Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 18-1

Seventeen-Year-Old Girl

SAMIR S. SHAH

HISTORY OF PRESENT ILLNESS

A 17-year-old girl presented to the emergency department after her second episode of passing out in a week. The first episode happened 7 days ago while she was walking home from school. She experienced a prodromal period of everything around her blackening and then awoke on the sidewalk with her friends around her. Her friends took her home that day. The next episode occurred shortly prior to presentation. She had just finished dinner and was walking into another room when a similar episode of darkening occurred and then she awoke on the floor. On review of systems, she was found to have had occasional episodes of shaking chills, tactile temperatures, and a 5-lb weight loss during a 2-week period. She was a senior in high school and planning on going to college. She was sexually active, but used protection every time. Her last menstrual period, which occurred 1 week ago, was normal.

MEDICAL HISTORY

The girl has been a healthy child and had never been hospitalized. She has three brothers who are also healthy. Her immunizations were up-to-date, including the human papilloma virus vaccine.

PHYSICAL EXAMINATION

T 38.2°C; HR 90 bpm; RR 20/min; BP 95/58 mmHg

Weight 75th percentile and Height 20th percentile

On examination she was alert and cooperative in no distress. She did not appear pale. Her head and neck examination was normal. Her lungs were clear to auscultation. Her cardiac examination was normal. Her abdomen was soft and there was no organomegaly or masses detected. Her neurologic examination was normal. Her skin examination revealed rashes all over her body (Figure 18-1).

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FIGURE 18-1. Photo of patient’s rash.

DIAGNOSTIC STUDIES

A complete blood count revealed a WBC count of 12 000 cells/mm3 (6% bands, 30% segmented neutrophils, 42% lymphocytes, 19% atypical lymphocytes, 3% monocytes), hemoglobin of 12.2 g/dL, and a platelet count of 14 000/mm3.

COURSE OF ILLNESS

She was admitted to the hospital for further evaluation. Due to the thrombocytopenia, fever, and weight loss, a bone marrow aspirate was performed.

DISCUSSION CASE 18-1

DIFFERENTIAL DIAGNOSIS

The presence of intermittent fever, petechial rash, thrombocytopenia, and 5-lb weight loss raise concern for neoplastic disorders, such as leukemia or lymphoma. Blast forms on peripheral smear are occasionally mistaken for atypical lymphocytes. However, they are also a marker for a potential Epstein-Barr virus (EBV) infection. More broadly, thrombocytopenia may be caused by increased platelet destruction or consumption or by impaired or ineffective platelet production. Infectious causes of platelet destruction include EBV, cytomegalovirus, human immunodeficiency virus, hepatitis B or C, toxoplasmosis, leptospirosis, syphilis, rickettsioses (e.g., Rocky Mountain spotted fever, ehrlichiosis, human granulocytic anaplasmosis), and bacterial sepsis. Idiopathic thrombocytopenic purpura is a frequent cause of thrombocytopenia in children that can have both an acute and chronic course. However, the incidence of ITP peaks at 3-5 years of age. Other immunologic causes of platelet destruction include systemic lupus erythematosus, autoimmune hemolytic anemia (Evan syndrome), and hyperthyroidism. Nonimmunologic causes include hemolytic-uremic syndrome and Kasabach-Merritt syndrome. Drug-induced thrombocytopenia should be considered if the patient is taking any medication, particularly sulfonamides, digoxin, quinine, quinidine, or chemotherapeutic agents. Disorders of impaired platelet production include marrow infiltrative processes such as leukemias, nutritional deficiencies (e.g., iron, folate, vitamin B12), and infection-associated suppression (e.g., EBV, HIV, parvovirus B9). Thrombocytopenia can occur after vaccination with MMR vaccine. Rare genetic disorders such as Fanconi anemia, Hermansky-Pudlak syndrome, thrombocytopenia with absent radii syndrome (TAR), Wiskott-Aldrich syndrome, May-Hegglin anomaly, and Bernard-Soulier disease are possibilities as well.

