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Official reprint from UpToDate® www.uptodate.com ©2017 UpToDate®

Infectious mononucleosis in adults and adolescents Authors: Mark D Aronson, MD, Paul G Auwaerter, MD, MBA, FIDSA Section Editors: Martin S Hirsch, MD, Sheldon L Kaplan, MD Deputy Editor: Jennifer Mitty, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2017. | This topic last updated: Jul 10, 2017. INTRODUCTION — Infectious mononucleosis (IM) is characterized by a triad of fever, tonsillar pharyngitis, and lymphadenopathy [1]. It was initially described as "Drusenfieber" or glandular fever in 1889, but 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]. Infectious mononucleosis in adults and adolescents will be reviewed here. 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".) EPIDEMIOLOGY — Epstein-Barr virus (EBV) is a widely disseminated herpesvirus that is 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 population groups with a worldwide distribution; approximately 90 to 95 percent of adults are eventually EBV-seropositive. By age four, EBV seroprevalence is close to 100 percent in developing countries and ranges from 25 to 50 percent in lower socioeconomic groups in the United States. Many attribute this finding to intense personal contact and poor personal hygiene among children, which provide opportunities for early acquisition and subsequent spread of EBV. EBV acquired during childhood years is often subclinical; less than 10 percent of children develop clinical infection despite the high rates of exposure. The incidence of symptomatic infection begins to rise in adolescent through adult years [5]. Large studies of infectious mononucleosis are now decades old, but traditionally the peak incidence of infection has been described in the 15 to 24-year age range [6]. Some data derived in the United Kingdom suggest that infectious mononucleosis (IM) cases may be occurring later in life with increasing severity, requiring hospitalization [7]. IM is relatively uncommon in adults, accounting for less than two percent of pharyngitis in adults [8]. The vast majority of adults are not susceptible to this infection because of prior exposure. The differences observed between infants and young adults with regard to symptomatic infection may relate to the size of the viral inoculum at the time of infection or to the intensity of cellular immune responses driven by EBV-infected B cells. The incidence of clinical infection is approximately 30 times higher in whites than blacks in the United States [9]. This may reflect both earlier exposures to EBV among the latter group and the higher frequency of asymptomatic infection when acquired by young children. In addition, IM occurs more frequently in same sex twins and first degree siblings, compared with second and third degree relatives [10]. Thus, genetic factors may influence who develops clinical disease. In one case series, GATA2

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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 [11]. TRANSMISSION Person-to-person — Following infectious mononucleosis, virus may be shed in salivary secretions at high levels for a prolonged period [12,13]. Oral shedding persists for a median duration of approximately six months after onset of illness [13], although it should be pointed out that once infected with Epstein-Barr virus (EBV), virus may be intermittently shed in the oropharynx for decades [12,14]. Although EBV primarily spreads via passage of saliva, it is not a particularly contagious disease. In a classic study conducted among college students, susceptible roommates of patients with either symptoms of infectious mononucleosis (IM) or asymptomatic viral shedding were no more likely to seroconvert or develop clinical illness than other college students without evidence of preexisting EBV infection [15]. The virus can persistently shed in the oropharynx of patients with IM for up to 18 months following clinical recovery; this may explain in part why only a small number of patients with IM recall previous contact with an infected individual [15,16]. Intrafamilial spread among siblings has also been reported [17]. Breastfeeding — EBV has been isolated in breast milk from healthy nursing mothers [18]. However, in one study, there was no difference in EBV seropositivity between exclusively nursed or bottle-fed infants, suggesting that breastfeeding is not an important route of transmission [18,19]. Sexual transmission — EBV has also been isolated in both cervical epithelial cells and in male seminal fluid, suggesting that transmission may also occur sexually [20-22]. In an epidemiologic study of more than 2000 university students in Scotland, questionnaires and serum samples were analyzed to examine risk factors for EBV seropositivity [23]. Sexual activity before college admission was significantly associated with an increased risk of EBV seropositivity. Furthermore, the risk of a seropositive status increased with the number of sexual partners. Despite the recovery of EBV in genital secretions, studies have been unable to discriminate with certainty whether EBV was acquired through an oral or genital route. In one prospective study that followed EBV antibody-negative university freshmen, the time to infection in individuals reporting deep kissing without coitus was similar to those who reported deep kissing plus coitus [13]. Both groups had a significantly higher risk of acute EBV infection than subjects reporting no kissing or coitus. PATHOGENESIS — Contact of Epstein-Barr virus (EBV) with oropharyngeal epithelial cells allows replication of the virus, release of EBV into the oropharyngeal secretions, and infection of B cells in the lymphoid-rich areas of the oropharynx [24]. EBV-infected B cells are responsible for the dissemination of infection throughout the lymphoreticular system. The incubation period prior to the development of symptoms averages four to eight weeks. A prospective study was performed in 20 subjects with serologically confirmed primary EBV infection to assess viral kinetics in various compartments, including whole blood, peripheral blood mononuclear cells, and oral wash fluid [25]. The median half-life of viral elimination from whole blood in 19 subjects was three days; quantity in this compartment correlated with severity of symptoms. In contrast, virus persisted at an elevated level for 32 weeks in the oropharynx in asymptomatic subjects, consistent with the theory that EBV is transmitted via saliva. Primary EBV infection of B lymphocytes induces circulating antibodies directed against viral and unrelated antigens found on sheep and horse red cells [26]. The latter antibodies, termed heterophile antibodies, are a heterogeneous group of mostly IgM antibodies that do not cross-react with EBV antigens [27,28]. Rarely, infected cells produce antineutrophil, antierythrocyte, and antiplatelet antibodies, which are responsible for some of the less common clinical manifestations associated with infectious mononucleosis (IM) (see

