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EBV infectious mononucleosis
Classification and external resources
Infectious mononucleosis, peripheral smear, high power showing reactive lymphocytes
ICD-10	B27.0
ICD-9	075
DiseasesDB	4387
MedlinePlus	000591
eMedicine	emerg/319 med/1499 ped/705
MeSH	D007244

Infectious mononucleosis (IM; also known as EBV infectious mononucleosis, Pfeifer's disease, Filatov's disease^[1] and sometimes colloquially as the kissing disease from its oral transmission or simply as mono in North America and as glandular fever in other English-speaking countries) is an infectious, widespread viral disease caused by the Epstein–Barr virus (EBV), one type of herpes virus, to which more than 90% of adults have been exposed.^[2] Occasionally, the symptoms can recur at a later period.^[3] Most people are exposed to the virus as children, when the disease produces no noticeable or only flu-like symptoms. In developing countries, people are exposed to the virus in early childhood more often than in developed countries. As a result, the disease in its observable form is more common in developed countries. It is most common among adolescents and young adults.^[4]

Especially in adolescents and young adults, the disease is characterized by fever, sore throat and fatigue, along with several other possible signs and symptoms. It is primarily diagnosed by observation of symptoms, but suspicion can be confirmed by several diagnostic tests.

The syndrome was described as an infectious process by Nil Filatov in 1887 and independently by Emil Pfeiffer in 1889.^[5][6][1]

Signs and symptoms[link]

Main symptoms of IM^[7][8][9]

The classic symptoms of mononucleosis are a sore throat, fever, fatigue, malaise, pharyngeal inflammation, vomiting, petechiae and loss of appetite. Common signs include lymphadenopathy (enlarged lymph nodes), splenomegaly (enlarged spleen), hepatitis (refers to inflammation of hepatocytes—cells in the liver) and hemolysis (the bursting of red blood cells). Older adults are less likely to have a sore throat or lymphadenopathy, but are instead more likely to present with hepatomegaly (enlargement of the liver) and jaundice. Rarer signs and symptoms include thrombocytopenia (lower levels of platelets), with or without pancytopenia (lower levels of all types of blood cells), splenic rupture, splenic hemorrhage, upper airway obstruction, pericarditis and pneumonitis. Another rare manifestation of mononucleosis is erythema multiforme.^[10][11]

Mononucleosis is sometimes accompanied by secondary cold agglutinin disease, an autoimmune disease, in which abnormal circulating antibodies directed against red blood cells can lead to a form of autoimmune hemolytic anemia. The cold agglutinin detected is of anti-i specificity.^[12][13] Patients with infectious mononucleosis are sometimes misdiagnosed with a streptococcal pharyngitis (because of the classical clinical triad of fever, pharyngitis and adenopathy) and are given antibiotics such as ampicillin or amoxicillin as treatment. Some studies indicate about 80–90% of patients with acute Epstein–Barr virus infection treated with such antibiotics develop a red, diffuse rash.^[14]

Pathophysiology[link]

Infectious mononucleosis occurs with infection by the Epstein–Barr virus.^[15]

The infection is spread via saliva, and has an incubation period of four to seven weeks.^[16] Symptoms usually persist for two to three weeks,^[17] but fatigue is often more prolonged.^[4]

The length of time that an individual remains contagious is unclear, but may be the highest during the first six weeks following infection. Some studies indicate that a person can spread the infection for many months after symptoms are completely gone, with one particular study indicating as long as 18 months.^[18]

The virus replicates first within epithelial cells in the pharynx (which causes pharyngitis, or sore throat), and later primarily within B cells (which are invaded via their CD21). The host immune response involves cytotoxic (CD8-positive) T cells against infected B lymphocytes, resulting in enlarged, atypical lymphocytes (Downey cells).^[19][20]

When the infection is acute (recent onset, instead of chronic), heterophile antibodies are produced.^[11]

Similar symptoms can be caused by cytomegalovirus, adenovirus, and Toxoplasma gondii, but will result in a negative heterophile antibody test.^[3][21]

Diagnosis[link]

Exudative pharyngitis in a person with infectious mononucleosis

Cervical lymphadenopathy in someone with infectious mononucleosis

The most commonly used diagnostic criterion is the presence of 50% lymphocytes with at least 10% atypical lymphocytes (large, irregular nuclei),^[10] while the person also has fever, pharyngitis and adenopathy. Furthermore, it should be confirmed by a serological test.^[11] The atypical lymphocytes resembled monocytes when they were first discovered, thus the term "mononucleosis" was coined. Diagnostic tests are used to confirm infectious mononucleosis, but the disease should be suspected from symptoms prior to the results from hematology.^[22] These criteria are specific; however, they are not particularly sensitive and are more useful for research than for clinical use. Only half the patients presenting with the symptoms held by mononucleosis and a positive heterophile antibody test (monospot test) meet the entire criteria. One key procedure is to differentiate between infectious mononucleosis and mononucleosis-like symptoms.

