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Infectious mononucleosis
Infectious mononucleosis
Infectious mononucleosis
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Infectious mononucleosis
Other namesGlandular fever, Pfeiffer's disease, Filatov's disease,[1] kissing disease
Swollen lymph nodes in the neck of a person with infectious mononucleosis
SpecialtyInfectious disease
SymptomsFever, sore throat, enlarged lymph nodes in the neck, fatigue[2]
ComplicationsSwelling of the liver or spleen[3]
Duration2–4 weeks[2]
CausesEpstein–Barr virus (EBV) usually spread via saliva[2]
Diagnostic methodBased on symptoms and blood tests[3]
TreatmentDrinking enough fluids, getting sufficient rest, pain medications such as paracetamol (acetaminophen) and ibuprofen[2][4]
Frequency45 per 100,000 per year (U.S.)[5]

Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–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 in fever, sore throat, enlarged lymph nodes in the neck, and fatigue.[2] Most people recover in two to four weeks; however, feeling tired may last for months.[2] The liver or spleen may also become swollen,[3] and in less than one percent of cases splenic rupture may occur.[6]

While usually caused by the Epstein–Barr virus, also known as human herpesvirus 4, which is a member of the herpesvirus family,[3] a few other viruses[3] and the protozoon Toxoplasma gondii[7] may also cause the disease. It is primarily spread through saliva but can rarely be spread through semen or blood.[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 specific antibodies.[3] Another typical finding is increased blood lymphocytes of which more than 10% are reactive.[3][9] The monospot test is not recommended for general use due to poor accuracy.[10]

There is no vaccine for EBV; however, there is ongoing 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 taking pain medications such as paracetamol (acetaminophen) and ibuprofen.[2][4]

Mononucleosis most commonly affects those between the ages of 15 and 24 years in the developed world.[9] In the developing 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]

Signs and symptoms

[edit]
Main symptoms of infectious mononucleosis[15]
Exudative pharyngitis in a person with infectious mononucleosis
Cross reaction rash
Rash from using penicillin while infected with IM[16]
Maculopapular rash from amoxicillin use during EBV infection
Maculopapular rash from amoxicillin use during EBV infection

The signs and symptoms of infectious mononucleosis vary with age.

Children

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Before puberty, the disease typically only produces flu-like symptoms, if any at all.[17] When found, symptoms tend to be similar to those of common throat infections (mild pharyngitis, with or without tonsillitis).[16]

Adolescents and young adults

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In adolescence and young adulthood, the disease presents with a characteristic triad:[18]

Another major symptom is feeling tired.[2] Headaches are common, and abdominal pains with nausea or vomiting 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 and body aches may also persist beyond 4 weeks.[16][24][25] Most people can resume their usual activities within 2–3 months.[24]

The most prominent sign of the disease is often pharyngitis, which is frequently accompanied by enlarged tonsils with pus—an exudate similar to that seen in cases of strep throat.[16] In about 50% of cases, small reddish-purple spots called petechiae can be seen on the roof of the mouth.[25] Palatal enanthem can also occur, but is relatively uncommon.[16]

A small minority of people spontaneously present a rash, usually on the arms or trunk, which can be macular (morbilliform) or papular.[16] Almost all people given amoxicillin or ampicillin eventually develop a generalized, itchy maculopapular rash, which however does not imply that the person will have adverse reactions to penicillins again in the future.[16][22] Occasional cases of erythema nodosum and erythema multiforme have been reported.[16] Seizures may also occasionally occur.[26]

Complications

[edit]

Spleen enlargement is common in the second and third weeks, although this may not be apparent on physical examination. Rarely, the spleen may rupture.[27] There may also be some enlargement of the liver.[25] Jaundice occurs only occasionally.[16][28]

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 the Epstein–Barr virus–associated lymphoproliferative diseases. Occasionally, the disease may persist and result in a chronic infection. This may develop into systemic EBV-positive T cell lymphoma.[29]

Older adults

[edit]

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 and jaundice.[25] People over 40 years of age are more likely to develop serious illness.[30]

Incubation period

[edit]

The exact length of time 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 be preceded by 1–2 weeks of fatigue, feeling unwell and body aches.[16]

Cause

[edit]

Epstein–Barr virus

[edit]
Main article: Epstein–Barr virus

About 90% of cases of infectious mononucleosis are caused by the Epstein–Barr virus, a member of the Herpesviridae family of DNA viruses. It is one of the most commonly found viruses 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's saliva, 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 develop infectious mononucleosis.[33]

Cytomegalovirus

[edit]
Main article: Human betaherpesvirus 5

About 5–7% of cases of infectious mononucleosis are caused by human cytomegalovirus (CMV), another type of herpes virus.[34] This virus is found in body fluids including saliva, urine, blood, tears,[35] breast milk and genital secretions.[36] A person becomes infected with this virus 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 with HIV, transplant recipients, and those with weak immune systems. For those with weak immune systems, cytomegalovirus can cause more serious illnesses such as pneumonia and inflammations of the retina, esophagus, liver, large intestine, and brain. Approximately 90% of the human population has been infected with cytomegalovirus by the time they reach adulthood. 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 in monocytes.[36]

Other causes

[edit]

Toxoplasma gondii, a parasitic protozoon, is responsible for less than 1% of the infectious mononucleosis cases. Viral hepatitis, adenovirus, rubella, and herpes simplex viruses have also been reported as rare causes of infectious mononucleosis.[7]

Transmission

[edit]

Epstein–Barr virus infection is spread via saliva, and has an incubation period of four to seven weeks.[38] The length of time that an individual remains contagious is unclear. The chances of passing the illness to someone else may be 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]

Pathophysiology

[edit]

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, reactive lymphocytes (Downey cells).[40]

When the infection is acute (recent onset, instead of chronic), heterophile antibodies are produced.[25]

Cytomegalovirus, adenovirus, and Toxoplasma gondii (toxoplasmosis) infections can cause symptoms similar to infectious mononucleosis, but a heterophile antibody test will test negative and differentiate those infections from infectious mononucleosis.[2][41]

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.[42][43]

Diagnosis

[edit]
Infectious mononucleosis, peripheral smear, high power showing reactive lymphocytes
Splenomegaly due to mononucleosis resulting in a subcapsular hematoma
Splenomegaly due to mononucleosis resulting in a subcapsular hematoma

The disease is diagnosed based on:

Physical examination

[edit]

