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

CASE 14-3

Twenty-Year-Old Boy

DEBRA BOYER

ALICIA CASEY

HISTORY OF PRESENT ILLNESS

The patient is a 20-year-old boy with a history of spina bifida. Six days prior to admission he reported fatigue and was unable to leave his house. During the next few days, he developed a fever, sore throat, and myalgias. Two days prior to admission, he noted increasing shortness of breath which was worse while lying supine. He described a “pounding” discomfort in his chest.

MEDICAL HISTORY

The boy was born at full term and found to have a meningomyelocele at birth. His spinal defect was at L3 and he underwent surgical correction when he was 4 days old. A ventriculoperitoneal (VP) shunt was placed in the first weeks of life. He has required several shunt revisions due to obstruction. The last revision was 6 years ago. He also has a history of bilateral club feet. Four months prior to admission he was diagnosed with pelvic osteomyelitis related to extension of a gluteal ulcer. He was treated with surgical debridement and 3 months of intravenous antibiotics.

He is able to walk with a brace and has a mild intellectual disability. At the time of presentation, he was not taking any medication. He had a tattoo drawn on his arm 2 weeks prior. There is a family history of asthma in his mother, and his father died at age 40 of a myocardial infarction.

PHYSICAL EXAMINATION

T 41.3°C; HR 138 bpm; RR 20/min; BP 113/80 mmHg; Oxygen saturation, 98% in room air

In general, he was an obese young boy in moderate respiratory distress. His oropharyngeal examination revealed an exudative pharyngitis. His cardiac examination revealed a normal S1 and S2 without murmur, rub, or gallop. His physical examination was otherwise unremarkable.

DIAGNOSTIC STUDIES

The complete blood count revealed a WBC count of 13 500 cells/mm3 with 42% segmented neutrophils, 26% lymphocytes, 18% atypical lymphocytes, and 1% monocytes. The hemoglobin was 11.3 gm/dL, and his platelets were 133 000/mm3. Electrolytes, blood urea nitrogen, and glucose were within normal limits. A serum creatinine was slightly elevated at 1.1 mg/dL. Total bilirubin was elevated at 4.0 mg/dL with an unconjugated fraction of 2.3 mg/dL. Aspartate aminotransferase and alanine amino-transferase were 246 U/L and 130 U/L, respectively. Erythrocyte sedimentation rate was mildly elevated at 44 mm/h. A chest roentgenogram revealed normal heart size and no pulmonary infiltrates.

COURSE OF ILLNESS

Prior to his arrival at the hospital, the patient was administered adenosine twice for tachycardia with heart rate above 160 bpm. This did not have any significant effect. On arrival in the emergency department, his chest pain resolved and his electrocardiogram abnormalities resolved. An echocardiogram demonstrated a shortening fraction of 28% and no wall motion abnormalities.

The boy was evaluated for a possible myocardial infarction, given his family history. His cardiac enzymes remained normal. He developed bilious emesis believed to be secondary to his hepatitis. He had a repeat electrocardiogram (Figure 14-4) and echocardiogram on arrival in the intensive care unit. The electrocardiogram suggested a diagnostic category and the specific cause was suggested by the initial laboratory testing and confirmed later by serologic testing.

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FIGURE 14-4. Electrocardiogram.

DISCUSSION CASE 14-3

DIFFERENTIAL DIAGNOSIS

The most common causes of chest pain in children and adolescents include musculoskeletal/chest wall pain, pulmonary causes, GI causes, and miscellaneous causes including psychogenic etiologies and hyperventilation. Chest pain due to cardiac conditions is rare, but warrants a high index of suspicion given the potential morbidity and mortality.

The concerning factors in this patient are his positional shortness of breath, his early family history of myocardial infarction, and his abnormal electrocardiogram. On presentation, he was tachycardic and febrile. Concern for a possible cardiac etiology should be raised in any child or adolescent with chest pain on exertion, palpitations, syncope, abnormal cardiac findings on examination or electrocardiogram, history of cardiac disorder, or with a family history of significant cardiac illness.

Cardiac etiologies for chest pain in the pediatric population include structural lesions causing left ventricular outflow tract obstruction, such as aortic stenosis, aortic dissection, rupture of aortic aneurysm, coronary artery abnormalities, pericarditis, myocarditis, cardiomyopathy, pulmonary hypertension, mitral valve prolapse, atrial myxomas, cardiac device complications, and drugs. A thorough history and physical examination will help to identify any findings concerning cardiac causes of chest pain. The complaint of chest pain may be the first indication that there is a cardiac issue in a pediatric patient. Patients with left ventricular outflow tract obstruction may have pain associated with dizziness and fatigue. Patients with hypertropic or dilated cardiomyopathy may present with chest pain, exercise intolerance, or fatigue. Chest pain occurs in patients with coronary artery disease due to myocardial ischemia. Unfortunately, these disorders may present with sudden death. In children, coronary artery disease can be the result of congenital abnormalities of the coronary arteries, secondary to hypertrophic cardiomyopathy, a result of Kawasaki disease, due to postcardiac surgical complications, or secondary to familial hypercholesterolemia. Patients with either corrected or uncorrected congenital heart disease, or with a history of cardiac transplantation, may complain of chest pain. In this population, chest pain must be carefully evaluated. Arrhythmias, such as supraventricular tachycardia and ventricular tachycardia, can also present with chest pain and palpitations. Finally, inflammatory/infectious causes, such as myocarditis and pericarditis, may also present with chest pain, often with a history of recent infection.

