Results Summary
What was the research about?
Kawasaki disease is a rare childhood illness that inflames blood vessels. Symptoms include high fever; rash; and swollen tongue, hands, and feet. The disease can sometimes cause a dangerous bulge, called an aneurysm, in the blood vessels that supply the heart.
Most children recover from Kawasaki disease after treatment with intravenous immunoglobulin, or IVIG. But in 10 to 20 percent of children, fever persists or returns, which doctors call resistant Kawasaki disease. These children have a high risk of aneurysm.
In this study, the research team looked at the safety and effectiveness of two treatments for children with resistant Kawasaki disease:
- A second dose of IVIG
- A medicine called infliximab
What were the results?
Infliximab was safe and effective for children with resistant Kawasaki disease. Compared with children who received a second dose of IVIG, children who received infliximab:
- Were less likely to have fever after treatment.
- Had shorter hospital stays.
- Had fewer side effects and serious adverse events such as anemia. The research team defined a serious adverse event as one that resulted in a hospital stay, disability, or even death.
The two treatments didn’t differ in:
- Heart scores that measure if a child has an aneurysm.
- Lab tests that measure inflammation.
Who was in the study?
The study included 103 children ages 4 weeks to 17 years with resistant Kawasaki disease. All received care at one of 30 health centers across the United States. Among children, 58 percent were White, 18 percent were Black or African American, 11 percent were Asian, 8 percent were more than one race, and less than 4 percent were unknown or other races. The average age was 2, and 57 percent were boys.
What did the research team do?
The research team assigned children by chance to receive either a second dose of IVIG or infliximab. All children had received a first dose of IVIG and had a fever that persisted or returned within 36 hours. Children who still had a fever seven days later took the other treatment.
Parents completed surveys about their child’s symptoms four times on the first day of treatment and then once daily for two weeks. Children had an echocardiogram when they started the study and two weeks after leaving the hospital. An echocardiogram uses sound waves to take pictures of the heart.
People who had Kawasaki disease as children, and parents of children with Kawasaki disease, gave input on the study.
What were the limits of the study?
Doctors across health centers may have interpreted echocardiogram results differently. Also, the study didn’t enroll children who already had aneurysms from Kawasaki disease. Results may differ for these patients.
Future research could look at the best dose of infliximab for children with resistant Kawasaki disease. Studies could also include children with heart damage from Kawasaki disease.
How can people use the results?
Doctors and parents can use these results when considering treatment for children with resistant Kawasaki disease.
Professional Abstract
Objective
To compare the effectiveness of infliximab versus a second dose of intravenous immunoglobulin (IVIG) in resolving fever among children with IVIG-resistant Kawasaki disease.
Study Design
| Design Element | Description |
|---|---|
| Design | Randomized controlled trial |
| Population | 103 children ages 4 weeks to 17 years with IVIG-resistant Kawasaki disease, defined as having a fever that persists or returns within 36 hours after initial IVIG infusion |
| Interventions/ Comparators |
|
| Outcomes |
Primary: resolution of fever within 24 hours of treatment and no recurrence Secondary: duration of fever after treatment; reduction of inflammation as measured by change in white blood cell count, absolute neutrophil count, and C-reactive protein concentration; change in worst coronary artery z-score, defined as the highest z-score for the right coronary artery and left anterior descending coronary artery; adverse events, defined as unfavorable changes in health; serious adverse events, defined as adverse events that resulted in prolonged hospitalization, significant disability, incapacity, or death; number of hospital days posttreatment |
| Timeframe | 7-day follow-up for primary outcome |
Kawasaki disease is a rare, systemic vasculitis of unknown etiology that affects infants and children and can damage the coronary arteries. Children with Kawasaki disease have symptoms such as fever, rash, swollen hands and feet, oral mucosal changes, and swollen lymph nodes. IVIG-resistant Kawasaki disease occurs when fever persists or returns within 36 hours of receiving an initial dose of IVIG.
This randomized controlled trial compared the effectiveness of infliximab versus IVIG in resolving fever; improving coronary artery measurement that indicates risk of an aneurysm; and reducing inflammation, adverse events, and hospitalization among children with IVIG-resistant Kawasaki disease.
Researchers randomly assigned children with IVIG-resistant Kawasaki disease to receive either infliximab or a second dose of IVIG. Children whose fever did not resolve within seven days after receiving their assigned medication switched to the other study medicine.
