Pediatric Mononucleosis and Epstein-Barr Virus Infection 

Updated: Mar 22, 2021
Author: Jaya Sureshbabu, MBBS, MRCPCH(UK), MRCPI(Paeds), MRCPS(Glasg), DCH(Glasg); Chief Editor: Russell W Steele, MD 

Overview

Practice Essentials

Infectious mononucleosis is a clinical syndrome caused mostly by Epstein-Barr virus (EBV), or human herpesvirus 4 (HHV-4), which is a γ-herpesvirus. EBV is widely disseminated; it is spread by intimate contact between asymptomatic EBV-infected persons who shed the virus and susceptible persons.

The most common manifestation of primary infection with EBV is acute infectious mononucleosis, which is a self-limiting clinical syndrome that most frequently affects adolescents and young adults. Classic symptoms include malaise, fever, sore throat, fatigue, and generalized adenopathy. Infectious mononucleosis is characterized by atypical-appearing mononuclear lymphocytes. It was known synonymously as "Drüsenfieber," or glandular fever, owing to pronounced generalized lymphadenopathy.

EBV is the first human virus confirmed to be an oncovirus and may give rise to various lymphoproliferative malignancies in immunocompromised hosts. It is associated with various tumors, including nasopharyngeal carcinoma, gastric carcinoma, lymphoreticular malignancies, and Burkitt lymphoma.[1, 2]

EBV causes 90% of cases of infectious mononucleosis. Primary infection with cytomegalovirus, Toxoplasma gondii, adenovirus, viral hepatitis, HIV, and rubella virus causes an infectious mononucleosis-like illness. The exact cause remains unknown in the majority of cases of EBV-negative infectious mononucleosis.

See Clues in the Oral Cavity: Are You Missing the Diagnosis?, a Critical Images slideshow, to help identify the causes of abnormalities of the oral cavity.

Acute infectious mononucleosis was first described in 1889 as acute glandular fever, an illness characterized by lymphadenopathy, fever, hepatosplenomegaly, malaise, and abdominal discomfort in adolescents and young adults. In 1920, Sprunt and associates applied the name infectious mononucleosis to cases of spontaneously resolving acute leukemia associated with blast-like cells in the blood. The distinctive mononuclear lymphocyte cell associated with EBV is known as a "Downey cell," after Hal Downey, who contributed to the characterization of it in 1923. In 1932, Paul and Bunnell discovered that serum from symptomatic patients had antibodies that agglutinate the red blood cells (RBCs) of unrelated species, the "heterophile antibodies." This finding allowed enhanced diagnostic accuracy of infectious mononucleosis, even if the exact virus had not been isolated.

In 1958, Denis Burkitt, who was a surgeon posted in Uganda during World War II, reported a specific type of cancer that was common in young children living across central Africa. These aggressive tumors – later named after him as Burkitt lymphoma – were caused by white blood cells multiplying out of control. Later in 1964, UK researcher Antony Epstein and his colleagues Yvonne Barr and Burt Achong collaborated with Denis Burkitt and looked at the Burkitt lymphoma cells from tumor specimens shipped from Uganda. They detected tiny virus particles under the electron microscope in those specimens. In 1965, the newly discovered first human oncovirus was named Epstein-Barr virus.[3]

The EBV DNA was fully sequenced in 1984.

The graph below demonstrates the antibody response to Epstein-Barr virus.

Infectious mononucleosis. Antibody response to Eps Infectious mononucleosis. Antibody response to Epstein-Barr virus. Adapted with permission from Johnson DH, Cunha BA. Epstein-Barr virus serology. Infect Dis Pract. 1995;19:26-27.

The search for the etiologic agent of infectious mononucleosis was unsuccessful for many years, partly because researchers did not appreciate that most primary infections are asymptomatic and that most adults are seropositive. In 1964, Epstein described the first human tumor virus when he found virus particles in a Burkitt lymphoma cell line.[4]  Henle et al reported the relationship between acute infectious mononucleosis and EBV in 1968.[5]  Subsequently, a large prospective study of students at Yale University firmly established EBV as the etiologic agent of infectious mononucleosis.[6]

Background

EBV is a double-stranded DNA virus with an envelope and is a member of the gammaherpes virus family (HHV-4). Types 1 and 2 are two distinct types of EBV (type A and B). Although previous studies suggested that EBV-1 (type A) virus infection was more prevalent in North America and Europe and that EBV-2 (type B) virus infection was more prevalent in Africa, more recent studies suggest that both strains are prevalent in the United States.[7]

The differences between the strains are due to the altered sequence of viral genes expressed during latent infection, which differ in their ability to transform B cells. EBV infection causes lifelong, persistent latent infection. No clinical differences have been identified between the two types. In immunocompromised persons, dual infections with two types have been documented, even though no much type-specific clinical manifestations have been noted.

EBV infects >95% of the world population. Infection with this virus in developing countries and among socioeconomically disadvantaged populations of developed countries usually occurs during infancy and early childhood. Primary infection during childhood is typically not apparent or is indistinguishable from other common childhood infections. In developing countries, EBV infection occurs early in life. Nearly the entire population of a developing country becomes infected before adolescence. Thus, symptomatic infectious mononucleosis is uncommon in such countries.

In adolescents and young adults, the primary EBV infection manifests in >50% of cases as the classic triad of fatigue, pharyngitis, and generalized lymphadenopathy. This syndrome is rarely apparent in children younger than 4 years of age or in adults older than 40 years, even though most of these individuals have already been infected by EBV. Infants and children younger than 4 years handle the virus better than adults. Once infected, EBV persists in the memory B-cell pool of healthy individuals, and any disruption of this interaction results in virus-associated B-cell tumors.

The association of EBV with epithelial cell tumors, specifically nasopharyngeal carcinoma (NPC) and EBV-positive gastric carcinoma (EBV-GC), is less clear and is currently thought to be caused by the aberrant establishment of virus latency in epithelial cells that display premalignant genetic changes.[8]

In areas with high standards of hygiene, such as the United States and western Europe, EBV infection may be delayed until adulthood and the incidence of infectious mononucleosis is higher than in developing countries. Generally, however, the incidence of infectious mononucleosis is showing a decreasing trend worldwide in the past decade.[9]

Pathophysiology

Primates are the only known reservoir of EBV.

EBV has lytic and latent life cycles. Primary infection with EBV is followed by latent infection, a characteristic of all herpesviruses.

EBV is present in oropharyngeal secretions and is most commonly transmitted through saliva. Usually EBV is shed in oral secretions by 20-30% of  immunocompetent individuals and about 60-90% of immunosuppressed patients for >6 months after an acute infection and then intermittently for life. 

The virus is transmitted through oral secretions, as occurs in "deep kissing" in adolescents or young adults, or by sharing water bottles and toys among children in preschool care areas. It has been suspected to be transmitted via penetrative sexual intercourse, because virus particles infect cervical mucosa in females, but confirmed reports of this mode of spreading are not available.[10] EBV is found in both female and male genital secretions in a lesser number compared with the presence of virus in saliva, especially type 2 virus.

Usually fomites and non-intimate contacts, such as living in same room, or environmental sources seldom contribute to the spread of EBV. Hence, outbreaks of infectious mononucleosis seldom occur. The virus can be transmitted to susceptible recipients by blood transfusion,[11]  solid organ transplantation, and hematopoietic cell transplantation.[12]

The reason for the prolonged incubation period for infectious mononucleosis is still unclear.

After initial inoculation, the virus replicates in nasopharyngeal epithelial cells. Cell lysis is associated with release of virions, with viral spread to contiguous structures, including salivary glands and oropharyngeal lymphoid tissues. During primary infection, viral replication is first detected in the oral cavity. EBV infects epithelial cells in tonsillar crypts and B cells in the parenchyma of the tonsil. It has been shown that virus derived from epithelial cells has a much higher entry efficiency for infecting B cells.

Further viral replication results in viremia and subsequently infection of the lymphoreticular system, including the liver, spleen, and B lymphocytes in peripheral blood. A rapid cellular response by T cells is crucial for suppression of the primary EBV infection and determines the clinical expression of the infection.

