Mononucleosis
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| Infectious mononucleosis Classification and external resources | |
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| Infectious Mononucleosis smear showing reactive (atypical) lymphocytes, in blue. | |
| ICD-10 | B27. |
| ICD-9 | 075 |
| DiseasesDB | 4387 |
| MedlinePlus | 000591 |
| eMedicine | emerg/319 med/1499 ped/705 |
| MeSH | D007244 |
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Overview
Infectious mononucleosis, also known as kissing disease, or Pfeiffer's disease, in North America as mono and more commonly known as glandular fever in other English-speaking countries. It occurs most commonly in adolescents and young adults, where it is characterized by fever, sore throat, muscle soreness, and fatigue. Infectious Mononucleosis typically produces a very mild illness in small children, but is usually asymptomatic. Mononucleosis is caused by the Epstein-Barr virus (EBV), which infects B cells (B-lymphocytes), producing a reactive lymphocytosis and atypical T cells (T-lymphocytes) known as Downey bodies.
The name comes because the number of mononuclear leukocytes (white blood cells with a one-lobed nucleus) rises significantly. There are two main types of mononuclear leukocytes: monocytes and lymphocytes. Normal blood values are 35% of all white blood cells. With infectious mononucleosis, this can rise to 50-70%. Also, the total white blood count may increase to 10,000-20,000 per cubic millimeter (normally 4,000-11,000).
Epidemiology and Demographics
Mononucleosis is typically 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.
The disease is 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. They normally account for about 35% of all white blood cells. With infectious mononucleosis, this can rise to 50-70%. Also, the total white blood count may increase to 10,000-20,000 per cubic millimeter.
Pathophysiology & Etiology
Transmission
- Saliva
- Epstein-Barr virus (EBV) shed for up to 18 months after primary infection
- Intermittent viral shedding thereafter in asymptomatic sero+ patients
- Increased viral shedding in immunocompromised patients
- Blood transfusion (rare)
Mononucleosis is typically transmitted from asymptomatic individuals through saliva, earning it the name "the kissing disease", or by sharing a drink, or sharing eating utensils. It may also be transmitted through blood. Individuals in close living arrangements nearly always pass the infection onto each other, although symptoms may not present for months or even years. As with many viral infections, such as chicken pox, antibodies are developed by individuals who become infected with the disease and recover. In most individuals, these antibodies remain in their system, creating lifelong immunity to further infections.[1]
Diagnosis
History and Symptoms
Symptoms
- Fever—this varies from mild to severe, but is seen in nearly all cases.
- Tender and enlarged/swollen lymph nodes—particularly the posterior cervical lymph nodes.
- Sore throat—White patches on the tonsils and back of the throat are often seen
- Muscle weakness and Mental fatigue (sometimes extreme)
Some patients also display:
- Enlarged spleen (splenomegaly, which may lead to rupture) and/or liver (hepatomegaly)
- Petechial hemorrhage
- Abdominal pain - a possible symptom of a potentially fatal rupture of the spleen.[1]
- Aching muscles
- Headache
- Loss of appetite
- Depression
- Skin rash
- Diarrhea
- Dizziness or disorientation
- Uncontrolled shaking at times
- Unable to swallow due to enlarged tonsils
- Dry cough
- Supra-orbital oedema—the eyes become puffy and swollen—may occur in the early stages of infection
After an initial prodrome of 1-2 weeks, the fatigue of infectious 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 Epstein-Barr virus do not show symptoms of the disease, but carry the virus. This is especially true in children, in whom infection seldom causes more than a very mild cold which often goes undiagnosed. Children are typically just carriers of the disease. This feature, along with mono's long (4 to 6 week) incubation period, makes epidemiological control of the disease impractical. About 6% of people who have had infectious mononucleosis will relapse.
Mononucleosis can cause the spleen to swell. Rupture may occur without trauma, but impact to the spleen is also a factor. Other complications include hepatitis (inflammation of the liver) causing elevation of serum bilirubin (in approximately 40% of patients), jaundice (approximately 5% of cases), and anemia (a deficiency of red blood cells). In rare cases, death may result from severe hepatitis or splenic rupture.
