IVIg with aspirin linked to reduced coronary aneurysms [Pediatrics Classics Series]

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1. Children with Kawasaki disease treated with a combined regimen of aspirin and intravenous gamma globulin had significantly lower rates of coronary artery aneurysms when compared to those receiving aspirin only.

2. Children treated with the combined regimen had significantly shorter fevers and a greater decrease in inflammatory markers when compared to those treated with aspirin alone.

Original Date of Publication: August 1986

Study Rundown: Kawasaki disease, also known as Kawasaki syndrome, is an inflammatory vascular condition characterized by persistent fever, oral erythema, conjunctivitis, lymphadenopathy, and rash with risk of lasting coronary artery aneurysm or ectasia. At the time of the current study, standard care for Kawasaki disease included aspirin, which was believed to aid in reducing inflammation, but not to stopping the disease’s cardiovascular complications. This study was the first to expand upon the proposed efficacy of high-dose intravenous gamma globulin (IVIg; also known as immuno-gamma globulin) in preventing Kawasaki-related cardiac problems when compared to aspirin. Prior studies used low-dose (100mg) IVIg and poor study design. Participants received either aspirin (100mg/kg every 16 hours), or both IVIg (400mg) and aspirin. Coronary artery pathology was assessed using echocardiography at 2 and 7 weeks after enrollment. Secondary outcomes included fever duration and reduction in inflammatory markers (white-cell count, absolute granulocyte count, alpha₁-antitrypsin level, absolute neutrophil count, and platelet count). Researchers found that children receiving combined therapy had significantly lower aneurysms, fever duration, and many significantly lower inflammatory markers by day 5 of treatment when compared to those receiving aspirin only. This study is limited in its lack of blinding among practitioners administering the treatment regimen and differences in hospitalization status (all patients undergoing IVIg required hospitalization, whereas those receiving aspirin only were not). This was the first study to provide evidence of the efficacy of high-dose IVIg in managing the cardiac and inflammatory outcomes of Kawasaki disease.

Click to read the study in The New England Journal of Medicine

In-Depth [multi-center, randomized trial]: From February 1984 to September 1985, 168 children with diagnosed Kawasaki disease were recruited from 6 care centers throughout the United States. Kawasaki disease was diagnosed in individuals with 5 of 6 clinical features (fever, nonexudative conjunctivitis, oral changes, extremity changes, rash, and cervical lymphadenopathy). Participants were randomized into 1 of 2 treatment groups: 100mg/kg of aspirin every 16 hours for 14 days (n = 84) or 400mg (high-dose) IVIg for the first four days of treatment along with the aspirin regimen described previously (n = 84). Demographics, baseline laboratory testing, and follow-up salicylate levels of the groups did not differ significantly. Presence of coronary artery aneurysms was assessed through 2-dimensional echocardiography completed at enrollment and then 2 weeks and 7 weeks later. Imaging was read by 2 pediatric echocardiographers blinded to the study. T-tests to compare means and Mantel-Haenszel methods along with logistic regression were completed to assess the effect of IVIg on the treatment regimen.

Three hundred eleven follow-up echocardiograms were completed. At 2-week follow-up, significantly fewer children in the combined treatment group had coronary artery abnormalities when compared to those treated only with aspirin (8% v. 23.1%, p < 0.01). This difference was also observed at 7-week follow-up (3.8% v. 17.7%, p = 0.005). When children with abnormalities at enrollment were excluded, these findings were upheld. Using Mantel-Haeszel methods and logistic regression, it was determined that at 2 weeks, children who had the combined treatment regimen were one third as likely to have coronary aneurysms and, at 7 weeks, one fifth as likely when compared to children treated with only aspirin (95% CI). Children treated with a combined regimen experienced a significantly greater drop in body temperature during the first 2 days of treatment than with aspirin (1.30 + 0.16˚C drop v. 0.42 + 0.11˚C, p = 0.001). By day 5 of treatment, those with treated with combined therapy had significant larger decreased in white cell count (p < 0.0001), absolute granulocytes (p = 0.0001), and alpha₁ anti-trypsin levels (p = 0.05 as a marker of inflammation). Absolute neutrophil count and platelet count did not differ by treatment group. No serious adverse effects of IVIg were experienced.

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