Symptomatic primary infection with EBV is usually followed by a latent stage. After acute EBV infection, latently infected lymphocytes and epithelial cells persist and are immortalized. In vivo, this allows perpetuation of infection, while, in vitro, immortalized cell lines are established. The latent infection is established by self-replicating extra-chromosomal nucleic acid, the episomes. During latency, infected B-lymphocytes are immortalized by the virus, which leads to a state of polyclonal activation to form continuous cell lines.[13]

Host immune response to the viral infection includes CD8+ T lymphocytes with suppressor and cytotoxic functions, the characteristic atypical lymphocytes found in the peripheral blood. The T lymphocytes are cytotoxic to the EBV-infected B cells and eventually reduce the number of EBV-infected B lymphocytes. In persons with an intact cellular immune response, the infection is controlled by cytotoxic T cells. The main reservoir for EBV reactivation and development of EBV-related malignancies is the memory-B cells.

Two strains, labeled EBV-1 and EBV-2 (also known as type A and type B), have been identified. Although the genes expressed during latent infection have some differences, the acute illnesses caused by the two strains are apparently identical. Both strains are prevalent throughout the world and can simultaneously infect the same person.

It is essential to know the structure of EBV and which proteins are expressed during different stages of its life cycle to understand the laboratory tests used to determine whether a patient has primary acute, convalescent, latent, or reactivation infection. EBV glycoprotein gp350 is important for attachment of the virus to B cells.[14]   Most prophylactic EBV vaccines have used gp350.

A mature infectious viral particle, which may be present in the cytoplasm of an epithelial cell, consists of a nucleoid, a capsid, and an envelope. The nucleoid contains linear double-stranded viral DNA. It is surrounded by the capsid. An envelope derived from the outer membrane or the nuclear membrane of the host cell encloses the capsid and nucleoid (ie, the nucleocapsid). The envelope also contains viral proteins that were constructed and placed in the host cell membrane before viral assembly began.

Antibodies produced in response to infection are directed against EBV structural proteins, such as viral capsid antigens (VCAs), early antigens (EAs), and EBV nuclear antigen (EBNA). These antibodies are used for the serologic diagnosis of EBV infection. In a healthy EBV-seropositive adult, approximately 0.005% of circulating B cells are infected with EBV.[15]

The receptor for the virus on epithelial cells and B lymphocytes is the CD21 molecule. To initiate cellular infection, a viral particle attaches via its major outer envelope glycoprotein to the EBV receptor CD21 on a B lymphocyte. EBV is then internalized into cytoplasmic vesicles. After fusion of the virus envelope with the vesicle membrane, the nucleocapsid is released into the cytoplasm. The nucleocapsid dissolves and the genome is transported to the cell nucleus, then the linear genome circularizes, forming an episome. The cell may then proceed with either lytic infection with release of infectious virus or latent infection of the host cell. B lymphocytes with latent infection undergo growth transformation.

Lytic infection occurs early after primary inoculation. As a result of lytic infection in oral epithelial cells, EBV can be found in the saliva for the first 12-18 months after acquisition of infection. Thereafter, epithelial cells and lymphocytes are latently infected, leading to release of mature virions. Thus, the virus can be isolated from the oral secretions of 20-30% of healthy latently infected individuals at any time.

In 1976, researchers at the Karolinska Institute in Sweden studied the chromosomes in cells from Burkitt lymphoma tumors. They noticed that the same chunk of one particular chromosome had broken off and re-attached to a different chromosome in all the cells. It turned out that the chunk of chromosome that had broken off contained c-myc, an oncogene. C-myc usually tells cells to divide when they are needed, and its activity is tightly controlled, but in the Burkitt lymphoma cells it had landed next to genes that are always turned on in white blood cells. This meant that c-myc became permanently switched on, giving the cells instructions to keep growing. Unbridled proliferative illnesses arise when cellular immunity is grossly defective.[16, 17]

A large analysis concluded that approximately 1 in every 10 stomach cancers contained EBV.[18]

A study by Langer-Gould et al reported that Epstein-Barr nuclear antigen-1 seropositivity was independently associated with increased risk of multiple sclerosis in all racial and ethnic groups.[19]

Etiology

EBV is the etiologic agent in approximately 90% of acute infectious mononucleosis cases. Several other viruses can cause infectious mononucleosis-like illnesses. About 5-10% of illnesses are caused by primary infections with the following:

  • Cytomegalovirus
  • Toxoplasma gondii
  • Adenovirus
  • Viral hepatitis (hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex viruses 1 and 2)
  • HIV
  • Rubella virus

The exact cause remains unknown in majority of EBV-negative infectious mononucleosis-like illnesses.

Epidemiology

The majority of patients with infectious mononucleosis are not hospitalized; hence, the availability of reliable data on the population incidence is limited. The incidence is estimated as between 20 and 70 per 100,000 persons/year. The age-specific distribution of cases reflects the clinical disease ratio of primary EBV infection, which is low in children. The low incidence among older adults reflects the low number of EBV-uninfected individuals. There seems to be no seasonal variation in incidence rates.

A statistically significant association of higher antibody prevalence is noted with each race/ethnicity group, older age, lack of health insurance, and lower household education and income. Factors clearly related to early acquisition of primary EBV infection include geographic region and race/ethnicity, crowding or sharing a bedroom, and socioeconomic status.[20]  

There is a complex interplay between age of acquisition, symptomatic versus asymptomatic infection, and the subsequent risk of EBV-associated cancers or autoimmune diseases. Younger age at the time of primary EBV infection was associated with elevated levels of EBV viremia throughout infancy, leading researchers to postulate that these infants were at higher risk for endemic Burkitt lymphoma.[21]  Children who acquired primary EBV infection at an earlier age had higher titers of IgG antibody against VCA, and children who were infected with “a large inoculum of EBV”  were at high risk for nasopharyngeal carcinoma.[8]  Age of primary EBV infection is an important factor in infectious mononucleosis, and hence it is an important consideration for EBV-related diseases.

United States statistics

Epstein-Barr virus is not a notifiable infection, and the exact frequency of symptomatic primary infection is not known. Incidence in the United States is reported as 500 per 100,000 persons per year.[22]  Antibody prevalence across all age groups of US children aged 6-19 years enrolled in the National Health and Nutrition Examination Surveys (NHANES) between 2003 and 2010 was substantially higher in non-Hispanic Blacks and Mexican Americans than in non-Hispanic Whites.[23]  In younger children, there seems to be greater disparity in antibody prevalence, especially in 6- to 8-year-olds between the races, even though it is similar among teenagers, probably owing to differences in social practices and family environment.

Approximately 50% of the US population is infected by the age of 5 years. During childhood, primary infection is usually asymptomatic or is associated with mild elevation of liver function test findings. EBV infection acquired during adolescence is asymptomatic or is associated with the syndrome of acute infectious mononucleosis. Approximately 90% of the US population is seropositive for EBV by age of 25 years.

The highest incidence is in individuals aged 15-24 years. However, changes in economic status may have changed both the age of initial infection and the incidence of infectious mononucleosis. In lower socioeconomic groups, EBV infection is more common, occurs at an earlier age, and is less likely to be associated with acute infectious mononucleosis.

Roommates of students with primary EBV infection develop seroconversion only at the same rate as the general population of college students[6] .

International statistics

EBV infection occurs with the same frequency and symptomatology in the developed nations of the world as in the United States.

Data from 1990 to 2016 from the Health Survey of England, UK, were analyzed for the seroprevalence of EBV for the process of vaccine trials. The survey showed that approximately 50% of individuals were infected before the age of 5 years. According to the data, seroprevalence in the 5- to 11-year age group was about 55%, which increased slightly in the 12- to 18-year age group, to 65-70%. High levels of infection were seen in the 19- to 24-year age group (about 88%) and in those older than 25 years (about 90%).[24]  

EBV is more frequently acquired in childhood in underdeveloped nations, and, therefore, the syndrome of acute infectious mononucleosis is unusual in these nations.