The presence of an enlarged spleen, and swollen posterior cervical, axillary, and inguinal 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 is 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 show petechiae in the palate.[25]

Heterophile antibody test

[edit]
Main article: Heterophile antibody test

The heterophile antibody test, also known as the monospot test, works by agglutination of red blood cells from guinea pigs, sheep and horses. 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).[25] Approximately 90% of diagnosed people 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.[44]

The monospot test is not recommended for general use by the CDC due to its poor accuracy.[10]

Serology

[edit]

Serologic tests detect antibodies directed against the Epstein–Barr virus. Immunoglobulin G (IgG), when positive, mainly reflects a past infection, whereas immunoglobulin 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 antibodies appear early after infection, and usually disappear within 4 to 6 weeks.[10]
  • Anti-VCA IgG antibodies appear in the acute phase of EBV infection, reach a maximum at 2 to 4 weeks after onset of symptoms, and thereafter decline slightly and persist 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 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]

Other tests

[edit]

Differential diagnosis

[edit]

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 consideration acute cytomegalovirus infection and Toxoplasma gondii infections. Because their management is similar, 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.[25]

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.[25]

People with infectious mononucleosis are sometimes misdiagnosed with a streptococcal pharyngitis (because of the symptoms of fever, pharyngitis and adenopathy) and are given antibiotics such as ampicillin or amoxicillin as treatment.[49]

Other conditions from which to distinguish infectious mononucleosis include leukemia, tonsillitis, diphtheria, common cold and influenza (flu).[44]

Treatment

[edit]

Infectious mononucleosis is generally self-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 of splenic rupture, experts advise avoidance of contact sports and other heavy physical activity, especially when involving increased abdominal pressure or the Valsalva maneuver (as in rowing or weight 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]

Medications

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Paracetamol (acetaminophen) and NSAIDs, such as ibuprofen, may be used to reduce fever and pain. Prednisone, a corticosteroid, while used to try to reduce throat pain or enlarged tonsils, remains controversial due to the lack of evidence that it is effective and the potential for side effects. Aspirin should not be given to under 16s due to the risk of Reye’s Syndrome.[52][53] Intravenous corticosteroids, usually hydrocortisone or dexamethasone, are not recommended for routine use but may be useful if there is a risk of airway obstruction, a very low platelet count, or hemolytic anemia.[54][55]

Antiviral agents act by inhibiting viral DNA replication.[34] There is little evidence to support the use of antivirals such as aciclovir and valacyclovir, 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 unpleasant side 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]

Although antibiotics exert no antiviral action they may be indicated to treat bacterial secondary infections of the throat,[59] such as with streptococcus (strep throat). However, ampicillin and amoxicillin are not recommended during acute Epstein–Barr virus infection as a diffuse rash may develop.[60]

Observation

[edit]

Splenomegaly is a common symptom of infectious mononucleosis, and healthcare providers may consider using abdominal 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. It should not be used in typical circumstances or to make routine decisions about fitness for playing sports.[61]

Prognosis

[edit]

Serious complications are uncommon, occurring in less than 5% of cases:[62][63]

Once the acute symptoms of an initial infection resolve, 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). During this phase, the virus can spread to others.[2][67][68]

History

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Further information: Epstein–Barr virus § History

The characteristic symptomatology of infectious mononucleosis does not appear to have been reported until the late nineteenth century.[69] In 1885, the renowned Russian pediatrician Nil Filatov reported an infectious process he called "idiopathic adenitis" exhibiting symptoms that correspond to infectious mononucleosis, and in 1889 a German balneologist and pediatrician, Emil Pfeiffer, independently reported similar cases (some of lesser severity) that tended to cluster in families, for which he coined the term Drüsenfieber ("glandular fever").[70][71][72]

The word mononucleosis has several senses,[73] but today it usually is used in the sense of infectious mononucleosis, which is caused by EBV.

Around the 1920s, infectious mononucleosis was unknown, and there were few tests to determine an infection. Before this, there were few cases disclosed, and one of these took place in 1896. This outbreak devastated an Ohio community. 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 the Bulletin 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 the heterophile antibody test.

The 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.[77] The 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.[78][79]

Yale School of Public Health epidemiologist Alfred S. Evans confirmed through testing that mononucleosis was transmitted mainly through kissing, leading to it being referred to colloquially as "the kissing disease".[80]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Infectious mononucleosis

View on Grokipedia
from Grokipedia
Infectious mononucleosis, often referred to as mono or the kissing disease, is a contagious viral illness primarily caused by the Epstein-Barr virus (EBV), a member of the herpesvirus family, and is characterized by symptoms including fever, , swollen lymph nodes, and profound fatigue. While EBV is the most common etiologic agent, other viruses such as (CMV), adenovirus, and rarely can produce a similar clinical . The disease typically manifests as a self-limiting with an of 4 to 6 weeks, during which the virus replicates in B lymphocytes and spreads systemically. Transmission occurs primarily through person-to-person contact via , such as kissing, sharing drinks, or utensils, though it can also spread through or in rare cases; the is shed in for weeks to months after symptom onset, with prolonged shedding possible in carriers. Epidemiologically, EBV is ubiquitous, with seroprevalence reaching up to 95% in adults worldwide, but symptomatic infectious mononucleosis is most common in adolescents and young adults aged 15 to 24 years, particularly in developed where primary is often delayed until this age group. In the United States, incidence rates are approximately twice as high among White individuals compared to Black individuals based on 2010-2021 data from the , and recent data indicate peak rates among females and those aged 15 to 19. The classic clinical presentation includes the triad of fever, (often with exudative mimicking strep throat), and posterior , accompanied by , , and in about 50% of cases; can persist for weeks to months even after other symptoms resolve. is supported by the (Monospot), which detects IgM antibodies and has high specificity (nearly 100%) but moderate sensitivity (around 85%), alongside peripheral blood findings of (>50% lymphocytes) and atypical lymphocytes (>10%). Serologic testing for EBV-specific antibodies (e.g., IgM to viral antigen) confirms acute infection when heterophile tests are negative. There is no specific antiviral treatment for infectious mononucleosis, as it is generally self-limited with symptoms resolving in 2 to 4 weeks; focuses on supportive care, including , hydration, over-the-counter analgesics for fever and pain, and avoidance of contact sports for at least 3 weeks due to the risk of splenic rupture. Corticosteroids may be used in severe cases involving airway obstruction or significant complications like , but antibiotics are ineffective against the viral cause and should only address secondary bacterial infections. Potential complications, though rare, include splenic rupture (most common in the first 3 weeks), neurologic issues such as Guillain-Barré syndrome, and chronic fatigue; in immunocompromised individuals, EBV can lead to or malignancies like . Prevention relies on good practices, such as not sharing personal items, though no is currently available.