DIAGNOSIS

Repeat electrocardiogram showed sinus tachycardia at 139 bpm with 2 mm ST segment elevations in leads V2 and V3 (Figure 14-4). Repeat echocardiogram revealed a left ventricular ejection fraction of 25% with dilated left and right ventricles. Cardiac catheterization demonstrated a left ventricle end-diastolic pressure of 16 mmHg and a cardiac index of 4.4 L/min. Soon after admission, he developed congestive heart failure with respiratory distress, diaphoresis, somnolence, and hypotension. He was ultimately treated with dopamine and dobutamine. To help determine the etiology of his myocarditis, Epstein-Barr virus (EBV) studies were sent. Monospot testing was positive. His course was also complicated by hepatitis, thrombocytopenia, and an atypical lymphocytosis. EBV viral capsid IgG (VCA) was 1:640; early antigen IgG (EA), 1:80; and Epstein-Barr nuclear antigen (ENBA) IgG, undetectable. He was diagnosed with probable acute EBV myocarditis.

INCIDENCE, EPIDEMIOLOGY, AND ETIOLOGY

EBV is a member of the herpes virus family and is also known as Human Herpes Virus 4. It is a relatively common infectious organism, causing a clinical syndrome of infectious mononucleosis. This syndrome is most frequently seen in adolescents and young adults. Boys and girls are affected equally, and approximately 90% of adults have evidence of past infection. There is no seasonal pattern to infections.

EBV believed to have low contagiousness and transmission generally requires close personal contact between individuals. This is why infectious mononucleosis has been termed “the kissing disease.” The virus is viable in saliva outside of the body for several hours. Intermittent excretion of the virus in saliva may persist lifelong.

The classical clinical syndrome consists of fever, pharyngitis with petichiae and exudate, lymph-adenopathy, atypical lymphocytosis, and fatigue developing after an incubation period of 30-50 days. Hepatosplenomegaly and rash are frequently observed with a morbilliform rash occurring more commonly in patients treated with antibiotics in the penicillin family. Most cases of EBV infection are self-limited, although rare complications can be seen. These complications can be multi-systemic and include hematologic, hepatorenal, splenic, dermatologic, immunologic, central nervous system, and cardiopulmonary complications. Lymphomas can occur after EBV infection in immunocompetent persons, as well as those with defects of cellular immunity.

Myocarditis in EBV infection is a rare, but well-described complication of EBV infection. In children and adolescents, myocarditis is an uncommon illness that can be associated with significant morbidity and mortality. Viruses are thought to be the most common etiologic agents causing acute lymphocytic myocarditis in both children and adults. Common viruses causing myocarditis include adenovirus, enterovirus (including coxsackie B and rhinovirus), parvovirus, cytomegalovirus, EBV, human herpesvirus 6, influenza, human metapneumovirus, respiratory syncytial virus, and HIV. Several patients with viral infections who will go on to develop myocarditis is unknown. Less commonly, myocarditis can occur as a complication of other nonviral infectious agents, such as Mycoplasma pneumoniaeChlamydophila pneumoniaBorrelia burgdorferiLysteria monocyto-genesClostridium perfringens, Staphylococcus, Streptococcus, Meningococcus, Diptheria, and Trypanosomacruzi. Also rare are noninfectious etiologies, such as drugs, hypersensitivity reactions, autoimmune diseases, vaccinations, and cancer.

CLINICAL PRESENTATION

Acute myocarditis in children presents with a wide range of signs and symptoms and because of the variable presentation it is often misdiagnosed. Often there is a recent history of respiratory or gastrointestinal illness prior to presentation. Presentation may include chest pain, respiratory symptoms, fevers, gastrointestinal complaints, cardiogenic shock, and sudden death. Some pediatric patients may present with acute fulminant myocarditis and some may present without obvious cardiac-related symptoms. Myocarditis is often more fulminant in children in comparison to adults. Newborns and infants with myocarditis may present with a decreased appetite, fever, irritability, and diaphoresis. Older children may complain of chest pain, shortness of breath, positional dyspnea, fatigue, fever, pallor, diaphoresis, palpitations, rashes, and decreased exercise tolerance. Physical examination is often nonspecific and may include tachycardia and tachypnea. With the development of congestive heart failure there may be jugular venous distention, hepatomegaly, and rales on pulmonary examination. As the disease progresses, respiratory distress can become more prominent. Arrhythmias can develop including ventricular tachycardia and conduction delays.

