on 27-Jul-2025 (Sun)

Infectious mononucleosis (IM) is characterized by a triad of fever, tonsillar pharyngitis, and lymphadenopathy [1]

While it was initially described as "Drüsenfieber" or glandular fever in 1889, the term "infectious mononucleosis" was later used in 1920 to describe six college students with a febrile illness characterized by absolute lymphocytosis and atypical mononuclear cells in the blood [ 2,3]

The relationship between Epstein-Barr virus (EBV) and IM was established when a laboratory worker was infected with EBV and developed IM and a newly positive heterophile test [ 4]. The atypical mononuclear cells detected in peripheral blood are now known to be activated CD8+ T lymphocytes responding to EBV-infected cells [5]

The virus has not been recovered from environmental sources, suggesting that humans are the major reservoir.

Antibodies to EBV have been demonstrated in all tested population groups worldwide; approximately 90 to 95 percent of adults are eventually EBV seropositive [ 6].

EBV acquired during childhood years is often subclinical; fewer than 10 percent of children develop clinical infection despite high exposure rates. The incidence of symptomatic infection begins to rise in adolescence and adulthood [7]

Large studies of IM are now decades old, but historically, the peak incidence of infection occurs in the 15- to 24-year age range [ 8,9].

IM is relatively uncommon in adults, accounting for less than 2 percent of pharyngitis causes [ 10]. However, some data suggest that IM cases are occurring later in life with increasing severity, sometimes requiring hospitalization [11].

The difference in clinical presentation observed between infants and young adults is poorly understood. Hypotheses include the viral inoculum size at the time of infection or the intensity of cellular immune responses driven by EBV-infected B cells.

In another case series, GATA2 deficiency was associated with severe primary EBV requiring hospitalization or hemophagocytic lymphohistiocytosis with lymphoma, suggesting that this genetic deficiency may influence disease presentation in some cases [13].

Transmission is primarily person to person through contact with salivary secretions. Oral shedding typically persists 6 to 18 months after initial infection [14,15]. Intermittent oral shedding has been reported decades after primary illness [16,17].

Although EBV primarily spreads via saliva exchange, it is not a particularly contagious disease. In one study conducted among college students, susceptible roommates of patients with either symptoms of IM or asymptomatic viral shedding were no more likely to seroconvert or develop clinical illness than other college students without evidence of pre-existing EBV infection [ 18].

EBV may also be transmitted through sexual contact. EBV has been detected in both cervical epithelial cells and male seminal fluid [19-21]

However, studies of sexually active individuals have been unable to distinguish between oral and genital routes of transmission with certainty, making further conclusions difficult. In one prospective study that followed first-year university students who were EBV antibody negative, the time to infection in individuals reporting deep kissing without coitus was similar to those who reported deep kissing with coitus [ 14]. Both groups had a significantly higher risk of acute EBV infection than subjects reporting no kissing or coitus.

Breastfeeding is not an important route of transmission. Although EBV has been isolated in breast milk from healthy nursing mothers [22], studies have not demonstrated a difference in EBV seropositivity between exclusively nursed or bottle-fed infants [22,23].

EBV makes initial contact with oropharyngeal epithelial cells, typically through exposure to infected saliva. This allows replication of the virus, the release of EBV into the oropharyngeal secretions, and infection of B cells in the lymphoid-rich areas of the oropharynx [24].

The incubation period prior to the development of symptoms averages four to eight weeks. During this time, lytic infection of B cells facilitates dissemination throughout the lymphoreticular system.

The atypical lymphocytes that appear in the peripheral blood of patients with acute IM between one and three weeks after the onset of symptoms are primarily activated CD8+ T cells (picture 1) [27-31].

Latently infected memory B cells with restricted expression of certain viral proteins serve as lifelong viral reservoirs, evading host immune surveillance [32]. Reactivation occurs periodically, during which time EBV is shed in oropharyngeal secretions.

IM typically presents with a constellation of the following signs and symptoms (table 1); however, no single symptom or sign is pathognomonic, and not every finding is present in every patient [14,35]

IM is often heralded by malaise, headache, and low-grade fever, followed by more specific signs of lymphadenopathy, pharyngitis, and absolute lymphocytosis with atypical lymphocytes (picture 1) [7,32,33].

Infectious prodrome – Most patients note fever, headache, and generalized malaise or myalgias as initial symptoms. As the illness progresses, fever may become persistent and severe [32]

Lymphadenopathy – Cervical lymph node involvement in IM is symmetric and more commonly involves the posterior cervical and posterior auricular nodes. The nodes may be large and moderately tender. Lymphadenopathy may also become more generalized over the disease course, which may distinguish IM from other causes of pharyngitis [10].

Lymphadenopathy in IM peaks in the first week and gradually subsides over two to three weeks

Pharyngitis – A history of sore throat is often accompanied by pharyngeal inflammation and tonsillar exudates, which can appear white, gray-green, or necrotic. Palatal petechiae with streaky hemorrhages and blotchy red macules are occasionally present; however, this finding is also seen in patients with streptococcal pharyngitis.

Fatigue – Fatigue may be persistent and severe. In a prospective study of 150 patients, most initial symptoms (eg, fever, sore throat) resolved in one month, but fatigue resolved more slowly and persisted in 13 percent of patients at six months [34]

Splenomegaly – Splenomegaly is seen in 50 to 60 percent of patients with IM and usually begins to recede by the third week of the illness [36].

Rash – In patients with IM, a generalized maculopapular, urticarial, or petechial rash is seen [37]. The maculopapular rash with IM (picture 2) was previously believed to be prompted by the administration of penicillin for presumed streptococcal pharyngitis [38,39]; however, the rash has also been observed with a variety of other antibiotics [40-43] or with no antibiotic exposure at all [44]

Hematologic abnormalities – The total white blood cell count in patients is usually elevated to 12,000 to 18,000/microL, although it may be much higher. The most common laboratory finding in IM is lymphocytosis, defined as an absolute count >4000/microL or a differential count >50 percent.