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below). An EBV-specific serologic response can also be documented, although this is necessary for less than 10 percent of heterophile antibody-negative IM cases. EBV-specific cytotoxic T-lymphocytes are considered essential in controlling acute and reactivation infection. T cell activation leads to a T helper 1-type profile with production of interleukin-2 and interferongamma cytokines [29]. 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 (HLA-DR+) CD8+ T-cells and also include CD16+ natural killer (NK) cells (picture 1) [30-34]. Despite these immune responses, which control the initial lytic infection, EBV becomes a lifelong infection as it establishes latency with periodic reactivation with oral shedding of EBV. On the other hand, insufficient cellular immune responses may result in a poorly-controlled EBV infection and/or generate an EBV-induced malignancy. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Malignancy'.) Even with sufficient immune responses, some epidemiological studies have linked IM to increased risks of other conditions, such as Hodgkin lymphoma [35,36]. Other studies have linked acquisition of infection to increased risks for autoimmune disorders, such as multiple sclerosis or systemic lupus erythematosus [37,38]. Such associations will require significant additional study to prove causation as well as whether they could be a result of direct viral, or rather immunological consequences. Such concerns have heightened interest in exploring potential preventative strategies, such as an EBV vaccine [39,40]. CLINICAL MANIFESTATIONS Classic IM — Typical features of infectious mononucleosis (IM) include fever, pharyngitis, adenopathy, fatigue, and atypical lymphocytosis (table 1) [41]. A review of over 500 patients found that lymphadenopathy was present in all patients, fever in 98 percent, and pharyngitis in 85 percent [42,43]. The syndrome is often heralded by malaise, headache, and low grade fever before development of these more specific signs [5,44]. Fatigue may be persistent and severe. In a prospective study of 150 patients, most initial symptoms (eg, fever, sore throat) had resolved by one month but fatigue resolved more slowly and persisted in 13 percent of patients at six months [43]. Fatigue appears to be more common with a more profound impact on studies and exercise abilities in young female university students compared with male students [45]. Lymph node involvement in IM is typically symmetric and more commonly involves the posterior cervical than the anterior chains. The posterior cervical nodes are deep to the sternocleidomastoid muscles and must be carefully palpated. The nodes may be large and moderately tender. Lymphadenopathy may also become more generalized, which distinguishes IM from other causes of pharyngitis [8]. Lymphadenopathy peaks in the first week and then gradually subsides over two to three weeks. A history of sore throat is often accompanied by pharyngeal inflammation and tonsillar exudates, which may appear white, gray-green, or even necrotic. Palatal petechiae with streaky hemorrhages and blotchy red macules are occasionally present; this finding may also be seen in patients with streptococcal pharyngitis. Rare complications of IM include peritonsillar abscess or airway occlusion secondary to edema of the soft palate and tonsils [46]. Clinical variants — There are a number of clinical variants of IM in which some but not all of the classic findings are present: ● Many patients with acute EBV infection have relatively mild disease, and some present with pharyngitis and tonsillitis in the absence of a full-blown IM syndrome [47]. Among 66 EBVseronegative university students who developed primary EBV infection, 77 percent had the usual IM

