Background— Triiodothyronine levels decrease in infants and children after cardiopulmonary bypass. We tested the primary hypothesis that triiodothyronine (T3) repletion is safe in this population and produces improvements in postoperative clinical outcome. Methods and Results— The TRICC study was a prospective, multicenter, double-blind, randomized, placebo-controlled trial in children younger than 2 years old undergoing heart surgery with cardiopulmonary bypass. Enrollment was stratified by surgical diagnosis. Time to extubation (TTE) was the primary outcome. Patients received intravenous T3 as Triostat (n=98) or placebo (n=95), and data were analyzed using Cox proportional hazards. Overall, TTE was similar between groups. There were no differences in adverse event rates, including arrhythmia. Prespecified analyses showed a significant interaction between age and treatment ( P =0.0012). For patients younger than 5 months, the hazard ratio (chance of extubation) for Triostat was 1.72. ( P =0.0216). Placebo median TTE was 98 hours with 95% confidence interval (CI) of 71 to 142 compared to Triostat TTE at 55 hours with CI of 44 to 92. TTE shortening corresponded to a reduction in inotropic agent use and improvement in cardiac function. For children 5 months of age, or older, Triostat produced a significant delay in median TTE: 16 hours (CI, 7–22) for placebo and 20 hours (CI, 16–45) for Triostat and (hazard ratio, 0.60; P =0.0220). Conclusions— T3 supplementation is safe. Analyses using age stratification indicate that T3 supplementation provides clinical advantages in patients younger than 5 months and no benefit for those older than 5 months. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00027417.

Background—: A functional polymorphism in the inhibitory IgG-Fc receptor gene Fc γ RIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki disease (KD), a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors ( Fc γ RIIA , Fc γ RIIIA , and Fc γ RIIIB ) also influence susceptibility, IVIG treatment response, and coronary artery disease in patients with KD. Methods and Results—: We genotyped polymorphisms in the activating Fc γ RIIA , Fc γ RIIIA , and Fc γ RIIIB using pyrosequencing in 443 patients with KD, including 266 trios and 150 single parent-child pairs, in northwest United States and genetically determined race with 155 ancestry informative markers. We used family-based association to test for transmission disequilibrium and further generated pseudosibling controls for comparisons with the cases. The Fc γ RIIA-131H variant showed an association with KD ( P =0.001) with an additive odds ratio (OR) of 1.51 (95% CI, 1.16–1.96; P =0.002) for the primary combined population, which persisted in both white ( P =0.04) and Asian ( P =0.01) subgroups and is consistent with the recent genome-wide association study. We also identified overtransmission of the Fc γ RIIIB neutrophil antigen 1 (NA1) variant among IVIG nonresponders ( P =0.0002) and specifically to white IVIG nonresponders ( P =0.007). ORs for overall and white nonresponders were 3.67 (95% CI, 1.75–7.66; P =0.0006) and 3.60 (95% CI, 1.34–9.70; P =0.01), respectively. Excess NA1 transmission also occurred in patients with KD with coronary artery disease (OR _additive , 2.13; 95% CI, 1.11–4.0; P =0.02). Conclusions—: A common variation in Fc γ RIIA is associated with increased KD susceptibility. The Fc γ RIIIB-NA1 variant, which confers higher affinity for IgG than the NA2 variant, is a determining factor for treatment response. These activating Fc γ R s play an important role in KD pathogenesis and the IVIG antiinflammatory mechanism.

Video Abstract Video Abstract Patients with Kawasaki disease can develop life-altering coronary arterial abnormalities, particularly in those resistant to intravenous immunoglobulin (IVIg) therapy. We tested the tumor necrosis factor α receptor antagonist etanercept for reducing both IVIg resistance and coronary artery (CA) disease progression. In a double-blind multicenter trial, patients with Kawasaki disease received either etanercept (0.8 mg/kg; n = 100) or placebo (n = 101) subcutaneously starting immediately after IVIg infusion. IVIg resistance was the primary outcome with prespecified subgroup analyses according to age, sex, and race. Secondary outcomes included echocardiographic CA measures within subgroups defined by coronary dilation (z score >2.5) at baseline. We used generalized estimating equations to analyze z score change and a prespecified algorithm for change in absolute diameters. IVIg resistance occurred in 22% (placebo) and 13% (etanercept) of patients (P = .10). Etanercept reduced IVIg resistance in patients >1 year of age (P = .03). In the entire population, 46 (23%) had a coronary z score >2.5 at baseline. Etanercept reduced coronary z score change in those with and without baseline dilation (P = .04 and P = .001); no improvement occurred in the analogous placebo groups. Etanercept (n = 22) reduced dilation progression compared with placebo (n = 24) by algorithm in those with baseline dilation (P = .03). No difference in the safety profile occurred between etanercept and placebo. Etanercept showed no significant benefit in IVIg resistance in the entire population. However, preplanned analyses showed benefit in patients >1 year. Importantly, etanercept appeared to ameliorate CA dilation, particularly in patients with baseline abnormalities.