Introduction

Kawasaki disease is a vasculitis of early childhood that has a propensity for affecting the coronary arteries. It is characterized by a cluster of symptoms and signs, which lead to the diagnosis of Kawasaki disease. It poses a diagnostic quandary for the primary physician because Kawasaki disease often mimics more common childhood illnesses presenting with fever. Moreover, in recent years, Kawasaki disease has presented in an atypical manner, making early diagnosis quite difficult. Therefore, in the present era, a primary care physician should be armed with a high index of suspicion when evaluating a febrile, irritable child. Left untreated, almost 20% to 25% of children with Kawasaki disease may develop aneurysms of coronary arteries. In the United States, the incidence of coronary artery aneurysms decreased to less than 5% after use of intravenous immunoglobulin (IVIG) became more widespread in the 1990s.1

Epidemiology

The majority of cases of Kawasaki disease occur between 6 months and 5 years of age. In the United States, the incidence of Kawasaki disease is highest in children of Asian descent (32.5 per 100,000 children under 5 years) and lowest in Caucasians (9.1 per 100,000 children under 5 years). The incidence rates are intermediate in African Americans and Hispanics.2 Children under 1 year of age have an increased propensity to develop coronary artery aneurysms. Kawasaki disease is prevalent year round but is punctuated by seasonal surges in winter and spring. Recurrences in the same patient and occurrences in siblings are noted occasionally. The incidence of Kawasaki disease is higher in children of parents who themselves have a past history of Kawasaki disease, which suggests that there may be a genetic predisposition of a child to Kawasaki disease.3

Pathogenesis

The hunt for a causative agent of Kawasaki disease has failed to find a definite agent, despite extensive research over the past 4 decades. Nevertheless, the clinical features, the seasonal outbreaks, and other epidemiologic characteristics strongly point toward an infectious agent. However, cultures and serologic tests against bacterial and viral agents have not been able to isolate a causative agent.

Theories

Superantigen Theory

In the mid-1990s, superantigens produced by group A Streptococcus pyogenes and Staphylococcus aureus were implicated as causative agents of Kawasaki disease.4 In the human body, in response to a conventional antigen, only a limited number of lymphocytes are activated, typically less than 1 cell per 10,000 lymphocytes. In contrast to conventional antigens, superantigens can lead to excessive stimulation of a larger number of lymphocytes (as many as 25% of circulating lymphocytes). This leads to uncoordinated and disproportionate release of inflammatory cytokines from activated T cells. The best characterized superantigens are the staphylococcal enterotoxins and the streptococcal pyrogenic exotoxins that trigger the staphylococcal and streptococcal toxic shock syndromes. Toxic shock syndrome and Kawasaki disease share many common clinical and immunologic features. Moreover, many Kawasaki disease patients were colonized with S aureus producing toxic shock syndrome toxin-1. Therefore, bacterial superantigens were implicated as causative agents of Kawasaki disease. However, more recently, a blinded, randomized, multicenter trial failed to find a statistically significant difference in the recovery of superantigen-producing S aureus and S. pyogenes in patients with Kawasaki disease.5 Hence, the superantigen theory cannot fully explain the etiology of Kawasaki disease.

Ribonucleic Acid (RNA) Virus Theory

In acute Kawasaki disease, it has been noted that immunoglobulin A (IgA) plasma cells infiltrate not only the walls of coronary arteries, but also the upper respiratory tract. This is reminiscent of a severe viral respiratory infection, such as influenza. This suggests that the microbe responsible for Kawasaki disease may enter the body via the respiratory tract. Synthetic monoclonal versions of the IgA antibody, found in the walls of the coronary arteries, have now been created in vitro. These synthetic antibodies, in turn, have been used to hunt down the Kawasaki disease–specific antigen found in inclusion bodies in bronchial epithelium and in macrophages.6 It has been proposed that in children an offending infectious agent enters through the respiratory tract and infects the ciliary bronchial epithelial cells, where it characteristically forms inclusion bodies. These inclusion bodies are characterized by aggregates of viral proteins and RNA. This suggests that the microbe responsible for Kawasaki disease may be a previously unidentified, ubiquitous RNA virus, with limited or no homology to presently known viruses.7 However, this viral agent will only cause Kawasaki disease in a genetically susceptible host (Figure 14-1). Present data suggest that in Kawasaki disease, IgA antibodies are formed against this unknown viral agent and, therefore, this response is not an autoimmune response. The lack of person-to-person transmission and the rarity of the disease in adults suggest that most humans have possibly experienced asymptomatic infections earlier in life and that there is widespread immunity in the community.

