Diagnosis

The typical patient with Kawasaki disease is a boy (1.5–1.7 male to 1 female incidence in the United States), aged 1 to 4 years old (76% of US patients are less than 5 years of age), who is appears unwell and is irritable. Kawasaki disease occurs most commonly in Japan, with an incidence of 217 per 100,000 children less than 5 years old. In the United States, passive surveillance data suggest that about 19 per 100,000 children develop Kawasaki disease. For unexplained reasons, the incidence has been increasing in Japan but has remained stable in the United States.

There is no diagnostic test for Kawasaki disease, thus diagnosis is based on a collection of criteria ( Box 1 ). These criteria are fever greater than 39°C for 5 or more days, and at least 4 of 5 specific clinical findings (conjunctivitis, cervical lymphadenopathy, changes to the extremities, rash, and erythema of the lips/oral mucosa), in the absence of another explanatory cause. The diagnosis can be made on day 4 of fever if 4 of the other 5 criteria are present. However, the criteria do not necessarily present concurrently, which can lead to delayed diagnosis.

The conjunctivitis of Kawasaki disease is bilateral, nonexudative, and typically is not painful. The extremity changes can be acute, including edema and/or induration, or can be delayed up to 2 to 3 weeks, as in the case of desquamation of the skin, which typically begins under the fingernails and can progress to include the palms and soles. The rash is most commonly an erythematous, maculopapular exanthem and can be especially prominent in the perineal area, which may peel during the acute illness. Cervical lymphadenopathy greater than 1.5 cm, which is usually located in the anterior chain and unilateral, is the least common of the 5 criteria. If a patient has exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, a bullous or vesicular rash, or generalized lymphadenopathy, Kawasaki disease is less likely, and alternative causes should be pursued.

There is no laboratory finding diagnostic of Kawasaki disease or included in the criteria, but several findings can be used to support the diagnosis. An increased erythrocyte sedimentation rate (ESR) is found in 60% of patients, increased C-reactive protein (CRP) in 80%, neutrophil-predominant leukocytosis in 50%, and sterile pyuria (>10 white blood cells per high-powered field) in 33%. Hyponatremia, increased transaminases (especially alanine aminotransferase [ALT]), dyslipidemia, hypoalbuminemia, anemia, and thrombocytosis (although usually not present until after day 7 of illness) are also frequent findings. Other common clinical findings include arthritis, hydrops of the gallbladder in 15% of patients, uveitis, and aseptic meningitis in 50% of patients with Kawasaki disease.

The American Heart Association criteria for the diagnosis of Kawasaki disease help prevent overdiagnosis but can fail to identify all patients with the condition. Patients with fever for more than 5 days but only 2 or 3 of the clinical criteria can be diagnosed with incomplete Kawasaki disease, which occurs in up to 15% to 20% of patients. Incomplete presentations are more common in infants less than 6 months of age or in older children. It has been advised that febrile infants without a fever source should have an echocardiogram after 7 days of fever to evaluate for Kawasaki disease to avoid missing an incomplete presentation. In most cases, Kawasaki disease is an isolated occurrence, but it can recur in about 3% of patients.

Multiple investigators have searched for a biomarker for use in the diagnosis of Kawasaki disease, particularly for cases that do not fulfill all the criteria, to help identify incomplete presentations. Several candidate proteins have been increased in the blood of patients with Kawasaki disease, including brain natriuretic peptide, S100 isoform A12, and meprin A, but none of these are in clinical use at this time.

Atypical presentations of Kawasaki disease can include the presence of myocarditis, pericarditis, or Kawasaki disease shock syndrome. Myocarditis can lead to ventricular dysfunction, valvular regurgitation from valvulitis, and conduction abnormalities. Kawasaki shock syndrome occurs in about 7% of cases, more commonly in older children, and can manifest with hypotension, hemodynamic instability, or more severe coronary artery involvement, and is often resistant to first-line treatment.

Coronary involvement in Kawasaki disease is evaluated at the time of diagnosis using echocardiography. Aneurysms are defined either by a coronary artery z score of greater than or equal to 2.5 (z scores reflect the intraluminal diameter relative to the patient’s body surface area) in the left anterior descending (LAD) artery or right coronary artery (RCA) or by any 3 of the following echocardiographic criteria: z score of 2 to 2.4, perivascular brightness, lack of vessel tapering, decreased left ventricular function, mitral regurgitation, or pericardial effusion. Aneurysms are most common in the proximal LAD and proximal RCA, followed by the left main coronary artery and left circumflex artery.

The incidence of coronary artery aneurysms in treated patients in the United States is approximately 4%, with a lower incidence of 1% historically reported in Japanese patients. However, recent data, suggest that Japanese patients are at higher risk of coronary artery aneurysms, as are younger patients, male patients, those patients treated more than 10 days after the onset of illness, and those patients refractory to initial treatment. Patients with incomplete Kawasaki disease also seem to be at higher risk for the development of aneurysms. All coronary artery aneurysms are not detected at the time of diagnosis, and follow-up echocardiography 6 to 8 weeks later is recommended for further evaluation. If no coronary dilatation is detected at that time, it is thought that the risk of future aneurysm development is so low that no further imaging is recommended.

