Chapter 63. Mononucleosis Syndromes

Infectious mononucleosis is a clinical syndrome classically defined by the presence of fever, lymphadenopathy, pharyngitis, and fatigue. The illness was first recognized in the late 19th century and termed “glandular fever” or “Drusenfieber” by German physicians who noted its frequent occurrence in the context of family outbreaks.1,2 In a 1920 Johns Hopkins Medical Bulletin, Sprunt and Evans described 6 previously healthy young adults with a febrile illness similar to glandular fever, and noted the presence of atypical lymphocytes in the peripheral blood smear; because of the predominance of these unusual mononuclear cells, they termed the syndrome “infectious mononucleosis.”3 Twelve years later while investigating rheumatic disease, Paul and Bunnell4 serendipitously noted that the serum of patients with symptoms of infectious mononucleosis contained high titers of antibodies that agglutinated sheep red blood cells, thus the detection of these “heterophile antibodies” became the first laboratory marker available to diagnose the illness. The association of Epstein-Barr virus (EBV) with infectious mononucleosis followed in the late 1960s when a laboratory technician working with specimens from patients with Burkitt's lymphoma, a condition which had recently been shown to be associated with EBV, accidentally became infected and developed clinical infectious mononucleosis.5,6

We now know that the majority of patients with infectious mononucleosis have an acute EBV infection; the symptoms are caused by another infectious agent in up to 10% of patients. This chapter will concentrate on EBV, the major infectious cause, but other important diagnostic considerations will also be addressed.

More than 95% of adults worldwide are EBV-seropositive.7,8 In lower socioeconomic classes and in underdeveloped countries, most children acquire the infection before the age of 5.9 Fewer than 10% of children younger than the age of 4, develop clinically apparent symptoms of EBV infection.10 This parallels the epidemiology of several of the other differential etiologies of infectious mononucleosis, including cytomegalovirus (CMV) and hepatitis A infections. Therefore, patients who present with symptomatic infectious mononucleosis are most often older children, adolescents, and young adults of middle to upper socioeconomic status.11

EBV is transmitted primarily by direct contact with oral secretions. Transmission via aerosol or fomites is uncommon given the virus’ poor ability to survive outside host body fluids. The incubation period, during which the virus may be communicated but the patient is asymptomatic, is approximately 4–6 weeks.12 Epidemics of viral spread have not been reported, suggesting fairly low transmission rates, and no seasonal predominance has been identified. Transmission by blood product transfusion has occasionally been documented. Additionally, the presence of the virus in cervical secretions suggests that sexual transmission may also occur. As is characteristic of the other members of the herpesvirus family, EBV exhibits the property of latency in the host, so that those who have been previously infected, often continue to intermittently shed virus, further contributing to the transmission of EBV. Immunosuppression in the host from any etiology will increase viral shedding in secretions.

After the initial infection and replication in oropharyngeal epithelial cells, EBV exhibits a predilection for B cells, which upon infection, have the potential for subsequent unlimited proliferation. Large numbers of these infected B cells circulate during the first few days of illness; these cells resemble plasma cells and produce large quantities of nonspecific antibodies, including the heterophile antibodies. The host immune response to this massive B-cell proliferation is to mount a counter suppressive T cell response, many of which are reactive and appear atypical, hence the atypical lymphocytosis seen on peripheral smear. This cellular (T cell) immune response is crucial to limiting EBV replication and EBV-induced B-cell proliferation; accordingly, the most severe disease manifestations occur in individuals with impaired cellular immunity.13

Both infected and reactive lymphocytes infiltrate the entire reticuloendothelial system, including the liver, spleen, and lymph nodes, which accounts for the enlargement of these organs on physical examination. Massive cytokine production and release by reactive T lymphocytes result in fever and the profound fatigue associated with acute infectious mononucleosis.13 Additionally, the large quantities of antibodies produced by infected B cells, some of which have been shown to be autoantibodies, are believed to account for some of the other diverse manifestations of infectious mononucleosis, including hematologic abnormalities such as hemolytic anemia, thrombocytopenia, and neutropenia.14

Common Manifestations

Most young children (toddlers and preschool aged) who become infected with EBV exhibit no or few nonspecific viral symptoms. Quite often, the acute illness mimics a viral upper respiratory infection with cough, rhinitis, and mild fever. For older children and adolescents, acute EBV infection is heralded by an initial prodrome, lasting up to 1 week, that consists of nonspecific constitutional symptoms including fatigue, malaise, anorexia, and headache. These symptoms usually increase in intensity as the classic triad of fever, pharyngitis and lymphadenopathy emerges as a prominent feature in more than 50% of adolescents and adults with infectious mononucleosis. The most common symptoms associated with infectious mononucleosis are presented in Table 63–1.