Clinical Presentation

There are no definitive laboratory tests for diagnosing Kawasaki disease, and the disease is often diagnosed by a constellation of clinical symptoms, signs, and some auxiliary laboratory data (eg, platelet count, erythrocyte sedimentation rate). The clinical diagnostic criteria of Kawasaki disease adopted by the American Heart Association (AHA) are outlined in Table 14-1. However, an overriding feature of Kawasaki disease is the high fever and extreme irritability. The latter is quite disproportionate when compared to other childhood febrile illnesses.

In addition to the principal clinical features described earlier, associated clinical characteristics may also be manifested in Kawasaki disease. Children may present with refusal to bear weight on their feet or refusal to move their arms, possibly due to arthralgia of several joints, small and large. The hepatobiliary system may be involved, resulting in hydrops of the gallbladder, hepatomegaly, transient jaundice, and elevated liver enzymes. In fact, hydrops of the gallbladder can be evaluated concurrently during echocardiography and can help clinch the diagnosis in atypical forms of this disease. The patient may also present with gastrointestinal complaints of diarrhea, abdominal pain, and vomiting, rarely masquerading as “acute abdomen.” Nonspecific symptoms of vomiting, diarrhea, abdominal pain, and cough that accompany many childhood febrile illnesses also accompany Kawasaki disease, and these symptoms should not dissuade the clinician from thinking of Kawasaki disease.

Atypical Kawasaki Disease

In about 15% to 20% of children, especially in infants under 6 months of age, the presentation of Kawasaki disease is atypical. This is also referred to as incomplete Kawasaki disease because only few of the classical signs are manifest. However, the general practitioner needs to remember that the incidence of coronary artery aneurysms is higher in this group of patients, if untreated. Therefore, a high index of suspicion should be maintained when evaluating a febrile child less than 1 year of age. Clinical findings of pharyngitis, presence of bullae in skin, exudative conjunctivitis, and generalized lymphadenopathy often suggest a non-Kawasaki type of illness. It should also be kept in perspective that IVIG treatment before day 5 of Kawasaki disease has not been associated with improved outcomes for coronary artery involvement. In fact, treatment before 5 days of the illness has often necessitated treatment with a second dose of IVIG.

Diagnosis

A scientific statement from the AHA provides us with an algorithm to diagnose atypical (incomplete) Kawasaki disease. A simplified version is depicted in Figure 14-2. Previous studies have shown that children treated after day 10 of illness were 2.8 times more likely to have coronary artery aneurysms than those who were treated earlier. A recent study from Taiwan reported that infants who were less than 6 months old were diagnosed with Kawasaki disease an average of 2 days later than older children; the diagnosis was made beyond 10 days in 50% of these children versus 22% of children who were 6 months old or older.8

Recently the AHA algorithm has been applied in a retrospective study from 4 U.S. centers. This study suggested that application of the AHA algorithm would have referred 95% of patients with incomplete Kawasaki disease for IVIG treatment. Only 70% of these patients would have been treated with IVIG infusions if clinicians had relied on fulfillment of the traditional complete case definition.9