Epidemiology

Prevalence and Incidence

Infectious mononucleosis, primarily caused by primary Epstein-Barr virus (EBV) , exhibits high global seroprevalence, with over 90% of adults worldwide being seropositive for EBV antibodies. Primary EBV is frequently asymptomatic during childhood, contributing to this widespread latent in the adult population. In the United States, the annual incidence of infectious mononucleosis is approximately 61 cases per 100,000 person-years ( from 2010–2021), with the highest rates observed in the 15-19 age group, reaching 481 cases per 100,000 person-years, particularly among females. rates have decreased significantly since 2010 across all age groups, including adolescents. Hospitalization rates among diagnosed cases have also increased over this period, reaching an overall 4.3%. Incidence is notably higher in developed countries, where primary EBV is often delayed until or early adulthood, leading to symptomatic mononucleosis in 30-50% of cases. In contrast, developing regions experience lower rates of symptomatic disease due to common early exposure, with approximately 50% of children seropositive by age 5.

Risk Factors and Demographics

Infectious mononucleosis exhibits peak incidence among adolescents and young adults aged 15 to 24 years, when primary Epstein-Barr virus (EBV) is most likely to manifest as symptomatic disease rather than , with highest rates in females aged 15-19. In this demographic, annual incidence rates typically range from 172 to 481 cases per 100,000 person-years (data from 2010–2021). Females experience a slightly higher overall rate of symptomatic infectious mononucleosis compared to males. Socioeconomic and racial factors significantly influence risk, with higher incidence observed in individuals from higher socioeconomic groups and Caucasian populations due to postponed EBV acquisition during childhood. In contrast, non-Caucasian ethnic groups and those from low-income backgrounds often undergo early seroconversion in infancy or , resulting in lower rates of symptomatic disease; for instance, incidence among individuals is approximately 30 times higher than among individuals, attributable to these disparities in exposure timing. Seroprevalence of EBV is generally higher among females across age groups, indicating earlier or more frequent exposure. Close-contact environments such as college dormitories and military barracks substantially elevate outbreak risk due to shared living spaces facilitating transmission. Annual incidence in settings ranges from 1% to 5% among susceptible students, while rates in military academies can reach 1,100 cases per 100,000 person-years; secondary attack rates among close contacts in these settings have been documented as high as 40% over several months of observation. Immunosuppressed individuals, such as those with or post-transplant patients on T-cell suppressing therapies, face an elevated risk of severe or atypical presentations of infectious mononucleosis, including uncontrolled EBV replication leading to . Males also demonstrate a predisposition to certain complications, such as splenic rupture, which occurs more frequently in male patients despite overall similar infection rates.

Signs and Symptoms

In Children

In children under 15 years of age, primary with Epstein-Barr virus (EBV), the primary cause of infectious mononucleosis, is often or manifests as a mild upper respiratory , with only a small proportion developing the classic syndrome of infectious mononucleosis. Studies indicate that while up to 90% of young children experience , symptomatic cases typically involve nonspecific symptoms rather than the severe triad seen in older groups. This age group has a higher likelihood of acquiring primary EBV early in life, leading to the establishment of lifelong viral latency in B lymphocytes without progression to the full mononucleosis syndrome. When symptoms do occur in children, they are generally mild and include low-grade fever, mild , and occasional , distinguishing them from the more pronounced and in adolescents. is rare in this population, occurring in less than 10% of cases, compared to higher rates in symptomatic older patients. These features contribute to the challenge of distinguishing EBV-related illness from other common pediatric viral infections. In young children under 5 years, EBV infection frequently mimics other viral illnesses such as adenovirus, presenting with subtle signs like low-grade fever and mild respiratory symptoms, while fatigue is less prominent than in older children. This mild presentation underscores the subclinical nature of most primary infections in , facilitating and long-term immunity without notable morbidity.

In Adolescents and Young Adults

Infectious mononucleosis typically presents with a classic triad of symptoms in adolescents and young adults aged 15 to 24 years, consisting of fever, , and posterior . The fever often reaches up to 40°C and persists for 1 to 2 weeks, while affects 70% to 80% of cases, manifesting as severe with tonsillar enlargement and white . Posterior is symmetrical and tender, commonly involving the neck and occasionally extending to other sites like the armpits. Profound fatigue is a hallmark symptom, often debilitating and lasting 2 to 4 weeks during the acute phase, though it may persist for up to 6 months in some individuals, significantly impacting daily activities. occurs in approximately 50% of cases, contributing to abdominal discomfort, while is less frequent, seen in 10% to 15% of patients. Additional signs include palatal petechiae, which appear as small red spots on the roof of the , and periorbital , often bilateral and affecting about one-third of cases. A develops in 70% to 90% of patients if or amoxicillin is administered, typically due to a reaction rather than the infection itself. Systemic symptoms such as and are common, further exacerbating discomfort and frequently leading to school or work during the illness. These manifestations distinguish the more severe, symptomatic form of the disease in this age group from milder or presentations in younger children.

In Older Adults

Infectious mononucleosis caused by Epstein-Barr virus (EBV) presents atypically in older adults, typically those over 40 years of age, with a lower frequency of classic symptoms compared to younger patients. occurs in approximately 47% of cases, and in about 43%, often leading to diagnostic delays as the illness may mimic other conditions such as or . In contrast, prolonged fever is nearly universal, affecting 95% of patients, while and dominate the clinical picture, frequently persisting for weeks to months and resembling systemic illnesses like or malignancy. Hepatic involvement is more prominent in this population, with hepatomegaly observed in 42% and hepatic dysfunction, including elevated alanine aminotransferase (ALT) levels, in up to 27% of cases; however, transaminitis can occur in 80% or more of EBV infections overall, though symptomatic is less common in youth. Splenomegaly is present in roughly 33% of older adults, lower than the rates seen in adolescents. Visceral complications, such as or neurological manifestations including Guillain-Barré syndrome, arise more frequently in older adults. Due to underlying comorbidities and atypical features, older adults face higher rates of complications, with occurring in up to 30% compared to less than 10% in younger individuals; recent data indicate increasing hospitalization rates among those with infectious mononucleosis, particularly influenced by age. These patients may require closer monitoring for organ-specific involvement, as detailed in the broader complications section, to prevent progression to or other rare sequelae.

