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خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : -37 مورد

Infectious mononucleosis

Infectious mononucleosis
Authors:
Mark D Aronson, MD
Paul G Auwaerter, MD, MBA, FIDSA
Section Editors:
Martin S Hirsch, MD
Sheldon L Kaplan, MD
Deputy Editors:
Karen Law, MD, FACP
Sheila Bond, MD
Literature review current through: Apr 2025. | This topic last updated: Feb 05, 2025.

INTRODUCTION — 

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].

This topic will review IM caused by EBV infection in adults and adolescents, including diagnosis and treatment. A complete description of EBV and other clinical manifestations of EBV infection (including malignancy) are discussed separately. (See "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Virology of Epstein-Barr virus".)

Other infectious agents may also cause a mononucleosis syndrome that resembles IM caused by EBV. These syndromes are discussed along with their causative agents:

●(See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'CMV mononucleosis'.)

●(See "Acute and early HIV infection: Pathogenesis and epidemiology".)

●(See "Toxoplasmosis: Acute systemic disease".)

●(See "Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults", section on 'Immunocompetent hosts'.)

The evaluation of acute pharyngitis in adults, for which IM is a diagnostic consideration, is also reviewed separately. (See "Evaluation of acute pharyngitis in adults".)

EPIDEMIOLOGY, TRANSMISSION, AND PATHOGENESIS — 

Epstein-Barr virus (EBV) is a widely disseminated herpesvirus spread by intimate contact between susceptible persons and EBV shedders. 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. Furthermore, why some exposed individuals develop IM but others do not is unknown. One study suggests that single-nucleotide polymorphisms within toll-like receptors may account for different courses of acute primary EBV infection [12]. 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 — 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].

Pathogenesis — 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. A robust cellular immune response with CD4+ and CD8+ T cell activation contributes to the symptoms of IM [25,26]. 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.

EBV virology is discussed in further detail separately. (See "Virology of Epstein-Barr virus".)

CLINICAL MANIFESTATIONS

Typical presentation — 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]. In one review of over 500 patients with IM, lymphadenopathy was present in all patients, fever in 98 percent, and pharyngitis in 85 percent [34]. 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]:

●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. (See "Evaluation of acute pharyngitis in adults".)

●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].

●Other symptoms – Other less common symptoms of IM include rhinitis, periorbital edema, and liver and spleen tenderness. Additional signs and symptoms are reviewed in the table (table 1).

Laboratory abnormalities

●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. The differential may also identify atypical lymphocytes (picture 1). These cells underlie the term "infectious mononucleosis" as they were originally described as monocytes in early case series [2,3]. The diagnostic accuracy of these tests is discussed below. (See 'Laboratory testing' below.)

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. (See 'Complications' below and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

●Liver function tests – Mildly elevated aminotransferases are seen in the majority of patients [34]. Rarely, severe hepatitis and cholestasis have been reported. (See 'Complications' below.)

Complications

●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 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]. (See "Pathogenesis and epidemiology of multiple sclerosis", section on 'Viral infections'.)

●HLH – EBV infection is a recognized trigger for HLH, a rapidly progressive, life-threatening syndrome of dysregulated immune system activation [58]. 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. Prompt recognition and hematology referral are critical components of HLH treatment. Further details on the diagnosis and treatment of HLH are discussed separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

●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]. A more detailed discussion of chronic active EBV infections is presented separately. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Chronic active EBV infection'.)

●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]. (See "Lemierre syndrome: Septic thrombophlebitis of the internal jugular vein", section on 'Pathogenesis'.)

Presentation in special populations

●Older adults – In older adults 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. (See 'Differential diagnosis' below and 'Patients who test negative' below.)

Additional details regarding CMV, HIV, and toxoplasma infection during pregnancy are presented separately:

•(See "Overview of TORCH infections".)

•(See "Cytomegalovirus infection in pregnancy".)

•(See "Prenatal evaluation of women with HIV in resource-abundant settings" and "Intrapartum and postpartum management of pregnant women with HIV in resource-abundant settings".)

•(See "Toxoplasmosis and pregnancy".)

There is little evidence of teratogenic risk to the fetus in women who develop EBV infection and IM during pregnancy [70]. Perinatal EBV infections are discussed separately in further detail. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Congenital and perinatal infections'.)

