Park's Pediatric Cardiology for Practitioners, 6th Ed.

Cardiovascular Infections

Included in this chapter are infective endocarditis (IE), myocarditis, pericarditis, Lyme carditis, and postperfusion syndrome. Other conditions in which the cause is not well established but the host’s immune response to an infective agent is thought to play a role are also included, such as Kawasaki’s disease and postpericardiotomy syndrome. Cardiac manifestations of human immunodeficiency virus (HIV) are also included.

Infective Endocarditis

Prevalence

Infective endocarditis accounts for 0.5 to 1 of every 1000 hospital admissions, excluding postoperative endocarditis.

Pathogenesis

1. Two factors are important in the pathogenesis of IE: (1) a damaged area of endothelium and (2) bacteremia, even transient. The presence of structural abnormalities of the heart or great arteries, with a significant pressure gradient or turbulence, produces endothelial damage. Such endothelial damage induces thrombus formation with deposition of sterile clumps of platelet and fibrin (nonbacterial thrombus). Prosthetic valves or prosthetic materials used in surgery also promote deposition of sterile thrombus. Nonbacterial thrombus provides a nidus for bacteria to adhere and eventually form infected vegetation. Platelets and fibrin are deposited over the organisms, leading to the enlargement of the vegetation.

2. Almost all patients who develop IE have a history of congenital or acquired heart disease. Drug addicts may develop endocarditis in the absence of known cardiac anomalies.

3. All congenital heart defects (CHDs), with the exception of secundum-type atrial septal defect (ASD), predispose to endocarditis. More frequently encountered defects are tetralogy of Fallot (TOF), ventricular septal defect (VSD), aortic valve disease, transposition of the great arteries (TGA), and systemic-to-PA shunt. Those with a prosthetic heart valve or prosthetic material in the heart are at particularly high risk of developing endocarditis. Patients with mitral valve prolapse (MVP) with mitral regurgitation (MR) and those with rheumatic MR also are vulnerable to IE.

4. Bacteremia resulting from dental procedures can cause IE. Bacteremia also occurs with activities such as chewing or brushing the teeth. Chewing with diseased teeth or gums may be the most frequent cause of bacteremia. Therefore, good dental hygiene is very important in the prevention of IE.

Pathology

Vegetation of IE is usually found on the low-pressure side of the defect, either around the defect or on the opposite surface of the defect where endothelial damage is established by the jet effect of the defect. For example, vegetations are found in the PA in patent ductus arteriosus (PDA) or systemic-to-PA shunts, on the atrial surface of the mitral valve in MR, on the ventricular surface of the aortic valve and mitral chordae in aortic regurgitation (AR), and on the superior surface of the aortic valve or at the site of a jet lesion in the aorta in patients with aortic stenosis (AS).

Microbiology

1. In the past, Streptococcus viridans, enterococci, and Staphylococcus aureus were responsible for more than 90% of the cases. In recent years, this frequency has decreased to 50% to 60%, with a concomitant increase in cases caused by fungi and HACEK organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella spp.). HACEK organisms are particularly common in neonates and immunocompromised children, accounting for 17% to 30% of cases.

2. α-Hemolytic streptococci (S. viridans) are the most common cause of endocarditis in patients who have had dental procedures or in those with carious teeth or periodontal disease.

3. Enterococci are the organisms most often found after genitourinary or gastrointestinal (GI) surgery or instrumentation.

4. The organisms most commonly found in postoperative endocarditis are staphylococci.

5. Intravenous (IV) drug abusers are at risk for IE caused by infection with S. aureus.

6. Fungal endocarditis (which has a poor prognosis) may occur in sick neonates, in patients who are on long-term antibiotic or steroid therapy, or after open heart surgery. Fungal endocarditis is often associated with very large friable vegetations; emboli from these vegetations frequently produce serious complications.

7. IE associated with indwelling vascular catheters, prosthetic material, and prosthetic valves is frequently caused by S. aureus or coagulase-negative staphylococci.

8. Among newborn infants, S. aureus, coagulase-negative staphylococci, and Candida spp. are the most common causes of IE.

9. A diagnosis of culture-negative endocarditis is made when a patient has clinical or echocardiographic evidence of endocarditis but persistently negative blood culture results. The most common cause of culture-negative endocarditis is current or recent antibiotic therapy or infection caused by a fastidious organism that grows poorly in vitro. Fungal endocarditis is a rare cause of culture-negative endocarditis. At times, the diagnosis can be made only by removal of vegetation (during surgery). In the United States, about 5% to 7% have culture-negative endocarditis.

Clinical Manifestations

History

1. Most patients have a history of an underlying heart defect. However, some patients with bicuspid aortic valve may not have been diagnosed with the defect before the onset of the endocarditis.

2. A history of a recent dental procedure or tonsillectomy is occasionally present, but a history of toothache (from dental or gingival disease) is more frequent than a history of a procedure.

3. Endocarditis is rare in infancy; at this age, it usually follows open heart surgery.

4. The onset is usually insidious with prolonged low-grade fever and somatic complaints, including fatigue, weakness, loss of appetite, pallor, arthralgia, myalgias, weight loss, and diaphoresis.

Physical Examination

1. Heart murmur is universal (100%). The appearance of a new heart murmur and an increase in the intensity of an existing murmur are important. However, many innocent heart murmurs are also of new onset.

2. Fever is common (80%–90%). Fever fluctuates between 101° and 103°F (38.3° and 39.4°C).

3. Splenomegaly is common (70%).

4. Skin manifestations (50%) (either secondary to microembolization or as an immunologic phenomenon) may be present in the following forms:

a. Petechiae on the skin, mucous membranes, or conjunctivae are the most frequent skin lesions.

b. Osler’s nodes (tender, pea-sized red nodes at the ends of the fingers or toes) are rare in children.

c. Janeway’s lesions (small, painless, hemorrhagic areas on the palms or soles) are rare.

d. Splinter hemorrhages (linear hemorrhagic streaks beneath the nails) also are rare.

5. Embolic or immunologic phenomena in other organs are present in 50% of cases:

a. Pulmonary emboli may occur in patients with VSD, PDA, or a systemic-to-PA shunt.

b. Seizures and hemiparesis are the result of embolization to the central nervous system (CNS) (20%) and are more common with left-sided defects such as aortic and mitral valve disease or with cyanotic heart disease.

c. Hematuria and renal failure may occur.

d. Roth’s spots (oval, retinal hemorrhages with pale centers located near the optic disc) occur in fewer than 5% of patients.

6. Carious teeth or periodontal or gingival disease is frequently present.

7. Clubbing of fingers in the absence of cyanosis develops rarely in more chronic cases.

8. Signs of heart failure may be present as a complication of the infection.

9. The clinical manifestations in a neonate with IE are nonspecific (respiratory distress, tachycardia) and may be indistinguishable from septicemia or congestive heart failure (CHF) from other causes. Embolic phenomena (such as osteomyelitis, meningitis, pneumonia) are common. They may have neurologic signs and symptoms (seizures, hemiparesis, apnea).

Laboratory Studies

1. Positive blood cultures are found in more than 90% of patients in the absence of previous antimicrobial therapy. Antimicrobial pretreatment reduces the yield of positive blood culture to 50% to 60%.

2. A complete blood cell count shows anemia, with hemoglobin levels lower than 12 g/100 mL (present in 80% of patients), and leukocytosis with a shift to the left. Patients with polycythemia preceding the onset of IE may have normal hemoglobin.

3. The sedimentation rate is increased unless there is polycythemia.

4. Microscopic hematuria is found in 30% of patients.

Echocardiography

Two-dimensional echocardiography is the main modality for detecting endocardial infection (Fig. 19-1). It detects the site of infection, extent of valvular damage, and cardiac function. Baseline evaluation of ventricular function and cardiac chamber dimension is important for comparison later in the course of the infection. Color Doppler is a sensitive modality for the detection of valvular regurgitation.

1. Certain echocardiographic findings are included as major criteria in the modified Duke criteria. They include:

a. Oscillating intracardiac mass on valves or supporting structures, in the path of regurgitation jets, or on implanted material

b. Abscesses

c. New partial dehiscence of prosthetic valve

d. New valvular regurgitation

2. Although standard transthoracic echocardiography (TTE) is sufficient in most clinical circumstances, transesophageal echocardiography (TEE) may be an important adjunct to TTE in the obese or very muscular adolescents, in postcardiac surgery patients, or in the presence of compromised respiratory function or pulmonary hyperinflation. TEE may be superior to TTE in identifying vegetations on prosthetic valves, detecting complications of LV outflow tract endocarditis (either valvular or subvalvular), and detecting aortic root abscess and involvement of sinus of Valsalva.

3. The absence of vegetations on echocardiography does not in itself rule out IE. Both TTE and TEE may produce false-negative results if vegetations are small or have already embolized, and they may miss initial perivalvular abscess. Repeat examinations are indicated if suspicion exists without diagnosis of IE or worrisome clinical course during early treatment of IE.