Incubation Period

The of infectious mononucleosis, primarily caused by Epstein-Barr virus (EBV), refers to the time from initial exposure to the onset of clinical symptoms, typically lasting 4 to 6 weeks. This duration, equivalent to 30 to 50 days, is longer than that of many other viral illnesses owing to the extended replication cycle of EBV in host B lymphocytes. In the early phase, during the first 1 to 2 weeks post-exposure, the infection is , with EBV initially binding to and entering B cells in the and lymphoid tissues, establishing a latent without significant or immune activation. Viral dissemination then progresses, with low-level replication detectable in the blood around 3 weeks before symptom onset, followed by increased shedding in the oral cavity approximately 1 week prior. Toward the later stages of the incubation period, around weeks 3 to 4, some individuals may experience prodromal symptoms such as mild or preceding the full clinical syndrome. The overall length can vary, influenced by factors including the initial and the host's immune competence, with shorter periods observed in young children or rare cases of reinfection in previously exposed individuals.

Complications

Infectious mononucleosis, primarily caused by Epstein-Barr virus (EBV), is generally self-limiting but can lead to rare acute complications that require prompt recognition to prevent morbidity. These include splenic rupture, airway obstruction, hematologic abnormalities, and neurological involvement, with incidences varying based on patient factors such as age and immune status. Splenic rupture is a life-threatening complication occurring in 0.1% to 0.5% of cases, with the highest risk during the second to third week after symptom onset due to splenomegaly from . To mitigate this risk, patients are advised to avoid contact sports and strenuous activities for 4 to 6 weeks post-diagnosis. Airway obstruction arises from severe tonsillar enlargement in 1% to 3.5% of patients, particularly children, potentially leading to respiratory compromise if unmanaged. Hematologic complications affect a subset of patients, including in about 1% to 3% of cases, often immune-mediated and self-resolving, in 1% to 2%, and rare instances of . Neurological manifestations are uncommon, with or reported in around 1% of cases and in less than 1%, typically presenting as aseptic processes linked to viral invasion or immune response. Prolonged symptoms beyond 6 months, affecting 10% to 20% of patients, may be associated with chronic fatigue syndrome, characterized by persistent fatigue and cognitive issues. Additionally, EBV infection from infectious mononucleosis confers a rare but elevated long-term risk for certain malignancies like Hodgkin's lymphoma and autoimmune conditions such as . In cases of mononucleosis-like illness due to cytomegalovirus (CMV), complications differ from EBV, featuring hepatitis with elevated liver enzymes but less extensive lymphoid tissue involvement, such as reduced tonsillar and cervical lymphadenopathy.

When to seek medical attention

The symptoms of infectious mononucleosis, including fever, sore throat (painful swallowing), and swollen lymph nodes, typically improve within a few weeks. However, medical attention should be sought if symptoms persist longer than 10 days or if any of the following develop: abdominal pain, breathing difficulty, persistent high fever (greater than 101.5 °F or 38.6 °C), severe sore throat or tonsillar swelling, severe headache, weakness in the arms or legs, or jaundice (yellowing of the skin or eyes). Immediate emergency care is required for sharp, sudden, severe abdominal pain (potential sign of splenic rupture), trouble breathing or swallowing, or stiff neck with severe weakness. These may indicate serious complications such as splenic rupture or airway obstruction, or other conditions requiring urgent intervention. Consult a healthcare provider if symptoms do not improve within one to two weeks, as persistent or recurring symptoms may require further evaluation to confirm the diagnosis, manage complications, or exclude alternative causes such as bacterial pharyngitis.

Causes

Epstein-Barr Virus

Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is a member of the gammaherpesvirus subfamily with a linear double-stranded DNA genome of approximately 172 kilobase pairs. This enveloped virus primarily targets B lymphocytes and establishes a lifelong latent infection in these cells following primary exposure. Worldwide, EBV infects more than 95% of adults, often during childhood or adolescence, though the infection may remain asymptomatic in many cases. EBV is the primary causative agent of infectious mononucleosis, accounting for 80% to 90% of symptomatic cases, particularly in adolescents and young adults. During acute infection, the virus replicates in epithelial cells of the oropharynx and then infects B cells, leading to the characteristic symptoms of mononucleosis as the initial manifestation of primary EBV exposure. Two main strains exist—type 1 and type 2—differentiated by variations in the EBV nuclear (EBNA)-2 and EBNA-3 genes; type 1 strains are more efficient at transforming B cells and are associated with higher lymphoproliferative potential, while type 1 strains predominate globally and type 2 are more common in certain regions such as parts of . Unlike , EBV exhibits no significant antigenic drift, maintaining stable genomic features across strains. Beyond mononucleosis, EBV demonstrates oncogenic potential, with strong associations to malignancies such as endemic and . In these cancers, latent viral proteins contribute to cellular transformation and immune evasion. A key viral oncoprotein, latent membrane protein 1 (LMP1), mimics CD40 receptor signaling to promote B-cell survival and proliferation by activating pathways like , independent of ligand binding. This enables persistent latency and underlies EBV's role in .

Cytomegalovirus and Other Pathogens

(CMV), a betaherpesvirus, is the most common non-Epstein-Barr virus (EBV) cause of infectious mononucleosis-like , accounting for approximately 5% to 7% of cases in immunocompetent individuals. Unlike EBV, which primarily targets B lymphocytes, CMV preferentially infects monocytes and macrophages, leading to a slower cycle that contributes to a more protracted clinical course. The caused by CMV shares core features with EBV-induced mononucleosis, including fever, , and atypical , but typically features less severe (present in about 39% of cases versus 79% for EBV) and reduced (about 20% versus 77% for EBV). Hepatic involvement is particularly prominent in CMV-associated mononucleosis, with elevated liver transaminases occurring in up to 92% of patients, often exceeding three times the upper limit of normal and reflecting greater emphasis on compared to the EBV form. In immunocompromised patients, such as those with or post-transplant, CMV mononucleosis-like illness becomes more prevalent and severe. Other pathogens rarely cause mononucleosis-like syndromes but must be considered in differential contexts. Acute infection, presenting as retroviral syndrome, mimics mononucleosis in ≤2% of cases, with prominent , mucocutaneous ulcers, and myalgias alongside fever and . Adenovirus infections predominantly feature severe and with milder systemic symptoms, while typically manifests as isolated without significant fever or . Human herpesviruses 6 and 7 (HHV-6/7) occasionally produce similar febrile illnesses with and encephalitis-like features, particularly in children. Bacterial pathogens, such as group A , can simulate early pharyngitis-dominant presentations but are generally distinguished by rapid response to antibiotics and absence of atypical lymphocytes.

