Infectious Diseases

Mononucleosis syndromes

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OVERVIEW: What every practitioner needs to know

Are you sure your patient has mononucleosis? What should you expect to find?

Common presentation

  • Classic triad generally seen in infectious mononucleosis:

    • fever, pharyngitis, and lymphadenopathy

  • Common symptoms:

    • fevers

    • pharyngitis

    • common symptoms also include malaise, fatigue, headaches, and mild depression

    • often presents differently in patients older than 40 years of age

  • Common physical findings:

    • lymphadenopathy (most often of the posterior cervical chain, but can also be seen in the axillary and inguinal nodes); nodes are classically large and can be moderately tender

    • tonsillar enlargement, often with an exudate which can be white, gray-green, or rarely necrotic

    • splenomegaly (50-60% of patients)

    • palatal petechiae (which rarely can be a sign of aplastic anemia, thrombocytopenia, or disseminated intravascular coagulation, all of which are rare but known complications of mononucleosis and should be ruled out)

    • periorbital edema

    • rash

    • less commonly prolonged fatigue, hypersomnia, and short-lived depressive disorders

    • rarely vaginal ulcers can be seen

Presentation in adults older than 40 years of age:

  • These patients are less likely than younger patients to have lymphadenopathy and pharyngitis; fever is generally the most prominent symptom and often lasts longer than 2 weeks.

  • They are more likely to have an elevated bilirubin level than younger patients (30% with bilirubin > 2.0 compared with < 9% of children and adolescents); therefore, jaundice is more common.

  • They generally have higher aspartate aminotransferase values.

  • They often have less significant lymphocytosis, shown by a complete blood count (CBC) test with differential; 16% with fewer than 5% atypical lymphocytes, and 23% with total lymphocyte counts below 50%.

  • The symptoms of mononucleosis can be more protracted in older adults.

Splenomegaly

  • Splenomegaly is noted in 50-60% of individuals with infectious mononucleosis.

  • Splenomegaly is caused by the infiltration of the spleen with lymphocytes and atypical lymphoid cells.

  • Physical exam has been found to be unreliable in diagnosing splenomegaly in tall individuals as their spleen size often falls outside of the normal range for the general population.

  • Physical exam for splenomegaly has a low sensitivity and moderate specificity.

  • One-time imaging with ultrasound to assess for splenomegaly is not recommended because of the wide range of "normal" spleen sizes, and the result is unlikely to change routine management. It is generally considered safe to return to light, non-contact athletic activities in 3 weeks, if afebrile with a good energy level. However, splenic rupture has been noted to occur as late as 7 weeks after the onset of infectious mononucleosis, therefore, it is difficult to recommend a return to contact sports before 7 weeks.

Rash

  • Common rashes include macular erythema, petechiae, and urticaria (3-10%); rarely erythema nodosum can be seen.

  • Administration of ampicillin, generally given because of a mistaken diagnosis of bacterial pharyngitis, will result in a maculopapular rash 90% of the time (however, this does not represent or predict an allergy to the penicillin drug class).

How did the patient develop mononucleosis? What was the primary source from which the infection spread?

Common modes of transmission

  • Mononucleosis is known as the "kissing disease". The primary mode of transmission is by saliva. Transmission among siblings is common due to close contact, sharing cups and utensils, etc

  • Long-term shedding of Epstein-Barr virus (EBV) in the saliva has been noted after infectious mononucleosis; patients have been noted to have low titers of EBV in their saliva up to 18 months after infectious mononucleosis. Therefore, transmission through contact with saliva often occurs from asymptomatic carriers, hence, the high rate of spread through kissing during adolescence.

Additional modes of transmission

  • EBV can also be transmitted sexually; documentation exists of EBV deoxyribonucleic acid (DNA) in male and female genital secretions.

  • There is evidence that EBV can also be transmitted via blood products from healthy donors.

  • There is evidence that EBV can be spread from a transplanted organ from a seropositive donor to an EBV seronegative recipient.

Sexual transmission of Epstein-Barr virus

  • EBV has been demonstrated in epithelial cells from the cervical canal in women and from the sulcus coronarius in men. Naher and colleagues examined EBV polymerase chain reaction (PCR) tests in 92 men and women from a sexually transmitted infection (STI) clinic in patients for which STIs had been excluded. These patients denied a history of infectious mononucleosis. EBV was noted in 27.7% (13 out of 47) of cervical specimens in women and 13.3% (6 out of 45 specimens) from the sulcus coronarius in men.

  • Two possible explanations exist:

    • Epithelial cells become infected with EBV via circulating B lymphocytes while "passing through." These B lymphocytes would have become infected during passage through the pharyngeal lymphoid tissue.

    • EBV is sexually transmitted.

Which individuals are of greater risk of developing mononucleosis?

  • Individuals who have not been infected with EBV during their early childhood are at greatest risk of infectious mononucleosis.

  • In an affluent/developing country, such as the United States, EBV infection is often delayed into adolescence or even adulthood, resulting in infectious mononucleosis rather than the asymptomatic or subclinical presentation that occurs more often in childhood.

  • Risk factors for seropositivity noted in one study of university students include female gender, older age (19 or older), the presence of more than one sibling, past residence in a tropical county, and sexual activity prior to coming to the university (with risk increasing significantly with the number of sexual partners).

  • Individuals with X-linked lymphoproliferative disorder, a rare fatal disease that affects young males that are healthy prior to infection with EBV, are at risk. Infection with EBV results in fulminant disease characterized by hepatic necrosis, aplastic anemia or pancytopenia, and sometimes bacterial or fungal super-infection. It is caused by a defect in the SH2D1A gene, which encodes a 128 amino acid protein involved in signal transduction pathways in T lymphocytes.

