Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter VII.5. Carditis
David K.M. Wong, MD
May 2003

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This is a 12 year old boy with a 2 day history of fever, nausea, vomiting, anorexia, chills, and night sweats. During the last 24 hours, his symptoms not only worsened, but he started complaining of shortness of breath. At this time, he is brought to the Emergency Department. His past medical history is only remarkable for a small ventricular septal defect which has never bothered him before. He denies any surgical history or past hospitalizations. Family history and social history are noncontributory.

Exam: VS T 38.5, pulse 140, BP 90/45, RR 40, oxygen saturation 92% on room air. Weight and height are at the 50th %ile. He is alert, subdued and somewhat toxic in appearance. Eyes are clear (no conjunctival hemorrhages). ENT exam is normal. His neck is supple without adenopathy. Lung exam reveals tachypnea and coarse bibasilar breath sounds, but no dullness to percussion or pleuritic chest pain. Cardiac exam reveals tachycardia, and a loud, harsh, blowing, grade 3/6, holosystolic murmur, heard best over the lower left sternal border, but no frictional rubs and no gallops. His abdominal exam is normal. No rashes or ecchymoses are noted. No neurological abnormalities are noted.

Chest x-ray identifies multiple delicate nodular opacities bilaterally. A CBC shows a WBC 25,500, with 22% bands, 63% segs, 10% lymphs, and 5% monos. Hgb 14.5, Hct 44%, platelet count 300,000. ESR is elevated at 92. Chemistry panel is within normal limits. Urinalysis reveals microscopic hematuria. Two blood cultures, each more than 12 hours apart, are still pending. EKG reveals a sinus tachycardia. An echocardiogram reveals a small VSD with minimal left-to-right shunt, but no vegetations or pericardial effusion. Ventricular and valvular function are normal.

Clinical course: He is admitted to the hospital for possible endocarditis. IV antibiotics (vancomycin and gentamicin) are started. A CT of the chest reveals evidence of septic emboli in both lungs. On the second hospital day, both blood cultures grow out Staph aureus. On hospital day 3, the Staph aureus is methicillin/oxacillin sensitive, so his antibiotics are changed to oxacillin. On hospital day 8, his temperature returns to normal and by the 6th week of IV antibiotic therapy, his subsequent blood cultures are negative and he is discharged home.


Carditis (inflammatory conditions of the heart) includes myocarditis, pericarditis and endocarditis. Endocarditis includes valvular inflammation (often called valvulitis). Aortitis is sometimes included in carditis. Endocarditis may be infectious or due to rheumatic fever. Pericarditis and myocarditis are usually viral or post-viral, but they may be due to rheumatic fever as well. Autoimmune conditions may also cause carditis. Rheumatic fever and autoimmune conditions are covered in separate respective chapters.

Infective Endocarditis

Prior to the era of antibiotics, patients suffering from infective endocarditis had mortality rates of nearly 100%. However, with the introduction of antibiotics, the present day mortality rate for this disease in the pediatric population ranges between 20-30%. The present trend for this disease has the average pediatric age of onset increasing from 5 to 12 years old. Some hypothesize the reason for this is due to the current increase in survival rate of children with congenital heart disease.

It is theorized that the cause of infective endocarditis stems from the hemodynamically turbulent flow which causes endothelial thickening that provides a place for a platelet and fibrin thrombus to develop. This site becomes the nidus of bacterial growth for susceptible adhesive microorganisms. Therefore, conditions which predispose turbulent blood flow in the heart are risk factors for infective endocarditis. Such conditions include ventricular septal defects (VSD), patent ductus arteriosus (PDA), aortic valvular disease, atrioventricular septal defect (AVSD, also known as endocardial cushion defect or AV canal), prosthetic valves, tetralogy of Fallot, and chronic rheumatic heart disease. In underdeveloped countries where rheumatic heart disease is common, it is the most common cause for infective endocarditis. However, congenital heart disease is the most common risk factor in pediatric practices of the United States. The mitral valve is the most commonly affected, followed by the aortic valve, then the tricuspid valve. Other risk factors include situations which increase the risk of bacteremia, such as: IV drug use (which predisposes infective endocarditis to the right side of the heart), indwelling IV catheters, intraarterial catheters, severe burns, dental procedures, or recent cardiac surgery.

