Infectious mononucleosis (IM,mono), also known asglandular fever, is an infection usually caused by theEpstein–Barr virus (EBV).[2][3] Most people are infected by the virus as children, when the disease produces few or no symptoms.[2] In young adults, the disease often results infever, sore throat,enlarged lymph nodes in the neck, andfatigue.[2] Most people recover in two to four weeks; however, feeling tired may last for months.[2] Theliver orspleen may also become swollen,[3] and in less than one percent of casessplenic rupture may occur.[6]
While usually caused by the Epstein–Barr virus, also known as human herpesvirus 4, which is a member of theherpesvirus family,[3] a few other viruses[3] and theprotozoonToxoplasma gondii[7] may also cause the disease. It is primarily spread throughsaliva but can rarely be spread throughsemen orblood.[2] Spread may occur by objects such as drinking glasses or toothbrushes or through a cough or sneeze.[2][8] Those who are infected can spread the disease weeks before symptoms develop.[2] Mono is primarily diagnosed based on the symptoms and can be confirmed with blood tests for specificantibodies.[3] Another typical finding isincreased blood lymphocytes of which more than 10% are reactive.[3][9] Themonospot test is not recommended for general use due to poor accuracy.[10]
There is novaccine for EBV; however, there isongoing research.[11][12] Infection can be prevented by not sharing personal items or saliva with an infected person.[2] Mono generally improves without any specific treatment.[2] Symptoms may be reduced by drinking enough fluids, getting sufficient rest, and takingpain medications such asparacetamol (acetaminophen) andibuprofen.[2][4]
Mononucleosis most commonly affects those between the ages of 15 and 24 years in thedeveloped world.[9] In thedeveloping world, people are more often infected in early childhood when there are fewer symptoms.[13] In those between 16 and 20 it is the cause of about 8% of sore throats.[9] About 45 out of 100,000 people develop infectious mono each year in the United States.[5] Nearly 95% of people have had an EBV infection by the time they are adults.[5] The disease occurs equally at all times of the year.[9] Mononucleosis was first described in the 1920s and is colloquially known as "the kissing disease".[14]
Main symptoms of infectious mononucleosis[15]Exudativepharyngitis in a person with infectious mononucleosisRash from using penicillin while infected with IM[16]Maculopapular rash from amoxicillin use during EBV infection
Thesigns andsymptoms of infectious mononucleosis vary with age.
Before puberty, the disease typically only producesflu-like symptoms, if any at all.[17] When found, symptoms tend to be similar to those of commonthroat infections (mildpharyngitis, with or withouttonsillitis).[16]
Another major symptom isfeeling tired.[2]Headaches are common, andabdominal pains withnausea orvomiting sometimes also occur.[18] Symptoms most often disappear after about 2–4 weeks.[2][22] However, fatigue and a general feeling of being unwell (malaise) may sometimes last for months.[16] Fatigue lasts more than one month in an estimated 28% of cases.[23] Mild fever, swollen neck glands andbody aches may also persist beyond 4 weeks.[16][24][25] Most people are able to resume their usual activities within 2–3 months.[24]
It generally gets better on its own in people who are otherwise healthy.[29] When caused by EBV, infectious mononucleosis is classified as one of theEpstein–Barr virus–associated lymphoproliferative diseases. Occasionally the disease may persist and result in a chronic infection. This may develop into systemic EBV-positive T celllymphoma.[29]
Infectious mononucleosis mainly affects younger adults.[16] When older adults do catch the disease, they less often have characteristic signs and symptoms such as the sore throat and lymphadenopathy.[16][25] Instead, they may primarily experience prolonged fever, fatigue, malaise and body pains.[16] They are more likely to have liver enlargement andjaundice.[25] People over 40 years of age are more likely to develop serious illness.[30]
The exact length oftime between infection and symptoms is unclear. A review of the literature made an estimate of 33–49 days.[31] In adolescents and young adults, symptoms are thought to appear around 4–6 weeks after initial infection.[16] Onset is often gradual, though it can be abrupt.[30] The main symptoms may bepreceded by 1–2 weeks of fatigue, feeling unwell and body aches.[16]
About 90% of cases of infectious mononucleosis are caused by theEpstein–Barr virus, a member of theHerpesviridae family ofDNA viruses. It is one of the most commonly foundviruses throughout the world. Contrary to common belief, the Epstein–Barr virus is not highly contagious. It can only be contracted through direct contact with an infected person'ssaliva, such as through kissing or sharing toothbrushes.[32] About 95% of the population has been exposed to this virus by the age of 40, but only 15–20% of teenagers and about 40% of exposed adults actually develop infectious mononucleosis.[33]