Beware: There are other diseases that can mimic mononucleosis:

The differential diagnosis is broad, but the main diagnoses that need ruled out include:

  • Cytomegalovirus (CMV) mononucleosis

  • Toxoplasma gondii infection

  • Acute retroviral syndrome due to HIV infection

  • HHV-6 (human herpes virus 6)

  • Adenovirus infection

  • Primary infection with herpes simplex virus type 1

  • Strep pyogenes pharyngitis ("strep throat")

Cytomegalovirus mononucleosis

Overview

  • CMV mononucleosis is estimated to comprise 7% of all infectious mononucleosis syndromes. Like EBV, it belongs to the herpes virus family, usually causes an asymptomatic infection early in life in most individuals, and then lies dormant and remains within the host for life. More than 80% of adults are seropositive. In addition, it can reactivate in the immunocompromised host (especially in the setting of AIDS, organ transplant, and individuals on immunosuppressive medications) and cause significant end-organ damage, including colitis, retinitis, and pneumonitis.

  • Similar to EBV, primary infection in adolescence or adulthood in the immunocompetent host can cause mononucleosis. Primary risk factors for CMV mononucleosis include close contact with young children (specifically younger than 2 years of age). Transmission is similar to EBV, as it is primarily spread by contact with saliva; CMV is also found in cervical and vaginal secretions, semen, breast milk, tears, urine, feces, and blood. Intermittent shedding during the host's lifetime can also occur, similar to EBV.

Diagnosis

  • Diagnosis is usually achieved by either serology or DNA PCR. Serology is best used to diagnose past infection (indicated by a negative CMV IgM and a positive CMV IgG). The difficulty with interpreting a positive CMV IgM is that it can sometimes indicate past infection, although a rise in IgM titers over time is more specific for acute infection. In addition, CMV IgM may not peak until 4-7 weeks after the start of infection, resulting in a false-negative result when tested early in the course of disease. CMV DNA PCR is a very sensitive test that can be used on multiple bodily samples, including plasma, urine, leukocytes, and serum. However, a positive result must be interpreted with caution, as active CMV replication may be present but not be causing any clinical disease. This is especially true in immunocompromised individuals (e.g., an AIDS patient with a low CD4 count).

  • The CMV direct antigenemia test is also useful, which utilizes monoclonal antibodies that bind to the CMV lower matrix protein pp65 to detect CMV in circulating neutrophils.

  • Microscopic exam can also be used to look for the characteristic intranuclear inclusions ("owl's eye"); however, false positives can occur as other viruses can present with the same finding.

Major similarities to infectious mononucleosis

  • Overall symptomatology is very similar, including fever, pharyngitis, lymphadenopathy, headaches, and a rash that generally appears after the prodrome period.

  • Atypical lymphocytes can be present.

  • Elevated hepatic transaminitis, generally less than 5 times the upper limit of normal, can occur.

  • Complications are similar, including Guillian-Barre syndrome, aseptic meningitis, hemolytic anemia, and thrombocytopenia.

  • The hypersensitivity drug rash from ampicillin seen with EBV-induced infectious mononucleosis can also be seen with CMV mononucleosis.

Major differences from infectious mononucleosis

  • Elevated transaminases are more frequent (up to 92%) than in EBV mononucleosis.

  • Signs and symptoms are generally less severe, especially the degree of lymphadenopathy, pharyngeal erythema, and splenomegaly.

Toxoplasma gondii

Overview

  • Toxoplasma gondii is a protozoan that can cause a mononucleosis syndrome in immunocompetent individuals. It is well known for causing disease through human contact with cat feces, as well as causing ring-enhancing lesions in the central nervous system (CNS) in AIDS patients. Its life cycle is completed in the feline intestinal tract, with oocysts shed in cat feces. In addition, in many parts of the world, people are infected through ingestion of cysts from undercooked meat. Diagnosis is especially important in pregnant women, as it can cause a congenital syndrome characterized by damage to the fetal nervous system. Serology is not particularly useful, as IgM can persist for years after acute infection. IgG avidity testing or DNA PCR should be used instead.

Major similarities to infectious mononucleosis

  • Disease in immunocompetent hosts can cause lymphadenopathy (generally cervical or occipital), constitutional symptoms, maculopapular rash, pharyngitis, and hepatosplenomegaly. Atypical lymphocytes may be present.

Major differences from infectious mononucleosis

  • There is no major difference in the clinical presentation. Prevalence in the United States is much lower than infectious mononucleosis. In a healthy individual, it is not always necessary to differentiate toxoplasmosis from mononucleosis, as both are self-limited. However, pregnancy would preclude diagnosis of toxoplasmosis because of the risk of damage to the fetus.

Acute retroviral syndrome

Overview

  • Acute retroviral syndrome is caused by primary infection with human immunodeficiency virus. This syndrome develops within 90% of patients within 6 months of acquiring HIV. The most common screening test, the HIV antibody enzyme-linked immunosorbent assay(ELISA), is often negative, because antibodies to HIV generally are not detectable during the first 2 weeks. Therefore, if suspicion is high, an HIV RNA viral load should also be checked.

Major similarities to infectious mononucleosis

  • Presenting signs and symptoms include pharyngitis, headache, malaise, fevers, lymphadenopathy, and maculopapular rash. Atypical lymphocytes are often present.

Major differences from infectious mononucleosis

  • Maculopapular rash starts on the face and upper chest, spreads to the extremities, and involves the palms and soles. Lymphadenopathy may be cervical but can also involve the axillary or occipital nodes. Mucocutaneous ulceration often occurs and is not seen in EBV mononucleosis, which is generally painful and well-demarcated. Ulcerations can be seen in the mouth or on the penis or anus.

Human herpes virus type 6 (HHV-6)

Overview

  • HHV-6 is a member of the herpes virus family along with EBV. Extremely common, its seroprevalence approaches 100% in adults. It is known for causing roseola infantum in childhood, also known as sixth disease or exanthema subitum, which is characterized by a maculopapular rash. Serology can be used for diagnosis, although anti-HHV6 IgM can be found circulating in the serum at any given time in 5% of healthy adults, leading to a false-positive diagnosis of acute infection. DNA PCR can be used for diagnosis as well, as it is highly sensitive and specific.

Major similarities to infectious mononucleosis

  • In adults, primary infection can present with a mononucleosis-like syndrome with prolonged fever, cervical lymphadenopathy, and atypical lymphocytosis.

