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You are in: eMedicine Specialties >
Rheumatology > Miscellaneous Inflammatory Arthritis
Kawasaki Disease
Article Last Updated: Aug 16, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Paul R Ogershok, MD, Associate Professor, Departments of Internal Medicine and Pediatrics, West Virginia University Hospital
Paul R Ogershok is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, Pennsylvania Medical Society, and West Virginia State Medical Association
Coauthor(s):
Martin Weisse, MD, Program Director, Associate Professor, Department of Pediatrics, West Virginia University
Editors: Kristine M Lohr, MD, Associate Chief, Program Director, Professor, Department of Internal Medicine, Division of Rheumatology, University of Tennessee School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Lawrence H Brent, MD, Associate Professor of Medicine, Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center; Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine; Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman, Department of Internal Medicine, Western Pennsylvania Hospital
Author and Editor Disclosure
Synonyms and related keywords:
KD, Kawasaki syndrome, Kawasaki's syndrome, Kawasaki disease, Kawasaki's disease, mucocutaneous lymph node syndrome, infantile periarteritis nodosa, vasculitis, atypical KD, incomplete KD, atypical Kawasaki disease, incomplete Kawasaki disease, polymorphous rash, bilateral conjunctival injection, erythematous rash
Background
In 1967, Tomisaku Kawasaki first described Kawasaki disease (KD) as a unique illness characterized by fever, rash, conjunctival injection, cervical lymphadenitis, inflammation of the lips and oral cavity, and erythema and edema of the hands and feet. Kawasaki disease is a generalized vasculitis of unknown etiology that has also been called mucocutaneous lymph node syndrome and infantile periarteritis nodosa. In developed countries, Kawasaki disease has replaced acute rheumatic fever as the most common cause of acquired heart disease in children.
Pathophysiology
The vasculitis is most severe in medium-sized arteries but can also occur in veins, capillaries, small arterioles, and larger arteries. In severely affected vessels, the media develops inflammation with necrosis of smooth muscle cells. The internal and external elastic laminae can split, leading to aneurysms. Four to 8 weeks after the onset of symptoms, inflammatory changes are less apparent and fibrous connective tissue begins to form within the vessel wall. The intima proliferates and thickens. The vessel wall eventually becomes narrowed or occluded owing to stenosis or a thrombus. Cardiovascular death usually occurs from a myocardial infarction secondary to thrombosis of a coronary aneurysm or from rupture of a large coronary aneurysm. The vasculitis also affects other medium-sized vessels, including the renal, paraovarian, paratesticular, mesenteric, pancreatic, iliac, hepatic, splenic, and axillary arteries, resulting in systemic aneurysms.
Frequency
United States
The mean annual incidence in children of non-Asian descent is 10 cases per 100,000 children younger than 5 years, and the mean annual incidence in children of Asian descent is 44 cases per 100,000 children younger than 5 years.
International
In Japan, the mean annual incidence is 95 cases per 100,000 children younger than 5 years.
Mortality/Morbidity
- Data are limited, but death occurs in approximately 1% of affected American children. In children younger than 1 year, the mortality rate may exceed 4%. In patients aged 1 year or older, the death rate is probably less than 1%.
- The average mortality rate in Japan is 0.1-0.3%.
- Coronary artery aneurysms develop in up to 25% of untreated patients. They develop in less than 5-10% of patients treated with intravenous gamma globulin before the 10th day of illness.
Race
The disease is more common in Asian children, especially those of Japanese descent.
Sex
- Disease occurs more often in males than in females (1.5:1).
- Death and serious complications are more common in males than females.
Age
- Most patients (ie, 80%) are affected when they are younger than 4 years; however, Kawasaki disease is rare in infants younger than 3 months. Kawasaki disease has been described in adolescents and adults.
- In the United States, the peak age of onset is 18-24 months.
- In Japan, the peak age of onset is 6-11 months.
History
- Classic history of Kawasaki disease
- Fever
- Conjunctival injection
- Mucositis
- Changes in the peripheral extremities
- Erythematous rash
- Enlarged cervical lymph nodes
- Other symptoms
- Extreme irritability
- Joint pain or edema
- Poor oral intake
- Refusal to ambulate
- Refusal to hold objects
- Abdominal pain
- Nausea
- Diarrhea
Physical
Diagnosis is based on established clinical diagnostic criteria, including severe fevers for 5 days and 4 of the 5 other signs listed below. Kawasaki disease is a diagnosis of exclusion, so other diseases with similar findings (see Differentials) must first be ruled out. Patients with fever who appear to have Kawasaki disease but do not meet criteria and have no other cause of their illness are said to have atypical or incomplete Kawasaki disease. Patients with fever duration of at least 5 days and fewer than 4 of the principal criteria can be diagnosed with Kawasaki disease when coronary artery abnormalities are revealed by an echocardiogram or an angiogram. In the presence of 4 or more of the criteria, this condition can be diagnosed on day 4 of fever.
