Genetic Findings May Point to Dx Test for Kawasaki Disease

VAIL, COLO. — By far the greatest need in Kawasaki disease is for a diagnostic laboratory test, and recent developments suggest that gene expression testing may be the answer.

“I don't think we're going to have a diagnostic test tomorrow, but with refinement I'm hopeful that gene expression profiling might be the basis of a diagnostic test,” Dr. Marsha Anderson said at a conference on pediatric infectious diseases sponsored by the Children's Hospital, Denver.

Patients who meet the original Kawasaki disease case definition are just the tip of the iceberg. That was acknowledged 5 years ago in the revised American Heart Association Kawasaki disease guidelines, which highlighted the diagnosis and treatment of what has come to be termed incomplete Kawasaki disease (Circulation 2004;110:2747–71).

Patients with incomplete Kawasaki disease—that is, with fewer than four of the standard criteria—are at increased risk of coronary artery complications, just like patients who meet the original diagnostic criteria, and they too respond to intravenous immunoglobulin. But the lack of a diagnostic test results in delays in diagnosis and treatment, which can have critical long-term impact.

“I suspect that once we get a diagnostic test, we're going to quadruple the number of patients. We're going to have patients we never dreamed had Kawasaki disease who turn out to have very mild forms of it,” said Dr. Anderson, a pediatric infectious disease specialist at the University of Colorado, Denver.

Strong evidence suggesting that genetic predisposition plays a role in the development of Kawasaki disease comes from Japan, where the disease incidence is 10- to 15-fold higher than in white populations. Japanese studies indicate that within 1 year after a first case occurs in a family, the incidence of Kawasaki disease in a sibling is 2.1%. And Kawasaki disease is twice as common in children whose parents had the disease.

Investigators at Stanford (Calif.) University are pursuing the genetic connection using DNA microarray technology to examine patterns of gene expression in whole blood from patients with acute and convalescent Kawasaki disease. They demonstrated that patients with Kawasaki disease had increased expression of clusters of genes that are associated with platelet and neutrophil activation, including genes coding for cell adhesion, innate immunity, and B-cell activation, whereas interferon-gamma was turned off.

They also reported that gene clusters that were turned on in Kawasaki disease were turned off in adenovirus infection, and vice versa. When blinded evaluators were asked to use a set of 38 gene transcripts to categorize 23 Kawasaki disease patients and 8 with adenovirus infections, they got the diagnosis right in 21 of 23 Kawasaki disease patients and in 7 of 8 with adenovirus (J. Infect. Dis. 2009;200:657–66). This is the most promising lead to date in the effort to develop a diagnostic test for Kawasaki disease, in Dr. Anderson's view.