Infectious mononucleosis

This article is about mononucleosis caused by Epstein–Barr virus. For mononucleosis caused by cytomegalovirus, see Cytomegalovirus.

EBV infectious mononucleosis
Classification and external resources
Infectious mono, 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 or glandular fever or Pfeiffer's disease or 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 symptoms 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

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

The classical symptoms of mononucleosis are a sore throat, fever, fatigue, some suffers are known to crave sugars in the form of fruits or starchy carbohydrated such as Pasta or potatoes 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). Often, if symptoms are not apparent in the first two days of possible viral infection, then mononucleosis is not present. 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 that approximately 80–90% of patients with acute Epstein–Barr virus infection treated with such antibiotics develop a red, diffuse rash.^[14]

Pathophysiology

Infectious mononucleosis occurs with infection by the Epstein–Barr virus.^[15] A similar condition can be caused by cytomegalovirus, but that one gives a negative on the heterophile antibody test.^[3] Because of this, some sources say that infectious mononucleosis is caused by the Epstein–Barr virus.^[16]

The infection is spread via saliva and has an incubation period of 4–7 weeks.^[17] Symptoms usually persist for 2–3 weeks,^[18] but fatigue is often more prolonged.^[4]

How long someone with the virus stays contagious after symptoms are gone is uncertain, but it is thought that the most contagious period lasts about 6 weeks after the onset of symptoms. Some studies indicate that a person can spread the infection for many months after the symptoms are completely gone, one particular study indicating as long as 18 months.^[19]

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).^[20][21]

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

Diagnosis

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.

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.^[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] 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, 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.^[11]

A fibrin ring granuloma may be present.

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.^[11]

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

Treatment

Self care

Infectious mononucleosis is generally self-limiting and 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

In terms of pharmacotherapies, non-steroidal anti-inflammatory drugs (NSAIDs) like 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 non-allergic rash close to 99% of the time.^[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

Serious complications are uncommon, occurring in less than 5% of cases:^[35][36]

• 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),^[37] but this has not been confirmed.
• Hematologic: Hemolytic anemia (direct Coombs test is positive) and various cytopenias; Bleeding (caused by thrombocytopenia).^[12]
• 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 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. Similar reactivation or chronic subclinical viral activity in susceptible hosts may trigger multiple host autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, antiphospholipid antibody syndrome, and multiple sclerosis. Such chronic immunologic stimulation may also trigger multiple type of cancers, particularly lymphoma—strongest cancer associations with EBV are nasopharyngeal carcinomas, Burkitt's lymphoma, and Hodgkin's lymphoma. EBV's potential to trigger such a wide range of autoimmune diseases and cancers probably relates to its primary infection of B lymphocytes (the primary antibody-producing cell of the immune system) and ability to alter both lymphocyte proliferation and lymphocyte antibody production.^[3][38][39]