Transmission

Infectious mononucleosis, primarily caused by the Epstein-Barr virus (EBV), is transmitted mainly through , earning it the nickname "kissing disease" due to close oral contact such as deep kissing. The virus spreads via direct exposure to infected , including through sharing utensils, drinks, or food, with secondary attack rates among susceptible household contacts estimated at around 19% within six months of an . Individuals remain infectious for several months after the onset of symptoms, with peak in occurring during the first six months post-infection, though shedding can persist for up to a year or longer in some cases. Transmission via or is rare, occurring in less than 1% of cases overall, but it poses a higher in seronegative recipients of EBV-positive donor material. EBV is not transmitted through airborne routes like respiratory droplets; instead, indirect contact via fomites such as contaminated surfaces carries limited , as the virus survives only for hours on dry inanimate objects while moisture is present. The , typically 4-6 weeks, can vary based on the size of the viral inoculum, with larger doses potentially shortening this timeframe in closed populations like families or boarding schools. Asymptomatic carriers play a key role in ongoing transmission, with 10-20% of EBV-seropositive individuals intermittently shedding the virus in saliva lifelong, facilitating spread without overt symptoms.

Pathogenesis

Viral Infection and Replication

Infectious mononucleosis is primarily caused by primary infection with Epstein-Barr virus (EBV), a herpesvirus that initiates its lifecycle in the oropharynx following transmission through . The enters host cells via the CD21 (, CR2) receptor, which is expressed on B lymphocytes and certain epithelial cells in the oropharyngeal mucosa; attachment is mediated by the viral envelope glycoprotein gp350 (also known as gp350/220), which binds with high affinity to CD21 to facilitate viral docking and subsequent entry through or fusion. This initial interaction allows EBV to target both epithelial cells and resting B cells in the oral cavity during the early , which typically lasts 4-6 weeks. Upon entry into oropharyngeal epithelial cells, EBV undergoes lytic replication, a process that produces infectious virions over the first 1-2 weeks of ; this phase involves sequential expression of immediate-early, early, and late viral genes, leading to viral , assembly of new virions, and cell that releases progeny into the oral secretions. These released virions then infect circulating B cells in the underlying lymphoid tissue, shifting the toward the hematopoietic compartment. In B cells, EBV establishes a latent by circularizing its linear into a closed circular DNA that persists extrachromosomally in the nucleus; this transformation is driven by the expression of key latent genes, including Epstein-Barr nuclear antigens (EBNA1, EBNA2, EBNA3s, and EBNALP) and latent membrane proteins (LMP1 and LMP2), which reprogram the host cell's growth and survival pathways to confer immortality and promote proliferation akin to lymphoblastoid cell lines. The transformed B cells disseminate systemically, leading to viral spread to lymphoid organs such as the tonsils, lymph nodes, and , where infected B cells expand clonally; , marked by detectable EBV DNA in peripheral blood, begins during the and peaks around the onset of clinical symptoms, reflecting widespread B-cell infection. During the acute phase of mononucleosis, EBV latency is characterized by Type III latency, a growth-promoting program with full expression of EBNA and LMP genes that supports B-cell proliferation in the absence of lytic replication. As the infection resolves, typically within weeks to months, the latency program switches to the more restricted Type I latency in long-lived memory B cells, where only EBNA1 is expressed to maintain the viral with minimal immune detection. This transition ensures lifelong viral persistence while limiting overt replication.

Host Immune Response

The host immune response to Epstein-Barr virus (EBV) in infectious mononucleosis primarily involves robust cellular and humoral components that target infected B cells and control , though this activation also contributes to clinical symptoms such as and . + T cells undergo massive expansion during acute infection, often comprising up to 50% of circulating lymphocytes and manifesting as atypical mononuclear cells that directly lyse EBV-infected B cells. This cytotoxic response, while essential for limiting viral spread, induces bystander tissue damage through release and , exacerbating symptoms like fever and exhaustion. The humoral features early production of IgM antibodies against EBV viral (VCA), detectable at symptom onset and typically resolving within 3-6 months, alongside persistent IgG antibodies to VCA that confer lifelong immunity. Additionally, non-specific heterophile antibodies, primarily IgM directed against horse red blood cells, arise in approximately 85% of adolescents and young adults with infectious mononucleosis, aiding in but not providing direct antiviral protection. A cytokine storm accompanies the acute phase, with elevated levels of interleukin-6 (IL-6) and interferon-γ (IFN-γ) driving fever, lymphoproliferation, and in nearly all patients. Natural killer (NK) cells play an early role in controlling the lytic replication phase by recognizing and eliminating infected cells before full T-cell activation. Regulatory T cells (Tregs) emerge to modulate this response, suppressing excessive activation to prevent and maintain immune . EBV induces polyclonal activation of B cells, leading to hypergammaglobulinemia as a hallmark of the infection, which reflects widespread B-cell proliferation independent of specific stimulation. In most cases, this response resolves with immune control, but failure of effective containment can rarely progress to chronic active EBV disease in less than 1% of primary infections, characterized by persistent and severe complications.

Diagnosis

Physical Examination

The physical examination for infectious mononucleosis begins with a detailed history to elicit clues suggestive of the condition. Patients often report recent close personal contact, such as kissing or sharing utensils, which facilitates transmission via , though the of 32 to 49 days may obscure recall of exposure. typically emerges insidiously as a prominent early symptom, accompanied by , , and , while the absence of helps distinguish it from common respiratory viral infections. On examination, generalized is a hallmark finding, with posterior cervical nodes most commonly affected—tender, enlarged to greater than 1 cm, and present in approximately 80% of cases—though axillary and inguinal involvement occurs in up to 23% and aids in raising suspicion. The frequently shows tonsillar enlargement with gray-white in about 50% to 60% of patients, and palatal petechiae at the hard-soft junction appear in roughly 25%, providing a more specific clue. Fever is noted in most cases, often with mild , while is palpable below the costal margin in approximately 50% of adolescents and adults, sometimes confirmed by dullness to percussion in the left upper quadrant. A may develop in nearly all patients if amoxicillin or is administered empirically, occurring in fewer than 5% otherwise. is uncommon on exam unless concurrent is present, and periorbital or mild may occasionally be appreciated in minority cases. These findings collectively support clinical suspicion, prompting further diagnostic evaluation to differentiate from conditions like .

