Infectious mononucleosis

• 1. Introduction

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  Infectious mononucleosis, also called mono or glandular fever, is caused by a virus that nearly 95% of adults have already carried. Most of them met it in childhood, when it produced few symptoms or none at all.

  For a teenager, the very same virus can mean weeks of fever, a raw throat and an exhaustion that lingers for months. So why does one germ behave so differently from one person to the next? How do doctors separate it from an ordinary sore throat? Why can a common antibiotic leave a patient covered in an itchy rash? And what becomes of the virus after the fever fades?

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• 2. Symptoms By Age

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  In the developed world, infectious mononucleosis most often strikes people between the ages of 15 and 24. Among those aged 16 to 20, it accounts for about 8% of sore throats. In the United States, roughly 45 out of every 100,000 people develop it each year. Cases appear equally at every time of year. In the developing world, people are more often infected in early childhood, when symptoms are slight.

  Children tend to get off lightly. Before puberty the illness usually amounts to flu-like symptoms, if anything. When signs do appear, they resemble an ordinary throat infection, with mild pharyngitis and sometimes tonsillitis.

  Three signs form the classic triad in adolescents and young adults. Fever usually lasts about 14 days and is often mild. The sore throat is typically severe for 3-5 days, then fades over the following 7-10 days. Swollen glands, which move freely under the skin, usually sit at the back of the neck and sometimes appear throughout the body. Tiredness is the other major complaint. Headaches are common, and some patients also suffer abdominal pain with nausea or vomiting.

  In about 50% of cases, tiny reddish-purple spots called petechiae dot the roof of the mouth. The throat itself is often the most striking sign, with enlarged tonsils coated in pus much like strep throat. A small minority of people develop a rash on the arms or trunk. Occasional cases of erythema nodosum and erythema multiforme have been reported, and seizures may rarely occur.

  Fatigue lasts longer than a month in an estimated 28% of cases. Most symptoms disappear after about 2-4 weeks. Mild fever, swollen neck glands and body aches can persist beyond 4 weeks. Most people return to their usual activities within 2-3 months.

  The interval between infection and illness remains unclear. One review of the literature estimated 33-49 days, and in young people symptoms are thought to appear around 4-6 weeks after infection. Onset is often gradual, though it can be abrupt. A week or two of fatigue, malaise and body aches may come first.

  After the age of 40, the picture changes. Older adults less often show a sore throat and swollen glands. Instead they may have a prolonged fever, fatigue, malaise and body pains, and they are more prone to liver enlargement and jaundice. People over 40 are more likely to develop serious illness.

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• 3. A Virus That Stays

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  About 90% of cases of infectious mononucleosis trace to the Epstein-Barr virus, also known as human herpesvirus 4. It belongs to the Herpesviridae family of DNA viruses and is among the most commonly found viruses anywhere in the world. Despite its reputation, it is not highly contagious. It passes through direct contact with an infected person's saliva, as in kissing or sharing a toothbrush. Drinking glasses, coughs and sneezes can also spread it, and semen or blood can do so rarely.

  Exposure and illness are very different things. Only 15-20% of infected teenagers and about 40% of exposed adults actually develop mononucleosis.

  The period when a person can pass the virus on is hard to pin down. Spread may begin weeks before any symptoms develop. The chances of infecting someone else may be highest during the first six weeks. Some studies suggest a person can remain contagious for many months, possibly up to a year and a half.

  Inside the body, the virus first multiplies in epithelial cells of the pharynx, which causes the sore throat. It then moves mostly into B cells, entering through a molecule on their surface known as CD21. The immune system answers with cytotoxic CD8-positive T cells that attack the infected B lymphocytes. The result is a crop of enlarged, reactive lymphocytes called Downey cells.

  Once a person is infected, the virus is carried for life. It typically lies dormant in B lymphocytes.

