Infectious mononucleosis (IM), also called glandular fever, is an illness usually caused by the Epstein–Barr virus (EBV). Most people get infected as children, but the illness often causes mild or no symptoms. In young adults, it often leads to fever, sore throat, swollen lymph nodes in the neck, and tiredness. Most people recover in two to four weeks, but tiredness may last for months. The liver or spleen may also swell, and in fewer than one percent of cases, the spleen may break.

While EBV is the main cause, other viruses and the parasite Toxoplasma gondii can also lead to the illness. It spreads mainly through saliva but can rarely spread through semen or blood. Sharing items like drinking glasses or toothbrushes, or coughing and sneezing, can also spread the infection. People may spread the disease before symptoms appear. Doctors usually diagnose mono based on symptoms and confirm it with blood tests that check for specific antibodies. A common finding is an increase in blood lymphocytes, with more than 10% being reactive. The monospot test is not recommended for general use because it is not very accurate.

There is no vaccine for EBV, but research is ongoing. To prevent infection, avoid sharing personal items or saliva with someone who is infected. Most people recover without special treatment. Drinking enough fluids, resting, and taking pain medicines like paracetamol (acetaminophen) or ibuprofen can help ease symptoms.

Mononucleosis most often affects people aged 15 to 24 in developed countries. In developing countries, it is more common in early childhood, when symptoms are usually mild. In those aged 16 to 20, it causes about 8% of sore throats. About 45 in every 100,000 people develop infectious mononucleosis each year in the United States. Nearly 95% of adults have had an EBV infection by the time they reach adulthood. The illness can occur at any time of the year. Mononucleosis was first described in the 1920s and is commonly called "the kissing disease."

Signs and symptoms

The signs and symptoms of infectious mononucleosis change depending on a person's age.

Before puberty, the illness may cause only mild symptoms similar to the flu, or no symptoms at all. If symptoms occur, they are often like those of a common throat infection, such as a mild sore throat with or without swollen tonsils.

During adolescence and young adulthood, the illness usually shows three main symptoms:
– Fever – often lasts about 14 days and is usually mild.
– Sore throat – severe for 3–5 days, then improves over the next 7–10 days.
– Swollen glands – movable and often found in the back of the neck (posterior cervical lymph nodes) or other parts of the body.

Other common symptoms include tiredness, headaches, and stomach pain with nausea or vomiting. Most symptoms usually go away after 2–4 weeks. However, tiredness and feeling unwell (malaise) may last for months. In about 28% of cases, tiredness continues for more than one month. Mild fever, swollen neck glands, and body aches may also last longer than 4 weeks. Most people can return to normal activities within 2–3 months.

A common sign is a sore throat, often with swollen tonsils that have white or yellow patches, similar to strep throat. In about half of cases, small red-purple spots (petechiae) may appear on the roof of the mouth. A rash on the mouth or throat (palatal enanthem) can also occur but is less common.

A small number of people develop a rash, usually on the arms or torso, which may look like flat or raised spots. Most people who take amoxicillin or ampicillin develop a widespread, itchy rash, but this does not mean they will have an allergic reaction to these medicines again. Rarely, other skin conditions like erythema nodosum or erythema multiforme may occur. Seizures are also uncommon.

The spleen often becomes enlarged during the second and third weeks of illness, though this may not be noticed during a physical exam. In rare cases, the spleen may rupture. The liver may also become slightly enlarged. Jaundice (yellowing of the skin or eyes) or liver inflammation caused by the Epstein-Barr virus occurs only occasionally.

Infectious mononucleosis usually improves on its own in healthy people. When caused by the Epstein-Barr virus (EBV), it is classified as a type of EBV-related lymphoproliferative disease. In rare cases, the illness may last longer and lead to a chronic infection, which could develop into a type of T cell lymphoma caused by EBV.