Major differences from infectious mononucleosis

  • Most other signs and lab abnormalities are not present (e.g., AST/ALT elevation, splenomegaly).

Adenovirus Infection

Overview

  • Known for causing respiratory tract infections and conjunctivitis in immunocompetent hosts (especially children), as well as hemorrhagic cystitis, pneumonitis, and colitis in immunocompromised hosts. In addition, it can cause a mononucleosis-like syndrome in healthy adults.

Major similarities to infectious mononucleosis

  • It can present with pharyngitis, fever, and cervical lymphadenopathy.

Major differences from infectious mononucleosis

  • Presenting signs and symptoms include conjunctivitis, tracheobronchitis, or atypical pneumonia.

  • Most other signs and lab abnormalities are not present (e.g., AST/ALT elevation, splenomegaly).

Primary infection with herpes simplex virus type 1 (HSV-1)

Overview

  • Primary infection with HSV-1 can present similarly to mononucleosis, as opposed to herpes labialis (which usually presents as a "cold sore"), which actually represents re-activation of HSV-1.

Major similarities to infectious mononucleosis

  • Presenting signs and symptoms include fever, pharyngitis with exudates, and prolonged cervical lymphadenopathy.

Major differences from infectious mononucleosis

  • Most other signs and lab abnormalities are not present (e.g., AST/ALT elevation, splenomegaly).

Pharyngitis with Strep pyogenes ("strep throat")

Overview

  • Strep pyogenes, which is a group A Beta-hemolytic strep species, is a common cause of sore throat, especially among children. The gold standard for diagnosis is throat culture. However, rapid streptococcal antigen testing is widely used as well.

Major similarities to infectious mononucleosis

  • Presenting signs and symptoms include pharyngitis often with exudates, as well as fever and lymphadenopathy (generally anterior cervical).

Major differences from infectious mononucleosis

  • Most other signs and lab abnormalities are not present (e.g., AST/ALT elevation, splenomegaly). Also, Strep pyogenes classically causes more severe odynophagia than infectious mononucleosis.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Heterophile antibody (monospot test): This is a latex agglutination assay using horse or sheep red blood cells (RBCs) as a substrate. Heterophile antibodies usually appear within 1 week, peak during the second or third week but can persist for up to 1 year. However, heterophile antibodies are negative in 25% of patients during the first week of illness. Sensitivity ranges between 70 and 92% and specificity 96 and 100%. False negatives occur mostly in young children, specifically up to 50% in children younger than 4 years of age. Beware of false-positive results in patients with HIV, lymphoma, systemic lupus erythematosus, rubella, parvovirus, and certain other viral infections.

  • CBC with differential: CBC with differential is used to look for lymphocytosis with atypical lymphocytes. Seventy percent of patients have atypical lymphocytes, which peak during the second or third week of illness. Detection of at least 10% atypical lymphocytes has a sensitivity of 75% and specificity of 92% for the diagnosis of infectious mononucleosis. Of note, atypical lymphocytes can also be found in toxoplasmosis, rubella, HHV-6, viral hepatitis, mumps, CMV, acute HIV, and certain drug reactions.

Results that confirm the diagnosis ]

EBV VCA (viral capsid antigen) IgM

  • ELISA has a sensitivity approaching 95% with a specificity of 99%. Anti-VCA (viral capsid antigen) IgM generally lasts 1-3 months. False-positive results can be caused by rheumatoid factor, often found in the setting of rheumatoid arthritis or hepatitis C infection. False positives can be avoided by using an IgG-inactivating reagent that removes rheumatoid factor. This test is generally considered the most valuable serologic marker for diagnosing acute infectious mononucleosis.

EBV VCA (viral capsid antigen) IgG

  • This characteristically peaks during acute illness, decreases over the next few weeks to months, and then persists at a low level throughout life. Therefore, a positive VCA IgG does not indicate chronic disease, but rather past infection. Sensitivity is roughly 71% and specificity 99% with the ELISA assay. High levels do not necessarily indicate acute disease.

EBNA (nuclear antigen) IgG

  • This appears 6-12 weeks after initial symptoms; therefore, it should not be present in acute mononucleosis. It is expressed in transformed or latently infected B-cells. Sensitivity is 99%. Of note, immunocompromised patients may not produce this antibody.

Common patterns of antibodies

  • Acute disease (infectious mononucleosis) includes (+) VCA IgM, (+) VCA IgG, and (-) EBNA IgG.

  • Past EBV infection (quiescent disease) includes (-) VCA IgM, (+) VCA IgG, and (+) EBNA IgG.

EBV lab testing for special cases

EBV DNA PCR

  • This is extremely sensitive and specific. A number of different assays are available to detect DNA in the serum, plasma, and in lymphocytes in peripheral blood. This is a good option for testing very early in disease (first few weeks) as serologic testing can be negative early in the disease process. PCR can also be helpful in immunocompromised patients, as they often have a less robust immune response to infection, as well as in patients who have received a significant amount of blood products. However, the level of serum EBV DNA does not correlate directly with clinical disease and should be interpreted with caution, especially in immunocompromised patients that may intermittently shed the virus.

  • PCR can also be used in high-risk patients to define the risk of post-transplant lymphoproliferative disease (for example, in solid organ or bone marrow transplant patients).

EA antibodies (early antigens)

  • There are two types: EA-R (restricted) and EA-D (diffuse).

  • EA-R (restricted): This indicates enhanced EBV replication or re-activation. High titers can be seen in patients with Burkitt's lymphoma or immunocompromised patients. It is rare in typical patients with infectious mononucleosis.

  • EA-D (diffuse): This is associated with recent infection, and 30% of patients never develop it. High titers are noted in patients with nasopharyngeal carcinoma. Levels of EA-D and VCA IgA can be followed to gauge tumor activity and therapeutic response in nasopharyngeal carcinoma.

Additional methods of testing

  • Electron microscopy allows visualization of the structure of the virus, revealing a large, enveloped virus for EBV. It is mainly used for research.

  • Immunohistochemistry can detect EBV antigens in numerous tissue specimens, including biopsy specimens. Generally, the antigens used are latent, such as EBNA or latent membrane protein (LMP).