Pathophysiology

Histologic analysis of vessels affected by inflammation in Kawasaki disease has been performed. Affected vessels first are noted to have edema of the media, with the internal elastic lamina remaining intact. At 7 to 9 days of illness, neutrophilic infiltration is noted, but this transitions to infiltration of lymphocytes, predominantly CD8+ T cells and immunoglobulin (Ig) A–secreting plasma cells, and the internal elastic lamina is destroyed. Fibroblast proliferation follows, leading to remodeling with fibrosis and scar formation. The exact triggers of this process are unknown but remain under investigation.

Approximately 1% of patients with Kawasaki disease have a family history of the condition, suggesting at least a partial genetic basis for the disease. This idea is supported by the finding that Asian populations retain the increased incidence of Kawasaki disease even after immigration to lower-incidence countries. For instance, the Japanese-American population of the state of Hawaii has an incidence of Kawasaki disease nearly equal to that found in Japan (210 per 100,000 children less than 5 years old). However, there is only a 13% concordance rate for the development of Kawasaki disease among twins, suggesting that there is a strong environmental component as well.

Recent advances in Kawasaki disease have included attempts to define genes involved in the pathogenesis, including multiple genome-wide association studies. These efforts have identified several biologically plausible genes based on the known role of their protein products in the immune system. A polymorphism in CD40 ligand, a molecule involved in the costimulation of T cells, has been identified as a possible contributor in Japanese patients. In both Japanese patients and patients of European ancestry, polymorphisms have been found in caspase-3, an enzyme fundamental to apoptosis, as well as in the high-affinity IgG receptor. Whether these findings will be proved to be clinically relevant in Kawasaki disease remains to be determined.

The most promising genetic finding thus far has been the identification of a polymorphism in the gene for inositol 1,4,5-triphosphate kinase-C (ITPKC), a negative regulator of calcium signaling in activated T cells. This polymorphism has been associated with susceptibility to the development of Kawasaki disease in Japanese patients and to the development of coronary artery aneurysms in both Japanese and US patients. This finding is particularly interesting because therapeutic agents that target calcium signaling pathways in T cells already exist, used most often for the prevention of solid organ transplant rejection, and are already being considered for use in Kawasaki disease (management of Kawasaki disease is discussed later). Given the increasing ease of this method and its power to identify single genes responsible for disease, the future of genetic studies in Kawasaki disease will likely be targeted at whole-exome sequencing of patients with particularly severe clinical manifestations, such as multiple giant coronary artery aneurysms.

Although the cause of Kawasaki disease is unclear, it is thought that genetic influences are only part of the picture. An infectious source has long been speculated and aggressively sought out but has not been discovered. There are several features of Kawasaki disease that support an infectious trigger in the setting of a genetically predisposed patient. However, a primarily autoimmune origin is generally thought to be less likely, because of the self-limited nature of most cases and the lack of recurrence. Seasonal variation to the incidence of Kawasaki disease supports an infectious source, although that seasonality is different in different locations: winter and early spring in the United States versus winter and midsummer in Japan. There are also clear episodes of epidemics of the disease, such as occurred in Japan in 1979, 1982, and 1986, and in Finland in 1982.

Antibodies synthesized using the immunoglobulin sequences of IgA plasma cells from patients with Kawasaki disease have recently been used to stain tissue sections from patients with Kawasaki disease and from control patients. These antibodies stained tissue from patients with Kawasaki disease but not from the controls. The staining was located in intracytoplasmic inclusion bodies, which contained a mixture of protein and RNA. It remains to be seen whether further investigation into this finding will lead to the identification of a previously unknown virus as a potential cause of Kawasaki disease.

Management

The American Heart Association guidelines for treatment of Kawasaki disease address both the need to acutely decrease vessel inflammation as well as prevention of thrombosis in the presence of coronary artery aneurysms, because dilation results in areas of stasis of blood flow. The mainstays of Kawasaki treatment are intravenous immunoglobulin (IVIG) and aspirin. Treatment in a patient who fulfills criteria for Kawasaki disease should not be delayed if an echocardiogram cannot immediately be performed.

In the United States, treatment using 2 g/kg of IVIG as a single infusion over 10 to 12 hours is recommended before day 10 of illness, and its use is supported by randomized, controlled evidence. Treatment before day 5 has not been shown to be of benefit and may lead to increased need for retreatment. In contrast, if a patient presents after 10 days, but has continuing signs of inflammation (such as persistent fever), that patient should still be treated. With IVIG treatment, the incidence of coronary artery aneurysms is decreased from between 20% and 25% to between 1% and 4%. Treatment with IVIG also decreases fever duration and markers of inflammation. The mechanism by which IVIG works is not clear, but many theories have been postulated, including IVIG neutralization of microbial toxins, impairment of an overabundant immune response (such as neutralizing host cytokines), decrease of endothelial activation, enhancement of T regulatory cell activity, or interference with production of antibody by B cells.