It is estimated that 80% of all pediatric infective endocarditis are due to alpha-hemolytic streptococci and S. aureus. Alpha-hemolytic streptococci (which includes strep viridans) are responsible for 75% of subacute endocarditis and S. aureus is responsible for 50-70% of acute endocarditis.

The clinical course of infective endocarditis varies from an acute to subacute course and is usually based on the offending microorganism. Traditionally, the microorganisms which are responsible for acute infective endocarditis include Staphylococcus aureus, Streptococcus pyogenes, or Neisseria gonorrhoeae. Microorganisms usually responsible for subacute infective endocarditis are the less virulent Streptococcus viridans (alpha strep). These distinctions, though useful clinically, do not always hold. Therefore, S. aureus may cause a subacute course, and S. viridans may be responsible for an acute endocarditis. In the pediatric setting, the clinical distinctions are still useful, perhaps more so than in the elderly population.

Acute infective endocarditis is characterized by a rapidly progressive clinical picture of sepsis, high fever, headaches, nausea, vomiting, diarrhea, cough, shortness of breath, and early cardiac decompensation. On the other hand, the subacute course is characterized as an insidious, flu-like syndrome, associated with malaise, anorexia, +/- fever. In the pediatric population, it is rare to find splinter hemorrhages, Osler nodes (painful, red, nodular lesions most commonly found on fingers), Janeway lesions (small, erythematous, nontender areas of the palms and soles), and Roth spots (retinal hemorrhages with central clearing). If the course is prolonged, then splenomegaly, weight loss, night sweats, anemia, or petechiae may develop. In 20% of infective endocarditis, a new cardiac murmur or change in a preexisting murmur occurs. A subacute course of infection is unusual under the age of 2 years old. Most patients with endocarditis younger than 2 will have an acute fulminating disease.

Embolic episodes may also be a part of the clinical course, however this is more common in adults than in children. Emboli originating from left-sided endocarditis may cause renal infarcts resulting in frank hematuria, splenic infarcts resulting in left flank pain, or stroke-like symptoms resulting from cerebral emboli. Emboli from right-sided endocarditis may cause chest pain and shortness of breath due to pulmonary embolism.

Several sources describe a diagnostic criteria (the Duke criteria) to allow early recognition of endocarditis, when vegetations are still too early to detect. A patient is considered to have infective endocarditis if 2 major criteria or 1 major plus 3 minor criteria are met. The major criteria are: positive blood cultures x2 and endocardial abnormalities on echocardiography. The minor criteria are: presence of a predisposing condition (i.e., valve abnormality), fever greater than 38 degrees C, embolic episode (i.e., splenic infarct), and immunologic phenomena (i.e., Osler nodes).

Blood cultures are the most valuable laboratory tests in making the diagnosis of infective endocarditis. Controversy lingers as to the exact number of cultures that should be obtained for each patient with suspected infective endocarditis. However, the collection of 2 to 3 blood cultures over a 24 hour period will suffice in most cases. Approximately 5% of patients with endocarditis will have negative blood cultures. In some cases, the microorganism contained in the vegetation are unexposed, encased in fibrin and platelets. Antibiotic therapy prior to obtaining blood cultures will reduce the likelihood of recovering the organism in the blood. Therefore, it is very important to obtain blood cultures prior to antibiotic treatment. Fungi or candida can cause endocarditis rarely, but these will eventually grow out of most blood cultures (though very slowly).

