Kawasaki Disease (KD, Kawasaki Syndrome, Mucocutaneous Lymph Node Syndrome)
Are You Confident of the Diagnosis?
What you should be alert for in the history
Kawasaki Disease (KD) is diagnosed based on clinical criteria with supporting laboratory data. Suspect the diagnosis in a child who has had a fever for at least 5 days and who fits at least four of the following five criteria:
Bilateral conjunctival injection
Changes in the oropharynx, including erythema and fissuring of the lips, "strawberry" tongue, erythema of oropharyngeal mucosa
Changes in the extremities, including edema of the dorsa of the hands and feet, palm and sole erythema, periungual desquamation in the convalescent phase
Cervical lymph node mass greater than or equal to 1.5cm (usually unilateral anterior cervical node mass)
Characteristic findings on physical examination
Febrile, irritable infant, child, or adolescent (age range 2 months to 20 years)
Vital signs: tachycardia out of proportion to fever
Skin: nonspecific eruption can be maculopapular, raised edematous plaques, target-like lesions, or urticarial lesions; erythroderma is rare; rash is NEVER frankly bullous or vesicular. Distribution is usually over both the trunk and extremities with 50% of patients having accentuation of the rash in the groin (often associated with acute desquamation). Rash usually spares the scalp, palms, and soles.
Bilateral conjunctival injection with sparing of the limbus, creating the appearance of a white halo around the iris; no exudate or excessive tearing; may have photophobia
Erythema with chapping or fissuring of the vermillion border; erythema of oropharyngeal mucosa WITHOUT discrete lesions such as Koplik spots, ulceration, or exudate on the tonsils; a strawberry tongue with loss of filiform papillae may be observed
Lung exam normal
Cardiac exam: may have S3 gallop, heard best at the apex with stethoscope bell
Abdominal exam: normal or right upper quadrant tenderness/fullness consistent with gallbladder hydrops; the spleen is NEVER enlarged
Genitourinary: urethral meatal erythema is observed in males
Extremities: edema of the dorsal hands/feet; erythema of palms/soles; small (PIP) joint or large (hips, knees, ankles) joint arthritis; periungual desquamation begins in the second to third week after fever onset; the transverse grooves of Beau's lines are seen on the fingernails and/or toenails at 4-6 weeks after fever onset
Neurologic exam: nonfocal; may have extreme irritability
Expected results of diagnostic studies
Complete blood count (CBC): increased white blood count (WBC), % polys, % bands, normocytic/normochromic anemia for age; increased platelet count
Elevated erythrocyte sedimentation rate (ESR)
Elevated c-reactive protein (CRP)
Elevated alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT)
Sterile pyuria on urinalysis
Skin biopsy: nonspecific edema, no evidence of small vessel vasculitis
Diagnosis is established by history, physical exam, and supporting labs. No other testing is indicated in classic cases. Refer for treatment and transthoracic echocardiographic exam.
Differential diagnosis can include adenovirus infection (rule out with direct fluorescent antibody testing of nasal secretions, polymerase chain reaction [PCR], or viral culture), enterovirus infection (rule out with PCR, viral culture), measles infection (rule out with antibody testing if not immunized), scarlet fever (rule out with rapid strep test and culture), and early Stevens-Johnson syndrome.
Who is at Risk for Developing this Disease?
KD is the most common cause of acquired heart disease in children of all races and ethnicities. The median age is 22 months, but young infants and young adults can also be affected. KD is over-represented among children of Asian and African-American descent. Review of administrative databases suggests that 5000-6000 new KD cases are diagnosed and treated each year in the United States. The overall incidence figures for the United States and Japan are 20 and 215 per 100 000 children under 5 yrs. of age, respectively.
What is the Cause of the Disease?
Etiology is unknown, although an infectious agent triggering an unusual immunologic response in genetically susceptible hosts is proposed. Genetic predisposition linked to polymorphisms in the calcineurin-NFAT and transforming growth factor-β pathways is a possible contributing factor.
KD is a self-limited vasculitis of medium-sized extra-parenchymal arteries with the coronary arteries as the principal target of the inflammatory response. Myocarditis of some degree is also present in all patients. Weakening of the arterial wall can result in coronary dilatation or aneurysm formation. Consequences of aneurysms include thrombosis, myocardial infarction, congestive heart failure, and sudden death.
Systemic Implications and Complications
Cardiac complications are the greatest concern. The illness is self-limited and will resolve, even in the absence of treatment.
Small and large joint arthritis is common and axial arthropathy can prevent a child from walking.
Respiratory (coryza, hoarseness, cough) and gastrointestinal (diarrhea, vomiting, abdominal pain) symptoms coexist with KD in approximately one-third of patients undergoing lumbar puncture.
Cerebrospinal fluid (CSF) profile may show a pleocytosis with normal CSF protein. A flare or first episode of atopic dermatitis or psoriasis can be precipitated by KD during the subacute phase.
