Michael Portman

Michael Portman

How has our understanding of Kawasaki disease etiology changed?

Dr. Michael Portman, director, Pediatric Cardiovascular Research, Seattle Children’s: Kawasaki disease (KD) is considered a systemic autoinflammatory disease and vasculitis that shows specific predilection for the coronary arteries, resulting in dilation or aneurysm formation. Many KD experts believe that the autoinflammatory response is triggered by environmental factors in genetically susceptible children. Over the past decade numerous genetic loci and polymorphisms have been identified as influencing KD susceptibility and treatment response. For instance, studies performed at Seattle Children’s Research Institute have highlighted the importance of polymorphisms for genes encoding Fcγ receptors, which regulate immune cell responses. The specific environmental factors have not been clearly identified but may be related to a common antigen carried by certain bacteria or viruses.

Is KD mainly an Asian disease?

Dr. Portman: KD is designated a “rare” or “orphan” disease by the National Institutes of Health and the Food and Drug Administration. The KD incidence is difficult to determine because of sporadic reporting by states, but probably between 5,000 and 7,000 cases per year occur in the United States. KD awareness by medical care providers seems to be improving through educational and media initiatives and is likely responsible in part for the increasing number of cases in the United States over the past decades. In Japan, where KD is endemic and reporting has been more consistent, the annual incidence has reached near 280 cases per 100,000 children. The incidence in the multiethnic U.S. population is much lower, estimated at 20 per 100,000. However, Seattle Children’s treats approximately 50 new cases per year, and only one-third are Asian descendants. Accordingly, suspicion should be high in all children with persistent fever and clinical symptoms suggestive of KD, regardless of their race and ethnicity.

What progress has been made over the past 10 years in diagnosing and treating KD?

Dr. Portman: The KD diagnosis remains challenging, with no total confirmation unless a patient exhibits coronary dilation or aneurysm on echocardiogram. The American Heart Association (AHA) released a scientific statement addressing diagnosis and treatment in 2017 after a 13-year gap in publication. However, many of the recommendations are based on relatively low grades of medical evidence. The recommendations included an algorithm for diagnosis based on clinical and laboratory findings, which have been incorporated into the Seattle Children’s KD clinical standard work pathway. The guidelines also described refined echocardiogram parameters and focused on the use of standardized z-scores, which account for a child’s body surface area as opposed to absolute measurements.

Progress in treatment of acute KD has been slow. Timely treatment with high-dose intravenous immunoglobulin (IVIG) and aspirin, supported by clinical trial data obtained in the 1980s, remains the standard. Though usually safe, some patients exhibit hypotension during the infusion. IVIG can also induce a severe hemolytic anemia, sometimes necessitating blood transfusion in already ill patients. Recent trials in Japan support the addition of a prolonged course of methyl-prednisolone in select patients who do not exhibit early coronary artery dilation. Patient selection in those trials depended on assignment by risk scores, which have been proven to have no value in non-Japanese KD populations. Early steroid use has not been shown as beneficial in North American trials. Nor has safety been clearly established for steroid use in patients with early coronary dilation.

Two randomized clinical trials have evaluated tumor necrosis factor alpha (TNF-α) antagonists as adjunctive treatment during acute KD. In the one trial, infliximab showed no clinically significant benefit other than impact on inflammatory parameters. In a multicenter study originating and directed from Seattle Children’s, etanercept, while safe, improved coronary outcome, particularly in those patients with early dilation. Those results were published in Pediatrics by the society journal for the American Academy of Pediatrics. Accordingly, Seattle Children’s cardiologists have committed to performing echocardiograms as early as possible in those presenting with KD signs and symptoms in order to determine patient candidacy for etanercept.

What is refractory KD and how do we treat it?

Dr. Portman: Patients with persistent or recurrent fever after 36 hours of completing their IVIG infusion are termed IVIG refractory or resistant. Fever can reappear up to several days after completing initial treatment, sometimes requiring readmission. These patients generally also show persistently elevated or resurging C-reactive protein levels and are at higher risk for coronary artery dilation than responsive KD patients.

No clinical trials have established definitive efficacy for any rescue treatment. The therapeutic approach to retreatment varies according to center, and the AHA statement suggests several options that show inconsistent responses in very small clinical trials. These include second-dose IVIG, variable steroid treatment options, and infliximab.

Seattle Children’s has traditionally used a second IVIG infusion, which has worked here in repressing fever in most of the refractory patients. The need for further treatment beyond the second IVIG dose is rare. Recent nationwide shortages of IVIG may force us to use the other options.

Seattle Children’s participates in the current ongoing multicenter randomized KIDCARE clinical trial, a study comparing efficacy for a second-dose IVIG versus infliximab for patients requiring rescue therapy for refractoriness.

What is the outcome for patients with KD?

Dr. Portman: Although most children with KD fully recover with no permanent sequelae, a subset develop persistent coronary artery dilation or aneurysms. Seattle Children’s data show that approximately 7% of patients treated within AHA guidelines still have persistent coronary artery aneurysms, while a somewhat larger percentage show milder forms of coronary vasculitis. These children require close follow-up by cardiologists, and their lives are significantly affected by the disease. Those with large or giant aneurysms require lifelong anticoagulation to prevent coronary thrombosis. Walls of the coronaries can thicken over time, causing stenosis or obliteration, possibly leading to myocardial infarction. These patients eventually need interventions on their coronary arteries such as angioplasty, stent placement, bypass surgery, or in the extreme, cardiac transplant.

Why is Seattle Children’s a lead institution for Kawasaki disease treatment and research?

Dr. Portman: Seattle Children’s Heart Center has established a multidisciplinary KD team and clinic, which receives referrals from across the United States and the Pacific Rim. Our team leads research in all aspects of KD. The study evaluating etanercept was primarily funded by the U.S. Food and Drug Administration. We are currently conducting clinical trials for refractory KD and testing newer antithrombotic drugs for efficacy in children with the disease. Seattle Children’s Research Institute, in partnership with the University of Alabama Birmingham, has been granted $3.5 million from the National Heart, Lung and Blood Institute (M. A. Portman, Principal Investigator) to determine genetic predictors of treatment response in KD. This study will perform whole-genome sequencing in saliva or blood samples from nearly 800 KD patients. Seattle Children’s also has active programs examining health quality of life and impact of diet on KD. Additionally, Seattle Children’s is partnering with industry to develop a much-needed biomarker for confirming KD diagnosis.

Seattle Children’s Kawasaki Disease Clinic provides effective transition to specialty cardiology clinics at the University of Washington when children reach adulthood.

Resources

McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927-e99.

Portman MA, Dahdah NS, Slee A, Olson AK, Choueiter NF, Soriano BD, et al. Etanercept With IVIg for Acute Kawasaki Disease: A Randomized Controlled Trial. Pediatrics. 2019;143(6). doi: 10.1542/peds.2018-3675

For questions or more information, email KawasakiDisease@SeattleChildrens.org.

Other specialty programs through the Heart Center include:

  • Turner Syndrome Clinic:brings together experts in cardiology, endocrinology, genetics and other specialties. About 1 in every 2,000 girls has Turner syndrome.
  • Arrhythmia Program: provides the latest technology and comprehensive treatment and evaluation to children and teens with heart rhythm problems. Seattle Children’s has three full-time pediatric electrophysiologists (heart doctors who specialize in treating heart rhythm problems in children).
  • Heart Failure Program: offers coordinated medical and surgical care for all types of heart failure, including cardiomyopathy.