Some patients also have mild relative and absolute neutropenia and thrombocytopenia.

Uncommon hematologic manifestations include microangiopathic or autoimmune hemolytic anemia, aplastic anemia, and disseminated intravascular coagulation [ 37].

Hemophagocytic lymphohistiocytosis (HLH) is a serious condition associated with multiple hematologic abnormalities, as shown below.

Liver function tests – Mildly elevated aminotransferases are seen in the majority of patients [34]. Rarely, severe hepatitis and cholestasis have been reported.

Splenic rupture – Splenic rupture is a rare, potentially life-threatening complication of IM that can also be the initial presenting symptom [45]. It is estimated to occur in one to two cases per thousand [46]; approximately 70 percent occur in males, usually under 30 years [47]. The typical manifestations are abdominal pain and/or a falling hematocrit [45]. Splenic rupture occurs spontaneously (eg, without precipitating trauma) in over one-half of patients, typically 14 days after symptom onset

Peritonsillar abscess and airway obstruction – Rare complications of IM include peritonsillar abscess and/or airway occlusion secondary to edema of the soft palate and tonsils [48]

Neurologic syndromes – Neurologic syndromes include Guillain-Barré syndrome, facial and other cranial nerve palsies [49-51], meningoencephalitis [52], aseptic meningitis, transverse myelitis, peripheral neuritis, optic neuritis, and encephalomyelitis [53].

Associations between Epstein-Barr virus (EBV) infection and the subsequent development of multiple sclerosis have been described, though a mechanism for pathogenesis is unclear [54-57].

When HLH is present alongside IM, fever is persistent and unremitting; lymphadenopathy may be more generalized; and laboratory studies show a combination of severely elevated liver tests, pancytopenia, and coagulopathy. Mental status changes or other neurologic manifestations may be present.

Chronic active EBV infection – Chronic active EBV infection is a rare, life-threatening lymphoproliferative disorder that may involve B lymphocytes, T lymphocytes, or natural killer cells. The syndrome is characterized by a persistent IM-like syndrome with fevers, pancytopenia, elevated liver function tests, and highly elevated levels of EBV viremia [59].

Other organ system manifestations – EBV can affect virtually any organ system and has been associated with diverse disease manifestations, including cholestasis, pneumonia, pleural effusions, myocarditis, pancreatitis, acalculous cholecystitis, mesenteric adenitis, myositis, acute kidney injury, glomerulonephritis, gastric pseudolymphoma, and genital ulceration [60-66]. Ascites and fatal cases of hepatitis have also been described [60-62]. Septic thrombophlebitis of the internal jugular vein as a complication of IM has been described, though a pathogenic mechanism is uncertain [67]

Age ≥40 – In patients older than age 40 with IM, lymphadenopathy and pharyngitis are less prominent (table 2) [37]. Fever and myalgia are common and can last for several weeks, often accompanied by elevated liver transaminases [37,68]. Older individuals may also have less prominent absolute lymphocytosis and fewer atypical lymphocytes [69]

Pregnant individuals – For pregnant patients with signs and symptoms of IM, the primary concern is differentiating IM caused by EBV from similar mononuclear syndromes due to cytomegalovirus (CMV), human immunodeficiency virus (HIV), and toxoplasma as these infections are associated with significant perinatal morbidity and mortality if left untreated.

There is little evidence of teratogenic risk to the fetus in women who develop EBV infection and IM during pregnancy [70].

Children – EBV infection in young children is usually asymptomatic, with less than 10 percent of children developing evidence of clinical infection [71]. Studies of IM in children describe nonspecific fever, malaise, pharyngitis, and respiratory symptoms similar to adults and additional findings unique to children, including failure to thrive, otitis media, abdominal complaints, and variable cervical adenopathy [71,72].

Among pediatric patients, atypical lymphocytosis is observed with increasing frequency with increasing age; this finding is rare in patients below the age of four [ 71].

Group A Streptococcus or other acute respiratory infections may cause acute pharyngitis.

Streptococcal infection is not usually accompanied by significant fatigue or splenomegaly; symptoms may be more acute in onset.

Arcanobacterium haemolyticum is noteworthy as a frequent cause of fever and pharyngitis in adolescents and young adults [73]

Primary cytomegalovirus (CMV), acute HIV, toxoplasma, human herpesvirus (HHV) 6, or HHV-7 infection may induce a similar mononuclear syndrome with atypical lymphocytosis, fever, lymphadenopathy, and mild pharyngitis [74-76].

Unlike IM, toxoplasma rarely causes pharyngitis, abnormal liver function tests, or atypical lymphocytes. In contrast, differentiating between IM caused by Epstein-Barr virus and a similar syndrome due to CMV or HIV infection is often not possible clinically, and additional diagnostic testing must be pursued [77,78].

Certain medications, such as phenytoin, carbamazepine, isoniazid, and minocycline, may induce a mononucleosis-like syndrome with atypical lymphocytosis [79-81]

Lymphoma is a consideration in patients with prominent lymphadenopathy, splenomegaly, and constitutional symptoms.

Epstein-Barr virus (EBV)-induced IM should be suspected in patients with fever, malaise, fatigue, prominent cervical lymphadenopathy, and pharyngitis [10,82].

The index of suspicion for IM is increased in a young adult patient with symptoms that develop over the course of 7 to 14 days, in contrast to the more sudden onset of symptoms in patients with bacterial or viral pharyngitis.

Palatal petechiae and splenomegaly highly suggest IM, while the absence of cervical lymphadenopathy and fatigue makes the diagnosis less likely [ 83,84]

The timing of onset of symptoms, including fever, oropharyngeal symptoms, and lymphadenopathy.

Rapid onset and escalation of symptoms over several days are more suggestive of acute bacterial pharyngitis or respiratory virus, whereas symptoms caused by acute EBV infection are more insidious and prolonged over one to two weeks or longer

General or constitutional symptoms, including fatigue, nausea, and anorexia. Significant weight loss is uncommon with IM and should prompt further evaluation for acute HIV infection, lymphoma, or chronic active EBV.