DIAGNOSIS

The petechial rash was consistent with her thrombocytopenia (Figure 18-1). The bone marrow aspirate revealed a normal marrow with increased megakaryocytes. The interpretation is that this is a clinical picture consistent with viral consumption of platelets. The EBV titers were positive for IgM and IgG antibody to viral capsid antigen. No Epstein-Barr nuclear antigen (EBNA) was detected. The diagnosis is EBV infection.

INCIDENCE AND EPIDEMIOLOGY

EBV is close to ubiquitous. It infects more than 90% of the population and persists for the lifetime of the host. Infection occurs at a later age in developed countries than in developing countries. This differential may be due to improved sanitary conditions and reduced population density in developed countries. The incidence of EBV infection is 50 per 100 000 individuals overall; however, it is 1 per 1000 individuals aged 15-25 years. The incubation period may last up to 30 days.

EBV is linked to infectious mononucleosis, Burkitt lymphoma, nasopharyngeal carcinoma, as well as other cancers. The virus is a member of the herpesvirus family. EBV binds to the CD21 molecule on the B-cell and gains entry into the cell. After infection of an epithelial cell in the oropharynx, the virus replicates and the cell ultimately dies. When EBV infects the B-cell, the virus becomes latent. However, unlike other herpes-virus infections, EBV does not recur. Infection is spread from person to person with contact of oral secretions. Transmission by aerosol or fomites is uncommon. The incubation period during which the virus may be communicated but the patient is asymptomatic is approximately 4 weeks; however, transmission rates are relatively low as evidenced by the absence of widespread EBV epidemics.

CLINICAL PRESENTATION

Young children with EBV exhibit no or few symptoms. Symptoms, when present, typically mimic viral respiratory infections with fever, cough, and rhinitis. While acute EBV infection is not synonymous with infectious mononucleosis (“mono”), infectious mononucleosis is the most commonly recognized clinical manifestation of EBV infection. Infectious mononucleosis typically presents with the triad of fever, tonsillopharyngitis, and lymphadenopathy. The pharyngitis is typically exudative. Lymphadenopathy is nontender and symmetrically involves the posterior cervical chains. Nausea, vomiting, and anorexia frequently occur which likely reflects the high prevalence of hepatitis (90% of patients may have a mild hepatitis). More than half of all patients with EBV infection will have splenomegaly; however, hepatomegaly is much less frequent. The acute symptoms resolve within 2 weeks, though fatigue may persist longer.

A minority of patients will have rashes which may be petechial, maculopapular, scarlatiniform, or urti-carial. Other less common systemic presentations of EBV infection include Guillain-Barré syndrome, facial nerve palsy, aseptic meningitis, meningoen-cephalitis, metamorphopsia (“Alice in Wonderland” syndrome in which there are bizarre perceptual distortions in shape or spatial relationships), transverse myelitis, peripheral neuropathy, optic neuritis, hemophagocytic lymphohistiocytosis, and, in boys, orchitis.

Complications from EBV infection include the possibility of a diffuse morbilliform rash if the patient is administered a penicillin drug, splenic rupture, upper airway obstruction, and lympho-proliferative disorders. Splenic rupture, which is more common in boys, has been reported to occur in 1 in 1000 cases typically on day 4-21 after the onset of symptoms. It may occur spontaneously and should be considered in any patient with left upper abdominal pain that radiates to the left shoulder. Airway obstruction is very rare, but carries significant morbidity and mortality. The airway compromise can be treated with steroids if necessary. Lymphoproliferative disorders can occur if there is decreased cellular immunity. It is the T-cell and natural killer cells that keep the latent EBV infection in check.

DIAGNOSTIC APPROACH

The diagnosis of an EBV infection is based on the correct clinical picture with supporting laboratory evidence.