In Africa, the virus is associated with endemic Burkitt lymphoma in the setting of co-infection with Plasmodium falciparum.[5]

High numbers of EBV episomes are found in the cells of undifferentiated or poorly differentiated nasopharyngeal carcinoma. This is the most common tumor in adult men in southern China and is also common in North American Inuits and North African Whites

Mode of transmission

EBV infection does not occur in epidemics and has relatively low transmissibility.

Kissing is the major route of transmission of primary EBV infection among adolescents and young adults. Penetrative sexual intercourse has been postulated to enhance transmission, but it was found that subjects reporting deep kissing with or without coitus had the same risk of primary EBV infection throughout their undergraduate years. Primary EBV infection can also be transmitted by blood transfusion,[11]  solid organ transplantation,[12]  and hematopoietic cell transplantation, but these routes account for relatively few cases overall.

Race-, sex-, and age-related demographics

Race

Epstein-Barr virus infection has no racial predilection; however, HLA-A2 haplotypes, which are more common in people of Chinese origin, are associated with a predisposition for nasopharyngeal carcinoma. The risk associated with HLA-A2 haplotypes is higher than any environmental risk posed by diet. First-generation US immigrants of Chinese origin have a higher risk for nasopharyngeal carcinoma.[25]

Large epidemiologic studies performed in the 1970s revealed that acute infectious mononucleosis was 30 times more likely to occur in Whites than in African Americans. However, this correlated with lower social economic status and earlier asymptomatic infection in African Americans and, therefore, did not reflect a true racial difference.

Sex

The incidence of infectious mononucleosis is the same in men and women, although the peak incidence occurs 2 years earlier in females. Postinfectious fatigue is more common in females.[26, 27]

Age

Epstein-Barr virus infection usually occurs during infancy or childhood and remains latent through life.

In developed nations, infection may not occur until adolescence or adulthood, and approximately 50% of adolescents who acquire Epstein-Barr virus develop the infectious mononucleosis syndrome.

Acute infectious mononucleosis has been reported in middle-aged and elderly adults; these individuals are usually heterophile antibody negative.

Prognosis

The prognosis for healthy persons with infectious mononucleosis is very good. Death is unusual in immunocompetent patients but can occur rarely due to airway obstruction, splenic rupture, neurologic complications, hemorrhage, or sometimes from secondary infection.

Morbidity/mortality

Most primary Epstein-Barr virus infections are asymptomatic. It is perhaps the most common reason for fever of unknown origin in young children and can present with fever in isolation or in the context of lymphadenopathy, fatigue, or nonspecific malaise.

Epstein-Barr virus infection is linked with numerous tumors. Endemic Burkitt lymphoma, the most common tumor of childhood in Africa, is associated with Epstein-Barr virus and malaria. Infection with P falciparum malaria stimulates polyclonal B-cell proliferation with Epstein-Barr virus infection and impairs the T-lymphocyte response to Epstein-Barr virus, apparently contributing to tumor pathogenesis.

In Asia, Epstein-Barr virus infection is related to development of nasopharyngeal carcinoma. Predisposing factors include a diet rich in nitrosamines, salted fish, Chinese race, and the HLA-A2 haplotype. Most non-Hodgkin lymphomas are associated with Epstein-Barr virus, and evidence of the Epstein-Barr virus genome is demonstrable in many of these tumors.

Epstein-Barr virus is also associated with Hodgkin lymphoma, in which the Epstein-Barr virus genome is present in the Reed-Sternberg cell. The EBNA1 protein interferes with tumor growth factor–beta signaling by downregulating Smad2; this interference with tumor-suppressor functions may contribute to tumor formation.[28]  In addition, the same protein may play a role in immune evasion via recruitment of regulatory T-helper cells.[29]  The precise mechanism by which Epstein-Barr virus may contribute to tumor pathogenesis are uncertain; some authors suggest that interleukin-10 may be linked to immune evasion, whereas others suggest it is linked to recovery.

Epstein-Barr virus infection in patients who are immunocompromised is associated with several syndromes and proliferative disorders.

Individuals with Duncan syndrome (ie, X-linked lymphoproliferative syndrome) may develop fatal primary Epstein-Barr virus infection due to a defect in the immune response to Epstein-Barr virus (poor anti-EBNA responses). The defective gene is the signaling lymphocyte activation molecule (SLAM)–associated protein (SAP) and is found on the X chromosome. Boys with Duncan syndrome often develop fatal massive hepatitis, hemophagocytosis, or a disseminated lymphoproliferative disorder triggered by primary Epstein-Barr virus infection. The median age of presentation is 2.5 years, with a median survival of 33 days. Survivors of the initial infection develop B-cell lymphoma or hypogammaglobulinemia and usually die by age 10 years. In children with Duncan Syndrome, the paucity of normal class-switched mature B cells means the virus instead establishes itself in nonswitched memory B cells (as opposed to naive or transitional B cells).[30]

Other congenital immunodeficiencies are associated with the development of Epstein-Barr virus–associated lymphoproliferative disorders. These include ataxia-telangiectasia, Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome, and common variable immunodeficiency.

Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal lymphoproliferative syndrome associated with Epstein-Barr virus and monoclonal or polyclonal expansion of B cells. It occurs in patients after organ transplantation, particularly after heart transplantation, and usually responds to decreased immune suppression.

Epstein-Barr virus–associated lymphomas occur in patients with secondary immunodeficiencies (eg, after cancer chemotherapy). Unfortunately, these tumors do not respond to decreased immunosuppression.

In patients with AIDS, Epstein-Barr virus is associated with hairy leukoplakia, leiomyosarcoma, CNS lymphoma, and lymphoid interstitial pneumonitis in children. However, only approximately one half of acquired immunodeficiency syndrome (AIDS)-associated Burkitt lymphomas contain Epstein-Barr virus genomes, which suggests a more complex interaction between chronic human immunodeficiency virus (HIV) infection and immune system defects. Acyclovir has been shown to have some potential benefit in treating patients with AIDS-associated Epstein-Barr virus disease.

Hemophagocytic lymphohistiocytosis (HLH) is an immune activation syndrome that can be triggered by EBV infection, especially in immunocompromised patients. HLH can also be triggered by other infections,[31]  and inherited HLH exists as well, which typically presents at a very young age.

HLH is characterized by multiorgan dysfunction and cytopenias, and laboratory findings that overlap with severe EBV infection and leukemia. Typical presentations are fever, hepatosplenomegaly, rash, and pancytopenia. Various laboratory findings are suggestive of HLH, including high ferritin, high triglycerides, and low fibrinogen, as well as cytopenia in at least 2 cell lines. The most specific serologic marker is high levels of soluble interleukin 2 receptor. Low natural killer cell number and activity is also a sensitive marker for HLH.

Complications

Antibiotic-induced rash (ampicillin rash)

A rash develops in nearly all adults (less commonly in children) 5-10 days after starting treatment with ampicillin, amoxicillin, or other beta-lactam antibiotics. It has also been associated with azithromycin. Even though it is associated with penicillins, this rash does not represent a true penicillin allergy. Rash is typically maculopapular and pruritic. It resolves in a few days when the antibiotic is discontinued.[32]

Splenic rupture

Owing to massive infiltration with lymphocytes, splenic rupture occurs in 0.1-0.5% of cases, with a mortality rate of up to 30%.[33]  The average time between onset of symptoms and rupture is 2 weeks (range, up to 8 weeks). The complication affects mostly males, with an average age of 22 years.

The spleen may dramatically enlarge and become vulnerable to spontaneous rupture, or rupture from minor trauma. However, a preceding history of trauma has been reported in only 14% of patients.[34]

The most common presenting symptom is abdominal pain, which is reported in 88% of patients.[34]

Although splenectomy is often performed in the majority of patients, careful serial observation or spleen-sparing interventions may be considered.[35] . Observation and supportive care may suffice occasionally in hemodynamically stable patients.