About 5–7% of cases of infectious mononucleosis is caused byhuman cytomegalovirus (CMV), another type ofherpes virus.[34] This virus is found in body fluids includingsaliva,urine,blood,tears,[35]breast milk and genital secretions.[36] A person becomes infected with thisvirus by direct contact with infected body fluids. Cytomegalovirus is most commonly transmitted through kissing and sexual intercourse. It can also be transferred from an infected mother to her unborn child. This virus is often "silent" because the signs and symptoms cannot be felt by the person infected.[35] However, it can cause life-threatening illness in infants, people withHIV,transplant recipients, and those with weakimmune systems. For those with weak immune systems, cytomegalovirus can cause more serious illnesses such aspneumonia and inflammations of theretina,esophagus,liver,large intestine, andbrain. Approximately 90% of the human population has been infected with cytomegalovirus by the time they reach adulthood, but most are unaware of the infection.[37] Once a person becomes infected with cytomegalovirus, the virus stays in their body throughout the person's lifetime. During this latent phase, the virus can be detected only inmonocytes.[36]
Epstein–Barr virus infection is spread viasaliva, and has anincubation period of four to seven weeks.[38] The length of time that an individual remainscontagious 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, possibly up to a year and a half.[39]
The virus replicates first withinepithelial cells in thepharynx (which causespharyngitis, or sore throat), and later primarily withinB cells (which are invaded via theirCD21). The host immune response involves cytotoxic (CD8-positive)T cells against infected B lymphocytes, resulting in enlarged, reactive lymphocytes (Downey cells).[40]
Infectious mononucleosis, peripheral smear, high power showing reactive lymphocytesSplenomegaly due to mononucleosis resulting in a subcapsular hematomaSplenomegaly due to mononucleosis resulting in a subcapsular hematoma
The presence of anenlarged spleen, and swollen posteriorcervical,axillary, andinguinal lymph nodes are the most useful to suspect a diagnosis of infectious mononucleosis. On the other hand, the absence of swollen cervical lymph nodes 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 an enlarged spleen means it should not be used as evidence against infectious mononucleosis.[25] A physical examination may also showpetechiae in thepalate.[25]
The heterophile antibody test, or monospot test, works by agglutination of red blood cells from guinea pigs, sheep and horses. This test is specific but not particularlysensitive (with afalse-negative rate of as high as 25% in the first week, 5–10% in the second, and 5% in the third).[25] About 90% of diagnosed people have heterophile antibodies by week 3, disappearing in under a year. Theantibodies involved in the test do not interact with the Epstein–Barr virus or any of itsantigens.[44]
The monospot test is not recommended for general use by theCDC due to its poor accuracy.[10]
Serologic tests detectantibodies directed against the Epstein–Barr virus.Immunoglobulin G (IgG), when positive, mainly reflects a past infection, whereasimmunoglobulin M (IgM) mainly reflects a current infection. EBV-targeting antibodies can also be classified according to which part of the virus they bind to:
Viral capsid antigen (VCA):
Anti-VCA IgM appear early after infection, and usually, disappear within 4 to 6 weeks.[10]
Anti-VCA IgG appears in the acute phase of EBV infection, reaches a maximum at 2 to 4 weeks after onset of symptoms and thereafter declines slightly and persists for the rest of a person’s life.[10]
Early antigen (EA)
Anti-EA IgG appears in the acute phase of illness and disappears after 3 to 6 months. It is associated with having an active infection. Yet, 20% of people may have antibodies against EA for years despite having no other sign of infection.[10]
EBV nuclear antigen (EBNA)
Antibody to EBNA slowly appears 2 to 4 months after the onset of symptoms and persists for the rest of a person’s life.[10]
When negative, these tests are more accurate than the heterophile antibody test in ruling out infectious mononucleosis. When positive, they feature similar specificity 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.[45]
Elevated hepatictransaminase levels are highly suggestive of infectious mononucleosis, occurring in up to 50% of people.[25]
Byblood film, one diagnostic criterion for infectious mononucleosis is the presence of 50%lymphocytes with at least 10%reactive lymphocytes (large, irregularnuclei),[44] while the person also has fever, pharyngitis, andswollen lymph nodes. The reactive lymphocytes resembledmonocytes when they were first discovered, thus the term "mononucleosis" was coined.
