Traci Alberti Infectious mononucleosis (IM) is an acute, self-limited, generally benign illness that occurs in both children and adults after primary infection with Epstein-Barr virus (EBV), cytomegalovirus (CMV), and other infectious agents. The classic manifestation of this syndrome includes fever, pharyngitis, lymphadenopathy, fatigue, and atypical lymphocytosis.1 In this chapter, the term Epstein-Barr virus–associated infectious mononucleosis (EBV-IM) is used to refer to IM caused by acute EBV infection. The term non–Epstein-Barr virus–associated infectious mononucleosis (non-EBV-IM) is used to refer to the clinical syndrome of IM that is caused by an agent other than EBV, such as CMV, Toxoplasma gondii, adenovirus, or hepatitis virus infection.1 Non-EBV-IM illnesses account for approximately 10% of all IM cases. IM refers to the triad of fever, pharyngitis, and lymphadenopathy regardless of the infectious agent. This chapter deals primarily with the presentation, evaluation, and management of EBV-IM, the most common type of acute IM, which is seen, at least serologically, in 20% to 70% of adolescents and young adults.2 EBV-IM occurs most often in adolescents and young adults, with the highest incidence occurring at ages 15 to 19 years In persons younger than 10 years and older than 30 years, the annual incidence of EBV-IM decreases dramatically to less than 1 case per 1000 persons, but mild infection in young adults may be underdiagnosed. It is most common in populations with many young adults, such as active-duty military personnel and college students, in whom the annual incidence ranges from 11 to 48 cases per 1000.1 The chance for development of IM after EBV infection appears to increase from childhood to young adulthood; it is estimated that less than 10% of children develop IM after EBV exposure, but up to 78% of adolescents have a chance for development of EBV-IM after acute EBV infection.3 IM is relatively uncommon in adults, accounting for less than 2% of adults who see their health care provider with a sore throat.3 IM can be caused by a variety of infectious agents other than EBV, including CMV, herpesvirus 6, human immunodeficiency virus (HIV), adenovirus, hepatitis A virus, influenza A and B viruses, and rubella virus.4 In addition, IM is also associated with some neoplasms. Transmission of IM varies, depending on the specific causative infectious agent. Transmission of EBV-IM occurs through exposure to oropharyngeal secretions, although blood products, genital secretions, and breast milk have also been reported as sources of transmission.4 EBV is a relatively fragile DNA herpesvirus that cannot survive for long outside the host. The virus initially infects the oral epithelial cells and then spreads to the B lymphocytes, which then circulate through the reticuloendothelial system, causing a significant but time-limited immunologic response. Many of the signs and symptoms associated with the clinical presentation of EBV-IM are the result of this immunologic response. The incubation time of EBV-IM is usually 4 to 8 weeks. Hepatic involvement associated with EBV-IM varies in severity and increases with age, ranging from 10% in young adults to 30% in older adults.3 Acute EBV infection stimulates the production of antibodies against EBV antigens, which remain present lifelong. The classic triad of symptoms of acute IM includes fever, pharyngitis, and lymphadenopathy. The typical adolescent with EBV-IM is seen with sore throat, fever, and lymph node and tonsillar enlargement. Additional common presenting symptoms include pharyngeal inflammation and transient palatal petechiae. Older adults are less likely to have sore throat and adenopathy but more likely to have hepatomegaly and jaundice.1 However, IM often manifests atypically, especially in young children and older adults, making diagnosis difficult. Pharyngitis is usually diffuse, with exudates present in approximately 30% of cases.5 Lymphadenopathy usually affects the anterior and posterior cervical chain and may also be diffuse. Temperatures may be as high as 40° C (104° F), and the elevation may last as long as 2 weeks. Symptoms that may precede as well as persist throughout the acute phase of illness include malaise, anorexia, and fatigue. Symptoms of EBV-IM usually peak approximately 7 days after onset and become less pronounced during the next 1 to 3 weeks. Fatigue can persist for several months. Reports indicate that splenic enlargement occurs in 40% to 100% of cases and can be confirmed with ultrasound.1,2 Less common signs and symptoms of EBV-IM include upper airway compromise, abdominal pain, rash, hepatomegaly, jaundice, and eyelid edema. A rash, which occurs in approximately 5% to 10% of individuals, may be macular, urticarial, petechial, or erythema multiforme.6 On physical examination, the patient may or may not appear ill, depending on degree of fever, associated signs and symptoms, and length of time since onset of symptoms. The classic clinical manifestation of fever, pharyngitis, and lymphadenopathy raises suspicion for EBV-IM. The anterior and posterior cervical chains should be assessed for lymphadenopathy, which may be diffuse. An abdominal examination identifies splenomegaly and hepatomegaly. Rash and jaundice should be noted because they are associated with EBV-IM, especially in older adults. A complete blood count (CBC) with differential will help identify absolute lymphocytosis, wherein more than 10% of cells are atypical. This is characteristic of IM, but not specific. The most useful laboratory test is the serologic test for heterophil antibodies. This will identify 85% of cases in older children and adults. It is possible for some infected persons to have a negative test result early in the illness, because circulating antibodies have not reached sufficient detectable levels. Repeat testing in 7 to 10 days is recommended if symptoms continue.7 A positive test result may remain positive for up to a year after initial illness. Absolute lymphocytosis with a positive heterophil antibody test is diagnostic of acute infectious mononucleosis. If the heterophil antibody test result is negative but EBV-IM is still highly suspected, further testing may be helpful. More sensitive tests have been developed that detect viral capsid antigen (VCA) immunoglobulins G (IgG) and M (IgM). When the results are negative, these tests are better than heterophil antibody tests in ruling out EBV-IM because they are better able to detect acute infection; but when the results are positive, the tests are similar in their ability to rule in disease.5,8 VCA IgG and IgM results typically become positive within 1 to 2 weeks of infection, but VCA IgM becomes undetectable after 6 months. Antibody to Epstein-Barr nuclear antigen (EBNA) is not usually detectable until 6 to 8 weeks after the onset of symptoms but can help distinguish between acute and previous infections. If EBNA is positive in the presence of acute symptoms and suspected IM, then previous infection is suggested. A throat culture should be considered because 3% to 30% of patients with IM also have streptococcal pharyngitis. Liver function tests (LFTs) may also be considered; liver enzymes are elevated in approximately 80% to 90% of persons with IM.1 Diagnostics Infectious Mononucleosis
Infectious Mononucleosis
Definition and Epidemiology
Pathophysiology
Clinical Presentation
Physical Examination
Diagnostics
Infectious Mononucleosis
Chapter 233
