Kawasaki Disease

Aka: Kawasaki Disease, Kawasaki's Disease, Kawasaki Syndrome, Mucocutaneous Lymph Node Syndrome, Infantile Polyarteritis

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II. Epidemiology: Incidence

  1. First described in Japan, 1967
    1. Kawasaki (1967) Arerugi 16(3): 178-222 [PubMed]
  2. Overall U.S.: 19 per 100,000 children <5 years (2000 U.S. cases/year)
    1. Japanese descent: 150 per 100,000 children <5 years
    2. Asian american children 2.5 times more likely than white children
    3. Black american children 1.5 times more likely than white children
  3. Age of onset
    1. Most cases (75-80%) occur by age 5 years old
    2. Peak age of onset: 1 to 2 years old
    3. Rare under 4 months of age
  4. Gender: Boys more often affected (by ratio of 1.5 to 1)
  5. More common in winter and spring (typically between January and March)
  6. Most common cause of acquired Coronary Artery Disease in children

III. Pathophysiology

  1. Inflammatory response to a trigger in a genetically susceptible host
  2. Idiopathic Vasculitis
    1. Affects small and medium sized vessels
    2. Inflammatory Cytokines (e.g. TNF, IL-6) promote Leukocyte mediated endothelial injury
  3. Postulated associations
    1. Retrovirus
    2. Rickettsia
    3. Coronaviruses

IV. Precautions

  1. Prolonged Fever should trigger consideration of Kawasaki Disease
    1. Culture negative shock
    2. Exudative Pharyngitis and Lymphadenopathy not responding to typical management
  2. Infants under 6 months of age often present atypically, and have the highest risk of Coronary Artery complications
    1. Have a high index of suspicion in unexplained or Prolonged Fever, irritability, Aseptic Meningitis
  3. Concurrent Viral Infection exam and lab findings do not exclude Kawasaki Disease
    1. Viral Infections are identified in up to 30-40% of cases

V. Symptoms

  1. Fever for 5 days or more
  2. Significant Irritability

VI. Diagnosis: Requires fever and 4 other criteria

  1. Fever prolonged more than 5 days (100%)
    1. Fever >102.2 F (often >104 F) with abrupt onset
    2. Duration: Averages 11 days untreated
  2. Polymorphous skin eruption on trunk (80-96%)
    1. Starts within first five days with a 7 day duration
    2. Involves extremities, trunk and perineal region
    3. May appear maculopapular, Scarlatina-form or Erythema Multiforme-like
    4. May appear morbiliform or Urticarial
    5. No bullae or vessicles
  3. Conjunctivitis (84-89%%)
    1. Bilateral Conjunctival injection (bulbar)
    2. No Ciliary Flush (no limbus injection)
    3. No photophobia
    4. No Eye Pain
    5. Non-purulent, non-exudative
    6. May be associated with painless Anterior Uveitis
  4. Acute Lymphadenopathy
    1. Typically a single, unilateral, minimally to non-tender node >1.5 cm (73%)
    2. Cervical Lymphadenopathy is most common
  5. Changes in hands and feet
    1. Edema or induration of hands and feet (65%)
      1. May be painful (e.g. refusal to walk)
    2. Red palms and soles (69%)
      1. Sharp demarcation at ankles and wrists
    3. Desquamation of fingertips (80%)
      1. Late sign occurs at 2-3 weeks after fever onset
      2. Starts at periungual area
      3. Fingernails may develop Beau Lines (transverse grooves)
  6. Mucus mebrane changes (92-96%)
    1. Dry, red, fissured, or vertically cracked lips
    2. Strawberry Tongue (erythematous Tongue with prominent papillae)
    3. Diffuse reddening of the oropharynx
    4. No focal lesions, exudates, Vesicles or ulcers