Infectious mononucleosis most often affects younger adults. Older adults who get the illness may not show typical symptoms like sore throat or swollen glands. Instead, they may experience prolonged fever, tiredness, feeling unwell, and body aches. Older adults are more likely to have an enlarged liver and jaundice. People over 40 are more likely to have serious illness.

The time between infection and symptoms is not exactly known. Studies suggest it may take 33–49 days. In adolescents and young adults, symptoms usually appear about 4–6 weeks after infection. Symptoms may start slowly, though they can also begin suddenly. The main symptoms may be preceded by 1–2 weeks of tiredness, feeling unwell, and body aches.

Cause

Infectious mononucleosis is most often caused by the Epstein–Barr virus, which belongs to a group of viruses called Herpesviridae. This virus is found in people around the world. Many people think this virus is very easy to spread, but it is not. It spreads only through direct contact with saliva, such as kissing or sharing a toothbrush. About 95% of people have been exposed to this virus by age 40, but only 15–20% of teenagers and about 40% of adults who are exposed develop infectious mononucleosis.

About 5–7% of infectious mononucleosis cases are caused by human cytomegalovirus (CMV), another type of herpes virus. This virus is present in body fluids like saliva, urine, blood, tears, breast milk, and genital secretions. People become infected by direct contact with these fluids. CMV is most often spread through kissing or sexual activity. It can also pass from a pregnant person to their unborn child. This virus often does not cause symptoms, but it can lead to serious illness in infants, people with HIV, transplant recipients, and those with weak immune systems. In people with weak immune systems, CMV can cause severe conditions such as pneumonia and inflammation in the retina, esophagus, liver, large intestine, and brain. About 90% of people are infected with CMV by adulthood, but most do not know they are infected. Once a person is infected, the virus remains in their body for life. During a period when the virus is not active, it can only be found in certain blood cells called monocytes.

Toxoplasma gondii, a parasitic protozoon, causes less than 1% of infectious mononucleosis cases. Other rare causes include viral hepatitis, adenovirus, rubella, and herpes simplex viruses.

Epstein–Barr virus spreads through saliva and has an incubation period of four to seven weeks. The length of time a person can spread the virus is not clear. The risk of passing the infection to others may be highest during the first six weeks after infection. Some studies suggest that a person may spread the infection for several months, possibly up to 18 months.

Pathophysiology

The virus copies itself first in cells lining the throat (causing pharyngitis, or sore throat) and later mainly in B cells (which are infected through a protein called CD21). The body’s immune response includes special white blood cells called cytotoxic T cells (CD8-positive) that attack infected B cells, leading to swollen, active lymphocytes (Downey cells).

When the infection is recent (acute) rather than long-term (chronic), the body produces heterophile antibodies.

Infections caused by cytomegalovirus, adenovirus, and Toxoplasma gondii (toxoplasmosis) can cause symptoms similar to infectious mononucleosis. However, these infections will test negative for heterophile antibodies, which helps distinguish them from infectious mononucleosis.

Mononucleosis may sometimes be accompanied by secondary cold agglutinin disease, an autoimmune condition where abnormal antibodies in the blood attack red blood cells, causing a type of autoimmune hemolytic anemia. The cold agglutinin detected has anti-i specificity.

Diagnosis

The disease is diagnosed based on:

The presence of an enlarged spleen and swollen lymph nodes in the neck (posterior cervical), underarms (axillary), and groin (inguinal) is most helpful in suspecting infectious mononucleosis. On the other hand, the absence of swollen neck lymph nodes and the lack of fatigue is most helpful in ruling out infectious mononucleosis. The physical exam is not very reliable for detecting an enlarged spleen, so it should not be used to argue against the diagnosis. A physical exam may also show small red spots (petechiae) on the roof of the mouth.

The heterophile antibody test, also called the monospot test, works by causing red blood cells from guinea pigs, sheep, and horses to clump together. This test is good at confirming the disease but may miss some cases (up to 25% in the first week, 5–10% in the second, and 5% in the third). About 90% of people diagnosed with the disease have these antibodies by week 3, and they usually disappear within a year. However, these antibodies do not interact with the Epstein–Barr virus or its parts.