Although aspirin is also recommended in the acute management of Kawasaki disease, there is no evidence that it improves outcomes; it has not been shown to decrease the incidence of coronary artery aneurysms. In the United States, it is typically given at high dosage (80–100 mg/kg/d divided into 4 doses) until the patient has been afebrile for 48 hours. The dosage is then decreased to 3 to 5 mg/kg/d and continued until the patient has the recommended 6-week to 8-week follow-up echocardiogram. The aspirin is discontinued at that time if there is no evidence of coronary involvement. If coronary artery aneurysms are present, the patient remains on low-dose aspirin until resolution of the aneurysms can be documented, or permanently if coronary changes persist. If the aneurysms are giant (>8 mm in diameter), anticoagulation with warfarin is also indicated. Low-molecular-weight heparin can also be used.

Despite it being a systemic vasculitis, systemic corticosteroid treatment of Kawasaki is not part of the standard initial management strategy. In the past, this was likely because of an early report (before IVIG was used for Kawasaki disease) suggesting that steroid use worsened coronary artery outcomes, which was based on unrandomized data and has not been supported by subsequent evidence. Recent randomized, controlled data in the United States showed no additional benefit from the addition of steroids to the standard initial management of Kawasaki disease. However, post hoc analysis of these data indicated that, in patients who failed initial management, coronary artery outcomes were better in patients who had received systemic corticosteroids. Recent studies from Japan have also suggested that patients at high risk of developing coronary artery aneurysms benefited from use of steroids in initial management. Efforts are now focused on developing ways to accurately identify high-risk patients who may benefit from initial use of adjunctive corticosteroids. No algorithms are currently available for this.

Approximately 10% to 15% of patients with Kawasaki disease have persistent fever despite treatment with IVIG. These patients are more likely to be male, have increased CRP or ALT, be thrombocytopenic, have recurrent Kawasaki disease, or have received initial IVIG treatment before day 5 of illness. Patients with IVIG-refractory disease are at increased risk of developing coronary artery aneurysms. In IVIG-refractory patients, the American Heart Association guidelines for treatment of Kawasaki disease recommend the use of a second dose of IVIG 2 g/kg. This second dose is effective at terminating fever in 80% of refractory patients.

Unlike initial management, decisions on how to treat patients with Kawasaki disease that has not responded to 2 doses of IVIG is guided mainly by case reports and small series. The most frequently used options include use of systemic corticosteroids or the use of tumor necrosis factor-alpha (TNF-α) inhibitors, mainly infliximab or etanercept. The guidelines from the American Heart Association, based on expert opinion, recommend the use of intravenous (IV) methylprednisolone 30 mg/kg daily for 1 to 3 days if there is disease persistence beyond the second dose of IVIG.

Use of TNF-α inhibitors is based on the finding of increased TNF in the serum of patients with Kawasaki disease, and on mouse models of Kawasaki disease showing that blockade of TNF or absence of TNF signaling decreases coronary artery inflammation. Infliximab has been shown to be safe when used in Kawasaki disease as second-line treatment in patients unresponsive to a first dose of IVIG, but this study was not powered to show whether there was a difference between treatment groups. A randomized, controlled trial of the use of infliximab as an adjunct to standard initial treatment is currently underway in the United States. A pilot study of etanercept has shown it to be well tolerated when used with initial IVIG treatment, and a randomized, controlled trial has been proposed to further investigate its potential to decrease IVIG-resistant disease.

Other agents have been used for IVIG-refractory Kawasaki disease and reported in case reports. Based on the recent findings (discussed earlier) of polymorphisms in the ITPKC gene associated with the development of coronary artery aneurysms in Kawasaki disease, use of cyclosporine for treatment-refractory disease has been reported. Cyclosporine interferes with calcium signaling in T cells, the pathway involving ITPKC. In 9 of 9 reported IVIG-refractory patients receiving cyclosporine, fever and markers of inflammation were decreased after cyclosporine use.

Prognosis

Algorithms for identifying patients at high risk for the development of coronary aneurysms ideally will be created and validated, and more intensive treatments can be directed to further reduce the incidence of cardiac sequelae of Kawasaki disease. At this time, patients who develop aneurysms are at risk for persistence of the aneurysms and the development of artery stenosis or thrombosis. However, half of aneurysms show angiographic evidence of resolution within 1 to 2 years of diagnosis. Aneurysms more likely to regress are those that are smaller, in patients less than 1 year of age, fusiform (vs saccular), and in a distal artery location. Giant aneurysms (those >8 mm) are unlikely to regress and can lead to stenosis or occlusion (74%), myocardial infarction (31%), and/or the need for coronary artery bypass grafting (19%).

Cardiology follow-up for patients with Kawasaki disease is determined by several factors. Patients with no aneurysms or regression of aneurysms by the 6-week to 8-week follow-up echocardiogram have no specific recommendation for follow-up aside from standard counseling regarding cardiac health. Patients with persistent aneurysms should be followed serially with cardiology evaluation and counseling, electrocardiogram, echocardiography, and stress testing, at intervals based on the degree of coronary artery dilatation, with activity restrictions based on the results of stress testing. Initial angiography within 6 to 12 months is recommended for patients with giant aneurysms and in other patients if ischemia is noted on stress testing. Evaluation using MRI, CT, or intraluminal ultrasound is still investigational.