- Fever
- Fever, usually more than 39.9°C, for at least 5 days
- High spiking and remittent
- Persists 1-2 weeks without treatment
- May not respond to antipyretics
- Usually resolves in 1-2 days after treatment with intravenous gamma globulin
- Other signs
- Bilateral conjunctival injection without exudate
- Dry, erythematous, fissured lips that bleed easily
- Erythema of the oral and pharyngeal mucosa
- Strawberry tongue with prominent papillae and erythema
- No oral exudates, ulcerations, or Koplik spots
- Hands and feet
- Erythema of palms and soles, often with healthy skin on wrists and ankles
- Edema
- Periungual desquamation of fingers and toes about 2 weeks after onset
- Transverse grooves across the nails (Beau lines) 1-2 months after onset
- Erythematous rash
- Nonspecific, diffuse, maculopapular erythematous rash
- Possible scarlatiniform or erythema multiforme–type rash with target lesions
- Groin erythema or desquamation
- Fine pustules over extensor surfaces of extremities
- No observable vesicles or bullae
- Cervical lymphadenopathy
- Node diameter larger than 1.5 cm
- Observed in approximately 50-75% of patients
- Node - Sometimes erythematous but is not fluctuant or purulent and is not responsive to antibiotics
- Exclusion of other diseases with similar findings
- Miscellaneous
- Arthralgia and arthritis involving multiple joints (eg, including hands, knees, ankles, hips)
- Lethargy, headache, and stiff neck secondary to aseptic meningitis
- Meatitis, vulvitis, urethritis
- Signs of congestive heart failure (eg, S3 gallop, cardiomegaly, tachypnea, tachycardia from myocarditis)
- Otitis media
- Right-upper-quadrant abdominal mass or guarding secondary to gallbladder hydrops
- Jaundice
- Diarrhea
- Erythema and induration at the site of Bacille Calmette-Guérin (BCG) inoculation (common in Japan)
- Chest pain, abdominal pain, shock and/or emesis secondary to myocardial infarction in older children
- Cardiac murmur due to acute mitral insufficiency
- Severe peripheral ischemia with gangrene (rare)
- Diagnostic guidelines for Kawasaki disease include fever lasting more than 5 days, plus 4 of the following 5 criteria (other illnesses with similar clinical signs must be excluded):
- Polymorphous rash
- Bilateral conjunctival injection
- One or more of the following mucous membrane changes:
- Diffuse injection of oral and pharyngeal mucosa
- Erythema or fissuring of the lips
- Strawberry tongue
- Acute, nonpurulent cervical lymphadenopathy (one lymph node must be >1.5 cm)
- One or more of the following extremity changes:
- Erythema of palms and/or soles
- Indurative edema of hands and/or feet
- Membranous desquamation of the fingertips
Causes
Although the etiology of Kawasaki disease is unknown, the acute presentation and the clustering of cases suggest an infectious etiology. The production of various inflammatory cytokines, including interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha, and interferon gamma, is increased and may mediate vascular endothelial damage. Some cases of Kawasaki disease show familial susceptibility. Children in Japan who had had parents with Kawasaki disease seem to have a more severe form of this disease and are more susceptible to recurrence. Kawasaki disease likely has a genetic susceptibility. A genome-wide linkage analysis of affected sibling pairs was performed in Japan, and a multipoint linkage analysis identified evidence of linkage on chromosome 12q24.
Acute Rheumatic Fever
Toxic Shock Syndrome
Other Problems to be Considered
Scarlet fever
Staphylococcal scalded skin syndrome
Stevens-Johnson syndrome
Drug reaction
Juvenile rheumatoid arthritis
Measles
Mercury poisoning
Other viral exanthems
Lab Studies
- CBC count
- Usually, the WBC count is elevated, with a predominance of immature and mature granulocytes.
- Normocytic anemia may occur.
- Thrombocytosis usually develops during the second or third week of illness, with an average range of 700,000/µL.
- Thrombocytopenia is associated with severe coronary artery disease and myocardial infarction.