Heterophile Antibody Test

The heterophile antibody test, also known as the Monospot test, serves as a rapid screening tool for diagnosing infectious mononucleosis primarily caused by Epstein-Barr virus in patients with compatible clinical symptoms. It detects IgM heterophile antibodies produced during acute infection through the Paul-Bunnell phenomenon, in which these antibodies cause of sheep or red blood cells but are not absorbed by guinea pig kidney extracts, distinguishing them from non-specific heterophile antibodies like Forssman antibodies. The procedure involves mixing a patient's serum or sample with antigen-coated latex particles or animal red blood cells on a slide, where visible indicates a positive result, typically obtained within 5 to 10 minutes. This quick, point-of-care method makes it suitable for initial evaluation following clinical suspicion from . The test exhibits a sensitivity of approximately 85% in adolescents and young adults, but sensitivity decreases to around 50% in children under 12 years and older adults, with a specificity of 94 to 95%. Heterophile antibodies generally appear 1 to 2 weeks after symptom onset, reach peak levels at 3 to 4 weeks, and become undetectable in most cases after 6 months. False-negative results occur frequently in early disease (within the first week, up to 25% of cases) and in approximately 10% of mononucleosis-like illnesses due to , which do not produce these antibodies. False positives are uncommon but can arise in conditions such as , , or certain autoimmune disorders. Importantly, the test shows no cross-reactivity with antibodies, aiding in differentiation from other viral causes.

Serological Tests

Serological tests for Epstein-Barr virus (EBV) are essential for confirming primary infection and distinguishing infectious mononucleosis (IM) from past exposure or reactivation, providing more precise timing than heterophile antibody tests, which have reduced sensitivity in children and young adults. These tests detect specific antibodies against EBV antigens, primarily viral capsid antigen (VCA) and EBV nuclear antigen (EBNA), using methods such as enzyme immunoassays (EIA) or immunofluorescence assays (IFA). VCA IgM antibodies appear early in the acute phase of EBV , typically becoming positive within the first 1-2 weeks of symptom onset and remaining detectable for 4-6 weeks, serving as a marker of recent primary . In contrast, VCA IgG antibodies emerge around 2-3 weeks after , peak at 2-4 weeks, and persist at lower levels for life, with high titers often indicating past exposure rather than acute . EBNA IgG antibodies develop later, usually 2-4 months after primary , and are absent during the acute phase of IM, remaining positive lifelong as evidence of resolved . Interpretation of these antibody profiles allows staging of EBV : a pattern of VCA IgM positive, VCA IgG negative, and EBNA IgG negative indicates acute primary , while VCA IgM negative, VCA IgG positive, and EBNA IgG positive suggests past . In cases where profiles are ambiguous, such as during early when VCA IgM may persist or VCA IgG is newly positive without EBNA, IgG testing can differentiate recent from past ; low reflects immature antibodies in acute or recent cases, whereas high indicates maturation over months.

Other Laboratory Tests

A (CBC) is a key supportive in infectious mononucleosis, often demonstrating with lymphocytes comprising more than 50% of the total . Atypical lymphocytes, referred to as Downey cells, typically account for more than 10% of the lymphocytes and are a characteristic finding that peaks during the first few weeks of illness. Mild is also common, occurring in 25-50% of cases with platelet counts ranging from 100,000 to 150,000 per microliter, though severe reductions are rare and may suggest alternative diagnoses. Liver function tests frequently reveal abnormalities, with elevations in (ALT) and aspartate aminotransferase (AST) observed in over 90% of patients, reflecting mild hepatocellular injury. levels are elevated in approximately 40% of cases but rarely exceed 2 mg/dL, and marked hyperbilirubinemia should prompt consideration of other etiologies such as . Quantitative (PCR) assays for Epstein-Barr virus (EBV) DNA provide a measure of , with acute infectious mononucleosis associated with high viral loads often exceeding 10,000 copies per milliliter in plasma or . This test is particularly valuable in immunocompromised individuals, such as transplant recipients, for detecting active infection, monitoring viral replication, and assessing risk of complications like . Abdominal imaging, primarily via , is employed to evaluate , a common feature in up to 50% of cases; a longitudinal splenic dimension greater than 13 cm on signifies significant enlargement and heightened risk of rupture. Computed tomography is generally avoided due to unless splenic rupture is clinically suspected, as suffices for initial assessment and monitoring. Urinalysis may occasionally show , attributed to immune complex deposition in the glomeruli, though this is typically mild and resolves with the underlying .

Differential Diagnosis

Infectious mononucleosis (IM) presents with symptoms such as fever, , lymphadenopathy, and , which overlap with several other conditions, necessitating careful differentiation to guide appropriate testing and . Common mimics include bacterial , other viral , hematologic malignancies, parasitic diseases, and hypersensitivity reactions. Clinical , findings, and specific laboratory tests are crucial for distinction, as heterophile antibody tests may be negative in non-Epstein-Barr virus (EBV) causes.
ConditionDistinguishing Clinical FeaturesKey Diagnostic Tests
Streptococcal pharyngitisAnterior cervical lymphadenopathy, absence of splenomegaly or posterior lymphadenopathy, prominent exudative tonsillitis without significant fatigue.Rapid antigen detection test or throat culture positive for group A Streptococcus.
Acute HIV infectionSimilar rash and profound fatigue; more prominent myalgias, mucocutaneous ulcerations, and potential early seroconversion illness without splenomegaly.HIV antigen/antibody combination assay or HIV RNA PCR; negative EBV-specific serology.
Cytomegalovirus (CMV) mononucleosisHeterophile antibody negative; more gastrointestinal symptoms like hepatitis, less severe pharyngitis, and milder atypical lymphocytosis (<10%).CMV IgM serology or PCR; absence of EBV viral capsid antigen IgM.
Leukemia (e.g., acute lymphoblastic)Persistent cytopenias, petechiae, or bruising; generalized lymphadenopathy with blasts on peripheral smear, unlike self-limited IM course.Peripheral blood smear showing blasts, flow cytometry, or bone marrow biopsy; negative heterophile and EBV serology.
ToxoplasmosisUnilateral cervical lymphadenopathy, history of cat exposure or undercooked meat; fatigue without prominent splenomegaly or pharyngitis.Toxoplasma gondii IgM serology; negative EBV and heterophile tests.
Drug reactionsRecent initiation of new medications (e.g., antibiotics); maculopapular rash or eosinophilia resolving upon drug discontinuation, without infectious markers.Clinical history of drug exposure and temporal resolution off the agent; exclusion of infectious serologies.