Occasionally, splenic infarction has also been reported.[36]

Neurologic complications

Encephalitis occurs usually during the first 2 weeks in 1% of adolescent and adult IM cases. In an etiological study of encephalitis in children, up to 6% of cases had strong evidence of current EBV infection.[37]

Other possible complications include aseptic meningitis, transverse myelitis, Guillain-Barre syndrome, cranial nerve palsies, sub-acute sclerosing panencephalitis, acute cerebellar ataxia, and rarely psychosis.

Autoimmune disease

An association between EBV infection and autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus, has been reported.

Malignancy

Because EBV is an oncovirus, long-term complications due to various malignancies involving lymphoreticular tissues can lead to varying degrees of morbidity and mortality.

EBV infection has been associated with a number of different malignancies of both lymphoid and epithelial origin, and it accounts for 1.8% of all cancer-related deaths worldwide.[37]   EBV infection is associated with nasopharyngeal carcinoma, Burkitt's lymphoma, and Hodgkin's disease in patients in developing countries. 

Patients with primary or aquired immunodeficiency, or those immunosuppressed by organ transplantation, are at increased risk for potentially fatal EBV-related lymphoproliferative disorders, such as post-transplant lymphoproliferative disorder, and B-cell lymphomas.[38]

Chronic fatigue syndrome

There is evidence of a distinct fatigue syndrome 6 months after diagnosis. A prospective study of patients with EBV-IM found that patients required nearly 2 months to achieve pre-illness functional status.[39]  Female sex and pre-morbid mood disorder are risk markers for post-IM fatigue.

Chronic fatigue should be present for at least 6 months for a diagnosis of chronic fatigue syndrome (CFS); post-IM fatigue may be of shorter duration.

The possibility that EBV infection leads to CFS has been reported in studies. No strong data exist to date to routinely implicate EBV as an etiologic agent.[40, 41]  Post-infective CFS can result from several viral and nonviral infections, which represent a common stereotyped outcome.

Younger patients with CFS after infectious mononucleosis who had long-term incapacity for work experienced marked improvement over time, and the long-term outcome is good.

Renal complications

Interstitial nephritis, myositis-associated acute kidney injury, hemolytic uremic syndrome, and jaundice-associated nephropathy have been reported in patients with acute symptomatic infectious mononucleosis. Rarely, the outcome is potentially fatal, and renal-replacement therapy may be required.[42]

Acute acalculous cholecystitis

 This can be an atypical clinical presentation of EBV infection.[43]

Chronic active infectious mononucleosis

Very rarely, few patients develop chronic active disease with intermittent or continuous symptoms of fever, hepatosplenomegaly, malaise and fatigue, abnormal liver function tests, and thrombocytopenia for over 6 months, which carries a poor prognosis with high mortality.[44]

Death is usually due to lymphoma, hemophagocytic syndrome, or fulminant hepatitis.

Patient Education

Following contact with the patient, carefully wash hands with soap and running water. Avoid any contact with the saliva of the affected patient. Advise patients that after sneezing and coughing they should clean up before touching other people. Tell patients to avoid sharing water bottles, eating and drinking containers, and utensils. In day care units, avoidance of sharing of cutlery and plates, which may be soiled with saliva, should be emphasized. Because transmissibility is low, there is no point in isolating affected patients.

Owing to splenomegaly, which can occur during the first 3 weeks of illness, the routine recommendation is to restrain from strenuous physical activity for up to 8 weeks or until all symptoms subside.[45]  A follow-up abdominal ultrasound scan to evaluate spleen size is helpful in advising patients who are athletes or those who participate in contact or collision sports. If no splenomegaly is detected, return to sports after 1 week can be allowed once symptoms subside.

 

Presentation

History

Infectious mononucleosis most often begins insidiously, with vague malaise, followed several days later by fever, fatigue, sore throat, and swollen posterior cervical lymph nodes. The prodrome period may last 1-2 weeks. Some patients experience an abrupt influenza-like onset, with fever, chills, body aches, retro-orbital headache, and sore throat.

The incubation period in adolescents is 4-7 weeks (32-48 days); however, it is shorter in young children, with a median duration of illness of 16 days, and the mean duration of 19 days, longer than other usual viral illnesses.[1, 6, 46]

 

Physical Examination

Sore throat, fatigue, headache, fever, body aches, decreased appetite, and abdominal discomfort are common symptoms.

Pharyngitis, tonsillar exudate, generalized lymphadenopathy, hepatosplenomegaly, eye lid edema, facial puffiness, maculopapular rash, and rarely jaundice are the frequent signs in EBV infection.

Sore throat is the most frequent presenting symptom, and occasionally pharyngitis is seen without sore throat. Many patients describe sore throat as the "worst" they have ever had. Pharyngitis is usually accompanied by marked tonsillar enlargement, occasionally with exudates. Another frequent feature is the presence of petechiae at the junction of the hard and soft palate. Because the pharyngitis resembles streptococcal infection, when ampicillin or amoxicillin is prescribed, virtually all patients develop an erythematous maculopapular rash ("ampicillin rash"). Otherwise 3-15% of patients develop a maculopapular rash, probably owing to immune-mediated vasculitis, and it resolves without specific treatment. In infants and  children, EBV infection is associated with Gianotti-Crosti syndrome, characterized by a symmetric rash on cheeks, extremities, and buttocks with multiple erythematous papules, which may coalesce into plaques and may persist for 15-50 days.

Fatigue and cervical adenopathy involving anterior and posterior nodes are seen in 90-95% of patients. Submandibular nodes and less commonly axillary and inguinal nodes are also enlarged. Epitrochlear lymphadenopathy is particularly suggestive of infectious mononucleosis if present.

Acute upper abdominal pain is present in about 30% patients owing to hepatitis, and left upper quadrant pain may be due to splenic enlargement. Hepatitis, documented by abnormal liver function tests, is seen in 80% of cases, and it should be considered as part of the acute disease rather than a complication. Liver involvement is subclinical in 90-95% of patients, but the remainder develop jaundice, and a few of them complain of tenderness in the right upper quadrant of the abdomen that is likely due to hepatic swelling with pressure on the liver capsule.

The spleen is often palpable 2-3 cm below the left costal margin and may be tender. The spleen rapidly enlarges over the first week of symptoms, usually decreasing in size over the next 7-10 days. The spleen can rupture from relatively minor trauma or even spontaneously. Acute severe abdominal pain should prompt suspicion of splenic rupture.

Flu-like symptoms such as headache, body ache, and chills are also common in young adults.

Eyelid edema, which gives the patient a slit-eyed appearance and may be accompanied by facial puffiness, is seen in 10% of patients. It is another symptom that is unusual in other viral illnesses and is a useful clinical clue in EBV infection (Hoagland sign).

Symptoms usually persist for 2-3 weeks, but fatigue is often more prolonged.

Infants and young children with primary infection are usually asymptomatic. Children younger than 4 years frequently have splenomegaly or hepatomegaly, rash, and nonspecific symptoms of an upper respiratory tract infection.

 

DDx

Diagnostic Considerations

The most widely cited Hoagland’s criteria for the diagnosis of infectious mononucleosis are as follows:

  • At least 50% lymphocytes
  • At least 10% atypical lymphocytes
  • In the presence of fever, pharyngitis, and adenopathy
  • Confirmed by a positive serologic test

Even though these criteria are quite specific, they are not highly sensitive and are most useful for research purposes. Only 50% of patients with symptoms suggestive of infectious mononucleosis and a positive heterophile antibody test meet all of Hoagland’s criteria.[47]

 

Differential Diagnoses

 

Workup

Approach Considerations

There is no definite evidence-based consensus or guidelines for criteria to diagnose Epstein-Barr virus (EBV) infection. Patients between 10 and 30 years of age with sore throat, fever, and significant anterior cervical adenopathy, fatigue, posterior cervical adenopathy, inguinal adenopathy, palatal petechiae, eyelid edema, and splenomegaly are at high risk for infectious mononucleosis.