The CDC does not recommend using the monospot test for general use because it is not very accurate.

Serologic tests look for antibodies that target the Epstein–Barr virus. Immunoglobulin G (IgG) antibodies usually mean a past infection, while immunoglobulin M (IgM) antibodies usually mean a current infection. These antibodies can be grouped based on which part of the virus they bind to:

• Viral capsid antigen (VCA)
• Early antigen (EA)
• Epstein–Barr nuclear antigen (EBNA)

When these tests are negative, they are more accurate than the heterophile antibody test in ruling out infectious mononucleosis. When they are positive, they are just as accurate as the heterophile test. These tests are helpful for diagnosing the disease in people with strong symptoms and a negative monospot test.

High levels of certain liver enzymes (hepatic transaminases) are strongly linked to infectious mononucleosis and occur in up to 50% of cases. Blood tests may show that at least 50% of blood cells are lymphocytes, with 10% being reactive lymphocytes (large, irregular-shaped cells). These reactive lymphocytes look like monocytes, which is why the disease is called "mononucleosis." A fibrin ring granuloma may also appear in the liver or bone marrow.

About 10% of people who seem to have infectious mononucleosis do not have an active Epstein–Barr virus infection. Other conditions that must be considered include acute cytomegalovirus infection and Toxoplasma gondii infection. These conditions are treated similarly, so it is not always possible to tell them apart. However, in pregnant women, it is important to distinguish mononucleosis from toxoplasmosis because it can harm the fetus.

Acute HIV infection can cause symptoms similar to infectious mononucleosis, so tests should be done for pregnant women for the same reason as toxoplasmosis.

People with infectious mononucleosis are sometimes misdiagnosed with streptococcal pharyngitis (because of symptoms like fever, sore throat, and swollen lymph nodes) and may be given antibiotics like ampicillin or amoxicillin.

Other conditions that must be considered include leukemia, tonsillitis, diphtheria, the common cold, and influenza (flu).

Treatment

Infectious mononucleosis usually improves on its own, so treatments focus on managing symptoms. Rest and returning to normal activities after the infection's worst phase depend on how much energy the person has. However, to lower the risk of spleen injury, doctors advise avoiding contact sports and heavy physical activity, especially those that increase pressure in the abdomen, such as rowing or weight training, for at least 3–4 weeks or until the spleen returns to its normal size, as determined by a healthcare provider.

Medications like paracetamol (acetaminophen) and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, can help reduce fever and pain. Prednisone, a type of steroid, may be used to ease throat pain or swollen tonsils, but its use is debated because there is little proof it works and it can cause side effects. Aspirin should not be given to people under 16 years old due to the risk of Reye syndrome. Intravenous steroids, such as hydrocortisone or dexamethasone, are not usually recommended but might be used if there is a risk of airway blockage, very low blood platelet levels, or hemolytic anemia.

Antiviral drugs work by stopping the virus from copying its DNA. There is limited evidence that antivirals like aciclovir and valacyclovir help with infectious mononucleosis, though they might reduce the spread of the virus early on. These drugs are costly, can lead to resistance, and may cause side effects in 1% to 10% of cases. They are not recommended for typical cases of infectious mononucleosis but may be used with steroids to treat severe complications caused by Epstein–Barr virus, such as meningitis, nerve issues, liver problems, or blood-related issues.

Antibiotics do not fight viruses but may be used to treat bacterial infections that occur alongside mononucleosis, such as strep throat. However, ampicillin and amoxicillin are not advised during active Epstein–Barr virus infection because they can cause a widespread rash.

Spleen enlargement is common in infectious mononucleosis, and doctors may use abdominal ultrasound to check the spleen's size. However, because spleen size varies a lot, ultrasound is not a reliable way to measure enlargement. It should not be used regularly or to decide if someone can safely play sports.

