Knowledge on rare diseases and orphan drugs

Although it has been reported worldwide, Kawasaki disease (KD) is over-expressed among Asian populations. In Europe, the annual incidence for children under 5 years of age ranges between 1/6,500-20,500. The disease is the most common cause of acquired heart disease in children in developed countries.

Median age of onset is 2 years (with 75% of patients being under 5 years old). Fever (greater than 39 degrees C) that persists for greater than 5 days when untreated is a constant feature. Children are usually very irritable. Additional typical manifestations of KD include extremity changes (erythema and edema of palms and soles that desquamate after 2-3 weeks, usually seen in the subacute phase), polymorphic skin rash (maculopapular, urticarial, or scarlatiniform rash), lymphadenopathy (cervical, often unilateral, greater than 1.5 cm diameter), non-exudative bilateral conjunctivitis, and involvement of lips and oral mucosa (erythema, strawberry tongue, lip fissures). CAA is a life threatening complication that usually occurs in the subacute phase (6 to 8 weeks after onset) in 20-35% of untreated children. The regression of giant CAA (greater than 8 mm) is very unlikely, while minor dilations are usually transient. Atypical manifestations include myocarditis pericarditis, valvular regurgitation, hepatitis, diarrhea, abdominal pains, hydrops of gallbladder, arthralgia, arthritis, myalgia, aseptic meningitis, sensorineural hearing loss, urethritis and sterile pyuria. KD is a risk factor for ischemic heart disease in adulthood.

Etiology is unknown but several pathogenic theories have been proposed (e.g. infection by a toxin-secreting microorganism and a superantigen-driven process). Genetics appear to play a major role, and the disease is much more common in Asian populations. Genome-wide studies have identified single nucleotide polymorphisms which would confer increased susceptibility to the disease and to its complications.

Diagnosis is clinical. Complete KD is defined by fever and 4/5 of the standard clinical criteria (extremity changes, polymorphous rash, conjunctival injection, changes in lips and oral cavity, and cervical lymphadenopathy greater than 1.5 cm diameter). Incomplete KD can be diagnosed in case of prolonged fever, 2-3/5 standard criteria, and specific signs of coronary disease, particularly CAA when other causes of coronary vasculitis are excluded. Laboratory findings (elevated inflammatory markers and liver enzymes, neutrophilia and thrombocytosis), though non-specific, are supportive. At diagnosis, patients must be investigated for coronary involvement via transthoracic echocardiography.

Differential diagnosis includes autoimmune and autoinflammatory diseases (e.g. systemic-onset JIA), bacterial infections (i.e. bacterial toxic shock syndrome, leptospirosis, adenophlegmon), viral infections (i.e. measles, enterovirus, Epstein-Barr virus), and toxin or drug reactions.

Early administration of intravenous immunoglobulin (IVIg) reduces the rate of coronary abnormalities to less than 5% of patients. IVIg is administrated at a single dose of 2 g/kg before the 10th day of onset, or even later if persistent inflammation. In case of treatment failure, IVIg readministration, corticosteroids, anakinra and infliximab may be considered as second line treatments. Aspirin (30-50 mg/kg/day) are usually given in the febrile phase, followed by low (antiplatelet) doses (3-5 mg/day) for 6-8 weeks. Following diagnosis, coronary involvement is monitored at 2 weeks and 6-8 weeks by transthoracic echocardiography.

Non-complicated cases resolve without sequelae, while patients with persistent CAA are at risk for major cardiovascular events and their long-term outcome may be complicated by premature ischemic heart disease.

Last update: February 2020 - Expert reviewer(s): Dr Caroline GALEOTTI - Pr Isabelle KONE-PAUT