Kawasaki Disease and Anti-Inflammatory Doses of Aspirin—A Complicated Relationship

Kawasaki disease (KD) is an acute febrile childhood illness and is the leading cause of acquired heart disease among children in high-income countries.The primary concern is the development of coronary artery aneurysms (CAAs), particularly large or giant CAAs that increase the risk of morbidity and mortality.The mainstay of acute KD management is intravenous immunoglobulin (IVIG) and aspirin (acetylsalicylic acid), and timely treatment with IVIG has been shown to decrease the risk of developing CAAs.Even before the introduction of IVIG as an effective therapy for KD in the 1980s, conventional therapy included aspirin for its anti-inflammatory effects at higher doses and its antiplatelet effects at lower doses.This practice continues today despite years of controversy and ample debate in the KD community about anti-inflammatory dosages of aspirin in terms of both effectiveness and appropriate dosing.North American centers traditionally have used high-dose aspirin (80-100 mg/kg per day) in the acute phase of KD, while centers in Japan have used medium-dose aspirin (30-50 mg/kg per day), citing concerns about potential adverse effects of higher doses. [1][2]2][3] After defervescence, low-dose aspirin (3-5 mg/kg per day) is typically continued for the antiplatelet effects for 6 to 8 weeks after disease onset and longer in the presence of CAAs.Despite this established use of anti-inflammatory doses of aspirin, there is mounting evidence that medium-dose or high-dose aspirin in the acute phase does not impact CAA outcomes.Recently, a retrospective cohort study in Japan compared CAA outcomes among patients receiving mediumdose aspirin (30-50 mg/kg per day) at 6 hospitals with patients who did not receive aspirin routinely at 2 other hospitals. 4The authors concluded that the lack of aspirin was noninferior to the use of medium-dose aspirin in the incidence of CAAs and suggested revisions to the KD guidelines regarding aspirin administration in the acute phase.In another multicenter retrospective cohort study across 5 centers in Canada, there was no difference in the development of CAAs between 2 centers that used low-dose aspirin in acute management and 3 centers that used high-dose aspirin (80 mg/kg per day). 5The authors suggested that aspirin doses above 3 to 5 mg/kg per day may not be indicated for acute management.Among several informative meta-analyses and systematic reviews, Huang et al 6 analyzed 6 retrospective studies of 1944 patients receiving various doses of aspirin, including no, low-dose, medium-dose, or high-dose aspirin, and there was no statistically significant difference observed in the risk of coronary artery lesion development, IVIG resistance, or duration of hospitalization.Kuo et al 7 performed a prospective, multicenter, noninferiority randomized clinical trial to address this ongoing issue.Across 5 hospitals in Taiwan, patients were randomized to receive either IVIG 2 g/kg over 12 hours along with high-dose aspirin (80-100 mg/kg per day) until fever subsided for 48 hours or IVIG 2 g/kg without high-dose aspirin.Both groups received low-dose aspirin once fever subsided, and the primary outcome was the development of CAAs at 6 to 8 weeks.Among 69 patients who received IVIG and high-dose aspirin, the prevalence of CAAs decreased from 13.0% (n = 9) at baseline to 2.9% (n = 2) at 6 weeks.Similarly, among 65 patients who received IVIG without high-dose aspirin, the prevalence of CAAs decreased from 10.8% (n = 7) at baseline to 1.5% (n = 1) at 6 weeks.There was no statistical difference, and the authors concluded that IVIG alone was not inferior to IVIG with high-dose aspirin in the acute phase of KD management.