Angioplasty or coronary artery stenting by interventional cardiology has only been performed in a small population of patients with Kawasaki disease. Good outcomes have been reported, especially if done within the first 2 years after disease onset, although there is a high rate of recurrence of stenosis. Coronary artery bypass grafting is sometimes required in patients with giant aneurysms and persistent ischemia, with reported outcomes of 95% survival at 25 years and 60% cardiac event–free survival at 25 years. Cardiac transplant is reserved only for a select set of patients with irreversible cardiac dysfunction and lesions that cannot be addressed with interventional cardiology procedures or surgical bypass grafting.

It was previously thought that patients with Kawasaki disease and coronary artery aneurysms that regress proceed to have a normal future cardiac risk. However, there is accumulating histologic and functional (vessel response to vasodilators) data that areas of previous aneurysm remain abnormal. This finding has led to speculation that these patients have an increased future cardiac risk, in particular in the development of atherosclerotic lesions in these previously dilated areas. At this time, there is no evidence available to suggest that these patients require more specialized cardiac follow-up than the standard counseling on lifestyle modifications that are suggested for all adult patients, including advice regarding abstinence from tobacco use, healthy diet choices, regular aerobic exercise to avoid the development of obesity, as well as treatment of hypertension and dyslipidemia when necessary. Future studies should include trials of statins in patients with Kawasaki disease who may be at risk of accelerated atherosclerosis.

Diagnosis

The typical patient with Kawasaki disease is a boy (1.5–1.7 male to 1 female incidence in the United States), aged 1 to 4 years old (76% of US patients are less than 5 years of age), who is appears unwell and is irritable. Kawasaki disease occurs most commonly in Japan, with an incidence of 217 per 100,000 children less than 5 years old. In the United States, passive surveillance data suggest that about 19 per 100,000 children develop Kawasaki disease. For unexplained reasons, the incidence has been increasing in Japan but has remained stable in the United States.

There is no diagnostic test for Kawasaki disease, thus diagnosis is based on a collection of criteria ( Box 1 ). These criteria are fever greater than 39°C for 5 or more days, and at least 4 of 5 specific clinical findings (conjunctivitis, cervical lymphadenopathy, changes to the extremities, rash, and erythema of the lips/oral mucosa), in the absence of another explanatory cause. The diagnosis can be made on day 4 of fever if 4 of the other 5 criteria are present. However, the criteria do not necessarily present concurrently, which can lead to delayed diagnosis.

The conjunctivitis of Kawasaki disease is bilateral, nonexudative, and typically is not painful. The extremity changes can be acute, including edema and/or induration, or can be delayed up to 2 to 3 weeks, as in the case of desquamation of the skin, which typically begins under the fingernails and can progress to include the palms and soles. The rash is most commonly an erythematous, maculopapular exanthem and can be especially prominent in the perineal area, which may peel during the acute illness. Cervical lymphadenopathy greater than 1.5 cm, which is usually located in the anterior chain and unilateral, is the least common of the 5 criteria. If a patient has exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, a bullous or vesicular rash, or generalized lymphadenopathy, Kawasaki disease is less likely, and alternative causes should be pursued.

There is no laboratory finding diagnostic of Kawasaki disease or included in the criteria, but several findings can be used to support the diagnosis. An increased erythrocyte sedimentation rate (ESR) is found in 60% of patients, increased C-reactive protein (CRP) in 80%, neutrophil-predominant leukocytosis in 50%, and sterile pyuria (>10 white blood cells per high-powered field) in 33%. Hyponatremia, increased transaminases (especially alanine aminotransferase [ALT]), dyslipidemia, hypoalbuminemia, anemia, and thrombocytosis (although usually not present until after day 7 of illness) are also frequent findings. Other common clinical findings include arthritis, hydrops of the gallbladder in 15% of patients, uveitis, and aseptic meningitis in 50% of patients with Kawasaki disease.

The American Heart Association criteria for the diagnosis of Kawasaki disease help prevent overdiagnosis but can fail to identify all patients with the condition. Patients with fever for more than 5 days but only 2 or 3 of the clinical criteria can be diagnosed with incomplete Kawasaki disease, which occurs in up to 15% to 20% of patients. Incomplete presentations are more common in infants less than 6 months of age or in older children. It has been advised that febrile infants without a fever source should have an echocardiogram after 7 days of fever to evaluate for Kawasaki disease to avoid missing an incomplete presentation. In most cases, Kawasaki disease is an isolated occurrence, but it can recur in about 3% of patients.

Multiple investigators have searched for a biomarker for use in the diagnosis of Kawasaki disease, particularly for cases that do not fulfill all the criteria, to help identify incomplete presentations. Several candidate proteins have been increased in the blood of patients with Kawasaki disease, including brain natriuretic peptide, S100 isoform A12, and meprin A, but none of these are in clinical use at this time.

Atypical presentations of Kawasaki disease can include the presence of myocarditis, pericarditis, or Kawasaki disease shock syndrome. Myocarditis can lead to ventricular dysfunction, valvular regurgitation from valvulitis, and conduction abnormalities. Kawasaki shock syndrome occurs in about 7% of cases, more commonly in older children, and can manifest with hypotension, hemodynamic instability, or more severe coronary artery involvement, and is often resistant to first-line treatment.