4. Conversely, a false-positive diagnosis is possible. An echogenic mass may represent a sterile thrombus, sterile prosthetic material, normal anatomic variation, an abnormal uninfected valve (previous scarring, severe myxomatous changes), or improper gain of the echocardiography machine. Echocardiographic evidence of vegetation may persist for months or years after bacteriologic cure.

5. Certain echocardiographic features suggest a high-risk case or a need for surgery:

a. Large vegetations (greatest risk when the vegetation is >10 mm)

b. Severe valvular regurgitation

c. Abscess cavities

d. Pseudoaneurysm

e. Valvular perforation or dehiscence

f. Decompensated heart failure

image

FIGURE 19-1 Echoes of aortic valve vegetation. A, Parasternal long-axis view of a young adult patient with a bicuspid aortic valve demonstrating vegetation on the aortic valve (arrow). Severe aortic regurgitation was present, with a dilated left ventricle (LV). B, Five-chamber transverse plane of a transesophageal echocardiographic image on the same patient that demonstrates vegetations and aortic valve anatomy more clearly than the ordinary two-dimensional echocardiography. Ao, aorta; LA, left atrium; RV, right ventricle.

Diagnosis

Recently, the American Heart Association (Baddour et al, 2005) has recommended the modified Duke Criteria in the diagnosis and management of IE. The usefulness of the criteria has been validated in clinical studies.

There are three categories of diagnostic possibilities using the modified Duke criteria: definite, possible, and rejected (Box 19-1).

1. A diagnosis of “definite” IE is made by pathological evidence and fulfillment of certain clinical criteria.

a. Pathological evidence of IE includes (1) demonstration of microorganism by culture, (2) histology in a vegetation or from an embolic sites or an intracardiac abscess, or histologic evidence of active endocarditis demonstrated in vegetation or intracardiac abscess.

b. Fulfillment of clinical criteria is met by the presence of two major criteria, one major and three minor criteria, or five minor criteria as described in Box 19-2. Major clinical criteria are (1) positive blood cultures for acceptable microorganism and (2) evidence of endocardial involvement, demonstrated by echocardiographic findings. A positive echocardiographic finding is considered a major criterion.

2. The category of possible” IE is made when one of the following is present:

a. One major criterion and one minor criterion

b. Three minor criteria

3. The other category of diagnosis is “rejected” IE, which is made:

a. When an alternative diagnosis is established

b. When clinical manifestations of IE have resolved within 4 days of antibiotic therapy

BOX 19-1 Definition of Infective Endocarditis According to the Modified Duke Criteria

Definite Infective Endocarditis

A. Pathological criteria

1. Microorganisms demonstrated by culture or histologic examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen or

2. Pathological lesions; vegetation or intracardiac abscess confirmed by histologic examination showing active endocarditis

B. Clinical criteria

1. Two major criteria or

2. One major criterion and three minor criteria or

3. Five minor criteria

Possible Infective Endocarditis

1. One major criterion and one minor criterion or

2. Three minor criteria

Rejected

1. Firm alternative diagnosis explaining evidence of IE or

2. Resolution of IE syndrome with antibiotic therapy for <4 days or

3. No pathological evidence of IE at surgery or autopsy with antibiotic therapy for <4 days or

4. Does not meet criteria for possible IE as above

IE, infective endocarditis.

Adapted from Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 111(23):e394-e433, 2005.

c. No pathological evidence is found on direct examination of the vegetation obtained from surgery or autopsy after antibiotic therapy for less than 4 days

d. When criteria for possible IE are not met

Management

1. Blood cultures are indicated for all patients with fever of unexplained origin and a pathologic heart murmur, a history of heart disease, or previous endocarditis.

a. Usually three blood cultures are drawn by separate venipunctures over 24 hours unless the patient is very ill. In 90% of cases, the causative agent is recovered from the first two cultures.

b. If there is no growth by the second day of incubation, two more may be obtained. There is no value in obtaining more than five blood cultures over 2 days unless the patient received prior antibiotic therapy.

c. It is not necessary to obtain the cultures at any particular phase of the fever cycle.

d. Adequate volume of blood must be obtained: 1 to 3 mL in infants and young children and 5 to 7 mL in older children are optimal.

e. Aerobic incubation alone suffices because it is rare for IE to be caused by anaerobic bacteria.

2. It is highly recommended that consultation from a local infectious disease specialist be obtained when IE is suspected or confirmed because antibiotics of choice are continually changing, and there may be special situation pertaining to the local area.

3. Initial empirical therapy is started with the following antibiotics while awaiting the results of blood cultures:

a. The usual initial regimen is an antistaphylococcal semisynthetic penicillin (nafcillin, oxacillin, or methicillin) and an aminoglycoside (gentamicin). This combination covers against S. viridans, S. aureus, and gram-negative organisms. Some experts add penicillin to the initial regimen to cover against S. viridans, although a semisynthetic penicillin is usually adequate for initial therapy.

b. If a methicillin-resistant S. aureus is suspected, vancomycin should be substituted for the semisynthetic penicillin.

BOX 19-2 Definition of Terms Used in the Modified Duke Criteria for the Diagnosis of Infective Endocarditis

Major Criteria

A. Blood culture positive for IE

1. Typical microorganisms consistent with IE from two separate blood cultures: Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus; or community-acquired enterococci in the absence of a primary focus or

2. Microorganisms consistent with IE from persistently positive blood cultures defined as follows: at least two positive cultures of blood samples drawn >12 h apart or all of three or a majority of four or more separate cultures of blood (with first and last sample drawn at least 1 h apart)

3. Single positive blood culture for Coxiella burnetii or anti–phase 1 IgG antibody titer >1:800

B. Evidence of endocardial involvement

Echocardiogram positive for IE (TEE is recommended for patients with prosthetic valves, rated at least “possible IE” by clinical criteria, or complicated IE [paravalvular abscess]; TTE as first test in other patients) defined as follows:

1. Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation or

2. Abscess or

3. New partial dehiscence of prosthetic valve or

4. New valvular regurgitation (worsening or changing or preexisting murmur not sufficient)

Minor Criteria

1. Predisposition, predisposing heart condition, or IDU

2. Fever, temperature >38°C

3. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway’s lesions

4. Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor

5. Microbiologic evidence: positive blood culture but does not meet a major criterion as noted above or serologic evidence of active infection with organism consistent with IE

HACEK, Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella spp.; IE, infective endocarditis; IDU, injection drug user; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.


 Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.

Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 111(23):e394-e433, 2005.

c. Vancomycin can be used in place of penicillin or a semisynthetic penicillin in penicillin-allergic patients.

4. The final selection of antibiotics depends on the organism isolated and the results of an antibiotic sensitivity test.

a. Streptococcal IE

(1) In general, patients with native cardiac valve IE caused by a highly sensitive S. viridans can be successfully treated with IV penicillin (or ceftriaxone given once daily) for 4 weeks. Alternatively, penicillin, ampicillin, or ceftriaxone combined with gentamicin for 2 weeks may be used.

(2) For IE caused by penicillin-resistant streptococci, 4 weeks of penicillin, ampicillin, or ceftriaxone combined with gentamicin for the first 2 weeks is recommended.

b. Staphylococcal endocarditis

(1) The drug of choice for native valve IE by methicillin-susceptible staphylococci is one of the semisynthetic β-lactamase–resistant penicillins (nafcillin, oxacillin, or methicillin) for a minimum of 6 weeks (with or without gentamicin for the first 3–5 days).

(2) Patients with methicillin-resistant native valve IE are treated with vancomycin for 6 weeks (with or without gentamicin for the first 3–5 days).

c. Enterococcus-caused native valve endocarditis usually requires a combination of IV penicillin or ampicillin together with gentamicin for 4 to 6 weeks. If patients are allergic to penicillin, vancomycin combined with gentamicin for 6 weeks is required.

d. HACEK organisms have begun to become resistant to ampicillin. Ceftriaxone or another third-generation cephalosporin alone or ampicillin plus gentamicin for 4 weeks is recommended. IE caused by other gram-negative bacteria (such as Escherichia coliPseudomonas aeruginosa, or Serratia marcescens) is treated with piperacillin or ceftazidime together with gentamicin for a minimum of 6 weeks.

e. Amphotericin B is the most effective agent for most fungal infections.

f. For culture-negative endocarditis, treatment is directed against staphylococci, streptococci, and the HACEK organisms using ceftriaxone and gentamicin. When staphylococcal IE is suspected, nafcillin should be added to the above therapy.

5. Patients with prosthetic valve endocarditis should be treated for 6 weeks based on the organism isolated and the results of the sensitivity test. Operative intervention may be necessary before the antibiotic therapy is completed if the clinical situation warrants (e.g., progressive CHF, significant malfunction of prosthetic valves, persistently positive blood cultures after 2 weeks of therapy). Bacteriologic relapse after an appropriate course of therapy also calls for operative intervention.