Recent sick contacts and their diagnoses, if known (eg, streptococcal pharyngitis, confirmed EBV, or other upper respiratory infection).

● Sexual activity, as this raises the possibility of HIV infection.

● Current medications, including recent antibiotics. Some anticonvulsants and antibiotics may cause a mononucleosis-like syndrome.

Oropharynx – We evaluate the pharynx for tonsillar enlargement, oropharyngeal or tonsillar exudates, and palatal petechiae. We also perform an otoscopic examination to rule out acute otitis media.

Salivary pooling, muffled voice, stridor, respiratory distress, or prominent peritonsillar abscess may indicate upper airway obstruction. These patients require emergency care for airway management, drainage, and/or surgical consultation.

Lymph nodes – Most adolescent and young adult patients with IM have cervical lymphadenopathy that is evident on physical examination [84]. Posterior cervical adenopathy is more specific for IM, as are axillary and inguinal adenopathy. A more detailed discussion of the evaluation of peripheral lymphadenopathy is presented separately. (See "Evaluation of peripheral lymphadenopathy in adults".)

Skin – When examining the face and exposed skin, providers should look for evidence of rash, which may be maculopapular, urticarial, or petechial. Periorbital or palpebral edema may also be noted.

Abdomen – We examine the abdomen for splenomegaly or hepatomegaly and associated tenderness.

Leukocytosis develops in the second or third week of illness, usually in the 10,000 to 20,000 cells/mL range [85].

The presence of both lymphocytosis ≥50 percent and atypical lymphocytes ≥10 percent strongly suggests IM in patients with consistent clinical features (in one systemic review, specificity was 0.99 [95% CI 0.92-1.0]) [ 84]. An absolute lymphocyte count greater than 4000/microL had a sensitivity of 0.97 and specificity of 0.96 (95% CI 0.82-0.99 and 0.84-0.98, respectively), and an atypical lymphocytosis ≥10 percent had a specificity of 0.92 for IM (95% CI 0.71-0.98). Specificity increased with increasing percent of atypical lymphocytes

If atypical lymphocytes are reported on an automated differential from a hematology analyzer, these should be confirmed by manual smear review since blasts and other abnormalities cannot be reliably distinguished from atypical lymphocytes in these systems [86].

Atypical lymphocytes may also be found in patients with toxoplasmosis, rubella, roseola, viral hepatitis, mumps, cytomegalovirus (CMV), acute HIV infection, and some drug reactions [37].

We test for HIV in all patients who are sexually active or have other risk factors for HIV, given its important treatment and transmission implications. We test for CMV and toxoplasmosis in patients with continued symptoms in whom initial testing for EBV is negative as EBV is more common and most uncomplicated cases resolve with supportive care regardless of etiology (see 'Establishing the diagnosis' below and 'Patients who test negative' below). The exception is in immunocompromised or pregnant patients, for whom specific treatment for CMV, HIV, or toxoplasmosis, if present, is indicated.

The following tests help to assess the severity of the disease, exclude alternate diagnoses, and evaluate for possible associated complications:

• Serum creatinine and electrolytes

• Liver function tests – Mildly elevated transaminases are common in uncomplicated IM. Severely elevated transaminases and/or cytopenias should prompt further evaluation for serious EBV-associated syndromes such as hemophagocytic lymphohistiocytosis.

The diagnosis of IM should be confirmed with EBV testing. Confirmatory testing assists with risk assessment for splenic rupture and patient education on the natural history of the disease, including persistent fatigue.

Epstein-Barr virus (EBV)-specific antibodies are the diagnostic gold standard as they have high sensitivity and specificity for IM (97 and 94 percent, respectively) in patients with a mononucleosis-type presentation (figure 1) [87].

EBV-specific antibodies are also the test of choice for diagnosing acute EBV infection in young children as heterophile antibody tests are more frequently negative in infants and children under four years of age [88-92].

Heterophile antibody testing is a reasonable alternative diagnostic test, especially in young adult patients with fever and pharyngitis, for whom the pretest probability of IM is high. This test has the advantage of faster turnaround and lower expense in some laboratories than EBV antibody testing but suffers from lower sensitivity and specificity (see 'Heterophile antibodies' below).

Types of antibodies – EBV-specific antibodies target several EBV antigens. In some settings, these antibodies are ordered individually. In other settings, they are offered as a diagnostic panel consisting of immunoglobulin (Ig) M and IgG viral capsid antigen (VCA) and EBV nuclear antigen (EBNA). Occasionally, early antigen (EA) is included in the diagnostic panel

VCA antibodies – EBV IgM and IgG VCA antibodies are directed against the VCA. Because of the long viral incubation period before symptoms develop, IgM VCA and IgG VCA antibodies are usually present at the onset of clinical illness [93]. IgM levels appear soon after EBV exposure and wane 6 to 12 weeks later; thus, they are a reliable marker of acute infection in a clinically appropriate picture. IgG VCA antibodies appear four to six weeks after exposure and persist for life (figure 1).

Rarely, EBV IgM antibodies persist beyond 12 weeks or reactivate from latency during the immune response to a non-EBV illness [94,95]. In such cases, additional testing for non-EBV-related causes of mononucleosis should be sent. Test results should be interpreted in the context of the time course of symptoms to differentiate between EBV and non-EBV illness (algorithm 1).

EBNA antibodies – IgG antibodies to EBNA appear six to eight weeks after exposure as the nuclear antigen is expressed during latency after the initial lytic phase is complete (figure 1). However, EBNA false negatives are also possible as the antibodies may not develop in up to 3 to 5 percent of previously healthy patients and 10 to 20 percent in immunosuppressed populations [93]. When positive, EBNA antibodies persist throughout life; their presence early in the course of an IM-like illness effectively excludes acute EBV infection and should prompt evaluation for non-EBV-related illness, as discussed below. (See 'Patients who test negative' below.)