  About 5-7% of cases come from human cytomegalovirus, another herpes virus. It lives in saliva, urine, blood, tears, breast milk and genital secretions. Kissing and sexual intercourse are the most common routes, and an infected mother can pass it to her unborn child. The infection is often silent. Yet it can threaten the lives of infants, people with HIV, transplant recipients and others with weak immune systems, causing pneumonia and inflammation of the retina, esophagus, liver, large intestine and brain. About 90% of people have been infected by adulthood, most without knowing. The virus then stays for life, detectable during its latent phase only in monocytes.

  The parasitic protozoon Toxoplasma gondii accounts for less than 1% of cases. Viral hepatitis, adenovirus, rubella and herpes simplex viruses have also been reported as rare causes.

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• 4. Telling It Apart

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  A swollen spleen and swollen lymph nodes in the neck, armpit and groin are the most useful findings when a doctor suspects mononucleosis. The absence of swollen neck glands and of fatigue is the best reason to doubt the diagnosis. A physical examination often misses an enlarged spleen, so a normal result there should never count against the illness.

  The heterophile antibody test, better known as the monospot test, works by clumping red blood cells taken from guinea pigs, sheep and horses. It is specific but not very sensitive. Its false-negative rate can reach 25% in the first week, 5-10% in the second and 5% in the third. About 90% of diagnosed people have the antibodies by week 3, and they vanish in under a year. Strangely, these antibodies do not react with the Epstein-Barr virus or any of its antigens. The CDC does not recommend the test for general use because of its poor accuracy.

  Serology looks for antibodies aimed at the virus itself. Immunoglobulin G mostly signals a past infection, while immunoglobulin M mostly signals a current one. Anti-VCA IgM appears early and usually disappears within 4 to 6 weeks. Anti-VCA IgG peaks 2 to 4 weeks after symptoms begin and then persists for life. Anti-EA IgG marks active infection and fades after 3 to 6 months, though 20% of people keep it for years. Antibody to EBNA appears slowly, 2 to 4 months after onset, and also lasts for life. When negative, these tests rule out the illness better than the monospot does, so they help in patients with highly suggestive symptoms and a negative monospot.

  Blood work adds more clues. A blood film showing 50% lymphocytes, at least 10% of them reactive, supports the diagnosis in a patient with fever, pharyngitis and swollen nodes. Raised liver enzymes called hepatic transaminases occur in up to 50% of people.

  About 10% of people who look like mononucleosis patients do not have an acute Epstein-Barr infection. Cytomegalovirus and Toxoplasma gondii are the usual alternatives, and since their management is similar, telling them apart is not always useful. In pregnant women, however, separating mononucleosis from toxoplasmosis matters because of the risk to the fetus. Acute HIV infection can also mimic mononucleosis, so pregnant women should be tested for it as well. Leukemia, tonsillitis, diphtheria, the common cold and influenza belong on the list of look-alikes.

  Some patients are misdiagnosed with strep throat because of the fever, sore throat and swollen glands, and they are given ampicillin or amoxicillin. Almost everyone who takes either drug during mononucleosis develops a generalized, itchy rash. That rash does not mean the person will react badly to penicillins in the future.

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• 5. Rest and Restraint

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  For the first 3-4 weeks of illness, experts advise against contact sports and other heavy exertion. The aim is to lower the risk of a ruptured spleen. Activities that raise abdominal pressure, such as rowing or weight training with the Valsalva maneuver, are a particular worry. The restriction lasts until a physician judges that the spleen has returned to normal size. Otherwise, the pace of recovery may reasonably follow the patient's energy levels.

  No vaccine exists for the Epstein-Barr virus, although research continues. Avoiding saliva and personal items shared with an infected person prevents infection. The illness generally improves without any specific treatment. Drinking enough fluids, resting and taking pain relievers can ease the symptoms.

  Paracetamol, also called acetaminophen, and NSAIDs such as ibuprofen can reduce fever and pain. Prednisone, a corticosteroid, is sometimes used for throat pain or enlarged tonsils but remains controversial. Evidence of benefit is lacking, and side effects are possible. Aspirin should not be given to anyone under 16 because of the risk of Reye syndrome. Intravenous hydrocortisone or dexamethasone is not routine, but may help when there is a danger of airway obstruction, a very low platelet count or hemolytic anemia.