  • Other forms of nucleic acid detection besides PCR include in situ hybridization, dot blotting, and southern blotting. The specificity of locating EBV DNA in specific tissue specimens can be decreased by circulating lymphocytes that may be present in certain tissues. Dot blotting and southern blotting utilize radionuclide probes based on sequences within the genome. Uses for southern blotting include determination of the clonality of EBV infection by comparison of different sections of genome. In situ hybridization is the most specific of the four methods of nucleic acid detection. The best target for in situ hybridization is the EBER 1 and 2 transcripts, which are RNA polymerase III transcripts. They are expressed in latently infected cells and are both numerous and dissimilar to mammalian RNA, making them good targets.

In cases of pregnant women

  • Recommended testing includes not only confirmatory testing for EBV (VCA IgM and IgG, EBNA), but also testing to rule out other pathogens that can present with mononucleosis-like syndromes, such as CMV, HIV, toxoplasma gondii, and HHV6.

What imaging studies will be helpful in making or excluding the diagnosis of mononucleosis?

  • For routine cases, imaging is not recommended. Imaging with abdominal ultrasound to measure spleen size to diagnose splenomegaly has no clear benefit and won't routinely change management.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

  • In most cases, a consult is not necessary. However, complications may dictate the need for assistance from a specific consult service. For example, hemolytic anemia or severe thrombocytopenia (which are both rare) may require a hematology consult for management recommendations, and bone marrow biopsy to rule out other diagnoses. Neurologic complications may require a neurology consult, and airway compromise with tonsillar enlargement should always prompt an otolaryngology or critical care consult for possible airway management.

If you decide the patient has mononucleosis, what therapies should you initiate immediately?

  • Treatment is supportive. Numerous studies of anti-viral medications (acyclovir, valacyclovir) and steroids have not shown a consistent benefit for treatment of infectious mononucleosis.

  • Suggested conservative measures include anti-pyretics, although aspirin should be avoided in the setting of thrombocytopenia because of the risk of bleeding. Stool softeners are recommended for treatment of constipation to avoid excess use of the Valsalva maneuver, which can rarely lead to splenic rupture secondary to increased intra-abdominal pressure. Avoiding excessive alcohol has been recommended to reduce the risk of liver failure in the setting of elevated hepatic transaminases.

If I am not sure what pathogen is causing the infection what anti-infective should I order?

  • The constellation of symptoms of infectious mononucleosis should not prompt empiric anti-infective therapy. The pathogens on the differential diagnosis (CMV, HIV, HHV6, toxoplasmosis gondii, Strep pharyngitis), when causing mononucleosis-like symptoms, generally do not cause rapid, aggressive disease that would require immediate treatment in an immunocompetent host (exceptions would include pregnancy).

There is currently no clear treatment for infectious mononucleosis beyond supportive measures. Acyclovir and steroids have been extensively studied.

Acyclovir/valacyclovir

  • Acyclovir has not been shown to reduce either the severity of symptoms or the incidence of acute complications in infectious mononucleosis.

  • Acyclovir has been shown to decrease oropharyngeal shedding of EBV measured at the end of a given treatment interval; however, no difference in shedding has been observed long-term.

  • Valacyclovir has also been investigated in small trials and has been noted in a few to significantly improve clinical symptoms, including severity of sore throat, headache, and fatigue during the treatment period. In addition, similar to acyclovir, the amount of EBV DNA in saliva was noted to significantly decrease during the treatment period but all subjects experienced a virologic rebound after the drug was discontinued. However, no large RCTs or meta-analyses exist to verify this result, so treatment should not be recommended.

Steroids

  • Steroids have not been shown to reduce symptoms of mononucleosis or time to resolution of symptoms. Improvement in sore throat has been demonstrated with oral dexamethasone at 12 hours in one emergency department based RCT in children, but this effect was lost at all later time points. In another small RCT, a 12-day taper of oral prednisone was shown to improve certain endpoints, including return to normothermia, decrease in white blood cell (WBC) count, and normalization of heterophil antibody titer, but all other endpoints were not significantly different from placebo.

  • Steroids are often used to treat certain complications of infectious mononucleosis, including airway obstruction and hematologic complications, including hemolytic anemia and severe thrombocytopenia.

What complications could arise as a consequence of mononucleosis?

Rare acute complications include:

  • Splenic rupture

  • Neurologic complications, which can include encephalitis, meningitis, cranial nerve palsies including Bell's palsy, seizures, transverse myelitis, optic neuritis, and Guillain-Barre syndrome

  • Airway obstruction

  • Myocarditis

  • Cardiac arrhythmias

  • Hepatitis/liver failure

  • Secondary bacterial infection

  • Thrombocytopenia

  • Hemolytic anemia

  • Neutropenia

Rare long-term complications and diseases related to EBV include:

  • Chronic Active EBV infection

  • Hogkin's disease

  • B-cell lymphoproliferative disease

  • Post-transplant lymphoproliferative disease

  • Nasopharyngeal carcinoma

  • Oral Hairy Leukoplakia in HIV/AIDs patients

  • Burkitt's lymphoma

  • Hemophagocytic lymphohistiocytosis

  • Possible link to multiple sclerosis

  • Possible link to lymphocytic interstitial pneumonia

Splenic rupture

Overview

  • It is a rare complication of infectious mononucleosis, estimated at 0.1-0.5% of cases.

  • The majority of cases occur within 3 weeks, but rupture has been reported to occur as late as 7 weeks.

  • Clinical presentation includes acute abdominal pain, especially in the left upper quadrant; signs and symptoms of hypovolemia or hemorrhagic shock may be present, such as tachycardia and hypotension.

  • Kehr's sign: Pain is referred to the left shoulder, which may be present in 50% of patients presenting with splenic rupture.

  • CT scan is recommended for diagnosis if the patient is reasonably stable, versus emergent laparotomy if unstable.

  • Splenic enlargement involves invasion of the spleen with lymphocytes and atypical lymphoid cells resulting in distortion of the splenic architecture and thinning of the splenic capsule.

