Kawasaki disease
Kawasaki disease (mucocutaneous lymph node syndrome) is a systemic vasculitis of unknown etiology. First described in Japan in 1967 by Dr. Tomisaku Kawasaki, it is a common cause of acquired cardiac disease among children in the United States, affecting at least 2500 children yearly. It is exclusively a childhood disease, with 80% of cases occurring by the age of 5 years. Occasionally, adolescents are diagnosed with this disease.
Coronary artery aneurysms are the most common and potentially dangerous sequelae of Kawasaki disease, occurring in one in four untreated patients. Mortality is 0.5%, usually from myocardial infarct, although severe myocarditis can occur. Other systemic arteries can be affected, and clinical overlap exists with a disseminated vasculitis, infantile polyarteritis nodosa.
Diagnosis
Clinical features
The illness is characterized by the following features: (a) bilateral conjunctivitis without discharge; (b) erythematous mouth and dry, fissured lips; (c) a generalized erythematous rash; (d) nonpitting, painful induration of the hands and feet, often with marked erythema of the palms and soles; and (e) lymphadenopathy (Table 9.1). Initially, these occur with a high persistent fever without obvious origin. Patients with 5 days or more of high fever and at least four of these five features have Kawasaki disease, analogous to the use of the Jones criteria for the diagnosis of rheumatic fever. Kawasaki disease is much more pleomorphic than rheumatic fever, and many cases of “atypical” Kawasaki disease occur. The diagnosis remains based on clinical and laboratory findings, as no definitive laboratory test exists.
Table 9.1 Clinical Features of Kawasaki Disease.
| Fever |
| Conjunctivitis, nonexudative and bilateral |
| Erythematous and fissured oral changes |
| Erythematous rash |
| Painful hand and foot induration |
| Lymphadenopathy |
Natural history
If untreated, Kawasaki disease is self-limited, with a mean duration of 12 days for fever, although irritability and anorexia, both prominent during the febrile acute phase, often persist for 2–3 weeks after the fever ends. During the subacute or convalescent phase, usually from day 10 to 20 after onset of fever, most patients have a highly specific pattern of desquamation of the hands and feet that begins periungual and proceeds proximally to involve the palms and soles. Occasionally, the perineal skin desquamates. The trunk and face do not peel, in contrast to scarlet fever.
Laboratory studies
Laboratory tests are supportive but not diagnostic. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and other acute-phase reactants are often very elevated. The platelet count is often normal throughout the acute phase (the first 10–14 days), so it cannot be used to exclude the diagnosis. An echocardiogram (or, if unavailable, a chest radiograph to screen for cardiomegaly) and 12-lead electrocardiogram are advisable at the time of diagnosis. Echocardiography during the acute phase usually does not show aneurysms; however, diffusely enlarged coronary arteries and other nonspecific signs of mild carditis may be present. Therefore, echocardiography cannot be used to “rule out” Kawasaki disease. The echocardiogram should be repeated at about 1 month after onset of illness, since coronary artery changes may have occurred by then. Patients with carditis or aneurysms detected early require more frequent follow-up.
Treatment
Aspirin
Aspirin does not decrease the incidence of aneurysm formation, even in anti-inflammatory doses (100 mg/kg/day), although it is indicated in low dose (3–5 mg/kg/day) for inhibition of platelet aggregation.
Intravenous gamma (immune) globulin (IVGG or IVIG)
IVIG is a preparation from human plasma containing mostly nonspecific polyclonal IgG from several thousand donors. Treatment with IVIG (2 g/kg as a single dose) within the first 10 days after onset of fever reduces the incidence of coronary artery aneurysm from 25 to ≤5%. Many patients show prompt and impressive resolution of fever and other acute-phase symptoms within hours after IVIG. Occasional patients require a second treatment because of failure to improve following the initial dose.
The mechanism of action is unknown but probably involves attenuation of an autoimmune response that may be the prime pathophysiologic factor in Kawasaki arteritis.
Adverse effects of IVIG treatment are rare, but hepatitis C infection was associated with some preparations several years ago. Continuing concern over the possibility of unknown transmissible agents and the high cost of IVIG have led to its overly conservative use in atypical Kawasaki disease. As a result, many patients not treated soon enough manifest aneurysms.
The authors recommend timely treatment with gamma-globulin whenever a reasonable suspicion of Kawasaki disease exists, even if less than five of the classic criteria are not met.
