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Infectious mononucleosis

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This article is about mononucleosis caused by Epstein–Barr virus. For mononucleosis caused by cytomegalovirus, see Human cytomegalovirus.
Infectious mononucleosis
SpecialtyInfectious diseases Edit this on Wikidata

Infectious mononucleosis (IM; also known as EBV infectious mononucleosis, Pfeiffer's disease,[1] Filatov's disease,[2] 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, against which over 90% of adults are likely to have acquired immunity by the age of 40.[3][4] 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 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. [5]

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. It is generally a self-limiting disease, and little treatment is normally required.

Signs and symptoms

[[File:Main symptoms of Infectious mononucleosis.png|thumb|Main symptoms of infectious mononucleosis[6][7]

The classic symptoms of mononucleosis are a sore throat, fever, fatigue, malaise, pharyngeal inflammation, vomiting, petechiae and loss of appetite. Symptoms usually persist for two to three weeks,[8] but can last for a couple of months. Fatigue symptoms often persist after the other symptoms have subsided.[5] 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] Another rare presentation is of a Lipschütz ulcer - an acute painful necrotic vulvar ulcer.[11]

Pathophysiology

Epstein–Barr virus infection is spread via saliva, and has an incubation period of four to seven weeks.[12]

The length of time that an individual remains contagious is unclear, but the chances of passing the illness to someone else may be the highest during the first six weeks following infection. Some studies indicate that a person can spread the infection for many months after symptoms are completely gone, with one particular study indicating as long as 18 months.[13]

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).[14]

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

Similar symptoms can be caused by cytomegalovirus, adenovirus, and Toxoplasma gondii, but will result in a negative heterophile antibody test.[3][15]

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.[16][17]

Diagnosis

[[File:MonoThroat.JPG|thumb|Exudative pharyngitis in a person with infectious mononucleosis]]

Cervical lymphadenopathy in a patient with infectious mononucleosis

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 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.[18] 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.

A few studies on infectious mononucleosis have been conducted 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, and posterior cervical, axillary and inguinal adenopathies 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 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] About 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, more sensitive tests 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]

A fibrin ring granuloma may be present.

Differential diagnosis

About 10% of people who present a clinical picture of infectious mononucleosis do not have an acute Epstein-Barr virus infection.[19] A differential diagnosis of acute infectious mononucleosis needs to take into consideration acute cytomegalovirus infection and Toxoplasma gondii infections. Because their management is much the same, it is not always helpful, or possible, to distinguish between Epstein-Barr virus mononucleosis and cytomegalovirus infection. However, in pregnant women, differentiation of mononucleosis from toxoplasmosis is important, since it 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]

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.

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

Treatment

Infectious mononucleosis is generally self-limiting, so only symptomatic and/or supportive treatments are used.[20] The need for rest and return to usual activities after the acute phase of the infection may reasonably be based on the person's general energy levels.[10] In particular, bed rest need not be prescribed, and a return to normal activities is desirable as soon as it is comfortable for them to be resumed (gradually, if necessary).[4] 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, paracetamol or NSAIDs, such as 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.[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] 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.[29]

Although antibiotics exert no antiviral action they may be indicated to treat bacterial secondary infections of the throat,[8] such as with streptococcus (strep throat). However, ampicillin and amoxicillin are contraindicated during acute Epstein–Barr virus infection since the vast majority of patients treated with them develop a diffuse non-allergic rash.[4][30][31][32]

Opioid analgesics are also relatively contraindicated due to risk of respiratory depression.[25]

Prognosis

Serious complications are uncommon, being absent in more than 95% of cases:[33][34]

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.[3][36][37]