EA – IgG antibodies to EA are present at the onset of clinical illness. There are two subsets of EA IgG: anti-D and anti-R. Anti-D antibodies, when present, are consistent with recent or active infection since titers disappear after recovery. However, because anti-D and anti-R antibodies are not expressed in a large proportion of patients, EA testing is of limited clinical utility.

EBV VCA IgM positive – The detection of IgM antibodies to EBV VCA suggests acute EBV infection is likely in a compatible clinical IM picture. EBNA antibodies assist with confirming acute EBV infection, as follows:

- EBNA negative – Confirms acute EBV infection. IgG VCA antibodies are usually also positive, though they may be negative initially in cases of very recent infection.

- EBNA positive, symptoms present for >4 weeks – EBV infection within the past three months.

- EBNA positive, symptoms present for ≤4 weeks – Inconclusive antibody profile as EBNA antibodies do not appear until 8 to 12 weeks after exposure. Positive EBNA antibodies in this setting likely reflect prior EBV infection remote from current symptoms.

The EBV IgM (+), EBNA (+) profile with symptoms ≤4 weeks indicates EBV is unlikely to be the cause of the IM-like illness. Rarely, VCA IgM antibodies may be falsely positive or may reflect reactivation of EBV from latency due to a robust immune response to a non-EBV illness. Additional testing for non-EBV-related causes of mononucleosis should be performed.

EBV VCA IgM negative – The absence of IgM antibodies to EBV VCA indicates that acute EBV infection is unlikely. IgG VCA and EBNA antibodies assist with distinguishing EBV-naïve individuals from recent or past EBV infection:

- VCA IgG and EBNA negative – EBV naïve (eg, no current or previous EBV infection). Additional evaluation for other conditions is warranted. (See 'Patients who test negative' below.)

- VCA IgG positive, EBNA positive – Past EBV infection, typically at least over three months.

- VCA IgG positive, EBNA negative – Either recent or past EBV infection, eg, within the last three months, as EBNA is expressed after the virus establishes latency, though false-negative EBNA may occur.

Although the Centers for Disease Control and Prevention recommends against heterophile antibodies due to their lower sensitivity and specificity for IM than EBV antibodies [96], heterophile testing remains in use because of technical ease, rapid turnaround, and low cost.

Clinical utility – In our experience, heterophile antibody testing is useful in evaluating young adults with fever and pharyngitis as results are available in many laboratories in less than one hour. In such patients, a positive heterophile test lowers the index of suspicion for streptococcal pharyngitis and supports a diagnosis of IM, especially when lymphocytosis and atypical lymphocytes are also noted [88].

Heterophile antibodies react to antigens from phylogenetically unrelated species, including horse red blood cells (used in the "Monospot" test) and sheep red blood cells (used in the classic Paul-Bunnell test). Newer heterophile antibody tests use ELISA (enzyme-linked immunosorbent assay) techniques.

The sensitivity and specificity of heterophile antibody tests range from 70 to 90 percent [88,97-100]. False-negative rates are highest at the onset of clinical symptoms (25 percent in the first week, 5 to 10 percent in the second week, and 5 percent in the third week) (figure 1) [82]. As a result, heterophile tests are useful when positive but can be insensitive.

Moreover, heterophile antibodies are more frequently negative in young children; therefore, EBV antibodies are the preferred diagnostic test for children under the age of four [88].

As above, a positive heterophile antibody can support the diagnosis of IM in the appropriate clinical setting (eg, a young adult with fever and pharyngitis). False-positive heterophile antibody results have been observed with autoimmune diseases, viral hepatitis, malignancy, toxoplasmosis, Lyme disease, and viral infections, including HIV, hepatitis viruses, dengue, and rubella [101,102]. Heterophile antibodies may also persist at low levels for up to one year after IM.

The use of EBV viral load in the diagnosis and management of transplant recipients, chronic active EBV infection, and EBV-related lymphoproliferative disorders is discussed in further detail separately. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Measurement of EBV viral load'.)

Patients with negative heterophile antibody testing – Confirmatory testing with EBV antibodies is warranted for patients with clinically suspected IM and negative heterophile antibody test results [106].

Since the sensitivity of the heterophile antibody test increases as the illness progresses, if EBV antibody testing is unavailable, the heterophile antibody test may be repeated one week later if symptoms persist and the diagnosis remains uncertain

Patients with negative EBV antibodies – Approximately 10 percent of patients presenting with symptoms suggestive of IM have a mononuclear syndrome caused by an infection other than EBV [107]. These patients have negative heterophile antibodies and negative EBV antibodies or an inconclusive EBV antibody profile as shown in the algorithm (algorithm 1).

In such cases, if the patient has persistent symptoms, we pursue additional testing for CMV, acute HIV, toxoplasmosis, and/or human herpesvirus types 6 and 7 based on the clinical scenario [74-76,108-110].

Supportive care for most patients — Supportive care is the mainstay of treatment for individuals with uncomplicated IM. Acetaminophen or nonsteroidal anti-inflammatory drugs can alleviate discomfort from fever, pharyngitis, and malaise. Patients should prioritize adequate rest, though complete bed rest is unnecessary. Strenuous activity should be avoided for at least three weeks.

Limited role for corticosteroids — We do not recommend corticosteroid therapy for uncomplicated cases of IM or for the treatment of IM-related fatigue, as the illness is typically self-limited and studies of corticosteroids in IM have shown only modest symptom relief [111-113]. Additionally, some experts note theoretical concerns with immunosuppression when treating a virus that is causally linked to autoimmune diseases and malignancy.

In a multicenter, placebo-controlled study of 94 patients with acute IM, the combination of prednisolone and acyclovir reduced oropharyngeal shedding of the virus but did not affect the duration of symptoms or lead to an earlier return to school or work [111]. A subsequent meta-analysis of seven studies found insufficient evidence to recommend steroid treatment for symptom relief; furthermore, two studies reported severe complications in patients assigned to the corticosteroid arm compared with placebo [112].