Prognosis

The overall recovery rate is 80% to 85%; it is 90% or better for S. viridans and enterococci and about 50% for Staphylococcus organisms. Fungal endocarditis is associated with a very poor outcome.

Prevention

In 2007, the American Heart Association (AHA) made a major change in the antibiotic prophylaxis against IE (Wilson et al, 2007). The same was recommended jointly by the American College of Cardiology (ACC) and the AHA in 2008 in a focused practice guideline (Nishimura et al, 2008). The following are the main reasons for the change in the long-standing tradition of antibiotic prophylaxis in patients with most of the CHDs.

1. An exceedingly small number of IE that could be caused by bacteremia-producing dental procedures. The estimated frequency of bacteremia during routine daily activities (e.g., chewing, toothbrushing, flossing, used of toothpicks, use of water irrigation devices, and other activities) far exceeds that occurring during dental procedures. For example, tooth brushing and flossing result in bacteremia 20% to 40% of the time and chewing food results in bacteremia 7% to 51% of the time. The cumulative risk over time of bacteremia from routine daily activities is estimated to be greater than 100,000 times compared with that resulting from dental procedures.

2. Besides, the ability of antibiotic therapy to prevent or reduce bacteremia is controversial, and nonfatal adverse reactions (e.g., rash, diarrhea, and GI upset) also occur frequently.

Therefore, an emphasis should be on maintaining good oral hygiene and eradicating dental disease to decrease the frequency of bacteremia from routine daily activities. The new guidelines recommend antibiotic prophylaxis only for cardiac conditions listed in Box 19-3. Procedures for which antibiotic prophylaxis is recommended and those for which it is not recommended are listed in Box 19-4. Note that prophylaxis is no longer recommended for routine bronchoscopy; it is recommended for tonsillectomy and adenoidectomy only in high-risk patients (see Box 19-4). Prophylaxis is no longer recommended for GI or genitourinary procedures, such as diagnostic esophagogastroduodenoscopy or colonoscopy. Regimens for dental and oral procedures are given in Table 19-1.

Special Situations

1. Patients already receiving antibiotics

a. Rheumatic fever prophylaxis: Rather than using a higher dose of the same antibiotic, use other antibiotics, such as clindamycin, azithromycin, or clarithromycin.

b. If possible, delay a dental procedure until at least 10 days after completion of the antibiotic therapy.

TABLE 19-1

PROPHYLACTIC REGIMENS FOR DENTAL PROCEDURES

image

IM, intramuscular; IV, intravenous.

 Or other first- or second-generation oral cephalosporin in equivalent adult or pediatric dosage.

 Cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema, or urticaria with penicillin or ampicillin.

BOX 19-3 Cardiac Conditions for Which Prophylaxis with Dental Procedures is Recommended

1. Patients with prosthetic cardiac valve or prosthetic material used for cardiac valve repair

2. Patients with previous IE

3. Patients with CHD:

a. Unrepaired cyanotic CHD, including palliative shunts and conduits

b. Completely repaired CHD with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure

c. Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibits endothelialization)

4. Cardiac transplantation recipients with valve regurgitation caused by a structurally abnormal valve

CHD, congenital heart disease; IE, infective endocarditis.


 Prophylaxis is recommended because endothelialization of prosthetic material occurs within 6 months after the procedure.

BOX 19-4 Procedures for Which Endocarditis Prophylaxis is Recommended

1. Dental procedures

All dental procedures that involve manipulation of gingival tissue of the periapical region of teeth or perforation of the oral mucosa. Antibiotic choices and dosages for dental procedures are shown in Table 19-1.

2. Respiratory tract procedures

a. Prophylaxis is recommended for the procedures that involve incision or biopsy of the respiratory mucosa, such as tonsillectomy and adenoidectomy.

b. Prophylaxis is not recommended for bronchoscopy (unless it involves incision of the mucosa, such as for abscess or empyema).

3. GI or GU procedures

a. No prophylaxis is used for diagnostic esophagogastroduodenoscopy or colonoscopy.

b. Prophylaxis is reasonable in patients with infected GI or GU tract (with amoxicillin or ampicillin to cover against enterococci).

4. Skin, skin structure, or musculoskeletal tissue

a. Prophylaxis is recommended for surgical procedures that involve infected skin, skin structure, or musculoskeletal tissue (with antibiotics against staphylococcus and ß-hemolytic streptococcus, such as antistaphylococcal penicillin or a cephalosporin).

b. Vancomycin or clindamycin is administered if unable to tolerate ß-lactam or if infection is caused by methicillin-resistant staphylococcus.

GI, gastrointestinal; GU, genitourinary.

2. Patients who undergo cardiac surgery: A careful preoperative dental evaluation is recommended so that required dental treatment may be completed whenever possible before cardiac valve surgery or replacement or repair of a CHD. Prophylaxis at the time of surgery should be directed primarily against staphylococci and should be of short duration. Prophylaxis should be initiated immediately before the operative procedure, repeated during prolonged procedures to maintain serum concentrations intraoperatively, and continued for no more than 48 hours postoperatively.

Myocarditis

Prevalence

Myocarditis severe enough to be recognized clinically is rare, but the prevalence of mild and subclinical cases is probably much higher.

Pathology

1. The principal mechanism of cardiac involvement in viral myocarditis is believed to be a cell-mediated immunologic reaction, not merely myocardial damage from viral replication. Isolation of virus from the myocardium is unusual at autopsy.

2. The inflamed myocardium is soft, flabby, and pale, with areas of scarring on gross examination. Microscopic examination reveals patchy infiltrations by plasma cells, mononuclear leukocytes, and some eosinophils during the acute phase and giant cell infiltration in the later stages.

Cause

1. In North America, viruses are probably the most common causes of myocarditis. Among viruses, adenovirus, coxsackievirus B, and echoviruses are the most common agents. Many other viruses (e.g., poliomyelitis, mumps, measles, rubella, cytomegalovirus [CMV], HIV, arboviruses, influenza) can cause myocarditis. In South America, Chagas’ disease (caused by Trypanosoma cruzi, a protozoan) is a common cause of myocarditis. Rarely, bacteria, rickettsia, fungi, protozoa, and parasites are the causative agents.

2. Immune-mediated diseases, including acute rheumatic fever and Kawasaki’s disease, may be the cause.

3. Collagen vascular diseases can cause myocarditis.

4. Toxic myocarditis (from drug ingestion, diphtheria exotoxin, and anoxic agents) occurs.

Clinical Manifestations

History

1. Older children may have a history of an upper respiratory infection.

2. The illness may have a sudden onset in newborns and small infants, with anorexia, vomiting, lethargy, and occasionally circulatory shock.

Physical Examination

1. The presentation depends on the patient’s age and the acute or chronic nature of the infection. In neonates and infants, signs of CHF may be present; these include poor heart tone, tachycardia, gallop rhythm, tachypnea, and (rarely) cyanosis. In older children, a gradual onset of CHF and arrhythmia are commonly seen.

2. A soft, systolic heart murmur and irregular rhythm caused by supraventricular or ventricular ectopic beats may be audible.

3. Hepatomegaly (evidence of viral hepatitis) may be present.

Electrocardiography

Any one or a combination of the following may be seen: low QRS voltages, ST-T changes, PR prolongation, prolongation of the QT interval, and arrhythmias (especially premature contractions).

Radiography

Cardiomegaly of varying degrees is the most important clinical sign of myocarditis.

Echocardiography

Echocardiography reveals cardiac chamber enlargement and impaired left ventricle (LV) function, often regional in nature. Occasionally, increased wall thickness and LV thrombi are found.

Laboratory Studies

1. Cardiac troponin levels (troponin I and T) and myocardial enzymes (creatine kinase [CK], MB isoenzyme of CK [CK-MB]) may be elevated. In children, the normal value of cardiac troponin I has been reported to be 2 ng/mL or less, and it is frequently below the level of detection for the assay. Troponin levels may be more sensitive than the cardiac enzymes.

2. Radionuclide scanning (after administration of gallium-67 or technetium-99m pyrophosphate) may identify inflammatory and necrotic changes characteristic of myocarditis.

3. Myocarditis can be confirmed by an endomyocardial biopsy.

Natural History

1. The mortality rate is as high as 75% in symptomatic neonates with acute viral myocarditis.

2. The majority of patients, especially those with mild inflammation, recover completely.

3. Some patients develop subacute or chronic myocarditis with persistent cardiomegaly (with or without signs of CHF) and ECG evidence of left ventricular hypertrophy (LVH) or biventricular hypertrophy (BVH). Clinically, these patients are indistinguishable from those with dilated cardiomyopathy. Myocarditis may be a precursor to idiopathic dilated cardiomyopathy in some cases.

