Infectious Mononucleosis in Adults and Adolescents

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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 interferon-
gamma 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 EBV-
seronegative 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-Barr 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 self-
limited. 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]. Twenty-
one (75 percent) of the patients in the primary EBV infection group, one (4 percent) of the EBV-
seronegative 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
9 de 26 21/09/2017 0:19
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
10 de 26 21/09/2017 0:19
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 placebo-
controlled 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
11 de 26 21/09/2017 0:19
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.
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infection. J Infect Dis 2003; 187:527.
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acute infectious mononucleosis. J Infect Dis 1991; 164:788.
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infections and exercise in high-performance athletes. Immunol Cell Biol 2000; 78:510.
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the detection of splenomegaly: a prospective study with multiple observers. J Gen Intern Med 1993;
8:69.
127. Ali J. Spontaneous rupture of the spleen in patients with infectious mononucleosis. Can J Surg 1993;
36:49.
128. Dommerby H, Stangerup SE, Stangerup M, Hancke S. Hepatosplenomegaly in infectious
mononucleosis, assessed by ultrasonic scanning. J Laryngol Otol 1986; 100:573.
129. Burroughs KE. Athletes resuming activity after infectious mononucleosis. Arch Fam Med 2000;
9:1122.
130. McIntyre OR, Ebaugh FG Jr. Palpable spleens in college freshmen. Ann Intern Med 1967; 66:301.
131. Hosey RG, Mattacola CG, Kriss V, et al. Ultrasound assessment of spleen size in collegiate athletes.
Br J Sports Med 2006; 40:251.
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mononucleosis: a review of the literature. Clin J Sport Med 2005; 15:410.
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Ann 1996; 25:585.
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who report failure to recover. Am J Med 2000; 109:531.
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by viral and non-viral pathogens: prospective cohort study. BMJ 2006; 333:575.
136. Katz BZ, Shiraishi Y, Mears CJ, et al. Chronic fatigue syndrome after infectious mononucleosis in
adolescents. Pediatrics 2009; 124:189.
137. Petersen I, Thomas JM, Hamilton WT, White PD. Risk and predictors of fatigue after infectious
mononucleosis in a large primary-care cohort. QJM 2006; 99:49.
138. Vernon SD, Whistler T, Cameron B, et al. Preliminary evidence of mitochondrial dysfunction
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140. White PD. What causes prolonged fatigue after infectious mononucleosis: and does it tell us
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Topic 8318 Version 23.0
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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
20 de 26 21/09/2017 0:19
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 <3
Modified from Chervenik, PA. Dis Mon 1974; 1:29.
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Clinical features of infectious mononeucleosis in younger and older age groups
Patients, percent
35 years 40 years
Lymphadenopathy 94 47
Pharyngitis 84 43
Fever 75 95
Splenomegaly 52 33
Hepatomegaly 12 42
Rash 10 12
Jaundice 9 27
Data in patients 35 years from Schooley, RT. In: Mandell, GL, Bennett, JE, Dolin, R (eds), Mandell, Douglas and
Bennett's Principles and Practice of Infectious Disease, 4th ed, Churchill Livingstone, Inc, New York 1995, p.1364.
Data in patients 40 years from Axelrod, P, Finestone, AJ. Am Fam Physician 1990; 42:1599.
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Rash in infectious mononucleosis
A generalized, erythematous, maculopapular eruption is often seen in patients

with infectious mononucleosis after the administration of ampicillin.
Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders
CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.
http://www.lww.com
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Frequency of common symptoms in acute HIV infection
Symptom No. patients Percent
Fever 200 96
Adenopathy 154 74
Pharyngitis 146 70
Rash 146 70
Myalgia/arthralgia 112 54
Diarrhea 67 32
Headache 66 32
Nausea/vomiting 56 27
Neuropathy 13 6
Encephalopathy 12 6
Adapted from Niu, MT, Stein, DS, Schnittman, SM, J Infect Dis 1993; 168:1490.
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Symptoms and signs in nine patients with spontaneous cytomegalovirus