Diagnostic Tests

The acute-phase reactants, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are virtually always elevated in Kawasaki disease and take about 8 weeks to return to normal. It is important that both are measured (not just 1) because the elevation in ESR and CRP may be variable and discordant in these patients. This is especially important during treatment with IVIG because IVIG itself causes elevation in ESR but does not affect the CRP levels. Therefore, for serial follow-up of the inflammatory response in IVIG-treated Kawasaki disease, CRP levels are preferably monitored, not the ESR. A complete blood cell count, differential, and platelet count are needed. Liver function tests should also be performed. A urine analysis should be sent to evaluate for sterile pyuria. Abdominal ultrasound should be performed to rule out gallbladder hydrops in patients with gastrointestinal symptoms. A chest x-ray should be performed in febrile patients with respiratory issues; in addition to evaluating the lung parenchyma, one can look for cardiomegaly or effusions. In some patients who present with fever and meningismus, a lumbar puncture with cell count, fluid glucose and protein levels, and fluid culture should be performed. Table 14-2 lists the supportive laboratory findings in Kawasaki disease.

Cardiac testing should include a baseline 12-lead electrocardiogram to assess for ST-segment or T-wave changes and a 2-dimensional and Doppler echocardiogram to assess for pericardial effusion, myocardial function, and valvulitis (aortic or mitral regurgitation) and for complete evaluation of both coronary arteries and their segments. Patients with congestive heart failure symptoms should be on telemetry to evaluate for arrhythmias.

Treatment

Acute Therapy

The combined use of IVIG and aspirin has now become the mainstay of treatment of the acute phase of Kawasaki disease (Table 14-3). Randomized clinical trials have established that a single infusion of IVIG in a dose of 2 g/kg, given within 5 to 10 days after the onset of fever in Kawasaki disease, eliminates fever in 85% of children within 36 hours and reduces the risk of coronary artery aneurysms significantly.10 In the pre-IVIG era, approximately 20% to 25% of patients developed coronary artery aneurysms. However, in the present era of high-dose IVIG therapy, only 5% of children may have coronary artery involvement (some with transient involvement) and 1% develop giant aneurysms (≥ 8 mm). Children who present after 10 days of fever should still be treated with IVIG, if fever is present or signs of inflammation (eg, elevated ESR or CRP) are detected. Approximately 10% to 15% of children with Kawasaki disease do not respond to the initial dose of IVIG and need retreatment. Factors that are associated with resistance to the first dose of IVIG are indicated in Table 14-4.

Outpatient Follow Up

For straightforward cases without major coronary involvement, echocardiograms are performed at the time of diagnosis and at 2 weeks and 6 to 8 weeks after diagnosis. Therefore, after discharge from the hospital, follow-up visits with a pediatric cardiologist are arranged at those intervals. If the coronary arteries show no involvement, low-dose aspirin therapy is stopped at 6 to 8 weeks or when the inflammatory parameters and platelet count have normalized. In some centers, echocardiograms and follow-ups are also performed at 6 months and 12 months after the diagnosis, at the discretion of the pediatric cardiologist. After 12 months, it is unlikely to see any further coronary artery involvement if the coronary arteries were normal at 6 to 8 weeks.

In patients with coronary artery involvement noted in the acute phase of the illness, the treatment and follow-up vary from a typical, uncomplicated case of Kawasaki disease. The classification of coronary aneurysms is outlined in Table 14-5. A giant coronary aneurysm is depicted in Figure 14-3. The same patient also developed a large pericardial effusion (Figure 14-4). The management of patients with coronary artery involvement follows the risk levels for developing coronary artery thrombosis and myocardial ischemia, proposed by the AHA scientific statement on Kawasaki disease.10 Such risk stratification may serve as a useful guide in management of these patients. However, patients are variable, and physicians have their own styles. Therefore, the recommendations made for treating coronary artery lesions in Table 14-6, take both the AHA risk stratification10 and the author’s personal experience into account.

Coronary aneurysms that grow rapidly in the acute phase of the disease are at greater risk for thrombosis. These patients should be monitored carefully and treated with β-blockers and a combination of low-dose aspirin and warfarin. In giant aneurysms, there is often narrowing of the coronary artery segments at either end of the aneurysm. This characteristic is responsible for stasis of the blood flow in the aneurysm, which increases the risk of coronary thrombosis. When multiple aneurysms are arranged in a row (pearl necklace pattern), areas of stenosis and aneurysms alternate with each other. This may result in repeated slowing of blood flow in the coronary arteries. It is postulated that such sluggish blood flow, in combination with an unknown vasculitic process that causes endothelial activation and increased platelet shear stress, may contribute to coronary artery thrombosis.