Management

1. One should attempt virus identification by viral cultures from the blood, stool, or throat washing. Acute and convalescent sera should be compared for serologic titer rise.

2. Bed rest and limitation in activities are recommended during the acute phase (because exercise intensifies the damage from myocarditis in experimental animals).

3. Anticongestive measures include the following:

a. Rapid-acting diuretics (furosemide or ethacrynic acid, 1 mg/kg, each one to three times a day)

b. Rapid-acting inotropic agents, such as dobutamine or dopamine, are useful in critically ill children.

c. Oxygen and bed rest are recommended. Use of a “cardiac chair” or “infant seat” relieves respiratory distress.

d. Digoxin may be given cautiously using half of the usual digitalizing dose (see Table 27-5) because some patients with myocarditis are exquisitely sensitive to the drug.

4. Recently, beneficial effects of high-dose gamma globulin (2 g/kg over 24 hours) have been reported. Gamma globulin was associated with better survival during the first year after presentation, echocardiographic evidence of smaller LV diastolic dimension, and higher fractional shortening compared with the control group. Myocardial damage in myocarditis is mediated in part by immunologic mechanisms, and a high dose of gamma globulin is an immunomodulatory agent, shown to be effective in myocarditis secondary to Kawasaki’s disease.

5. Angiotensin-converting enzyme inhibitors, such as captopril, may prove beneficial in the acute phase (as demonstrated in animal experiments).

6. Arrhythmias should be treated aggressively and may require the use of IV amiodarone.

7. The role of corticosteroids is unclear at this time except in the treatment of severe rheumatic carditis.

8. Specific therapies include antitoxin in diphtheritic myocarditis.

Pericarditis

Cause

1. Viral infection is probably the most common cause of pericarditis, particularly in infancy. Many viruses similar to those listed in the section on myocarditis can cause pericarditis.

2. Acute rheumatic fever is a common cause of pericarditis, especially in certain parts of the world (see also Chapter 20).

3. Bacterial infection (purulent pericarditis) is a rare, serious form of pericarditis. Commonly encountered are S. aureusStreptococcus pneumoniaeHaemophilus influenzaeNeisseria meningitidis, and streptococci.

4. Tuberculosis is an occasional cause of constrictive pericarditis with an insidious onset.

5. Heart surgery is a possible cause (see Postpericardiotomy Syndrome).

6. Collagen disease such as rheumatoid arthritis (see Chapter 23) can cause pericarditis.

7. Pericarditis can be a complication of oncologic disease or its therapy, including radiation.

8. Uremia (uremic pericarditis) is a rare cause.

Pathology

The parietal and visceral surfaces of the pericardium are inflamed. Pericardial effusion may be serofibrinous, hemorrhagic, or purulent. Effusion may be completely absorbed or may result in pericardial thickening or chronic constriction (constrictive pericarditis).

Pathophysiology

The pathogenesis of symptoms and signs of pericardial effusion is determined by two factors: the speed of fluid accumulation and the competence of the myocardium. A rapid accumulation of a large amount of pericardial fluid produces more serious circulatory embarrassment. A slow accumulation of a relatively small amount of fluid may result in serious circulatory embarrassment (cardiac tamponade) if the extent of myocarditis is significant. Slow accumulation of a large amount of fluid may be accommodated by stretching of the pericardium if the myocardium is intact.

With the development of pericardial tamponade, several compensatory mechanisms are triggered, including systemic and pulmonary venous constriction to improve diastolic filling, an increase in systemic vascular resistance to raise falling blood pressure, and tachycardia to improve cardiac output.

Clinical Manifestations

History

1. The patient may have a history of upper respiratory tract infection.

2. Precordial pain (dull, aching, or stabbing) with occasional radiation to the shoulder and neck may be a presenting complaint. The pain may be relieved by leaning forward and may be made worse by the supine position or deep inspiration.

3. Fever of varying degrees may be present.

Physical Examination

1. Pericardial friction rub (a grating, to-and-fro sound in phase with the heart sounds) is the cardinal physical sign.

2. The heart is quiet and hypodynamic in the presence of a large amount of pericardial effusion.

3. Pulsus paradoxus is characteristic of pericardial effusion with tamponade (see Chapter 2 and Fig. 2-2).

4. Heart murmur is usually absent, although it may be present in acute rheumatic carditis (see Chapter 20).

5. In children with purulent pericarditis, septic fever (101°–105° F [38.3°–40.5°C]), tachycardia, chest pain, and dyspnea are almost always present.

6. Signs of cardiac tamponade may be present: distant heart sounds, tachycardia, pulsus paradoxus, hepatomegaly, venous distention, and occasional hypotension with peripheral vasoconstriction. Cardiac tamponade occurs more commonly in purulent pericarditis than in other forms of pericarditis.

Electrocardiography

1. The low-voltage QRS complex caused by pericardial effusion is characteristic but not a constant finding.

2. The following time-dependent changes secondary to myocardial involvement may occur (see Fig. 3-25):

a. Initial ST segment elevation

b. Return of the ST segment to the baseline with inversion of T waves (2–4 weeks after onset)

Chest Radiography

1. A varying degree of cardiomegaly is present.

2. A pear-shaped or water-bottle-shaped heart is characteristic of a large effusion.

3. Pulmonary vascular markings may be increased if cardiac tamponade develops. Tamponade may occur without enlargement of the cardiac silhouette if it develops quickly.

Echocardiography

Echocardiography is the most useful tool in establishing the diagnosis of pericardial effusion. It appears as an echo-free space between the epicardium (visceral pericardium) and the parietal pericardium.

1. Pericardial effusion first appears posteriorly in the dependent portion of the pericardial sac. The presence of a small amount of effusion posteriorly without anterior effusion suggests a small pericardial effusion. A small amount of fluid, which appears only in systole, is normal.

2. With larger effusion, the fluid also appears anteriorly. The larger the echo-free space, the larger the pericardial effusion. With very large effusions, the swinging motion of the heart may be imaged.

3. In patients with chronic effusion, fibrinous strands and other organized materials can be seen in the pericardial fluid, which may lead to fluid loculations.

4. Echocardiography is very helpful in detecting cardiac tamponade. Helpful two-dimensional echocardiographic findings of tamponade are as follows:

a. Collapse of the right atrium (RA) in late diastole (Fig. 19-2) (because the pressure in the pericardial sac exceeds the pressure within the RA at end diastole when the atrium has emptied)

b. Collapse or indentation of the right ventricular (RV) free wall, especially the outflow tract

Management

1. Pericardiocentesis or surgical drainage to identify the cause of the pericarditis is mandatory, especially when purulent or tuberculous pericarditis is suspected. A drainage catheter may be left in place with intermittent low-pressure drainage.

image

FIGURE 19-2 Subcostal four-chamber view demonstrating pericardial effusion (PE) and collapse of the right atrial wall (large arrow), a sign of cardiac tamponade. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

2. Pericardial fluid studies include cell counts and differential, glucose, and protein concentrations; histologic examination of cells; Gram and acid-fast stains; and viral, bacterial, and fungal cultures.

3. For cardiac tamponade, urgent decompression by surgical drainage or pericardiocentesis is indicated. While getting ready for the procedure, fluid push with Plasmanate should be given to increase central venous pressure and thereby improve cardiac filling, which can provide temporary emergency stabilization.

4. Urgent surgical drainage of the pericardium is indicated when purulent pericarditis is suspected. This must be followed by IV antibiotic therapy for 4 to 6 weeks.

5. There is no specific treatment for viral pericarditis.

6. Treatment focuses on the basic disease itself (e.g., uremia, collagen disease).

7. Salicylates are given for precordial pain and nonbacterial or rheumatic pericarditis.

8. Corticosteroid therapy may be indicated in children with severe rheumatic carditis or postpericardiotomy syndrome.

Constrictive Pericarditis

Although rare in children, constrictive pericarditis may be associated with an earlier viral pericarditis, tuberculosis, incomplete drainage of purulent pericarditis, hemopericardium, mediastinal irradiation, neoplastic infiltration, or connective tissue disorders. In this condition, a fibrotic, thickened, and adherent pericardium restricts diastolic filling of the heart.

Diagnosis of constrictive pericarditis is suggested by the following clinical findings:

1. Signs of elevated jugular venous pressure occur.

2. Hepatomegaly with ascites and systemic edema may be present.

3. Diastolic pericardial knock, which resembles the opening snap, is often heard along the left sternal border in the absence of heart murmur.

4. Chest radiograph may show calcification of the pericardium, enlargement of the superior vena cava (SVC) and left atrium (LA), and pleural effusion.

5. The ECG may show low QRS voltages, T-wave inversion or flattening, and left atrial hypertrophy (LAH). Atrial fibrillation occasionally is seen.