mononucleosis
Number of patients
Symptoms
Malaise 9
Fever 8
Chills 6
Myalgia 6
Sore throat 5
Headache 4
Anorexia 3
Abdominal pain 2
Signs
Pharyngeal erythema 5
Lymphadenopathy 5
Rash* 5
Splenomegaly 3
Hepatomegaly 0
Exudative pharyngitis 0
* Includes one patient whose rash was associated with ampicillin therapy.
Modified from Jordan, MC, Rousseau, W, Stewart, JA, et al. Spontaneous cytomegalovirus mononucleosis. Clinical and
laboratory observations in nine cases. Ann Intern Med 1973; 79:153.
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Contributor Disclosures
Mark D Aronson, MD Nothing to disclose Paul G Auwaerter, MD, MBA, FIDSA Nothing to
disclose Martin S Hirsch, MD Nothing to disclose Sheldon L Kaplan, MD Grant/Research/Clinical Trial
Support: Pfizer [S. pneumoniae (PCV13, Linezolid)]; Cubist [S. aureus (Tedizolid)]; Forest Lab
[Osteomyelitis (Ceftaroline)]. Consultant/Advisory Boards: Pfizer [S. pneumoniae (PCV13, Linezolid); S.
aureus (vaccine development)]; Theravance [S. aureus (Telavancin)]. Jennifer Mitty, MD, MPH Nothing
to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy
26 de 26 21/09/2017 0:19

Infectious Mononucleosis in Adults and Adolescents - UpToDate

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Infectious mononucleosis in adults and adolescents - UpToDate https://www.uptodate.com/contents/infectious-mononucleosis-in-adult...

Official reprint from UpToDate

Authors: Mark D Aronson, MD, Paul G Auwaerter, MD, MBA, FIDSA

INTRODUCTION Infectious mononucleosis (IM) is characterized by a triad of fever, tonsillar

EPIDEMIOLOGY Epstein-Barr virus (EBV) is a widely disseminated herpesvirus that is spread by

Person-to-person Following infectious mononucleosis, virus may be shed in salivary secretions at

Other clinical manifestations

Splenomegaly and splenic rupture Splenomegaly is seen in 50 to 60 percent of patients with IM

Unusual hematologic manifestations include hemolytic anemia, thrombocytopenia, aplastic anemia,

General approach Epstein-Barr virus (EBV)-induced infectious mononucleosis (IM) should be

Heterophile antibodies Heterophile antibodies react to antigens from phylogenetically unrelated

EBV-specific antibodies As noted above, measurement of EBV-specific antibodies is usually not

EBV-NEGATIVE MONONUCLEOSIS Approximately 10 percent of mononucleosis-like cases are not

Toxoplasmosis Toxoplasmosis causes a syndrome characterized predominantly by fever and

Complications including airway obstruction Corticosteroids, as well as emergent consultation with

A conservative synthesis of retrospective studies yields the following suggestions [125]:

PREVENTION At present there is no commercially available vaccine to prevent Epstein-Barr virus

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

SUMMARY AND RECOMMENDATIONS

Rare complications include splenic rupture and airway obstruction.

Common laboratory findings include an absolute or relative lymphocytosis, an increased proportion of

In individuals with impending airway obstruction, we suggest corticosteroids, as well as emergent

Use of UpToDate is subject to the Subscription and License Agreement.

4. Henle G, Henle W, Diehl V. Relation of Burkitt's tumor-associated herpes-ytpe virus to infectious

Topic 8318 Version 23.0

Atypical lymphocytes in infectious mononucleosis

Peripheral smear from a patient with infectious mononucleosis shows three

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 55986 Version 2.0

Clinical manifestations of infectious mononucleosis

Symptoms and signs Frequency, percent

Malaise and fatigue 90-100

Sore throat, dysphagia 80-85

Ocular muscle pain 10-20

Chest pain 5-20

Periorbital edema 25-40

Palatal enanthem 25-35

Liver and spleen tenderness 15-30

Skin rash 3-6

Modified from Chervenik, PA. Dis Mon 1974; 1:29.

Graphic 57448 Version 1.0

Clinical features of infectious mononeucleosis in younger and older age groups

Graphic 62342 Version 1.0

Rash in infectious mononucleosis

A generalized, erythematous, maculopapular eruption is often seen in patients

Frequency of common symptoms in acute HIV infection

Symptom No. patients Percent

Graphic 82487 Version 1.0

Symptoms and signs in nine patients with spontaneous cytomegalovirus

Graphic 78849 Version 1.0

Conflict of interest policy

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