Less Common Manifestations

A number of multisystem clinical signs and symptoms are manifested by a smaller number of patients. Children of all ages may complain of rhinitis, mild cough or periorbital edema, the latter of which may have resolved prior to presentation. Some patients may report diffuse vague abdominal pain, and a few may even demonstrate localized left upper quadrant pain that may occur with significant splenic enlargement. Splenomegaly can be detected on physical examination in approximately half of all patients with acute infectious mononucleosis. In such cases, the spleen is rarely palpable more than 3 cm below the left costal margin; massive splenomegaly is rare.

A few patients may present with a rash during the acute symptomatic of infectious mononucleosis. This rash is highly variable in appearance and may be maculopapular, scarlatinaform, urticarial, or erythema multiforme; it is more common in older children.15 A minority of patients may present with symptoms of hepatitis including jaundice and right upper quadrant abdominal pain or with other gastrointestinal complaints, including anorexia and nausea. In males, unilateral orchitis may be an initial complaint suggesting acute EBV infection.

Physical Examination

Almost 95% of children with acute EBV infection demonstrate nontender lymphadenopathy. The adenopathy is most often confined to the anterior and posterior cervical chains, but is occasionally generalized and involves the axillary and inguinal nodes. Inflamed tonsillopharyngeal tissue, often with an exudate and palatal petechiae resembling a streptococcal pharyngitis, is seen in infectious mononucleosis. In fact, up to 18% of children with infectious mononucleosis may demonstrate the presence of group A beta-hemolytic Streptococcus on rapid testing or culture, although it is unclear whether these children are actually coinfected or represent streptococcal carriers. The lack of clinical improvement within 48 hours on appropriate antibiotics should suggest infectious mononucleosis as the underlying etiology of the pharyngitis.16 Hepatic and/or splenic enlargement is common in all patients with acute infectious mononucleosis, but is more common in children younger than 4 years of age.15

Other disease entities may produce infectious mononucleosis-like syndromes, most of which are caused by other infections (Table 63–2). The most common of these is acute CMV infection which also may produce generalized lymphadenopathy, fever, splenomegaly and malaise in acutely infected, previously healthy hosts. Unlike with EBV, in CMV infections, pharyngitis and atypical lymphocytosis on peripheral blood smear are less prominent presenting features. Toxoplasmosis can also cause a clinical presentation quite similar to acute EBV infection, so obtaining pertinent history regarding cat exposures (e.g., litterbox contact, soil contamination) may be helpful. It is also crucial to ask about relevant risk factors on interview as acute HIV infection may be indistinguishable from infectious mononucleosis as well.

Other infectious etiologies that may present like acute infectious mononucleosis include viral hepatitis (hepatitis A especially), adenovirus, or rubella, however, history or physical or laboratory findings can often help to differentiate these entities. Patients with viral hepatitis usually demonstrate significant elevations in liver enzymes as opposed to the modest increases seen with infectious mononucleosis and the diagnosis of rubella becomes apparent once the exanthem appears. The pharyngitis of EBV infection may clinically mimic group A streptococcal pharyngitis.

Malignancies, particularly leukemias and lymphomas, may also mimic infectious mononucleosis when presenting as fever, malaise, fatigue, and lymphadenopathy. On occasion, patients with a drug reaction to certain medications, particularly dilantin or sulfa-containing drugs, may have fever and lymphadenopathy that mimic infectious mononucleosis.

Isolation of EBV is possible using specialized laboratory techniques, but given the complexity of the methods required for cell culture, these tests are primarily conducted in research laboratories and are not widely available. Studies have demonstrated that real-time polymerase chain reaction assays that quantitate EBV in the blood are quite sensitive for diagnosing acute infectious mononucleosis, particularly early in infection and in young children17,18; however, these tests are very expensive and often not readily available commercially. Given these restrictions, neither of these methods of laboratory diagnosis has utility in the setting of diagnosing infectious mononucleosis in otherwise healthy children.

The diagnosis of acute EBV infection relies on serologic testing that is readily available from most hospital-based and commercial laboratories. The most rapid methods detect the presence of heterophile antibodies. The heterophile antibody is a non-specific IgM (immunoglobulin M) antibody response to a variety of infectious, inflammatory, and autoimmune stimuli. The heterophile antibody test for EBV includes an intermediate step that removes most non-EBV stimulated heterophile antibody. In EBV-infected patients, it appears during the first 2 weeks after infection and may last up to 6 months. Detection of these antibodies identifies up to 85% of older children and adolescents from the second week of illness and beyond; these tests are less reliable in younger children and are often negative in EBV-infected children younger than 4 years. False-positive results have been reported in several disorders including leukemia, lymphoma, and Gaucher disease.