6. M-mode echocardiography may reveal two parallel lines representing the thickened visceral and parietal pericardia or multiple dense echoes. Two-dimensional echocardiography shows (a) a thickened pericardium, (b) a dilated inferior vena cava and hepatic vein, and (c) paradoxical septal motion and abrupt displacement of the interventricular septum during early diastolic filling (“septal bounce”) (not specific for this condition). Doppler examination of the mitral inflow reveals findings of diastolic dysfunction (see Fig. 18-6) and a marked respiratory variation in diastolic inflow tracings.

7. Cardiac catheterization may document the presence of constrictive physiology.

a. The RA and LA pressures, ventricular end-diastolic pressures, and PA wedge pressure are all elevated and usually equalized.

b. Ventricular pressure waveforms demonstrate the characteristic “square root sign” (in which there is an early rapid fall in diastolic pressure followed by a rapid rise to an elevated diastolic plateau).

The treatment for constrictive pericarditis is complete resection of the pericardium; symptomatic improvement occurs in 75% of patients.

Kawasaki’s Disease

Cause and Epidemiology

1. The cause of Kawasaki’s disease (also called mucocutaneous lymph node syndrome) is not known. Most investigators believe that the disease is related to, if not caused by, an infectious disease. The disease is probably driven by abnormalities of the immune system initiated by the infectious insult.

2. Children of all racial and ethnic groups are affected, although it is more common in Asians and Pacific islanders. The male-to-female ratio is 1.5 to 1. In the United States, Kawasaki’s disease is more common during the winter and early spring months.

3. It occurs primarily in young children, with a peak incidence between 1 and 2 years of age; 80% of patients are younger than 4 years of age, and 50% are younger than 2 years of age. Cases in children older than 8 years and younger than 3 months of age are uncommon.

Pathology

1. During the first 10 days after the onset of fever, generalized microvasculitis occurs throughout the body, with a predilection for the coronary arteries. Other arteries such as the iliac, femoral, axillary, and renal arteries are less frequently involved.

2. Coronary artery aneurysm develops in 15% to 20% during the acute phase and persists for 1 to 3 weeks. It tends to develop most frequently in the proximal segment of the major coronary arteries and may assume fusiform, saccular, cylindrical, or beads-on-a-string appearance.

3. During the acute phase, there is pancarditis, with inflammation of the atrioventricular (AV) conduction system (which can produce AV block), myocardium (myocardial dysfunction, CHF), pericardium (pericardial effusion), and endocardium (with aortic and mitral valve involvement).

4. Late changes (after 40 days) consist of healing and fibrosis in the coronary arteries, with thrombus formation and stenosis in the postaneurysmal segment and myocardial fibrosis from old myocardial infarction (MI).

5. The elevated platelet count seen in this condition contributes to coronary thrombosis.

Clinical Manifestations

The clinical course of the disease can be divided into three phases: acute, subacute, and convalescent. Each phase of the disease is characterized by unique symptoms and signs. Only clinical features seen in the acute phase are important in making the diagnosis of the disease, and they are discussed in depth.

Acute Phase (First 10 Days)

1. Six signs that compose the principal clinical features of Kawasaki’s disease are present during the acute phase (Box 19-5).

a. The onset of illness is abrupt, with a high fever, usually above 39°C (102°F) and in many cases above 40°C (104°F). Fever persists for a mean of 11 days without treatment. With appropriate therapy, the fever usually resolves within 2 days of treatment. Within 2 to 5 days after the onset of fever, other principal features develop.

b. Conjunctivitis occurs shortly after the onset of fever. It is not associated with exudate, being different from that seen in other conditions such as measles, Stevens-Johnson syndrome, or viral conjunctivitis. Conjunctivitis resolves rapidly.

BOX 19-5 Principal Clinical Features for Diagnosis of Kawasaki’s Disease

• Fever persisting at least 5 days

• Presence of at least 4 of the following principal features:

1. Changes in extremities:

Acute: erythema of palms and soles; edema of hands and feet

Subacute: periungual peeling of fingers and toes in weeks 2 and 3

2. Polymorphous exanthema

3. Bilateral bulbar conjunctival injection without exudates

4. Changes in the lips and oral cavity: erythema, lips cracking, strawberry tongue, diffuse injection of oral and pharyngeal mucosa

5. Cervical lymphadenopathy (>1.5 cm in diameter), usually unilateral

• Exclusion of other diseases with similar findings (see Differential Diagnosis)

Adapted from Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 114:1708-1733, 2004.

c. Changes in the lips and oral cavity include (1) erythema, dryness, fissuring, peeling, cracking, and bleeding of the lips; (2) “strawberry tongue” that is indistinguishable from scarlet fever; (3) diffuse erythema of the oropharyngeal mucosa. Oral ulceration and pharyngeal exudates are not seen.

d. Changes in the hands and feet consist of erythema of the palms and soles, firm edema, and sometimes painful induration. Desquamation of hands and feet takes place within 2 to 3 weeks.

e. The rash usually appears within 5 days of the onset of fever and may take many forms (except bullous and vesicular eruptions) even in the same patient. The most common is a nonspecific, diffuse maculopapular eruption. Its distribution is extensive involving the trunk and extremities, with accentuation in the perineal region (where early desquamation may occur); desquamation usually occurs by days 5 to 7.

f. Cervical lymph node enlargement is the least common of the principal clinical features, occurring in approximately 50% of patients. The firm swelling is usually unilateral, involves more than one node measuring larger than 1.5 cm in diameter, and is confined to the anterior cervical triangle.

2. Cardiovascular abnormalities result from involvement of the pericardium, myocardium, endocardium, valves, and coronary arteries, with some or all of the following manifestations:

a. Tachycardia, gallop rhythm, or other signs of heart failure

b. LV dysfunction with cardiomegaly (myocarditis)

c. Pericardial effusion

d. Mitral valve regurgitation murmur

e. Chest radiographs may show cardiomegaly if myocarditis or significant coronary artery abnormality or valvular regurgitation is present.

f. ECG changes may include arrhythmias, prolonged PR interval (occurring in up to 60%), and nonspecific ST-T changes. Abnormal Q waves (wide and deep) in the limb leads or precordial leads suggest MI.

g. Coronary artery abnormalities are seen initially at the end of the first week through the second week of illness (see below for further discussion).

3. Involvement of other organ systems is also frequent during the acute phase.

a. Musculoskeletal system: Arthritis or arthralgia of multiple joints (30%) involving small joints as well as large joints

b. Genitourinary system: Sterile pyuria (60%)

c. GI system: Abdominal pain with diarrhea (20%), liver dysfunction (40%), hydrops of the gallbladder (10%, demonstrable by abdominal ultrasonography) with jaundice

d. CNS: Irritability, lethargy or semicoma, aseptic meningitis (25%), and sensory neuronal hearing loss

4. Laboratory studies: Even though laboratory results are nonspecific, they provide diagnostic support of the disease during the acute phase. For example, Kawasaki’s disease is unlikely if acute phase reactants and platelet counts are normal after 7 days of the illness.

a. Marked leukocytosis with a shift to the left and anemia are common.

b. Acute phase reactant levels (C-reactive protein [CRP] levels, erythrocyte sedimentation rate [ESR]) are always elevated, which are uncommon with viral illnesses. An elevated ESR (but not CRP) can be caused by intravenous immunoglobulin (IVIG) infusion per se.

c. Thrombocytosis (usually >450,000 /mm3) occurs after day 7 of the illness, sometimes reaching 600,000 to greater than 1 million/mm3 during the subacute phase. A low platelet count suggests viral illnesses.

d. Pyuria (caused by urethritis) is common on microscopic examination.

e. Liver enzymes are moderately elevated (more than two times the upper limit of normal) in 40% of patients, hypoalbuminemia, and mild hyperbilirubinemia may be present in 10%.

f. Elevated serum cardiac troponin I may occur, which suggests myocardial damage.

g. Lipid abnormalities are common. Decreased levels of high-density lipoprotein are present during the illness and follow-up for more than 3 years, especially in patients with persistent coronary artery abnormalities. The total cholesterol level is normal, but the triglyceride level tends to be high. Repeat measurement is recommended 1 year later in patients with abnormal lipid profiles.

5. Echocardiography: The main purpose of an echocardiographic study during the acute phase is to detect coronary artery aneurysm and other cardiac dysfunction.

a. Coronary artery aneurysm rarely occurs before day 10 of illness. During this period, other echocardiographic findings may suggest cardiac involvement.

(1) Perivascular brightness and ectasia (dilatation) may represent coronary arteritis (before aneurysm formation)

(2) Decreased LV systolic function with increased LV dimensions

(3) Mild mitral valve regurgitation (presumably from myocarditis, MI, or coronary artery occlusion)

(4) Pericardial effusion

b. Multiple echocardiographic views should be obtained to visualize all major coronary artery segments (left main coronary artery [LMCA], left anterior descending [LAD], left circumflex coronary artery [LCX], and right coronary artery [RCA]).

c. The configuration (saccular, fusiform, ectatic), size, and number of aneurysm and the presence or absence of intraluminal or mural thrombi should be assessed. Aneurysms are classified as saccular (nearly equal axial and lateral diameters), fusiform (symmetric dilatation with gradual proximal and distal tapering), and ectatic (dilated without segmental aneurysm). “Giant” aneurysm is present when the diameter of the aneurysm is 8 mm or larger. Figure 19-3 shows a large saccular aneurysm of the RCA.

