Kawasaki Disease in Children
Introduction to Kawasaki Disease in Children
Kawasaki Disease (KD), also known as Kawasaki syndrome or mucocutaneous lymph node syndrome, is an acute, self-limited vasculitis of unknown etiology that primarily affects children. It was first described in 1967 by Dr. Tomisaku Kawasaki in Japan.
KD is characterized by systemic inflammation in medium-sized arteries throughout the body, with a predilection for the coronary arteries. It is the leading cause of acquired heart disease in children in developed countries. The disease typically affects children under five years of age but can occur in older children and, rarely, in adults.
Early recognition and prompt treatment are crucial to prevent long-term complications, particularly coronary artery aneurysms. Despite significant advances in understanding and managing KD, its exact cause remains elusive, making it a subject of ongoing research in pediatric medicine.
Epidemiology of Kawasaki Disease
Kawasaki Disease exhibits distinct epidemiological patterns:
- Age Distribution:
- Peak incidence between 6 months and 5 years of age
- 80% of cases occur in children under 5 years
- Rare in infants <3 months and children >8 years
- Gender Distribution:
- Males are affected 1.5 times more frequently than females
- Geographical Distribution:
- Highest incidence in Japan (308 per 100,000 children <5 years)
- Increasing incidence in many countries, including the US (25 per 100,000 children <5 years)
- Higher rates in children of Asian and Pacific Islander descent
- Seasonal Variation:
- Higher incidence in winter and spring in temperate climates
- Clustered outbreaks reported, suggesting infectious trigger
- Recurrence Rate:
- Approximately 3% of cases in Japan
- Lower recurrence rates in other countries
The increasing incidence worldwide, particularly in developed countries, may be due to improved recognition and diagnosis, but true increases in disease occurrence cannot be ruled out.
Etiology and Pathogenesis
The exact cause of Kawasaki Disease remains unknown, but current evidence suggests a complex interplay between genetic susceptibility and environmental triggers:
Genetic Factors:
- Higher incidence in Asian populations suggests genetic predisposition
- Increased risk in siblings of affected children (10-fold higher)
- Associated genes include:
- ITPKC (inositol 1,4,5-trisphosphate 3-kinase C)
- CASP3 (caspase 3)
- FCGR2A (Fc fragment of IgG receptor IIa)
Environmental Triggers:
- Infectious agents proposed but not conclusively proven:
- Viruses (e.g., novel RNA virus, coronavirus)
- Bacteria (e.g., Staphylococcus aureus, Streptococcus species)
- Seasonal patterns and geographical clusters support infectious etiology
- Superantigen-mediated process has been suggested
Immunological Mechanisms:
KD involves a complex cascade of immunological events:
- Activation of innate immune system
- T cell activation and proliferation
- Massive cytokine production (cytokine storm)
- Activation of endothelial cells
- Infiltration of vessel walls by neutrophils, CD8+ T cells, and IgA-producing plasma cells
The resultant inflammation leads to damage in medium-sized arteries, particularly the coronary arteries, potentially resulting in aneurysm formation.
Clinical Manifestations of Kawasaki Disease
Kawasaki Disease typically progresses through three stages, each with characteristic features:
1. Acute Febrile Phase (1-2 weeks):
- High fever (≥38.5°C or 101.3°F), usually unresponsive to antipyretics
- Bilateral non-exudative conjunctivitis
- Oral mucosa changes:
- Erythema and cracking of lips
- Strawberry tongue
- Diffuse oral and pharyngeal mucositis
- Polymorphous skin rash
- Erythema and edema of hands and feet
- Cervical lymphadenopathy (usually unilateral, ≥1.5 cm diameter)
2. Subacute Phase (2-4 weeks):
- Resolution of fever
- Desquamation of fingers and toes
- Arthritis or arthralgias
- Thrombocytosis
3. Convalescent Phase (4-8 weeks):
- Resolution of all clinical signs
- Continued risk of coronary artery abnormalities
Other Clinical Features:
- Cardiovascular: Myocarditis, pericarditis, valvulitis
- Gastrointestinal: Abdominal pain, vomiting, diarrhea, hepatitis
- Respiratory: Cough, rhinorrhea
- Neurological: Irritability, aseptic meningitis
- Musculoskeletal: Arthritis, arthralgia
- Genitourinary: Urethritis, meatitis
It's important to note that not all features need to be present for diagnosis, and some patients may present with incomplete or atypical Kawasaki Disease.
Diagnosis of Kawasaki Disease
Diagnosing Kawasaki Disease can be challenging due to its variable presentation and lack of a specific diagnostic test. The diagnosis is based on clinical criteria and supported by laboratory findings.