  • Rupture generally occurs after sudden compression of the spleen, which is susceptible due to a thinned capsule and enlargement.

  • Compression results in a sudden increase in portal venous pressure causing vascular engorgement. This can occur from contraction of the diaphragm (e.g., from the Valsalva maneuver) or abdominal trauma (classic association is contact sports, such as football).

Management of splenic rupture

  • Growing evidence suggests that, in some cases, non-operative, conservative management of splenic rupture may be appropriate.

  • Risks of splenectomy include overwhelming sepsis later in life. Asplenic patients are at higher risk of infection with polysaccharide encapsulated bacteria, specifically Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. The risk of overwhelming sepsis in an asplenic patient is 1-3%, and mortality is estimated at 50-80%.

  • Methods of splenic conservation include splenorrhaphy, partial splenectomy, and splenic artery embolectomy.

  • Non-operative management has been suggested in patients who are hemodynamically stable and who have low transfusion requirements (noted as <4 units of packed red cells).

  • It is unclear how long and how well the diseased spleen will heal, so follow-up imaging with ultrasound every 3-6 months until normal splenic architecture is visualized is suggested.

Hepatitis/liver failure

  • Mild elevations of transminases (AST and ALT) to 2-3x the upper limit of normal is most common, but rarely jaundice and hepatitis with higher levels of AST and ALT can occur (5-10x the upper limit of normal). It is important to also exclude hemolytic anemia as a cause of jaundice in infectious mononucleosis.

  • In cases in which AST and ALT are greater than 10 times the upper limit of normal, alternative diagnoses should be sought.

  • Hepatomegaly is noted in 6-14% of patients.

  • Fulminant hepatic failure can occur but is rare; most cases have been noted in patients with immunodeficiencies, such as HIV, X-linked lymphoproliferative disease, and bone marrow transplant.

  • Chronic liver disease is not seen.

  • Treatment is supportive.

Hepatitis due to EBV: anatomic findings and histology

  • Abdominal ultrasound may reveal hepatomegaly, adenopathy in the porta hepatis, and periportal edema.

  • Rare findings include gallbladder thickening and ascites.

  • Hepatocyte findings include swelling and vacuolization.

  • Infiltration with lymphocytes and monocytes in periportal areas occurs.

  • Sinusoidal invasion by monocytes in an "Indian Bead" pattern occurs.

  • Areas of scattered focal necrosis occur.

  • Mild swelling of bile ducts, but rarely obstruction, occurs.

Thrombocytopenia

  • It is usually mild-moderate in 50% of patients.

  • Severe thrombocytopenia is rare: 0.9% (7/760 of cases) in one series of patients with infectious mononucleosis over a 9 year time frame.

  • Bone marrow biopsy generally reveals an increased number of megakaryocytes.

  • It is postulated to be an immune-mediated process, based on response to steroids and bone marrow biopsy findings.

Chronic active EBV infection

  • Results in severe, chronic recurrent symptoms of infectious mononucleosis after a primary infection with EBV in an immunocompetent host

  • Noted to have a marked increase of EBV load in the peripheral blood

  • Complications include interstitial pneumonia, bone marrow hypoplasia, uveitis, hepatitis, and splenomegaly.

  • Has a high morbidity and mortality

  • Treatment includes bone marrow transplantation and immunotherapy.

Post-transplantation lymphoproliferative disease

  • Heterogenous group of abnormal lymphoid proliferations that occur after solid organ or hematopoietic transplantation

  • EBV positive in 60-70%

  • Range of disease is wide, from hyperplasia to aggressive lymphoma, including CNS disease.

  • Occurs at a median of 36-40 months after transplant

  • Mortality ranges from 50 to 70%

  • Pathogenesis involves depressed T-cell function due to immunosuppression, resulting in increased B-cell proliferation. In the setting of EBV positivity, latently infected B-cells are able to proliferate and can lead to lymphoma. The EBV is generally from the recipient, rather than the donor, and represents reactivation of latent EBV, not acute infectious mononucleosis.

  • Risk factors include an EBV negative recipient, EBV positive donor, CMV disease, fewer HLA matches, pre-transplant malignancy, and younger age. Risk increases with increasing degree of immunosuppression.

  • Risk is 1-3% after liver or kidney transplantation, 3-9% after heart or lung transplantation, or greater than10% after intestinal or multi-organ transplantation.

  • Presenting symptoms include B symptoms (fever, night sweats) and/or transplanted organ dysfunction as the lymphoma can invade or compress the graft. However, direct organ involvement is rare (15-30%) versus extra-nodal disease in 75-85%.

  • CNS involvement in 10-15%; typically CNS lymphoma

  • Most are of B-cell origin; T or NK lesions in only 10-15% (of note, most T or NK lesions are EBV negative)

  • There are four categories: early, polymorphic, monomorphic, and classical Hodgkin's lymphoma

  • In comparison to EBV positive disease, EBV negative disease is more often of the monomorphic type; more often late-occurring; and the median time to development of post-transplant lymphoproliferative disease (PTLD) is later, specifically 69 months compared to 11.5 months in one series.

  • Treatment options include reducing immunosuppression, chemotherapy, rituximab, surgery, and radiation.

Oral hairy leukoplakia in HIV/AIDs patients

  • It is a "hairy" appearing, asymptomatic white plaque located on the tongue and sometimes the buccal mucosa in HIV patients.

  • Statistically more EBV DNA has been detected in the epithelial lesions of oral hairy leukoplakia in patients with HIV when compared to normal buccal mucosa.

  • However, the exact role of EBV in the pathogenesis of oral hairy leukoplakia is unclear given that EBV positive and negative specimens of oral hairy leukoplakia are clinically indistinguishable.

  • In addition, EBV can be found in the oropharynx of some HIV patients without oral hairy leukoplakia.

  • Treatment of oral hairy leukoplakia with oral acyclovir has been shown to result in regression, re-occurs once therapy is stopped.

Hemophagocytic lymphohistiocytosis

  • It is a disease characterized by fever, hepatosplenomegaly, and cytopenias. It involves accumulation of lymphocytes and macrophages, sometimes with hemophagocytosis in numerous organs, including the spleen, lymph nodes, bone marrow, liver, and cerebrospinal fluid (CSF).

