A 19-year-old student presents to the university health center with several days of fever, sore throat, malaise, and a rash that developed today. She first started feeling ill 10 days ago with general malaise, headache, and nausea. Four days ago she developed a temperature of 103°F (39.4°C) that has persisted. She has worsening sore throat and difficulty swallowing solid foods; she is drinking well. She denies emesis, diarrhea, or sick contacts. She takes an oral contraceptive daily and took two doses of ampicillin yesterday (left over from a prior illness). On examination, she is well developed with a diffuse morbilliform rash. She appears tired but in no distress. Her temperature is 102.2° F (39°C). She has mild supraorbital edema; bilaterally enlarged tonsils that are coated with a shaggy gray exudate; a few petechiae on the palate and uvula; bilateral posterior cervical lymphadenopathy; and a spleen that is palpable 3 cm below the costal margin. Laboratory data include a white blood cell (WBC) count of 17,000 cells/mm3 with 50% lymphocytes, 15% atypical lymphocytes, and platelet count of 100,000/mm3.
What is the most likely diagnosis?
What is the best study to quickly confirm this diagnosis?
What is the best management for this condition?
What is the expected course of this condition?
ANSWERS TO CASE 37: Acute Epstein-Barr Viral Infection (Infectious Mononucleosis)
Summary: A female college student has 10 days of malaise, headache, and nausea. She now has a fever, sore throat, and morbilliform rash after taking ampicillin. Her examination reveals a fever, rash, tonsillar hypertrophy with exudate, posterior cervical lymphadenopathy, and splenomegaly. She has an elevated WBC count with a lymphocytic predominance, and a mild thrombocytopenia.
• Most likely diagnosis: Epstein-Barr virus (EBV) infection (infectious mononucleosis).
• Best study: Assay for heterophil antibodies (Monospot).
• Best management: Symptomatic care, avoidance of contact sports while the spleen is enlarged (usually 1-3 months).
• Expected course: Acute illness lasts 2 to 4 weeks, with gradual recovery; splenic rupture is a rare but potentially fatal complication. Rarely, some patients have persistent fatigue.
1. Describe the presenting signs and symptoms of acute EBV infection.
2. Contrast EBV infection symptoms in young children with those in adolescents and adults.
3. List potential complications of acute EBV infection.
This case is typical for adolescents with primary EBV infection, although supraorbital edema occurs in only 10% to 20% of patients. Differential diagnosis includes group A β-hemolytic streptococcal pharyngitis, but it typically does not have a prodrome similar to this case or cause splenomegaly. Acute cytomegalovirus (CMV) infection is another possibility; similarities include splenomegaly, fever, and atypical lymphocytosis, but exudative sore throat and posterior cervical lymphadenopathy occur less frequently. Although the patient denied recent ill contacts, EBV infection has a 30- to 50-day incubation; further questioning revealed that her boyfriend had similar symptoms 6 weeks ago. Rash is seen less commonly in adolescents with EBV, but many patients develop a morbilliform rash in response to ampicillin, amoxicillin, or penicillin.
EPSTEIN-BARR VIRUS (EBV): A double-stranded DNA herpes virus that infects human oropharyngeal and salivary tissues and B lymphocytes. It can cause persistent viral shedding, is associated with oral hairy leukoplakia in HIV-infected adults and lymphoid interstitial pneumonitis in HIV-infected children, and causes several malignancies.
INFECTIOUS MONONUCLEOSIS: The typical EBV presentation in older children and adolescents. Fever, posterior cervical adenopathy, and sore throat are seen in more than 80% of cases.
EBV is ubiquitous in humans. In developing nations, infection occurs in almost all children by 6 years of age. In the industrialized world, about half of adolescents have serologic evidence of previous EBV infection; 10% to 15% of previously uninfected college students seroconvert each year. The virus is excreted in saliva; infection results from mucosal contact with an infected individual or from contact with a contaminated fomite. Shedding of Epstein-Barr virus in the saliva after an acute infection can continue for more than 6 months, and occurs intermittently thereafter for life.
After an infection occurs, EBV replicates in the oropharyngeal epithelium and later in the B lymphocytes. A prodromal period may last for 1 to 2 weeks, with vague findings of fever, nausea, malaise, headache, sore throat, and abdominal pain. The sore throat and fever gradually worsen and frequently cause a patient to seek medical help. Physical findings during an acute infection may include generalized lymph-adenopathy, splenomegaly, and tonsillar enlargement with exudate. Less common findings include a rash and hepatomegaly.
Primary EBV infection presents as typical infectious mononucleosis in older children and adults, but this presentation is less common in young children and infants. In small children, many infections are asymptomatic. In others, fever may be the only presenting sign. Additional acute findings in small children include otitis media, abdominal pain, and diarrhea. Hepatomegaly and rash are seen more often in small children than in older individuals.
The Monospot is a useful diagnostic test in children older than approximately 5 years; the results are unreliable in younger children. Early in the illness the Monospot may be falsely negative. More definitive testing includes assays of EBV viral capsid antigen (EBV-VCA), early antigen (EA), and Epstein-Barr nuclear antigen (EBNA). Typically, immunoglobulin (Ig) G and IgM antibodies to EBV-VCA appear first. Anti-EBNA antibodies appear 1 to 2 months following infection and persist for years. Anti-EA antibodies are seen in most children during acute infection and persist for years in approximately one-third of patients. VCA-IgG and EBNA-IgG antibodies indicate past infection. EBV polymerase chain reaction (PCR) is also commercially available, and is distinguished from the above studies by testing for antigen rather than antibody. Other laboratory findings include a lymphocytic leukocytosis, with approximately 20% to 40% atypical lymphocytes. Mild thrombocytopenia is common, only rarely precipitating bleeding or purpura. More than half of patients with EBV infection develop mildly elevated liver function tests, but jaundice is uncommon.