●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]. Primary EBV infection in children is discussed separately in further detail. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Primary EBV infection in infants and children'.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of IM includes other infections, medication effects, and malignancy, all of which may present with a combination of fever, pharyngitis, and lymphadenopathy. In some cases, clinical findings may help differentiate these conditions from IM, while additional diagnostic testing may be required for other presentations:

●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].

Fever, adenopathy, and tonsillar exudate are less likely with viral pharyngitis. Infectious causes of acute pharyngitis are discussed in further detail separately. (See "Evaluation of acute pharyngitis in adults", section on 'Infectious causes'.)

●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]. Diagnostic testing is particularly important if the patient is pregnant since CMV, HIV, and toxoplasma infections can have significant adverse effects on pregnancy outcomes. (See 'Patients who test negative' below.)

●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.

DIAGNOSIS

When to suspect IM — 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 if these symptoms and signs present in a young adult and if they develop over the course of 7 to 14 days, in contrast to the more sudden onset of symptoms in patients with other causes of acute pharyngitis. Palatal petechiae and splenomegaly highly suggest IM, while the absence of cervical lymphadenopathy and fatigue makes the diagnosis less likely [83,84]. Other conditions with similar signs and symptoms are discussed separately. (See 'Differential diagnosis' above.)

Initial evaluation

History and physical examination — The history in patients suspected of IM should assess the extent of symptoms and exclude alternative diagnoses. The history should focus on the following:

●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. (See 'Differential diagnosis' above.)

The physical examination should focus particular attention on the following areas:

●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. (See 'Management of complications' below and "Peritonsillar cellulitis and abscess".)

●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.

Laboratory testing — Laboratory evaluation for suspected IM includes the following:

●Epstein-Barr virus (EBV) testing – The choice of EBV test is discussed below. (See 'Establishing the diagnosis' below.)

●Complete blood count (CBC) and differential – We check a CBC in all patients. 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 is highly specific for the diagnosis of 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]. (See "Automated complete blood count (CBC)", section on 'WBC parameters'.)

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]. (See 'Differential diagnosis' above.)

●Additional laboratory testing – 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. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

•Testing for group A Streptococcus (GAS) pharyngitis – Testing with either a rapid antigen detection test or nucleic acid amplification test for streptococcal pharyngitis assists with narrowing the differential diagnosis. Test results also inform treatment as antibiotic therapy is indicated when streptococcal testing is positive. (See "Evaluation of acute pharyngitis in adults".)

•Testing for other causes of mononuclear syndromes – Differentiating between IM caused by EBV and a similar syndrome due to CMV, HIV, or toxoplasmosis infection is often not possible clinically. 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. (See 'Presentation in special populations' above.)

Testing for HIV, CMV, and toxoplasmosis are discussed in further detail separately:

-(See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

-(See "Approach to the diagnosis of cytomegalovirus infection".)

-(See "Toxoplasmosis: Acute systemic disease".)

Establishing the diagnosis — 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.

EBV-specific antibodies — 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]. Therefore, a positive result reduces the need for additional testing (algorithm 1).

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). We also use EBV-specific antibodies as confirmatory testing when heterophile antibodies return a negative result.

●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 peak two to four 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 begin to appear six to eight weeks after the onset of symptoms 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.

●Test interpretation – Because EBV antibody profiles change as the disease progresses (figure 1), results must be interpreted along with the time course of the patient's symptoms (algorithm 1):

•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 symptom onset. 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. (See 'Differential diagnosis' above and 'Patients who test negative' below.)

•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.

Heterophile antibodies — Heterophile antibodies (eg, the "Monospot" test) can also be used for diagnosing IM, especially in settings where the pretest probability of IM is high or EBV antibodies are not available [1]. 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. (See 'EBV-specific antibodies' above.)

●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]. This testing strategy facilitates a clear therapeutic plan for which antibiotic therapy is not indicated.

●Test characteristics – 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].

●Test interpretation – 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.

Because of the possibility of false-negative results, patients with clinically suspected IM who have negative heterophile antibody testing warrant additional diagnostic evaluation. (See 'Patients who test negative' below.)