History

Further information: Epstein-Barr virus § History

Surprisingly perhaps, the characteristic symptomatology of infectious mononucleosis does not appear to have been reported until the late nineteenth century.[38] In 1887, the renowned Russian pediatrician Nil Filatov reported an infectious process he called "idiopathic denitis" exhibiting symptoms that correspond to infectious mononucleosis,[2][39] and around the same time (in 1889) a German balneologist and pediatrician, Emil Pfeiffer, independently reported similar more or less severe cases clustering in families, for which he coined the term "Drüsenfieber" ("glandular fever").[40][41] The term "infectious mononucleosis" was coined in 1920 by Thomas P. Sprunt and Frank A. Evans in a classic clinical description of the disease published in the Bulletin of the Johns Hopkins Hospital, entitled "Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis)".[40][42]

Epstein-Barr virus was first identified in Burkitt's lymphoma cells by Michael Anthony Epstein and Yvonne Barr at the University of Bristol in 1964. The causative link with infectious mononucleosis was uncovered in 1967 by Werner and Gertrude Henle at the Children's Hospital of Philadelphia, after a laboratory technician handling the virus contracted the disease: comparison of serum samples collected from the technician before and after the onset revealed development of antibodies to the virus.[43]

Notes

  1. ^ Emil Pfeiffer at Who Named It?
  2. ^ a b Filatov's disease at Who Named It?
  3. ^ a b c d e "Epstein-Barr Virus and Infectious Mononucleosis". CDC A–Z Index. National Center for Infectious Diseases. 16. Retrieved December 6, 2009. {{cite web}}: Check date values in: |date= and |year= / |date= mismatch (help); Unknown parameter |month= ignored (help)
  4. ^ a b c "Glandular fever". NICE Clinical Knowledge Summaries. cks.nice.org.uk. 2010. Retrieved 15 June 2013.
  5. ^ a b "Infectious Mononucleosis (mono, EBV mononucleosis)". Health.state.ny.us. Retrieved 2009-11-27.
  6. ^ MedicineNet - infectious mononucleosis article Retrieved on 7 Mars, 2009
  7. ^ a b WebMD > Infectious Mononucleosis Last Updated: September 19, 2007. Retrieved on 7 Mars, 2009
  8. ^ a b "Glandular fever - NHS". National Health Service (NHS). 2010-09-09. Retrieved 2010-09-09.
  9. ^ a b c d Longmore, Murray (2007). Oxford Handbook of Clinical Medicine, 7th edition. Oxford University Press. p. 389. ISBN 0-19-856837-1. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  10. ^ a b c d e f g h Ebell MH (2004). "Epstein-Barr virus infectious mononucleosis". American Family Physician. 70 (7): 1279–87. PMID 15508538. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ Burguete Archel E, Ruiz Goikoetxea M, Recari Elizalde E, Beristain Rementería X, Gómez Gómez L, Iceta Lizarraga A (2013) Lipschütz ulcer in a 17-month-old girl: a rare manifestation of Epstein-Barr primoinfection. Eur J Pediatr
  12. ^ Cozad J (1996). "Infectious mononucleosis". The Nurse Practitioner. 21 (3): 14–6, 23, 27–8. doi:10.1097/00006205-199603000-00002. PMID 8710247. {{cite journal}}: Unknown parameter |month= ignored (help)
  13. ^ "How Long Is Mono Contagious?". Kidshealth.org. Retrieved 2009-11-27.
  14. ^ ped/705 at eMedicine
  15. ^ "The Lymphatic System". Lymphangiomatosis & Gorham's disease Alliance. Retrieved 2010-02-08.
  16. ^ a b Ghosh, Amit K.; Habermann, Thomas (2007). Mayo Clinic Internal Medicine Concise Textbook. Informa Healthcare. ISBN 1-4200-6749-4.{{cite book}}: CS1 maint: multiple names: authors list (link)
  17. ^ Rosenfield RE (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  18. ^ Hoagland RJ (1975). "Infectious mononucleosis". Primary care. 2 (2): 295–307. PMID 1046252. {{cite journal}}: Unknown parameter |month= ignored (help)
