OVERVIEW: What every practitioner needs to know
Are you sure your patient has Epstein-Barr virus infection? What are the typical findings for this disease?
Infectious mononucleosis (IM) usually consists of a classic triad of fever, sore throat/pharyngitis, and lymphadenopathy (often bilateral cervical). Other common signs and symptoms include fatigue, hepatosplenomegaly, jaundice, rash, headache, and malaise. The monospot (heterophile) assay usually produces positive results, especially in adolescents and young adults.
Aside from the complications that can occur in normal children (see below), there are patients with either known or suspected immunodeficiencies who experience a more severe form of disease, usually after primary infection with Epstein-Barr virus (EBV). The major known immune deficiencies recognized in patients who go on to manifest these more severe forms of EBV infection include transplant recipients, patients with HIV infection (although with modern combination antiretroviral therapy these are now fortunately quite rare), and patients with known genetic disorders (e.g., X-linked lymphoproliferative disease or perforin deficiency).
The pathophysiology involved is usually related to either an inability to limit the primary EBV infection, an overexuberant immunologic response to the virus or defective apoptosis. Manifestations of EBV infection in these patients include fatal IM, lymphoma, pneumonitis, hemophagocytic syndrome, and bone marow insufficiency.
What other disease/condition shares some of these symptoms?
EBV causes nearly all cases of heterophile antibody–positive IM and about half of all cases of heterophile antibody–negative IM. Other causes of heterophile antibody–negative mononucleosis syndromes include cytomegalovirus, toxoplasmosis, HIV (in the presence of risk factors) , hepatitis A and B, adenovirus, human herpesviruses 6, 7, and 8, and rubella.
What caused this disease to develop at this time?
Mononucleosis usually develops in adolescents and young adults who have escaped primary EBV infection when younger. Thus it is seen mainly in individuals belonging to higher socioeconomic groups in developed countries.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
The complete blood count will often show greater than 10% atypical lymphocytes in older adolescents and adults. The heterophile antibody test (monospot) is the most common test used to diagnose IM. In the right clinical setting, it is very specific (90%-98% in most studies) and fairly sensitive (about 90%). It is less sensitive in younger children.
In doubtful cases, specific EBV serologic tests can be performed; primary EBV infection is usually diagnosed with either a positive IgM viral capsid antibody titer alone or a positive IgG viral capsid antibody titer in the presence of a negative result on convalescent antibody testing (Epstein-Barr nuclear antigen [EBNA]). Polymerase chain reaction (PCR) testing of blood is not indicated for the usual case of mononucleosis in an otherwise healthy host.
Would imaging studies be helpful? If so, which ones?
No imaging studies are useful.
If you are able to confirm that the patient has Epstein-Barr infection, what treatment should be initiated?
IM is a self-limited disease, and therefore treatment is usually supportive. Bed rest, acetaminophen, and saline gargles are usually prescribed acutely for the fatigue, fever, and sore throat. In severe cases, an opioid may be required. Up to 20%-30% of adolescents and young adults who seek care for IM are prescribed steroids, although a recent Cochrane review concluded that there was insufficient evidence to recommend their use. Steroids may be useful, however, for treating serious complications of IM such as airway obstruction or thrombocytopenic purpura.
Antiherpes viral agents, which have only limited activity against EBV (acyclovir, valacyclovir, gancyclovir, and valganciclovir) have not been shown to be of clinical benefit in most cases of IM; in cases of severe complications (e.g., encephalitis in an otherwise normal host) or in an immunocompromised host, these drugs are often used based on anecdotal data.
What are the adverse effects associated with each treatment option?
There are reports of neurologic complications and secondary bacterial infections after the use of steroids to treat IM in the otherwise normal host. Gancyclovir and valganciclovir can be nephrotoxic.
If antibiotics (usually amoxacillin) are used to treat the pharyngitis, usually because it is mistaken for group A streptococcal pharyngitis, a rash (usually maculopapular) will develop in up to 50% of patients.
What are the possible outcomes of Epstein-Barr virus infection?
The prognosis of IM is usually excellent. Neurologic complications (e.g., asceptic meningitis, encephalitis, Guillain-Barre syndrome, optic neuritis, cranial nerve palsies, transverse myelitis, or acute cerebellar ataxia) can occur in 1%-5% of patients, either in isolation or as part of the clinical syndrome of IM. Hematologic complications, which are usually mild, can occur in up to 25% of patients and most commonly include thrombocytopenic purpura or hemolytic anemia.
Myocarditis, genital ulcers, and other complications have been reported. Airway compromise from massive lymphadenopathy is rare. Death after IM is extremely rare. From 1932-1970, only 20 well-documented deaths were attributable to IM, and their causes, in decreasing order of frequency, were neurologic, secondary infections, splenic rupture, hepatic failure, and myocarditis.
What causes this disease and how frequent is it?
The epidemiology of primary EBV infection must be distinguished from that of IM, its most common symptomatic manifestation. In developing countries and in lower socioeconomic groups of industrialized nations, up to 90% of children contract EBV infection by age 8 years. In contrast, in higher socioeconomic groups, 30%-75% of adolescents are EBV seronegative.