- Acute-phase reactants
- Erythrocyte sedimentation rate, C-reactive protein levels, and alpha1-antitrypsin levels are elevated.
- The serum complement level is normal or elevated.
- Liver enzymes
- Transaminase values are mildly elevated in 40% of affected patients.
- Bilirubin values are elevated in 10% of affected patients.
- Urinalysis: Mild-to-moderate pyuria of urethral origin and proteinuria may occur.
- Cardiac enzyme levels (eg, creatine kinase [CK], creatine kinase myocardial band [CK-MB], cardiac troponin, lactate dehydrogenase [LD-1 >LD-2]) are elevated during a myocardial infarction.
- 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 myocardial infarction.
Imaging Studies
- Obtain a chest radiograph to exclude cardiomegaly or subclinical pneumonitis.
- Echocardiography
- Perform at baseline to exclude coronary artery aneurysms and evidence of myocarditis, valvulitis, or pericardial effusion.
- In children, ensure that a pediatric cardiologist performs this study because of familiarity with coronary artery diameters. Diffuse dilatation of coronary lumina can be observed in 50% of patients by the 10th day of illness.
- Coronary CT angiography and magnetic resonance angiography may also prove beneficial in the evaluation and follow-up of the coronary arteries.
Medical Care
The main goal of treatment is to prevent coronary artery disease and to relieve symptoms. Full doses of intravenous gamma globulin (IVIG) at 2 g/kg comprise the mainstay of treatment.
Aspirin has always been part of the traditional treatment of this disorder. Some studies suggest that high- or medium-dose aspirin may have no effect on the response rate of IVIG, duration of fever, or incidence of coronary artery aneurysms despite treatment before or after 5 days of therapy. Randomized controlled trial outcomes are insufficient to indicate whether children with this disorder should continue to receive salicylate as part of the treatment regimen.
Corticosteroids have always been a controversial treatment of this disorder and not well studied. One multicenter prospective randomized trial in Japan was performed to determine if the addition of corticosteroids to IVIG would affect coronary artery abnormalities before the 1-month echocardiographic assessment, duration of fever, time to normalization of serum C-reactive protein levels, and the rate of initial treatment failure that requires additional therapy. The combination of corticosteroids and IVIG was found to significantly decrease coronary artery abnormalities, duration of fever, C-reactive protein levels, and initial treatment failure. Another randomized trial in the United States that added a single dose of methylprednisolone (30 mg/kg) to conventional therapy saw a reduction in the erythrocyte sedimentation rate at 1 week, but no difference in coronary artery abnormalities. Admit all patients to the hospital for administration of intravenous gamma globulin and for observation until fever is controlled.
Closely monitor cardiovascular function.
Consultations
- Consult with pediatric or adult cardiologists for the following:
- Children or adults with significant coronary artery disease
- Timing of subsequent echocardiographic studies
- Anticoagulation therapy in patients with large aneurysms
- Other studies to assess cardiac function (eg, stress testing, coronary artery angiography)
- Consult with pediatric or adult infectious disease specialists to exclude infectious disease as a cause of fever.
- Consult with pediatric or adult rheumatologists to exclude other causes of vasculitis and connective-tissue diseases
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Blood products
These agents are used to improve clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes.
| Drug Name | Immune globulin, intravenous, IVIG (Gammagard, Gamimune) |
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| Description | Reduces the prevalence of coronary abnormalities. Leads to rapid defervescence and more rapid normalization of acute-phase reactants. |
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| Adult Dose | 2 g/kg IV infusion over 10-12 h; closely monitor vital signs during infusion |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | No absolute contraindication; IVIG-sensitive patients who are IgA deficient should receive IVIG preparations with no IgA |
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| Interactions | Antibodies in the globulin preparation may interfere with response to live viral vaccines (eg, measles, mumps, rubella); defer using live viral vaccines until approximately 3 mo after immunoglobulin administration; no known drug interactions |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus
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| Precautions | Anaphylactic shock, aseptic meningitis, back pain, chills, diaphoresis, hypotension, injection site reaction, myalgia, nausea and vomiting may occur; consider checking serum IgA before IVIG and using IgA-depleted IVIG (G-Gard-SD) if indicated; IVIG may increase serum viscosity and thromboembolic events |
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Drug Category: Salicylates
These agents may reduce inflammatory reactions and may improve hemostatic parameters.