Specific EBV serologies are required for younger children with illness suspicious for infectious mononucleosis and for those who test negative on heterophile antibody testing but have a clinical presentation and history compatible with acute infectious mononucleosis. Unlike with many other viral infections where paired acute and convalescent specimens are needed, a single serum sample can usually confirm the diagnosis of acute EBV given the varying kinetics of the antibodies produced after primary infection.

The first antibodies made against EBV are the IgM and Immunoglobulin G (IgG) antibodies directed against the viral capsid antigen of EBV (anti-VCA IgM and IgG). Anti-VCA IgM antibody occurs within 1–2 weeks after infection but usually is gone by 3 months after infection; likewise, anti-VCA IgG occurs early after infection, but persists for life.19 Antibodies against the EBV early antigen (anti-EA) occur next, several weeks to months after infection; in most individuals, these antibodies disappear by 6–12 months, but occasionally may last for several years after infection.20 The anti-EBNA (EBV nuclear antigen) antibody occurs several weeks to months after acute infection and also persists indefinitely (see Figure 63–1).

As with other IgM laboratory methodologies, there are numerous technical difficulties and a relatively high number of false positives as a result of rheumatoid factors in the blood, such that a positive anti-VCA IgM antibody alone is not diagnostic. The presence of anti-VCA IgM in combination with anti-VCA IgG, while in the absence of anti-EBNA, is diagnostic for acute EBV infection. The presence of anti-VCA IgG and anti-VCA EBNA is diagnostic for a past infection (see Table 63–3).

Although not diagnostic, other laboratory markers are suggestive and corroborate clinical suspicion for EBV infectious mononucleosis. Even without the clinical finding of hepatomegaly or jaundice, hepatic enzymes are often elevated, although usually only 2–3 fold. On a peripheral blood smear, lymphocytes account for more than 50% of the peripheral white blood cells and, typically, at least 10% are atypical lymphocytes. However, atypical lymphocytosis is a nonspecific finding and can be seen with other infectious etiologies of infectious mononucleosis-like illness. Other abnormal hematologic parameters may also be revealed on a complete blood count that may be attributed to a variety of immune-mediated events, including anemia, neutropenia and/or thrombocytopenia. The neutropenia is mild with absolute neutrophil counts ranging from 2000/mm3 to 3000/mm3, although profound neutropenia has also been reported. Most children develop a mild thrombocytopenia but the platelet count is rarely less than 100,000/mm3. Abnormalities of prothrombin and partial thromboplastin times are uncommon and typically occur in the context of EBV-related septicemia or severe hepatitis. Hematologic abnormalities typically resolve within one month of diagnosis.

For most patients with a primary EBV infection, infectious mononucleosis is a self-limited disease with no sequelae. In rare instances, however, serious or life-threatening consequences may occur and should be recognized.

One serious and somewhat common complication of acute infectious mononucleosis is significant tonsillar hypertrophy resulting in airway compromise. This complication may occur at any age but younger children are more often and more severely affected. When administered early, corticosteroids may prevent severe obstruction otherwise resulting in endotracheal intubation, but occasionally the onset of airway compromise may be precipitous.

A variety of central nervous system complications may occur in a small number of patients including meningitis or encephalitis, cranial nerve palsies, transverse myelitis, Guillain-Barré syndrome or Reye syndrome. Occasionally there have been descriptions of patients with the so-called metamorphopsia or the “Alice in Wonderland Syndrome” in which there are bizarre perceptual distortions of size, shape, and spatial relationships.

Hematologic abnormalities resulting from immune-mediated mechanisms of cell destruction may vary in degree of severity. If Coombs test is positive hemolytic anemia may be seen as well as neutropenia secondary to anti-neutrophil antibodies. More than 50% of all patients will develop a mild thrombocytopenia, usually not less than 100,000/mm3 but rarely a clinical picture of thrombotic thrombocytopenic purpura will result in platelet counts low enough to result in bleeding.

Cardiac manifestations including myocarditis or pericarditis may be life-threatening and must be recognized early for possible therapy. Rarely, EBV infection may cause pneumonia.

The most feared complication is splenic rupture, which has been estimated to occur in 0.1–0.5% of patients with acute EBV infection.21 Although clearly uncommon, this complication has resulted in numerous deaths and careful evaluation for the presence of splenomegaly and subsequent appropriate patient counseling is critical. This complication is more often seen in males, usually within the first 3 weeks of acute illness,22 and may be spontaneous, without history of antecedent trauma.