Intravenous immunoglobulin (IVIG) 2g/kg over 10 hours
Aspirin 80-100mg/kg/day p.o. divided q 6h until afebrile, then 3-5 mg/kg/day p.o. until ESR and platelet count have returned to normal
Addition of steroids to initial therapy is without benefit
Optimal Therapeutic Approach for this Disease
All patients should receive standard therapy with IVIG and aspirin. IVIG-resistance is defined as persistent or recrudescent fever 36 hours after the end of the IVIG infusion. Patients who are IVIG-resistant can be treated with a second dose of IVIG (2g/kg) or with infliximab (5 mg/kg IV over 2 hours).
The role of pulse methylprednisolone, with or without subsequent oral prednisone, is controversial in this setting.
All patients should have an echocardiogram at the time of diagnosis and again in the subacute phase. Some centers repeat echoes at 2 weeks, 6 weeks, and 1 year after diagnosis.
Patients less than 3 years of age should be sedated for optimal visualization of the coronary arteries. Internal dimension of the right coronary and left anterior descending coronary arteries should be normalized for body surface area and expressed as Z scores (standard deviation units from the mean). Patients should be followed by a pediatric cardiologist or KD specialist.
Unusual Clinical Scenarios to Consider in Patient Management
The dermatologist may be consulted in cases of atypical or incomplete KD.
Patients may present with an incomplete clinical picture (only two to three of the clinical criteria). The diagnosis may be aided by performing an echocardiogram looking for the characteristic changes associated with acute KD.
Other diagnostic options that may be helpful include a slit lamp examination for anterior uveitis and a skin biopsy to rule out another vasculitic process. Abdominal ultrasound to confirm hydrops of the gallbladder, and neck ultrasound to rule out bacterial cervical adenitis, may be helpful in selected patients.
There is no single laboratory diagnostic test that confirms the diagnosis of KD. Patients referred to the dermatologist because of periungual desquamation in the convalescent phase should have an echocardiogram and laboratory testing to assess for level of inflammation. Patients with coronary artery abnormalities or an elevated ESR should be treated with IVIG plus aspirin even if fever has remitted.
What is the Evidence?
Newburger, JW, Takahashi, M, Gerber, MA. "Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association". Circulation. vol. 110. Nov 26 2004. pp. 2747-71.(The definitive guide to diagnosis and treatment that establishes the medicolegal standard of practice in the United States. Exhaustive references and a helpful algorithm to diagnose incomplete KD. Guidelines have been validated in retrospective cohort study [Yellen et al. 2010].)
Burns, JC, Glode, MP. "Kawasaki syndrome". Lancet. vol. 364. Aug 7 2004. pp. 533-44.(Detailed summary of history and clinical presentation. Good photographs and helpful algorithms.)
Burns, JC, Kushner, HI, Bastian, JF. "Kawasaki disease: a brief history". Pediatrics. vol. 106. Aug 2000. pp. E27.(Provides details of the discovery of KD and framing of KD as a new clinical entity in Japan in 1967. Also describes the independent, co-discovery of KD in Hawaii by Melish and Hicks in 1974.)
Burns, JC, Mason, WH, Glode, MP. "Clinical and epidemiologic characteristics of patients referred for evaluation of possible Kawasaki disease. United States Multicenter Kawasaki Disease Study Group". J Pediatr. vol. 118. May 1991. pp. 680-6.(Remains the best source for laboratory values in acute KD and clinical signs NOT associated with KD.)
Newburger, JW, Takahashi, M, Beiser, AS. "A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome". N Engl J Med. vol. 324. June 6 1991. pp. 1633-19.(The original landmark paper that established IVIG plus aspirin as effective therapy for KD.)
Burns, JC, Best, BM, Mejias, A. "Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease". J Pediatr. vol. 153. Dec 2008. pp. 833-8.(Describes Phase I clinical trial of TNF-alpha blockade as rescue therapy for patients with IVIG-resistance. Established infliximab as safe and well-tolerated in this patient population.)
Tremoulet, AH, Best, BM, Song, S. "Resistance to intravenous immunoglobulin in children with Kawasaki disease". J Pediatr. vol. 153. Jul 2008. pp. 117-21.(Definitive description of clinical and laboratory data in the United States of patients with IVIG-resistance. Demonstrates failure to predict IVIG resistance in patients in the United States using scoring systems devised in Japan.)
Patel, RM, Shulman, ST. "Kawasaki disease: a comprehensive review of treatment options". J Clin Pharm Ther. vol. 40. 2015. pp. 620-5.
Haddock, ES, Calame, A, Shimizu, C, Tremoulet, AH, Burns, JC, Tom, WL. "Psoriasiform eruptions during Kawasaki disease (KD): A distinct phenotype". J Am Acad Dermatol. vol. 75. 2016. pp. 69-76.e2.
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