Kawasaki Disease

Introduction

Kawasaki Disease is a multisystem inflammatory disease that affects mostly infants and children. It has replaced rheumatic fever as the most common cause of acquired heart disease in North America, Japan, and Europe.  The major morbidity and mortality from Kawasaki Disease is in the development of coronary artery aneurysms, which is why diagnosis and timely treatment is critical.

Epidemiology

1. Incidence is 2/100,000/yr in African Americans and Caucasians and 5/100,000/yr. in Asians
2. Peak age is 18-24 months and 80-90% are less than 5 years old. M:F=1.5:1

Etiology

1. Unknown although infectious agent highly suspicious because of seasonal peak in summer and winter and self limiting course
2. Studies have shown an immunomodulatory course, wtih decreased CD8+ cytotoxic T cells and an abundance of circulating B cells that produce immunoglobulins, as well as increased monocyte concentration.

Diagnosis

1. The presence of unexplained fever for 5 days or more and the presence of 4 of the following 5 (CRASH mnemonic) findings;
   • C - Conjunctival injection, generally bilateral and bulbar without discharge and sparing of the limbus
   • R - Rash, generally polymorphous and generalized, never vesicular or bullous, may have perineal desquamation
   • A - Adenopathy, non-suppurative, generally cervical, and greater or equal to 1.5 cm in size
   • S - Strawberry tongue, or other mucous membrane changes such as dryness and fissuring of the lips, erythema of the oral mucosa
   • H - Hand and feet changes, generally with swelling, periungal desquamation of fingers and toes, erythema of palms and soles.

A child showing the characteristic "strawberry tongue" seen in Kawasaki disease
https://en.wikipedia.org/wiki/Kawasaki_disease

2. Incomplete or Atypical Kawasaki Disease is characterized by fever >5 days (must have fever for at least 5 days, even with incomplete Kawasaki Disease) and 2-3 of the above clinical criteria and includes laboratory workup based on the algorithm below

       
Evaluation of suspected incomplete Kawasaki disease.
(1) In the absence of gold standard for diagnosis, this algorithm cannot be evidence based but rather represents the informed opinion of the expert committee. Consultation with an expert should be sought anytime assistance is needed. (2) Infants 6 months old on day ?7 of fever without other explanation should undergo laboratory testing and, if evidence of systemic inflammation is found, an echocardiogram, even if the infants have no clinical criteria. (3) Characteristics suggesting disease other than Kawasaki disease include exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider alternative diagnoses. (4) Supplemental laboratory criteria include albumin 3.0 g/dL, anemia for age, elevation of alanine aminotransferase, platelets after 7 days ?450 000/mm3, white blood cell count ?15 000/mm3, and urine ?10 white blood cells/high-power field. (5) Can treat before performing echocardiogram. (6) Echocardiogram is considered positive for purposes of this algorithm if any of 3 conditions are met: z score of LAD or RCA ?2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or ?3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased LV function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2–2.5. (7) If the echocardiogram is positive, treatment should be given to children within 10 days of fever onset and those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation. (8) Typical peeling begins under nail bed of fingers then toes. 

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.  Pediatrics 2004;114:1708–1733; Newburger, et al - CLICK ON LINK ABOVE FOR ARTICLE

Other Clinical Findings

1. Pronounced irritability
2. Abdominal pain and pseudobstruction
3. Diarrhea and vomiting
4. Mild hepatic dysfunction
5. Urethritis with sterile pyuria
6. Arthralgias and arthritis
7. Aseptic meningitis
8. Hydrops of the Gallbladder
9. CHF, myocarditis, pericarditis, mitral insufficiency
10. Coronary Aneurysms - develop in ~20% of untreated patients and < 5% of treated patients. Higher incidence in < 1 year of age, males, and when here has been prolonged fever and inflammation.

Angiography showing ectatic LAD, with largest aneurysm = 6.5 mm in diameter -https://en.wikipedia.org/wiki/Kawasaki_disease

Laboratory findings

1. Elevated acute phase reactants -CRP, ESR, Thrombocytosis, leukocytosis
2. Normochromic normocytic anemia
3. Sterile pyuria
4. Mild elevation of liver enzymes and bilirubin
5. Mononuclear cells in the CSF

Time Course

Clinical manifestations and time course of Kawasaki disease
https://en.wikipedia.org/wiki/Kawasaki_disease

Diagnostic Work-up

1. When there is clinical suspicion of Kawasaki Disease, an Echocardiogram should be performed.
2. Other etiologies of the clinical picture must be ruled out such as easles, Scarlet Fever, Drug reactions, other viral illnesses, RMSF, Leptospirosis
3. Clinical Diagnosis

Management

1. IVIG - usually rapid response with child becoming afebrile and feeling better, and remarkably less irritable. 
2. High Dose Aspirin - continue until patient is afebrile and in patients without coronary aneurysms, low dose ASA until all markers of inflammation are normal. IVIG and ASA decrease the incidence of coronary artery aneurysms from 20% to between 3-5%.
3. 10-15% of children may have persistent fever despite IVIG.  Failure to respond to IVIG may require another dose, however most children are not retreated until 36 hours after the first dose.
4. A further 4% of patients will fail to respond to two doses of IVIG. Failure to respond to two doses may require a third dose with 60% response.  Failure to respond may also require the use of infliximab and corticosteroids.  However, recent studies have shown limited efficacy of infliximab, and use of corticosteroids is controversial.
5. Follow-up with cardiologist. Coronary aneurysms may not be present on the initial echocardiogram, and thus require periodic cardiac examinations and continuance of low dose ASA.  The echocardiogram is generally repeated 2 and 6 weeks of illness.  If an aneurysm is detected, more frequent and continued monitoring is required.
6. Vaccination with flu shot is important for the child and the family in order to prevent possible Reye's syndrome.
7. Live vaccinations should be postponed for at least 11 months after the last IVIG dose because of decreased immunogenicity of the vaccine.  In instances of measels outbreaks or varicella exposure, the vaccines may be given however they must be repeated 11 months after the last IVIG dose.

Prognosis

1. Risk of mortality from Kawasaki Disease is rare
2. Morbidity is related to the degree of coronary aneurysm

• Aneurysms 8 mm or larger are more at risk for myocardial infarction from coronary artery occlusion. 
• Those smaller than 8 mm tend to regress some over time
• Those smaller than 6 mm generally fully resolve.

Despite resolution of the aneurysm, vascularity of the vessel does not return to normal, thus it is very important that individuals with coronary artery aneurysms be followed indefinetly by cardiologists for changes and monitoring.

References

1. Anderson  M. et. al. (2005). Delayed diagnosis of Kawasaki syndrome: an analysis of the problem. Pediatrics, e428.
2. Burns J.C. et. al. (2000). Kawasaki disease: a brief history. Pediatrics,  106(e27).
3. Eagle K. (1995). Kawasaki disease. NEJM, 333(21), 1391.
4. Freeman A. and Shulman S. (2003). Refractory Kawasaki disease. Ped Inf Disease Journal, 23(5).
5. Newburger, J.W. et.al. (2004). Diagnosis, treatment, and mangement of Kawasaki disease. Pediatrics, 114(6), 1708-1733.
6. Son M.B. et. al. (2009). Treatment of Kawasaki disease:  analysis of 27 US pediatric hospitals from 2001 to 2006. Pediatrics, 124(1), 1-8.
7. Tremoulet A. (2012). Infliximab showed no benefit in children with Kawasaki disease. Infectious Diseases in Children.