One important complication to note is the rare instance of death associated with EBV infection in children. This complication most often occurs when there is an uncontrolled lymphoproliferative response to EBV infection and often is associated with hemophagocytic syndrome.23 This syndrome, also called hemophagocytic lymphohistiocytosis, occurs when activated macrophages engulf bone marrow cells (leukocytes, erythrocytes, and platelets, including their precursors); clinically these patients demonstrate fever, splenomegaly, pancytopenia, and an extremely elevated serum ferritin. This syndrome may occur sporadically, most often in association with EBV,24 but has also been associated with a number of other viral infections (viral-associated hemophagocytic syndrome). Most significantly, this syndrome may often be seen in children with an underlying immunodeficiency of the cellular immune response called X-linked lymphoproliferative syndrome (XLP).23 These children present with fulminant disseminated primary EBV infection and have an inadequate or deficient cellular response resulting in lack of control of viral replication. Children with XLP are usually boys who present in the first decade of life with no prior history consistent with immune deficiency. They present with an infectious mononucleosis-like illness that rapidly progresses to fulminant hepatic failure and multiple cytopenias. It is fatal in approximately two-thirds of these individuals, and survivors often go on to develop hypogammaglobulinemia and/or B-cell lymphoma.25

For the most part, the management of infectious mononucleosis from acute EBV infection in a healthy patient is supportive. Rest, hydration, and analgesics for both fever and pharyngitis relief are encouraged. It is important to inform patients and their families of the often protracted nature of the recovery from infectious mononucleosis, as many patients have persistent fatigue for up to 3 or 4 months.

Of significant importance is the assessment of splenomegaly in patients with acute infectious mononucleosis; these patients and their parents must be counseled to ensure strenuous exercise and contact sports are avoided for at least 3–4 weeks after the onset of symptoms, or longer if the spleen is still palpably enlarged, to reduce the risk of splenic rupture.22

The use of steroids to ameliorate the duration of symptoms of EBV infectious mononucleosis has been debated, however, current recommendations are to reserve them for the most extreme and life-threatening complications of the illness. These situations may include: Marked tonsillar hypertrophy with resulting airway compromise, cardiac impairment, massive splenomegaly, hemolytic anemia or hemophagocytic syndrome. Steroids, when used for severe complications of infectious mononucleosis, are usually of short course; variable regimens have been suggested, but one commonly recommended is 1 mg/kg/day (maximum dose, 20 mg) for 7 days with subsequent tapering.26

Although acyclovir has in vitro activity against many herpesviruses including EBV, numerous studies have demonstrated this antiviral agent has little or no clinical benefit in the situation of uncomplicated infectious mononucleosis in a previously healthy child.27 Likewise, unless there is a demonstrable concurrent bacterial infection, antibiotics should not be used. If antibiotic therapy is indicated, ampicillin and amoxicillin should be avoided as these agents will precipitate a significant rash in more than 80% of EBV-infected patients. This rash is usually maculopapular in nature and presents 5–9 days into therapy, but does not represent a true penicillin allergy.

Most healthy children, adolescents and young adults recover within 1–2 months with no medical intervention and no resulting sequelae. Numerous attempts to associate EBV infection with other disease syndromes have been made, but none have been definitively substantiated. The best studied of these entities is Chronic Fatigue Syndrome, an illness characterized by persisting fatigue, weakness, myalgia and arthralgias, and occasionally lymphadenopathy, pharyngitis and low-grade fevers. Although studies have not supported an association with chronic fatigue syndrome, experts do recognize the entity of chronic active EBV in the rare patient with fever, hepatosplenomegaly, and fatigue persisting for a year or occasionally more after an acute infectious mononucleosis illness. These patients are distinct in that they have demonstrable organ dysfunction directly attributable to EBV by immunohistochemical staining.28 Additionally, they have extremely high serum EBV viral loads by polymerase chain reaction, and markedly elevated anti-VCA and EA antibody titers, but never demonstrate antibody to EBNA.29

• Infectious mononucleosis is defined by the clinical triad of fever, pharyngitis and lymphadenopathy.
• The EBV is responsible for most infectious mononucleosis cases.
• Heterophile antibody tests are sensitive for the diagnosis of infectious mononucleosis in older children and adults, but EBV-specific serologic testing is necessary for children younger than 4 years.
• A common complication of infectious mononucleosis is splenomegaly with the associated risk of splenic rupture; thorough counseling regarding avoidance of contact sports for at least one month after diagnosis, or until the spleen is no longer palpable, is crucial.