Kawasaki syndrome M30.3

Author: Prof. Dr. med. Peter Altmeyer

Last updated on: 24.05.2022

Synonym(s)

acute febrile mucocutaneous lymphadenopathy syndrome; Kawasaki disease; Kawasaki fever; Kawasaki Fever; Lymphadenopathy syndrome acute febrile mucocutaneous; Mucocutaneous lymph node syndrome

History
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Kawasaki 1967

Definition
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Probably immunologically mediated diffuse vasculitis, occurring predominantly in childhood, clinically characterized by high fever, enlarged cervical lymph nodes, skin and mucous membrane infestation and complicated in 15-25% of cases by the onset of myocarditis and coronariitis with consecutive thrombus and aneurysm formation in the coronary vessels.

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Occurrence/Epidemiology
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Rare disease, highest incidence in Japan (4-6,000 diseases/year or 140/100,000/year). In Southeast Asia the incidence in children <5 years is 112/100,000 per year, in Europe 8.1/100,000 per year and in Germany approximately 8/100,000 per year.

Etiopathogenesis
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Unexplained, pathogen-induced triggering is probable (e.g. SARS-Cov-19) There is also a genetic predisposition. Change in an activity of a C-kinase that intervenes in the activation of T-lymphocytes (1,4,5-triphosphatase-3-kinase C). Several susceptibility genes are also known to play a role in the pathogenesis of the disease: ITPKC, CASP3, CD40 and ORAI(Onouchi Y 2018).

Manifestation
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Mostly occurring in infants aged 1-5 years, rarely in young adults. Slight emphasis on the male sex.

Clinical features
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Accommodation/General: High fever resistant to antibiotics, persisting for more than 5 days. Conjunctivitis (>75%). Painful, cervical lymph node swelling (25-75%), pharyngitis (90%)

Integument: Bright red, cracked lips, diffuse redness of the mucous membranes of the mouth and throat, possibly raspberry tongue (90%). Palmoplantar erythema (50-85%) with oedematous transformation (50-85%); after 2-3 weeks of desquamation, which begins crescent-shaped at the fingertips. Later Beau-Reilsche transverse furrows of the fingernails.

Polymorphic exanthema: morbilli- or scarlatiniform, erythema exsudativum multiforme-like(70-90%).

Other accompanying symptoms: gastroenteritis, urethritis, abacterial meningitis, arthralgia, gallbladder hydrops.

Complicative are cardiac symptoms which can occur 12-28 days after infection. They manifest themselves as coronaritis and can lead to (giant) aneurysms, thrombosis, arrhythmias, stenosis, myocardial infarction, heart failure, PAD.

Laboratory
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Leukocyturia and proteinuria, pronounced leukocytosis with left-shift, CRP and alpha-2-globulins increased Thrombocytosis from the 2nd week of illness.

Differential diagnosis
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Scarlet fe ver: Clinical picture, pathogen detection, antistreptolysin titer (AST) rise (8-14 days after fresh infection at the earliest, baseline and control values), Dick test, extinction phenomenon.

Measles: Clinical picture with typical exanthema and enanthema (palate, tonsils, uvula). Titer increase by 2 levels in the haemagglutination inhibition test.

Infectious mononucleosis: generalized lymphadenopathy, splenomegaly, morbilliform exanthema, + serology.

Brucellosis; Weil 's disease: rare

Multisystemic inflammatory syndrome in association with COVID-19 (evidence of a previous or still active COVID-19 disease)

Acute rheumatic fever: carditis, polyarthritis (migratory), chorea minor (Sydenham), erythema marginatum rheumaticum (formerly also eythema anulare rheumaticum), and subcutaneous nodules (rheumatoid nodules). Secondary criteria: fever, arthralgias.

Hand-foot-and-mouth disease: fever, usually no severe feeling of illness, painful vesicles.

Still's syndrome: long-term course with recurrent fevers.

Erythema exsudativum multiforme: typical clinical morphology of the exanthema with cocards

Multisystemic inflammatory syndrome associated with COVID-19, often a severe disease in children and adolescents. The phenotype resembles Kawasaki syndrome. Dermatological findings include severe febrile general symptoms, maculopapular exanthema, concunctivitis, cheilites, palmar erythema, and hand and foot edema.

Complication(s)
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In 20% of cases, vasculitis leads to aneurysm formation, mainly in the area of the coronary arteries. After months mostly regression.

Therapy
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See Table 1.

Progression/forecast
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Early diagnosis and therapy is important.

Untreated, the disease can heal completely within 12-28 days.

The frequent (dreaded) cardiac complications occur 12-28 days after the onset of the disease.

The lethality rate is about 1-2%, mainly due to heart attacks.

Decisive for the course and prognosis is the extent of vascular involvement.