A white blood cell (WBC) count and heterophile antibody test should be done, along with a rapid test for streptococcal pharyngitis. If the patient has more than 20% atypical lymphocytes or more than 50% lymphocytes, with at least 10% atypical lymphocytes, infectious mononucleosis is quite likely, and further confirmation of the diagnosis is not needed. A positive result of a heterophile antibody test also is strong evidence in favor of a diagnosis of infectious mononucleosis.[48]

A negative result of an antibody test, particularly during the first week of illness, may indicate that the patient does not have infectious mononucleosis or it could be an infectious mononucleosis-like illness. A second heterophile antibody test can be ordered after 1-2 weeks in such cases.[46]  If confirmatory testing is required, viral capsid antigen (VCA)-IgM antibody testing should be done, and a negative result strongly rules out infectious mononucleosis.

Laboratory Studies

Classic criteria

 Hoagland’s criteria

The 3 classic criteria for laboratory confirmation of acute infectious mononucleosis include (1) lymphocytosis, (2) the presence of at least 10% atypical lymphocytes on peripheral smear, and (3) a positive serologic test result for EBV with typical clinical features of EBV infection

Complete blood cell count

Leukocytosis with a WBC count of 10,000-20,000 cells/mL (10-20 X 109/L) is found in 40-70% of patients with acute infectious mononucleosis. By the second week of illness, approximately 10% of patients have a WBC count greater than 25,000 cells/mL.

Lymphocytosis is most severe during the second and third week of illness and lasts for 2-6 weeks. Usually, 20-40% of the lymphocytes are atypical, although not all patients have more than 10% atypical lymphocytes.

The atypical lymphocytes are mature T cells, which are antigenically stimulated. They are larger with eccentrically placed indented and folded nucleus  and have a lower nuclear-to-cytoplasm ratio (Downey cells).[49]  Most of these atypical lymphocytes are polyclonal-activated CD8 cytotoxic-suppressor T lymphocytes, although CD4 helper T cells and CD11 natural killer cells are also present.

Mild thrombocytopenia occurs in 25-50% of patients. Only rarely purpura is seen.

Liver function tests

Most (ie, 80-100%) of patients with acute infectious mononucleosis have elevated liver enzymes, even though jaundice is not usually present.

Alkaline phosphatase, aspartate aminotransferase (AST), and bilirubin levels peak 5-14 days after onset, and gamma-glutamyltransferase (GGT) levels peak at 1-3 weeks after onset.

Occasionally, GGT levels remain mildly elevated for as long as 12 months, but most liver function test results are normal within 3 months.

Lactic acid dehydrogenase (LDH) levels are increased in approximately 95% of patients.

Serum ferritin can also be increased.

Heterophile antibody test

Heterophile antibody tests are rapid, inexpensive, and specific tests that can be performed from the onset of symptoms of infectious mononucleosis.

Epstein-Barr virus infection stimulates polyclonal secretion of antibodies by infected B cells. Transient production of heterophile antibodies is seen in EBV infection and is known as Paul-Bunnell antibodies.[50] These are antibodies that agglutinate cells from other species and are not directed against Epstein-Barr virus. The Paul-Bunnell test for heterophile antibodies is based on the fact that serum obtained from patients with acute mononucleosis contains antibodies that agglutinate sheep, or more sensitivity, horse red blood cells (RBCs) but not guinea pig kidney cells in a tube dilution assay. Similar response is seen in serum sickness and rheumatic diseases but with different adsorption property. Thus, in terms of adsorbing infectious mononucleosis heterophile antibodies, clinicians use the saying, "Cow can, pig can't." Titers above 1:28 or higher than 1:40 are considered positive, depending on the dilution system used..

In this latex agglutination assay, serum from a patient with infectious mononucleosis agglutinates sheep RBCs after adsorption with guinea pig cells, but no agglutination occurs after adsorption with bovine RBCs.

Titer level does not correlate with the severity of clinical illness. Even though the tests have low sensitivity and low negative predictive value in young children under the age of 4, in adolescents, heterophile antibody tests have high specificity and sensitivity in the diagnosis of primary acute EBV infection.

Heterophile antibodies are measurable in approximately 50% of patients in the first week of illness, and 60-90% of patients have test results that are positive for heterophile antibodies in the second or third weeks. The titer begins to decline during the fourth or fifth week and is often less than 1:40 within 2-3 months after onset of symptoms.

As many as 20% of patients have positive titer results 1-2 years after acquisition. Also, because horse RBC agglutinins are more sensitive than sheep RBCs, 75% of patients have positive horse RBC agglutinin findings at 1 year.

Only 10-30% of children younger than 2 years and 50-75% of children aged 2-4 years develop heterophile antibodies with primary Epstein-Barr virus infection.

Monospot test

The Monospot test is a rapid slide agglutination test that was developed to measure acute infectious mononucleosis heterophile antibodies in a rapid qualitative fashion. Slide tests use either horse RBCs or bovine RBCs. Horse RBCs are more sensitive than sheep RBCs or bovine RBCs and can be treated with formalin to extend the shelf life of the test. Bovine RBCs are specific for acute infectious mononucleosis heterophile antibodies and, thus, do not require differential adsorption.[50]

All commercial kits for rapid diagnosis of acute infectious mononucleosis heterophile antibodies have low sensitivity (63-84%), with a negative predictive value of more than 10%.

Spot tests rarely yield false-positive results in patients with lymphoma or hepatitis.

Epstein-Barr virus serology

In young children, virus-specific serology appears to have better sensitivity, but there is cross-reaction with other herpesvirus infections, a longer turnaround time, and it is more expensive to perform.

Infection with Epstein-Barr virus is characterized by development of the specific antibodies to antigenic components of the virus. These antigens appear at different stages of infection and differ in lytic versus latent infection. Antibodies to Epstein-Barr virus antigens measured for clinical purposes include antibodies to viral capsid antigen (VCA), early antigens (EAs), and EB nuclear antigen (EBNA). EAs are expressed early in the lytic cycle, whereas VCA and membrane antigens are structural viral proteins expressed late in the lytic cycle. EBNA is expressed in latently infected cells.[51]

Antibodies to membrane antigens are not usually measured, but their presence correlates with viral-neutralizing activity. Antibodies to these proteins are measured with enzyme immunoassays, indirect immunofluorescence assays, and immunoblot assays.

EAs are expressed in cells early in the lytic cycle. These antigens are nonstructural Epstein-Barr virus proteins, which are classified into 2 groups based on cell distribution and stability with methanol treatment.

The restricted component of early antigens (EA/R) is found in the cytoplasm of infected cells and is methanol sensitive. Antibody to EA/R is usually measurable in children younger than 4 years with primary Epstein-Barr virus infection or in patients with nonsymptomatic infection.

Approximately 80% of patients with infectious mononucleosis have antibodies to the diffuse-staining component of EA (EA/D).

EA/D antibody levels are elevated in patients with nasopharyngeal carcinoma, and the levels of antibodies to EA/R are high in individuals with Epstein-Barr virus–associated Burkitt lymphoma. Patients who are immunocompromised and have persistent or reactivated Epstein-Barr virus infections often have high levels of antibodies to EA/D or EA/R.

In early primary Epstein-Barr virus infection, oropharyngeal epithelial cells are lytically infected, and the above antigens are expressed. Antibodies are measurable at the onset of clinical symptoms or even earlier.

Although not always measurable, EA antibody levels increase upon symptom onset. EA/D is more common, although EA/R is present more often in patients with asymptomatic infection or in children younger than 4 years. The levels of antibodies to EA rise for 3-4 weeks, then usually quickly decline to undetectable levels by 3-4 months, although low levels may be intermittently detected for years. However, in patients with a more prolonged symptomatic illness, EA/D may become unmeasurable, and EA/R results may become positive.

VCA-IgM levels are usually measurable at symptom onset, peak at 2-3 weeks, and then decline and become unmeasurable within 3-4 months. VCA-IgG levels rise shortly after symptom onset, peak at 2-3 months, then drop slightly but persist for life. Antibodies to EBNA appear during convalescence and remain present for life.

