Clinical manifestations

Presentation and course

Classically, Kawasaki disease is a triphasic, multisystemic inflammatory syndrome. The acute phase encompasses days 0 to 10 and is characterized by the presence of a persistent fever. The fever is accompanied by conjunctivitis, changes of the oral mucosa, rash, extremity changes, and lymphadenopathy. The presence or absence of these signs is paramount to the diagnosis of Kawasaki disease. Fever is the sine qua non of Kawasaki disease. In the acute phase, fever is generally greater than 39ºC and unresponsive to antibiotics. The fevers occur on consecutive days and persist throughout the day. Changes of the mucosal membranes observed during this phase include conjunctivitis and changes in the oral mucosa. Changes in the mucosal surfaces are useful in differentiating Kawasaki disease from other etiologies. Conjunctivitis noted in Kawasaki disease is described as bilateral and nonpurulent, and it spares the limbus. Conjunctivitis is reported in more than 85% of Kawasaki disease cases (12). Abnormalities of the oral mucosa occur in 85% of children with Kawasaki disease. Characteristics include red, dry, vertically cracked lips; diffuse erythema of the oropharynx; and swelling of the lingual papillae with sloughing of the mucosa (“strawberry tongue”). A polymorphous rash is seen in more than 80% of Kawasaki disease cases. This rash may be maculopapular, morbilliform, or similar to erythroderma. Bullous, vesicular, and purpuric rash are atypical for Kawasaki disease and should indicate another diagnosis. Extremity changes occur in up to 75% of children during the acute phase. Classic extremity changes during this period include palmar, plantar, and periungual erythema and swelling. Cervical lymphadenopathy is the least consistent clinical finding in Kawasaki disease, occurring in up to 70% of patients. The lymph nodes are frequently greater than 1.5 cm, tender, and unilateral.

Table 1. Frequency of Clinical Findings in Kawasaki Disease

(13).

Children with Kawasaki disease may also experience abnormalities of the cardiac, neurologic, gastrointestinal, and musculoskeletal systems during the acute phase. A majority of patients exhibit signs of cardiovascular abnormalities, most commonly tachycardia. Children may also have evidence of myocarditis, indicated by the presence of an S3 gallop in addition to tachycardia out of proportion to hydration status or fever. Given the irritability and fever noted in patients with Kawasaki disease, many children will undergo an evaluation for presumed meningitis. Other neurologic or ocular manifestations include febrile seizures, facial palsy, anterior uveitis, and sensorineuronal hearing loss. Gastrointestinal symptoms occur in up to one third of patients with Kawasaki disease. Abdominal pain may be significant, and children with Kawasaki disease may be misdiagnosed with acute appendicitis. An acute polyarthritis involving the small joints may also be found in patients with Kawasaki disease during the acute phase. For an excellent review of these associated symptoms, see the endorsed clinical report from the American Academy of Pediatrics and the American Heart Association (33).

It is during the subacute phase (days 10 to 40 after onset of fever) when the most serious complication of Kawasaki disease - coronary artery aneurysms - typically evolve. Only a minority of children will present with coronary artery abnormalities at the time of diagnosis. The risk of aneurysm rupture is highest during the subacute phase (10). The fever, mucosal changes, and extremity changes gradually resolve during the subacute phase, but additional symptoms may occur. New extremity changes characterized by periungual desquamation may manifest during this time. Arthritis occurring in the subacute stage usually involves the large joints.

In the convalescent phase (day 40 and beyond), children are frequently asymptomatic but progressive stenosis of the coronary arteries may lead to the development of ischemic symptoms. The risk of myocardial infarction from this progressive stenosis is highest during the year after the diagnosis of Kawasaki disease. Beau lines - transverse grooves in the nails - may also be observed during the convalescent phase.

Diagnostic guidelines for the classification of patients with Kawasaki disease have existed for over 20 years and have been reviewed by experts in the United States and Japan (33; 03; 30; 45). Fevers must be present for 5 consecutive days. Additionally, 4 out of the following 5 signs must be present: bilateral nonpurulent conjunctivitis, changes in the oral mucosa, polymorphous exanthem, extremity changes (erythema and swelling of the hands and feet in the acute phase or characteristic periungual desquamation in the convalescent phase), and cervical lymphadenopathy. The diagnosis of Kawasaki disease may also be given if coronary artery abnormalities are detected in a patient with 5 consecutive days of fever and only 2 or 3 of the clinical characteristics, or in patients fulfilling 4 out of 5 clinical criteria with less than 5 days of fever (33). Most patients develop signs sufficient for the diagnosis of Kawasaki disease within 5 days of fever onset. However, a subgroup of patients develops these signs more slowly, making diagnosis more difficult. Patients with “slow-onset” Kawasaki disease will frequently have evidence of mucosal involvement prior to day 5, which should heighten suspicion for Kawasaki disease. Most importantly, patients with a delayed diagnosis of Kawasaki disease suffer from an increased number of coronary artery aneurysms, thus, emphasizing the importance of physician awareness (02). Ideally, attempts should be made to diagnose and treat patients prior to day 10 of illness, but care must be taken not to assign the diagnosis without substantial evidence supporting Kawasaki disease.