About 10% of people who present a clinical picture of infectious mononucleosis do not have an acute Epstein–Barr-virus infection.[48] A differential diagnosis of acute infectious mononucleosis needs to take into considerationacute cytomegalovirus infection andToxoplasma 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 fromtoxoplasmosis is important, since it is associated with significant consequences for thefetus.[25]
AcuteHIV infection can mimic signs similar to those of infectious mononucleosis, and tests should be performed for pregnant women for the same reason as toxoplasmosis.[25]
Infectious mononucleosis is generallyself-limiting, so only symptomatic or supportive treatments are used.[50] 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.[25] Nevertheless, in an effort to decrease the risk ofsplenic rupture, experts advise avoidance ofcontact sports and other heavy physical activity, especially when involving increased abdominal pressure or theValsalva maneuver (as inrowing orweight training), for at least the first 3–4 weeks of illness or until enlargement of the spleen has resolved, as determined by a treating physician.[25][51]
Antiviral agents act by inhibiting viral DNA replication.[34] There is little evidence to support the use of antivirals such asaciclovir andvalacyclovir although they may reduce initial viral shedding.[56][57] Antivirals are expensive, risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasantside effects.[34] Although antivirals are not recommended for people with simple infectious mononucleosis, they may be useful (in conjunction with steroids) in the management of severe EBV manifestations, such as EBV meningitis, peripheral neuritis, hepatitis, or hematologic complications.[58]
Splenomegaly is a common symptom of infectious mononucleosis and health care providers may consider usingabdominal ultrasonography to get insight into the enlargement of a person's spleen.[61] However, because spleen size varies greatly, ultrasonography is not a valid technique for assessing spleen enlargement and should not be used in typical circumstances or to make routine decisions about fitness for playing sports.[61]
Once the acute symptoms of an initial infection disappear, they often do not return. But once infected, the person carries the virus for the rest of their life. The virus typically lives dormant in B lymphocytes. Independent infections of mononucleosis may be contracted multiple times, regardless of whether the person is already carrying the virus dormant. Periodically, the virus can reactivate, during which time the person is again infectious, but usually without any symptoms of illness.[2] Usually, a person with IM 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.[2][67][68]
The characteristic symptomatology of infectious mononucleosis does not appear to have been reported until the late nineteenth century.[69] In 1885, the renowned Russian pediatricianNil Filatov reported an infectious process he called "idiopathic adenitis" exhibiting symptoms that correspond to infectious mononucleosis, and in 1889 a Germanbalneologist and pediatrician,Emil Pfeiffer, independently reported similar cases (some of lesser severity) that tended to cluster in families, for which he coined the termDrüsenfieber ("glandular fever").[70][71][72]
The wordmononucleosis has severalsenses,[73] but today it usually is used in the sense of infectious mononucleosis, which is caused by EBV.
Around the 1920s, infectious mononucleosis was not known and there were few tests to determine an infection. Before this there were not many cases disclosed besides a few and one of these would take place in 1896. This outbreak infected an Ohio community which ended leaving them devastated. Epidemics seemed to keep reappearing here and there including an outbreak that happened in which 87 people were infected in the Falcon Islands.[tone] Some other outbreaks that occurred around this time would include some nurseries and boarding schools and also the U.S. Naval Base, Coronado, California, where hundreds were infected by this virus.[74]
The term "infectious mononucleosis" was coined in 1920 by Thomas Peck Sprunt and Frank Alexander Evans in a classic clinical description of the disease published in theBulletin of the Johns Hopkins Hospital, entitled "Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis)".[70][75] A lab test for infectious mononucleosis was developed in 1931 by Yale School of Public Health Professor John Rodman Paul and Walls Willard Bunnell based on their discovery of heterophile antibodies in the sera of persons with the disease.[76] The Paul-Bunnell Test or PBT was later replaced by theheterophile antibody test.
Yale School of Public Health epidemiologist Alfred E. Evans confirmed through testing that mononucleosis was transmitted mainly through kissing, leading to it being referred to colloquially as "the kissing disease".[80]
^abcdeEbell MH, Call M, Shinholser J, Gardner J (12 April 2016). "Does This Patient Have Infectious Mononucleosis?: The Rational Clinical Examination Systematic Review".JAMA.315 (14):1502–9.doi:10.1001/jama.2016.2111.PMID27115266.