  19. ^ Bravender, T (August 2010). "Epstein-Barr virus, cytomegalovirus, and infectious mononucleosis". Adolescent medicine: state of the art reviews. 21 (2): 251–64, ix. PMID 21047028.
  20. ^ Mark H. Beers ... (2006). The Merck manual of diagnosis and therapy (18th ed.). Whitehouse Station (NJ): Merck Research Laboratories. ISBN 0-911910-18-2. {{cite book}}: Unknown parameter |editors= ignored (|editor= suggested) (help)
  21. ^ National Center for Emergency Medicine Informatics - Mononucleosis http://www.ncemi.org/cse/cse0314.htm
  22. ^ Candy B, Hotopf M (2006). Candy, Bridget (ed.). "Steroids for symptom control in infectious mononucleosis". Cochrane Database Syst Rev. 3 (3): CD004402. doi:10.1002/14651858.CD004402.pub2. PMID 16856045.
  23. ^ 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.
  24. ^ "Infectious Mononucleosis". WebMD. January 24, 2006. Retrieved 2006-07-10.
  25. ^ a b Antibiotic Expert Group. Therapeutic guidelines: Antibiotic. 13th ed. North Melbourne: Therapeutic Guidelines; 2006.
  26. ^ 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.
  27. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Simon (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  29. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ Mulroy R (1973). "Amoxycillin rash in infectious mononucleosis". Br Med J. 1 (5852): 554. doi:10.1136/bmj.1.5852.554. PMC 1588712. PMID 4266345. {{cite journal}}: Unknown parameter |month= ignored (help)
  31. ^ Kagan, B (1977). "Ampicillin rash". Western Journal of Medicine. 126 (4): 333–335. PMC 1237570. PMID 855325.
  32. ^ van der Linden PD, van der Lei J, Vlug AE, Stricker BH (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
    Yet another reported risk is given in:
    * Wargo KA, McConnell V, Jennings M (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 {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  33. ^ Jensen, Hal B (2000). "Acute complications of Epstein-Barr virus infectious mononucleosis". Current Opinion in Pediatrics. 12 (3). Lippincott Williams & Wilkins, Inc.: 263–268. doi:10.1097/00008480-200006000-00016. ISSN 1040-8703. PMID 10836164. {{cite journal}}: Unknown parameter |month= ignored (help)
  34. ^ Aghenta A; Osowo, A; Thomas, J (2008). "Symptomatic atrial fibrillation with infectious mononucleosis". Canadian Family Physician. 54 (5). College of Family Physicians of Canada: 695–696. PMC 2377232. PMID 18474702. {{cite journal}}: Unknown parameter |month= ignored (help)
  35. ^ 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.
  36. ^ Sitki-Green D, Covington M, Raab-Traub N (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  37. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  38. ^ Altschuler, EL (1 September 1999). "Antiquity of Epstein-Barr virus, Sjögren's syndrome, and Hodgkin's disease--historical concordance and discordance". Journal of the National Cancer Institute. 91 (17): 1512–3. doi:10.1093/jnci/91.17.1512A. PMID 10469761. Retrieved 17 June 2013.
  39. ^ Н. Филатов: Лекции об острых инфекционных болезнях у детей (N. Filatov: Lektsii ob ostrikh infeksionnîkh boleznyakh u dietei). 2 volumes. Moscow, A. Lang, 1887.
  40. ^ a b Evans, AS (March 1974). "The history of infectious mononucleosis". The American journal of the medical sciences. 267 (3): 189–95. PMID 4363554. Retrieved 17 June 2013.
  41. ^ E. Pfeiffer: Drüsenfieber. Jahrbuch für Kinderheilkunde und physische Erziehung, Wien, 1889, 29: 257–264.
  42. ^ Sprunt TPV, Evans FA. Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis). Bulletin of the Johns Hopkins Hospital. Baltimore, 1920;31:410-417.
  43. ^ Miller, George (December 21, 2006). "Book Review: Epstein–Barr Virus". New England Journal of Medicine. 355 (25): 2708–2709. doi:10.1056/NEJMbkrev39523. Retrieved 17 June 2013.

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