Clinical findings seen during the subacute phase and convalescent phase are not important in diagnosis or planning management, but they are more or less useful in confirming the diagnosis at a later time.

Subacute Phase (11–25 Days after Onset)

1. Desquamation of the tips of the fingers and toes is characteristic.

2. Rash, fever, and lymphadenopathy disappear.

3. Significant cardiovascular changes, including coronary aneurysm, pericardial effusion, CHF, and MI, occur in this phase. Approximately 20% of patients manifest coronary artery aneurysm on echocardiography.

4. Thrombocytosis also occurs during this period, peaking at 2 weeks or more after the onset of the illness.

image

FIGURE 19-3 Parasternal short-axis view from a patient with Kawasaki’s disease. There is a large saccular aneurysm (arrow) of the right coronary artery. A, anterior; AO, aorta; MPA, main pulmonary artery; R, right; RA, right atrium; RV, right ventricle. (From Snider AR, Serwer GA: Echocardiography in Pediatric Heart Disease. St. Louis, Mosby, 1990.)

Convalescent Phase

This phase lasts until the elevated ESR and platelet count return to normal. Deep transverse grooves (Beau’s lines) may appear across the fingernails and toenails.

Diagnosis

There is no specific diagnostic test or pathognomonic clinical feature of Kawasaki’s disease. The diagnosis of Kawasaki’s disease relies on clinical criteria. Box 19-5 lists the principal clinical features that establish the diagnosis. In cases with less than full criteria for the disease (incomplete Kawasaki’s disease), other clinical and laboratory findings (as discussed earlier) may aid physicians in making decision to initiate treatment. One could also consider the Harada score (see below) in the decision making to initiate treatment.

1. The presence of fever for 5 days or longer and at least four of the five principal criteria (see Box 19-5) are required to make the diagnosis of Kawasaki’s disease. More than 90% of patients have fever plus the first four of the five signs, but only about 50% of patients have lymphadenopathy.

2. However, patients with fever for 5 days or longer and fewer than four criteria can be diagnosed as having Kawasaki’s disease when a coronary artery abnormality is detected. Indeed, a substantial fraction of children with Kawasaki’s disease with coronary artery anomalies never meet the diagnostic criteria. However, coronary aneurysm rarely occurs before day 10 of Kawasaki’s disease. During this period, perivascular brightness or ectasia (dilatation) of the coronary artery, decreased LV systolic function, mild MR, or pericardial effusion may be present instead.

3. In the presence of four or more principal criteria plus fever, a diagnosis of Kawasaki’s disease can be made on day 4 of illness rather than waiting until day 5 of illness. (However, there appears to be no advantage giving IVIG before 5 days of illness in preventing coronary artery aneurysm.)

4. Incomplete (preferable to “atypical”) Kawasaki’s disease with two or three principal clinical features creates a management problem. Incomplete Kawasaki’s disease is more common in young infants than older children. Given the potential serious consequences of missing the diagnosis of Kawasaki’s disease in patients with incomplete manifestations of the principal clinical features, together with the efficiency and safety of early treatment with IVIG, physicians should not wait for full manifestations of the disease but should consider other clinical manifestations and laboratory findings in deciding whether or not to initiate treatment.

a. When incomplete Kawasaki’s disease is suspected, some laboratory tests should be obtained because their results are similar to those found in complete cases.

(1) Abnormal acute phase reactants (CRP ≥3.0 mg/dL and ESR ≥40 mm/hr) are very helpful.

(2) Other helpful supplemental laboratory tests (with their abnormal values shown in parentheses) are serum albumin (≤3.0 g/dL), anemia for age, alanine aminotransferase (>50 or 60 U/L), platelets after 7 days (≥450,000/mm3), white blood cell count (≥15,000/mm3), and urine white blood cell count (≥10 cells/high-power field).

(3) Patients with positive acute phase reactants plus three or more abnormal supplemental laboratory test results may be given treatment along with echocardiographic studies. Even if there are fewer than three abnormal laboratory test results, patients with abnormal echocardiographic findings qualify for treatment.

b. Echocardiographic studies should also be obtained, especially in young infants with fever for longer than 7 days.

5. The detection of coronary artery abnormalities relies on the measurement of the proximal coronary artery segments. Kurotobi et al (2002) published the mean and prediction limits of 2 and 3 standard deviations (SDs) of major coronary artery segments in normal infants and children and those with Kawasaki’s disease, which are shown in Appendix D (Table D-6). One must measure the dimension at a specific point as shown in the figure in Table D-6. The LMCA is measured at a point between the ostium and the first bifurcation of the artery, the LAD distal to and away from the bifurcation of the branch from the LMCA and the RCA in the relatively straight section of the artery just after rightward turn from the initial anterior course of the artery.

A coronary dimension that is greater than +3 SD in one of the three proximal segments (LMCA, LAD, and RCA) or one that is greater than +2.5 SD in two proximal segments is highly unusual in the normal population (Kurotobi et al, 2002).

6. The Harada score has been devised to predict increased risk of developing coronary aneurysm. According to this score, when assessed in the first 9 days of the illness, the presence of four of the following criteria indicates a case at high risk for future development of coronary artery aneurysm: (a) white blood cell count above 12,000/mm3, (b) platelet count above 350,000/mm3, (c) CRP greater than +3, (d) hematocrit less than 35%, (e) albumin less than 3.5 g/dL, (f) age 12 months or younger, and (g) male sex. These criteria have been adopted by the AHA Committee.

Differential Diagnosis

One must rule out diseases with similar manifestations through appropriate cultures and the use of laboratory tests (Box 19-6). Measles and group A β-hemolytic streptococcal infection most closely mimic Kawasaki’s disease. Children with Kawasaki’s disease are extremely irritable (often inconsolable). In addition, children with Kawasaki’s disease are less likely to have exudative conjunctivitis, pharyngitis, generalized lymphadenopathy, or discrete intraoral lesions (Koplik’s spot) and are more likely to have a perineal distribution of their rash. Other diseases with findings similar to Kawasaki’s disease, such as viral exanthems, drug reactions, juvenile rheumatoid arthritis, and Rocky Mountain spotted fever, require differentiation. Viral illness is more likely if acute phase reactants and platelet counts are normal after 7 days of the illness.

Management

No specific therapy is available. Two goals of therapy are reduction of inflammation within the coronary artery and in the myocardium (by IV gamma globulin) and prevention of thrombosis by inhibition of platelet aggregation (by aspirin).

1. A high-dose (2 g/kg), single infusion (given in a 10- to 12-hour infusion) of IVIG with aspirin (80–100 mg/kg per day) given within 10 days and, if possible, within 7 days of illness is considered the treatment of choice.

2. IVIG, not aspirin, significantly reduces the prevalence of coronary artery abnormalities. Aspirin only helps reduce thrombus formation but does not reduce coronary artery aneurysm.

a. After IVIG infusion, two thirds of patients become afebrile by 24 hours after completion of infusion; 90% are afebrile by 48 hours.

b. A repeat dose (2 g/kg) of IVIG is indicated in children with a persistent fever.

c. IVIG given before 5 days of illness appears no more likely to prevent coronary aneurysm but was associated with increased need for retreatment with gamma globulin for persistent or recrudescent fever.

d. Gamma globulin should be given even after day 10 of illness if the patient has persistent fever, aneurysms, or ongoing systemic inflammation (by ESR or CRP).

e. Measles and varicella immunization should be deferred for 11 months after a child receives high-dose IVIG.

BOX 19-6 Differential Diagnosis of Kawasaki’s Disease

Viral infections (e.g., measles, adenovirus, enterovirus, Epstein-Barr virus)

Scarlet fever

Staphylococcal scalded skin syndrome

Toxic shock syndrome

Bacterial cervical lymphadenopathy

Drug hypersensitivity reaction

Stevens-Johnson syndrome

Juvenile rheumatoid arthritis

Rocky Mountain spotted fever

Leptospirosis

Mercury hypersensitivity reaction (acrodynia)

3. Aspirin has antiinflammatory effects at high doses (80–100 mg/kg/day) and an antiplatelet action at low doses (3–5 kg/day).

a. The initial high dose of aspirin is reduced to 3 to 5 mg/kg/day in a single dose after the child has been afebrile for 48 to 72 hours. Some physicians continue high-dose aspirin until day 14 of illness and for 48 to 72 hours or more after fever cessation.

b. Aspirin is continued until the patient shows no evidence of coronary changes by 6 to 8 weeks after the onset of illness.

c. For children who develop coronary abnormalities, aspirin may be continued indefinitely.

d. Some Japanese authorities recommend the antiplatelet dose of aspirin from the onset because the high dose does not have antiplatelet action; does not appear to reduce coronary aneurysm; and may result in increased frequency of hepatotoxicity, GI irritation and bleeding, and Reye’s syndrome.