  • The secondary form generally results from excess immunological activation, caused by numerous etiologies, including EBV infection. Other causes include malignancy, infection (viral, bacterial and fungal), and rheumatoid disorders.

  • Five of the eight following criteria are required for diagnosis: fever, splenomegaly, cytopenias, hypertriglyceridemia, hemophagocytosis (in bone marrow, spleen, or lymph nodes), low or absent NK cell activity, hyperferritinemia, and high levels of sIL-2r.

  • Treatment includes steroids, immunosuppression (including cyclosporine), and chemotherapy.

Link to multiple sclerosis

  • Meta-analysis results suggest that the risk for multiple sclerosis is increased in patients who developed infectious mononucleosis from EBV rather than the more common asymptomatic or subclinical EBV infection that often occurs in childhood.

  • Evidence used in the meta-analysis is based on case control and cohort studies rather than RCTs.

Possible Link to Lymphocytic Interstitial Pneumonia (LIP)

  • LIP is a pulmonary lymphoproliferative disorder of unknown etiology characterized by expansion of alveolar septa by prominent mononuclear cell infiltrates.

  • Small studies have demonstrated a greater prevalence and density of EBV in lung tissue from patients with LIP than in non-diseased lungs or in lungs from patients with idiopathic pulmonary fibrosis, used as a control group.

  • The exact role of EBV in LIP remains to be determined.

What should you tell the family about the patient's prognosis?

  • Prognosis is excellent, and patients generally make a full recovery, but it often takes 3-6 weeks for symptoms to resolve.

  • Adolescents need to avoid sports for at least 3 weeks and can return if afebrile and without any significant associated abnormalities. This recommendation is based on the observation that most splenic rupture occurs within the first 3 weeks of illness. The time-frame for returning to contact sports is more controversial than non-contact sports given that splenic rupture has been noted to occur as late as 7 weeks.

  • Fatality is very rare and generally results from infrequent complications, such as splenic rupture, airway obstruction, fulminant hepatitis, and neurologic complications.

How do you contract mononucleosis and how frequent is this disease?

Modes of transmission

  • The primary mode of transmission is via saliva, but sexual transmission and transmission via blood and in transplanted organs have also been noted.

  • Transmission among siblings is common via contact with oral secretions (e.g., from sharing utensils or cups).

  • Long-term shedding of EBV in the saliva has been noted after infectious mononucleosis; patients may have low titers of EBV in saliva for up to 18 months after infectious mononucleosis.

  • As many as 20% of healthy carriers intermittently shed virus.

  • Special precautions against transmission are not necessary, as most people are seropositive, but avoiding contact with saliva and hand washing is recommended.

Frequency of disease

  • 95% of adults worldwide are infected with EBV.

  • In the United States and other industrialized countries, one-half of the population contracts primary EBV infection between 1 and 5 years of age, in comparison to developing countries where most EBV infection occurs in early childhood. Infection is usually subclinical in childhood. Primary EBV infection is rare in the first year of life, presumably due to the protective effect of maternal antibodies. Primary EBV infection in children is associated with low socioeconomic status, poor hygiene, and crowding, which are all more common in developing than in developed countries.

  • In the United States, roughly one-half of adolescents are still susceptible to infectious mononucleosis in their teens and early adulthood, and a majority of those still susceptible develop EBV in the form of infectious mononucleosis. The highest incidence is the 15-24 year old age group.

  • 3-10% of adults older than 40 years of age have never been infected with EBV.

  • In the United States, rates of infectious mononucleosis are 30 times higher among white than black children. The reason for this is unclear.

Other epidemiologic features include:

  • No clear annual cycles or seasonal changes

  • No predisposition on the basis of sex

Epidemiology studies

Long-term shedding/transmission

  • Fafi-Kremer and colleagues conducted a small longitudinal study examining the shedding of EBV in the saliva in adults after infectious mononucleosis. In a group of 20 healthy adults with a mean age of 20 years of age, high amounts of EBV DNA in the saliva was noted in all patients studied at 6 months after infectious mononucleosis. EBV carriers without recent infectious mononucleosis (defined by positive EBV VCA IgG) also exhibited intermittent EBV DNA in the saliva, but the amount was significantly lower than in those recently infected. This study confirms that seronegative individuals are often infected through contact with oral secretions (generally thought to be from kissing) from seropositive, asymptomatic individuals, and the likelihood of transmission is inversely correlated with length of time from infection.

  • Naher and clleagues conducted a study examining the prevalence of EBV DNA by PCR in genital secretions of 92 healthy adults seen at a STI clinic after STIs had been excluded. All patients denied a history of infectious mononucleosis. EBV DNA was noted in 27.7% (13 of 47) of cervical specimens in women and 13.3% (6 of 45 specimens) from the sulcus coronarius in men.

Risk factors

  • Higgins and colleagues conducted a retrospective study of approximately 1500 seropositive university students in Scotland, examining risk factors for EBV seropositivity. Risk factors for seropositivity included female gender, older age (19 years of age or older), the presence of more than one sibling, past residence in a tropical county (Africa 1st, South America 2nd), and sexual activity prior to coming to the university (with risk increasing significantly with the number of sexual partners).

  • Zoonotic transmission is not known to occur (transmission from animals); EBV infection is only known to occur in humans.

What pathogens are responsible for this disease?

  • Ebstein-Barr virus

How do these pathogens cause mononucleosis?

General information

  • Epstein-Barr virus is a member of the gamma herpes virus family and is also known as human herpes virus 4. There are seven other known members of the herpes virus family: herpes simplex virus 1 and 2, varicella zoster virus, cytomegalovirus, human herpesvirus 6, human herpesvirus 7, and human herpesvirus 8.

Viral structure

  • EBV is made up of a protein core wrapped with DNA; the core is surrounded by a nucleocapsid, protein tegumen and outer envelope.

  • It contains a double-stranded genome of approximately 172kb.

Life cycle

  • EBV exhibits tropism primarily for mucosal surfaces, but also for epithelial cells.