DIAGNOSTIC APPROACH

Acute myocarditis is a difficult diagnosis to make and it is appropriate to have a high index of suspicion for this in the appropriate setting. If EBV is suspected as a possible cause of myocarditis, studies should be sent to confirm this diagnosis.

MYOCARDITIS DIAGNOSIS

Laboratory investigations. Measurement of cardiac enzymes and inflammatory markers are often obtained during the work up for myocarditis. Troponin levels are not elevated in all patients with myocarditis, but this is a sensitive marker of myocardial damage. Patients with myocarditis may have elevation of inflammatory mediators, but this is also nonspecific.

Electrocardiogram (ECG). Patients with myocarditis may develop nonspecific ECG changes including sinus tachycardia, low-voltage QRS complexes, T waves abnormalities, ST-segment changes, abnormal axis, heart block, ventricular hypertrophy, and atrial enlargement. Findings indicative myocardial infarction may be found.

Echocardiogram. When myocarditis is suspected, echocardiographic evaluation is essential. Findings include atrial dilation, atrioventricular valve regurgitation, and evidence of systolic dysfunction. This may be accompanied by pericardial effusion and possibly tamponade.

Chest roentgenogram. With myocarditis, the chest roentgenogram may reveal cardiomegaly, pulmonary congestion, and pleural effusions.

Endomyocardial biopsy. This remains the gold standard for diagnosis. The histologic criteria for diagnosis included inflammatory cell infiltrate and cardiac myocyte necrosis. Because tissue involvement is patchy and it is risky and difficult to obtain samples, endomyocardial biopsy is only recommended in specific cases.

Cardiac magnetic resonance imaging (MRI). In adults this is known to be a useful noninvasive technique for the diagnosis of myocarditis. Patchy subepicardial tissue involvement with edema, inflammation, and scarring is seen. There is not sufficient experience in making the diagnosis of myocarditis using cardiac MRI in pediatric patients, but further studies are ongoing.

EBV DIAGNOSIS

Complete blood count. In the setting of acute EBV infection, one will generally see a lymphocytosis. Classically, the patient will have more than 10% atypical lymphocytes.

Monospot. This tests for the presence of heterophile antibodies which are found in approximately 85% of older children and adults with EBV infection. This antibody appears during the first 2 weeks of infection and gradually disappears over 6 months. It is important to know that the heterophile antibody test will often be negative in children younger than 4 years of age.

EBV-specific antibodies. Antibody testing to EBV antigens is useful in the diagnosis when evaluating patients with negative heterophile antibody testing. EBV viral capsid antigen (VCA) testing is most commonly performed to evaluate for EBV infection. EBV VCA IgG rises high early in the illness and persist for life, so this testing is not useful for the diagnosis of acute infection. Testing for EBV VCA IgM and EBV early antigen (EA) is useful to identify active and recent infections. Antibody to EBV nuclear antigen (NA) is not present until several weeks to months postinfection. The presence of EBV VCA IgM and absence of NA antibodies is considered diagnostic of acute EBV infection.

EBV viral isolation/detection. Isolation of EBV from oral secretions is possible, but difficult and does not indicate acute infection. Testing for the presence EBV DNA by PCR, or RNA by RT-PCR on blood or tissue specimens may be useful in selected cases including patients with immune dysfunction.

Liver function tests. Many patients will develop hepatitis from an EBV infection, with elevated aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase. Patients may also develop hyperbilirubinemia.

TREATMENT

Patients who present with myocarditis should be treated supportively. Therapy may include observation, medications for heart failure, and cardiogenic shock including inotropes, afterload reducers, diuretics and antiarrhythmics, mechanical ventilation, temporary cardiac pacing, and mechanical circulatory support. The use of immunomodulatory therapy for treatment of acute myocarditis is not routinely recommended, but may be considered in certain groups of patients. Restriction of activity following acute myocarditis is generally recommended, although the effect of exercise on patients with myocarditis has not been studied.

The use of steroids for the treatment of EBV myocarditis is recommended as in other cases of complicated EBV infection. The combination of steroids and antiviral agents for the treatment of complicated EBV in immunocompetent individuals has been debated and is described in several case reports/case series. However, this combination has not been rigorously studied as the disease entity is relatively rare. In the presence of severe complications this combination could be considered.

SUGGESTED READINGS

1. Reddy S, Singh H. Chest pain in children and adolescents. Pediatr Rev. 2010;31(1):e1-e9.

2. American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.

3. Sagar S, Liu P, Copper L. Myocarditis. Lancet. 2012; 379(9817):738-747. [Epub Dec 18, 2011.]

4. Rafailidis P, Mavros M, Kapaskelis A, Falagas M. Antiviral treatment for severe EBV infections in apparently immunocompetent patients. J Clin Virol. 2010;49(3):151-157. [Epub Aug 24, 2010].

5. Simpson K, Canter C. Acute myocarditis in children. Expert Rev Cardiovasc Ther. 2011;9(6):771-783.