Young children who acquire primary EBV infection usually do so asymptomatically, or with only mild, nonspecific symptoms. In contrast, 1%-5% of susceptible adolescents and adults contract EBV infection annually, and about half manifest symptomatic IM. The annual incidence of IM in the United States is about 500/100,000 individuals; the peak ages affected are 15-24 years of age.
EBV is shed in oropharyngeal secretions during acute infection and intermittently thereafter; these secretions are the major source of infectious virus. Infection is usually transmitted through close personal contact, such as parents kissing their children or toddlers sharing toys. EBV may also be contracted sexually. Infection is only modestly communicable and secondary attack rates are low. Rarely, transmission of EBV through blood transfusion has been documented.
How do these pathogens/genes/exposures cause the disease?
It is thought that the more robust immune system of the adolescent or young adult is necessary for primary EBV infection to manifest as acute IM.
What complications might you expect from the disease or treatment of the disease?
Splenic rupture: Moderate enlargement of the spleen occurs in about 20% of patients with IM between the second and third weeks of illness and is usually asymptomatic. Once splenomegaly is detected, repeated examination of the spleen should be avoided because of the rare possibility of precipitating splenic rupture, which can lead to hemorrhage, shock, or death. Spontaneous, atraumatic splenic rupture occurs in at most 1/500-1/1600 cases of IM. Most cases of splenic rupture occur within 3 weeks of the diagnosis of IM, although it can occur as long as 7 weeks after.
Liver disease: Moderately elevated levels of hepatic transaminases are found in more than 65% of patients with IM, hepatomegaly is present in 10%-35%, and hyperbilirubinemia in up to 25%, yet jaundice develops in less than 5% of patients and is usually mild; direct hyperbilirubinemia is typical. Hepatitis may be associated with anorexia, nausea, and vomiting.
Rash: The incidence of dermatitis in IM ranges from 3%-19%, and the rash is usually located on the trunk and arms; rarely, palmar dermatitis occurs. The rash appears during the first few days of illness, lasts 1-6 days, and can be erythematous, macular, papular, or morbilliform; occasionally urticarial or scarlatiniform; and rarely, petechial, vesicular, umbilicated, or hemorrhagic. A rash will also develop in about half of patients given certain antibiotics (see above).
Pulmonary manifestations: Paroxysmal cough and radiographic findings of patchy alveolar and interstitial pneumonia develop in a small percentage of patients. Pleural effusion (and ascites) can also occur.
Hematologic Manifestations: During the first week of illness, leukopenia or leukocytosis can be so prominent that leukemia is suspected. Rare hematologic complications include aplastic anemia, agranulocytosis, agammaglobulinemia, hemolytic uremic syndrome, and disseminated intravascular coagulation.
Miscellaneous Manifestations: Unilateral or bilateral orchitis can be seen. Renal complications include interstitial nephritis, acute renal failure, and glomerulonephritis. Electrocardiographic abnormalities, as well as pericarditis and myocarditis, have been reported. Endocrinopathies include thyroiditis and polyglandular syndrome. Arthritis, pancreatitis, proctitis, ocular involvement, genital ulcerations, necrotizing epiglottitis, cholecystitis, extrahepatic biliary obstruction, and hydrops of the gallbladder have also been reported.
Are additional laboratory studies available; even some that are not widely available?
Replicating EBV can be detected by the virus’ ability to immortalize cultured lymphocytes from an EBV-seronegative individual. These EBV-naive cells (usually umbilical cord blood lymphocytes) are exposed to saliva, peripheral blood, or lymph nodes from an infected individual, and if they become immortalized, undergo lymphoblastoid transformation, which is scored by light microscopy. This immortalization assay is time-consuming (6-8 weeks), and requires specialized tissue culture facilities.
Viral antigens representative of the latent life cycle of EBV (e.g., EBNA) can be found in infected tissue. These antigens are usually detected microscopically by immunofluorescence or immunoperoxidase staining, or by Western blot or immunoblotting of proteins.
The most specific method for demonstrating EBV in pathologic material is nucleic acid hybridization. Two techniques are currently used: (1) in situ hybridization, which identifies the cells that contain EBV nucleic acid and (2) PCR, which amplifies a segment of DNA. PCR is generally more sensitive than immortalization assays.
In many cases of acute infection, EBV DNA can be detected in blood by PCR. EBV DNA loads in the blood correlate with severity of disease; median amounts of EBV DNA in the blood during acute IM are 103-104 genome copies/mL. In situ hybridization is a specific and sensitive technique for detecting EBV-infected cells in pathologic specimens; often the number and type of infected cells can also be determined.
How can Epstein-Barr virus infection be prevented?
There is no available vaccine or drug that can reliably prevent infection with EBV. In certain rare situations it may be desirable to prevent EBV infection in a compromised host, in which case monthly infusions of intravenous immunoglobulin can be considered.
Because the virus is ubiquitous, there are no behavioral means that can be used to prevent infection.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has Epstein-Barr virus infection? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- If you are able to confirm that the patient has Epstein-Barr infection, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of Epstein-Barr virus infection?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can Epstein-Barr virus infection be prevented?