| Drug Name | Aspirin (Anacin, Ascriptin, Bayer Aspirin) |
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| Description | Aspirin is administered for its anti-inflammatory and antithrombotic effects. |
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| Adult Dose | Acute phase: 80-100 mg/kg/d PO in tid/qid doses 36 h after defervescence: 3-5 mg/kg/d PO qam; usually continue for 3 mo until erythrocyte sedimentation rate and platelet count return to normal; in Japan, clinicians generally use a lower antipyretic dose of 30-50 mg/kg/d |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; anemia; aspirin-sensitive asthma; bone marrow depression; breastfeeding; coagulopathy; G-6-PD deficiency; hepatic disease; hypoprothrombinemia; influenza; peptic ulcer disease; renal failure; surgery; tartrazine dye hypersensitivity; thrombocytopenia; urticaria; varicella; vitamin K deficiency |
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| Interactions | Do not administer if patient is consuming anticoagulants; effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate levels, additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize effects of probenecid and increase toxicity of phenytoin and valproic acid; doses greater than 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus
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| Precautions | Obtain aspirin level if vomiting, hyperpnea, lethargy, or liver function abnormalities develop; decrease risk of Reye syndrome by discontinuing if varicella or influenza occur; aspirin is associated with abdominal pain, agranulocytosis, angioedema, aplastic anemia, bleeding, bronchospasm, dizziness, dyspepsia, elevated hepatic enzyme levels, encephalopathy, erythema nodosum, GI bleeding, hepatitis, hyperuricemia, interstitial nephritis; maculopapular rash, nausea, vomiting, purpura, renal papillary necrosis, Reye syndrome, rhinitis, Stevens-Johnson syndrome, thrombocytopenia, tinnitus, toxic epidermal necrolysis, and urticaria |
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Further Inpatient Care
- Admit an affected patient to the hospital and administer intravenous gamma globulin. Consider aspirin and/or corticosteroids and observe until fever is controlled.
- Carefully monitor cardiovascular performance.
- Once the fever resolves, significant congestive heart failure or myocardial dysfunction is unlikely.
Further Outpatient Care
- Re-evaluate all patients within 1 week of hospital discharge.
- Schedule the patient for a repeat echocardiography 21-28 days after the onset of fever.
- Further echocardiograms are usually unnecessary if baseline and 3- to 4-week echocardiograms fail to reveal any evidence of coronary aneurysms.
- Patients with no cardiac changes on echocardiogram at any stage do not require activity restrictions or medications beyond 3 months after the initial illness.
- Ensure that a patient with coronary artery aneurysms or other cardiac abnormalities receives further care, as dictated by a cardiologist.
Transfer
- Transfer any patient with suspected Kawasaki disease to a facility that has skilled clinicians and a pediatric or adult cardiologist to evaluate the echocardiogram.
Complications
- Cardiovascular
- Once fever has resolved, significant heart failure or myocardial dysfunction is unlikely.
- Diffuse coronary artery ectasia and aneurysm formation, giant aneurysm (internal luminal diameter >8 mm)
- Myocardial infarction may occur.
- Myocarditis is common but rarely causes congestive heart failure.
- Valvulitis, usually mitral, occurs in only 1% of patients and rarely merits valve replacement.
- Pericarditis with small pericardial effusions occurs in 25% of patients who are acutely ill.
- Systemic artery aneurysms may occur.
- Rupture of coronary artery aneurysm with hemopericardium is possible.
- Other complications
- Extreme irritability, especially in younger infants
- Aseptic meningitis
- Arthritis
- Mild hepatic dysfunction, rarely jaundice
- Gallbladder hydrops (may be demonstrated on sonogram, but the condition usually resolves without surgical intervention)
- Diarrhea
- Pneumonitis
- Otitis media
- Erythema and induration at the site of BCG inoculation
- Peripheral extremity gangrene (extremely rare)
Patient Education
- The recurrence rate in Japan is 3% and approximately 1% in North America.
Medical/Legal Pitfalls
- Failure to diagnose Kawasaki disease before 10 days of illness so that intravenous gamma globulin can be given to help prevent coronary artery aneurysms is a medicolegal pitfall.
- If the diagnosis cannot be confirmed but is suspected, quickly refer the patient to a center with experience in Kawasaki disease.
| Media file 1:
Clinical manifestations and time course of Kawasaki disease. |
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| Media file 2:
Oral manifestations of Kawasaki disease: red lips and strawberry tongue. |
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Media type: Photo
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Kawasaki Disease excerpt Article Last Updated: Aug 16, 2007
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