Notes

1. ^ ^{a b} synd/1811 at Who Named It?
2. ^ http://www.kenyon.edu/x26163.xml
3. ^ ^{a b c d} "Epstein-Barr Virus and Infectious Mononucleosis". CDC A–Z Index. National Center for Infectious Diseases. 16. http://www.cdc.gov/ncidod/diseases/ebv.htm. Retrieved December 6, 2009. 
4. ^ ^{a b} "Infectious Mononucleosis (mono, EBV mononucleosis)". Health.state.ny.us. http://www.health.state.ny.us/diseases/communicable/mononucleosis/fact_sheet.htm. Retrieved 2009-11-27. 
5. ^ Н. Филатов: Лекции об острых инфекционных болезнях у детей (N. Filatov: Lektsii ob ostrikh infeksionnîkh boleznyakh u dietei). 2 volumes. Moscow, A. Lang, 1887.
6. ^ E. Pfeiffer: Drüsenfieber. Jahrbuch für Kinderheilkunde und physische Erziehung, Wien, 1889, 29: 257–264.
7. ^ MedicineNet - infectious mononucleosis article Retrieved on 7 Mars, 2009
8. ^ ^{a b} WebMD > Infectious Mononucleosis Last Updated: September 19, 2007. Retrieved on 7 Mars, 2009
9. ^ (History section of) eMedicine Specialties > Infectious Diseases > Infectious Mononucleosis. Author: Burke A Cunha, MD, Professor of Medicine
10. ^ ^{a b c d} Longmore, Murray; Ian Wilkinson, Tom Turmezei, Chee Kay Cheung (2007). Oxford Handbook of Clinical Medicine, 7th edition. Oxford University Press. p. 389. ISBN 0-19-856837-1. 
11. ^ ^{a b c d e f g} Ebell MH (November 2004). "Epstein-Barr virus infectious mononucleosis". American Family Physician 70 (7): 1279–87. PMID 15508538. 
12. ^ ^{a b} Ghosh, Amit K.; Habermann, Thomas (2007). Mayo Clinic Internal Medicine Concise Textbook. Informa Healthcare. ISBN 1-4200-6749-4. 
13. ^ Rosenfield RE; Schmidt PJ, Calvo RC, McGinniss MH (1965). "Anti-i, a frequent cold agglutinin in infectious mononucleosis". Vox Sanguinis 10 (5): 631–634. doi:10.1111/j.1423-0410.1965.tb01418.x. PMID 5864820. 
14. ^ Kagan, B (1977). "Ampicillin rash". Western Journal of Medicine 126 (4): 333–335. PMC 1237570. PMID 855325. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1237570. 
15. ^ "infectious mononucleosis" at Dorland's Medical Dictionary
16. ^ http://www.gorhams.dk/html/the_lymphatic_system.html | title=The Lymphatic System |publisher="Lymphangiomatosis & Gorham's disease Alliance |accessdate=2010-02-08
17. ^ Cozad J (March 1996). "Infectious mononucleosis". The Nurse Practitioner 21 (3): 14–6, 23, 27–8. doi:10.1097/00006205-199603000-00002. PMID 8710247. 
18. ^ "Glandular fever - NHS". National Health Service (NHS). 2010-09-09. http://www.nhs.uk/Conditions/Glandular-fever/Pages/Introduction.aspx. Retrieved 2010-09-09. 
19. ^ "How Long Is Mono Contagious?". Kidshealth.org. http://kidshealth.org/teen/infections/common/mono_contagious.html. Retrieved 2009-11-27. 
20. ^ ped/705 at eMedicine
21. ^ Infectious mononucleosis.
22. ^ Hoagland RJ (June 1975). "Infectious mononucleosis". Primary care 2 (2): 295–307. PMID 1046252. 
23. ^ Mark H. Beers ... (2006). Beers MH, Porter RS, Jones TV, Kaplan JL, Berkwits M, editors.. ed. The Merck manual of diagnosis and therapy (18th ed.). Whitehouse Station (NJ): Merck Research Laboratories. ISBN 0-911910-18-2. 
24. ^ National Center for Emergency Medicine Informatics - Mononucleosis http://www.ncemi.org/cse/cse0314.htm
25. ^ Candy B, Hotopf M (2006). Candy, Bridget. ed. "Steroids for symptom control in infectious mononucleosis". Cochrane Database Syst Rev 3: CD004402. doi:10.1002/14651858.CD004402.pub2. PMID 16856045. 
26. ^ Candy B, Hotopf M. (2006). Candy, Bridget. ed. "Steroids for symptom control in infectious mononucleosis". Cochrane Database of Systematic Reviews 3 (4): CD004402. doi:10.1002/14651858.CD004402.pub2. PMID 16856045. 
27. ^ "Infectious Mononucleosis". WebMD. January 24, 2006. http://www.webmd.com/hw/infection/hw168622.asp. Retrieved 2006-07-10. 
28. ^ ^{a b} Antibiotic Expert Group. Therapeutic guidelines: Antibiotic. 13th ed. North Melbourne: Therapeutic Guidelines; 2006.
29. ^ Torre D, Tambini R (1999). "Acyclovir for treatment of infectious mononucleosis: a meta-analysis". Scand. J. Infect. Dis. 31 (6): 543–7. doi:10.1080/00365549950164409. PMID 10680982. 
30. ^ Balfour HH, Hokanson KM, Schacherer RM (2007). "A virologic pilot study of valacyclovir in infectious mononucleosis". J. Clin. Virol. 39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002. PMID 17369082. 
31. ^ Simon (March 2003). "The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study". International Pediatrics 18 (3): 164–169. 
32. ^ Rafailidis PI, Mavros MN, Kapaskelis A, Falagas, ME (2010). "Antiviral treatment for severe EBV infections in apparently immunocompetent patients". J. Clin. Virol. 49 (3): 151–7. doi:10.1016/j.jcv.2010.07.008. PMID 20739216. 
33. ^ Mulroy R (March 1973). "Amoxycillin rash in infectious mononucleosis". Br Med J 1 (5852): 554. doi:10.1136/bmj.1.5852.554. PMC 1588712. PMID 4266345. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1588712. 
34. ^ van der Linden PD, van der Lei J, Vlug AE, Stricker BH (August 1998). "Skin reactions to antibacterial agents in general practice". J Clin Epidemiol 51 (8): 703–8. doi:10.1016/S0895-4356(98)00041-9. PMID 9743319. "infectious mononucleosis increased the risk of rash in amoxicillin users with a factor of 58." 
    Yet another reported risk is given in:
    * Wargo KA, McConnell V, Jennings M (September 2005). "Amoxicillin/telithromycin-induced rash in infectious mononucleosis". Ann Pharmacother 39 (9): 1577. doi:10.1345/aph.1G140. PMID 16046485. "Approximately 70-100% of patients who receive a ß-lactam antibiotic while infected with the Epstein–Barr virus will develop a maculopapular rash" 
35. ^ Jensen, Hal B (June 2000). "Acute complications of Epstein-Barr virus infectious mononucleosis". Current Opinion in Pediatrics (Lippincott Williams & Wilkins, Inc.) 12 (3): 263–268. doi:10.1097/00008480-200006000-00016. ISSN 1040-8703. PMID 10836164. 
36. ^ Aghenta A; Osowo, A; Thomas, J (May 2008). "Symptomatic atrial fibrillation with infectious mononucleosis". Canadian Family Physician (College of Family Physicians of Canada) 54 (5): 695–696. PMC 2377232. PMID 18474702. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2377232. 
37. ^ Ascherio A, Munger KL (2007). "Environmental risk factors for multiple sclerosis. Part I: the role of infection". Ann. Neurol. 61 (4): 288–99. doi:10.1002/ana.21117. PMID 17444504. 
38. ^ Sitki-Green D, Covington M, Raab-Traub N (February; 77(3): 2003). "Compartmentalization and Transmission of Multiple Epstein-Barr Virus Strains in Asymptomatic Carriers". Journal of Virology 77 (3): 1840–1847. doi:10.1128/JVI.77.3.1840-1847.2003. PMC 140987. PMID 12525618. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=140987. 
39. ^ Hadinoto V, Shapiro M, Greenough TC, Sullivan JL, Luzuriaga K, Thorley-Lawson DA (February 1, 2008). "On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis". Blood 111 (3): 1420–1427. doi:10.1182/blood-2007-06-093278. PMC 2214734. PMID 17991806. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2214734.