VII. Diagnosis: Incomplete Kawasaki Disease (met by 9.6% of cases, esp. young infants and older children)

  1. Fever for at least 5 days AND
  2. Two or three main criteria above (incomplete criteria) AND
  3. Erythrocyte Sedimentation Rate (ESR) >40 mm/h or C-Reactive Protein >=3 mg/dl AND
  4. One of the two following criteria
    1. Coronary Artery Abnormalities on Transthoracic Echocardiogram OR
    2. Three or more laboratory findings
      1. Anemia for age
      2. Thrombocytosis with Platelet Count >450,000 after day 7 of fever
      3. Hypoalbuminemia <= 3 g/dl
      4. Alanine Transaminase (ALT) increased
      5. Leukocytosis with White Blood Cell Count >15,000/uL
      6. Sterile pyuria with >10 White Blood Cells on urine microscopy

VIII. Findings: Other Associated

  1. Urethritis with sterile pyuria (75%)
  2. Polyarthralgia
  3. Aseptic Meningitis (25%)
  4. Rhinorrhea and cough may be present in some cases
  5. Gastrointestinal Symptoms
    1. Abdominal Pain and Diarrhea (25%)
    2. Obstructive Jaundice with acute gallbladder hydrops
    3. Vomiting
  6. Cardiac Disease (20%)
    1. Pericardial Effusion
    2. Congestive Heart Failure
    3. Arrhythmias (e.g. Tachycardia)
    4. Valvular dysfunction (25%)
      1. Mitral Regurgitation (most common)
      2. Aortic root dilatation
    5. Coronary Artery anomalies (see below)
    6. Gallup Rhythm
    7. Accentuated flow murmur

IX. Differential Diagnosis

  1. Juvenile Rheumatoid Arthritis
  2. Reactive Infectious Mucocutaneous Eruption (RIME)
  3. Hypersensitivity Reaction
    1. Medication allergy
    2. Mercury Poisoning
    3. Serum Sickness
    4. Stevens-Johnson Syndrome
  4. Bacterial Infection
    1. Leptospirosis
    2. Rocky Mountain Spotted Fever
    3. Scarlet Fever
    4. Staphylococcal Scalded Skin Syndrome
    5. Toxic Shock Syndrome
    6. Meningitis
  5. Viral Infection
    1. Mononucleosis
    2. Measles
    3. Adenovirus
    4. Parvovirus B19

X. Labs

  1. Complete Blood Count with differential cell count
    1. Anemia
    2. Leukocytosis (>15,000/uL)
    3. Thrombocytosis (>500,000/uL)
      1. Often delayed until 2-3 weeks after fever onset
  2. Erythrocyte Sedimentation Rate >40 mm/hr (may be >100)
  3. C-Reactive Protein (CRP) >3 mg/dl
    1. Preferred (unlike ESR, CRP is not altered with IVIG administration)
  4. Basic chemistry panel
    1. Hyponatremia
  5. Liver Function Tests
    1. Increased liver enzymes (esp. serum transaminases AST and ALT, and GGT)
    2. Hypoalbuminemia may predict a more prolonged, severe course
  6. Blood Culture
  7. Throat Culture
  8. Antistreptolysin-O Titer (ASO Titer)
  9. Urinalysis
    1. Sterile pyuria in >33% of cases
  10. Consider Lumbar Puncture if Meningitis suspected
    1. Pleocytosis may be seen in Kawasaki's

XI. Diagnostics

  1. Electrocardiogram (EKG)
    1. May demonstrate strain pattern (ST and T Wave changes)
  2. Chest XRay
    1. Observe for cardiomegaly
  3. MRI Coronary Angiography
    1. May be used when Echocardiogram is non-diagnostic (esp. circumflex, distal vessels)
    2. May demonstrate Coronary Artery stenosis, thrombi or intimal hyperplasia

