Approach Considerations
Complete KD is a clinical diagnosis; no laboratory or imaging evaluations are required aside from echocardiography once the diagnosis is made. Pre-diagnosis laboratory and imaging evaluations are of greater utility for cases of incomplete KD, when the diagnosis is suspected but the patient does not meet criteria for complete KD. Normal results on some studies can help narrow the differential diagnosis; however, it should be noted that KD can occur concurrently with other diseases that mimic its findings, including respiratory viruses.
A typical initial laboratory evaluation may include a complete blood count (CBC), electrolyte panel, renal function testing, liver enzymes, albumin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and urinalysis. Certain laboratory abnormalities coincide with various stages. On complete blood counts, mild-to-moderate normochromic anemia is often observed in the acute stage. During the subacute stage, thrombocytosis is common. The platelet count begins to rise in the second week and continues to rise during the third week. Platelet counts average 700,000/μL, but levels as high as 2 million have been observed. Thrombocytopenia is associated with severe coronary artery disease and MI; rarely, it may be associated with disseminated intravascular coagulation. Hypoalbuminemia may be present and is often associated with more severe and prolonged illness. Acute-phase reactants are almost universally elevated at presentation. Sterile pyuria is also sometimes present due to urethral inflammation. In the convalescent stage, the levels of platelets and other markers begin to return to values within the reference range. Laboratory values may require 6-8 weeks to normalize.
Research is ongoing to attempt to identify specific biomarkers to aid in the diagnosis of KD. Recently, 2 urine proteins have been identified as potential biomarkers of KD: meprin A and filamin C. Meprin A is an immune regulator, and filamin C is associated with endothelial and myocardial cell injury. [60, 61]
Diagnostics for Cardiac Complications
Echocardiography is the study of choice to evaluate for CAAs, in both fully manifested and suspected incomplete cases of KD. Serial echocardiograms should be obtained, preferably at the time of KD diagnosis, at 1-2 weeks, and at 5-6 weeks after the onset of the illness. These may need to be performed more frequently in high-risk patients. [56, 62, 4]
On electrocardiography (ECG), tachycardia, prolonged PR interval, ST-T wave changes, and decreased voltage of R waves may indicate myocarditis. Q waves or ST-T wave changes may indicate MI.
Cardiac enzyme levels (creatine kinase, troponin) are elevated during an MI.
A select group of patients may require cardiac catheterization and angiography. Cardiac angiography provides a more detailed study of the arteries, but it is associated with greater risks of rupture, especially when performed in the acute phase of the illness; it should be limited to select cases. Coronary computed tomography angiography (CTA) and magnetic resonance angiography (MRA) may also prove beneficial in the evaluation and follow-up of the coronary arteries. [63, 64]
Studies for Selected Patients
Abdominal imaging may be indicated depending on the patient's clinic presentation. Liver and gallbladder ultrasonography may be necessary if liver or gallbladder dysfunction is suspected. Acute distention of the gallbladder (hydrops) is identified on abdominal ultrasonography in 15% of patients. Gallbladder hydrops usually resolves without surgical intervention.
Scrotal ultrasound may be indicated if concerning signs or symptoms are present. Although epididymitis is generally an inflammatory process that affects boys aged 9-14 years, it can be observed in younger boys with Henoch-Schönlein purpura and KD.
Arthrocentesis may be indicated in patients with joint involvement to rule out septic arthritis. Joint fluid analysis in patients with KD typically shows numerous white blood cells, ranging from 125,000-300,000/µL, with normal glucose levels and negative culture results.
Lumbar puncture may be indicated in patients with clinical signs suggesting meningitis. In children who undergo lumbar puncture, 50% show evidence of aseptic meningitis with a predominance of mononuclear cells, along with normal glucose and protein levels.
Diagnosis of Incomplete Kawasaki Disease
In some cases, patients have prolonged fever and some of the principal clinical features of KD but not as many as are required to meet standard diagnostic criteria. Hence, the term "incomplete" rather than "atypical" is used to describe these cases. The AHA recommends that when fever for 5 days or longer plus 2 or 3 of the principal clinical features are present without an alternative explanation, a C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) should be obtained. If the CRP level is less than 3 mg/dL and the ESR is less than 40 mm/hr, the child is monitored clinically. Re-evaluation of these laboratory markers takes place if fevers persist, and an echocardiogram is performed if skin peeling develops.
If the CRP is 3 mg/dL or higher and/or the ESR is 40 mm/hr or more, the next step is to obtain supplemental laboratory studies. Abnormal limits include the following:
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Albumin 3 g/dL or less
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Anemia for age
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Elevated ALT level
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Platelets >450,000 (after 7 days of fever)
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WBC count 15,000/mm3 or greater
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Urine WBC 10/hpf or greater
If 3 or more supplemental laboratory criteria are positive, a diagnosis of incomplete KD is made. The child should have an echocardiogram and be treated. Alternatively, if a patient has a positive echocardiogram with or without positive supplemental laboratory criteria, the patient should be treated.
