens present in the oropharynx

• Petechial hemorrhages present in the posterior oropharynx are characteristic of infectious mononucleosis

• Edema of the uvula is rare but if present differentiates mononucleosis from all other types of pharyngitis

Infectious mononucleosis should be differentiated from other diseases that cause runny nose, cough, and constitutional symptoms.

Disease	History	Physical examination	Laboratory or radiological findings
Acute viral nasopharyngitis	Symptoms start with sore throat, nasal congestion, and runny nose. Cough that may persist after resolution of the other symptoms. Fever is not common.	Nasal mucosa is congested and hyperemic. Pharynx is typically normal.	Diagnosis is usually clinical; lab tests are rarely needed. The virus can be cultured on human lung cells, but it takes time. PCR is rapid and accurate, but is done only when the infecting virus strain in immunocompromised patients needs to be known.
Allergic rhinitis	Characterized by repeated paroxysms of rhinorrhea, sneezing, and cough. Symptoms may be related to a specific season of the year, hence the name “seasonal allergies.”	Rhinorrhea discharge is usually clear and watery. Examination of the nose reveals a crease below the nasal bridge, formed from repeated pulling of the nose secondary to irritation. Edema in the area below the eye, if associated conjunctivitis is present.	Skin testing using intradermal skin prick tests to determine the specific allergens causing allergic rhinitis. Serum immune assays to determine IgE levels in the serum.
Acute sinusitis	Presents with symptoms similar to URTIs (sneezing, cough, and runny nose). Symptoms last for a longer time (about 10 days), with a peak between the 4th and 6th days. Usually, acute sinusitis is not associated with fever.	Inspection may show erythema and edema over the involved sinus. Palpation of sinuses shows tenderness. Transillumination of the sinuses may show opacity.	X-ray and CT may show air fluid level or bubbles in the affected sinuses. Culture of the nasal secretions is of limited use in acute sinusitis, as may be contaminated by nasal flora.
Infectious mononucleosis	Symptoms are like the symptoms of pharyngitis, which include: Sore throat and difficulty swallowing Fever Fatigue Lymphadenopathy (especially in the posterior cervical region)	Abdominal examination reveals splenomegaly. Maculopapular rash may be present.	Positive monospot test. Elevated liver enzymes.

Cytomegalovirus vs EBV

• Almost all cases of mononucleosis are caused by the EBV; however, cytomegalovirus can produce a similar symptoms but milder and with less throat pain and no rash.

• Extreme fatigue, bilateral supra-orbital edema, tender bilateral lymphadenopathy, splenomegaly, elevated liver function tests are characteristic of mononucleosis and may or may not be present in cytomegalovirus infections.

• Although, due to the presence of the atypical lymphocytes on the blood smear in both conditions, some physicians confusingly used to include both infections under the diagnosis of "mononucleosis," though EBV is by definition the infection that must be present for this illness.

• An elevated antibody (IgM) titer specific for CMV helps to differentiate it from EBV infection

Toxoplasmosis vs EBV

• In pregnant women, it is imperative to differentiate mononucleosis from toxoplasmosis as toxo is associated with significant consequences in the fetus.

• In contrast to tender bilateral lymphadenopathy observed in patients with mononucleosis, toxo causes unilateral lymphadenopathy.

• In addition, normal to moderately elevated white blood cell count, particularly the number of lymphocytes is observed with mononucleosis; while, in patients infected with toxo, the white blood cell count is typically normal.

Viral Hepatitis vs EBV

• Liver function tests may show a moderate elevation of liver enzyme levels in nearly 90% of patients infected with mononucleosis. On the contrary, there is a significant increase in enzyme levels observed in patients with viral hepatitis.

References

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Natural History, Complications & Prognosis

Natural History

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Overview

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.

Recovery

• 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.

Reactivation

• 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

• The course of the disease can also be chronic with symptoms lasting for months or years. This variant of mononucleosis has been referred to as chronic EBV syndrome or chronic fatigue syndrome.

• Although the most recent medical studies have discounted the link between chronic EBV infection and chronic fatigue syndrome, some patients anecdotally report that chronic fatigue lasting for years after mononucleosis is part of a CFS.

• 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. Additionally, chronic fatigue states appear to occur in 10% of those who contract mononucleosis.

• 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.

Complications

• 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:

• Guillain-Barre syndrome
• Meningitis
• Seizures
• Temporary facial paralysis (Bell's palsy)
• Uncoordinated movements (ataxia)

• Secondary bacterial throat infection
• Spleen rupture (rare; avoid pressure on the spleen)

Prognosis

• 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.

References

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Complications

Overview

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.

Complications

Rare fatal complications

• Severe hepatitis
• Splenic rupture
• Airway obstruction secondary to adenopathy

Non-fatal complications

Uncommon, non-fatal complications exist, including various forms of CNS and hematological affection.

• Hematological:

• Autoimmune hemolytic anemia indicated by a positive direct Coombs test
• Thrombocytopenia
• Granulocytopenia
• Splenic rupture which may occur without trauma, but impact to the spleen also adds as a contributing factor.

• Neurological:

• Cranial nerve palsies (Bell's palsy)
• Encephalitis
• Meningitis
• Hemiplegia
• Transverse myelitis
• EBV infection has also been proposed as a risk factor for the development of multiple sclerosis(MS) , but this has not been affirmed.

• Cardiology:

• Pericarditis
• Myocarditis

• Hepatology:

• Hepatitis causing elevation of serum bilirubin (in approximately 40% of patients)

References

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Prognosis

Overview

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.

Prognosis

• Once the acute symptoms of an initial infection disappear, they often do not return. But once infected, the patient carries the virus for the rest of their life. The virus typically lives dormantly in B lymphocytes. Independent infections of mononucleosis may be contracted multiple times, regardless of whether the patient is already carrying the virus dormantly.

• Periodically, the virus can reactivate, during which time the patient is again infectious, but usually without any symptoms of illness. Usually, a patient has few, if any, further symptoms or problems from the latent B lymphocyte infection. However, in susceptible hosts under the appropriate environmental stressors, reactivation of the virus is observed and known to cause vague subclinical symptoms or remain mostly asymptomatic and is diagnosed by positive serologic response. Additionally, its imperative to note that during this phase the virus can spread to others.

• Similar such reactivation or chronic sub-clinical viral activity in susceptible hosts may trigger multiple host autoimmune diseases and cancers secondary to EBV's predilection to B lymphocytes (the primary antibody-producing cell of the immune system) and its ability to alter both lymphocyte proliferation and lymphocyte antibody production.

• Commonly caused autoimmune diseases include:

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Sjogren's syndrome
• Antiphospholipid antibody syndrome
• Multiple sclerosis

• Chronic immunologic stimulation by the virus, particularly causes lymphoma including:

• Nasopharyngeal carcinomas
• Burkitt's lymphoma
• Hodgkin's lymphoma

Mortality & Morbidity

• Fatalities from mononucleosis are extremely rare in developed nations.

• However, potential mortal complications include:

• Bacterial superinfections,
• Splenic rupture,
• Hepatic failure secondary to extensive hepatic necrosis caused by proliferation of EBV,
• Development of viral myocarditis,
• Post transplant lymphoproliferative disorder (PTLD) secondary to EBV infection has emerged as a significant cause of morbidity & mortality in solid organ transplant recipients.

References

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Diagnosis

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Treatment

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