Table 2. Criteria for the Diagnosis of Kawasaki Disease

Diagnosis may be made on day 4 of illness when more than 4 criteria are present.

Patients with more than 5 days of fever and less than 4 clinical criteria who have evidence of echocardiographic abnormalities may also be diagnosed with Kawasaki disease.

Patients with fever and less than 4 of the required clinical criteria may be diagnosed and treated for incomplete Kawasaki disease. This presentation should be termed incomplete Kawasaki disease rather than atypical Kawasaki disease as these patients present with symptoms typical of Kawasaki disease yet fail to fulfill classic Kawasaki disease criteria. Children diagnosed with incomplete Kawasaki disease tend to be younger (median age less than 18 months) compared to traditional Kawasaki disease patients. As with complete Kawasaki disease, fever and oral mucosal changes are the most frequently noted signs in patients diagnosed with incomplete Kawasaki disease, followed by extremity changes, especially desquamation, and conjunctivitis. Rash and cervical lymphadenopathy are the least commonly noted signs with incomplete Kawasaki disease (20; 23). The laboratory profiles in these patients are similar to patients fulfilling traditional diagnostic criteria and may be used by experienced clinicians to heighten the clinical suspicion of Kawasaki disease. Although these patients are not at increased risk for coronary artery abnormalities, echocardiography may be useful in patients with an indefinite diagnosis. Guidelines to aid the clinician in this scenario have been published (33).

Prognosis and complications

Almost all patients who develop coronary artery aneurysms do so within 8 weeks of the onset of fever. Generally, 50% of these lesions will resolve within 12 months. The likelihood of regression is dependent on several factors but most heavily depends on aneurysm size, with giant aneurysms (larger than 8 mm) carrying lowest probability of regression and highest risk of subsequent morbidity and mortality. The overall case fatality rate in the United States is 0.17% with a majority of deaths occurring in the first 12 months from either acute myocardial infarction or aneurysm rupture (15).

Clinical vignette

A 4-year-old female was admitted to the hospital after having fever of up to 103.5ºF for 5 consecutive days. Physical exam revealed an uncomfortable, irritable, but consolable female child who was tachycardic with normal blood pressure. She had bilateral, nonpurulent conjunctival injection with sparing of the limbus and erythematous lips with diffuse, nonexudative injection of the oropharynx. Her neck exam revealed bilateral, non-tender anterior chain lymphadenopathy. Palmar erythema and nonpitting edema of the hands, along with blanching, erythematous, maculopapular lesions on the trunk and proximal extremities, were noted. Laboratory exam showed a white blood cell count of 18,000 (normal: 5 to 15.5 x 103 mm3) with 85% neutrophils and 10% lymphocytes. Hemoglobin, hematocrit, red blood cell indices, and platelets were normal. Her erythrocyte sedimentation rate was elevated at 58 mm/hr (normal: 0 to 20 mm/hr) via Westergren Method and her C-reactive protein was 8.3 mg/dL (normal: less than 0.8 mg/dL). Sodium electrolytes, including creatinine, were normal, except for a mild elevation of her blood urea nitrogen at 28 mg/dL (normal: 7 to 22 mg/dL). Her aspartate and alanine aminotransferase levels were mildly elevated at 62 IU/L (normal: 0 to 35 U/L) and 79 IU/L (normal: 1 to 30 IU/L), respectively. The patient had indirect hyperbilirubinemia at 6 mg/dL (1 mg/dL). A urine specimen had trace protein with 26 white blood cells (normal: less than 9 white blood cells per high powered field), and was negative for casts, red blood cells, or organisms. The patient was initially treated with intravenous fluids and acetaminophen. Chest x-ray, blood cultures, urine cultures, and nasopharyngeal viral cultures were negative. On day 7 of her illness, a diagnosis of Kawasaki disease was made and an echocardiogram was obtained, which was normal. The patient was given a single dose of 2 g/kg intravenous immunoglobulin in conjunction with 25 mg/kg aspirin 4 times a day. The patient defervesced 24 hours later, and she remained afebrile during the remainder of her hospital stay. A repeat echocardiogram performed 6 weeks later was normal.