Airway obstruction – Patients with respiratory distress or airway occlusion from abscess or edema of the soft palate and tonsils warrant urgent referral to the emergency department for airway management, abscess drainage, and consultation with surgery or otolaryngology. We treat such patients with high-dose intravenous corticosteroids to reduce edema and avoid airway compromise.

Data on dosing and duration of corticosteroid therapy are limited [116,117]. One case series described children with impending airway closure who were treated successfully with dexamethasone 0.25 mg/kg every six hours, but no information was given on the duration of treatment [116]. Once clinical improvement has been achieved, we taper the corticosteroid dose slowly over 7 to 14 days and monitor for sustained improvement.

Splenic rupture – Splenic rupture is a rare complication of IM related to splenomegaly associated with the condition. Patients present with severe, acute abdominal pain. Both traumatic and spontaneous splenic ruptures related to IM have been reported [45]. While the traditional mainstay of treatment is splenectomy, successful nonsurgical management of hemodynamically stable patients with close observation has been reported [47].

Other organ system complications – Corticosteroid therapy may also be considered for patients with severe, overwhelming, life-threatening EBV infection (eg, fulminant liver failure) or other complications such as severe hemolytic or aplastic anemia. Data supporting the benefit of corticosteroids in these settings are limited to case reports and anecdotal experiences.

Most individuals with primary Epstein-Barr virus (EBV) infection recover uneventfully and develop durable immunity. Acute symptoms generally resolve in one to two weeks.

Fatigue and poor functional status can persist for months [ 118-120]. Approximately 10 percent of individuals have persistent fatigue six months after symptom onset [119-121]. This rate declines over subsequent months, and most individuals recover completely over time. Persistent fatigue has been associated with the initial severity of illness [119-121], female sex [122,123], and premorbid mood disorders [123]. Abnormalities in mitochondrial function and variable neuroendocrine-immune gene expression are two proposed mechanisms [124-126].

Advice for all patients:

• All patients should refrain from sports during the first two to three weeks of illness.

• Initial activity resumption should be reduced compared with the premorbid state, with a gradual increase as tolerated.

• Although most patients recover within two to four weeks, for some patients, fatigue may last for weeks to months.

Guidance for athletic activity:

• For noncontact sports, training can resume three weeks after symptom onset. Participants should avoid activities that may induce chest or abdominal trauma.

• For strenuous contact sports (including football, gymnastics, rugby, hockey, lacrosse, wrestling, diving, and basketball) and activities associated with increased intra-abdominal pressure (such as weightlifting), patients may resume activity no sooner than four weeks after illness onset.

For patients with previous clinical or radiographic evidence of splenomegaly, we confirm the resolution of splenomegaly with an ultrasound at four to seven weeks, before the resumption of strenuous contact sports. Most cases of IM-related splenic rupture occur within four weeks of symptom onset, though rupture at seven weeks after symptom onset has been reported [127,128].

• Patients should be reminded that returning to preillness fitness may take three or more months.

More than 50 percent of patients with IM develop splenic enlargement within the first two weeks of symptoms. The risk of spontaneous or traumatic splenic rupture in the setting of IM is highest within 2 to 21 days of symptom onset [129]. Descriptions of splenic rupture after the fourth week are rare [127,130]

Given the lack of prospective data, recommendations to resume sports are somewhat arbitrary and depend on the type of activity. For example, some guidelines permit the resumption of noncontact sports at 14 to 21 days, with a longer duration of rest for high-impact contact sports [ 131-134]. Others advocate a universal four-week time frame regardless of activity level [135].

Confirmation of the resolution of splenomegaly as a prerequisite for a return to sports remains a debated issue. Splenic palpation or percussion is generally unreliable [136]. Clinical outcomes data do not support routine ultrasonography for most patients [137-139]. We pursue an ultrasound in select patients resuming strenuous contact sports, as above.

EBV is the primary agent of infectious mononucleosis (IM), persists asymptomatically for life in nearly all adults, and is associated with the development of B cell lymphomas, T cell lymphomas, Hodgkin lymphoma, nasopharyngeal carcinoma, and gastric carcinomas in certain patients [1]

Reactivation disease is not a prominent issue with EBV, in contrast to other common herpesviruses, but it has been associated with an aggressive lymphoproliferative disorder in transplant recipients [ 2].

Approximately 90 to 95 percent of adults are EBV antibody seropositive; however, studies suggest that primary EBV infection may be occurring at a later age in children residing in the developed world. As an example, in a large public university in the United States, the seroprevalence of EBV antibodies among entering freshman declined from 64 percent in 2006 to 52 percent in 2022 [3,4]

The principal human host cells for EBV are limited to B lymphocytes, T lymphocytes, NK cells, epithelial cells and myocytes.

Unlike herpes simplex (HSV) or cytomegalovirus (CMV), EBV is capable of transforming B cells but does not routinely display a cytopathic effect.

Intrauterine infection with EBV is rare because fewer than 5 percent of pregnant women are susceptible to the virus. In addition, prospective studies of susceptible (ie, seronegative) women have not found evidence of congenital abnormalities among infants of women who did develop primary EBV infection during pregnancy [7].

Chronic active Epstein-Barr virus (CAEBV) infection is a rare, life-threatening lymphoproliferative disorder that may involve B lymphocytes, T lymphocytes, or NK cells. The syndrome is characterized by a persistent infectious mononucleosis (IM)-like syndrome and EBV viremia [12]. Clinical manifestations may include fever, swelling of lymph nodes, and hepatosplenomegaly along with liver function test abnormalities and cytopenias [13].

Patients with untreated T cell CAEBV often develop systemic organ disease due to T cell infiltration of tissues, hemophagocytic lymphocytosis, liver failure, or coronary artery aneurysms [ 14,15].

Diagnostic criteria are not well defined, but the presence of persistent viremia and hypogammaglobulinemia, as well as the detection of a clonal proliferation of B, T, or NK cell population, support the diagnosis [16].