Corticosteroids and other immune mediators
Steroids in high intravenous doses over several days have been successful in up to 10% of patients who fail to respond to IVIG. Oral steroids are not a substitute for IVIG, as data from the pre-IVIG era suggest that the risk of aneurysms was unchanged or possibly higher than with aspirin alone.
Other agents, including monoclonal antibodies, infliximab, and related drugs, often relieve signs of inflammation in children who appear to fail IVIG treatment, yet prevention of aneurysms is unproven.
Follow-up care
Echocardiography
Because the peak time to detect an aneurysm by echocardiography or angiography is 30 days after onset and resolution of fever, a normal echocardiogram during the febrile period does not exclude this vascular complication. Echocardiography should be repeated 4–6 weeks after the onset of illness.
Laboratory
A striking finding during the convalescent phase, thrombocytosis (often >1,000,000/mm3) does not peak until the second week after onset of fever. Therefore, a normal platelet count during the acute phase cannot be used as evidence against a diagnosis of Kawasaki disease. The ESR slowly falls to normal over several weeks.
Low-dose aspirin
Low-dose aspirin should be started for its antiplatelet effect, although some have advocated high-dose aspirin for a variable period to aid resolution of inflammation before commencing low-dose aspirin.
Since occasional patients may manifest aneurysm several months later, an echocardiogram 4–6 months after onset of illness may be obtained and, if coronary arteries are normal, aspirin is discontinued.
Low-dose aspirin may confer a small risk during certain viral illnesses; it should be temporarily suspended during acute varicella or influenza and perhaps after varicella vaccination.
Recurrent disease
As in rheumatic fever, recurrent disease can develop, requiring retreatment with IVIG and aspirin and resetting of follow-up echocardiography. The risk is approximately 1:50, with most cases recurring within the first few months of the initial episode.
Coronary aneurysm
The natural history of patients who develop coronary artery aneurysms varies. In 90% of patients the aneurysms resolve on echocardiogram, although some have continued narrowing of the coronary artery lumen leading to stenotic lesions. Coronary artery stenoses may be impossible to image by echocardiography, and catheterization may be indicated.
In children with anginal symptoms or ECG abnormalities who have fully recovered from acute Kawasaki disease and who have no echocardiographically apparent lesions, nuclear myocardial perfusion scans at rest and with exercise may help in differentiating benign chest pain from true ischemia and/or infarct.
The effect of childhood Kawasaki disease (without aneurysms) on the risk of coronary atherosclerosis in adulthood is unknown.
Rheumatic fever
Rheumatic fever is a systemic disease affecting several organ systems, including the heart. It is a sequel of group A beta-hemolytic streptococcal infections, usually tonsillopharyngitis, and develops in <1% of infected patients. Rheumatic fever usually develops 10 days to 2 weeks following a streptococcal pharyngitis that almost always is associated with fever greater than 101 °F (38.3 °C), sore throat, and cervical adenitis. The pathogenesis of the systemic manifestations is unknown.
Despite a minor resurgence in the 1980s, the incidence of rheumatic fever in North America decreased markedly in the last half of the twentieth century. Worldwide, however, rheumatic fever remains the most common cause of acquired heart disease in the young.
Rheumatic fever is diagnosed by use of the modified Jones criteria (Table 9.2). These criteria comprise the various combinations of clinical and laboratory manifestations reflecting the multiple sites of disease involvement. There must be two major criteria or one major and two minor criteria, plus evidence of a preceding streptococcal infection, to diagnose acute rheumatic fever.
Table 9.2 Modified Jones Criteria for the Diagnosis of Acute Rheumatic Fever.
| Major criteria: |
| Carditisa |
| Arthritis |
| Choreaa |
| Erythema marginatum |
| Subcutaneous nodules |
| Minor criteria: |
| Arthralgia |
| Prolongation of the PR interval |
| Elevated acute phase reactants (e.g. ESR) |
| Fever |
| Other: |
| Previous history of rheumatic fevera |
a See exceptions noted.
Evidence of prior streptococcal infection is necessary before these criteria are considered.