Prognosis

Serious complications are rare, happening in fewer than 5% of cases:

• Problems affecting the brain and nervous system (CNS) may include meningitis, encephalitis, paralysis on one side of the body, Guillain–Barré syndrome, and transverse myelitis. A past infection called mononucleosis has been linked to the development of multiple sclerosis.
• Blood-related issues: Hemolytic anemia (a test called the direct Coombs test is positive), low levels of blood cells (cytopenias), and bleeding (caused by low platelet counts, or thrombocytopenia) may occur.
• Mild jaundice (yellowing of the skin and eyes)
• Hepatitis (inflammation of the liver) caused by the Epstein–Barr virus is uncommon.
• Blockage of the upper airway due to enlarged tonsils is uncommon.
• A severe disease course in people with weakened immune systems is uncommon.
• Rupture of the spleen is uncommon.
• Inflammation of the heart muscle (myocarditis) and the lining around the heart (pericarditis) are uncommon.
• Postural orthostatic tachycardia syndrome
• Myalgic encephalomyelitis/chronic fatigue syndrome
• Cancers linked to the Epstein–Barr virus include Burkitt's lymphoma, Hodgkin's lymphoma, and other types of lymphoma, as well as cancers of the nose and throat (nasopharyngeal carcinoma) and stomach (gastric carcinoma).
• Hemophagocytic lymphohistiocytosis

After the symptoms of the initial infection improve, they usually do not return. However, once infected, the virus remains in the body for life. The virus typically stays inactive in a type of white blood cell called B lymphocytes. People can catch mononucleosis more than once, even if the virus is already inactive in their body. At times, the virus may become active again, making the person infectious, though they often do not feel sick. Most people with mononucleosis experience few or no further symptoms from the inactive virus in B lymphocytes. However, in people with weakened immune systems or under certain stressful conditions, the virus may reactivate and cause mild physical symptoms (or may not cause noticeable symptoms). During this time, the virus can spread to others.

History

The symptoms of infectious mononucleosis were not widely reported until the late 1800s. In 1885, a famous Russian pediatrician named Nil Filatov described an illness called "idiopathic adenitis" with symptoms similar to infectious mononucleosis. In 1889, a German doctor named Emil Pfeiffer reported similar cases, some less severe, that often occurred within families. He called the illness "glandular fever."

The word "mononucleosis" has several meanings, but today it most often refers to infectious mononucleosis, which is caused by the Epstein-Barr virus (EBV). The term "infectious mononucleosis" was first used in 1920 by Thomas Peck Sprunt and Frank Alexander Evans in a medical paper titled "Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis)," published in the Bulletin of the Johns Hopkins Hospital.

In 1931, John Rodman Paul and Walls Willard Bunnell from Yale School of Public Health created a lab test for infectious mononucleosis. They discovered heterophile antibodies in the blood of people with the disease, leading to the Paul-Bunnell Test (PBT). This test was later replaced by the heterophile antibody test.

Before the disease was clearly identified, it was often called "glandular fever," and few tests existed to confirm infections. Notable outbreaks in the late 1800s and early 1900s include a large case in an Ohio community in 1896, an outbreak with 87 infections in the Falkland Islands, and an outbreak at the U.S. Naval Base in Coronado, California, where 220 people were infected.

The Epstein-Barr virus was first found in cells from Burkitt's lymphoma by Michael Anthony Epstein and Yvonne Barr at the University of Bristol in 1964. Scientists later linked the virus to infectious mononucleosis in 1967 when a lab worker who handled the virus became sick. Comparing blood samples before and after the illness showed the worker developed antibodies to the virus.

In 1956, Alfred S. Evans, an epidemiologist from Yale School of Public Health, confirmed through testing that mononucleosis spreads mainly through kissing. This led to the illness being called "the kissing disease."