Diagnostic Criteria:
Classic KD is diagnosed when a patient has fever for ≥5 days (or fever until the date of IVIG administration if given before day 5 of fever), and at least 4 of the following 5 principal clinical features:
- Bilateral bulbar conjunctival injection
- Oral mucosal changes
- Peripheral extremity changes
- Polymorphous exanthem
- Cervical lymphadenopathy (≥1.5 cm diameter)
Laboratory Findings:
- Elevated inflammatory markers: ESR, CRP
- Leukocytosis with neutrophil predominance
- Anemia
- Thrombocytosis (typically in subacute phase)
- Hypoalbuminemia
- Elevated liver enzymes
- Sterile pyuria
Cardiac Evaluation:
- Echocardiography: To assess coronary arteries and cardiac function
- ECG: May show arrhythmias, conduction abnormalities
Incomplete Kawasaki Disease:
Patients with fever ≥5 days and 2-3 clinical criteria should be evaluated for incomplete KD, especially infants and children >5 years. Supplemental laboratory criteria and echocardiography may be used for diagnosis.
Differential Diagnosis:
Consider other conditions that may mimic KD:
- Viral infections (e.g., adenovirus, measles)
- Scarlet fever
- Staphylococcal scalded skin syndrome
- Drug hypersensitivity reactions
- Systemic juvenile idiopathic arthritis
Early diagnosis is crucial for timely treatment to prevent coronary artery complications. Consultation with a pediatric infectious disease specialist or rheumatologist may be helpful in challenging cases.
Treatment of Kawasaki Disease
The primary goals of treatment in Kawasaki Disease are to reduce inflammation and prevent the development of coronary artery abnormalities. Timely initiation of therapy is crucial for optimal outcomes.
Initial Treatment:
- Intravenous Immunoglobulin (IVIG):
- Dose: 2 g/kg as a single infusion over 10-12 hours
- Should be administered within 10 days of illness onset, ideally within 7 days
- Aspirin:
- High-dose (30-50 mg/kg/day divided into 4 doses) during acute phase
- Reduced to low-dose (3-5 mg/kg/day) after fever resolution
Treatment of IVIG-Resistant KD:
10-20% of patients may not respond to initial IVIG treatment. Options include:
- Second dose of IVIG (2 g/kg)
- Corticosteroids:
- Methylprednisolone pulse therapy (30 mg/kg/day for 3 days)
- Oral prednisone taper
- Infliximab (TNF-α inhibitor): 5 mg/kg single infusion
- Cyclosporine A
- Anakinra (IL-1 receptor antagonist)
Ongoing Management:
- Continue low-dose aspirin until 6-8 weeks after onset and normalization of inflammatory markers
- For patients with coronary artery aneurysms, long-term aspirin and potentially additional anticoagulation may be necessary
Monitoring:
- Serial echocardiograms:
- At diagnosis, 2 weeks, and 6-8 weeks after treatment
- More frequent for those with coronary abnormalities
- Regular follow-up with pediatric cardiologist
Long-term Management:
Based on risk stratification according to the degree of coronary artery involvement:
- Counseling on heart-healthy lifestyle
- Management of cardiovascular risk factors
- Possible stress testing or coronary angiography for high-risk patients
Treatment decisions should be made in consultation with pediatric specialists experienced in managing Kawasaki Disease, considering the individual patient's clinical presentation and risk factors.
Complications of Kawasaki Disease
While Kawasaki Disease is generally a self-limited condition, it can lead to significant complications, particularly involving the cardiovascular system:
1. Cardiovascular Complications:
- Coronary Artery Aneurysms:
- Most serious complication, occurring in 15-25% of untreated patients
- Risk reduced to 3-5% with timely IVIG treatment
- Can lead to thrombosis, stenosis, or myocardial infarction
- Myocarditis and Myocardial Dysfunction
- Pericarditis and Pericardial Effusion
- Valvular Regurgitation
- Systemic Arterial Aneurysms (rare)
2. Non-Cardiovascular Complications:
- Macrophage Activation Syndrome (rare but potentially life-threatening)
- Neurological:
- Aseptic meningitis
- Facial nerve palsy
- Sensorineural hearing loss
- Musculoskeletal:
- Arthritis
- Osteonecrosis
- Gastrointestinal:
- Gallbladder hydrops
- Pancreatitis
- Ocular:
- Anterior uveitis
- Optic disc swelling
3. Long-term Sequelae:
- Increased Cardiovascular Risk:
- Even in patients without coronary artery aneurysms, there may be endothelial dysfunction and increased carotid intima-media thickness
- Potential for accelerated atherosclerosis
- Psychological:
- Increased risk of internalizing behavior problems
- Possible cognitive effects, particularly in those with significant coronary involvement
Early recognition and prompt treatment of Kawasaki Disease are crucial in preventing these complications, particularly coronary artery aneurysms. Long-term follow-up is essential, especially for patients who developed coronary abnormalities during the acute phase of the illness.