Limited role for routine EBV PCR testing — Epstein-Barr virus (EBV) viral load is accomplished through polymerase chain reaction (PCR) assays on blood or plasma [103,104]. Viral genomes can be detected in the blood in 40 to 70 percent of patients at symptom onset, depending upon which assay is used; this increases to 90 percent approximately two weeks after onset [105].

We do not routinely order EBV viral load when diagnosing IM, as it confers no additional therapeutic guidance over EBV-specific antibodies. The exception is in rare cases of atypical or early primary EBV and scenarios where EBV antibodies are nondiagnostic. (See 'Patients who test negative' below.)

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 who test negative — Patients with clinically suspected IM and negative EBV testing results should be tested for GAS pharyngitis if not already done (see "Evaluation of acute pharyngitis in adults"). Additional evaluation is indicated as follows:

●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. (See 'EBV-specific antibodies' above.)

●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].

The clinical presentation of these infections is discussed in detail separately:

•(See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'CMV mononucleosis' and "Approach to the diagnosis of cytomegalovirus infection".)

•(See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

•(See "Toxoplasmosis: Acute systemic disease".)

•(See "Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults", section on 'Immunocompetent hosts'.)

•(See "Human herpesvirus 7 infection".)

EBV PCR may ordered in rare circumstances where EBV remains highly suspected despite nondiagnostic EBV antibodies (figure 1). (See 'Limited role for routine EBV PCR testing' above.)

Unexplained, persistent lymphadenopathy in the setting of fever and other constitutional symptoms should prompt additional evaluation for possible malignancy or infectious etiologies. A detailed discussion of the evaluation of peripheral lymphadenopathy is presented separately. (See "Evaluation of peripheral lymphadenopathy in adults", section on 'Evaluation'.)

TREATMENT

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. (See 'Return to activity' below.)

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. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Complications' and "Clinical manifestations and treatment of Epstein-Barr virus infection", section on '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].

Corticosteroids are used in the management of patients with Epstein-Barr virus (EBV)-associated airway compromise and other serious complications, as below. (See 'Management of complications' below.)

No role for antiviral treatment — We do not recommend the antiviral acyclovir to treat IM. Patients with IM treated with acyclovir demonstrated only mild, short-term suppression of oral viral shedding without additional clinical benefit [111,114,115]. Acyclovir is a nucleoside analog that inhibits EBV deoxyribonucleic acid polymerase, thereby reducing EBV replication.

Management of complications

●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]. The management of acute splenic injury is discussed separately in further detail. (See "Management of splenic injury in the adult trauma patient".)

●Hemophagocytic lymphohistiocytosis (HLH) – Patients with HLH associated with EBV require urgent consultation with a hematologist. Inpatient care may be warranted, especially if the patient is hemodynamically unstable or with evidence of deteriorating organ function. Further details on the management of HLH are discussed separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

●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.

PROGNOSIS — 

Most individuals with primary Epstein-Barr virus 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].

RETURN TO ACTIVITY — 

We prefer a conservative approach to resuming activity based on the risk of splenic rupture and the possibility of persistent fatigue in some individuals:

●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. (See 'Prognosis' above.)

●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), we recommend a minimum of four weeks after illness onset before resuming activity.

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.

Advice for reducing Epstein-Barr virus transmission among household contacts of patients with IM is discussed separately. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Prevention'.)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Mononucleosis (The Basics)")

●Beyond the Basics topic (see "Patient education: Infectious mononucleosis (mono) in adults and adolescents (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Infectious mononucleosis (IM) is an acute febrile illness due to Epstein-Barr virus (EBV) infection, which occurs mainly in adolescents and young adults. Transmission is primarily person to person through contact with salivary secretions. (See 'Epidemiology, transmission, and pathogenesis' above.)

●Clinical manifestations – IM is characterized by fever, pharyngitis, fatigue, and cervical lymphadenopathy, primarily in adolescents and young adults (table 1). Some patients may also have splenomegaly and palatal petechiae. Common laboratory findings include an absolute or relative lymphocytosis, atypical lymphocytes (picture 1), and elevated aminotransferases. (See 'Clinical manifestations' above.)

●Differential diagnosis – Other diagnoses to consider include group A Streptococcus (GAS) pharyngitis or other acute respiratory infections, cytomegalovirus (CMV), acute HIV infection, and toxoplasma. Lymphoma may also present with prominent lymphadenopathy, splenomegaly, and constitutional symptoms. (See 'Differential diagnosis' above.)