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syndrome, 12 percent had atypical symptoms, and only 11 percent were asymptomatic [13]. ● Many patients present with fever and lymphadenopathy without pharyngitis, the so-called "typhoidal form" of illness. Many of these patients are heterophile antibody-negative, and should be termed "heterophile-negative IM". Other infectious causes of heterophile antibody-negative IM include most importantly cytomegalovirus (CMV) [48], or acute human immunodeficiency virus (HIV) [49], with other infections such as toxoplasmosis [50], human herpesvirus type 6 (HHV-6) [51], and HHV-7 [52] possible. (See 'Differential diagnosis' below and 'Diagnosis' below.) ● Very young or older adults frequently do not develop the classic clinical syndrome (table 2) [53]. In a study of patients ages 40 to 78, pharyngitis and myalgia were the most frequent complaints, while cervical lymphadenopathy was less commonly noted on physical examination [54]. Fever is common among older individuals and can last for several weeks [53]. Other clinical manifestations Splenomegaly and splenic rupture — Splenomegaly is seen in 50 to 60 percent of patients with IM and usually begins to recede by the third week of the illness [55]. Splenic rupture is a rare, but potentially life-threatening complication of IM. It is estimated to occur in one to two cases per thousand [56]; approximately 70 percent occur in males, usually under 30 years [57]. The typical manifestations are abdominal pain and/or a falling hematocrit [58]. When splenic rupture occurs, it does so spontaneously in over one-half of patients. It typically occurs about 14 days after symptom onset; however, it can range from four days to as far as eight weeks. In some cases, it can be the presenting symptom [58]. The management of splenic rupture is similar to other forms of splenic injury. Nonoperative treatment with intensive supportive care and splenic preservation is preferred, but some require splenectomy [59]. Despite its life-threatening potential, fatality from IM-related splenic rupture is rare. Infarctions of the spleen have also been described as a rare consequence of IM. Of the 19 reported cases, abdominal pain is usually described, although in some cases, infarction can be an incidental finding [60]. Rash — A generalized maculopapular, urticarial, or petechial rash is occasionally seen, while erythema nodosum is rare [53]. A maculopapular rash almost always occurs following the administration of ampicillin or amoxicillin, although it has been also described occasionally with a variety of other antibiotics including azithromycin [61], levofloxacin [62], piperacillin/tazobactam [63], and cephalexin (picture 2) [64]. The incidence of rash associated with beta-lactams initially was reported to be as high as 70 to 90 percent, but is probably lower [50]. The mechanism responsible for the rash is not well understood. Development of a drug-related rash during IM does not appear to presage a true drug allergy, as patients subsequently tolerate ampicillin without an adverse reaction. Neurologic syndromes — Neurologic syndromes include Guillain-Barré syndrome, facial and other cranial nerve palsies [65-67], meningoencephalitis [68], aseptic meningitis, transverse myelitis, peripheral neuritis, optic neuritis, and encephalomyelitis [69]. These manifestations tend to occur two to four weeks or more after initial symptom onset. There may also be an association between a clinical presentation of IM and the subsequent development of multiple sclerosis [70,71]. Other — EBV can affect virtually any organ system and has been associated with such diverse disease manifestations as hepatitis or cholestasis [72,73], pneumonia, pleural effusions [74], myocarditis, pancreatitis and acalculous cholecystitis [75], mesenteric adenitis, myositis, acute renal failure [76], glomerulonephritis, gastric pseudolymphoma [77], and genital ulceration [78]. Jaundice and hepatomegaly

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are less common, although ascites [72,74] and fatal cases of hepatitis have been described [73]. EBV infection during pregnancy — There is little evidence of a teratogenic risk to the fetus in women who develop infection during pregnancy [79]. Transplacental transmission of EBV appears to be rare [80]. LABORATORY ABNORMALITIES Hematologic abnormalities — The most common laboratory finding in association with infectious mononucleosis (IM) is lymphocytosis, defined as an absolute count >4500/microL or, on peripheral smear, a differential count >50 percent. The smear may also identify significant atypical lymphocytosis, defined as more than 10 percent of total lymphocytes. The majority of reactive lymphocytes in patients with IM are CD8+ cytotoxic T cells. In one study, the severity of illness correlated with the magnitude of CD8+ lymphocytosis (as well as with blood Epstein-Barr viral (EBV) load) [13]. (See 'Hematologic findings' below and 'Detection of EBV virus' below.) The total white blood cell count in patients with IM averages 12,000 to 18,000/microL, although it may be much higher. Some patients have a mild relative and absolute neutropenia and thrombocytopenia. These are generally benign findings that are self-limited. Unusual hematologic manifestations include hemolytic anemia, thrombocytopenia, aplastic anemia, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, and disseminated intravascular coagulation. Some of these complications result from EBV-induced production of antibodies directed against red blood cells, white blood cells, and platelets [53]. The hemolytic anemia is typically associated with an anti-i cold agglutinin [81]. (See "Pathogenesis of autoimmune hemolytic anemia: Cold agglutinin disease".) Liver function tests — Elevated aminotransferases are seen in the vast majority of patients, but are selflimited. Abnormal liver function tests in a patient with pharyngitis strongly suggest the diagnostic possibility of IM. DIFFERENTIAL DIAGNOSIS — Patients with fever, pharyngitis, and lymphadenopathy may have streptococcal, cytomegalovirus, acute HIV, or, rarely, toxoplasma infection [48-50]. Streptococcal infection is not usually accompanied by significant fatigue or splenomegaly on examination. Pharyngitis associated with cytomegalovirus (CMV) tends to be extremely mild, if present at all, but may cause liver function test elevations, as does acute Epstein-Barr virus (EBV). Differentiating between infectious mononucleosis (IM) caused by EBV and a similar syndrome due to CMV or HIV infection is often not possible clinically. 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 'EBV-negative mononucleosis' below and "Cytomegalovirus infection in pregnancy" and "Overview of TORCH infections", section on 'Clinical features of TORCH infections'.) A mononucleosis syndrome with atypical lymphocytosis can also be induced by several drugs, particularly anticonvulsants such as phenytoin, carbamazepine, and antibiotics, such as isoniazid or minocycline [82-84]. Patients with lymphadenopathy and splenomegaly may also have lymphoma. DIAGNOSIS General approach — Epstein-Barr virus (EBV)-induced infectious mononucleosis (IM) should be suspected when an adolescent or young adult complains of sore throat, fever, and malaise and also has lymphadenopathy and pharyngitis on physical examination [8,85]. The presence of palatal petechiae, splenomegaly, and posterior cervical adenopathy are highly suggestive of IM, while the absence of cervical lymphadenopathy and fatigue make the diagnosis less likely [86,87]. Supportive evidence of EBV infection is derived from the observation of lymphocytosis and increased