Primary acute Epstein-Barr virus infection is associated with VCA-IgM, VCA-IgG, and absent EBNA antibodies.

The antibody pattern in recent infection (3-12 mo) includes positive findings for VCA-IgG and EBNA antibodies, negative VCA-IgM antibodies, and, usually, positive EA antibodies.

After 12 months, the pattern is the same as in recent infection, except EA antibodies are not present.[1]

EBV viral polymerase chain reaction (PCR)

Viral PCR can be performed on whole blood and can be either qualitative or quantitative. Quantitative PCR can be useful in investigating EBV-associated disease in the context of immunosuppressed or immunodeficient patients. The symptoms of severe EBV-associated disease may mimic those of malignancy, graft-versus-host disease, or organ rejection, and measuring the viral load can help with deciding whether to increase or decrease immunosuppressive medications or perform further invasive testing.

Quantitative PCR can be used to measure Epstein-Barr virus DNA in plasma during acute infectious mononucleosis. Levels decline during convalescence and are rarely measurable in latently infected individuals. However, Epstein-Barr virus DNA in serum may be detectable with PCR with reactivation of infection, such as in patients with PTLD.

An Epstein-Barr early region (EBER) probe can be used to identify the Epstein-Barr virus messenger RNA in the nuclei of Epstein-Barr virus–infected lymphoid cells by in situ hybridization.

Studies have suggested that quantitative PCR in bronchoalveolar lavage fluid (BALF) for Epstein-Barr virus may be predictive of PTLD in lung-transplant recipients and is superior to plasma levels.[52]

In some patients who have an immune deficiency, the serologic response to EBV may be blunted or absent; the only way to detect EBV in that setting is with the use of PCR.

Longitudinal tracking of the quantitative viral load can help with judging the effectiveness of antiviral medications or the immune response to the infection.

Pathology/histology

Viral inclusions may be visible. Certain EBV-associated tumors, such as Hodgkin's lymphoma, have characteristic histology (eg, Reed Sternberg cells). In situ testing with DNA probes or immunohistochemistry for viral proteins can be done further to demonstrate infection.

Imaging Studies

Acute infectious mononucleosis

No specific imaging studies are indicated in diagnosing acute infectious mononucleosis.

Chest radiography reveals mediastinal adenopathy in fewer than 1% of patients. Mediastinal lymph node enlargement should prompt consideration of other diagnoses.

Clinical examination is less reliable to assess splenomegaly, and an ultrasound scan is confirmatory to measure splenic size. Almost always splenic rupture occurs in the first 3 weeks. If splenomegaly is detected, contact sports must be avoided at least for 6 weeks and follow-up ultrasound scans are required. 

Abdominal CT scanning is the preferred imaging modality to assess for splenic rupture if suspected.

Lateral neck films are occasionally helpful to document tonsillar hypertrophy and exclude epiglottis or retropharyngeal abscess in a patient with upper airway obstruction or stridor, which can be present in EBV-infected young adults.

Post-transplant lympho-proliferative disorder (PTLD)

In bone marrow or solid organ transplant patients with PTLD, chest radiography may reveal nodular lesions. Chest CT scanning with contrast may reveal the characteristic peripheral nodules, and abdominal CT scanning with contrast can define the extent of intra-abdominal lesions.

Histologic Findings

Acute infectious mononucleosis

Serum

Epstein-Barr virus infection is characterized by the presence of atypical lymphocytes in the peripheral blood. The cells are activated CD8 T cells, which are not infected but are mobilized to destroy the infected B cells.

Lymph nodes

During acute mononucleosis, lymph nodes are enlarged, with enlarged germinal centers and lymphoid follicles. Perifollicular areas of the tonsils contain many infected B lymphocytes, which express Epstein-Barr virus–specific antigens, including LMP1, EBNA1, and EBNA2.

Spleen

The spleen is larger, with lymphocytic infiltration of the capsule and trabeculae. Pleomorphic blast cells are present in the hyperplastic red pulp. Vascular congestion is coupled with focal and subcapsular hemorrhages.

Liver

Histologic changes in the liver are usually minimal, with mild swelling in hepatic sites and bile ducts and lymphocytic portal infiltration.

CNS

In fatal infectious mononucleosis, degenerative changes are observed in the neurons of the CNS. Neuronal degeneration, perivascular cuffing, and astrocytic hyperplasia may be present.

PTLD

PTLD is characterized by homogeneous lymphocytic proliferation with an immunoblastic component. Lesions may efface lymphoid organ architecture or develop ectopically in nonlymphoid organs. The Epstein-Barr virus–infected cells in patients with PTLD express EBER.

HLH

Demonstration of hemophagocytosis in a bone marrow aspirate is diagnostic for hemophagocytic lymphohistiocytosis (HLH), although nonspecific findings such as dyserythropoiesis are common.

 

Treatment

Approach Considerations

The mainstay of treatment for infectious mononucleosis is supportive care, including adequate hydration, nonsteroidal anti-inflammatory drugs or acetaminophen, and throat lozenges or sprays.[46]

If diagnosis is firmly established, only supportive care is required in the absence of significant complications.

There is no currently accepted specific treatment for infectious mononucleosis. Acyclovir and valacyclovir have an antiviral effect in vivo. A clinical benefit has not been convincingly demonstrated to date.[53]  Acyclovir combined with prednisolone inhibited oropharyngeal Epstein-Barr virus (EBV) replication without affecting duration of clinical symptoms or development of EBV-specific cellular immunity.[54]

Ganciclovir and valganciclovir have been used to treat EBV infections in immunocompromised hosts, but there are no controlled trials demonstrating clinical efficacy. Corticosteroids are often prescribed to treat inflammatory complications, such as airway obstruction, or autoimmune phenomena, such as anemia and thrombocytopenia, but the value of these drugs is controversial and they may impair clearance of the viral load.[22]

Patients with uncomplicated infectious mononucleosis rarely require inpatient therapy.

Hospitalization is warranted in the presence of splenic rupture, airway compromise, dehydration, significant thrombocytopenia or hemolytic anemia, and neurologic or other major complications.

Transfer to a tertiary care center may be necessary for the treatment of significant complications.

Medical Care

Infectious mononucleosis is a self-limited illness that does not usually require specific therapy in patients with mild or moderate illness. However, if the tonsils are markedly enlarged (kissing tonsils) or if the patient has prolonged illness, most experts recommend a short course of steroids (1-2 mg/kg of prednisone daily for 3-7 days).

Because of low transmissibility of Epstein-Barr virus (EBV), isolation is not indicated.

Most affected individuals can be evaluated and treated as outpatients. Inpatient therapy of medical and surgical complications may be required.

Patients with chronic post–Epstein-Barr virus fatigue (chronic fatigue syndrome [CFS]) may benefit from psychological and behavioral approaches.[55]

Surgical Care

Splenic rupture is an acute abdominal emergency that usually requires surgical intervention.[34]  Rupture may occur with trauma as minor as palpation, and is occasionally the presenting symptom.

Diagnosis can be confirmed using imaging procedures or peritoneal lavage in an unstable patient.

Splenectomy is usually required. Occasionally, observation and supportive measures are adequate treatment for a hemodynamically stable patient.

Although partial splenectomy or suturing the capsular tear has been advocated to preserve splenic function, the acute changes that led to rupture militate against the success of this approach.

Consultations

Surgical consultation should be sought when the patient has abdominal pain or evidence of shock.

Consultation with the appropriate subspecialist is indicated for management of significant complications (eg, infectious diseases, hematology/oncology, immunology).

Diet and Activity

Diet

No dietary modifications are required.

Activity

Acceptable activity level during the acute illness depends on severity of the patient's symptoms.

Extreme fatigue may require bed rest for 1-2 weeks or even more.

Malaise may persist for 2-3 months, and activity can increase as tolerated.

Patients should not participate in contact sports or heavy lifting for at least 2-3 weeks, although some authors recommend avoiding activities that may cause splenic trauma for 2 months.[33, 34]

Prevention

 

 

 

 

Long-Term Monitoring

Monitoring for long-term complications

EBV infection has been associated with a number of different malignancies of both lymphoid and epithelial origin and accounts for 1.8% of all cancer-related deaths worldwide. 