  Abdominal ultrasound might seem a natural way to check an enlarged spleen. Because normal spleen size varies so widely, though, the technique is not a valid measure. It should not be used routinely, nor to decide whether someone is fit to play sports.

  Aciclovir and valacyclovir work by blocking viral DNA replication. Little evidence supports their use, although they may reduce initial viral shedding. They are expensive, they risk fostering drug resistance, and in 1% to 10% of cases they cause unpleasant side effects. For simple mononucleosis they are not recommended. Combined with steroids, they may help in severe cases such as EBV meningitis, peripheral neuritis, hepatitis or blood complications.

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• 6. Rare Complications

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  Serious complications occur in fewer than 5% of cases. The spleen commonly enlarges in the second and third weeks, and in under 1% of cases it ruptures. The liver may swell somewhat, and jaundice or hepatitis caused by the virus is occasional.

  Neurological problems include meningitis, encephalitis, hemiplegia, Guillain-Barre syndrome and transverse myelitis. Having had mononucleosis has also been linked to the later development of multiple sclerosis. Blood complications include hemolytic anemia, various cytopenias, and bleeding caused by a low platelet count. Some patients develop secondary cold agglutinin disease. In this autoimmune condition, abnormal antibodies attack red blood cells and can cause a form of hemolytic anemia.

  Other complications are rare. They include airway obstruction from swollen tonsils, inflammation of the heart muscle or its lining, and fulminant disease in people with weakened immunity. Postural orthostatic tachycardia syndrome and myalgic encephalomyelitis, also called chronic fatigue syndrome, appear on the list as well, along with hemophagocytic lymphohistiocytosis.

  After the first illness, a person can catch mononucleosis more than once, even while already carrying the dormant virus. The virus can also reactivate. During those periods the person is again infectious, usually without any symptoms. In susceptible people under environmental stress, reactivation may bring vague physical symptoms. In some patients the disease persists as a chronic infection, which may develop into systemic EBV-positive T cell lymphoma.

  The cancers associated with the Epstein-Barr virus include Burkitt's lymphoma, Hodgkin's lymphoma, lymphomas in general, and nasopharyngeal and gastric carcinoma.

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• 7. Naming the Illness

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  In 1885, the renowned Russian pediatrician Nil Filatov reported an illness he called idiopathic adenitis, with symptoms that match mononucleosis. In 1889, the German balneologist and pediatrician Emil Pfeiffer independently described similar cases, some milder, that clustered in families. He coined the term Drüsenfieber, meaning glandular fever. Before that, the characteristic symptoms do not appear to have been reported at all.

  Outbreaks from this era are well documented. A large one struck an Ohio community in 1896. In the Falkland Islands, 87 people in one community were infected. At the U.S. Naval Base in Coronado, California, 220 individuals caught the illness.

  In 1920, Thomas Peck Sprunt and Frank Alexander Evans coined the term infectious mononucleosis. Their classic clinical description appeared in the Bulletin of the Johns Hopkins Hospital under the title Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis). The name came from the reactive lymphocytes, which resembled monocytes when first discovered.

  A laboratory test followed in 1931. Yale School of Public Health professor John Rodman Paul and Walls Willard Bunnell developed it after discovering heterophile antibodies in the blood of patients. It was known as the Paul-Bunnell Test, and the heterophile antibody test later replaced it.

  The virus itself was identified in 1964 by Michael Anthony Epstein and Yvonne Barr at the University of Bristol, in Burkitt's lymphoma cells. The link to mononucleosis emerged in 1967 at the Children's Hospital of Philadelphia. Werner and Gertrude Henle found that a laboratory technician handling the virus had fallen ill. Serum samples taken before and after the onset showed that the technician had developed antibodies to it.

  Yale School of Public Health epidemiologist Alfred S. Evans confirmed through testing that the illness spreads mainly through kissing. That finding gave it the colloquial name the kissing disease. A vaccine against the Epstein-Barr virus does not yet exist, but research toward one is ongoing.

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