●Diagnosis – Laboratory evaluation includes EBV testing, complete blood count, and evaluation for streptococcal pharyngitis by culture or antigen testing. The presence of lymphocytosis ≥50 percent and atypical lymphocytes ≥10 percent is highly specific for diagnosing IM in patients with consistent clinical features. (See 'Diagnosis' above.)

A diagnosis of IM is confirmed with one of the following EBV tests (figure 1) (see 'Establishing the diagnosis' above):

•EBV-specific antibodies – EBV-specific antibodies are the gold standard test for diagnosing EBV as they have high sensitivity and specificity for IM. Results should be interpreted in the context of the time course of symptoms as EBV antibody profiles change over time (algorithm 1). (See 'EBV-specific antibodies' above.)

•Heterophile antibodies – Heterophile antibodies (eg, the "Monospot" test) are also a reasonable diagnostic test. In patients with high clinical suspicion (eg, a young adult with fever and pharyngitis), heterophile tests are useful as results are rapidly available. This facilitates a clear therapeutic plan in patients whose primary diagnostic concern is differentiating between streptococcal pharyngitis and IM. (See 'Heterophile antibodies' above.)

Because of the possibility of false-negative results, patients with a negative initial heterophile test and persistent symptoms should have confirmatory testing with EBV-specific antibodies (preferred) or repeat heterophile testing one week later.

●Patients who test negative – Negative EBV antibodies or repeat heterophile tests in patients with persistent symptoms should prompt evaluation for other causes of a mononucleosis syndrome, including CMV, HIV, toxoplasmosis, human herpesvirus (HHV) 6, and HHV-7 (algorithm 1). Diagnostic testing is particularly important if the patient is pregnant since CMV, HIV, and toxoplasma can have significant adverse effects on pregnancy outcomes. (See 'Presentation in special populations' above and 'Patients who test negative' above.)

Testing for GAS pharyngitis should also be performed. (See "Evaluation of acute pharyngitis in adults".)

●Treatment – Supportive care is the mainstay of IM treatment.

We suggest against the routine use of corticosteroids in uncomplicated IM (Grade 2C). Corticosteroids may result in modest symptom relief but are of limited utility as the illness is typically self-limited.

However, in patients with airway obstruction from associated abscess or tonsillar edema, we suggest high-dose intravenous corticosteroids to reduce edema and avoid airway compromise (Grade 2C). Limited evidence suggests corticosteroid treatment reduces airway compromise requiring intubation. The typical dose is dexamethasone 0.25 mg/kg every six hours, followed by a taper over 7 to 14 days after clinical improvement. (See 'Limited role for corticosteroids' above and 'Management of complications' above.)

Acyclovir offers no clinically meaningful benefit in the treatment of IM. (See 'No role for antiviral treatment' above.)

●Return to activity – Resumption of activity is based on the risk of splenic rupture and persistent fatigue. All patients should refrain from sports during the first two to three weeks of illness. Initial resumption of activity should be at reduced levels, with a gradual increase as tolerated.

For noncontact sports, training can resume three weeks after symptom onset.

For strenuous contact sports and activities associated with increased intra-abdominal pressure (such as weightlifting), we suggest resumption of activity four weeks after illness onset. For patients with previous clinical or radiographic evidence of splenomegaly, before resumption of strenuous contact sports, we confirm the resolution of splenomegaly with an ultrasound at four to seven weeks. (See 'Return to activity' above.)

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Topic 8318 Version 47.0

References

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6 : Common questions about infectious mononucleosis.

7 : Common questions about infectious mononucleosis.

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11 : The changing epidemiology of infectious mononucleosis?

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14 : Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students.

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17 : Infectious mononucleosis and Epstein-Barr virus.

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36 : Oropharyngotonsillitis associated with nonprimary Epstein-Barr virus infection.

37 : Infectious mononucleosis in middle age.

38 : Antibiotic-Induced Rash in Patients With Infectious Mononucleosis.

39 : Incidence of rash after amoxicillin treatment in children with infectious mononucleosis.

40 : Azithromycin eruption in infectious mononucleosis: a proposed mechanism of interaction.

41 : Quinolone drug rash in a patient with infectious mononucleosis.