The criteria for association of EBV with cancer includes the following:

  • Finding the viral genome in every tumor cell
  • Presence of viral gene expression
  • Evidence that EBV is clonal (or oligoclonal) in the tumor cells

Each year worldwide there are about 84,000 cases of gastric carcinoma, 78,000 cases of nasopharyngeal carcinoma, 29,000 cases of Hodgkin lymphoma, 7000 cases of Burkitt lymphoma, and 2000 cases of lymphoma in transplant recipients associated with EBV[56] . About 9% of gastric carcinomas are associated with EBV; 90% of gastric lymphoepitheliomas, 7% of moderately to well-differentiated adenocarcinomas, and 6% of poorly differentiated gastric adenocarcinomas are EBV-positive. Virtually all anaplastic nasopharyngeal carcinomas contain EBV genomes. The incidence of nasopharyngeal carcinoma is particularly high in southern China with a rate of 80 per 100,000 in men > 40 years old. In developed countries about 30-40% of Hodgkin lymphomas are EBV-positive, whereas 80-90% of these lymphomas are EBV-positive in developing countries. About 85% of Burkitt lymphomas in Africa are EBV-positive, whereas about 15% of these tumors in the United States are virus-positive.[14]

In sub-Sahara Africa, the incidence of Burkitt lymphoma is 20 per 100,000 in children between the ages of 5 and 9 years old. The rate of EBV post-transplant lymphomas varies among the type of transplant ranging from about 1% in renal and hematopoietic stem cell transplant recipients to about 10% in intestinal transplant recipients.

Up to 10% of seronegative children receiving a solid organ transplant may develop EBV post-transplant lymphoproliferative disease. Patients with primary or aquired immunodeficiency are at increased risk for potentially fatal EBV-related lymphoproliferative disorders, such as post-transplant lymphoproliferative disorder, and B-cell lymphoma. Patients with HIV are at increased risk for EBV-associated malignancies including Burkitt lymphoma, diffuse large B cell lymphoma, Hodgkin lymphoma, immunoblastic lymphoma, primary central nervous system lymphoma, and smooth muscle tumors.[14]

 

 

 

Guidelines

Guidelines Summary

Guidelines on the diagnosis, prevention, prophylaxis, and treatment of Epstein-Barr virus (EBV)–related post transplant lymphoproliferative disorders in allogeneic hematopoietic stem cell transplant patients were published in 2016 by the Sixth European Conference on Infections in Leukemia. The guidelines recommend rituximab, immunosuppression reduction, and EBV-specific cytotoxic T-cell therapy as first-line treatment in these patients. Unselected donor lymphocyte infusions and chemotherapy are recommended as second-line options, while antiviral drugs are not recommended for prophylaxis, with evidence indicating that they are ineffective against latent EBV.[57]

A Cochrane review, which included 7 randomized controlled trials and 333 patients, found that the efficacy of antivirals (eg, acyclovir, valaciclovir) in infectious mononucleosis is uncertain, and the quality of evidence is very low.[53]  An improvement in time taken to recover (by 5 days) occurred in patients who received antiviral treatment, but the result was not precise and measurement for improvement was not clearly defined.

 

Medication

Medication Summary

Acute infectious mononucleosis is treated symptomatically. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat fever and discomfort. Corticosteroids do not significantly alter the course of infectious mononucleosis. Although they ameliorate symptoms, corticosteroids should not be used in the treatment of uncomplicated disease. They are used in patients with significant upper airway obstruction due to tonsillar or lymph node hypertrophy and in patients with severe thrombocytopenia or hemolytic anemia.

Numerous drugs inhibit Epstein-Barr virus (EBV) replication in vitro. Nonetheless, antiviral agents are not beneficial in patients with uncomplicated infectious mononucleosis. However, antiviral agents are used in the treatment of patients with interstitial pneumonitis, X-linked lymphoproliferative syndrome, PTLD, HLH, and other lymphoproliferative disorders.[58, 59, 60, 61] Intravenous immunoglobulin may be considered to modulate immune function in the presence of disease complications due to autoantibodies.

New therapies, including the use of interferon alpha and the infusion of donor T cells or Epstein-Barr virus–specific cytotoxic T cells, are being studied.

Glucocorticoids

Class Summary

Corticosteroids are potent anti-inflammatory drugs that also modify the immune response. They are used to decrease the size of tonsils and upper airway lymph nodes in the presence of airway compromise and possible upper airway obstruction. They may be useful to treat severe thrombocytopenia or hemolytic anemia. Whether prednisone should be used for myocarditis, pericarditis, or CNS system involvement is unclear.

Prednisone (Deltasone, Liquid Prep, Meticorten, Orasone, Prednicen-M, Sterapred)

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Antiviral Agents

Class Summary

Numerous drugs inhibit Epstein-Barr virus replication in vitro. These include acyclovir, desciclovir, ganciclovir, interferon-alfa, interferon-gamma, adenine arabinoside, and phosphonoacetic acid. Acyclovir, which inhibits viral shedding from the oropharynx, is the only antiviral drug used to treat infectious mononucleosis in placebo-controlled clinical trials. However, the clinical course is not significantly affected in patients with uncomplicated infectious mononucleosis.

Foscarnet (Foscavir)

Foscarnet, a pyrophosphate analog, has been reported to be active against acyclovir- or ganciclovir-resistant herpes family viruses, including HSV, CMV, VZV, and EBV. Most of the data regarding its use in severe EBV infection are from isolated case reports, but they are generally positive.

Acyclovir (Zovirax)

Strains of HSV1 are most sensitive, followed by HSV2. Acyclovir also is sensitive to other herpesviruses, including, in descending order, varicella zoster, EBV, and CMV.

Immunoglobulins

Class Summary

Intravenous immunoglobulin is used to modulate immune function in the presence of autoantibodies. It has been used successfully in the treatment of immune thrombocytopenia associated with infectious mononucleosis.

Intravenous immunoglobulin (Gammagard S/D, Gammar-P, Polygam)

Intravenous immunoglobulin neutralizes circulating myelin antibodies through antiidiotypic antibodies; it down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks the complement cascade; promotes remyelination; and may increase CSF IgG (10%).

 

Follow-up

Inpatient & Outpatient Medications

Nonspecific treatment includes saline gargles and acetaminophen or ibuprofen for sore throat, fever, and myalgia. Constipation may be treated with a laxative.

Acyclovir has no demonstrable benefit for treatment of uncomplicated infectious mononucleosis in placebo-controlled trials.

Various therapies are used for complications of Epstein-Barr virus (EBV) infection, although only a few have been studied in controlled trials. Corticosteroids are used for treatment of severe airway obstruction due to tonsillar enlargement, hemolytic anemia, and severe thrombocytopenia. They may decrease the duration of febrile illness and constitutional symptoms, but their routine use for treatment of a virus known to be related to tumor development is discouraged.

Interferon-alfa decreases shedding of Epstein-Barr virus in renal transplant recipients.[62]

Acyclovir and desciclovir can reverse Epstein-Barr virus–associated hairy leukoplakia in patients with HIV.[63] Acyclovir has been used to treat interstitial pneumonitis,[64] X-linked lymphoproliferative syndrome, and lymphoproliferative disorders. Posttransplant lymphoproliferative disorder (PTLD) has been treated with ganciclovir and cytomegalovirus (CMV) intravenous immunoglobulin (CytoGam). High-dose (20mg/kg/dose q8 hours, IV) is probably required to be effective.

Immune thrombocytopenia has been treated with intravenous immunoglobulin.[65]

Whether corticosteroids are beneficial or harmful in patients with encephalitis, pericarditis, and myocarditis is unclear.

Combination therapy with corticosteroids and acyclovir has been reported, with varying outcomes.

Deterrence/Prevention

Patients with primary infectious mononucleosis do not require any isolation. Epstein-Barr virus has low transmissibility and cannot be acquired from environmental surfaces or fomites.