Treatment

Supportive Care

Supportive care forms the cornerstone of for infectious mononucleosis, focusing on symptom alleviation and recovery promotion without specific antiviral . Patients are advised to prioritize rest and stress management during the acute phase and recovery, typically involving for the first 1-2 weeks when is most pronounced, as psychological stress can contribute to Epstein-Barr virus reactivation, followed by a gradual return to normal activities, starting with gentle exercises such as short walks, as symptoms improve. This approach helps mitigate exhaustion and supports immune function, with full energy restoration potentially taking 2-3 months in some cases. Maintaining adequate hydration is essential to counteract risks from fever and , with recommendations to consume 2-3 liters of fluids daily, including , juices, and broths. should emphasize a soft diet to ease with a , incorporating easily digestible foods like soups, , and mashed items while avoiding , spicy, salty, or hard-to-chew options that may exacerbate discomfort. Alcohol consumption must be strictly avoided during recovery to prevent additional liver strain, given the virus's potential hepatotoxic effects. Activity restrictions are critical, particularly to safeguard against splenic complications; individuals with should refrain from contact sports, heavy lifting, or strenuous exercise for at least 3 weeks from symptom onset, or longer if splenomegaly persists, as confirmed by follow-up imaging if necessary. Patients should monitor for signs of splenic rupture, such as sudden left upper , and seek immediate medical attention if these occur. For symptom relief, non-pharmacologic measures include gargling with warm salt water (1/4 teaspoon salt in 8 ounces of water) several times daily to soothe , and using a to moisten ambient air, which can reduce throat irritation and ease breathing. Acetaminophen or ibuprofen may be used for fever and , but aspirin should be avoided in children and adolescents due to the risk of Reye's syndrome. Major health organizations, including the Centers for Disease Control and Prevention (CDC), Mayo Clinic, and WebMD, do not provide specific guidance or precautions regarding sauna use, heat exposure, hot baths, or similar heat-related activities during recovery from infectious mononucleosis. Management emphasizes rest, adequate hydration, over-the-counter pain relievers such as acetaminophen or ibuprofen for fever and sore throat, and avoiding contact sports or heavy lifting for several weeks to prevent splenic rupture.

Pharmacological Interventions

Analgesics such as ibuprofen are commonly used for managing pain, fever, and in infectious mononucleosis, with typical adult dosing of 400-600 mg every 6-8 hours as needed. However, nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen should be avoided in patients with to prevent risks. Corticosteroids, particularly at a dose of 1 mg/kg/day for 5-7 days, are indicated for severe complications such as airway compromise due to tonsillar enlargement or significant ; they are not recommended for routine symptom relief in uncomplicated infections. Antiviral medications including acyclovir and are not routinely recommended for infectious mononucleosis, as they do not provide clinical benefits in uncomplicated cases according to 2024 reviews, though they may be considered for chronic active Epstein-Barr virus infection. Ampicillin and amoxicillin should be avoided in patients with suspected infectious mononucleosis, as they are associated with a in 70-100% of cases based on classic studies, though more recent data suggest rates around 30-50%. Per 2025 guidelines, routine antiviral therapy remains unadvised for acute infectious mononucleosis, but rituximab may be used in rare instances of severe polyclonal B-cell proliferation associated with persistent Epstein-Barr infection.

Prognosis

Short-Term Recovery

Infectious mononucleosis typically resolves in the acute phase within 2 to 4 weeks for most individuals, with symptoms such as fever abating first, often within 7 to 10 days, followed by improving by around 2 weeks. Supportive measures, including rest and hydration, facilitate this timeline by addressing common symptoms like and . Approximately 80% of patients return to normal activities by 1 month post-onset, though may persist longer, regressing in 4 to 6 weeks as the returns to normal size. Factors influencing slower short-term recovery include older age, which correlates with prolonged and symptom duration, elevated viral loads exceeding 10^5 copies/mL in blood, and underlying comorbidities that impair . Hospitalization occurs in only 5-10% of cases, primarily for or close observation of severe symptoms, with an average length of stay of 3 to 5 days.

Long-Term Outcomes

A significant proportion of individuals recovering from infectious mononucleosis experience persistent as part of a post-viral . In adolescents, approximately 13% meet criteria for chronic six months post-infection, with symptoms such as profound tiredness, , and sleep disturbances continuing beyond this period in 10-20% of cases. This often resolves spontaneously, with about 80% of affected individuals showing improvement by one year, though a smaller subset (around 7%) may persist up to 24 months, particularly among females with higher initial symptom severity. Infectious mononucleosis is associated with an elevated long-term risk of certain malignancies and neurological conditions due to Epstein-Barr virus latency. Individuals with a history of infectious mononucleosis face a fourfold increased risk of Epstein-Barr virus-positive , with this (4.0; 95% CI, 3.4-4.5) persisting for up to 20 years post-infection. Similarly, the condition markedly heightens the risk of ; a 2022 of over 10 million U.S. found a 32-fold (HR 32.4; 95% CI, 4.3-245.3) for multiple sclerosis development following Epstein-Barr virus , often manifesting as infectious mononucleosis in adolescents and young adults. Young adults with infectious mononucleosis history warrant monitoring for , as the virus's oncogenic potential in lymphoid tissues elevates vigilance in this demographic. Chronic active Epstein-Barr virus infection represents a rare and severe , occurring in fewer than 0.1% of cases, characterized by persistent high viral DNA loads and without resolution. This condition carries high mortality, with approximately 50% fatality in untreated patients due to lymphoproliferation, opportunistic infections, or multi-organ failure, though offers potential cure despite associated risks. Serologically, recovery from infectious mononucleosis leads to lifelong positivity for IgG antibodies to viral capsid antigen and Epstein-Barr nuclear antigen, conferring immunity against reinfection and subsequent mononucleosis episodes, while the virus maintains latency with possible reactivation under . As of 2025, EBV infection via infectious mononucleosis is strongly linked to , with emerging evidence suggesting associations with other autoimmune diseases such as systemic .