  • Two theories exist regarding initiation of infection in the host. The first involves direct infection of the tonsillar epithelial cells with EBV, via oral spread, followed by lytic replication and spread to underlying B cells. The second hypothesis states that EBV directly infects B-cells via Waldeyer's ring.

  • The incubation period is estimated at 30-50 days from the time of infection to the manifestation of symptoms.

Lytic phase

  • The lytic phase involves production of virus involved in infection of the host and later in additional viral production and spread to new hosts.

  • The lytic phase involves three types of proteins: the immediate-early, early, and late lytic proteins. The early antigens (EAs) are produced prior to viral DNA synthesis and include EA-D (diffuse) and EA-R (restricted). The late lytic phase involves production of the viral capsid antigens (VCA), which are the structural proteins of the capsid. The membrane antigens (MAs) are polypeptides expressed on the cell surface before and after viral DNA synthesis.

Latent phase

  • EBV switches into the latent phase after infection and can remain in this state for years, circulating in memory B-cells. It can switch back into the lytic phase to produce new virus to infect another host, in which new virus is produced in Waldeyer's ring after differentiation of B-cells into plasma cells. The latent phase allows EBV to effectively hide from the host's immune system, as no viral proteins are expressed on the cell surface and, therefore, the memory B-cells are not detected by the immune system and destroyed. This allows EBV to exist in the host for life, generally without causing any symptoms as long as the host remains immunocompetent.

  • The latent phase proteins include 6 Epstein-Barr nuclear antigens (EBNAs 1, 2, 3a, 3b, 3c, and leader protein), as well as 3 latent membrane proteins (LMP 1, 2A, and 2B) and 2 short EBV-encoded RNAs (EBAR 1 and 2). The cell surface antigen recognized by cytotoxic T-cells is made up of LMP1 and EBNA2 in addition to the major histocompatibility complex.

What other additional laboratory findings may be ordered?

  • Liver function tests: Mild elevations in AST, ALT, and/or LDH are present in 80-90% of patients. Patients are generally asymptomatic. Alkaline phosphatase is elevated in 60% of cases and bilirubin in 45%. Elevations generally occur during the second week of illness and resolve within 2-6 weeks.

  • Platelet count: Thrombocytopenia is noted to be mild-moderate in 50% of patients. Severe thrombocytopenia is rare.

  • Hemoglobin: If anemia is severe, and especially if jaundice is present, then hemolytic anemia should be ruled out. Additional labs would include serum total and unconjugated bilirubin, LDH, haptoglobin, and reticulocyte count.

How can mononucleosis be prevented?

  • Infectious mononucleosis can be prevented by limiting oral and sexual contacts, as the most common mode of EBV transmission is contact with saliva. Other methods of prevention include hand washing and avoiding shared utensils or cups within a household.

  • Overall it is difficult for a person to avoid contracting infectious mononucleosis if they are seronegative, as it is shed intermittently from asymptomatic, seropositive hosts throughout life.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Adler-Storthz, KG, Ficarra, Woods, KV. "Prevalence of Epstein-Barr virus and human papillomavirus in oral mucosa of HIV-infected patients". J Oral Pathol Med. vol. 21. 1992. pp. 164-70.

(This is a study examining the presence of EBV DNA in tissue specimens of oral hairy leukoplakia in HIV patients compared to normal buccal mucosa of controls.)

Asgari, MM, Begos, DG. "Spontaneous splenic rupture in infectious mononucleosis: a review". Yale J Biol Med. vol. 70. 1997. pp. 175-82.

(This is a review of splenic rupture and management in the setting of infectious mononucleosis.)

Auwaerter, PG. "Infectious mononucleosis in middle age". J Am Med Assoc. vol. 281. 1999. pp. 5.

(This is a review of infectious mononucleosis focusing on middle age adults.)

Balfour, HH, Hokanson, KM, Schacherer, RM. "A virologic pilot study of valacyclovir in infectious mononucleosis". J Clin Virol. vol. 39. 2007. pp. 16-21.

(This is a small, randomized, controlled but non-blinded trial examining the effect of valacyclovir on the amount of EBV DNA in oral and blood compartments, as well as clinical improvement.)

Bolden, KJ. "Corticosteroids in the treatment of infectious mononucleosis". J Royal College Gen Practitioners. vol. 22. 1972. pp. 87.

(This is a randomized, double-blinded, placebo-controlled trial of 26 university students with infectious mononucleosis.)

Candy, B, Hotopf, M. "Steroids for symptom control in infectious mononucleosis". 2010.

(Cochrane review utilizing seven randomized controlled trials examining treatment with steroids for infectious mononucleosis. It is noted by authors that some of the trials included were of poor quality.)

Crum, NF. "Epstein-Barr virus hepatitis: case series and review". Southern Med J. vol. 99. 2006. pp. 5.

(This is a review of hepatitis in infectious mononucleosis.)

Evens, AM, Roy, R, Sterrenberg, D. "Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy". Curr Oncol Rep. vol. 12. 2010. pp. 383-394.

(This is a general review of PTLD.)

Fafi-Kremer, S, Morand, P, Brion, JP. "Long-term shedding of infectious Epstein-Barr virus after infectious mononucleosis". J Infect Dis. vol. 191. 2005. pp. 985-9.

(This is a small longitudinal study examining the shedding of EBV in the saliva in adults after infectious mononucleosis.)

Henter, JI, Horne, A, Arico, M. "Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis". Pediatric Blood Cancer. vol. 48. 2007. pp. 124-31.

(This is a review of hemophagocytic lymphohistiocytosis with focus on treatment.)

Higgins, CD, Swerdlow, AJ, Macsween, KF. "A study of risk factors for acquisition of Epstein-Barr virus and its subtypes". J Infect Dis. vol. 195. 2007. pp. 474-82.

(This is a retrospective study of approximately 2000 university students looking at risk factors for EBV seropositivity.)

Hinedi, TB, Koff, RS. "Cholestatic hepatitis induced by Epstein-Barr virus infection in an adult". Digestive Dis Sci. vol. 48. 2003. pp. 539-41.