Other laboratory tests are not as helpful in making the diagnosis of infective endocarditis, but they may be helpful in monitoring clinical progress. Elevated erythrocyte sedimentation rate (ESR) is commonly found in both acute and subacute endocarditis. During antibiotic therapy, a decrease of the ESR signifies that the treatment is most likely effective. Like many other infectious diseases, a leukocytosis with an accompanying left shift may be seen, although this is more common in the acute setting than the subacute course. Microscopic or macroscopic hematuria is also a common laboratory finding. Microscopic hematuria is most likely due to immune complex depositions in the glomeruli, whereas macroscopic hematuria is most likely a result from renal embolization. If the course is chronic, such as in the subacute cases, normocytic/microcytic anemia may occur.

The most helpful diagnostic procedure is echocardiography. Echocardiography is most helpful in children with normal cardiac anatomy or with isolated valvular abnormalities. However, this procedure is not 100% sensitive or specific, therefore a negative echocardiogram does not rule out endocarditis. Recently, transesophageal echocardiography (TEE) has had better results than the transthoracic approach in adults. Although, TEE is currently used intraoperatively in children, the usefulness for this procedure in children with endocarditis remains uncertain.

The differential diagnosis for infective endocarditis is complex since this disease has variable clinical presentations. Because infective endocarditis commonly presents with fever, arthralgias, and a positive rheumatoid factor; juvenile rheumatoid arthritis, Kawasaki's disease, rheumatic fever and other connective tissue disorders should be considered in the differential diagnosis. Neurologic manifestations from infective endocarditis may also mimic that of meningitis, cerebritis, or toxic encephalopathy. If hematuria is present, one must also consider other renal diseases. If S. aureus bacteremia along with an increasing ESR is present in a patient with infective endocarditis, one must consider osteomyelitis or septic arthritis. Cardiac myxomas or rheumatic carditis must also be considered if a patient presents with a new or changing heart murmur. The diagnosis of infective endocarditis should be considered in any child with persistent unexplained fevers especially if they are considered at high risk such as history of congenital heart defects or IV drug use.

Isolation of the infecting microorganism by blood culture is extremely important, not only in making the diagnosis, but also in planning for treatment. The microorganisms that are revealed from the blood cultures will strongly determine the type of antibiotic regimen to be used. The physician must be guided by the antibiotic susceptibility pattern. Although antibiotic regimens vary depending on the infective microorganism, one general principle is true in the treatment of infective endocarditis: complete eradication of the infecting microorganism with bactericidal agents will usually require weeks of therapy. For example, patients with blood cultures that grow out Streptococci will require 4 weeks of penicillin G and patients with Staph. aureus will require 6 weeks of oxacillin (if they are methicillin/oxacillin sensitive). Initially when blood cultures are still pending, empiric antibiotics should be started. Empiric therapy includes coverage for the common, Streptococci and S. aureus, but also for the less common MRSA (methicillin resistant Staph aureus) and Gram negatives, therefore vancomycin and gentamicin are the preferred regimen.

Determination of MIC and MBC levels for the causative bacteria will assist in determining the potential for outpatient treatment with oral antibiotics (refer to the chapter on MIC and MBC levels).

Obtaining occasional blood cultures during the first 8 weeks after cessation of treatment is warranted, because most relapses occur during this period. There are several common indications for surgery. These include a significant embolic event, persistent infection, and progressive congestive heart failure especially when the aortic or mitral valve is involved.

Prophylactic antibiotics are recommended for children who are at risk to develop infective endocarditis, while undergoing procedures that may induce a bacteremia. At risk patients include those who have significant heart defects associated with turbulent blood flow (e.g., VSD, mitral valve prolapse, etc.), prosthetic conduits, or prosthetic heart valves. The recommended antibiotic regimens for prophylaxis include amoxicillin 50mg/kg PO 1 hour before the procedure or ampicillin 50mg/kg IM or IV within 30 minutes of the procedure. If the patient is allergic to penicillin, an alternate drug may include clindamycin 20 mg/kg PO 1 hour before procedure or cefazolin 25mg/kg IM or IV within 30 minutes of the procedure. In general, any dental or surgical procedure involving the respiratory, gastrointestinal, or genitourinary tract that induces bleeding from the gingival or mucosal surface, can predispose at risk patients to bacteremia. Therefore, antibiotic prophylaxis should be considered in these situations. The maintenance of optimal dental care and oral hygiene is also important for children at risk for infective endocarditis.