Infection complications are rare but can be life-threatening. Neurologic sequelae include Bell palsy, seizures, aseptic meningitis or encephalitis, Guillain-Barré syndrome, optic neuritis, and transverse myelitis. Parotitis, orchitis, or pancreatitis may develop. Airway compromise may result from tonsillar hypertrophy; treatment may include steroids. Splenomegaly is seen in approximately half of those with infectious mononucleosis; rupture is rare, but the blood loss is life-threatening.
Typical infectious mononucleosis requires only rest. Strict bed rest is not useful except for patients with debilitating fatigue. Children with splenomegaly should avoid contact sports to prevent splenic rupture until the enlargement resolves. Acyclovir, which is effective in slowing viral replication, does not affect disease severity or outcome.
Epstein-Barr virus initially was identified from Burkitt lymphoma tumor cells and was the first virus associated with human malignancy. Other associated malignancies include Hodgkin disease, nasopharyngeal carcinoma, and lymphoproliferative disorders. Epstein-Barr virus can stimulate hemophagocytic syndrome. HIV-infected patients may develop oral hairy leukoplakia, smooth muscle tumors, and lymphoid interstitial pneumonitis with EBV infection.
37.1 A 17-year-old adolescent male has left shoulder and left upper quadrant abdominal tenderness and vomiting. He reports having “mono” last month but says he is completely recovered. He was playing flag football with friends when the pain started an hour ago. On examination, his heart rate is 150 bpm and his blood pressure is 80/50 mm Hg. He is pale, weak, and seems disoriented. He has diffuse rebound abdominal tenderness. Emergent management includes which of the following?
A. Laparoscopic appendectomy
B. Fluid resuscitation and blood transfusion
C. Intravenous antibiotics
D. Hospital admission for observation
E. Synchronized cardioversion for supraventricular tachycardia
37.2 You are in a small town practicing pediatrics and have been asked to see a 2-year-old boy in consultation. His general practice doctor admitted him to the hospital 2 days ago because of 3 days of fever. He has generalized lymph-adenopathy but is otherwise well. Results of Monospot, HIV testing, and CMV antigen tests are negative; his liver function test values are mildly elevated. His physician diagnosed the boy’s 7-year-old sibling with “mono” the month prior. You should suggest which of the following?
A. Start intravenous immunoglobulin and obtain an echocardiogram; the patient likely has Kawasaki disease.
B. Send an EBV culture for confirmation of the physician’s suspicions.
C. Acyclovir treatment because he has an exposure history positive for EBV.
D. Obtain EBV-VCA IgG and IgM, EBV-EA, and EBV-NA tests.
E. Liver imaging with ultrasonography or computed tomography.
37.3 The mother of a 15-year-old adolescent female recently diagnosed with infectious mononucleosis calls for more information. She reports that her daughter, although tired, seems comfortable and is recovering nicely. She remembers that her 20-year-old son had “mono” when he was 10 years old, and he received an oral medicine. She requests the same medication for her daughter. Which of the following is the most appropriate course of action?
A. Explain that medications are not routinely used in EBV infection.
B. Call the pharmacy and order oral prednisone 50 mg daily for 5 days (1 mg/kg/d).
C. Call the pharmacy and order oral acyclovir 250 mg four times per day (20 mg/kg/d).
D. Have her come to the clinic for a single dose of 50 mg intravenous methylprednisolone (1 mg/kg).
E. Call the pharmacy and order oral amoxicillin 250 mg three times per day for 7 days.
37.4 A teenage boy arrives for a check-up. His friend recently was diagnosed with mononucleosis. He is worried he will contract it. Which of the following is true regarding transmission of EBV?
A. It is common among casual friends.
B. It occurs only in immunodeficient individuals.
C. It requires close contact with saliva (ie, kissing or drinking from the same cup).
D. It is passed only through sexual contact with an infected individual.
E. It does not occur after the infected person recovers from the initial infection.
37.1 B. The patient described is in hypovolemic shock and likely has splenic rupture with intraperitoneal bleeding. He will die shortly if not aggressively resuscitated with fluids and blood. Evaluation by a surgeon for potential removal of the ruptured spleen should follow quickly.
37.2 D. The Monospot heterophil antibody test, useful in older children, is not so reliable in younger children. Antibodies against specific EBV antigens are more helpful in this age group. No imaging study is diagnostic for EBV, and acyclovir is not indicated for EBV exposure. EBV culture is not readily available except in reference laboratories; the antibody studies described above typically are adequate to make the diagnosis. While Kawasaki disease must be considered in patients with persistent fever, the exposure history makes EBV more likely.
37.3 A. Supportive care alone usually is required for a patient with acute EBV infection. Steroids have been used historically; current literature suggests their use only in impending airway compromise due to tonsillar hypertrophy or other life-threatening complications. Acyclovir suppresses viral shedding acutely but has no long-term benefit and is not routinely recommended. Amoxicillin and ampicillin are ineffective antiviral medications and induce a rash in some EBV-infected patients.
37.4 C. EBV is excreted in saliva and is transmitted through mucosal contact with an infected individual (as in kissing) or through a contaminated object. Virus is shed for a prolonged period after symptoms resolve and is intermittently reactivated and shed for years asymptomatically.
Most adults show evidence of past Epstein-Barr virus infection; it is a common infection worldwide.
Children in industrialized nations usually are infected with EBV infection later in life than are children in developing countries.
Diagnosis of Epstein-Barr virus infection in young children is best achieved by specific antibody assays.
Infectious mononucleosis is self-limited and usually does not require treatment. Occasional complications of Epstein-Barr virus infection may require steroid administration.
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