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Pediatric Diseases:Kawasaki Disease

Risk factor for cardiac infarct development.

Kawasaki Disease is an acute febrile illness which appears more commonly among infants. It is Vasculitis syndrome which middle to small size inflammation of muscular artery is its primary pathological lesions. In case of no treatment has conducted, Coronary artery lesion (CAL) is combined on coronary artery with 25 to 30% ratio. And this pathological change becomes a risk factor for cardiac infarct due to the formation of blood clot. Therefore, it becomes important to extinct the severe inflammation reaction by prompt acute phase treatment, and to inhibit the development of blood vessel pathological change. Original article is reported by Tomitaro Kawasaki in 1967, then half century has been passed but still it remains to be identified.

Kawasaki Disease, when no treatment, Coronary Artery lesion is combined at 1 out of 3 to 4 people

Contrast image of right Coronary artery
Contrast image of left Coronary artery

Numbers of patient is ever increasing.

National survey for Kawasaki Disease is conducting approximately every 2 years since 1970. Since national fad is recognized in 1979, 1982 and 1986, annual numbers of patients is transitioned around 5,000, but shows increasing tendency from latter half of 1990. Annual numbers of patients are raised above 10,000 in 2005, and ever increasing since then.

In recent 23rd National Survey for Kawasaki Disease, numbers of patients in 2014 shows the record-high 15,979. Also, disease prevalence shows 302.5 per 100k of 0 to 4 years old infants in 2013, and 308.0 in 2014. It breaks the record-high number every year. Although the numbers of children are decreasing due to the declining birth rate, absolute number itself is increasing every year since 1990s. Thus, accumulated numbers of patients exceed 300,000.

Kawasaki Disease is mainly affected with infants, its disease prevalence is 66.2% under age 3, 88.2% under age 5, and peak prevalence period is in late infancy (6 to 11 months). According to the latest national survey, approximately 92% patients get an acute phase medical treatment using immune globulin. Acute phase cardiac lesion is seen with 9.3% and such insult remains as after effect on and after 30 sick days at 2.8% ratio. The ratio of sibling case where brother-sister are affected is 1.5%, 0.89% for either one of parents with a history of Kawasaki Disease, and 3.5% for recurrent case.

Triggered by excess immune reaction?

Various theories are discussed as the cause of Kawasaki Disease, but it is still unknown. In the past, the thought which some kind of infection disease is backgrounded is commonly spread around, but recently the thought becomes as main stream that pathogenic microbe like fungus, virus or rickettsia may break into the body triggers the excess immune reaction (natural immunity), then certain disease state, which appears out with any one of these microbes, are hidden in the body.

From the facts such as, three epidemic period exists in the past, and frequency of occurrence of Kawasaki Disease decreases in September to November period where both bacteria and virus decrease, involvement of infection factor is considered. Bacteria, Virus, rickettsia, chlamydia, fungus are considered as the cause of disease. Up until now, bacterial broth test, virus separation, analysis using serum antibody titer are energetically conducted, but no reproducible results are obtained. Research (Metagenome analysis) from gene analysis view point using next generation sequencer is to be conducted since 2009, so that cyclopaedically virus research, like cyclopaedically mapping of nucleic acid sequence, and selecting microbe which is related to pathological condition, are proceeded.

It is suggested that genetic factor contributes to this disease since disease prevalence in Japan is 10 to 20 times higher than the one in European countries, and occurrence frequency amongst sibling cases and Japanese (Japanese descent) are high. Until now, by means of Genome Wide Approach which searches disease susceptibility gene from every genome, Kawasaki disease susceptibility gene (ITPKC, CASP3) is identified. Also, by means of genome-wide association study (GWAS), B lymphoid tyrosine kinase (BLK), human leukocyte antigen (HLA), CD40, FCGR2A are reported as Kawasaki disease susceptibility gene. From the result of these gene analysis, although sufficient verification has not yet been gained to explain development of Kawasaki Disease, but the polytypic combination of ITPKC and CASP3 gene is significantly related to treatment-resistance or CAL Complication risk. Application usage for tailor-made treatment is therefore expected in the future.

Clinical condition of Kawasaki disease.

Clinical condition in acute phase of Kawasaki Disease is characterized in excess activation of innate immune system, and it is combined with the increase of inflammatory cytokine and chemokine. Then it is considered that these factors set up derivation of fever, increase of acute protein production or neutrophil in blood, and inflammation of blood vessel.

Currently, fundamental research using various kind of experimental animal and Research using Kawasaki Disease specific iPS cell, are energetically conducting. Therefore, detail of onset factor of Kawasaki Disease, clarification of clinical condition, and furthermore mechanism of vascular sequelae, are gradually going to be apparent.

Diagnose with five matches from major symptom.

There is no specific diagnostic method observed from examination findings for the diagnostic of Kawasaki Disease. It is done in accordance with the guideline for Kawasaki Disease (5th Revision by Kawasaki Disease Research Group of Ministry of Health, Labor and Welfare)

Kawasaki Disease (MCLS, Mucocutaneous Lymph Node Syndrome)

Kawasaki Disease is an acute febrile illness with unknown cause which appears more commonly amongst infants and characterized with entire body inflammation of blood vessel.