^abcdefghijklmnopqCohen JI (2008). "Epstein-Barr Infections, Including Infectious Mononucleosis". In Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J (eds.).Harrison's principles of internal medicine (17th ed.). New York: McGraw-Hill Medical Publishing Division. pp. 380–91.ISBN978-0-07-146633-2.
^abJohannsen EC, Kaye, KM (2009). "Epstein-Barr virus (infectious mononucleosis, Epstein-Barr virus-associated malignant disease, and other diseases)". In Mandell, GL, Bennett, JE, Dolin, R (eds.).Mandell, Douglas, and Bennett's principles and practice of infectious disease (7th ed.). Philadelphia: Churchill Livingstone.ISBN978-0-443-06839-3.
^abLuzuriaga K, Sullivan, JL (May 27, 2010). "Infectious mononucleosis".The New England Journal of Medicine.362 (21):1993–2000.doi:10.1056/NEJMcp1001116.PMID20505178.
^Richardson M, Elliman, D, Maguire, H, Simpson, J, Nicoll, A (April 2001). "Evidence base of incubation periods, periods of infectiousness and exclusion policies for the control of communicable diseases in schools and preschools".The Pediatric Infectious Disease Journal.20 (4):380–91.doi:10.1097/00006454-200104000-00004.PMID11332662.S2CID7700827.
^Elana Pearl Ben-Joseph."How Long Is Mono Contagious?". Kidshealth.org.Archived from the original on 2016-11-19. Retrieved2016-11-19. Date reviewed: January 2013
^abcLongmore M, Ian Wilkinson, Tom Turmezei, Chee Kay Cheung (2007).Oxford Handbook of Clinical Medicine, 7th edition. Oxford University Press. p. 389.ISBN978-0-19-856837-7.
^Stuempfig ND, Seroy J (2023),"Monospot Test",StatPearls, Treasure Island (FL): StatPearls Publishing,PMID30969561,archived from the original on 2024-04-06, retrieved2023-06-15
^Ruel M, Sevestre H, Henry-Biabaud E, Courouce AM, Capron JP, Erlinger S (December 1992). "Fibrin ring granulomas in hepatitis A".Digestive Diseases and Sciences.37 (12):1915–1917.doi:10.1007/BF01308088.PMID1473440.S2CID25008261.
^Chung HJ, Chi HS, Jang S, Park CJ (1 February 2010). "Epstein-Barr Virus Infection Associated With Bone Marrow Fibrin-Ring Granuloma".American Journal of Clinical Pathology.133 (2):300–304.doi:10.1309/AJCPB7SX7QXASPSK.PMID20093240.
^Bravender T (August 2010). "Epstein-Barr virus, cytomegalovirus, and infectious mononucleosis".Adolescent Medicine: State of the Art Reviews.21 (2):251–64, ix.PMID21047028.
^"Mononucleosis".The Lecturio Medical Concept Library. 4 August 2020.Archived from the original on 11 August 2021. Retrieved11 August 2021.
^Torre D, Tambini R, Tambini (1999). "Acyclovir for treatment of infectious mononucleosis: a meta-analysis".Scand. J. Infect. Dis.31 (6):543–47.doi:10.1080/00365549950164409.PMID10680982.
^Rafailidis PI, Mavros MN, Kapaskelis A, Falagas ME (2010). "Antiviral treatment for severe EBV infections in apparently immunocompetent patients".J. Clin. Virol.49 (3):151–57.doi:10.1016/j.jcv.2010.07.008.PMID20739216.
Putukian M, O'Connor FG, Stricker P, McGrew C, Hosey RG, Gordon SM, Kinderknecht J, Kriss V, Landry G (Jul 2008). "Mononucleosis and athletic participation: an evidence-based subject review".Clinical Journal of Sport Medicine.18 (4):309–15.doi:10.1097/JSM.0b013e31817e34f8.PMID18614881.S2CID23780443.
Spielmann AL, DeLong DM, Kliewer MA (Jan 2005). "Sonographic evaluation of spleen size in tall healthy athletes".AJR. American Journal of Roentgenology.184 (1):45–9.doi:10.2214/ajr.184.1.01840045.PMID15615949.
^Н. Филатов: Лекции об острых инфекционных болезнях у детей [N. Filatov: Lektsii ob ostrikh infeksionnîkh boleznyakh u dietei]. 2 volumes. Moscow, A. Lang, 1887.
^E. Pfeiffer: Drüsenfieber. Jahrbuch für Kinderheilkunde und physische Erziehung, Wien, 1889, 29: 257–264.