At present, the mortality rate is between 20 and 30%. Mortality rates are slightly higher in patients with acute staphylococcal infection, fungal infection, and prosthetic valve endocarditis. Mortality may be caused by sudden perforation of the aortic valve with severe aortic insufficiency, chordal rupture with resultant mitral insufficiency, myocardial infarction, or intramyocardial abscess formation with the development of a myocarditis.

Myocarditis

Myocarditis is defined as an inflammatory response within the myocardium. The categories of myocarditis are divided into infectious myocarditis and generalized autoimmune myocarditis. In either case, the histological features of the myocardium reveal myocardial necrosis with accompanying inflammatory reactions.

The most common cause of pediatric infectious myocarditis in the western world is viral in nature. Any virus may cause this, but the most notable viruses are coxsackie viruses, echovirus, influenza virus, mumps, and rubella. Non-viral infectious myocarditis may include protozoan infections, Lyme disease, hemolytic uremic syndrome or complications from tuberculosis. Whatever the suspecting etiological may be, the pathophysiology remains unknown. Some speculate infectious myocarditis may result from toxins secondary to the infectious agent, others speculate the mechanism is secondary to an immune reaction.

The clinical manifestations of this disease, varies from the more common subacute course to the severe course which manifests as heart failure that may be accompanied by arrhythmias. There is no single characteristic profile for infectious myocarditis. A nonspecific systemic viral infection is usually followed by a latent period. The latent period is followed by variable nonspecific signs and symptoms such as fever, diarrhea, anorexia, pallor, mild jaundice, or lethargy. Diminished heart tones may be the only clinical clue pointing toward myocarditis. If the disease progresses, cardiac enlargement may ensue, along with a nonspecific cardiac arrhythmia. The end result may eventually lead to symptoms of heart failure, such as tachypnea, dyspnea, and fatigue.

Much like the clinical manifestations, results from laboratory and investigational tests are often variable. Erythrocyte sedimentation rate, white blood cell count, and cardiac enzymes tend to vary from elevated to normal, depending on the severity of the disease. Chest radiographs may show an enlarged heart and depending on the severity of the heart failure, pulmonary venous congestion may be present. Electrocardiographic (EKG) abnormalities are common, but only nonspecific findings are present in infectious myocarditis. Often, a sinus tachycardia is present, with lowering of the QRS complexes in the standard leads and/or precordial leads. The T-waves may be flattened or inverted with changes in the ST segment. Echocardiography may reveal a nonspecific dilation of the heart chambers, most commonly the left ventricle. The left atrium may be enlarged if mitral insufficiency is present. The main importance of an echocardiogram is to exclude a pericardial effusion and to assess myocardial contractility. In addition to the echocardiogram, radionuclide angiography has been used to perform serial measurements of the left ventricular function. Controversy remains on routine endomyocardial biopsies for suspected myocarditis because the pathology is often patchy, therefore a negative biopsy cannot exclude the diagnosis. Essentially, the diagnosis of infectious myocarditis is a diagnosis of exclusion.

The treatment of myocarditis most often focuses on the treatment of arrhythmias and congestive heart failure. If an infectious agent is identified, then the appropriate therapy should be instituted, however in most cases no infectious agent will be found. Treatment of the heart failure consists of bedrest, oxygen, and congestive heart failure treatment (e.g., inotropes, diuretics and ACE inhibitors). Digoxin is controversial since this drug may induce ventricular arrhythmias. Other controversial and unproven treatment therapies include drugs that decrease the inflammatory response such as corticosteroids, immunosuppressive agents, and high-dose IV immunoglobulins.

The prognosis of the subacute course of myocarditis is good. Most patients will recover in several weeks to months with the heart size reverting back to normal within a year. However, in cases where heart failure recurs, the prognosis is poor.