Biological basis

Etiology and pathogenesis

Despite vigorous attempts, the exact etiology of Kawasaki disease remains elusive. Considerable debate surrounds the identity of the inciting event in Kawasaki disease. One prominent theory is that a ubiquitous infectious agent incites an inflammatory response resulting in the clinical syndrome of Kawasaki disease. To support this theory, Rowley and colleagues used cadaveric tissue from patients with Kawasaki disease to document the immunologic changes occurring in Kawasaki disease. They have found that arterial tissues from patients with fatal Kawasaki disease are infiltrated with oligoclonal IgA-secreting plasma cells (42). The same group went on to clone several of the more prominent IgA genes from these tissue samples and produce synthetic human antibodies. These synthetic antibodies have been found to selectively stain ciliated bronchoepithelium (41). They have found these antibodies selectively bind to inclusion bodies in the ciliated tissue (40). These inclusion bodies appear similar in morphology to inclusion bodies seen in Paramyxoviridae infections. Moreover, all synthetic antibodies reacted with the inclusion body with variable avidity, indicative of an antigen-specific immune response.

A second, widely held theory is that exposure to an antigen with superantigenic properties causes Kawasaki disease. To review, a superantigen is an antigen that has the ability to cross-link class II major histocompatibility proteins to variable regions of the T-cell receptor beta chain. This can stimulate up to 20% of all T-cells (44; 39). The superantigen hypothesis is supported by the following observations:

Regardless of the exact antigenic stimulus, evidence exists of widespread activation of both the innate and adaptive immune systems in Kawasaki disease. Investigations into the role of innate immunity in Kawasaki disease has revealed polymorphisms in the promoter of CD14 toll-like receptor (34) as well as the gene encoding mannose-binding lectin protein (a plasma protein with antimicrobial properties) (06). Elevated serum levels of a neutrophil-derived proinflammatory protein, S100A12, and neutrophil-derived elastases have also been documented in patients with Kawasaki disease (51; 07). The interaction of S100A12 and its multiligand receptor, receptor for advanced glycosylation end-products (RAGE), results in activation of the nuclear factor-kappa B pathway and upregulation in transcription of proinflammatory cytokine genes (28). Blockade of this pathway may be a potential target for therapy (43).

The humoral arm of the adaptive immune system plays an important role in the development of Kawasaki disease. Studies have shown expansion of oligoclonal B cells and infiltration of IgA secreting plasma cells into affected tissue in Kawasaki disease (42). The cell-mediated arm exhibits restrictions of the T-cell receptor and a high number of CD8+ T-cells are found within coronary artery tissue (09). Elevated levels of interleukin-1, interleukin-6, tumor necrosis factor-alpha, and neopterin are evidence of widespread macrophage activation.

The widespread activation of the immune system results in upregulation of endothelial surface adhesion molecules promoting migration of activated monocytes and neutrophils. Acute histologic changes include the accumulation of neutrophils in all layers of the heart and infiltration of mononuclear cells and IgA secreting plasma cells into the coronary vasculature. As the acute neutrophilic phase wanes, a chronic inflammatory response follows, during which an accumulation of mononuclear cells and a gradual degradation of the internal elastic lamina and tunica media most likely is mediated by a group of proteins called elastases. Elastases, such as matrix metalloproteinases, are proteins with the ability to degrade collagen and elastin. Matrix metalloproteinases-9 has been implicated in coronary artery aneurysm formation in Kawasaki disease. Matrix metalloproteinases-9 is produced by smooth muscle cells and B- and T-lymphocytes. The expression of matrix metalloproteinases-9 is increased by interleukin-2, tumor necrosis factor-alpha, and interferon gamma, all of which have been shown to be increased in Kawasaki disease. Matrix metalloproteinases-9 is found in coronary artery tissue from patients with Kawasaki disease both with and without coronary artery aneurysms but not in control tissues. Matrix metalloproteinases-9 is also significantly increased in the myointimal layers of coronary artery aneurysms as well as in the vascular smooth muscle and myocardium. Interestingly, matrix metalloproteinases-9 is also found in noncoronary arterial tissues in Kawasaki disease. Matrix metalloproteinases-9’s natural inhibitor, tissue inhibitor of matrix metalloproteinase, does not exhibit increased expression in coronary artery aneurysm tissue when compared to controls. Serum levels of promatrix metalloproteinases-9 are also elevated in Kawasaki disease but active levels of the enzyme are normal. The overall effect may be that the initial antigenic stimulus triggers a specific inflammatory cytokine profile that activates different cell types at the level of the coronary arteries to cause an imbalance of matrix metalloproteinases-9 and its inhibitor tissue inhibitor of matrix metalloproteinase. This imbalance results in the breakdown of the extracellular matrix within the coronary artery and the resultant dilation and aneurysm formation. Fibrosis follows this initial necrotic insult and results in stenotic lesions at risk for thrombotic occlusion.