The study included 103 children with IVIG-resistant Kawasaki disease treated at one of 30 health centers across the United States. Of these children, 58% were White, 18% were Black or African American, 11% were Asian, 8% were multiple races, and less than 4% were unknown race or other races. The average age was 2, and 57% were male.
Parents completed questionnaires about children’s symptoms four times within the first 24 hours after their children started treatment, and then recorded symptoms and temperatures once daily for two weeks. Children had an echocardiogram at baseline and two weeks after hospital discharge.
People who had Kawasaki disease as children and parents of children with Kawasaki disease provided input on the study.
Results
Compared with children who received a second dose of IVIG, children who received infliximab:
- Were more likely to achieve resolution of fever (odds ratio=3.12; 95% confidence interval: 1.36, 7.52)
- Had fewer days in the hospital after treatment (mean days=3.2 versus 4.5; p<0.001)
- Experienced fewer adverse events (45 versus 65; p=0.029) and serious adverse events (15 versus 36; p<0.001)
Median coronary artery z-scores and laboratory measures of inflammation did not differ significantly between the two treatments.
Limitations
Because the study did not use a central laboratory to read the echocardiograms, health centers may have interpreted the results differently. The study did not enroll children who already had aneurysms from Kawasaki disease at baseline. Results may differ for these patients.
Conclusions and Relevance
In this study, compared with a second dose of IVIG, infliximab was a safe and effective treatment for children with IVIG-resistant Kawasaki disease.
Future Research Needs
Future research could evaluate the optimal dose of infliximab for children with IVIG-resistant Kawasaki disease. Studies could also compare treatment options for children with heart damage from Kawasaki disease.
COVID-19-Related Study
Summary
This study received additional funding in 2020 to quickly initiate new research related to COVID-19. The additional research is in progress. PCORI will post the research findings on this page once the results are final.
A new, rare health problem that can look like Kawasaki disease has appeared in children living in communities heavily affected by COVID-19. With this enhancement, the research team will describe the clinical features and collect blood samples from children with this new health problem and compare the clinical features to Kawasaki disease.
To learn about children’s history of exposure and initial symptoms, the parents will complete a questionnaire. The study will make use of the network of Kawasaki disease research experts and clinical centers used in the original award.
Enhancement Award Amount: $199,500
Final Research Report
View this project's final research report.
Journal Citations
The KIDCARE Study compared treatment strategies for resistant Kawasaki disease. The research team assessed the effectiveness of a medicine called infliximab compared to giving a second dose of IVIG. More than 100 children who had resistant disease and received care at 30 health centers across the United States were evaluated. The team found that children who received infliximab had shorter hospital stays and experienced fewer side effects, including anemia, than those given a second dose of IVIG. This is one of few trials to evaluate therapies for a rare group of patients experiencing the already rare condition of Kawasaki disease. These study findings were published in The Lancet Child & Adolescent Health.
Results of This Project
Related Journal Citations
Peer-Review Summary
Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.
The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments.
Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:
- The reviewers asked the researchers to confirm their statements regarding the amount of missing data in the study, in particular whether each participant had seven days of follow-up outcomes for analyses. The researchers included that information in their participant flow diagram, noting that three patients did not have those outcomes available for seven days. The reviewers also commented on the substantial missing data in the secondary outcomes of symptom reporting, which the researchers acknowledged in their limitations section.
- The reviewers questioned the generalizability of the study results given the apparent exclusion of more severely affected children who would be taking steroids. The researchers noted that in some clinic sites included in this study, the standard of care for children who have had one round intravenous immunoglobulin (IVIG) and aspirin treatment and who then become febrile is immediate treatment with IVIG again. Only children in clinics that did not apply this automatic second round of IVIG were included in the study and randomized to IVIG or infliximab. The researchers acknowledged that the study recruitment might have therefore been biased toward lower-risk patients, reducing the generalizability of the results.
- Reviewers noted that fever after IVIG treatment could be a side effect of the treatment or an indication of disease activity, and asked whether the researchers were able to identify the cause of the fever. The researchers explained that fever caused by IVIG treatment usually manifests within a few hours after administration, but the outcome of fever reduction was measured 24 hours after administration. If fever persisted at that point, patients would be switched to the other treatment condition.
Conflict of Interest Disclosures
Project Information
Patient / Caregiver Partners
- Greg Chin, KD Foundation
Other Stakeholder Partners
No information provided by awardee.