A common misconception is to label patients with fatigue alone as having chronic EBV based only upon positive serologic markers without any of the above abnormalities. However, IgG antibodies to antiviral capsid antigen (VCA) and Epstein-Barr nuclear antigen (EBNA) are present for life in patients with prior EBV exposure and are not markers of an active process suggesting true chronic active EBV infection

While the pathogenesis is not well understood, EBV infection of hematopoietic stem cells may be the initiating factor in CAEBV [17]. EBV sequencing studies have found that certain intragenic deletions are associated with CAEBV and NK lymphoproliferative disorders [18]. Early data suggest the effect of the deletions is to simultaneously promote more efficient lytic cycle reactivation, avert cell lysis, and drive lymphomagenesis.

The only treatment regimen that has been curative is hematopoietic stem cell transplantation [15,19]. Other treatment options that have been used include high-dose corticosteroids or antiviral therapy (eg, ganciclovir) used individually or in combination with proteasome inhibitors (eg, bortezomib) or histone deacetylase inhibitors [20].

Multiple sclerosis (MS) — EBV infection has been associated with MS for several decades. Early studies showed that EBV infection was more prevalent in patients with MS and that EBV-specific antibodies were higher when compared with controls [21]. Subsequent seroepidemiologic studies further supported EBV as a cofactor for the development of MS [22]. A cohort study, which compared 801 individuals who developed MS with 1577 controls, found that the risk of developing MS was 32-fold higher following EBV infection but not after infection with other viruses [23].

Mechanistic studies to explain the role of EBV in the pathogenesis of MS are incomplete with molecular mimicry recently being the most plausible hypothesis [24,25].

Oral hairy leukoplakia — Another EBV-mediated mucocutaneous manifestation is oral hairy leukoplakia (OHL), which is an unusual disease of the lingual squamous epithelium [26]. OHL generally affects the lateral portions of the tongue, although the floor of the mouth, the palate, or the buccal mucosa may also be involved. The lesions are described as white corrugated painless plaques that, unlike candida, cannot be scraped from the surface to which they adhere (picture 2). They are not generally associated with fever.

The OHL lesions, while initially described in individuals with human immunodeficiency virus (HIV) infection, can also be seen in other immunocompromised patients (eg, organ transplant recipients, patients with malignancy, those receiving systemic or inhaled steroids) [26-28]. Rare cases have been reported in immunocompetent individuals, but evaluation for underlying immune suppression has not always been reported [28]. The use of potent antiretroviral therapy appears to have reduced the incidence of OHL in persons with HIV [29,30].

OHL is associated with intense EBV replication and the action of EBV-encoded proteins such as latent membrane protein-1 [26]. In addition, studies in which EBV replication has been suppressed by valacyclovir have demonstrated persistent, nonproductive EBV infection and continued EBV entry from the blood into the tongue [31]. These observations suggest a role for entry, persistence, and reactivation of oral epithelial EBV in the pathogenesis of OHL.

OHL is not considered a premalignant lesion, being unlikely to progress to squamous cell carcinoma [26]. Anecdotal treatment with zidovudine, acyclovir, ganciclovir, foscarnet, and topical podophyllin or isotretinoin has been reported, although therapy is usually not indicated.

Lymphoproliferative disorders — EBV infection is associated with a variety of lymphoproliferative disorders [32]. More than a dozen single gene mutations causing primary immune deficiency disorders are associated with severe EBV–induced disease [33,34].

Hemophagocytic lymphohistiocytosis — EBV is one of the recognized initiating causes of hemophagocytic lymphohistiocytosis (HLH), a potentially fatal disorder characterized clinically by persistent fever, hepatosplenomegaly, cytopenias and characterized pathologically by generalized histiocytic proliferation and hemophagocytosis (picture 3) [35]. Patients with this unusual syndrome present with fever, generalized lymphadenopathy, hepatosplenomegaly, hepatitis, pancytopenia and coagulopathy. T cell proliferation is a primary feature of HLH.

Lymphomatoid granulomatosis — Lymphomatoid granulomatosis is an angiodestructive disorder of the lymphoid system, which has been associated with EBV infection. In most cases, EBV infected B cells are present, and the B cell proliferation is clonal [36,37]. Patients often have evidence of immunodeficiency including congenital and acquired conditions such as HIV infection [38]. Clinical features include fever, cough, malaise, weight loss, with involvement of lung, kidney, liver, skin and subcutaneous tissue, and the central nervous system (CNS) with typical histologic changes [39-41]. It appears to arise from EBV-infected B cells and affected patients may respond to interferon alfa [42].

X-linked lymphoproliferative disease — X-linked lymphoproliferative (XLP) disease is characterized by a selective immunodeficiency to EBV, manifested by severe or fatal IM and acquired immunodeficiency [33]. Two genetic defects that cause XLP have been identified. XLP1, the more common of the two forms, is due to a defect in a gene (ie, SH2D1A) that encodes a protein, which plays an important role in signal transduction pathways in T lymphocytes. This mutation prevents normal activation-induced cell death, resulting in the uncontrolled CD8 T cell proliferation that is observed in patients with XLP. XLP2 is due to a defect in the XIAP gene that encodes the X-linked inhibitor of apoptosis.

Post-transplant lymphoproliferative disease — EBV is associated with the majority of cases of post-transplant lymphoproliferative disease (PTLD) [43]. The abnormalities range from benign polyclonal B cell proliferation to malignant B cell lymphoma. The frequency of PTLD is related to the degree and type of immunosuppression and is most common in EBV-negative recipients who develop primary EBV infection, usually from a graft from an EBV-positive donor [44].

Malignancies include Burkitt lymphoma, tumors in patients with HIV, Hodgkin lymphoma, nasopharyngeal and other head and neck carcinomas, gastric carcinoma, and T cell lymphoma. Recent studies by Li et al have shown that EBNA 1, the only EBV protein expressed in all EBV-associated malignancies, binds to a specific palindromic DNA sequence on chromosome 11 resulting in breaks and genome instability [45].