4. A concomitant use of corticosteroids has been reported to reduce the duration of fever and possibly the incidence of coronary aneurysm (Okada et al, 2003). An earlier study, before IVIG was available, suggested that corticosteroids exert a detrimental effect with increased incidence of coronary aneurysm. Therefore, the usefulness of steroids in the initial treatment of Kawasaki’s disease is not well established at this time.

5. Recently, the administration of infliximab, another antiinflammatory agent, has increased in the United States despite the absence of clinical evidence of its efficacy (Son et al, 2009). Infliximab, a monoclonal antibody to tumor necrosis factor α (TNF-α), blocks the attachment of TNF-α to T cells, ameliorating the inflammatory response. Because TNF-α has inflammatory and thrombotic properties, blocking its actions appears to be a logical approach. Infliximab has been approved by the Food and Drug Administration (FDA) for use in children with Crohn’s disease.

6. For patients who continue to be febrile after IVIG (occurring in about 10% of patients), repeat IVIG (2 g/kg) is generally recommended. If the patient continues to have fever despite two or more courses of IVIG, the use of corticosteroid therapy may be tried.

7. In patients with large coronary artery aneurysm, administration of abciximab, a platelet glycoprotein IIb/IIIa receptor inhibitor, was associated with greater regression of the aneurysm compared with patients who received only the standard treatment (γ-globulin, aspirin) at 4 to 6 months of follow-up (Williams et al, 2002).

8. In patients with coronary artery aneurysm, therapeutic regimens used depend on the severity of coronary involvement.

a. For mild and stable disease, low-dose aspirin may be appropriate.

b. With increasing severity and extent of coronary involvement, the combination of aspirin with other antiplatelet agents (e.g., dipyridamole [Persantine], clopidogrel [Plavix]) may be more effective in suppressing platelet activation.

c. For giant aneurysm or the combination of stenosis and aneurysm, low-dose aspirin together with warfarin (with international normalized ratio maintained at 2.0–2.5) should be used.

Natural History

Kawasaki’s disease is a self-limited disease for most patients. Cardiovascular involvement is the most serious complication.

1. Coronary aneurysm develops in 15% to 25% of untreated patients and is responsible for MI (<5%) and mortality (1%–5%). Significantly higher temperature (101.3°F [38.5°C] on days 9–12) and longer duration of fever (more than 14 days) appear to be risk factors for coronary aneurysm. Despite prompt treatment with high-dose IVIG, at least transient coronary artery abnormalities develop in 5% of the patients and giant aneurysm in 1%.

2. Angiographic resolution of aneurysm 1 to 2 years after the illness occurs in 50% to 67% of the patients, but these arteries do not dilate in response to exercise or coronary vasodilators. In some patients, stenosis, tortuosity, and thrombosis of the coronary arteries result. The resolution appears to be more likely to occur with a smaller aneurysm, age at onset younger than 1 year, fusiform rather than saccular aneurysm, and aneurysm located at a distal coronary segment.

3. More than 70% of MIs occur in the first year after onset of the disease without warning symptoms or signs. Giant aneurysm (>8 mm) is associated with a greater morbidity and mortality (because of thrombotic occlusion or stenotic obstruction and subsequent MI).

4. If the coronary arteries remain normal throughout the first month after onset, subsequent development of a new coronary lesion is extremely unusual.

Long-Term Follow-up

Serial cardiology follow-up is important for evaluation of the cardiac status. The recommendations of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, American Heart Association (2004) are summarized in Table 19-2.

1. For children with no or transient coronary abnormalities, aspirin is discontinued after 6 to 8 weeks. No follow-up diagnostic tests are indicated. Only periodic counseling is recommended.

2. If the patient has a coronary aneurysm, low-dose aspirin is continued indefinitely. With a large aneurysm, a combination of aspirin and warfarin is indicated.

3. Varying levels of activity restriction are indicated in patients who have coronary artery aneurysm (see Table 19-2).

4. Echocardiography: In the absence of coronary artery abnormalities in the first 6 to 8 weeks, follow-up echocardiograms are not indicated. If significant abnormalities of the coronary vessels, LV dysfunction, or valvular regurgitation are found, the echocardiogram should be repeated at 6- to 12-month intervals.

5. Exercise stress testing or myocardial perfusion evaluation is indicated in children with coronary artery aneurysms at 1- to 2-year intervals.

6. Occasionally, coronary angiography may be indicated in infants with large aneurysms or stenosis, in patients with symptoms suggestive of ischemia, in patients with positive exercise tests or thallium study findings, and those with evidence of MI.

7. Rarely, for patients with evidence of reversible ischemia from coronary artery stenosis (demonstrable on stress imaging tests), percutaneous intervention, such as balloon angioplasty, rotational atherectomy, stenting, or a combination of these procedures may be indicated (Ishii et al, 2002). On rare occasions, coronary artery bypass surgery may be indicated. The internal mammary artery graft may be used for bypass surgery.

Lyme Carditis

Prevalence

Lyme carditis occurs in about 10% of patients with Lyme disease.

Cause and Pathology

1. Lyme disease is the leading tickborne illness in North America and Europe. The disease is endemic in three U.S. regions: the Northeast (most commonly in coastal areas from Maryland to northern Massachusetts), the upper Midwest (Wisconsin and Minnesota), and the Far West (California and Oregon). The disease has been reported from every part of the world, including most of the United States. The disease is named after the town of Old Lyme, Connecticut, where a number of cases were identified in 1975.

2. It is caused by the spirochete Borrelia burgdorferi, which is carried by hard-bodied ticks (e.g., Ixodes dammini). The spirochete initially produces a characteristic skin lesion (erythema chronicum migrans) and then spreads through the lymphatics and bloodstream and disseminates to other organs, including the heart and the central and peripheral nervous system.

3. The organism can be found in the heart and other parts of the body and is responsible for the clinical symptoms and signs.

TABLE 19-2

FOLLOW-UP RECOMMENDATIONS ACCORDING TO THE DEGREE OF CORONARY ARTERY INVOLVEMENT

image

ECG, electrocardiography; LMWH, low-molecular-weight heparin; INR, international normalized ratio.

Modified from Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: A statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 114:1708-1733, 2004.

Clinical Manifestations

1. Most cases are identified during the summer months, and a history of tick bites may be elicited.

2. Lyme disease can be divided into three stages.

a. Stage 1 (localized erythema migrans) begins 3 to 30 days after the tick bite with the onset of influenza-like symptoms (fever, headache, myalgia, arthralgias, malaise) and the characteristic rash, erythema chronicum migrans. The skin lesion, seen in 60% to 80% of patients at the site of the tick bite, begins as a macule or papule followed by progressive expansion of an erythematous ring over approximately 7 days. The ring may be as large as 15 cm with red borders and central clearing, most often appearing on the thigh, groin, or axilla. Erythema migrans lesions usually fade within 3 to 4 weeks, but they may recur.

b. Stage 2 (disseminated infection) starts 2 to 12 weeks after the tick bite. Neurologic (10% to 15%) and cardiac (10%) manifestations occur in this stage. The classic triad of Lyme neuroborreliosis includes aseptic meningitis, cranial nerve palsies (most commonly, unilateral or bilateral Bell’s palsy), and peripheral radiculoneuropathy. The most common cardiac manifestation is fluctuating AV block (see later discussion), although myocarditis, pericarditis, and LV dysfunction can occur.

c. Stage 3 (persistent infection) manifests as large-joint arthritis weeks to years after stage 2 and is seen in about 50% of the patients not previously treated. In general, joint manifestation is self-limited but may recur in patients who do not receive appropriate antibiotic therapy.

3. Cardiac manifestations occur in about 10% of cases. They generally appear 4 to 8 weeks after the initial illness, but their appearance can vary from 4 days to 7 months. The most common cardiac manifestation is varying degrees of AV block, occurring in up to 87% of cases. More than 95% of these patients show first-degree AV block at some time in their course. Up to 50% develop complete heart block, and some of them develop permanent heart block. First-degree AV block can change to complete heart block within minutes.

Diagnosis

1. The diagnosis is suggested by the presence of the distinctive erythema chronicum migrans and other features of Lyme disease. A history of tick exposure (e.g., travel to an endemic area) and any of the manifestations of stages 2 and 3 are important clues to the disease. The presence of AV block alone is not specific for Lyme carditis; it can be caused by other infective agents, such as viral infections (coxsackievirus A and B, echovirus, mumps, polio), rickettsial infections, Treponema pallidum, Yersinia enterocolitica, toxoplasmosis, diphtheria, and Chagas’ disease.