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circulating atypical lymphocytes along with a positive heterophile antibody test. Occasionally EBV-specific antibodies are warranted. (See 'Diagnosis' above.) Patients with fever, lymphadenopathy, and pharyngitis should also have a diagnostic evaluation for streptococcal infection by culture or antigen testing. (See "Evaluation of acute pharyngitis in adults".) Hematologic findings — The most common laboratory finding in association with IM is lymphocytosis, defined as an absolute count >4500/microL or, on peripheral smear, a differential count >50 percent. The smear may also identify significant atypical lymphocytosis, defined as more than 10 percent of total lymphocytes (picture 1). In a review of 156 heterophile-positive patients, a lymphocytosis ≥50 percent was seen in two-thirds percent of heterophile-positive patients and an atypical lymphocytosis of ≥10 percent was present in 75 percent of patients [88]. The specificity of these two findings, compared to a heterophile-negative control group with similar manifestations, was 85 and 92 percent, respectively. Atypical lymphocytes may also be found in patients with toxoplasmosis, rubella, roseola, viral hepatitis, mumps, CMV, acute HIV infection, and some drug reactions [53]. On the other hand, older individuals may have less prominent absolute lymphocytosis and fewer atypical lymphocytes [89]. When an automated differential from a hematology analyzer flags a specimen as possibly containing atypical lymphocytes, the smear should be reviewed manually since blasts and other abnormalities cannot be reliably distinguished from atypical lymphocytes in these systems [88]. (See "Automated hematology instrumentation", section on 'Leukocyte counting errors'.) Heterophile antibodies — Heterophile antibodies react to antigens from phylogenetically unrelated species. They agglutinate sheep red blood cells (the classic Paul-Bunnell test), horse red blood cells (used in the "Monospot" test), and ox and goat erythrocytes. The Monospot is a latex agglutination assay using horse erythrocytes as the substrate [90,91]. Other rapid diagnostic tests use ELISA (enzyme-linked immunosorbent assay) techniques. The sensitivity and specificity of the rapid kits approach 85 and 100 percent, respectively [92]. Reactive heterophile antibodies in a patient with a compatible syndrome are diagnostic of EBV infection and are therefore the diagnostic test of choice in most clinical settings in North America [1]. No further testing for specific antibodies to EBV is warranted in such patients with a reactive heterophile antibody. Although they are highly specific in the appropriate clinical setting, heterophile antibodies are somewhat insensitive. The false negative rates are highest during the beginning of clinical symptoms (25 percent in the first week; 5 to 10 percent in the second week, 5 percent in the third week) [86]. In patients with a compatible syndrome, heterophile antibodies can be repeated if the patient is early in their clinical illness. More specific EBV testing can be pursued in those with more prolonged illness or in those who do not fit classic diagnostic criteria (see 'EBV-specific antibodies' below). In Europe, these EBV-specific antibodies are used routinely for the diagnosis of IM, instead of heterophile antibody assays. Rare false-positive heterophile tests have been reported in patients with leukemia, lymphoma, pancreatic cancer, systemic lupus erythematosus, HIV infection, and rubella [93]. In addition, heterophile antibodies can persist at low levels for up to one year after IM. Up to 10 percent of patients with a mononucleosis syndrome do not have an acute EBV infection as confirmed by more specific antibody testing. These patients have alternative etiologies for their mononucleosis-like illness. (See 'EBV-negative mononucleosis' below.) The heterophile test does not have the same specificity and sensitivity in young children, and EBV-specific antibodies viral capsid antigen (VCA) IgM and IgG are favored [94]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Primary EBV infection in infants and children'.)

