Mononucleosis pathophysiology: Difference between revisions

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{{Mononucleosis}}
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==Overview==
==Overview==
Epstein-Barr virus, frequently referred to as [[EBV]], is a member of the herpesvirus family and one of the most common human viruses. '''''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.
Epstein-Barr virus, frequently referred to as [[EBV]], is a member of the [[herpes|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.
 
==Transmission==
*Transmission of [[EBV]] requires intimate contact with the saliva of an infected person.
 
*'''''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''''' (rare)
 
*Individuals in close living arrangements nearly always pass the infection onto each other, although symptoms may not present for months or even years.


==Pathophysiology==
==Pathophysiology==
*Following intimate contact with infected saliva, the [[EBV|virus]] infects [[B cells]] located in the oropharyngeal epithelium and subsequently spreads to involve the [[lymph nodes]], [[liver]] and [[spleen]].  
*Following intimate contact with infected saliva, the [[EBV|virus]] infects [[B cells]] located in the oropharyngeal epithelium and subsequently spreads to involve the [[lymph nodes]], [[liver]] and [[spleen]].  


*'''''Humoral response:''''' As with many viral infections, such as [[chicken pox]], [[antibody|antibodies]] to the viral antigens are developed with resultant recovery from acute illness.  
*Mononucleosis was so-named because the count of mononuclear leucocytes ([[white blood cells]] with a one-lobed nucleus) rises significantly.
:*In addition, these [[antibody|antibodies]] remain in the system for most individuals, creating a '''''lifelong immunity''''' to further infections.<ref>{{cite web |title=Mononucleosis -- Causes |url=http://www.emedicinehealth.com/mononucleosis/page2_em.htm |date=12/7/2007 |publisher=eMedicineHealth |accessdate=2008-03-01}}</ref>
:*There are two main types of mononuclear leucocytes: [[monocyte]]s and [[lymphocyte]]s.
:*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]], [[antibody|antibodies]] to the viral antigens are developed with resultant recovery from acute illness.  
:*In addition, these [[antibody|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.
:*Also, assessment of these specific antibodies forms the basis to diagnose mononucleosis in patients with atypical presentation or in heterophile negative cases.


*'''''Cellular response:'''''
*Cellular response:
:*Is required to control the proliferation of infected [[B cells]].
:*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]].
:*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]].
:*Ineffective cellular response results in excessive proliferation of [[B cells]] with resultant EBV-associated malignancies such as [[Burkitt's lymphoma]] and [[nasopharyngeal carcinoma]].


==Pathophysiology based on clinical presentation==
===Transmission===
===Intial Prodrome===
*Transmission of [[EBV]] requires intimate contact with the saliva of an infected person.  
*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===
*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.
*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===
*Modes of transmission include:
*After an initial prodrome, the [[fatigue]] of mononucleosis often lasts from 1-2 months.
:* 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


*The virus can remain dormant in the [[B cells]] indefinitely after symptoms have disappeared, and resurface at a later date.  
:* Blood transfusion is rare.


*Many people exposed to the [[EBV|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.  
*Individuals in close living arrangements nearly always pass the infection onto each other, although symptoms may not present for months or even years.


*This dormant feature combined with long (4 to 6 week) incubation period of the disease, makes epidemiological control of the disease impractical.
===Electron Microscopy===
 
===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 [[EBV|chronic EBV syndrome]] or [[chronic fatigue syndrome]].
 
*Although the most recent medical studies have discounted the link between [[EBV|chronic EBV infection]] and [[chronic fatigue syndrome]], some patients anecdotally report that chronic fatigue lasting for years after mononucleosis is part of a [[chronic fatigue syndrome|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 [[chronic fatigue syndrome|CFS]]. Also, some of this confusion may be attributed to the use of a new, broadened revision of the [[chronic fatigue syndrome|CFS research criteria]], which has been criticised as overly inclusive.
 
:*However, current studies suggest that '''''there is an association''''' between infectious mononucleosis and [[chronic fatigue syndrome|CFS]] <ref> 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
</ref>. Additionally, [[chronic fatigue syndrome|chronic fatigue states]] appear to occur in 10% of those who contract mononucleosis.<ref>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 </ref>
 
*While [[chronic fatigue syndrome|chronic fatigue]] may rather be a common side effect of infectious mononucleosis, it should be noted that [[chronic fatigue syndrome|CFS]] is more than [[fatigue|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 [[chronic fatigue syndrome|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 [[chronic fatigue syndrome|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 [[chronic fatigue syndrome|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.
 
==Electron microscopy==
[[image:Epstein Barr Virus virions EM 10.1371 journal.pbio.0030430.g001-L.JPG|Two Epstein-Barr [[Virion#Structure|virions]]|250px|left]]
[[image:Epstein Barr Virus virions EM 10.1371 journal.pbio.0030430.g001-L.JPG|Two Epstein-Barr [[Virion#Structure|virions]]|250px|left]]
<br clear="left"/>
<br clear="left"/>


==Microscopic pathology==
===Microscopic Pathology===
Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission. [http://www.peir.net © PEIR, University of Alabama at Birmingham, Department of Pathology]
Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission. [http://www.peir.net © PEIR, University of Alabama at Birmingham, Department of Pathology]


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==References==
==References==
{{reflist|2}}
{{Reflist|2}}


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Latest revision as of 18:06, 18 September 2017

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

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
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)

    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

  • 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: 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.

    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)

    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

    LYMPH NODE: INFECTIOUS MONONUCLEOSIS, LYMPH NODE

  • BLOOD: INFECTIOUS MONONUCLEOSIS; PERIPHERAL BLOOD

    BLOOD: INFECTIOUS MONONUCLEOSIS; PERIPHERAL BLOOD

  • EYE AND OCULAR ADNEXA: BURKITT LYMPHOMA Bilateral involvement.

    EYE AND OCULAR ADNEXA: BURKITT LYMPHOMA Bilateral involvement.

  • EYE AND OCULAR ADNEXA: BURKITT LYMPHOMA Lymphoblastic tumor with numerous mitotic figures.

    EYE AND OCULAR ADNEXA: BURKITT LYMPHOMA Lymphoblastic tumor with numerous mitotic figures.

References


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