2. Although cultivation or visualization of B. burgdorferi is the most reliable technique to confirm the diagnosis, this test is rarely positive.

3. Enzyme-linked immunosorbent assays (ELISAs) are probably more accurate than indirect immunofluorescence assays. The diagnosis of Lyme disease is confirmed if there is a single titer greater than 1:256 or a fourfold increase in antibody titer over time and compatible clinical symptoms.

Management

1. Doxycycline (100 mg twice a day orally for 14–21 days) is the drug of choice for children older than 8 years of age. For children younger than 8 years of age, amoxicillin (25–50 mg/kg per day orally divided into two doses for 2 to 3 weeks) is the drug of choice. For patients allergic to penicillin, cefuroxime axetil is an alternative.

2. If antibiotic therapy is begun in stage 1, the duration of the skin lesion is shortened, and subsequent complications can be averted. Antibiotic treatment also improves cardiac and neurologic symptoms.

3. Heart block responds to antibiotic treatment, usually within 6 weeks, and has a good prognosis.

4. For high-level AV block, temporary pacing may be indicated (in up to one third of patients).

5. Recently, a Lyme disease vaccine (LYMErix, SmithKline Beecham) was licensed by the U.S. FDA for persons 15 to 70 years of age. The vaccine seems to be safe and effective, but its cost effectiveness has yet to be determined.

Postpericardiotomy Syndrome

Postpericardiotomy syndrome is a febrile illness with inflammatory reaction of the pericardium and pleura that develops after surgery involving pericardiotomy. It is believed to be an autoimmune response to damaged myocardium or pericardium or blood in the pericardial sac. There is also possibility of anti-heart antibodies created idiopathically or caused by concurrent cross-reactivity of the antibodies produced against viral antigens. However, the latter assumption is not fully proven because of conflicting studies. The incidence is about 25% to 30% of patients who receive pericardiotomy. A nonsurgical example of this syndrome is seen after MI (Dressler’s syndrome) and traumatic hemopericardium. It can occur after percutaneous coronary intervention or after pacemaker or pacemaker wire placement.

Clinical Manifestations

1. The onset of the syndrome is a few weeks to a few months (median, 4 weeks) after cardiac surgery that involves pericardiotomy. It is rare in infants younger than 2 years of age.

2. The syndrome is characterized by fever and chest pain. Fever may be sustained or spike up to 104°F (40°C). Chest pain may be severe, caused by both pericarditis and pleuritis. Chest pain resulting from pericardial effusion radiates to the left side of the chest and shoulder and worsens in a supine position. Pleural pain worsens on deep inspiration. On physical examination, pericardial and pleural friction rubs and hepatomegaly are usually present. Tachycardia, tachypnea, rising venous pressure, and falling arterial pressure with a paradoxical pulse are signs of cardiac tamponade.

3. Chest radiographs show an enlarged cardiac silhouette and pleural effusion, especially on the left. The ECG shows persistent ST-segment elevation and flat or inverted T waves in the limb leads and left precordial leads.

4. Echocardiography is the most reliable test in confirming the presence and amount of pericardial effusion and in evaluating evidence of cardiac tamponade.

5. Leukocytosis with a shift to the left and an elevated ESR rate are present. Acute phase reactant (ESR, CRP) levels are elevated.

6. Although the disease is self-limited, its duration is highly variable; the median duration is 2 to 3 weeks. Recurrences are common, appearing in 21% of patients.

Management

1. Bed rest is all that is needed for mild cases.

2. Nonsteroidal antiinflammatory agents, such as ibuprofen or indomethacin, may be effective in most cases.

3. In severe cases, moderate doses of corticosteroids may be indicated for a few days if the diagnosis is secure and infection has been ruled out. A more prompt response is seen with steroid therapy, but a serious drawback is the tendency for the condition to rebound after withdrawal of the drug, with some patients becoming steroid bound.

4. Emergency pericardiocentesis may be required if signs of cardiac tamponade are present.

5. Diuretics may be used for pleural effusion.

6. Pericardiectomy may be necessary in patients with recurrent effusion.

Postperfusion Syndrome

Postperfusion syndrome, which occurs only after open-heart surgery using a pump oxygenator, is caused by CMV infection. The virus may be transmitted to the patient from a viremia from healthy donors. The syndrome has almost disappeared because freshly drawn blood is no longer used except in patients with severe cyanotic heart defects.

Clinical Manifestations

1. The onset is 4 to 6 weeks after cardiac surgery using cardiopulmonary bypass.

2. The syndrome is characterized by the triad of fever, splenomegaly, and atypical lymphocytosis. Hepatomegaly is also common. Low-grade fever, with elevations to 100° to 102°F (37.7°–38.8°C) occur. Malaise and anorexia are commonly present.

3. The fever and atypical lymphocytosis are short-term manifestations (lasting about 2 weeks), but splenomegaly usually lasts 3 to 4 weeks to 3 to 4 months. No recurrence has been reported.

4. The white blood cell count may be normal, but atypical lymphocytes are seen in the peripheral smears. CMV may be demonstrated in the urine, or a changing titer to the virus may be demonstrated in the serum.

Management

1. No specific treatment is available.

2. The syndrome is self-limited, lasting for a week to a few months.

Human Immunodeficiency Virus Infection

Infection with HIV has become a major pediatric health concern in the United States and around the world. The clinical manifestations of HIV infection are well known to primary care physicians, but the significance of cardiovascular manifestations (cardiomyopathy) is less well known.

Clinical Manifestations

1. Initial symptoms may be subtle or nonspecific. Recurrent infections by opportunistic infective agents and by encapsulated organisms are common (occurring in 20%). GI candidiasis, periodontal disease, oral or esophageal ulcerations, and chronic or recurrent diarrhea with failure to thrive are frequent. Elevation of hepatic transaminases with or without cholestasis occasionally occurs. Anemia (occurring in 20%–70%), leukopenia, neutropenia, and thrombocytopenia (occurring in 10%–20%) may be seen. In contrast to adults, malignancies (non-Hodgkin’s lymphoma, primary CNS lymphoma, and leiomyosarcoma) are infrequent in children (2% of cases).

2. CNS involvement in perinatally infected children occurs in 40% to 90%, with a median age of 19 months. Progressive encephalitis is the most common form of CNS manifestation, with loss of motor development, cognitive deterioration, and acquired microcephaly. Imaging may show cerebral atrophy (in 85%), increased ventricular size, and basal ganglia calcifications.

3. In children, the prevalence of cardiovascular manifestations is about 20%, and these manifestations are importantly related to prognosis. HIV RNA transcripts have been found in the myocardium of patients with cardiomyopathy. The virus may infect the structure directly or may have an indirect role in the pathogenesis of myocardial manifestations. Coinfection with other viruses, such as Epstein-Barr virus and CMV; malnutrition; and wasting may also contribute to the cardiac-related morbidity and mortality and the overall mortality.

Common cardiovascular manifestations include cardiomyopathy, myocarditis, pericarditis, cardiac arrhythmias, and chronic CHF. The ECG and echocardiographic studies are helpful in detecting preclinical abnormalities of the cardiovascular system.

a. Cardiac examination may reveal sinus tachycardia (in 64% of cases), gallop rhythm, tachypnea, and hepatosplenomegaly—all signs of CHF.

b. Besides tachycardia, the ECG may show atrial and ventricular ectopic beats and second-degree AV block.

c. Echocardiographic studies may demonstrate diminished LV contractility (in 26%), with some patients having dilated cardiomyopathy and others having hypertrophy of the LV. Pericardial effusions are frequent (26%), caused by opportunistic viral and bacterial infections, including mycobacteria. Occasionally, cardiac tamponade develops, which requires emergency pericardiocentesis. Calcification of cardiac valves also occurs. The incidence of these abnormalities is higher in vertically infected children than in an uninfected cohort from HIV-infected mothers.

d. The presence of pericardial effusion correlates highly with pleural effusion and ascites. Thus, in children with pleural effusion or ascites, pericardial effusion and cardiac abnormalities should be suspected.

Prognosis

The disease progresses more rapidly in children than in infected adults. Cardiac dysfunction is a predictor of poor prognosis. In children, the 1-year mortality rate after the diagnosis of CHF is about 70%, and most children with CHF die within 2 years of the diagnosis. If cardiac abnormalities are diagnosed early, preventive and therapeutic strategies for progressive LV dysfunction can be applied.

Management

1. It has been shown that monthly IV infusion of immune globulin improves LV function in HIV-infected patients. This suggests that the LV dysfunction may be immunologically mediated.

2. An early study indicates that zidovudine neither worsens nor ameliorates progressive cardiac changes in HIV-infected patients.

3. Antibiotics are indicated when there is a bacterial infection of the pericardium or other structures.

4. Emergency pericardiocentesis may be required when tamponade is present.

5. If CHF develops, anticongestive measures, including diuretics, inotropic agents, and afterload-reducing agents, are indicated.