The proof of streptococcal infection can be established by either of two methods. The first is the recovery of beta-hemolytic streptococcus by throat culture. This finding must be interpreted with care because streptococcal carrier states exist and are not considered a streptococcal infection. The second is finding an increase in streptococcal antibodies. Following a streptococcal infection, antibodies to various streptococcal components, such as antistreptolysin-O (ASO) and antideoxyribonuclease B (DNase B), rise significantly. Titers for several antibodies should be measured because an individual may not form antibodies to each streptococcal product. Significant antibody rise indicates a recent streptococcal infection and is more meaningful than isolating beta-hemolytic streptococcus on a throat culture.
Diagnosis
Jones criteria
Five major and four minor criteria (Table 9.2) can be used to fulfill the Jones criteria.
Major criteria
Carditis
Carditis can involve any layer of the heart. Pericarditis can occur in this disease and can be suspected by the occurrence of chest pain that may be referred to the abdomen or shoulders. It is diagnosed by finding a pericardial friction rub, ST segment elevation/depression on the electrocardiogram, or thickened pericardium or effusion by echocardiogram.
Cardiac enlargement or cardiac failure without evidence of valvar anomalies is evidence of myocardial involvement. Rarely, cardiac failure occurs from myocardial involvement itself. Various degrees of heart block, gallop rhythm, and muffled heart sounds are other manifestations of myocarditis. Prolonged PR interval in itself is not a criterion for carditis.
Valvulitis is the most serious manifestation of carditis because it can lead to permanent cardiac sequelae. Both the aortic and mitral valves may be involved acutely. Three types of murmurs may be present that suggest acute rheumatic fever. (a) An apical pansystolic murmur of mitral regurgitation is the most frequently occurring murmur. (b) At times a mid-diastolic murmur may also be heard at the apex. The origin of this murmur is unknown, but it is perhaps related to turbulence from either valvulitis or blood flow into a dilated left ventricle. (c) An early diastolic murmur of aortic regurgitation may be found during the acute episode but is more frequently a late manifestation. Aortic stenosis does not occur during the acute episode of rheumatic fever.
These valvar abnormalities, particularly aortic and mitral regurgitation, may be demonstrated by echocardiography and color Doppler.
The role of echocardiography in diagnosing subclinical valvar changes is under study. It has not been adopted in the United States, but is used as a criterion for diagnosis of carditis in some parts of the world where rheumatic fever is common.
Arthritis
Typically, arthritis is migratory and several joints may be involved, often sequentially, but at a given time there may be involvement of only one joint. Usually the large joints are involved. Diagnosis of arthritis rests on finding warm and tender joints that are painful on movement. The changes are not permanent.
Chorea
Chorea is a late manifestation of rheumatic fever and often develops several months after the streptococcal infection. At that time, other manifestations of rheumatic fever may not be found. The presence of chorea alone is sufficient for the diagnosis of rheumatic fever, as there are virtually no other causes in childhood, although lupus must be excluded. Chorea is more common in females and prior to puberty.
Chorea is characterized by involuntary, nonrepetitive, purposeless motions, often associated with emotional instability. The parents may complain that their child is clumsy, is fidgety, cries easily, or has difficulty in writing or reading.
Classic physical findings of chorea exist. The milkmaid (or grip) sign describes the fibrillatory nature of a hand grasp. Other findings are related to exaggerated muscle movements, such as the hyperextension of the hands or apposition of the backs of the hands when the arms are extended above the head. Although lasting for months in some children, it is not usually permanent.
Erythema marginatum
Erythema marginatum is a fleeting, characteristic cutaneous finding. It is characterized by pink macules with distinct sharp margins; these change rapidly in contour. Warmth tends to bring out these lesions. With time the center fades, whereas the margin persists as a circular or serpentine border.
Subcutaneous nodules
Subcutaneous nodules are a rare manifestation of rheumatic fever, occurring late in the course of the disease. These are non-tender, firm, pea-like nodules over the extensor surfaces, particularly over the knees, elbows, and spine. They have a strong association with chronic carditis.
Minor criteria
Arthralgia
The symptom of painful joints without subjective evidence of arthritis may be used as a minor criterion, if arthritis has not been used as a major one.
Prolongation of the PR interval
This can be used as a minor criterion, if carditis has not been used as a major one.
Acute-phase reactants
Laboratory evidence of acute inflammation, such as elevated ESR or CRP, meets requirements for a minor criterion.
Fever
The temperature is usually in the range 101–102 °F (38.3–38.9 °C).