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EBV-specific antibodies — As noted above, measurement of EBV-specific antibodies is usually not necessary since the vast majority of patients are heterophile positive. However, testing for EBV-specific antibodies may be warranted in patients with suspected IM who have a negative heterophile test [95]. IgM and IgG antibodies directed against viral capsid antigen have high sensitivity and specificity for the diagnosis of IM (97 and 94 percent, respectively) [96]. Viral capsid antigen — IgM and IgG antibodies directed against the Epstein-Barr VCA are usually present at the onset of clinical illness because of the long viral incubation period. IgM levels wane approximately three months later; thus, they are a good marker of acute infection. IgG VCA antibodies persist for life and are a marker of EBV infection. Results of viral capsid antigen testing need to be interpreted within the appropriate clinical context. Although the presence of IgM VCA antibodies is highly suggestive of acute EBV infection, other herpesviruses (eg, CMV) can induce IgM antibodies to cell lines that express EBV antigens. In addition, during illnesses associated with intense immune activation, serologic EBV reactivation with detectable EBV IgM VCA antibodies has been described in the absence of clinical IM [97]. A number of other antibodies are expressed in individuals exposed to EBV, a few of which may also be used for diagnostic purposes. (See "Virology of Epstein-Barr virus".) Nuclear antigen — IgG antibodies to EBV nuclear antigen (EBNA, a protein expressed only when the virus begins to establish latency) begin to appear 6 to 12 weeks after the onset of symptoms and persist throughout life; their presence early in the course of an illness effectively excludes acute EBV infection. Thus, while the presence of IgM VCA antibodies suggests the likely presence of acute EBV infection, the diagnosis is most certain in the presence of IgM VCA and the absence of IgG EBNA antibodies. Early antigen — IgG antibodies to early antigen (EA) are present at the onset of clinical illness. There are two subsets of EA IgG: anti-D and anti-R. The presence of anti-D antibodies is consistent with recent infection since titers disappear after recovery, but their absence does not exclude acute illness because the antibodies are not expressed in a significant number of patients. Anti-R antibodies are only occasionally present in IM. Serum IgA antibody — In a study of 15 individuals with primary EBV infection, serum IgA antibodies against early lytic antigens were detected using flow cytometry [98]. Furthermore, levels of IgA antibodies rapidly declined one month after onset of acute illness, while IgM antibodies continued to be produced. The role that serum IgA antibodies will have in the diagnosis of IM is unclear pending further study. Detection of EBV virus — EBV DNA quantification can be accomplished through polymerase chain reaction assays on blood or plasma [99,100]. One study evaluated the clinical utility of detecting EBV viremia with real-time PCR in children with primary EBV infection compared with controls [101]. Twentyone (75 percent) of the patients in the primary EBV infection group, one (4 percent) of the EBVseronegative patients and none of the EBV-seropositive patients had detectable EBV DNA. Within the primary infection group, those with detectable virus were more likely to have lymphadenopathy, higher atypical lymphocytes counts, and higher aminotransferases than those without detectable virus. In a study of university students with acute EBV infection, severity of illness correlated with blood EBV load [13]. However, this quantitative assessment of EBV viral load is not recommend for immunocompetent patients with suspected EBV infection since it offers no therapeutic guidance. The use of PCR in the management of transplant recipients who develop lymphoproliferative disorders related to EBV infection is discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Measurement of Epstein-Barr viral load'.)

