of ivig resistance in patients with kawasaki disease could accurately distinguish the resistance. salicylate therapy, particularly aspirin, remains an important part of the treatment (though questioned by some) but salicylates alone are not as effective as ivig. there is limited evidence to indicate whether children should continue to receive salicylate as part of their treatment. aspirin therapy is started at high doses until the fever subsides, and then is continued at a low dose when the patient returns home, usually for two months to prevent blood clots from forming. except for kawasaki disease and a few other indications, aspirin is otherwise normally not recommended for children due to its association with reye syndrome. because children with kawasaki disease will be taking aspirin for up to several months, vaccination against varicella and influenza is required, as these infections are most likely to cause reye syndrome. high-dose aspirin is associated with anemia and does not confer benefit to disease outcomes. about 15-20% of children following the initial ivig infusion show persistent or recurrent fever and are classified as ivig-resistant. while the use of tnf alpha blockers (tnf-α) may reduce treatment resistance and the infusion reaction after treatment initiation, further research is needed. due to the potential involvement of the upregulated calcium-nuclear factor of activated t cells pathway in the development of the disease, a 2019 study found that the combination of ciclosporin and ivig infusion can suppress coronary artery abnormalities. further research is needed to determine which patients would respond best to this treatment. corticosteroids have also been used, especially when other treatments fail or symptoms recur, but in a randomized controlled trial, the addition of corticosteroid to immune globulin and aspirin did not improve outcome. additionally, corticosteroid use in the setting of kawasaki disease is associated with increased risk of coronary artery aneurysm, so its use is generally contraindicated in this setting. in cases of kawasaki disease refractory to ivig, cyclophosphamide and plasma exchange have been investigated as possible treatments, with variable outcomes. however, a cochrane review published in 2017 (updated in 2022) found that, in children, the use of corticosteroids in the acute phase of kd was associated with improved coronary artery abnormalities, shorter hospital stays, a decreased duration of clinical symptoms, and reduced inflammatory marker levels. patient populations based in asia, people with higher risk scores, and those receiving longer steroid treatment may have greater benefit from steroid use. prognosis with early treatment, rapid recovery from the acute symptoms can be expected, and the risk of coronary artery aneurysms is greatly reduced. untreated, the acute symptoms of kawasaki disease are self-limited (i.e. the patient will recover eventually), but the risk of coronary artery involvement is much greater, even many years later. many cases of myocardial infarction in young adults have now been attributed to kawasaki disease that went undiagnosed during childhood. overall, about 2% of patients die from complications of coronary vasculitis. laboratory evidence of increased inflammation combined with demographic features (male sex, age less than six months or greater than eight years) and incomplete response to ivig therapy create a profile of a high-risk patient with kawasaki disease. the likelihood that an aneurysm will resolve appears to be determined in large measure by its initial size, in which the smaller aneurysms have a greater likelihood of regression. other factors are positively associated with the regression of aneurysms, including being younger than a year old at the onset of kawasaki disease, fusiform rather than saccular aneurysm morphology, and an aneurysm location in a distal coronary segment. the highest rate of progression to stenosis occurs among those who develop large aneurysms. the worst prognosis occurs in children with giant aneurysms. this severe outcome may require further treatment such as percutaneous transluminal angioplasty, coronary artery stenting, bypass grafting, and even cardiac transplantation. a relapse of symptoms may occur soon after initial treatment with ivig. this usually requires rehospitalization and retreatment. treatment with ivig can cause allergic and nonallergic acute reactions, aseptic meningitis, fluid overload, and rarely, other serious reactions. overall, life-threatening complications resulting from therapy for kawasaki disease are exceedingly rare, especially compared with the risk of nontreatment. evidence indicates kawasaki disease produces altered lipid metabolism that persists beyond the clinical resolution of the disease. rarely, recurrence can occur in kawasaki disease with or without treatment. epidemiology kawasaki disease affects boys more than girls, with people of asian ethnicity, particularly japanese people. the higher incidence in asian populations is thought to be linked to genetic susceptibility. incidence rates vary between countries. currently, kawasaki disease is the most commonly diagnosed pediatric vasculitis in the world. by far, the highest incidence of kawasaki disease occurs in japan, with the most recent study placing the attack rate at 218.6 per 100,000 children less than five years of age (about one in 450 children). at this present attack rate, more than one in 150 children in japan will develop kawasaki disease during their lifetimes. however, its incidence in the united states is increasing. kawasaki disease is predominantly a disease of young children, with 80% of patients younger than five years of age. about 2,000–4,000 cases are identified in the u.s. each year (9 to 19 per 100,000 children younger than five years of age). in the continental united states, kawasaki disease is more common during the winter and early spring, boys with the disease outnumber girls by ≈1.5–1.7:1, and 76% of affected children are less than 5 years of age. in the united kingdom, prior to 2000, it was diagnosed in fewer than one in every 25,000 people per year. incidence of the disease doubled from 1991 to 2000, however, with four cases per 100,000 children in 1991 compared with a rise of eight cases per 100,000 in 2000. by 2017, this figure had risen to 12 in 100,000 people with 419 diagnosed cases of kawasaki disease in the united kingdom. in japan, the rate is 240 in every 100,000 people. coronary artery aneurysms due to kawasaki disease are believed to account for 5% of acute coronary syndrome cases in adults under 40 years of age. history the disease was first reported by tomisaku kawasaki in a four-year-old child with a rash and fever at the red cross hospital in tokyo in january 1961, and he later published a report on 50 similar cases. later, kawasaki and colleagues were persuaded of definite cardiac involvement when they studied and reported 23 cases, of which 11 (48%) patients had abnormalities detected by an electrocardiogram. in 1974, the first description of this disorder was published in the english-language literature. in 1976, melish et al. described the same illness in 16 children in hawaii. melish and kawasaki had independently developed the same diagnostic criteria for the disorder, which are still used today to make the diagnosis of classic kawasaki disease. dr. kawasaki died on june 5, 2020, at the age of 95. a question was raised whether the disease only started during the period between 1960 and 1970, but later a preserved heart of a seven-year-old boy who died in 1870 was examined and showed three aneurysms of the coronary arteries with clots, as well as pathologic changes consistent with kawasaki disease. kawasaki disease is now recognized worldwide. why cases began to emerge across all continents around the 1960s and 1970s is unclear. possible explanations could include confusion with other diseases such as scarlet fever, and easier recognition stemming from modern healthcare factors such as the widespread use of antibiotics. in particular, old pathological descriptions from western countries of infantile polyarteritis nodosa coincide with reports of fatal cases of kawasaki disease. in the united states and other developed nations, kawasaki disease appears to have replaced acute rheumatic fever as the most common cause of acquired heart disease in children.