Infectious Mononucleosis (IM) (also known as EBV Infectious Mononucleosis or Pfeiffer's Disease or Filatov's Disease^[1] and colloquially as kissing disease—from its oral transmission—or as mono in North America and as glandular fever in other English-speaking countries) is an infectious, very 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] Most people are exposed to the virus as children, when the disease produces no noticeable symptoms or only flu-like symptoms. In underdeveloped countries, people are exposed to the virus in early childhood more often than in developed countries, which is why the disease in its observable form is more common in developed countries. It is most common among adolescents and young adults. ^[3]

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^[4] in 1887 and independently by Emil Pfeiffer^[5] in 1889.^[1]

Signs and symptoms

Main symptoms of IM^[6][7][8]

A cross reaction rash that was developed by using Penicillin while infected with IM.

The classical symptoms of mononucleosis are a sore throat, fever, fatigue, weight loss, malaise, pharyngeal inflammation, 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.^[9][10]

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.^[11] 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.^[12]

Pathophysiology

Infectious mononucleosis occurs with infection by the Epstein-Barr virus.^[13] 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".^[14]

The infection is spread via saliva and has an incubation period of 4–7 weeks.^[15]

Doctors and researchers are not exactly sure how long someone with the virus stays contagious after symptoms are gone. But it's generally believed that a person can spread the infection for many months after the symptoms are completely gone — some studies show as long as 18 months.^[16]

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).^[17][18]

When the infection is acute (recent onset, instead of chronic), heterophile antibodies are produced.^[10]

Diagnosis

The most commonly used diagnostic criterion is the presence of 50% lymphocytes with at least 10% atypical lymphocytes (large, irregular nuclei),^[9] while the person also has fever, pharyngitis and adenopathy. Furthermore, it should be confirmed by a serological test.^[10] The atypical lymphocytes resembled monocytes when they were first discovered, thus the moniker "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.^[19] 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.

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 it should not be used as evidence against infectious mononucleosis.^[10]

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).^[10] 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.^[9] More recently, tests that are more sensitive 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.^[10]

Differential diagnosis

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.^[10]

Other conditions from which to distinguish infectious mononucleosis include leukemia, diphtheria, common cold and influenza (the flu).^[9]

Treatment

Self care

Infectious mononucleosis is generally self-limiting and only symptomatic and/or supportive treatments are used.^[20] 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 or splenomegaly has resolved, as determined by a treating physician.^[7]

Medications

In terms of pharmacotherapies, acetaminophen/paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) 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.^[21][22] Intravenous corticosteroids, usually hydrocortisone or dexamethasone, are not recommended for routine use^[23] but may be useful if there is a risk of airway obstruction, severe thrombocytopenia, or hemolytic anemia.^[24][25] There is little evidence to support the use of aciclovir, although it may reduce initial viral shedding.^[26] 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.^[27][28] Antibiotics are not used as they are ineffective against viral infections. The antibiotics ampicillin and later the related amoxicillin^[29] 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.^[30] 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.^[24]

Prognosis

Serious complications are uncommon, occurring in less than 5% of cases:^[31][32]

• CNS: 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),^[33] but this has not been confirmed.
• Hematologic: Hemolytic anemia (direct Coombs test is positive) and various cytopenias; Bleeding (caused by thrombocytopenia).^[11]
• Mild jaundice
• Hepatitis (rare)
• Upper airway obstruction (tonsillar hypertrophy) (rare)
• Fulminant disease course (immunocompromised patients) (rare)
• Splenic rupture (rare)
• Myocarditis and pericarditis (rare)

Once the acute symptoms of an initial infection disappear, they will not return. An asymptomatic carrier state exists with a reservoir of infected immune cells. Studies indicate that there is reactivation of the virus which may be accompanied by physical complaints or may be subclinical, and during this phase it can be spread to others. There is the possibility that chronically infected immune cells can, on occasion, develop into Burkitt's lymphoma or Hodgkin's lymphoma.^[34][35][36]