Avoid contact with saliva. Epstein-Barr virus is present in throat washings of individuals with acute infectious mononucleosis. Virus can be cultured from the oropharynx for up to 18 months. It can be recovered from the oropharynx of 10-20% of healthy adults. Epstein-Barr virus infection is usually acquired through contact between a susceptible individual and the saliva of an asymptomatic individual who is shedding Epstein-Barr virus. In young children, saliva is spread by drooling and hand-to-mouth behaviors. In adolescents, infected saliva may be transferred by kissing, hence the label "kissing disease."

Use good hand washing techniques with adequate soap and water 

Do not kiss children on the mouth.

Maintain clean conditions, especially when young children are present (eg, in daycare), and avoid children sharing the toys.

Epstein-Barr virus can be transmitted by blood transfusion and by bone marrow transplantation. However, because the organism is so common, no procedures are in place to prevent this.

Vaccine development is proceeding, although the role of a vaccine is unclear.[13, 66, 67, 68] . 

Complications

Complications encountered after infectious mononucleosis include the following:

  • Acute interstitial nephritis
  • Hemolytic anemia
  • Myocarditis and cardiac conduction abnormalities
  • Neurologic abnormalities, multiple sclerosis
  • Cranial nerve palsies
  • Encephalitis
  • Aseptic meningitis
  • Mononeuropathies
  • Retrobulbar neuritis
  • Thrombocytopenia
  • Upper airway obstruction due swollen tonsils

Hepatitis develops in more than 90% of patients with infectious mononucleosis. Liver function test results are mildly elevated but are usually no more than 2-3 times the reference range. Bilirubin levels are elevated in approximately 45% of patients, but jaundice occurs in only 5%. Liver abnormalities are most pronounced in the second and third weeks of illness.

Approximately 50% of patients with infectious mononucleosis develop mild thrombocytopenia. The platelet count is usually 100,000-140,000/mL. The platelet count usually reaches its nadir approximately 1 week after symptom onset and then gradually improves over the next 3-4 weeks. Thrombocytopenia may be caused by the production of antiplatelet antibodies and peripheral destruction, especially in the enlarged spleen.

Hemolytic anemia occurs in 0.5-3% of patients with infectious mononucleosis. Hemolytic anemia has been associated with cold-reactive antibodies, with anti-I antibodies, and with autoantibodies to triphosphate isomerase. Hemolysis is usually mild and is most significant during the second and third weeks of symptoms.

Upper airway obstruction due to hypertrophy of tonsils and other lymph nodes in the Waldeyer ring occurs in 0.1-1% of patients. Treatment with corticosteroids may be beneficial. Patients with severe tonsillar and lymph node enlargement with impending airway obstruction may require intubation or tracheostomy. Patients who require hospitalization may have concurrent streptococcal pharyngitis. Two thirds of patients admitted with infectious mononucleosis with upper airway obstruction and dehydration have alpha-hemolytic Streptococcus infection, usually due to group C streptococci.

Splenic rupture occurs in 0.1-0.2% of patients with infectious mononucleosis. A literature review by Bartlett et al indicated that the risk of splenic rupture is greatest in males under 30 years with infectious mononucleosis symptom onset within the previous 4 weeks.[69] Rupture may be spontaneous, although the patient often has a history of some antecedent trauma. Rupture is most likely during the second and third weeks of clinical symptoms. Patients can present with mild-to-severe abdominal pain below the left costal margin, sometimes with radiation to the left shoulder and supraclavicular area. Massive bleeding may be accompanied by peritoneal irritation and shifting dullness. Shock may be the only presenting symptom. Because bradycardia is common in infectious mononucleosis, tachycardia with pulse of faster than 100 beats per minute is an important sign. Neutrophilia (instead of lymphocytosis) can occur. Surgical intervention is usually required.

Hematologic complications are as follows:

  • Epstein-Barr virus has been implicated in hemophagocytic syndrome.[70, 71, 72]

  • Immune thrombocytopenic purpura occurs and may evolve to aplastic anemia. Aplastic anemia and neutropenia are sometimes associated with antineutrophil antibodies.

  • Epstein-Barr virus infection may accelerate hemolytic anemia in individuals with congenital spherocytosis or hereditary elliptocytosis.

  • Disseminated intravascular coagulation associated with hepatic necrosis has occurred.

Neurologic complications are as follows:

  • Neurologic complications occur in less than 1% of patients with Epstein-Barr virus infections and usually develop during the first 2 weeks. In some patients, especially children, the neurologic symptoms are the only clinical manifestation of infectious mononucleosis[73] . Patients are often negative for the heterophile antibody. However, these complications are often severe. Complete recovery is the rule, but fatalities do occur.

  • Primary Epstein-Barr virus infection has been associated with aseptic meningitis, acute viral encephalitis,and meningoencephalopathy. Hypoglossal nerve palsy, Bell palsy, brachial plexus neuropathy, and multiple cranial nerve palsies have been described. Guillain-Barré syndrome, autonomic neuropathy, GI dysfunction secondary to selective cholinergic dysautonomia, acute cerebellar ataxia, and transverse myelitis also have been reported. Metamorphopsia (ie, Alice in Wonderland syndrome) has been described.rarely.

Cardiac and pulmonary complications are as follows:

  • Pulmonary complications are extremely rare, although upper airway obstruction due to lymphoid hypertrophy is relatively common. Chronic interstitial pneumonitis and pleural effusion have been associated with Epstein-Barr virus infection.

  • Cardiac abnormalities that can occur with Epstein-Barr virus infection include myocarditis and pericarditis.

Autoimmune complications are as follows:

  • Haemolytic anaemia is reported in patients who had infectious mononucleosis

  • Infectious mononucleosis stimulates production of many antibodies not directed against Epstein-Barr virus. These include autoantibodies, anti-I antibodies, cold hemolysins, antinuclear antibodies, rheumatoid factors, cryoglobulins, and circulating immune complexes. These antibodies may precipitate autoimmune syndromes.

Miscellaneous complications are as follows:

  • Renal disorders associated with Epstein-Barr virus infection include interstitial nephritis, renal failure, and paroxysmal nocturnal hemoglobinuria.

  • After cardiac bypass or transfusion, an infectious mononucleosis–like syndrome has been described. Epstein-Barr virus may cause this, but it is more commonly associated with primary CMV infection.

  • Chronic fatigue syndrome- 20 % feel fatigue at 2 months and 13% at 6 months after primary infectious mononucleosis[73] . Myalgias, depression and hypersomnia is also reported to be associated with Epstein-Barr virus infection.

Prognosis

Immunocompetent individuals with acute infectious mononucleosis have a good prognosis, with full recovery expected within several months.

The common hematologic and hepatic complications resolve in 2-3 months.

Neurologic complications usually resolve quickly in children. Adults are more likely to be left with neurologic deficits.

All individuals develop latent infection, which usually remains asymptomatic.

Long-term fatigue can occur, is more common in females, and can last 1-2 years or longer. This is separate from the chronic fatigue syndrome mentioned above (although post–Epstein-Barr virus fatigue can occur, chronic fatigue syndrome has not been causally linked to Epstein-Barr virus).

Patient Education

Educate patient and family about risk of splenic rupture and the need to refrain from contact sports for 2 months.

Inform patient and family about usual course of symptoms with acute infectious mononucleosis.

For patient education resources, see the CDC website and hand-out, Bacterial and Viral Infection Center .

Vaccine

An effective vaccine gainst EBV is currently unavailable.

The prevalence of EBV infection is so coommon and the fact that EBV act as cofactor for development of several epithelial and lymphoid cell malignancies, the necessity for an effective vaccine is so desirable even though the feasibilty seems to difficult now.

The first EBV vaccine trial in humans used live recombinant vaccinia virus expressing gp350.[74]

A monomeric EBV gp350 vaccine in a phase 2 trial was shown to reduce the incidence of infectious mononucleosis, but not the rate of EBV infection, hence newer formulations of gp350 including multimeric forms, virus-like particles, and nanoparticles may be more effective.[14]