Coronary involvement in Kawasaki disease is evaluated at the time of diagnosis using echocardiography. Aneurysms are defined either by a coronary artery z score of greater than or equal to 2.5 (z scores reflect the intraluminal diameter relative to the patient’s body surface area) in the left anterior descending (LAD) artery or right coronary artery (RCA) or by any 3 of the following echocardiographic criteria: z score of 2 to 2.4, perivascular brightness, lack of vessel tapering, decreased left ventricular function, mitral regurgitation, or pericardial effusion. Aneurysms are most common in the proximal LAD and proximal RCA, followed by the left main coronary artery and left circumflex artery.

The incidence of coronary artery aneurysms in treated patients in the United States is approximately 4%, with a lower incidence of 1% historically reported in Japanese patients. However, recent data, suggest that Japanese patients are at higher risk of coronary artery aneurysms, as are younger patients, male patients, those patients treated more than 10 days after the onset of illness, and those patients refractory to initial treatment. Patients with incomplete Kawasaki disease also seem to be at higher risk for the development of aneurysms. All coronary artery aneurysms are not detected at the time of diagnosis, and follow-up echocardiography 6 to 8 weeks later is recommended for further evaluation. If no coronary dilatation is detected at that time, it is thought that the risk of future aneurysm development is so low that no further imaging is recommended.

Pathophysiology

Histologic analysis of vessels affected by inflammation in Kawasaki disease has been performed. Affected vessels first are noted to have edema of the media, with the internal elastic lamina remaining intact. At 7 to 9 days of illness, neutrophilic infiltration is noted, but this transitions to infiltration of lymphocytes, predominantly CD8+ T cells and immunoglobulin (Ig) A–secreting plasma cells, and the internal elastic lamina is destroyed. Fibroblast proliferation follows, leading to remodeling with fibrosis and scar formation. The exact triggers of this process are unknown but remain under investigation.

Approximately 1% of patients with Kawasaki disease have a family history of the condition, suggesting at least a partial genetic basis for the disease. This idea is supported by the finding that Asian populations retain the increased incidence of Kawasaki disease even after immigration to lower-incidence countries. For instance, the Japanese-American population of the state of Hawaii has an incidence of Kawasaki disease nearly equal to that found in Japan (210 per 100,000 children less than 5 years old). However, there is only a 13% concordance rate for the development of Kawasaki disease among twins, suggesting that there is a strong environmental component as well.

Recent advances in Kawasaki disease have included attempts to define genes involved in the pathogenesis, including multiple genome-wide association studies. These efforts have identified several biologically plausible genes based on the known role of their protein products in the immune system. A polymorphism in CD40 ligand, a molecule involved in the costimulation of T cells, has been identified as a possible contributor in Japanese patients. In both Japanese patients and patients of European ancestry, polymorphisms have been found in caspase-3, an enzyme fundamental to apoptosis, as well as in the high-affinity IgG receptor. Whether these findings will be proved to be clinically relevant in Kawasaki disease remains to be determined.

The most promising genetic finding thus far has been the identification of a polymorphism in the gene for inositol 1,4,5-triphosphate kinase-C (ITPKC), a negative regulator of calcium signaling in activated T cells. This polymorphism has been associated with susceptibility to the development of Kawasaki disease in Japanese patients and to the development of coronary artery aneurysms in both Japanese and US patients. This finding is particularly interesting because therapeutic agents that target calcium signaling pathways in T cells already exist, used most often for the prevention of solid organ transplant rejection, and are already being considered for use in Kawasaki disease (management of Kawasaki disease is discussed later). Given the increasing ease of this method and its power to identify single genes responsible for disease, the future of genetic studies in Kawasaki disease will likely be targeted at whole-exome sequencing of patients with particularly severe clinical manifestations, such as multiple giant coronary artery aneurysms.

Although the cause of Kawasaki disease is unclear, it is thought that genetic influences are only part of the picture. An infectious source has long been speculated and aggressively sought out but has not been discovered. There are several features of Kawasaki disease that support an infectious trigger in the setting of a genetically predisposed patient. However, a primarily autoimmune origin is generally thought to be less likely, because of the self-limited nature of most cases and the lack of recurrence. Seasonal variation to the incidence of Kawasaki disease supports an infectious source, although that seasonality is different in different locations: winter and early spring in the United States versus winter and midsummer in Japan. There are also clear episodes of epidemics of the disease, such as occurred in Japan in 1979, 1982, and 1986, and in Finland in 1982.

Antibodies synthesized using the immunoglobulin sequences of IgA plasma cells from patients with Kawasaki disease have recently been used to stain tissue sections from patients with Kawasaki disease and from control patients. These antibodies stained tissue from patients with Kawasaki disease but not from the controls. The staining was located in intracytoplasmic inclusion bodies, which contained a mixture of protein and RNA. It remains to be seen whether further investigation into this finding will lead to the identification of a previously unknown virus as a potential cause of Kawasaki disease.