Usually, the longer the infected person experiences the symptoms, the more the infection weakens the person's immune system, and hence the longer s/he will need to recover. 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.
Although all cases of mononucleosis are caused by the E.B. virus, cytomegalovirus can produce a similar illness, usually with less throat pain. 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. Symptoms similar to those of mononucleosis can be caused by adenovirus, acute HIV infection and the protozoan Toxoplasma gondii.
Atypical presentations of mononucleosis/EBV infection
In small children, the course of the disease is frequently asymptomatic. The course of the disease can also be chronic. Some patients suffer fever, tiredness, lassitude (abnormal fatigue), depression, lethargy, and chronic lymph node swelling, 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 (CFS). In case of a weakening of the immune system, a reactivation of the Epstein-Barr Virus is possible; in CFS there is evidence of immune activation also.
Although studies conducted by the CDC and others have discounted a link between EBV and CFS, some patients anecdotally report that chronic fatigue lasting for years after mono 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. Current studies suggest there is an association between infectious mononucleosis and CFS [1]. "Chronic fatigue states" appear to occur in 10% of those who contract mononucleosis[1] Some confusion here may be due to the use of a new, broadened revision of the CFS research criteria, which has been criticised as overly inclusive. Although chronic fatigue may then be a rather 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 (see "Mortality/morbidity" below). Additionally some CFS patients do not describe fatigue as their worst problem.
Perhaps a 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
Physical Examination
Appearance of the Patient
Skin
- Jaundice may be present in some cases
Eyes
- Supra-orbital oedema—the eyes become puffy and swollen—may occur in the early stages of infection
Ear Nose and Throat
- White patches on the tonsils and back of the throat are often seen
- Tender and enlarged/swollen lymph nodes—particularly the posterior cervical lymph nodes, on both sides of the neck.
Abdomen
- * Enlarged spleen (splenomegaly, which may lead to rupture) and/or liver (hepatomegaly)
Genitourinary
- Enlarged prostate
Laboratory Findings
Mononucleosis causes so-called heterophile antibodies, which cause agglutination (sticking together) of non-human red blood cells, to appear in the patient's blood. The monospot is a non-specific test that screens for mononucleosis by looking for these antibodies. Confirmation of the exact etiology can be obtained through tests to detect specific antibodies to the causative viruses. The spot test may be negative in the first week, so negative tests are often repeated at a later date. Since the spot test is usually negative in children less than 6-8 years old, an EBV serology test should be done on them if mononucleosis is suspected. An older test for heterophile antibodies is the Paul-Bunnell test, in which the patient's serum is mixed with sheep red blood cells and checked for agglutination of these cells.
- Heterophile Antibody (AB)
- ABs reactive against sheep (and horse) red bloood cells (rbcs)
- Present in 90-95% of adults with mono
- Negative in 10-15% during 1st week of illness
- Detectable up to 1 year after initial symptoms
- Heterophile titer or monospot = diagnostic test of choice*
- Atypical Lymphocytosis
- >10% atypical lymphs
- Present in ~ 75%
- Other Findings
- Mild polyclonal increase in immunoglobin G (IgG), IgM, IgA
- Transaminitis
- Specific Tests
- For use only in atypical or heterophile negative cases
| AB | Time of Appearance | Persistence | % Patients + |
| VCA-IgM | At Clinical Presentation | 1-3 Months | 100% |
| VCA-IgG | At Clinical Presentation | Lifelong | 100% |
| EA IgG | Peak 3-4 Weeks After Onset | 3-6 Months | 70% |
| EBNA IgG | 6-12 Weeks After Onset | Lifelong | 100% |
If a patient has a positive mono test, an increased number of white blood cells, reactive lymphocytes, and symptoms of mononucleosis, then they will be diagnosed with infectious mononucleosis. If symptoms and reactive lymphocytes are present but the mono test is negative, then it may be too early to detect the heterophile antibodies or the affected patient may be in the small number of people who do not make heterophile antibodies. Other EBV antibodies and/or a repeat mono test may be performed to help confirm or rule out the mononucleosis diagnosis.[1]
Common Tests for Mononucleosis Include:[1][1]
- A monospot test - Heterophile antibodies are present in about 80%-90% of people with mono. They form in response to infection with Epstein-Barr virus as well as in other infections. It is important to note that:
- This test result is frequently false negative in young children or early in the course of the disease.