42 : Rash associated with piperacillin/tazobactam administration in infectious mononucleosis.

43 : Cephalexin rash in infectious mononucleosis.

44 : Do penicillins really increase the frequency of a rash when given during Epstein-Barr Virus primary infection?

45 : Spontaneous rupture of the spleen detected on CT as the initial manifestation of infectious mononucleosis.

46 : Spontaneous rupture of the spleen in patients with infectious mononucleosis.

47 : Splenic rupture in infectious mononucleosis: A systematic review of published case reports.

48 : Peritonsillar abscess and infectious mononucleosis: an association or a different presentation of the same condition.

49 : Parotid mass: Epstein-Barr virus and facial paralysis.

50 : Multiple cranial nerve palsies as a complication of infectious mononucleosis due to inflammatory lesion in jugular foramen.

51 : Simultaneous vocal fold and tongue paresis secondary to Epstein-Barr virus infection.

52 : Epstein-Barr virus meningoencephalitis with a lymphoma-like response in an immunocompetent host.

53 : Epstein-Barr virus encephalomyelitis diagnosed by polymerase chain reaction: detection of the genome in the CSF.

54 : Multiple sclerosis and antecedent infections: a case-control study.

55 : Multiple sclerosis and age at infection with common viruses.

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57 : "Alice in wonderland" syndrome: a manifestation of infectious mononucleosis in children.

58 : Clinical warning of hemophagocytic syndrome caused by Epstein-Barr virus.

59 : The chronic mononucleosis syndrome.

60 : Ascites and severe hepatitis complicating Epstein-Barr infection.

61 : Infectious mononucleosis hepatitis: report of two patients.

62 : Just another simple case of infectious mononucleosis?

63 : Pancreatitis and cholecystitis in primary acute symptomatic Epstein-Barr virus infection - Systematic review of the literature.

64 : Acute renal failure: unusual complication of Epstein-Barr virus-induced infectious mononucleosis.

65 : Epstein-Barr virus-related gastric pseudolymphoma in infectious mononucleosis.

66 : Necrotizing genital ulcerations in a premenarcheal female with mononucleosis.

67 : Lemierre's and Lemierre's-like syndromes in association with infectious mononucleosis.

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69 : Infectious mononucleosis in older adults.

70 : Epstein-Barr virus infection in pregnancy--a prospective controlled study.

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72 : Infectious mononucleosis and Epstein-Barr virus in childhood.

73 : Arcanobacterium haemolyticum in children with presumed streptococcal pharyngotonsillitis or scarlet fever.

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75 : Clinical picture of primary HIV infection presenting as a glandular-fever-like illness.

76 : Heterophil-negative infectious mononucleosis and mononucleosis-like illnesses. Laboratory confirmation of 43 cases.

77 : Cytomegalovirus as a possible cause of a disease resembling infectious mononucleosis.

78 : Spontaneous cytomegalovirus mononucleosis. Clinical and laboratory observations in nine cases.

79 : Mononucleosis-like illness as a manifestation of carbamazepine-induced anticonvulsant hypersensitivity syndrome.

80 : An infectious mononucleosis-like syndrome induced by minocycline: a third pattern of adverse drug reaction.

81 : Phenytoin hypersensitivity hepatitis and mononucleosis syndrome.

82 : Diagnostic evaluation of mononucleosis-like illnesses.

83 : Epstein-Barr virus infectious mononucleosis.

84 : Does This Patient Have Infectious Mononucleosis?: The Rational Clinical Examination Systematic Review.

85 : Accuracy of Signs, Symptoms, and Hematologic Parameters for the Diagnosis of Infectious Mononucleosis: A Systematic Review and Meta-Analysis.

86 : Infectious mononucleosis in an outpatient population: diagnostic utility of 2 automated hematology analyzers and the sensitivity and specificity of Hoagland's criteria in heterophile-positive patients.

87 : Evaluation of 12 commercial tests for detection of Epstein-Barr virus-specific and heterophile antibodies.

88 : How to use…the Monospot and other heterophile antibody tests.

89 : Clinical and laboratory evaluation of infants and children with Epstein-Barr virus-induced infectious mononucleosis: report of 32 patients (aged 10-48 months).

90 : Clinical characteristics and laboratory findings in Danish children hospitalized with primary Epstein-Barr virus infection.