Thrombotic occlusion of an aneurysmal or stenotic coronary artery is a catastrophic event and the main cause of death in Kawasaki disease. In Japanese children, the greatest risk of suffering a myocardial infarction has been within the first year of the illness. Thrombolytic therapy may be lifesaving in this circumstance. However, the experience of using thrombolytic agents in children is quite meager. Therefore, the guidelines for using thrombolytic agents have been extrapolated from adult clinical trials treating acute coronary syndromes. Thrombolytic agents like streptokinase and tissue plasminogen activator have been used successfully in limited groups of children. Borrowing from the success in adults with acute coronary syndrome, abciximab, a platelet glycoprotein IIb/IIIa receptor inhibitor, has been used with some success in a small number of children.

Noncardiac Issues in Kawasaki Disease

Vaccinations

Patients with Kawasaki disease receiving IVIG treatment should have their measles-mumps-rubella and varicella vaccinations delayed for about a year because the specific antiviral antibody in IVIG may interfere with the immune response to live-virus vaccines. Other vaccinations do not need to be delayed.

Influenza Vaccine

Reyes syndrome has not been seen in patients receiving low dose aspirin in recent decades. Nevertheless, children on long-term aspirin should be immunized with yearly influenza vaccine.

Antipyretics

Ibuprofen should be avoided in children taking aspirin because it may interfere with the antiplatelet effects of aspirin.

Infliximab Treatment

Newer agents like infliximab, used in IVIG-resistant cases of Kawasaki disease, may cause reactivation of latent tuberculosis infection. This is further complicated by the fact that during acute Kawasaki disease, patients may be anergic and may not respond to skin tests for tuberculosis. In addition, the primary doctor should be aware that acute inflammation at the site of a previous bacillus Calmette-Guérin vaccine is a characteristic feature of Kawasaki disease.

Summary

Kawasaki disease is probably caused by single virus or a group of similar viruses in a small cohort of genetically predisposed children. In these children, the offending infectious agent possibly enters through the respiratory tract and infects the ciliary bronchial epithelial cells, where it characteristically forms cytoplasmic inclusion bodies. It then enters macrophages and is carried in the blood stream to the coronary arteries. An antigen–antibody cascade ensues, which in turn causes destruction of collagen and elastin in the walls of the coronary arteries, resulting in aneurysms. Kawasaki disease should be suspected in young children with persistent, high fever, even if full diagnostic criteria are absent. A high index of suspicion is of paramount importance. Treatment with IVIG reduces the risk of coronary artery aneurysms from 20% to less than 5%. About 10% to 15% of children with Kawasaki disease fail to respond to the initial dose of IVIG. In resistance cases, retreatment with additional doses of IVIG or intravenous methylprednisone may be necessary.

Definitions and Epidemiology

Acute rheumatic fever is the most common cause of acquired heart disease in the world, affecting some 20 million people. It is associated with group A β-hemolytic streptococcal (GAS) (S. pyogenes) infections. In decades past, it was a leading cause of cardiovascular death and disability in the United States. The arrival of the antibiotic era led to a remarkable decrease in rheumatic fever in westernized nations, but in less industrialized nations and developing countries, this disease continues to exist and results in significant morbidity and mortality. Cases of rheumatic fever still occur annually in the United States, and the etiology, presenting symptoms, and diagnosis are very important issues for medical personnel to understand. The late-term consequences of untreated rheumatic fever can be serious chronic cardiac disease, which impacts upon lifestyle and longevity. Conversely, the overdiagnosis of this condition has repercussions related to unnecessary long-term antibiotic prophylaxis.