Prevention

Behavioral Measures

To prevent the transmission of infectious mononucleosis, primarily caused by Epstein-Barr virus (EBV), individuals should avoid close personal contact such as kissing during the acute phase of illness and for several months to a year afterward, as in can persist. Sharing drinks, food, cups, utensils, or other items that come into contact with should also be avoided during this period to minimize the risk of spreading the virus through oral secretions. In household settings, practicing good hand hygiene, such as frequent washing with and water, is essential to reduce indirect transmission, particularly after contact with potentially contaminated surfaces or items. Additionally, personal items like toothbrushes and razors should not be shared, as these can harbor and facilitate EBV spread among family members or close contacts. Symptomatic individuals, especially during the 2-4 weeks when fever, , and are prominent, should take precautions to isolate from high-risk groups such as immunocompromised persons, including avoiding shared living spaces or close interactions to prevent potential severe complications in vulnerable populations. For sexual activity, using condoms during oral-genital contact can reduce the low but possible risk of transmission through or genital secretions, though EBV is not considered a primary . In school or work environments, routine exclusion of individuals with infectious mononucleosis is not recommended unless complications like necessitate rest, as the virus spreads primarily through direct contact rather than casual interaction. Instead, education on recognizing symptoms—such as persistent , swollen nodes, and fever—and promoting awareness of avoidance measures among students or employees can help limit outbreaks in communal settings.

Vaccine Development

As of 2025, no licensed vaccine exists for Epstein-Barr virus (EBV), the primary causative agent of infectious mononucleosis, due to the virus's complex life cycle involving both lytic replication and latent persistence in B cells, which hinders the induction of comprehensive protective immunity. Promising vaccine candidates target key viral glycoproteins to elicit neutralizing antibodies against EBV entry into host cells. Moderna's mRNA-1189, an mRNA-based vaccine encoding gp350, gH/gL, gp42, and gB to block B-cell and epithelial cell infection, entered phase 1 trials in 2022 and advanced to phase 2 by 2024, with ongoing enrollment in 2025. Earlier phase 1 data indicated strong immunogenicity, though specific seroconversion rates have not been publicly detailed beyond general reports of effective antibody production. Complementing this, subunit vaccines based on gp350 have shown efficacy in preventing infectious mononucleosis; a phase 2 trial of a recombinant gp350 vaccine in EBV-seronegative adolescents reported 78% efficacy (95% CI: 1%-96%) against disease development, with 98.7% seroconversion in recipients. Additional candidates, such as ModeX Therapeutics' multivalent nanoparticle vaccine targeting gH/gL/gp42 in collaboration with Merck, initiated phase 1 trials in early 2025 to assess safety in healthy adults. In August 2025, the National Institutes of Health launched a phase 1 clinical trial of a new EBV vaccine candidate aimed at preventing infection. Key challenges in EBV vaccine development include achieving a balanced against both lytic-phase for neutralizing antibodies and latent-phase proteins for T-cell mediated control, while mitigating risks of oncogenesis from latent expression that could potentially promote EBV-associated malignancies. Given significant EBV-associated , including links to , developing effective against EBV remains a priority.

History

Early Descriptions

The initial clinical recognition of infectious mononucleosis dates back to the late , when Russian pediatrician Nil Filatov described cases of acute infectious lymphadenitis in children, characterized by fever, , and enlarged lymph nodes, in 1885. Four years later, in 1889, German physician Emil Pfeiffer provided a more detailed account of the condition, terming it "Drüsenfieber" or glandular fever, based on observations of benign, self-resolving episodes primarily in pediatric patients involving , fever, and exudative . Pfeiffer emphasized its infectious nature and distinction from other febrile illnesses, though he did not identify a causative agent. The term "infectious mononucleosis" was coined in 1920 by American physicians Thomas P. Sprunt and Frank A. Evans in a report published in the Bulletin of the , describing five cases of acute illness with fever, , , and notable mononuclear in the peripheral blood. Their analysis highlighted the reactive nature of the , distinguishing it from leukemic processes, and proposed the name to reflect the infectious and characteristic blood findings. During the and , infectious mononucleosis gained recognition as a distinct, self-limited disease, separate from conditions like or agranulocytic , with emphasis on its benign course and resolution without specific therapy. A key diagnostic advance came in with the development of the Paul-Bunnell test by John R. Paul and Wallace W. Bunnell, which detected heterophile antibodies in patient sera that agglutinated sheep red blood cells, providing a serological marker specific to the illness. Early epidemiological observations in noted outbreaks among adolescents and young adults in close-contact settings such as boarding schools and military barracks, underscoring its contagious spread through . Prior to the identification of Epstein-Barr virus, the condition was attributed to an unknown viral agent, with postmortem examinations in rare fatal cases revealing diffuse in lymph nodes, , and tonsils, consistent with a systemic lymphoproliferative response.

Discovery of the Causative Agent

In 1964, researchers Michael A. Epstein, Bert G. Achong, and Yvonne M. Barr identified herpesvirus-like particles in electron micrographs of cultured lymphoblastoid cells derived from a of Burkitt's lymphoma in an African child, marking the first visualization of what would become known as the Epstein-Barr virus (EBV). This discovery was published in a seminal report that established the viral association with the malignancy, though its broader clinical implications remained unclear at the time. By 1966, Gertrude and Werner Henle advanced EBV detection through the development of an immunofluorescence assay targeting viral capsid antigens in Burkitt's lymphoma-derived cell lines, enabling the measurement of specific antibodies in human sera. This technique revealed elevated EBV antibodies in patients with infectious mononucleosis (IM), suggesting a potential link between the virus and the syndrome characterized by fever, , and . In 1968, the Henles and their colleagues provided definitive serological evidence linking EBV to IM causation, demonstrating that nearly all acute IM cases showed to EBV-specific antibodies, while prior sera from the same individuals lacked them; this was particularly evident in prospective studies of college students during outbreaks, where EBV infection preceded clinical symptoms in seronegative individuals. These findings confirmed EBV as the primary etiologic agent of IM, shifting the understanding from a heterophile antibody-associated to a . During the 1970s, molecular studies solidified EBV's tropism for B lymphocytes, with experiments showing that the virus selectively infected and transformed B cells , as evidenced by expression of EBV nuclear antigens and immortalization of cell lines. This B-cell specificity was further corroborated in the through receptor-binding assays identifying complement receptor CR2 (CD21) as the viral entry point, underpinning EBV's role in both IM pathogenesis and oncogenesis. By the 2020s, the etiological link between EBV and IM was firmly established, with ongoing research highlighting its contributions to autoimmunity, including a 32-fold increased risk of following EBV , as demonstrated in large cohort analyses.

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