XII. Imaging: Echocardiogram Coronary Artery evaluation

  1. Initial Echocardiogram at presentation
  2. Follow-up Echocardiogram at 2 weeks and 6-8 weeks
  3. Indications for Echocardiogram at 6-12 months
    1. Abnormalities on prior Echocardiograms
    2. AHA guidelines currently recommend in all patients
    3. However no benefit if prior Echocardiograms normal
    4. Tuohy (2001) Am J Cardiol 88:328-30 [PubMed]
  4. Measurements
    1. Coronary Artery lumen diameter is compared with BSA to generate a Z-Score
      1. Z-Score >2.5 are suggestive of Kawasaki Disease
    2. Vessels
      1. Left anterior descending branch
      2. Proximal right Coronary Artery
  5. Findings
    1. Coronary Artery changes
      1. Acute: Tapering, perivascular brightness, ectasia
      2. Late: Coronary Artery aneurysm
    2. Other variable changes
      1. Decreased ventricular function
      2. Pericardial Effusion

XIII. Evaluation

  1. Diagnostic criteria met (five days of fever and 4 of the 5 other findings present)
    1. Treat as Kawasaki Disease
    2. May also treat at 4 days if criteria otherwise met
    3. Also see alternative criteria listed above
  2. Diagnostic criteria not met (five days of fever with only 2-3 other findings)
    1. CRP <3 mg/dl and ESR <40 mm/h
      1. Discharge home with follow-up
      2. Repeat labs and evaluation if fever persists an additional 2 days
      3. Obtain Echocardiogram if peeling occurs (regardless of fever resolution)
    2. CRP >3 mg/dl or ESR >40 mm/h
      1. Obtain additional criteria (requires 3 or more)
        1. Serum Albumin <3 g/dl
        2. Anemia
        3. Serum ALT increased
        4. White Blood Cell Count >12,000
        5. Platelet Count >450,000
        6. Sterile pyuria
      2. Three or more additional criteria present
        1. Treat as Kawasaki Disease
        2. Obtain Echocardiogram
      3. Less than three additional criteria
        1. Obtain Echocardiogram
        2. If Echocardiogram positive, treat as Kawasaki Disease
        3. If Echocardiogram negative, but fever persists, repeat the Echocardiogram

XIV. Management

  1. Admission
  2. Hydration
  3. Obtain Rheumatology and Cardiology Consultation
  4. Observe for and treat Congestive Heart Failure
  5. Cardiac monitoring in all patients
  6. Start treatment as soon as possible
    1. Especially within 10 days of onset
    2. Do not delay for Echocardiogram if diagnostic criteria are met
  7. Aspirin
    1. Postulated to reduce inflammation and thrombus formation
      1. However does not reduce coronary aneurysm formation
    2. Dosing
      1. Initial: 20-25 mg/kg every 6 hours
      2. Later: 3-5 mg/kg/day once daily for 6-8 weeks
        1. Start after fever has resolved at least 2 days OR
        2. 14 days passes since onset of illness
      3. Longterm
        1. May be indicated indefinately if coronary anomalies are identified
        2. Precautions should be taken against Reye Syndrome if longterm Aspirin is used
          1. Influenza Vaccine
          2. Varicella Vaccine
          3. Post-exposure precautions
  8. Intravenous Gamma Globulin (IVIG)
    1. Dose: 2 g/kg infused over 8-12 hours
    2. Must be given early in disease to be efficacious
    3. Consider repeating for a second dose if still febrile after first dose
    4. Risk of Hypotension and Seizures
    5. Avoid live virus Vaccines for 11 months after IVIG
    6. Efficacy
      1. Effect likely based on reducing Cytokines, antibodies and T-Cell activity
      2. Reduces Coronary Artery anomaly risk from 25% to 5%
      3. Reduces giant aneurysm risk to <1%
  9. Corticosteroids
    1. May be used in combination with IVIG to reduce the risk of coronary anomalies
      1. Corticosteroids independently lower risk of coronary anomalies (NNT 10)
    2. Most indicated in the 10-20% of cases refractory to IVIG and Aspirin (see below)
    3. Considered in patients at high risk for IVIG resistance
      1. Coronary Artery Aneurysm at diagnosis
      2. Age <12 months
      3. Kawasaki Shock Syndrome
      4. Kawasaki Disease with Macrophage activation syndrome
    4. References
      1. Beck (2023) Am Fam Physician 107(1): 20-1 [PubMed]
      2. Chen (2013) Heart 99(2): 76-82 [PubMed]
      3. Green (2022) Cochrane Database Syst Rev (5): CD011188 [PubMed]
  10. Refractory cases (10-20%, fever persists or recurs 36 hours after initial IVIG)
    1. Repeat IVIG 2 g/kg
    2. Consider Corticosteroids
    3. Variable evidence for Infliximab (Remicade)
      1. Tremoulet (2014) Lancet 383(9930): 1731-8 [PubMed]