Unlike Kawasaki disease, acute rheumatic fever is a disease more prevalent in school-age children and young adults, generally 5 to 15 years of age. It is not generally seen in children less than 5 years of age. There is no gender preference. There are racial and ethnic differences. The seasonal variation in the United States coincides with GAS infections, particularly in the winter and spring of temperate climates. The incidence is 0.5 to 3 per 100,000 population. In non-Western countries, the incidence is greater than 10 per 100,000 population. There are regions of the world that have a very high incidence of rheumatic fever including sub-Saharan Africa, south central Asia, South America, and the aboriginal populations of Australia and New Zealand. In the United States, there were resurgences in rheumatic fever in several states including Hawaii, Utah, New York, and Pennsylvania in the 1980s. One explanation for these resurgences was that the rheumatogenic strains of GAS had dramatically decreased for several decades after the onset of the antibiotic era. The reappearance of more virulent M-protein serotypes of GAS in recent decades led to recurrent outbreaks of rheumatic fever. There is also an implication of regional variation, because rheumatic fever is less common in the southern United States.11

Genetic predisposition appears to play a role in susceptibility to rheumatic fever when exposed to GAS infections. Genetic variation in the emm gene that codes for the M protein has been linked to varying manifestations of disease.12 In the United States, rheumatic fever is more common in Asians and Pacific Islanders compared to Caucasians. Sixty percent (60%) of patients with chorea are female. Rheumatic fever is species specific, occurring only in humans. As such, there is no animal model for this disease.

Pathogenesis

All cases of rheumatic fever are preceded by a Lancefield GAS infection of the upper respiratory tract (ie, tonsillopharyngitis). If the streptococcal infection is untreated, there is risk of developing rheumatic fever in approximately 3% of cases. If the infection is appropriately treated with antibiotics, then the risk of developing rheumatic fever is markedly diminished.13 The manifestations of rheumatic fever are not related to direct infection of the tissues by GAS. Rather, there is an autoimmune response, comprising both humoral and cellular mechanisms, implicated in a susceptible host (Figure 14-5). The M protein of the bacterial wall in certain strains of GAS (“rheumatogenic strains”) serves as an antigenic stimulus in the host. The susceptible host mounts an autoimmune response to various components of the bacterium (the M protein, the streptococcal carbohydrate, the streptococcal protoplast membrane, and capsule hyaluronidate), which has so-called “antigenic mimicry” with certain tissues in the host. As such, the immune cascade that is meant to eradicate the GAS actually causes inflammation and damage in host organs, including the heart, brain, skin, and joints.

Like Kawasaki disease, the cardiac involvement in rheumatic fever occurs at all levels and should be considered a pancarditis. Clinical manifestations include myocarditis, valvulitis, pericarditis, and conduction abnormalities. The pathognomonic histologic lesion of rheumatic fever is the Aschoff body, described by Aschoff in 1904. These lesions are found only in the myocardium and consist of a perivascular infiltrate of large cells with basophilic cytoplasm and polymorphous nuclei in a rosette pattern around an avascular center of fibrinoid material. It is mostly seen in patients with a chronic myocarditis, often with recurrences of rheumatic fever. The most common cardiac manifestation of rheumatic fever is valvulitis, with inflammation of the endocardium and connective tissues of the heart, including the chordal apparatus. Mitral valve involvement is most common (>80% of patients), followed by aortic valve disease (~20% of patients). Tricuspid valve involvement is uncommon, and pulmonary valve disease is rare. If left unchecked, chronic valvar inflammation can result in thickened, scarred mitral and aortic valves, leading to chronic regurgitation and/or stenosis. In particular, late mitral stenosis due to rheumatic fever is the leading cause of cardiovascular morbidity and mortality in developing countries.

Pericardial inflammation and effusion are due to a serositis. Fibrinous exudates and serosanguinous fluid can be seen. Inflammation of the conduction system can cause varying degrees of atrioventricular block, most commonly first-degree atrioventricular block. Rarely, complete or third-degree atrioventricular block may occur and further compound hemodynamic instability.