Prognosis of Kawasaki Disease
The prognosis of Kawasaki Disease is generally favorable, especially with timely diagnosis and appropriate treatment. However, outcomes can vary based on several factors:
Short-term Prognosis:
- Mortality:
- Acute phase mortality is rare (<0.1% in Japan)
- Slightly higher in Western countries (0.17% in the US)
- Coronary Artery Aneurysms:
- Incidence reduced from 25% to 3-5% with IVIG treatment
- Higher risk in males, younger children (<1 year), and those with delayed treatment
- Recurrence:
- 3-4% chance of recurrence, usually within 2 years of initial episode
Long-term Prognosis:
- Patients without Coronary Artery Abnormalities:
- Generally excellent prognosis
- No significant difference in cardiovascular health compared to general population
- Patients with Coronary Artery Abnormalities:
- Prognosis depends on size and location of aneurysms
- Small to medium aneurysms often regress within 1-2 years
- Giant aneurysms (>8 mm) have higher risk of thrombosis, stenosis, and myocardial infarction
Factors Influencing Prognosis:
- Timing of Treatment:
- Earlier treatment (within 10 days of fever onset) associated with better outcomes
- Response to Initial Treatment:
- IVIG resistance associated with higher risk of coronary abnormalities
- Age at Onset:
- Infants <1 year and adolescents >9 years at higher risk for coronary aneurysms
- Gender:
- Males at higher risk for severe coronary artery abnormalities
Long-term Follow-up:
The American Heart Association recommends risk stratification and tailored follow-up based on the degree of coronary involvement:
- No coronary involvement: Follow-up every 3-5 years
- Small aneurysms: Annual cardiology follow-up with echocardiogram and ECG
- Large or giant aneurysms: More frequent follow-up, stress tests, and possibly coronary angiography
While most patients with Kawasaki Disease have a good prognosis, ongoing research is needed to understand the long-term cardiovascular risks and to improve outcomes for those with severe coronary involvement.
Kawasaki Disease in Children
- What is Kawasaki Disease?
An acute, self-limited vasculitis primarily affecting medium-sized arteries in children - What is the typical age range for Kawasaki Disease?
Children under 5 years old, with a peak incidence between 18-24 months - What are the five cardinal features of Kawasaki Disease?
Fever, bilateral conjunctival injection, changes in lips and oral cavity, polymorphous rash, cervical lymphadenopathy, and changes in extremities - How long must the fever persist to meet the diagnostic criteria for Kawasaki Disease?
At least 5 days - What is the most serious complication of Kawasaki Disease?
Coronary artery aneurysms - What is the first-line treatment for Kawasaki Disease?
Intravenous immunoglobulin (IVIG) and high-dose aspirin - When should IVIG be administered in Kawasaki Disease?
Within the first 10 days of illness onset, ideally within 7 days - What is the recommended dose of IVIG for Kawasaki Disease?
2 g/kg as a single infusion - What is the purpose of aspirin in treating Kawasaki Disease?
To reduce inflammation and prevent thrombosis - What is the most common cause of long-term morbidity and mortality in Kawasaki Disease?
Coronary artery abnormalities - How soon after fever onset do coronary artery aneurysms typically develop?
Usually within the first 4 weeks - What percentage of untreated patients develop coronary artery abnormalities?
Approximately 25% - What is the gold standard for detecting coronary artery abnormalities in Kawasaki Disease?
Echocardiography - What is incomplete or atypical Kawasaki Disease?
When a patient has fever and some, but not all, of the principal clinical features - What is the male to female ratio in Kawasaki Disease?
Approximately 1.5:1 - What is the recurrence rate of Kawasaki Disease?
Approximately 3-4% - What is the role of corticosteroids in treating Kawasaki Disease?
They may be used in IVIG-resistant cases or high-risk patients - What is the "strawberry tongue" associated with Kawasaki Disease?
A bright red tongue with prominent papillae - What type of rash is typically seen in Kawasaki Disease?
A polymorphous, non-vesicular rash - What changes in the extremities are seen in the acute phase of Kawasaki Disease?
Erythema and edema of hands and feet - What changes in the extremities are seen in the subacute phase of Kawasaki Disease?
Periungual desquamation (peeling of skin around nails) - What is the BCG reaction sometimes seen in Kawasaki Disease?
Erythema or crust formation at the site of previous BCG vaccination - What is the typical duration of the acute phase of Kawasaki Disease?
1-2 weeks - What cardiac complication, other than coronary artery aneurysms, can occur in Kawasaki Disease?
Myocarditis - What is the role of Z-scores in evaluating coronary arteries in Kawasaki Disease?
To standardize measurements based on body surface area and determine the degree of dilation - What is the most common non-cardiac complication of Kawasaki Disease?
Arthritis - What is the significance of thrombocytosis in Kawasaki Disease?
It typically occurs in the second week and may increase the risk of thrombosis - What is the recommended duration of low-dose aspirin therapy after the acute phase?
6-8 weeks, if no coronary artery abnormalities are present - What is the role of TNF-α inhibitors in treating Kawasaki Disease?
They may be used in refractory cases not responding to IVIG and corticosteroids - What long-term follow-up is recommended for patients with a history of Kawasaki Disease?
Regular cardiac evaluations, frequency depending on the presence and severity of coronary artery abnormalities