If fewer than 3 supplemental laboratory criteria are positive, the child is monitored clinically. Re-evaluation of these laboratory studies takes place if fevers persist, and an echocardiogram is performed if skin peeling develops. [56]
As alluded to above, some patients have been found to not meet the laboratory criteria but developed coronary artery abnormalities seen on echocardiography that were consistent with KD. [65] Clinical judgment is required to determine if and when supplemental laboratory criteria should be strictly followed versus when an echocardiogram should be obtained regardless of laboratory results.
It is critical to note that certain patient populations may present with prolonged fever but with very few to none of the principal clinical features or laboratory findings. This includes infants < 6 months old and adolescents. Unfortunately, while the diagnosis is exceedingly difficult to make in these scenarios, these patients are at high risk for cardiac complications. Therefore, the diagnosis of KD and treatment with IVIG should also be considered for patients with isolated prolonged fever of unclear etiology, or prolonged fever with any of the following clinical findings:
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Irritability
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Aseptic meningitis
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Unexplained or culture-negative shock
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Isolated cervical lymphadenitis unresponsive to antibiotics
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Retropharyngeal/parapharyngeal phlegmon unresponsive to antibiotics
Case reports have also highlighed exceedingly rare and unusual presentations of KD. Hinze et al reported a case of KD in a 3-month-old boy manifested by typical signs and CAAs but without fever. [66] Other unusual presentations (GI bleeding, lupus-like illness in a recurrent case, rhabdomyolysis) have been published as well. [22]
Echocardiography
Echocardiography should be performed to evaluate for CAAs during the acute stage. In order of highest to lowest frequency, the involvement of the coronary arteries is as follows:
Proximal left anterior descending and right coronary arteries
Left main coronary artery
Left circumflex artery
Distal right coronary artery
Posterior descending artery
In addition to evaluating the coronary arteries for dilation and thrombosis, the baseline echocardiogram is also performed to evaluate for other signs of cardiac involvement. This includes aortic root dilation, depressed contractility, ventricular and valvular dysfunction, and pericardial effusion.
Diffuse dilatation of coronary lumina can be observed in 50% of patients by the 10th day of illness. In children, pediatric cardiologists should ideally perform this study, because they are familiar with coronary artery diameter normal values. Coronary artery dimensions must be adjusted for body surface area to accurately identify dilation. A basic rule is that if the internal diameter of a segment is greater than 1.5 times that of an adjacent segment, then dilation probably exists.
The echocardiogram should be repeated at 1-2 weeks and then 5-6 weeks after disease onset; echocardiograms may need to be performed more frequently in high-risk patients. [56, 62, 4] Frequency of subsequent echocardiography and/or additional cardiac imaging is dependent on the disease severity and the expert opinion of pediatric cardiologists.
In a study that examined echocardiograms obtained at diagnosis and 1 and 5 weeks after diagnosis from 198 patients, Printz et al concluded that non-coronary cardiac abnormalities were associated with coronary artery dilation and laboratory evidence of inflammation within the first 5 weeks after the diagnosis of KD. Left ventricular systolic dysfunction was noted in 20% of patients and coronary artery dilation in 29%. Mitral regurgitation was present in 27% of patients and aortic root dilation in 8%. [67]
MRA and CT
While echocardiography is the preferred initial imaging modality for KD, CTA, MRA, and/or cardiac catheterization are often later utilized in cases of children with significant coronary artery aneurysms. This is at the discretion of pediatric cardiologists. [63, 64]
Histologic Findings
Biopsy is rarely performed or necessary to make the diagnosis; therefore, most specimens are obtained from autopsies or from patients who have had diseased arterial segments removed during bypass operations. Early findings show acute destruction of the media of the vessels by neutrophils, with loss of elastic fibers. Later, the infiltrate is replaced by lymphocytes, monocytes, and fibroblasts involved in arterial remodeling. Chronic lesions show intimal proliferation, neoangiogenesis, and vascular occlusion.
Weedon summarized the reported findings of KD as follows:
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Lymphocytes and mononuclear cells manifest in a perivascular fashion
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Edema of the papillary dermis may be present
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Pustules with small intraepidermal and subcorneal abscesses unrelated to eccrine ducts may be present
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One report noted subtle vascular alterations, subendothelial edema, focal endothelial cell necrosis, and vascular deposition of minute quantities of fibrinoid material
Upon ultrastructural examination, myocardial changes reveal hypertrophy, various degrees of degeneration, proliferation and abnormality of mitochondria, infiltration of a small number of lymphocytes, and fibrosis. Coronary microvascular lesions are characterized by the following:
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Microvascular dilatation
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Endothelial cell injury
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Platelet aggregation with thrombosis
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Stenotic lumen with thickened walls in the small arterioles [68]
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Kawasaki disease: Patchy generalized macular erythema, which is also typical of some viral exanthems.
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Kawasaki disease: Peeling and erythema of the fingertips.
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Kawasaki disease: Strawberry tongue.
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Pediatrics, Kawasaki disease. Note the appearance of the hand and lips. Photo courtesy of Sam Richardson, MD.
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Clinical manifestations and time course of Kawasaki disease.
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Oral manifestations of Kawasaki disease: red lips and strawberry tongue.
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Video overview of Kawasaki disease pathophysiology, symptoms, diagnosis, and treatment.