(This is a review of cholestatic hepatitis in infectious mononucleosis, specifically examining six case reports found through review of the literature.)

Hurt, C, Tammaro, D. "Diagnostic evaluation of mononucleosis-like illnesses". Am J Med. vol. 120. 2007. pp. 10.

(This is a review of causes of mononucleosis-like syndromes, covering CMV, HHV-6, acute retroviral syndrome, adenovirus, HSV1, toxoplasma gondii, and strep pyogenes.)

Jenson H.B., MD. "Virologic diagnosis, viral monitoring, and treatment of Epstein-Barr virus infectious mononucleosis". Curr Infect Dis Rep. vol. 6. 2004. pp. 200-7.

(This is a review focusing on virology and diagnosis.)

Kaan, PM, Hegele, RG, Hayashi, S. "Expression of bcl-2 and Epstein-Barr virus LMP1 in lymphocyte interstitial pneumonia". Thorax. vol. 52. 1997. pp. 12-6.

(This is a small study using immunohistochemical analysis of an EBV protein (LMP1) to examine lung tissue from patients with lymphocyte interstitial pneumonia as compared to controls (healthy as well as patients with interstitial pulmonary fibrosis).)

Kano, Y, Shiohara, T. "Current understanding of cytomegalovirus infection in immunocompetent individuals". J Dermatol Sci. vol. 22. 2000. pp. 3.

(This is a review of CMV in immunocompetent individuals.)

Luzuriaga, K, Sullivan, JL. "Infectious mononucleosis". N Engl J Med. vol. 362. 2010. pp. 1993-2000.

(This is a general review of infectious mononucleosis.)

Macsween, KF, Crawford, DH. "Epstein-Barr virus - recent advances". Lancet Infect Dis. vol. 3. 2003. pp. 131-40.

(This is a general review of Epstein-Barr virus.)

McCorkle, R, Thomas, B, Suffaletto, H. "Normative spleen size in tall athletes: implications for safe return to contact sports after infectious mononucleosis". Clin J Sport Med. vol. 20. 2010. pp. 6.

(This is a prospective cohort observational study examining normal spleen size in tall, healthy athletes.)

Naher, H, Gissmann, L, Freese, UK. "Subclinical Epstein-Barr virus infection of both the male and female genital tract - indication for sexual transmission". J Invest Derm. vol. 98. 1992. pp. 791-3.

(This is a study examining the prevalence of EBV DNA by PCR in genital secretions of healthy adults seen at a STI clinic.)

Putukian, M, O'Connor, FG, Stricker, P. "Mononucleosis and athletic participation: an evidence-based subject review". Clin J Sports Med. vol. 18. 2008. pp. 309-15.

(This is a review of infectious mononucleosis with a focus on return to athletics, based on case reports.)

Resnick, L, Herbst, JS, Ablashi, DV. "Regression of oral hairy leukoplakia after orally administered acyclovir therapy". J Am Med Assoc. vol. 259. 1988. pp. 384-8.

(This is a small non-randomized, non-blinded study examining the efficacy of oral acyclovir for the treatment oral hairy leukoplakia in AIDS patients.)

Roy, M, Bailey, B, Amre, DK. "Dexamethasone for the treatment of sore throat in children with suspected infectious mononucleosis". Arch Pediatrics Adolescent Med. vol. 158. 2004. pp. 250-4.

(This is a randomized, double-blind, placebo-controlled trial involving 40 pediatric patients seen in the emergency department examining improvement in sore throat with dexamethasone.)

Steeper, TA, Horwitz, CA, Moore, SB. "Severe thrombocytopenia in Epstein-Barr virus-induced mononucleosis". Western J Med. vol. 150. 1989. pp. 170-3.

(This is a review of case reports in the literature of severe thrombocytopenia due to infectious mononucleosis.)

Stephenson, JT, DuBois, JJ. "Non-operative management of spontaneous splenic rupture in infectious mononucleosis: a case report and review of the literature". Pediatrics. vol. 120. 2007. pp. 432-5.

(This is a literature review of non-operative management of splenic rupture, examining mostly case reports.)

Taylor, GH. "Cytomegalovirus". Am Fam Physician. vol. 67. 2003. pp. 3.

(This is a general review of CMV.)

Thacker, EL, Mirzaei, F, Ascherio, A. "Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis". Ann Neurol. vol. 59. 2006. pp. 499-503.

(This is a meta-analysis involving 11 case control and 3 cohort studies examining the link between multiple sclerosis and infectious mononucleosis. Results must be viewed with caution, as this meta-analysis is based on cohort and case controls, as RCTs do not exist. The authors note that many studies assess for a history of infectious mononucleosis using questionnaires, therefore, recall bias is potentially a factor.)

Torre, D, Tambini, R. "Acyclovir for treatment of infectious mononucleosis: a meta-analysis". Scandinavian J Infect Dis. vol. 31. 1999. pp. 543-47.

(This is a meta-analysis utilizing five double-blinded, placebo, randomized controlled trials examining acyclovir treatment of infectious mononucleosis.)

Van der Horst, C, Joncas, J, Ahronheim, G. "Lack of effect of peroral acyclovir for the treatment of acute infectious mononucleosis". J Infect Dis. vol. 164. 1991. pp. 788-92.

(This is a multicenter, randomized double-blinded, placebo-controlled study of 120 patients examining the effect of oral acyclovir on the clinical characteristics, including time to resolution of symptoms.)

Vetsika, E.K., Callan, M. "Infectious mononucleosis and Epstein-Barr virus". Exp Rev Mol Med. vol. 6. 2004. pp. 123.

(This is a general review of infectious mononucleosis.)

DRG CODES and expected length of stay

DRG code

DRG code for infectious mononucleosis is 075

Related DRG codes

DRG code for acute pharyngitis is 462

DRG code for lymphadenopathy is 785.6

The vast majority of patients with infectious mononucleosis do not require admission to the hospital. Reasons for admission may include severe complications (e.g., splenic rupture, severe hepatitis, etc.), and, in these cases, admission length could vary considerably based on the specific complication.

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