Management

The American Heart Association guidelines for treatment of Kawasaki disease address both the need to acutely decrease vessel inflammation as well as prevention of thrombosis in the presence of coronary artery aneurysms, because dilation results in areas of stasis of blood flow. The mainstays of Kawasaki treatment are intravenous immunoglobulin (IVIG) and aspirin. Treatment in a patient who fulfills criteria for Kawasaki disease should not be delayed if an echocardiogram cannot immediately be performed.

In the United States, treatment using 2 g/kg of IVIG as a single infusion over 10 to 12 hours is recommended before day 10 of illness, and its use is supported by randomized, controlled evidence. Treatment before day 5 has not been shown to be of benefit and may lead to increased need for retreatment. In contrast, if a patient presents after 10 days, but has continuing signs of inflammation (such as persistent fever), that patient should still be treated. With IVIG treatment, the incidence of coronary artery aneurysms is decreased from between 20% and 25% to between 1% and 4%. Treatment with IVIG also decreases fever duration and markers of inflammation. The mechanism by which IVIG works is not clear, but many theories have been postulated, including IVIG neutralization of microbial toxins, impairment of an overabundant immune response (such as neutralizing host cytokines), decrease of endothelial activation, enhancement of T regulatory cell activity, or interference with production of antibody by B cells.

Although aspirin is also recommended in the acute management of Kawasaki disease, there is no evidence that it improves outcomes; it has not been shown to decrease the incidence of coronary artery aneurysms. In the United States, it is typically given at high dosage (80–100 mg/kg/d divided into 4 doses) until the patient has been afebrile for 48 hours. The dosage is then decreased to 3 to 5 mg/kg/d and continued until the patient has the recommended 6-week to 8-week follow-up echocardiogram. The aspirin is discontinued at that time if there is no evidence of coronary involvement. If coronary artery aneurysms are present, the patient remains on low-dose aspirin until resolution of the aneurysms can be documented, or permanently if coronary changes persist. If the aneurysms are giant (>8 mm in diameter), anticoagulation with warfarin is also indicated. Low-molecular-weight heparin can also be used.

Despite it being a systemic vasculitis, systemic corticosteroid treatment of Kawasaki is not part of the standard initial management strategy. In the past, this was likely because of an early report (before IVIG was used for Kawasaki disease) suggesting that steroid use worsened coronary artery outcomes, which was based on unrandomized data and has not been supported by subsequent evidence. Recent randomized, controlled data in the United States showed no additional benefit from the addition of steroids to the standard initial management of Kawasaki disease. However, post hoc analysis of these data indicated that, in patients who failed initial management, coronary artery outcomes were better in patients who had received systemic corticosteroids. Recent studies from Japan have also suggested that patients at high risk of developing coronary artery aneurysms benefited from use of steroids in initial management. Efforts are now focused on developing ways to accurately identify high-risk patients who may benefit from initial use of adjunctive corticosteroids. No algorithms are currently available for this.

Approximately 10% to 15% of patients with Kawasaki disease have persistent fever despite treatment with IVIG. These patients are more likely to be male, have increased CRP or ALT, be thrombocytopenic, have recurrent Kawasaki disease, or have received initial IVIG treatment before day 5 of illness. Patients with IVIG-refractory disease are at increased risk of developing coronary artery aneurysms. In IVIG-refractory patients, the American Heart Association guidelines for treatment of Kawasaki disease recommend the use of a second dose of IVIG 2 g/kg. This second dose is effective at terminating fever in 80% of refractory patients.

Unlike initial management, decisions on how to treat patients with Kawasaki disease that has not responded to 2 doses of IVIG is guided mainly by case reports and small series. The most frequently used options include use of systemic corticosteroids or the use of tumor necrosis factor-alpha (TNF-α) inhibitors, mainly infliximab or etanercept. The guidelines from the American Heart Association, based on expert opinion, recommend the use of intravenous (IV) methylprednisolone 30 mg/kg daily for 1 to 3 days if there is disease persistence beyond the second dose of IVIG.

Use of TNF-α inhibitors is based on the finding of increased TNF in the serum of patients with Kawasaki disease, and on mouse models of Kawasaki disease showing that blockade of TNF or absence of TNF signaling decreases coronary artery inflammation. Infliximab has been shown to be safe when used in Kawasaki disease as second-line treatment in patients unresponsive to a first dose of IVIG, but this study was not powered to show whether there was a difference between treatment groups. A randomized, controlled trial of the use of infliximab as an adjunct to standard initial treatment is currently underway in the United States. A pilot study of etanercept has shown it to be well tolerated when used with initial IVIG treatment, and a randomized, controlled trial has been proposed to further investigate its potential to decrease IVIG-resistant disease.

Other agents have been used for IVIG-refractory Kawasaki disease and reported in case reports. Based on the recent findings (discussed earlier) of polymorphisms in the ITPKC gene associated with the development of coronary artery aneurysms in Kawasaki disease, use of cyclosporine for treatment-refractory disease has been reported. Cyclosporine interferes with calcium signaling in T cells, the pathway involving ITPKC. In 9 of 9 reported IVIG-refractory patients receiving cyclosporine, fever and markers of inflammation were decreased after cyclosporine use.