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Summary — Patients with suspected IM based upon the history and physical examination should have a white blood cell count with differential and a heterophile test. If the heterophile test is positive, no further testing is necessary if the clinical scenario is compatible with typical IM. If the heterophile test is negative, but there is still a strong clinical suspicion of EBV infection, the Monospot test can be repeated since testing can be negative early in clinical illness. If the clinical syndrome is prolonged, or if the patient does not have a classic EBV syndrome, IgM and IgG VCA and EBNA antibodies should be measured. The presence of IgG EBNA within four weeks of symptom onset excludes acute primary EBV infection as an explanation and therefore should prompt consideration of EBV-negative causes of mononucleosis. EBV-NEGATIVE MONONUCLEOSIS — Approximately 10 percent of mononucleosis-like cases are not caused by Epstein-Barr virus (EBV) [102]. Other agents that produce a similar clinical syndrome include cytomegalovirus (CMV) [48], HIV [49], toxoplasmosis [103], human herpesvirus type 6 (HHV-6) [51], hepatitis B [104], and possibly HHV-7 [52]. Primary HIV infection — Primary HIV infection causes a febrile illness resembling mononucleosis [49]. The most common findings are fever, sore throat, myalgias, and lymphadenopathy (table 3) [105]. (See "Acute and early HIV infection: Pathogenesis and epidemiology".) The following features may help to distinguish primary HIV infection from IM: ● Mucocutaneous ulceration is unusual in IM; its presence should heighten the suspicion for acute HIV infection. ● Rash is less common in IM (unless antibiotics have been administered), but is seen frequently in the setting of primary HIV infection within 48 to 72 hours after the onset of fever. The heterophile test is typically negative during acute HIV infection [106]; false positive heterophile tests have been rarely reported [107,108]. Atypical lymphocytes also may be present in acute HIV infection although the overall incidence of atypical lymphocytosis is lower in HIV infection and the percentage of atypical cells is usually lower than that seen with EBV. Patients who present with a heterophile-negative mononucleosis-like syndrome should have quantitative plasma HIV RNA and HIV antibody testing to rule out primary HIV infection since early diagnosis is important for patient management and to decrease the risk of transmission to others. (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Diagnosis'.) Cytomegalovirus — CMV causes a syndrome that is similar but often milder than EBV-associated IM (table 4) [109,110]. The illness is characterized primarily by prolonged fever, less prominent lymphadenopathy, and absent or mild pharyngitis. Hepatitis is nearly universal. The hematologic picture resembles that of EBV infection. The disease is self-limited and the great majority of patients recover with no sequelae. The diagnosis can be supported by the identification of IgM antibodies to CMV. (See "Overview of diagnostic tests for cytomegalovirus infection".) Toxoplasmosis — Toxoplasmosis causes a syndrome characterized predominantly by fever and lymphadenopathy [103]. It rarely causes pharyngitis or abnormal liver function tests, and is not associated with the characteristic hematologic abnormalities seen with CMV and EBV infections. Human herpesvirus — Symptomatic primary infection with HHV-6 or HHV-7 is uncommon in adults. However, a mononucleosis-like syndrome of varying severity with prolonged lymphadenopathy has been described in association with HHV-6 seroconversion in adults. (See "Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults", section on 'Immunocompetent hosts'.) CHRONIC OR PERSISTENT EBV INFECTION — Chronic active Epstein-Barr virus (EBV) infection is a

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rare disorder, characterized by persistent infectious mononucleosis (IM)-like symptoms and prolonged active EBV infection [111]. Symptoms can include fever, swelling of lymph nodes, and hepatosplenomegaly along with liver function test abnormalities and cytopenias [112]. Persistent infection is best defined through detection of EBV DNA in peripheral blood at high levels [112]. Treatment regimens for this illness have not been established [113]. 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. As previously mentioned, IgG antibodies to VCA and EBNA are present for life in patients with prior EBV exposure and are not markers of active process suggesting true chronic acute EBV infection. (See 'EBV-specific antibodies' above.) EBV infection has also received a great deal of attention in past years as a possible etiologic agent for chronic fatigue syndrome (CFS), also known as systemic exertion intolerance disease (SEID). This topic is discussed in detail elsewhere. (See "Clinical features and diagnosis of chronic fatigue syndrome (systemic exertion intolerance disease)".) TREATMENT — Primary Epstein-Barr virus (EBV) infections rarely require more than supportive therapy. Symptomatic treatment — The mainstay of treatment for individuals with infectious mononucleosis (IM) is supportive care. Acetaminophen or nonsteroidal anti-inflammatory drugs are recommended for the treatment of fever, throat discomfort, and malaise. Provision of adequate fluids and nutrition is also important. It is prudent to get adequate rest, although complete bed rest is unnecessary. The use of corticosteroids in the treatment of EBV-induced IM has been controversial. In a multicenter, placebo-controlled study of 94 patients with acute IM, the combination of acyclovir and prednisolone reduced oropharyngeal shedding of the virus but did not affect the duration of symptoms or lead to an earlier return to school or work [114]. 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 to placebo [115]. We do not recommend corticosteroid therapy for routine cases of IM since it is generally a self-limited illness and there are theoretical concerns about immunosuppression during clinical illness with a virus that has been causally linked to a variety of malignancies. However, corticosteroids may be considered in the management of patients with some EBV-associated complications. Complications including airway obstruction — Corticosteroids, as well as emergent consultation with an otolaryngologist, are warranted in individuals with impending airway obstruction (manifested clinically by difficulty breathing or dyspnea in the recumbent position). Data on dosing and duration of corticosteroid therapy is scant. One case series described children with impending airway closure who were treated successfully with high-dose corticosteroids (eg, dexamethasone 0.25 mg/kg every six hours) but no information was given on duration of treatment [116]. Once clinical improvement has been achieved, tapering the corticosteroid dose slowly (eg, over 7 to 14 days) is likely prudent. Corticosteroid therapy may be also considered in those with severe overwhelming life-threatening infection (eg, fulminant liver failure) or other complications such as severe hemolytic or aplastic anemia. Data supporting benefit of corticosteroids in these settings are less robust than what is found for the treatment of IM-related airway obstruction. Despite lack of evidence, one recent retrospective study of 206 patients with IM treated at a single tertiary medical center found that 45 percent received corticosteroids mainly for constitutional symptoms; only 8 percent of patients were treated based on traditional criteria [117]. Antiviral treatment — Acyclovir is a nucleoside analogue that inhibits permissive EBV infection through inhibition of EBV DNA polymerase but has no effect on latent infection or ability to cure the infection. (See "Acyclovir: An overview".) Specific therapy of acute EBV infections with intravenous and oral formulations