Tables
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Therapy recommendations for Kawasaki syndrome (modified according to Cremer)

Medication	Example preparation	Indication	Dosage	Duration
Gamma globulin and acetylsalicylic acid	Intratect	Standard therapy	Gamma globulin preparation with intact Fc segment 2 g/kg bw as a short infusion in 5% glucose Lsg.	Single dose over 12 hrs i.v.
			In combination with:
	ASS
			Acetylsalicylic acid at a dose of at least 100 mg/kg bw (often up to 150 mg/kg bw in younger children, possibly less in older children). Frequent ASA level determinations (therapeutic level between 1530 mg/dl or 1.12.2 mmol/l). Reduce ASA to 3 mg/kg bw from the third week of illness or one week after fever resolution.	Total duration 3 months. Longer therapy (at least 2 years) for patients with proven coronary artery changes.

Gamma globulin and acetylsalicylic acid.	Intratect	Standard therapy if initiation of therapy is possible in the first week of illness, especially in high-risk children (< 2 years).	Gamma globulin preparation with intact Fc segment, 400 mg/kg bw as a short infusion in 5% glucose Lsg.	Over 5 days.
			In combination with:
	ASS		Acetylsalicylic acid 30-50 mg/kg bw until fever is relieved, then 5 mg/kg bw.

Prednisolone and acetylsalicylic acid	Decortin H Tbl.	Alternative therapy if gamma globulin could not be started in the 1st phase of the disease or if fever has not broken with this therapy.	Prednisolone 2 mg/kg bw/day (1st week) in 3-4 ED.	Over 3 weeks, then tapering off within 1 week. 4 weeks beyond discontinuation of prednisolone therapy. Discontinue therapy only when echocardiography is unremarkable and platelets and ESR normalized.
			In combination with:
	ASA		Acetylsalicylic acid 30-50 mg/kg bw/day until fever resolution, then 5 mg/kg bw/day.

Monotherapy with acetylsalicylic acid	ASS	Only for very mild forms of progression!	60-100 (-130) mg/kg bw/day in 4 ED. Target acetylsalicylic acid level 20-25 mg/dl. In the case of fever, dose reduction in the 2nd week to 50 mg/kg bw/day. From the 3rd week (thrombocytosis!) 3-5 mg/kg bw/day 1 time/day for platelet inhibition.	Therapy discontinuation after 6 weeks if echocardiography is unremarkable and platelets and BKS normalized.

Note(s)
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Worldwide, 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared to have a milder clinical course in children compared with adults. European and US pediatricians increasingly noticed cases of myocarditis sharing some clinical features with toxic shock syndrome, Kawasaki syndrome, and macrophage activation syndrome in otherwise healthy patients (Berardicurti O et al. 2020). The spectrum of severity ranged from standard hospitalization to treatment in the pediatric intensive care unit (Ebina-Shibuya R et al. 2020). The term multisystemic inflammatory syndrome was introduced for this new Kawasaki-like syndrome in associationCOVID-19 .

Literature
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Berardicurti O et al (2020) The wide spectrum of Kawasaki-like disease associated with SARS-CoV-2 infection. Expert Rev Clin Immunol 16:1205-1215.
Cheung YF et al (2004) Novel and traditional cardiovascular risk factors in children after Kawasaki disease: implications for premature atherosclerosis. J Am Coll Cardiol 43: 120-124.
Cremer H (1990) The Kawasaki syndrome (mucocutaneous lymph node syndrome). Dt Ärztebl 87: 1526-1531
Dajani AS, Taubert KA, Gerber MA et al (1993) Diagnosis and therapy of Kawasaki disease in children. Circulation 87: 1776-1780
Ebina-Shibuya R et al (2020) Multisystem Inflammatory Syndrome in Children (MIS-C) with COVID-19: Insights from simultaneous familial Kawasaki Disease cases. Int J Infect Dis 97:371-373.
Kawasaki T (1967) Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the finger and toes in children. Jap J Allerg 16: 178.
Lee CS, Lim HW (2003) Cutaneous diseases in Asians. Dermatol Clin 21: 669-677.
Machet L et al (1990) Kawasaki disease in a young adult with perineal rash. Br J Dermatol 123: 413
Nadel S, Levin M (1993) Kawasaki disease. Curr Opin Pediatr 5: 29-34.
Onouchi Y (2018) The genetics of Kawasaki disease. Int J Rheum Dis 21:26-30.
Shaukat N, Ashraf S, Mebewu A et al (1993) Myocardial infarction in a young adult due to Kawasaki disease. A case report and review of the late cardiological sequelae of Kawasaki disease. Int J Cardiol 39: 222-226
Teraki Y et al (1994) Dermatoses described in Japan. Dermatologist 45: 125-131
Wortman DW (1992) Kawasaki syndrome. Semin Dermatol 11: 37-47