Epidemiology

Kawasaki disease is one of the most common pediatric vasculitides. Asian countries exhibit the greatest incidence of Kawasaki disease, with Japan having the highest annual incidence at 110 to 130 per 100,000 children (49; 04). Passive surveillance data reported by the Centers for Disease Control and Prevention place the overall incidence of Kawasaki disease in the United States at 9 to 30 per 100,000 in children less than age 5 years. Children of Asian and Pacific Island descent exhibit the highest annual incidence followed by Black, Hispanic, and Caucasian children (15; 22). The median age of onset in the United States is 2 years, with more than 75% of cases occurring before age 5 years (22), but neonatal and adult cases of Kawasaki disease have been reported in the literature. Kawasaki disease affecting children younger than 1 year of age or older than 8 years is less likely to be recognized and appropriately treated (37) and carries increased risk of coronary artery lesions. Males are more frequently diagnosed with Kawasaki disease than females (1.5:1) (22). Some studies have reported that the incidence of Kawasaki disease is rising (50), whereas other studies have refuted this finding (16).

Epidemiological data in Kawasaki disease have led experts to believe an infectious agent is responsible for the illness. Multiple studies have documented the seasonality of Kawasaki disease, with the highest rates occurring in the winter and spring months. One study showed that Kawasaki disease occurrence was positively associated with average monthly snowfall and inversely associated with average monthly temperature (01). Numerous outbreaks of Kawasaki disease cases have been reported by the United States Centers for Disease Control and Prevention. In Japan, household contacts of children with Kawasaki disease have a 10- to 15-fold increase in relative risk of developing Kawasaki disease (19).

Coronavirus disease 2019 (COVID-19) has been linked with multisystem inflammatory syndrome in children (MIS-C). Many children meet criteria for complete or incomplete Kawasaki disease. In contrast to Kawasaki syndrome, multisystem inflammatory syndrome in children seems to preferentially affect Black and Hispanic children that are older (average 9 to 11 years of age). There appears to be a time lag between the peak of COVID-19 and the occurrence of multisystem inflammatory syndrome in children cases in the population (14; 48).

Prevention

There are currently no reported methods in the primary prevention of Kawasaki disease.

Differential diagnosis

The differential diagnosis of Kawasaki disease is broad given its similarities to infectious-mediated illnesses. Serious bacterial infections and toxin-mediated illness such as scarlet fever, toxic-shock syndrome, and staphylococcal scalded skin syndrome can all present with fever and rash similar to that of Kawasaki disease. Kawasaki disease patients are often first treated with antimicrobials pending culture results. Viral infections such as adenovirus, Epstein-Barr virus, and enterovirus can also mimic Kawasaki disease. Drug reactions and Stevens-Johnson syndrome should also be considered in the work-up of Kawasaki disease.

Diagnostic workup

Once a patient fulfills diagnostic criteria for Kawasaki disease, an echocardiogram should be immediately obtained and treatment should be initiated. Normal echocardiographic findings should not influence a clinician's decision to initiate treatment. Electrocardiographic changes consistent with myocarditis may be present, including PR segment prolongation, R-wave depression, and T-wave flattening. Changes consistent with acute myocardial infarction may rarely be seen. Apart from the classic coronary artery aneurysms, echocardiograms performed during the acute phase of the illness may exhibit “brightness” of the coronary arteries, depressed myocardial function, valvular abnormalities, or pericardial effusions. Coronary artery abnormalities may be classified as ectatic (larger than normal artery lacking a specific segmental dilatation), saccular aneurysms (equal lateral and axial diameters), and fusiform aneurysms (symmetric dilation with gradual tapering at the proximal and distal ends) (33). Changes noted in the coronary arteries should be corrected for body surface area and reported as z scores. The proximal left anterior descending coronary artery is most frequently affected followed by the proximal right anterior descending and the left medial coronary artery. Less frequently involved are the left circumflex, distal right coronary artery and the junction of the right circumflex or coronary artery, and posterior descending coronary artery. Almost three quarters of patients with coronary artery abnormalities have more than 1 vessel involved (33).