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of acyclovir has been studied [114,118]. Short-term suppression of oral viral shedding can be demonstrated, but significant clinical benefit has not been shown. A meta-analysis of five randomized controlled trials of acyclovir in the treatment of acute IM, including two trials of intravenous therapy in patients with severe disease, also failed to show a clinical benefit compared to placebo [119]. These results are not surprising since ongoing viral replication plays a less significant role in the symptomatic phase of EBV-induced IM than the host immune responses. RETURN TO SPORTS — Since infectious mononucleosis (IM) mostly affects teenagers and young adults, many of whom participate in competitive sports and other forms of exercise, a common question is when to recommend resumption of athletic activities. More than 50 percent of patients with IM develop splenic enlargement within the first two weeks of symptoms; as a result, the central issue is avoiding activities that may precipitate splenic rupture, while a secondary consideration relates to resumption of training in an athlete complaining of fatigue. Avoiding splenic rupture — All athletes should refrain from sport activities during early illness. As recuperation occurs, clinicians should keep in mind that spontaneous or traumatic splenic rupture in the setting of IM appears to be most likely within 2 to 21 days after the onset of clinical symptoms [120]. Descriptions of splenic rupture after the fourth week are rare [59,121]. Recommendations to resume sports are somewhat arbitrary given the lack of prospective data. Several authors recommend potential resumption of all sport activities, except for strenuous contact sports, no earlier than 21 days after illness onset [122,123]. Others advocate a more universal four week time frame regardless of activity level [124]. A conservative synthesis of retrospective studies yields the following suggestions [125]: ● For athletes planning to resume non-contact sports, training can be gradually restarted starting three weeks from symptom onset. This recommendation assumes that participants avoid any activities capable of causing chest or abdominal trauma. ● For strenuous contact sports (including football, gymnastics, rugby, hockey, lacrosse, wrestling, diving, and basketball) or activities associated with increased intraabdominal pressure (such as weightlifting) that may carry a higher risk of splenic injury, we recommend waiting a minimum of four weeks after illness onset. Ways in which to document that the spleen has returned to normal size vary from practitioner to practitioner. Splenic palpation or percussion is generally unreliable in athletes with firm abdominal musculature, although experienced examiners can trust a positive finding of enlargement [126]. The safest option may be obtaining an ultrasound examination to document resolution of splenomegaly [127,128]. However, the use of imaging studies before a return to sports remains a debated issue due to a lack of clinical outcomes data and the cost of ultrasound [129]. Some patients with IM appear to have splenic enlargement that persists on serial ultrasound studies. This may be due to the occasional long-term splenomegaly seen after IM or to "normal" splenomegaly that may be observed in 3 to 7 percent of healthy young adults [130,131]. Since seven weeks is among the latest descriptions of IM-related splenic rupture, clinical judgment must dictate when to allow an athlete with splenomegaly that persists beyond seven to eight weeks to resume strenuous sports [121]. Routine ultrasonography is not needed in most patients; the decision to obtain imaging should be influenced by whether the patient is returning to contact sports [132]. Fatigue — A common sense approach to resumption of training suggests that clinicians wait for resolution of objective symptoms as well as an improvement in the athlete's sense of well-being. For the first few days, athletes should train at reduced levels compared to their premorbid state, increasing activities

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gradually as tolerated [133]. Competitive athletes may not attain pre-illness levels of fitness for three or more months. The physician should be especially careful when giving recommendations to athletes who may be unduly pressured by themselves or others to resume strenuous activity too soon. PROGNOSIS — The vast majority of individuals with primary Epstein-Barr virus (EBV) infection recover uneventfully and develop durable immunity controlling the latent virus. Most acute symptoms resolve in one to two weeks, although fatigue and poor functional status can persist for months [134,135]. A prospective study of infectious mononucleosis (IM) (and other acute infections) found that 11 percent of individuals fit criteria for chronic fatigue syndrome six months after symptom onset [135]. A subsequent study in adolescents noted that as many as 7 and 5 percent met that syndrome definition at 12 months and 24 months, respectively [136]. Some studies suggest that female gender [45,137] and a premorbid mood disorder [137] may be risk factors for persistent fatigue. The reason why some patients do not return to prior health is unclear, but some studies show abnormalities in mitochondrial function, as well as message levels for a variety of regulatory molecules [138-140]. EBV has been associated with a variety of malignancies, particularly lymphoma. Many of these infections are subclinical, but Hodgkin lymphoma has been associated with a history of infectious mononucleosis. (See "The role of Epstein-Barr virus in Hodgkin lymphoma" and "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Malignancy'.) PREVENTION — At present there is no commercially available vaccine to prevent Epstein-Barr virus (EBV) infection. Glycoprotein 350, a viral antigen expressed on the EBV capsid, enables entry of virus into B cells and is targeted by the immune system during natural infection [141]. One phase two placebocontrolled trial evaluated a recombinant gp350 vaccine in 181 volunteers and found that although the number of cases of infectious mononucleosis was decreased in the vaccine group, gp350 did not prevent asymptomatic infection [40]. Return to school or work — Since EBV may be shed intermittently for months to years in people who have acquired infection, and the source of infection is rarely known in the patient who develops infectious mononucleosis, there are no restrictions regarding recently ill IM patients for returning to school or to the workplace. The decision to return to full activities should be guided by the level of fatigue and other constitutional symptoms. 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 e-mail 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