Serositis of the synovium is the cause of the migratory arthritis that is the hallmark of rheumatic fever. Vasculitis is the mechanism behind skin manifestations of erythema multiforme and renal and pulmonary symptoms. Central nervous system involvement, such as Sydenham chorea, is also thought to be due to vasculitis of the basal ganglia and cerebellum.

Clinical Presentation

Historically, before the patient presents with symptoms of rheumatic fever, the patient must have experienced a primary GAS infection of the upper respiratory tract. Classically, this manifests as fever, sore throat, painful swallowing, and headache. On examination, there can be pharyngeal erythema with or without exudates, cervical lymphadenopathy, a swollen uvula, and in some cases, a scarlatiniform rash. There may be a history of exposure to others with similar symptoms and known GAS infection. In some cases, patients with rheumatic fever have laboratory evidence of a previous GAS infection but do not have a classic history for an upper respiratory infection. Once the patient has had the exposure to GAS, there is a “latent period” that ranges from 10 to 30 days, averaging 3 weeks, before the symptoms of rheumatic fever appear.

The manifestations of rheumatic fever have been fairly stable over the decades (Table 14-7). Generally, there is some degree of fever present. Approximately 65% to 70% present with migratory arthritis, approximately 50% show some degree of carditis, and only 15% to 20% present with chorea. Erythema multiforme is an uncommon finding. This rash occurs in less than 10% of patients. Subcutaneous nodules are also rare and more likely to occur in patients with chronic inflammation from recurrent rheumatic fever.

Carditis

Carditis is the most serious of the manifestations of rheumatic fever, and it is the most likely cause of morbidity and mortality. The degree of cardiac involvement can be quite variable, ranging from only mild valve disease to life-threatening myocarditis and cardiac failure. In the patient with significant carditis and myocardial dysfunction, one may appreciate tachycardia, a gallop rhythm, and new cardiac murmurs. A long systolic murmur of mitral regurgitation may be heard at the lower sternal border and apex. An early high-pitched diastolic murmur of aortic regurgitation may be heard along the left sternal border. Aortic regurgitation is best auscultated with the patient erect and leaning forward. In severe aortic regurgitation, the pulse pressure may be wide and the pulses bounding. An irregular heart rate could be due to ventricular ectopy or second-degree atrioventricular block due to severe myocardial inflammation. In the most severe cases, bradycardia and low cardiac output may be due to third-degree atrioventricular block. The patient with congestive heart failure may show signs of tachypnea, pallor, fatigue, malaise, loss of appetite, and gastrointestinal symptoms such as nausea and vomiting.

Arthritis

Arthritis is the most common presentation of rheumatic fever. It can be transient, asymmetric, and migratory. The joints are painful, warm, red, and swollen. The pain is classically present at rest and worse with motion. The large joints involved are usually the knees and ankles, plus wrists and elbows. The arthritis of rheumatic fever is generally self-limited to 1 to 2 weeks. Classically, the arthritis is very responsive to salicylates (aspirin).

Central Nervous System

Chorea is a form of involuntary, purposeless movement. In rheumatic fever, this has been termed Sydenham chorea. In decades past, it was also known as “St. Vitus’ dance.” It affects 15% to 20% of patients, mostly female, with rheumatic fever. Unlike the cardiac and joint manifestations of rheumatic fever, the central nervous system manifestations have a longer latent period and do not generally appear until 3 or more months after infection with GAS. Clinical signs of cardiac involvement are rare at the time of diagnosis, but late mitral regurgitation has been found in some patients, so they need the same evaluation as patients who present with carditis.

Sydenham chorea most frequently involves the muscles of the face and extremities and is evident when the patient is awake and stressed. It disappears with sleep. Classic manifestations include extension of the arms over the head with pronation of the hands and “milkmaid fingers,” where there is irregular contraction of the fingers upon squeezing. The fingers also hyperextend (“spoon”) when extended outward. Speech is halting, and handwriting is unsteady. Notably there are significant personality changes with emotional lability, restlessness, and inappropriate behavior. Generally these symptoms resolve after a couple of weeks.