Other investigations during the evaluation of a patient with suspected Kawasaki disease are directed toward ruling out other possible etiologies as well as delineating involvement of other organ systems. Complete blood cell counts often show leukocytosis with a neutrophilic predominance. Depending on the duration of inflammatory symptoms, a normocytic, normochromic anemia may be noted. Thrombocytosis is characteristically seen in the subacute and convalescent phase. The erythrocyte sedimentation rate and C-reactive protein levels are frequently elevated during the acute phase and then normalize during the subacute phase. Hyponatremia and hypoalbuminemia may be noted as signs of increased vascular permeability and may be a risk factor in the development of coronary artery lesions. Depending on the patient’s hydration status, abnormalities in serum chloride, bicarbonate, blood urea nitrogen, and creatinine may also be observed. Examination of the urine may exhibit sterile pyuria. Serum transaminases may also be increased in patients with Kawasaki disease and alanine aminotransferase levels may correlate with risk for coronary artery aneurysm formation (47). Hyperbilirubinemia with elevation of gamma-GTP and alkaline phosphatase may represent biliary hydrops. Ultrasound may demonstrate acute acalculous hydrops. Serum troponin levels may also be elevated, indicative of myocardial damage (26). CSF examination may reveal evidence of aseptic meningitis, such as pleocytosis with a mononuclear predominance and normal glucose and protein (17). Arthrocentesis of inflamed joints typically demonstrates highly elevated white blood cell counts with normal cultures and gram stain. Microbiological testing for infectious agents are commonly negative, although up to one third of patients meeting clinical criteria for Kawasaki disease will be found to have an infectious source (05).

Table 3. Suggested Evaluations in Suspected Kawasaki disease

Management

Intravenous immunoglobulin is of primary importance in the treatment of Kawasaki disease. Multiple studies have documented the efficacy of IVIG in the prevention of coronary artery aneurysms (32; 36). The beneficial properties of IVIG are dose dependent and may also be dependent on the brand of IVIG used (46). All patients should receive 2 g/kg IVIG as a single infusion in combination with high-dose aspirin (30 to 50 mg/kg divided 4 times a day) (30). Attempts should be made to treat patients prior to the 10th day of illness. Diagnosis and treatment of Kawasaki disease prior to day 5 does not significantly decrease the risk of coronary artery aneurysms and may increase the need for retreatment. However, patients presenting after the 10th day of illness with coronary artery aneurysms, persistent fevers, or who have elevated inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) should also be treated with IVIG. Moderate-dose aspirin should be continued until the patient is afebrile for 48 to 72 hours. At that time, the aspirin dose should be lowered to antiplatelet levels (3 to 5 mg/kg divided 4 times a day) and continued until a repeat echocardiogram is completed 6 to 8 weeks later. If the repeat echocardiogram is normal, the aspirin may be discontinued. In patients with coronary artery aneurysms, low-dose aspirin should be continued indefinitely. A joint consensus statement by the American Academy of Pediatrics and the American Heart Association reviews the treatment recommendations for Kawasaki disease (33; 38; 30; 45).

Controversy surrounds the treatment of the approximately 10% of patients who fail to respond to IVIG and moderate-dose aspirin. Treatment failure is defined as persistent fever or fever recurrence 24 to 48 hours in a patient previously treated with an appropriate dose of IVIG. A majority of experts suggest administering a second dose of IVIG at 2 mg/kg. However, there may be mounting evidence supporting the role of steroids in these patients. This may be particularly true in patients at risk of a more severe outcome, based on Kobayashi score greater than 5 or other risk factors for IVIG resistance (27). Other agents, such as infliximab (a chimeric murine/human IgG1 monoclonal antibody that binds to tumor necrosis factor-alpha-1), have been effective in small series of patients with refractory Kawasaki disease (11; 21), but further studies are needed. Failure to respond to a second dose of IVIG should prompt the clinician to reconsider the diagnosis of Kawasaki disease, and consultation with a pediatric rheumatologist should be sought.

Table 4. Treatment of Kawasaki Disease

Outcomes

Cardiac sequelae are the source of almost all morbidity and mortality in patients with Kawasaki disease. Untreated, up to 25% of Kawasaki disease patients will develop coronary artery abnormalities. Timely treatment with intravenous immunoglobulin and moderate-dose aspirin reduces the risk of developing coronary artery aneurysms to less than 5%. Acute abnormalities due to inflammatory myocarditis usually resolve with administration of immunosuppressive therapy.

Special considerations

Pregnancy

Treatment of pregnant patients should be done in conjunction with these patients’ obstetricians.