Finding a distinctive set of clinical and non-specialized laboratory abnormalities is usually sufficient to make the EBV IM diagnosis (Table 185.2). The EBV IM diagnosis is highly likely in persons presenting with the clinical triad of fever, pharyngitis, and cervical lymphadenopathy; absolute peripheral lymphocytosis; atypical lymphocytosis that is >10% of the differential; and heterophile antibodies. As these criteria are relaxed, the probability of EBV causing the mononucleosis (mono)-like syndrome decreases accordingly. Conversely, failure to fulfill these criteria does not rule out EBV. Heterophile antibody is not detected in approximately 5% to 20% of EBV IM cases and might not become detectable until later in the illness. Atypical lymphocytosis may not peak until later in the illness. Unusual clinical presentations are more likely to occur in infants, young children, older adults, and immunosuppressed persons.

Malaise and fatigue are often prominent IM symptoms, may take more time to resolve than other symptoms, and tend to linger for longer periods in patients having higher severity of acute illness. Convalescence for fatigue and impaired functional status occasionally drags out to 6 months after the acute illness, but this is neither the result of EBV activity nor marked by abnormal physical examination, serological, or laboratory findings. In a recent study, sore throat was the most common IM symptom in young adults. Mild retro-orbital headache is common and short-lived. Upper respiratory tract symptoms may also be present.

Fever in the range of 38°C to 39.5°C (+/− sweats and chills) is common, subsides in 1 to 2 weeks, and rarely persists for up to 4 weeks. Fever above 40°C should prompt a search for superimposed bacterial infection (i.e., bacterial pharyngitis or peritonsillar abscess). Exudative tonsillopharyngitis is a common finding in EBV IM and usually resolves in the first 2 weeks of illness. Petechiae may appear on the uvula and at the junction of soft and hard palates. Symmetric posterior cervical lymphadenopathy elevates IM in the differential diagnosis, whereas anterior cervical lymphadenopathy has many potential etiologies. EBV IM-related lymphadenopathy may take several weeks to resolve. Splenomegaly is common. Mild abdominal discomfort may be present. Severe abdominal pain or left upper quadrant abdominal pain radiating to the left shoulder raises concern of splenic rupture or infarction. Biochemical findings of mild-to-moderate hepatitis are common, though transaminase levels >500 IU/L and jaundice are possible. Rash is infrequent in adolescents and adults; it typically appears as a faint morbilliform eruption. Peripheral blood lymphocytosis often peaks during the second or third week of illness. Mild neutropenia and thrombocytopenia are common.

In elderly persons, the illness of primary EBV infection is less likely to include pharyngitis, lymphadenopathy, splenomegaly, and atypical lymphocytosis, and is more likely to have unusual features, i.e., jaundice or prolonged febrile course. Infants and young children are more likely to have a heterophile-negative illness with coryza, exudative pharyngitis, rash, and hepatosplenomegaly.

Complications

Approximately 1% of persons with EBV IM experience a complication. Various types of complications are possible (Table 185.3). In some cases, the complication overshadows the other IM features or is not accompanied by typical IM symptoms or signs. Most complications resolve without sequelae. Rare fatalities have resulted from encephalitis, splenic rupture, hepatic failure, myocarditis, or neutropenia-associated sepsis. Impending airway obstruction results from tonsillar lymphoid hyperplasia and edema. Enlarged spleens are susceptible to traumatic rupture; spontaneous rupture or infarction is rare. Hemolytic anemia, thrombocytopenia, or neutropenia may develop in relation to autoantibody production. Cytopenia is usually self-limiting. Aplastic anemia and hemophagocytic syndrome are rare life-threatening complications. Neurologic complications take on forms of encephalitis, cerebellitis, meningitis, optic neuritis, peripheral neuritis, facial nerve palsy, and Guillain–Barré syndrome.

EBV IM may evolve into a life-threatening lymphoproliferative disorder in persons with profound acquired or congenital cellular immunodeficiency. In a rare inherited disease, the X-linked lymphoproliferative syndrome, young males develop fulminant EBV IM. Many die of hemorrhage and infection; survivors have aplastic anemia, dysgammaglobulinemia, and lymphoma. EBV very rarely causes chronic active infection that results in interstitial pneumonitis, massive lymphadenopathy, hepatosplenomegaly, bone marrow failure, dysgammaglobulinemia, Guillain–Barré syndrome, and uveitis. These patients have high EBV burden in blood or tissues, as well as very high titers of EBV-specific antibodies. Chronic fatigue syndrome is not driven by EBV, but does rarely follow an acute EBV IM episode.

Laboratory testing

Serum heterophile IgM antibodies of the Paul–Bunnell–Davidsohn type are a reliable proxy indicator of EBV IM. These antibodies are distinguished from Forssman and serum sickness heterophile antibodies (that also bind to animal red blood cell components), may not be detected until the second or third week of illness, and fade away in 3 to 6 months. Their levels do not correlate with severity of illness. Contemporary methods of standard, automated, and point-of-care heterophile antibody testing rarely find presence of these antibodies in sera of patients with other clinical conditions, i.e., viral hepatitis, primary human immunodeficiency virus (HIV) infection, malaria, babesiosis, and lymphoma.

EBV-specific antibody testing is performed when key features of IM are lacking or atypical. Measurement of antibodies against viral capsid antigen (anti-VCA) and EBV nuclear antigens (anti-EBNA) in immunocompetent persons is usually sufficient to provide the results needed to confirm or reject the diagnosis of primary EBV infection. Detection of anti-VCA IgM, which is present in 85% to 95% of IM cases, substantiates the diagnosis. Anti-VCA IgM fades away in weeks to months after the acute illness. Anti-VCA IgG seroconversion from negative to positive detection in acute illness and convalescence, respectively, is confirmation of the diagnosis. However, anti-VCA IgG seroconversion is an infrequent finding, because anti-VCA IgG is often near peak level during the acute illness. Anti-VCA IgG persists for life. Undetectable levels of anti-EBNA antibodies in conjunction with presence of anti-VCA IgM or IgG also marks a primary EBV infection. Anti-EBNA antibodies usually become detectable in convalescence and persist for life.

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