XV. Complications: General

  1. Early complications
    1. Myocarditis
    2. Pericarditis
    3. Valvular insufficiency (esp. mitral insufficiency, and to a lesser extent Aortic Insufficiency)
    4. Arrhythmia (esp. Tachycardia)
    5. Kawasaki Disease Shock Syndrome (7% of cases)
      1. Presents with Tachycardia and Hypotension
      2. Cardiovascular collapse often refractory to IVIG
      3. Manage with volume expanders and Vasopressors
  2. Late complications (>1-2 weeks)
    1. Coronary Artery aneurysm (see below)

XVI. Complications: Coronary Artery aneurysm

  1. Incidence
    1. Occurs in 15-20% of untreated Kawasaki's Disease
    2. Occurs in 2-5% of treated Kawasaki's Disease
  2. Mechanism: Coronary ArteryVasculitis
  3. Occurs 2-4 weeks after onset of illness
  4. Most aneurysms regress in 1-2 year
    1. Spontaneously resolve in 33-66% of cases
  5. Most common coronary arteries affected
    1. Proximal left anterior descending artery
    2. Proximal right Coronary Artery
  6. Associated Risks
    1. Subsequent stenosis
    2. Thrombosis leading to Myocardial Infarction
    3. Sudden Death
  7. Risk Stratification
    1. Based on Echocardiogram results (see above)
    2. Risk Level 1: Normal coronary arteries on imaging
      1. May stop Aspirin at 8 weeks following onset
      2. No Physical Activity restrictions after first 6-8 weeks
      3. Life-long counseling on Cardiac Risk Factors every 5 years
        1. Long-term endothelial dysfunction risk
    3. Risk Level 2: Transient coronary ectasia, dilation (resolves in first 6-8 weeks)
      1. Same approach as Risk Level 1
    4. Risk Level 3: Coronary aneurysms 3-6 mm (Z-Score 3-7)
      1. Aspirin 3-5 mg/kg daily for >8 weeks and until aneurysm regresses
      2. Stress Test every 2 years before sports if age >10
      3. Annual cardiology follow-up Echocardiogram and Electrocardiogram
      4. Avoid contact or high-impact sports if on antiplatelet agents
    5. Risk Level 4: coronary aneurysms >6 mm (large) or multiple
      1. Long-term Aspirin
      2. Warfarin (INR 2-2.5) or LMWH (Xa 0.5-1) for giant aneurysms
      3. Annual cardiac stress test
      4. Cardiology follow-up with Echocardiogram and Electrocardiogram every 6 months
      5. Cardiac angiogram 6-12 months after illness
      6. Avoid Collision Sports
    6. Risk Level 5: Obstructed Coronary Artery aneurysms
      1. Includes recommendations for risk level 4
      2. Beta Blocker

XVII. References

  1. Claudius in Majoewsky (2012) EM:Rap 12(11): 8-9
  2. Pacheco and Rawani-Patel (2019) Crit Dec Emerg Med 33(5): 3-11
  3. Darby (2021) Am Fam Physician 104(3): 244-52 [PubMed]
  4. Dummer (2004) Progress Pediatr Cardiol 19:129-35 [PubMed]
  5. Freeman (2006) Am Fam Physician 74:1141-50 [PubMed]
  6. Newburger (2004) Pediatrics 114:1708-33 [PubMed]
  7. Newburger (2004) Circulation 110(17): 2747-71 [PubMed]
  8. Saguil (2015) Am Fam Physician 91(6): 365-71 [PubMed]

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