Burkitt lymphoma — Burkitt lymphoma (BL), which is characteristically localized in the jaw, is the most common childhood malignancy in equatorial Africa [46]. More than 95 percent of African children are infected with EBV by age three, whereas, in affluent countries, primary infection is often delayed until adolescence [47].

Tumor cells from areas where BL is endemic contain copies of the EBV genome more frequently than sporadic cases of BL from areas of low incidence (>95 percent versus 15 to 20 percent) [48,49]. Analysis of the EBV genome terminal repeat frequency in endemic Burkitt lymphomas has demonstrated that the tumors originate in the lineage of a single EBV-infected B cell [50-52].

Effect of coinfection with malaria — Malaria and EBV infection are considered cofactors in the genesis of Burkitt lymphoma [59]. An epidemiologic link is suggested by the number of endemic cases that occur in discrete geographic climates located along the malaria belt across Africa.

Various hypotheses have been proposed to explain the role of malaria in pathogenesis. These include:

● Acute malaria infection may increase the EBV viremia set point. One study of quantitative EBV genome loads within peripheral blood mononuclear cells among 57 EBV-seropositive Gambian children suggested that acute malaria was associated with a sixfold increase in viremia compared to age-matched EBV-seropositive controls without malaria [60].

● Malaria may provide a chronic stimulus for reactivation of EBV in latently infected B lymphocytes [59]. In one study of 43 children with malaria, anti-malarial therapy led to a significant decline in EBV deoxyribonucleic acid (DNA) plasma levels by day 14 of treatment [47]. The clearance of circulating EBV after antimalarial treatment suggests a direct relationship between active malaria infection and reactivation of EBV.

● Chronic reactivation of EBV, caused by malaria infection, may impair EBV-specific T cell immunity through exhaustion and lead to loss of viral control [59].

These findings correlate with epidemiologic data, which show a peak incidence of Burkitt lymphoma in children ranging in age from five to nine years.

Non-Hodgkin lymphoma – Non-Hodgkin lymphomas (NHL) occur approximately 60 to 100 times more frequently than expected in patients infected with the human immunodeficiency virus (HIV) [61,62]. These tumors are often associated with EBV infection [63,64]. A study conducted in Los Angeles county from 1984 to 1992 showed that EBV was associated with 39 of 59 (66 percent) HIV-related systemic lymphomas [63]. Analysis of EBV terminal repeats in these lymphomas again confirmed their monoclonal origin, and c-myc rearrangements were noted in 40 percent.

HIV associated NHL, usually of B cell origin, is a relatively late manifestation of HIV infection [61,67]. For unknown reasons, a much higher percentage of EBV-associated NHLs in HIV-infected patients present as primary CNS lymphomas [62].

Given the profound immune defects in some HIV-infected patients, along with the known role of cytotoxic lymphocytes in controlling EBV-induced proliferation, it is not surprising that the number of EBV-infected B cells in the peripheral blood of patients with HIV may be higher than in the general population [65]. Furthermore, the development of lymphoma may be preceded by a decline in EBV-specific cytotoxic lymphocytes, suggesting that failing EBV control may be an important pathogenetic step [66].

Smooth muscle tumors – Children infected with HIV appear to have a higher propensity for developing smooth muscle tumors (leiomyomas and leiomyosarcomas), which are ordinarily very rare [68,69]. EBV probably plays a pathogenic role in the development of these tumors as illustrated by the following observations:

• EBV can infect smooth muscle cells in HIV-infected individuals, and high levels of EBV genomes have been found in tumor tissue [69]

• Smooth-muscle tumors containing clonal EBV developed in three children after liver transplantation [70].

Hodgkin lymphoma — EBV genomic DNA was first reported in tissue specimens from patients with Hodgkin lymphoma (HL) in 1987 [71]. The finding that the malignant cells in HL, including the characteristic Reed-Sternberg cells, contain the EBV genome in up to 50 percent of "Western" cases supports a pathogenic role for EBV in this malignancy [72].

Nasopharyngeal carcinoma — Nasopharyngeal carcinoma is relatively rare in most populations. However, it is one of the most common cancers in southern China with age-adjusted incidence rates of up to 55 per 100,000 [83]. In contrast to Burkitt lymphoma, the association of EBV with nasopharyngeal carcinoma is highly consistent in both low- and high-incidence areas and EBV is present in every anaplastic nasopharyngeal carcinoma cell [84]

Gastric carcinoma — It is estimated that 9 to 10 percent of gastric carcinomas worldwide carry the EBV genome. EBV-induced gastric carcinoma may be one of the most common EBV malignancies.

EBV-induced gastric carcinomas usually involve the upper third of the stomach and, like nasopharyngeal carcinoma, levels of EBV VCA IgA antibodies are higher in individuals who subsequently develop EBV-induced gastric carcinoma compared with controls [90].

T cell lymphoma — T cells are also susceptible to EBV infection as illustrated in studies of EBV-infected tonsillar tissues in individuals with IM [91]. This observation is consistent with the description of T cell lymphomas in individuals with chronic EBV infection [92].

A fulminant form of T cell lymphoma has been described following acute EBV infection. One series of five patients described a clinical illness characterized by fever, hepatosplenomegaly and pancytopenia; significant erythrophagocytosis was detected in tissue specimen [94].

Nasal/nasal type angiocentric lymphoma — Nasal/nasal type angiocentric lymphomas are rare diseases that are endemic to Asian countries as well as Central and South America [95-97]. The sites of involvement include the nasal septum, palate, GI tract, and less commonly skin, testis and peripheral nerve. EBV is found in virtually all cases in the neoplastic cells. Although originally thought to be T cells, the malignant cells express CD2, CD56 but lack CD3 and T cell receptor gene rearrangements [98]. Thus, these tumors are probably of NK cell origin.