Prognosis

Algorithms for identifying patients at high risk for the development of coronary aneurysms ideally will be created and validated, and more intensive treatments can be directed to further reduce the incidence of cardiac sequelae of Kawasaki disease. At this time, patients who develop aneurysms are at risk for persistence of the aneurysms and the development of artery stenosis or thrombosis. However, half of aneurysms show angiographic evidence of resolution within 1 to 2 years of diagnosis. Aneurysms more likely to regress are those that are smaller, in patients less than 1 year of age, fusiform (vs saccular), and in a distal artery location. Giant aneurysms (those >8 mm) are unlikely to regress and can lead to stenosis or occlusion (74%), myocardial infarction (31%), and/or the need for coronary artery bypass grafting (19%).

Cardiology follow-up for patients with Kawasaki disease is determined by several factors. Patients with no aneurysms or regression of aneurysms by the 6-week to 8-week follow-up echocardiogram have no specific recommendation for follow-up aside from standard counseling regarding cardiac health. Patients with persistent aneurysms should be followed serially with cardiology evaluation and counseling, electrocardiogram, echocardiography, and stress testing, at intervals based on the degree of coronary artery dilatation, with activity restrictions based on the results of stress testing. Initial angiography within 6 to 12 months is recommended for patients with giant aneurysms and in other patients if ischemia is noted on stress testing. Evaluation using MRI, CT, or intraluminal ultrasound is still investigational.

Angioplasty or coronary artery stenting by interventional cardiology has only been performed in a small population of patients with Kawasaki disease. Good outcomes have been reported, especially if done within the first 2 years after disease onset, although there is a high rate of recurrence of stenosis. Coronary artery bypass grafting is sometimes required in patients with giant aneurysms and persistent ischemia, with reported outcomes of 95% survival at 25 years and 60% cardiac event–free survival at 25 years. Cardiac transplant is reserved only for a select set of patients with irreversible cardiac dysfunction and lesions that cannot be addressed with interventional cardiology procedures or surgical bypass grafting.

It was previously thought that patients with Kawasaki disease and coronary artery aneurysms that regress proceed to have a normal future cardiac risk. However, there is accumulating histologic and functional (vessel response to vasodilators) data that areas of previous aneurysm remain abnormal. This finding has led to speculation that these patients have an increased future cardiac risk, in particular in the development of atherosclerotic lesions in these previously dilated areas. At this time, there is no evidence available to suggest that these patients require more specialized cardiac follow-up than the standard counseling on lifestyle modifications that are suggested for all adult patients, including advice regarding abstinence from tobacco use, healthy diet choices, regular aerobic exercise to avoid the development of obesity, as well as treatment of hypertension and dyslipidemia when necessary. Future studies should include trials of statins in patients with Kawasaki disease who may be at risk of accelerated atherosclerosis.

Epidemiology

The prevalence of ARF varies with the geographic region, rural versus urban setting, socioeconomic conditions, and age group. Although the incidence and prevalence of ARF and RHD have been decreasing in developed countries since the early 1900s, they continue to be major causes of morbidity and mortality among young people in developing countries. In 2005, Carepetis and colleagues estimated that 15.6 million to 19.6 million people worldwide have RHD, and at least 2.4 million people were children aged 5 to 14 years. They also estimated that at least 200,000 to 250,000 premature cardiovascular deaths are caused by RHD every year.

The highest incidence of ARF has been reported among the Aboriginals and Torres Strait islanders of Australia and the Maoris of New Zealand. In 2000, Oen and colleagues compared the incidence rate of ARF per 100,000 persons in each region. Incidence was low in industrialized nations (0.23–1.14), 15.2 among African American populations in Florida, 125 in Sri Lanka, 142 among Maori in New Zealand, 206 in Samoans in Hawaii, and up to 650 in Australian aboriginal groups. Although the incidence of ARF has decreased in all regions over the past 20 years, the reported prevalence of RHD is increasing in all regions except for Europe, which may be because of advances in medical and surgical treatments for RHD that have led to increased survival in these patients, as well as increased screening for RHD by echocardiography in countries with high disease prevalence. The incidence of RHD does not necessarily correspond with that of ARF, and the explanation is likely multifactorial. In 2005, the incidence of RHD was highest in Africa, the Pacific, and south-central Asia.

ARF and RHD are more common in rural than urban populations. ARF is also more common in low socioeconomic areas, which could be secondary to limited access to medical care, poor medical attention, hygiene, malnutrition, poor adherence to prophylaxis, and increased household crowding leading to increased streptococcal exposure. Most studies have shown that men and women are equally affected; however, from a recent worldwide epidemiologic study, there is a slight male predominance.

The initial attack of ARF is most common just before adolescence, ranging from 5 to 14 years old, less common near the end of the second decade, and rare in adults older than age 35 years. ARF can also first occur in children younger than 5 years, representing approximately 5% to 10% of patients with ARF. RHD usually results from the cumulative damage of recurrent episodes of ARF, thus the prevalence of RHD increases with age, peaking in adults aged 25 to 34 years, reflecting ARF activity in previous decades.