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● Infectious mononucleosis (IM) is an acute illness due to Epstein-Barr virus (EBV) infection, which occurs mainly in adolescents and young adults. (See 'Epidemiology' above.) ● IM is classically characterized by fever, pharyngitis, fatigue, and lymphadenopathy. Other findings can include splenomegaly and palatal petechiae. Cervical lymphadenopathy tends to involve the posterior chain of lymph nodes. (See 'Clinical manifestations' above.) ● Rare complications include splenic rupture and airway obstruction. ● A generalized maculopapular, urticarial, or petechial rash is occasionally seen. Rash is more common following the administration of ampicillin or amoxicillin. ● Common laboratory findings include an absolute or relative lymphocytosis, an increased proportion of atypical lymphocytes, and elevated aminotransferases. (See 'Laboratory abnormalities' above.) ● Patients with suspected IM, based upon the history and physical examination, should have a white blood cell count with differential and a heterophile test. In addition, patients should also have a diagnostic evaluation for streptococcal infection by culture or antigen testing. (See 'Diagnosis' above.) ● In a patient with a compatible syndrome and a negative heterophile antibody, the Monospot test can be repeated since this test can be negative during the first week of clinical illness. EBV-specific antibodies (eg, viral capsid antigen IgM and IgG and early nuclear antigen antibodies) should be ordered if the patient has a repeatedly negative Monospot. (See 'Diagnosis' above.) ● The presence of IgG EBNA, or the absence of IgG and IgM VCA, excludes acute primary EBV infection and should prompt consideration of alternative etiologies of a mononucleosis-like illness, such as cytomegalovirus (CMV), primary HIV infection, and toxoplasmosis. The most important diagnosis to exclude is primary HIV infection; this can be accomplished with both quantitative HIV RNA and HIV antibody testing. The evaluation for CMV takes on great importance in the pregnant female. (See 'EBV-negative mononucleosis' above.) ● We recommend NOT administering acyclovir for IM (Grade 1B). Primary EBV infections rarely require more than supportive therapy. (See 'Treatment' above.) ● In individuals with impending airway obstruction, we suggest corticosteroids, as well as emergent consultation with an otolaryngologist (Grade 2B). (See 'Treatment' above.) ● For athletes planning to resume non-contact sports, training can be gradually restarted three weeks from symptom onset. For strenuous contact sports or activities associated with increased intraabdominal pressure, we suggest waiting a minimum of four weeks after illness onset (Grade 2C). (See 'Return to sports' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Evans AS, Niederman JC, Cenabre LC, et al. A prospective evaluation of heterophile and EpsteinBarr virus-specific IgM antibody tests in clinical and subclinical infectious mononucleosis: Specificity and sensitivity of the tests and persistence of antibody. J Infect Dis 1975; 132:546. 2. Evans AS. The history of infectious mononucleosis. Am J Med Sci 1974; 267:189. 3. Sprunt TP, Evans FA. Mononucleosis leukocytosis in reaction to acute infections (infectious mononucleosis). John Hopkins Hosp Bull 1920; 31:409.

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GRAPHICS Atypical lymphocytes in infectious mononucleosis

Peripheral smear from a patient with infectious mononucleosis shows three atypical lymphocytes with generous cytoplasm. Courtesy of Carola von Kapff, SH (ASCP). Graphic 55986 Version 2.0

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Clinical manifestations of infectious mononucleosis Symptoms and signs

Frequency, percent

Symptoms Malaise and fatigue

90-100

Sweats

80-95

Sore throat, dysphagia

80-85

Anorexia

50-80

Nausea

50-70

Headache

40-70

Chills

40-60

Cough

30-50

Myalgia

12-30

Ocular muscle pain

10-20

Chest pain

5-20

Arthralgia

5-10

Photophobia

5-10

Signs Adenopathy

100

Fever

80-95

Pharyngitis

65-85

Splenomegaly

50-60

Bradycardia

35-50

Periorbital edema

25-40

Palatal enanthem

25-35

Liver and spleen tenderness

15-30

Hepatomegaly

15-25

Rhinitis

10-25

Jaundice

5-10

Skin rash

3-6

Pneumonitis