Generalized autoimmune myocarditis is often one aspect of a syndrome secondary to a collagen or connective tissue disease. Autoimmune myocarditis is found infrequently in children. The more common cardiac finding in SLE is pericarditis.

Pericarditis

Pericarditis is defined as an inflammatory reaction of the pericardium. Etiologies include acute bacterial pericarditis, acute viral pericarditis, postpericardiotomy syndrome, acute rheumatic fever and uremia. Echocardiography is the most important diagnostic test, which will reveal the presence of a pericardial effusion surrounding the heart. Moderate pericardial effusion secondary to pericarditis may also show up on x-ray as an enlarged cardiac silhouette but the x-ray will not be able to distinguish pericardial effusion from myocardial dilation. In borderline cases, comparisons of previous x-rays may prove helpful. Electrocardiography (EKG) may be useful in the initial stage of the disease, when ST segments are elevated in all leads except V1 and aVR. After a few hours to days, the ST segments may return to baseline, and the T waves become flat. A low voltage (low amplitude) EKG may be seen if the pericardial effusion is large enough.

Much like infective endocarditis, the incidence of acute bacterial pericarditis has dramatically declined since the development of antibiotics. The most common settings for acute bacterial pericarditis include septicemia or hematogenous or direct spread into the pericardium from another site, such as with pyelonephritis, osteomyelitis, tonsillitis, bacterial pneumonia and empyema. The common microorganisms responsible for most acute bacterial pericarditis are Haemophilus influenzae type B, Staphylococcus aureus, pneumococcus, meningococcus, streptococcus species and tuberculosis infection. Patients with acute bacterial pericarditis will usually manifest with acute onset of chest pain, high fever, tachycardia, frictional rub, tachypnea and toxemia. Acute bacterial pericarditis often is associated with an infection elsewhere, therefore an intensive search for the primary source is essential. Blood cultures are important and it is recommended that three to five sets should be obtained in the first 1 or 2 days after admission. These blood cultures are positive 40-80% of the time and the appropriate antimicrobial agent given for 4 to 6 weeks should be chosen based on the susceptibility testing. Acid-fast stains for tuberculosis of the sputum, gastric contents, or urine are considered if blood cultures come back negative.

Acute viral pericarditis is often associated with the aforementioned viral myocarditis. And like the viral myocarditis, the most common viral agents responsible for viral pericarditis include group B coxsackie virus, echovirus, adenovirus, and influenza virus. The clinical manifestations of the viral myocarditis usually dominate over the clinical manifestations of the viral pericarditis. The typical signs and symptoms of acute viral pericarditis include a low-grade temperature, chest pain, and a frictional rub. The therapy for acute viral pericarditis is symptomatic. This includes bedrest, in particular patients who also have myocarditis. The prognosis of viral pericarditis is good and often self-limiting, with complete recovery in 3 to 4 weeks.

Similar to the adult pericarditis following a myocardial infarction, known as Dressler's syndrome, an episode of acute pericarditis in children following cardiac surgery which includes opening of the pericardium (post-pericardiotomy syndrome). The pathogenesis is unclear, however anti-myocardial antibodies and eosinophilia point toward an autoimmune etiology. Cardiac tamponade may occur, which may be treated with a pericardiocentesis, however in most cases of post-pericardiotomy syndrome, the disease is self-limiting in 2 to 3 weeks. The most important treatment is bedrest. Salicylates may be used to lower the temperatures and chest pain. In the severely ill child, a course of prednisolone may be effective.


Questions

1. What is the most common microorganism found in pediatric infective endocarditis?
. . . . . a. Staph aureus.
. . . . . b. Strep viridans
. . . . . c. E. coli
. . . . . d. Pneumococci
. . . . . e. Strep pyogenes

2. What is the preferred antibiotic treatment for the microorganism in question 1?
. . . . . a. Penicillin G x 2 weeks
. . . . . b. Penicillin G x 4 weeks
. . . . . c. Oxacillin x 6 weeks

3. Which microorganism(s) will most likely NOT manifest as an acute infective endocarditis in the pediatric setting?
. . . . . a. S. aureus
. . . . . b. Neisseria
. . . . . c. Strep. pyogenes
. . . . . d. HACEK (Haemophilus species (H. parainfluenzae, H. aphrophilus, and H. paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species).