Pathogenesis of Carditis in ARF

Streptococcus pyogenes , or group A beta-hemolytic streptococci (GAS), have long been known to be associated with the development of ARF. This knowledge is supported by the observations that outbreaks of ARF have followed outbreaks of pharyngitis and that increasing antistreptococcal antibodies are seen in patients with ARF. Because GAS possess antigens and superantigens that can stimulate B and T cells to respond to self-proteins, a hypothesis of molecular mimicry between bacterial antigens (M protein and carbohydrate antigen ) and cardiac proteins, particularly alpha-helical proteins such as myosin, laminin, and vimentin, on host tissues has been proposed. The M protein is a major virulence factor for GAS, and initial observations showed that strains with certain serotypes of M protein were particularly associated with outbreak of ARF, giving rise to the hypothesis of so-called rheumatogenic strains of GAS. However, with the advances of immunologic studies, the antibodies that target heart valves in humans are now thought to perhaps not target the M protein, but rather the carbohydrate antigen on certain streptococcal strains. Studies by Adderson and colleagues of antistreptococcal/antiheart monoclonal antibodies from rheumatic carditis have revealed that cardiac myosin and N -acetyl-B- d -glucosamine (NABG), the dominant epitope of the group A carbohydrate antigen, are the cross-reactive antigens involved in antibody deposition on valves. However, myosin is present in myocardium but not in valve tissues, which are the major site affected by ARF. A subsequent study of mice immunized with streptococcal pyrogenic exotoxin B showed that the mice developed autoantibodies that can cross react with NABG and endothelial cells, again supporting the molecular mimicry hypothesis and possibly explaining the valvulitis in patients with RHD. In addition, a recent study showed the presence of anti–endothelial cell antibodies (AECA) in 40% of Yemeni patients with RHD. A subsequent study by this group showed that vimentin is the potential autoantigen for AECA. They were able to show cross reactivity of purified antivimentin antibodies with heat shock protein-70 and streptopain streptococcal proteins, and these antibodies were able to activate microvascular cardiac endothelium by amplifying the inflammatory response in RHD.

Given that pathologic and immunologic findings suggest that the primary site of rheumatic fever–related damage is the subendothelial collagen matrix, another hypothesis of ARF has recently emerged. Studies by Dinkla and colleagues suggest that M protein of rheumatogenic streptococcal strains binds and forms a complex with the CB3 region in human collagen type IV in subendothelial basement membranes, and that this immune complex might initiate an autoantibody response to the collagen as seen in patients with Goodpasture or Alport syndromes. Moreover, these antibodies do not cross react with M proteins, and this hypothesis argues against the molecular mimicry concept. Further studies are ongoing to test this hypothesis.

Host susceptibility that is genetically determined has also been presumed to play a role in the pathogenesis of ARF, because of the difference of its prevalence in each geographic region, increased risk of RHD in certain populations, the tendency for outbreaks to occur within families, and the strong association with the monozygosity and concordance rate of ARF. With advances in genetic studies, different human leukocyte antigen (HLA) class II antigen associations have been observed in several populations. Several studies have reported an association of ARF with various genetic polymorphisms involved in regulation of both innate and adaptive immunity, including mannose-binding lectin, toll-like receptor-2 and ficolin-2, interleukin (IL)-1 receptor antagonist, TNF-α, transforming growth factor beta (TGF-β), cytotoxic T-lymphocyte antigen 4 (CTLA-4), IL-6, IL-10, and angiotensin-converting enzyme (ACE).

Based on the molecular mimicry hypothesis, following a streptococcal infection, the susceptible host develops cross-reactive autoantibodies against group A streptococcal carbohydrate antigen, cardiac myosin in the myocardium, and endothelial cells of the valves. The valves become inflamed with expression of vascular cell adhesion molecule-1. After this event, CD4+ and CD8+ T cells infiltrate through the endothelium/endocardium into the valve. The valve becomes scarred with eventual neovascularization and progressive, chronic valvular disease. In the past, ARF was thought to occur only following streptococcal pharyngitis, not impetigo and skin infections. However, there is some epidemiologic evidence to suggest that skin strains of GAS may play a role in the pathogenesis of ARF. Further studies need to be performed to prove direct causation of ARF after skin infection.

Diagnosis of ARF

The clinical manifestations of ARF occur 2 to 6 weeks after streptococcal pharyngitis. The diagnostic criteria for ARF were first developed by Jones in 1944 and have been revised over the years, with the most recent revision in 1992. The criteria are divided into major and minor criteria ( Table 1 ). The diagnosis of ARF is made by the presence of 2 major criteria or of 1 major and 2 minor criteria, plus evidence of a preceding streptococcal infection. Clinicians should be aware that the Jones criteria were developed for, and are applicable only to, initial attacks of ARF. A diagnosis of ARF can be made without fulfilling criteria if any of these are present: chorea, indolent carditis, or recurrent episodes of ARF. Patients with chorea and indolent carditis are not required to have evidence of streptococcal infection, because these can be late manifestations of ARF. Diagnosis of recurrent episodes of ARF can be based on only minor manifestations and evidence of recent streptococcal infection in patients with preexisting RHD, because patients with RHD have a high risk of carditis in recurrent ARF. In developing countries, especially among high-incident indigenous populations, epidemiologists have noted that strict application of the updated Jones criteria may result in underdiagnosis of ARF.

Table 1

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