91 : Primary Epstein-Barr virus infection in early childhood.

92 : Primary Epstein-Barr virus infection in early childhood.

93 : Virological Markers in Epstein-Barr Virus-Associated Diseases.

94 : Serological diagnosis of Epstein-Barr virus infection: Problems and solutions.

95 : Measurement of heterophil antibody and antibodies to EB viral capsid antigen IgG and IgM in suspected cases of infectious mononucleosis.

96 : Measurement of heterophil antibody and antibodies to EB viral capsid antigen IgG and IgM in suspected cases of infectious mononucleosis.

97 : Use of Monospot Testing in the Diagnosis of Infectious Mononucleosis in the Collegiate Student-Athlete Population.

98 : A comparison of the Monospot with the Paul-Bunnell test in infectious mononucleosis and other diseases.

99 : Monospot: a differential slide test for infectious mononucleosis.

100 : Comparative evaluation of nine kits for rapid diagnosis of infectious mononucleosis and Epstein-Barr virus-specific serology.

101 : False-positive serology in infectious monoucleosis.

102 : False-Positive Monospot in a Returning Traveler with Dengue Fever.

103 : Quantitation of Epstein-Barr virus mRNA using reverse transcription and real-time PCR.

104 : Assessment of automated DNA extraction coupled with real-time PCR for measuring Epstein-Barr virus load in whole blood, peripheral mononuclear cells and plasma.

105 : The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events.

106 : Infections in heterophile-negative patients.

107 : Infectious mononucleosis and related syndromes.

108 : The spectrum of clinical and laboratory findings resulting from human herpesvirus-6 (HHV-6) in patients with mononucleosis-like illnesses not resulting from Epstein-Barr virus or cytomegalovirus.

109 : Isolation of human herpesvirus 7 from a child with symptoms mimicking chronic Epstein-Barr virus infection.

110 : Primary human immunodeficiency virus type 1 infection: review of pathogenesis and early treatment intervention in humans and animal retrovirus infections.

111 : Acyclovir and prednisolone treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-controlled study.

112 : Steroids for symptom control in infectious mononucleosis.

113 : Physical activity considerations in children and adolescents with viral infections.

114 : Lack of effect of peroral acyclovir for the treatment of acute infectious mononucleosis.

115 : Acyclovir for treatment of infectious mononucleosis: a meta-analysis.

116 : Airway obstruction in children with infectious mononucleosis.

117 : Upper airway obstruction in infectious mononucleosis.

118 : Acute infectious mononucleosis: characteristics of patients who report failure to recover.

119 : Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.

120 : A Validated Scale for Assessing the Severity of Acute Infectious Mononucleosis.

121 : Chronic fatigue syndrome after infectious mononucleosis in adolescents.

122 : Infectious mononucleosis in university students in the United kingdom: evaluation of the clinical features and consequences of the disease.

123 : Risk and predictors of fatigue after infectious mononucleosis in a large primary-care cohort.

124 : Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus.

125 : Correlation of psycho-neuroendocrine-immune (PNI) gene expression with symptoms of acute infectious mononucleosis.

126 : What causes prolonged fatigue after infectious mononucleosis: and does it tell us anything about chronic fatigue syndrome?

127 : Spontaneous splenic rupture in infectious mononucleosis: sonographic diagnosis and follow-up.

128 : Determination of safe return to play for athletes recovering from infectious mononucleosis: a review of the literature.

129 : Infectious mononucleosis and the spleen.

130 : Spontaneous splenic rupture in infectious mononucleosis: a review.

131 : Infectious mononucleosis in the athlete. Diagnosis, complications, and management.

132 : When to resume sports after infectious mononucleosis. How soon is safe?

133 : Infectious mononucleosis: return to play.

134 : American Medical Society of Sports Medicine Position Statement: Mononucleosis and Athletic Participation.

135 : Special feature for the Olympics: effects of exercise on the immune system: infections and exercise in high-performance athletes.

136 : Examiner dependence on physical diagnostic tests for the detection of splenomegaly: a prospective study with multiple observers.

137 : Spontaneous rupture of the spleen in patients with infectious mononucleosis.

138 : Hepatosplenomegaly in infectious mononucleosis, assessed by ultrasonic scanning.

139 : Athletes resuming activity after infectious mononucleosis.