- The qualitative heterophile antibody test (Monospot) gives either a positive or negative result. The monospot test is 70-92% sensitive and 96-100% specific.[1] This test is commercially-available, takes minutes to perform and provides rapid results.
- Epstein-Barr virus specific antibody testing may be used for people with suspected mononucleosis who have heterophile antibody test results that are negative. It can also be used to test for atypical cases of mononucleosis or in young children who are suspected of having mononucleosis.
- Epstein-Barr virus antigen by immunofluorescence
- Epstein-Barr virus antibody titers - to help distinguish acute infection from past infection with EBV
- Early antigen
- Viral capsid antigen
- Epstein-Barr nuclear antigen
- A complete blood count with differential
- The total white blood cell count may to be high because of the infection.
- The presence of atypical lymphocytes (often recorded by automated blood analyser machines as an increase in the monocycte count) is characteristic of EBV infection.
- Elevation of the lymphocycte count above 35% of the total white cell count has a specificity of 100% and a sensitivity of 90% for the detection of glandular fever.[1]
- Liver function tests - These may show an elevation of liver enzyme levels in nearly 90% of people with mono.
Risk Stratification and Prognosis
Complications
- Heme
- Autoimmune hemolytic anemia
- Thrombocytopenia
- Granulocytopenia
- Splenic rupture
- Neuro
- Cranial nerve palsies (Bell’s palsy)
- Encephalitis
- Liver
- Cardiac
- Respiratory
- Airway obstruction (adenopathy)
Fatalities from mononucleosis are near impossible in developed nations.
Uncommon, nonfatal complications exist, including various forms of CNS and hematological affection:
- CNS: Meningitis, encephalitis, hemiplegia and transverse myelitis. EBV infection has also been proposed as a risk factor for the development of multiple sclerosis (MS)[1], but this has not been affirmed.
- Hematologic: EBV can cause autoimmune hemolytic anemia (direct Coombs test is positive) and various cytopenias.
Treatment
- Supportive
- No contact sports for 6-8 weeks
Infectious mononucleosis is generally self-limiting and only symptomatic and/or supportive treatments are used.[1] Rest is recommended during the acute phase of the infection, but activity should be resumed once acute symptoms have resolved. Nevertheless heavy physical activity and contact sports should be avoided to abrogate the risk of splenic rupture, for at least one month following initial infection and until splenomegaly has resolved, as determined by ultrasound scan.[1]
In terms of pharmacotherapies, acetaminophen/paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) may be used to reduce fever and pain – aspirin is not used due to the risk of Reye's syndrome in children and young adults. Intravenous corticosteroids, usually hydrocortisone or dexamethasone, are not recommended for routine use[1] but may be useful if there is a risk of airway obstruction, severe thrombocytopenia, or hemolytic anemia.[1][1]
There is little evidence to support the use of aciclovir, although it may reduce initial viral shedding.[1] However, the antiviral drug valacyclovir has recently been 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. [1][1][1] Antibiotics are not used as they are ineffective against viral infections. The antibiotics amoxicillin and ampicillin are contraindicated in the case of any coinciding bacterial infections during mononucleosis because their use can frequently precipitate a non-allergic rash. In a small percentage of cases, mononucleosis infection is complicated by co-infection with streptococcal infection in the throat and tonsils (strep throat). Penicillin or other antibiotics (with the exception of the two mentioned above) should be administered to treat the strep throat. Opioid analgesics are also contraindicated due to risk of respiratory depression.[1]
Pharmacotherapy
- Acyclovir decreases oropharyngeal viral shedding, but no clinical benefit
- Glucocorticoids indicated only if:
- Airway obstruction
- Severe autoimmune hemolytic anemia (AIHA)
- Severe thrombocytopenia
References
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