4. Does the pediatric case presented at the beginning of this chapter meet the Duke Criteria for Diagnosis of infective endocarditis?
. . . . . a. Yes.
. . . . . b. No.
. . . . . c. Need more information.

5. What type of prophylactic antibiotic against infective endocarditis would you prescribe to a nine-year old female, with a past medical history only remarkable for an allergic reaction to penicillin, scheduled for a tooth extraction the next day?
. . . . . a. Amoxicillin.
. . . . . b. Ampicillin.
. . . . . c. Clindamycin.
. . . . . d. Cefazolin.
. . . . . e. None.

6. What is the most common microorganism that causes pediatric infectious myocarditis in the United States?
. . . . . a. Strep viridans.
. . . . . b. Tuberculosis.
. . . . . c. Staph aureus.
. . . . . d. E. coli.
. . . . . e. Virus.

7. Which of the following answer is the most severe clinical manifestation commonly found in pediatric myocarditis?
. . . . . a. Myocardial infarction.
. . . . . b. Heart failure.
. . . . . c. Pericarditis.
. . . . . d. SLE.
. . . . . e. None of the above.

8. Which is the most helpful test to diagnose pericarditis?
. . . . . a. Cardiac enzymes.
. . . . . b. EKG.
. . . . . c. Echocardiogram.
. . . . . d. X-ray of the heart silhouette.
. . . . . e. Answers b and d.

9. Which of the following is/are treatments options for pediatric postpericardiotomy syndrome?
. . . . . a. Salicylates.
. . . . . b. Pericardiocentesis.
. . . . . c. Bed rest.
. . . . . d. Prednisolone.
. . . . . e. All of the above.


References

1. Shinebourne EA. Chapter 66 - Infective Endocarditis. In: Anderson RH, Baker, EJ, Maccartney FJ, et al (eds). Paediatric Cardiology, 2nd edition. 2002, Churchill Livingstone, pp. 1759-1776.

2. Friedman RA, Starke JR. Chapter 78 - Infective Endocarditis. In: Garson A, Bricker JT, Fisher DJ, Neish SR (eds). The Science and Practice of Pediatric Cardiology, 2nd edition. 1998, Baltimore: Williams and Wilkins, pp. 1759-1775.

3. Dajani AS, Taubert KA. Chapter 65 - Infective Endocarditis. In: Allen HD, Gutgesell HP, Clark EB, Driscoll DJ (eds). Heart Disease in Infants, Children, and Adolescents, 6th edition. 2001, Baltimore: Lippincott Williams and Wilkins, pp. 1297-1308.

4. Danilowicz D. Infective Endocarditis. Pediatr Rev 1995;16(4):148-154.

5. Baker E. Chapter 63 - Non-rheumatic Inflammatory Heart Disease. In: Anderson RH, Baker EJ, Maccartney FJ, et al (eds). Paediatric Cardiology, 2nd edition. 2002, Churchill Livingstone, pp. 1699-1711.


Answers to questions

1. b.

2. b. Choice a is too short of a course and choice c is the preferred treatment for S. aureus infective endocarditis.

3. d.

4. a. The patient had positive blood cultures (1 major), and (3 minors) fever greater than 38 degrees C, a predisposing structural cardiovascular lesion (VSD), and evidence of an immunologic phenomenon (microscopic hematuria).

5. e. No antibiotics are needed, because this particular patient has no risk factors for infective endocarditis.

6. e.

7. b. Although c may be associated with viral myocarditis, viral pericarditis is most likely self-limiting.

8. c. Answers b and d may not show any abnormal findings.

9. e.


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