Infectious mononucleosis

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EBV infectious mononucleosis (also known as Pfeiffer's disease, colloquially as the kissing disease, from its oral distribution or as mono in Northern America and more commonly known as glandular fever in other English-speaking countries) is an infectious, viral disease which most commonly occurs in adolescents and young adults. It 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 Emil Pfeiffer in 1889.^[1][2]

[edit] Signs and symptoms

Main symptoms of IM.^{[3] [4] [5]}

Mononucleosis has a set of common symptoms that are usually presented in the individual with the disease. The classical symptoms are a sore throat, fever, fatigue, weight loss, malaise, pharyngeal inflammation and petechiae, and common signs include lymphadenopathy (enlarged lymph nodes), splenomegaly (enlarged spleen), hepatitis (refers to inflammatory 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 white blood cells)), splenic rupture, splenic hemorrhage, upper airway obstruction, pericarditis and pneumonitis. Another rare manifestation of mononucleosis is erythema multiforme.^[6][7]

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.^[8] 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 that approximately 80-90% of patients with acute Epstein Barr virus infection treated with such antibiotics develop a red, diffuse rash. ^[9]

[edit] Pathophysiology

Infectious mononucleosis occurs with infection by the Epstein-Barr virus.^[10] (A similar condition can be caused by cytomegalovirus. Because of this, some sources say that infectious mononucleosis is "usually caused by the Epstein-Barr virus"^[11]. Other sources reserve a different term, "cytomegalovirus mononucleosis", for mononucleosis caused by cytomegalovirus.^[12]. Some sources state that infectious mononucleosis can also be caused by toxoplasmosis or viral hepatitis.^[13])

The infection is spread via saliva and has an incubation period of up to 8 weeks.

The virus replicates first within epithelial cells in the pharynx (which causes 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).^[14][15]

When the infection is acute (recent onset, instead of chronic), heterophile antibodies are produced.^[7]

[edit] Diagnosis

Peripheral blood smear (low power) showing lymphocytosis from a 16-year-old male with pharyngitis.

The most commonly used diagnostic criteria is the presence of 50% lymphocytes with at least 10% atypical lymphocytes (large, irregular nuclei^[6]), while the person also has fever, pharyngitis and adenopathy. Furthermore, it should be confirmed by a serological test.^[7] Diagnostic tests are used to confirm infectious mononucleosis but the disease should be suspected from symptoms prior to the results from hematology.^[16] 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 syndromes.

There have been few studies on infectious mononucleosis 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, posterior cervical adenopathy, axillary adenopathy, and inguinal adenopathy 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 that is should not be used as evidence against infectious mononucleosis.^[7]

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).^[7] 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.^[6] More recently, tests that are more sensitive have been developed such as the Immunoglobulin G (IgG) and immuno 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, whilst not normally recognisable 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, occuring in up to 50% of patients.^[7]

[edit] Differential diagnosis

Diagnosis of acute infectious mononucleosis should also take into consideration acute cytomegalovirus 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 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.^[7]

Other conditions from which to distinguish infectious mononucleosis include leukemia, diphtheria, common cold and influenza (the flu).^[6]

[edit] Treatment

Infectious mononucleosis is generally self-limiting and only symptomatic and/or supportive treatments are used.^[17] 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 mitigate the risk of splenic rupture, for at least one month following initial infection and until splenomegaly has resolved, as determined by ultrasound scan.^[17]

In terms of pharmacotherapies, acetaminophen/paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) may be used to reduce fever and pain. Intravenous corticosteroids, usually hydrocortisone or dexamethasone, are not recommended for routine use^[18] but may be useful if there is a risk of airway obstruction, severe thrombocytopenia, or hemolytic anemia.^[19][20] There is little evidence to support the use of aciclovir, although it may reduce initial viral shedding.^[21] 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. ^[22][23] Antibiotics are not used as they are ineffective against viral infections. The antibiotics ampicillin and later the related amoxicillin^[24] are relatively contraindicated in the case of any coinciding bacterial infections during mononucleosis because their use precipitates a non-allergic rash close to 99% of the time.^[25] 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.^[19]

[edit] Prognosis

Uncommon and potentially fatal complications occur in 5% of cases^[26]:

• CNS: Meningitis, encephalitis, hemiplegia, and transverse myelitis. EBV infection has also been proposed as a risk factor for the development of multiple sclerosis (MS)^[27], but this has not been confirmed.
• Hematologic: EBV can cause autoimmune hemolytic anemia (direct Coombs test is positive) and various cytopenias.
• Fulminant disease course (immunocompromised patients)
• Severe tonsillar hypertrophy and upper airway obstruction
• Splenic rupture
• Neurologic involvement e.g. Guillain-Barré syndrome
• Myocarditis and pericarditis
• Bleeding (caused by thrombocytopenia)^[8]

[edit] References

[edit] External links

• Infectious mononucleosis symptoms, causes, diagnosis, treatment, and general information