In most of the EBV-associated malignancies in which the stage of the virus life cycle has been characterized, there is little evidence for permissive (lytic) infection. Since acyclovir is only effective in inhibiting replication of linear EBV DNA there is little to be gained by its use in diseases associated with latent infection. There is anecdotal support for the use of acyclovir in EBV-induced hemophagocytic lymphohistiocytosis where evidence of replicating EBV was demonstrated [35]

Other therapies — Immunomodulating therapy is the main treatment option for EBV-associated lymphoproliferative disorders; these are discussed elsewhere. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Anecdotal use of immunomodulating agents (eg, interleukin-2, interferon alfa, intravenous immunoglobulins, and anti-CD20 therapy) has also been reported in EBV-associated diseases. As an example, case reports suggest rituximab has been used to successfully treat EBV-related pediatric meningoencephalitis refractory to immunoglobulin and corticosteroid therapy [101]. However, there are no high-quality clinical trials demonstrating these agents are beneficial for primary infection or acute complications.

Reducing exposure to EBV — For patients with active EBV infection (eg, primary, chronic active), measures such as frequent handwashing and not sharing eating utensils, drinking glasses, and toothbrushes may reduce transmission of EBV to others. Although there are no data to guide this approach, studies suggest that primary EBV infection may be occurring at a later age in children residing in the developed world [3], and it is possible that delayed acquisition of primary EBV infection is related to good hygiene.

In patients undergoing solid organ or hematopoietic cell transplant, exposure to EBV may be prevented by selecting EBV-naïve donors for EBV-naïve recipients; however this is not always possible. Thus, patients are typically monitored for EBV infection, and strategies to reduce the risk of post-transplant lymphoproliferative disease are implemented if EBV viremia is detected. This is discussed in detail elsewhere.

Investigational vaccines — There are currently no EBV vaccines available for clinical use, but this is an area of active investigation [102].

The large body of evidence implicating EBV in the etiology of a variety of human neoplasms has made the prospect of developing a viral-based vaccine effective against human cancers very appealing. Glycoprotein (gp) 350/220 is one of the most abundant viral proteins present in lytically infected cell plasma membranes and the most abundant protein on the outer surface of the virus coat; it also binds to the CD21 receptor on the B cell which is responsible for the initiation of infection. In addition, most of the human EBV neutralizing antibody response is directed against gp350/220 [103,104]. For these reasons, gp350/220 is the major EBV lytic-cycle gene being pursued in the development of a subunit vaccine.

Historical accounts of infectious mononucleosis often attribute the initial description of the disease to Filatov or Pfeiffer, who nearly simultaneously at the end of the 19th century described an illness characterized by malaise, fever, hepatosplenomegaly, lymphadenopathy, and abdominal discomfort.1,2 This illness came to be known as Drusenfieber (glandular fever); however, without specific techniques with which to establish the diagnosis, the concept of Drusenfieber as a clinical entity fell into disrepute.

Between 1910 and 1920 a number of observers reported cases of apparent spontaneous remission of leukemia, with a clinical course that is consistent with resolution of infectious mononucleosis.3,4

The establishment of infectious mononucleosis as a clinical entity is credited to Sprunt and Evans,5 who in 1920 described six cases of fever, lymphadenopathy, and prostration that occurred in previously healthy young adults. The authors pointed out the mononuclear lymphocytosis that developed in each of the patients and contrasted the pathologic appearance of these lymphocytes with the uniform lymphocyte morphol- ogy observed in children with other infections.

A major advance occurred in 1932, when Paul and Bunnell,7 investigating immunologic mechanisms in serum sickness, unexpectedly encountered high titers of spontaneously occurring sheep red blood cell (RBC) agglutinins (heterophile antibodies) in the sera of patients with infectious mononucleosis.

During the 1940s and 1950s substantial efforts were made to detect a causative agent for infectious mononucleosis. Attempts to culture etiologically related bacteria and viruses from patients with infectious mononucleosis proved unsuccessful. The disease could not be transmitted to animals.

Interpretation of experimental attempts to transmit the disease to humans was hindered by the failure to appreciate the wide- spread occurrence of asymptomatic infection in preadolescents and the absence of a serologic marker of immunity.8–10

With specific antibody tests for EBV, it became apparent that 10% to 20% of the cases of mononucleosis, of which most were heterophile negative, were caused by other agents, the most frequent of which was cytomegalovirus (CMV)

The identification of EBV followed the description by Burkitt11 in 1958 of an unusual lymphoma with a predilection for the head and neck. The geographic distribution of this tumor paralleled that of certain mosquito-borne diseases in Africa, and a search for an etiologically related arbovirus was undertaken. Epstein and associates12 in 1964 described the presence of particles that resembled herpesviruses in tissue cultures of biopsy specimens from patients with Burkitt lymphoma.

EBV induces a broad spectrum of illness in humans. Classic or typical infectious mononucleosis is an acute illness characterized clinically by sore throat, fever, and lymphadenopathy; serologically by the transient appearance of heterophile antibodies; and hematologically by a mono- nuclear leukocytosis that consists, in part, of atypical lymphocytes (Table 138.3)

Specific serologic tests for EBV infection indicate that infection results in a spectrum of clinical manifestations. Attempts to exclude cases that fail to meet the classic criteria for infectious mononucleosis result in artificial and often misleading distinctions.

The age of the patient has a profound influence on the clinical expression of EBV infection. In children primary EBV infection is often asymptomatic. Young children may be more likely to exhibit rashes, neutropenia, or pneumonia than individuals with primary EBV infection at an older age.138

Clinically apparent infections in very young children are heterophile negative in about one-half of the cases.139 The proportions of clinically apparent disease and of heterophile-positive cases increase with age.

By 4 years of age 80% of children with primary EBV infection are heterophile antibody positive.140 During the course of the illness 90% of the adolescents with clinically apparent infectious mononucleosis should be heterophile positive.

Because of previously existing immunity, the disease is less common in older patients. When it does occur, however, clinical and serologic manifestations are similar to those found in adolescents.141