Treatment
Bedrest
This should be prescribed for the duration of the acute febrile period of the illness. Then gradual increases in activity should be allowed, provided that there is no recurrence of signs or symptoms. Serial determination of ESR is helpful in reaching decisions concerning activity levels. The return to full activity may be achieved by 6 weeks in patients with arthritis as the only major criterion; but in those with carditis, 3 months is advisable.
Salicylates
Salicylates are preferred to reduce the inflammatory response, and arthritis promptly improves. Aspirin does not improve the natural history of carditis or valvulitis. Temperature associated with rheumatic fever returns to normal within a few days. Aspirin is administered in a dose sufficient to achieve a blood salicylate level of approximately 20 mg/dL (1.45 mmol/L); usually this dosage is about 75–100 mg/kg/day. Salicylates are continued until the ESR is normal, and then tapered.
Corticosteroids
Steroids have been used to treat acute rheumatic fever, but there is no evidence that they are better than aspirin in preventing cardiac valvar damage. Steroids may, however, lead to a more prompt reduction in symptoms than aspirin. Since steroids are more hazardous, their use should be reserved for patients with severe pancarditis.
A patient with acute rheumatic fever should be treated for streptococcal infection even if streptococcal cultures are negative, as described later in the section “Prevention of Acute Rheumatic Fever.”
Rheumatic fever prophylaxis (“secondary” prophylaxis)
Once patients have had an episode of rheumatic fever, the risk of developing a second episode is higher, particularly within the first 5 years. A slight added risk continues throughout life. Since rheumatic fever develops following a streptococcal infection, preventive measures are directed at eliminating such infections in susceptible individuals.
The American Heart Association has recommended that all patients with a history of rheumatic fever be placed on long-term penicillin prophylaxis. The duration of prophylaxis is partly determined by the presence or absence of carditis, but for children it is a minimum of 5 years or until 21 years of age, whichever is longer; some authorities recommend lifelong prophylaxis in all patients.
Prevention of acute rheumatic fever (“primary” prophylaxis)
Physicians should prevent the initial episode of rheumatic fever by recognition and proper treatment of group A beta-hemolytic streptococcal infections. Only by adequate treatment of such infections can rheumatic fever be prevented. The throat of any child with the symptoms and findings of tonsillopharyngitis should be tested, because the absolute clinical differentiation of streptococcal versus viral infection is not possible.
Two types of tests are available: culture and rapid screening tests. Rapid streptococcal tests that detect the group A carbohydrate antigen are highly specific, so positive results do not demand additional culture. However, the rapid tests vary in sensitivity, so a negative result should be backed up with culture. If beta-hemolytic streptococcus is present, the throat culture becomes positive within 24 hours. The child with a positive culture may be treated; to initiate treatment at the time of culturing the child is unnecessary, since antibiotic treatment does not alter the early course of acute streptococcal tonsillopharyngitis. The aim of treatment of this infection is the eradication of the streptococcus.
Long-term care
After the acute episode of rheumatic fever, the patient should be seen periodically. The purposes of these visits are to (a) emphasize the continuing need for penicillin prophylaxis for rheumatic fever and (b) to observe for the development of valvar rheumatic heart disease.
In half of patients with evidence of valvar abnormality during the acute episode, the murmurs disappear, but over a period of years the other half may develop more severe cardiac manifestations, such as mitral stenosis, mitral regurgitation, or aortic regurgitation. These patients may ultimately require a cardiac operation or intervention.
Myocardial diseases
The term myocardial disease includes a variety of conditions affecting principally the myocardium that lead to similar clinical and physiologic states. It excludes obvious valvar heart disease, cardiac malformations, hypertension, and coronary arterial disease.
Despite the various etiologic factors of myocardial disease, the major signs and symptoms are similar. Because of the myocardial involvement, there is failure of the heart to (a) act as a pump, (b) initiate and maintain its rhythm, and (c) maintain its architecture. Each of these three effects of myocardial involvement has clinical and laboratory findings in common.
The inability of the myocardium to act efficiently as a pump is shown clinically by features of congestion and inadequate forward flow of blood. Symptoms of fatigue, angina, dizziness, and exercise intolerance indicate inadequate systemic output. Signs of congestive cardiac failure are found: pulmonary edema, dyspnea, hepatomegaly, peripheral edema, and gallop rhythm.
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