A few studies on infectious mononucleosis have been conducted in a primary care environment, the best of which studied 700 patients, of which 15 were found to have mononucleosis upon a heterophile antibody test. More useful in a diagnostic sense are the signs and symptoms themselves. The presence of splenomegaly, and posterior cervical, axillary and inguinal^{[disambiguation needed ]} adenopathies are the most useful to suspect a diagnosis of infectious mononucleosis. On the other hand, the absence of cervical adenopathy and fatigue are the most useful to dismiss the idea of infectious mononucleosis as the correct diagnosis. The insensitivity of the physical examination in detecting splenomegaly means it should not be used as evidence against infectious mononucleosis.^[11]

In the past, the most common test for diagnosing infectious mononucleosis was the heterophile antibody test, which involves testing heterophile antibodies by agglutination of guinea pig, sheep and horse red blood cells. As with the aforementioned criteria, this test is specific but not particularly sensitive (with a false-negative rate of as high as 25% in the first week, 5–10% in the second and 5% in the third).^[11] About 90% of patients have heterophile antibodies by week 3, disappearing in under a year. The antibodies involved in the test do not interact with the Epstein–Barr virus or any of its antigens.^[10] More recently, more sensitive tests have been developed, such as the immunoglobulin G (IgG) and immunoglobulin M (IgM) tests. IgG, when positive, reflects a past infection, whereas IgM reflects a current infection. When negative, these tests are more accurate in ruling out infectious mononucleosis. However, when positive, they feature similar sensitivities to the heterophile antibody test. Therefore, these tests are useful for diagnosing infectious mononucleosis in people with highly suggestive symptoms and a negative heterophile antibody test. Another test searches for the Epstein–Barr nuclear antigen, while it is not normally recognizable until several weeks into the disease, and is useful for distinguishing between a recent-onset of infectious mononucleosis and symptoms caused by a previous infection. Elevated hepatic transaminase levels is highly suggestive of infectious mononucleosis, occurring in up to 50% of patients.^[11]

A fibrin ring granuloma may be present.

Differential diagnosis[link]

Diagnosis of acute infectious mononucleosis should also take into consideration acute cytomegalovirus infection and Toxoplasma gondii infections. These diseases are clinically very similar by their signs and symptoms. Because their management is much the same, it is not always helpful, or possible, to distinguish between EBV mononucleosis and cytomegalovirus infection. However, in pregnant women, differentiation of mononucleosis from toxoplasmosis is associated with significant consequences for the fetus.

Acute HIV infection can mimic signs similar to those of infectious mononucleosis, and tests should be performed for pregnant women for the same reason as toxoplasmosis.^[11]

Other conditions from which to distinguish infectious mononucleosis include leukemia, tonsillitis, diphtheria, common cold and influenza (flu).^[10]

Treatment[link]

Infectious mononucleosis is generally self-limiting, so only symptomatic and/or supportive treatments are used.^[23] Rest is recommended during the acute phase of the infection, but activity should^{[citation needed]} be resumed once acute symptoms have resolved. Nevertheless, heavy physical activity and contact sports should be avoided to mitigate the risk of splenic rupture, for at least one month following initial infection or splenomegaly has resolved, as determined by a treating physician.^[8]

Medications[link]

In terms of pharmacotherapies, NSAIDs, such as ibuprofen, may be used to reduce fever and pain. Prednisone, a corticosteroid, is commonly used as an anti-inflammatory to reduce symptoms of pharyngeal pain, odynophagia, or enlarged tonsils, although its use remains controversial due to the rather limited benefit and the potential of side effects.^[24][25] Intravenous corticosteroids, usually hydrocortisone or dexamethasone, are not recommended for routine use^[26] but may be useful if there is a risk of airway obstruction, severe thrombocytopenia, or hemolytic anemia.^[27][28] There is little evidence to support the use of aciclovir, although it may reduce initial viral shedding.^[29] 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.^[30][31] Although antivirals are not recommended for patients presenting with simple infectious mononucleosis, they may be useful (in conjunction with steroids) in the management of patients with severe EBV manifestations, such as EBV meningitis, peripheral neuritis, hepatitis, or hematologic complications.^[32] Antibiotics are not used, as they are ineffective against viral infections. The antibiotics ampicillin and later the related amoxicillin^[33] are relatively contraindicated in the case of any coinciding bacterial infections during mononucleosis because their use precipitates a nonallergic rash in close to 99% of the patients.^[34]

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 relatively contraindicated due to risk of respiratory depression.^[28]

Prognosis[link]

Serious complications are uncommon, being absent in more than 95% of cases:^[35][36]

• CNS complications include meningitis, encephalitis, hemiplegia, Guillain-Barré syndrome, and transverse myelitis. EBV infection has also been proposed as a risk factor for the development of multiple sclerosis (MS),^[37] but this has not been confirmed.
• Hematologic: Hemolytic anemia (direct Coombs test is positive) and various cytopenias, and bleeding (caused by thrombocytopenia) can occur.^[12]
• Mild jaundice
• Hepatitis with EBV is rare.
• Upper airway obstruction from tonsillar hypertrophy is rare.
• Fulminant disease course of immunocompromised patients is rare.
• Splenic rupture is rare.
• Myocarditis and pericarditis are rare.
• Transgender cross overs can occur when men begin to produce more estrogen, but this is rare. It is especially common in athletes and bodybuilders who use creatine.

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 his or her 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.^[3] 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, the virus can reactivate and cause vague physical symptoms (or may be subclinical), and during this phase the virus can spread to others. ^[3][38][39]

See also[link]

• List of cutaneous conditions

Notes[link]