Complete blood count. The complete blood count typically reveals a leukocytosis, though neutropenia is relatively common; the differential count usually reveals lymphocyte predominance with greater than 10% atypical lymphocytes. Other viruses that cause atypical lymphocytes include cytomegalovirus, human immunodeficiency virus, hepatitis, and measles; however, only EBV and cytomegalovirus have greater than 10% atypical lymphocytes. Mild thrombocytopenia is common; the platelet count rarely decreased below 100 000 platelets/mm3. Anemia is typically not associated with EBV, but if present consider autoimmune hemolysis (which occurs in less than 1% of patients) or splenic rupture.

Hepatic transaminases. Hepatic transaminases may be mildly elevated (two- to threefold).

Heterophile antibodies. Heterophile antibodies (e.g., Monospot), which agglutinate sheep or horse red blood cells, may be positive. These antibodies typically appear within 2 weeks of infection and may persist for as long as 6 months. Younger children are less likely than older children to have heterophile antibodies. False-positive monospot results may occur with leukemia, lymphoma, and Gaucher disease.

EBV-specific antibodies. EBV antibody titers may be sent for confirmation of disease. IgM and IgG antibodies directed against viral capsid antigen (anti-VCA IgM and IgG) appear first and are always present during the symptomatic phase (Table 18-3). The IgM is transient, disappearing within 2-3 months, while the IgG antibodies persist. Antibodies against EBV early antigen (anti-EA) typically increase several weeks after infection and disappear by 12 months. Anti-Epstein-Barr virus nuclear antigen antibody (anti-EBNA) appears last (usually >6 weeks after infection) and persists indefinitely. The presence of anti-EBNA antibodies excludes the possibility of acute infection.

TABLE 18-3. Interpretation of Epstein-Barr virus antibodies.

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EBV polymerase chain reaction. EBV polymerase chain reaction (PCR) has limited utility in the acute infectious stage. It may be transiently positive in acute infections, but it is also usually positive in those who have had a past EBV infection in whom the current symptoms may be unrelated to EBV. It is most useful in immune compromised hosts at risk for lymphoproliferative disorder.

TREATMENT

The mainstay of treatment is supportive care including adequate rest, fluids, and antipyretics. Although antivirals such as acyclovir demonstrate in vitro activity against EBV, there is no clinical benefit in uncomplicated mononucleosis in an otherwise healthy child. In the absence of concurrent bacterial infection, antibiotics should not be used. If antibiotic therapy is necessary, aminopenicillins (e.g., amoxicillin, ampicillin) should be avoided as these agents cause a rash, typically manifesting after the first few days of therapy. The rash is maculopapular, pruritic, and prolonged. Its appearance is not a contraindication to future aminopenicillin use. Systemic corticosteroids are not routinely recommended, but can be considered when there are complications such as tonsillar hypertrophy causing airway obstruction, massive splenomegaly, myocarditis, pericarditis, or significant hemolysis. Because of the possibility of splenic rupture, patients should avoid contact sports for at least 1 month or until the resolution of the splenomegaly.

SUGGESTED READINGS

1. Marshall BC, Koch WC. Mononucleosis syndromes. In: Shah SS, ed. Pediatric Practice: Infectious Diseases. New York: McGraw-Hill Medical; 2009:658-664.

2. Cohen JI. Epstein-Barr virus infection. New Engl J Med. 2000;343:481-492.

3. Durbin WA, Sullivan JL. Epstein-Barr virus infection. Pediatr Rev. 1994;15:63-68.

4. Straus SE, Cohen JI, Tosato G, Meier J. Epstein-Barr virus infections: biology, pathogenesis, and management. Ann Intern Med. 1993;118:45-58.

5. Schneider H, Adams O, Weiss C, Merz U, Schroten H, Tenenbaum T. Clinical characteristics of children with viral single- and co-infections and a petechial rash. Pediatr Infect Dis J. 2012 [PMID 23249918].