Major symptom

  • Fever continue more than 5 days
  • hyperemia on bulbar conjunctiva of both eyes
  • Blushing mouth lips, red strawberry tongue
  • Undefined rash
  • Hardened Edema on limbs, Erythema of palm
    palmoplantar or finger toe tip
  • non-infected Cervical lymph node swelling

Mucocutaneous Lymph Node Syndrome combined with specific desquamation of the fingers and toes: clinical observation of 50 own experiments case.
(Tomisaku Kawasaki Allergy 1967,16,178)

Diagnose as Kawasaki Disease when 5 symptoms or more are associated out of below listed 6 major symptoms.

When only 4 symptoms are recognized out of above 6 major symptoms, but when coronary fistula (i.e. enlargement) is identified by 2D echocardiography or cardiac angiography during the course and other disease is excluded, it is diagnosed as Kawasaki Disease.

There exists 15 to 20% “Kawasaki Disease aborted type” where symptom does not fulfill a criterion of Guideline for Diagnosis and is considered as Kawasaki Disease because of the denial of other disease thus considered as Kawasaki Disease. Aborted type does ever mean a mild case, and likely associated with cardiac complication, it is recommended to start treatment next to no time.

Disease which requires the differentiation

  1. a.Yersinia Infection
  2. There is a case where similar symptom of Kawasaki Disease appears in Yersinia pseudotuberculosis (Yp) infection, and 10% among them fulfill the diagnosis criterion. Also, there is cases where coronary artery aneurysm/dilatation.
  3. b.Canker Rash
  4. Rose pink punctate rash, then later diffuse erythema is observed. There is a case showing strawberry tongue. Rash may be withdrawn in approximately 1 week, then later abrasion or desquamation will be seen for few weeks.
  5. c.Adenoviral Infection
  6. Conjunctival congestion by fever onset, inflammation of pharynx and conjunctivitis are three major symptoms in pharyngoconjunctival fever.
  7. d.Juvenile Idiopathic Arthritis
  8. Systemic arthritis is defined as arthritis which is associated with fever of a remittent type continues more than 2 weeks, and with one or more following symptoms, (1) Transient and non-stationary erythema, (2) Generalized lymph node enlargement, (3) Hepatic or spleen enlargement, (4) Inflammation of a serous membrane.
  9. f.Others
  10. Repetition is not so high, but there is a case which is arising secondary in immediately after other disease so that relativity is strongly suspected. Especially, EB Virus infection, measles, influenza, yersinia infection, staphylococcic infection, hemolytic streptococcal infection and mycoplasma infection are subject to be distinguished.

Even though only 4 symptoms are recognized from above 6 major symptoms, when coronary aneurysm (including so called enlargement) is distinguished and other disease are excluded, then it is diagnosed as Kawasaki Disease.

Acute Phase Treatment.

Immunoglobulin Super Mass (IVIG) single dose is the most reliable anti-inflammatory therapy at this moment and decline of fever is gained in 80% of the cases. On the contrary, there exists IVIG refractory case with 10 to 20%. In this IVIG refractory case, coronary artery disorder is associated with 7 times higher rate, with comparison of IVIG reaction case.

Trial for stratified treatment using the IVIG Refractory Case Prediction Score.

With using IVIG Refractory Case Prediction Score developed in 2006, randomized controlled study is carried out for the purpose of stratified treatment for severe Kawasaki Disease patients. In 2012, it is reported one after the other that IVIG+ Steroid early phase combined administration has significantly reduced the repetition of coronary artery lesion complication.

Revised edition of Acute Phase Treatment Guideline

New guideline is reported in 2012. Its general outline is as follows.

Consider for prognosis in accordance with internal diameter of hepatic artery.

Prognostic factors in Kawasaki Disease are expansion of coronary artery or coronary artery aneurysm. Up to now, prognosis is considered as follows.


Hepatic Artery pathological lesion and long-term prognosis among anamnestic patient of the matured Kawasaki Disease

Recently, by the examination of angioscopy, intravascular echo, vascular function test, or vascular echo, probability is indicated that Kawasaki disease inflammation of blood vessel may turn into the risk factor for arterial sclerosis.

Also, from National Research by Japan Kawasaki Disease Society, and collaborative research with Japanese Circulation Society (Japan Cardiovascular Society), it is clearly articulated that the onset of coronary artery event (acute cardiac infarction, acute coronary syndromes) which do not directly relate to coronary artery aneurysm or stenotic lesion, have seen amongst adult case. Just 50 years had passed since Kawasaki Disease reported, it is considered as necessary to study further in long term bases.

Especially, for not only anamnestic patient with coronary artery sequelae but also adult patients without having echocardiographic examination, opinion indicates that long term prognosis is necessary to be kept in mind. Under these circumstances, necessity of further ongoing inquest is pointed out regarding the prognosis or management of patient in remote phase.