Kawasaki Disease Has Multiple Triggers, Study Finds

by NCN Health And Science Team Posted on November 12th, 2018

Houston, Texas, USA : Researchers at University of California San Diego School of Medicine, Scripps Institution of Oceanography, and international collaborators have evidence that Kawasaki Disease (KD) does not have a single cause. By studying weather patterns and geographical distributions of patients in San Diego, the research team determined that this inflammatory disease likely has multiple environmental triggers influenced by a combination of temperature, precipitation and wind patterns. Results are published in the  online edition of Scientific Reports.

“We are seeing firsthand evidence of these weather patterns in San Diego, where eight children have recently been diagnosed with Kawasaki Disease. Recent low pressure systems in San Diego have been associated with two distinct clusters of the disease,” said Jane C. Burns, MD, pediatrician at Rady Children’s Hospital-San Diego and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine. “Our research is pointing towards an association between the large-scale environment, what’s going on with our climate on a large scale, and the occurrence of these clusters.”

Kawasaki disease is the most common acquired heart disease in children. Untreated, roughly one-quarter of children with KD develop coronary artery aneurysms—balloon-like bulges of heart vessels—that may ultimately result in heart attacks, congestive heart failure or sudden death.

Burns and her team examined 1,164 cases of KD treated at Rady Children’s Hospital over 15 years. Noticeable clusters of KD cases were often associated with distinct atmospheric patterns that are suspected to transport or concentrate agents that result in KD. Days preceding and during the KD clusters exhibited higher than average atmospheric pressure and warmer conditions in Southern California, along with a high pressure feature south of the Aleutian Islands.

“For the first time, we have evidence that there is more than one trigger for Kawasaki Disease. Up until now, scientists have been looking for one ‘thing’ that triggers KD,” said Burns. “Now we see that there are distinct clusters of the disease with different patterns suggesting varying causes.”

Gene expression analysis further revealed distinct groups of KD patients based on their gene expression pattern, and that the different groups were associated with certain clinical characteristics.

“Our data suggest that one or more environmental triggers exist, and that episodic exposures are influenced at least in part by regional weather conditions. We propose that characterization of the environmental factors that trigger KD in genetically susceptible children should focus on aerosols inhaled by patients who share common disease characteristics,” said Burns who has studied KD for more than 35 years.

Although KD is estimated to affect fewer than 6,000 children in the U.S. each year, the incidence is rising in San Diego County. While the average incidence per 100,000 children less than 5 years of age residing in San Diego County was approximately 10 for the decade of the 1990s, the estimate from 2006 to 2015 was 25.5. This increase may be attributed to the efforts of the KD team at Rady Children’s Hospital to teach local physicians how to diagnose KD. Or it may be due to increasing exposure to the environmental triggers of the disease.

Prevalence rates of KD are increasing among children in Asia. Japan has the highest incidence rate, with more than 16,000 new cases per year. One in every 60 boys and one in every 75 girls in Japan will develop KD during childhood.

Incidence rates in the U.S. are approximately 19 to 25 cases per 100,000 children under age 5—but are higher in children of Asian descent. Predictive models estimate that by 2030, 1 in every 1,600 American adults will have been affected by the disease.

In a second study researchers identified a potential diagnostic test for Kawasaki disease

Researchers identify potential diagnostic test for Kawasaki disease

For the first time, researchers at University of California San Diego School of Medicine and Imperial College London, with international collaborators, have determined that Kawasaki Disease (KD) can be accurately diagnosed on the basis of the pattern of host gene expression in whole blood. The finding could lead to a diagnostic blood test to distinguish KD from other infectious and inflammatory conditions.

Results of the international study published in JAMA Pediatrics.

Kawasaki disease is the most common acquired heart disease in children. Untreated, roughly one-quarter of children with KD develop coronary artery aneurysms—balloon-like bulges of heart vessels—that may ultimately result in heart attacks, congestive heart failure or sudden death.

“As there is no diagnostic test for Kawasaki disease, late diagnosis often results in delayed or missed treatment and an increased risk of coronary artery aneurysms,” said Jane C. Burns, MD, pediatrician at Rady Children’s Hospital-San Diego and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine. “We sought to identify a whole blood gene expression signature that distinguishes children with KD in the first week of illness.”

Researchers used a case-control approach, including children recruited in hospitals in the United Kingdom, Spain, Netherlands and U.S., with KD or similar illnesses. The majority of study participants with KD came from Rady Children’s Hospital-San Diego. The overall study group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, 242 bacterial or viral infections) and 55 healthy controls.

The researchers looked for tell-tale transcription in blood samples. Transcription is the first step in gene expression, in which information from a gene is used to construct a functional product, such as a protein.

“A 13-transcript blood gene expression signature distinguished KD from the range of infectious and inflammatory conditions with which it is often clinically confused,” said Burns. “A test incorporating the 13-transcripts might enable earlier diagnosis and treatment of KD, preventing cardiac complications and reducing inappropriate treatment in those with other diseases. Our findings represent a step toward better diagnosis based on molecular signatures rather than clinical criteria.”

Burns said there is currently no point-of-service test for KD. Engineers will have to devise a blood testing method that can be adapted to the emergency department or hospital lab setting to help bring these research findings into practice.

“We are already in discussions with a number of biotechnology companies that might help us turn our gene signature into a test,” said Michael Levin, Professor of Paediatrics & International Child Health at Imperial College. “An accurate test for KD could prevent many children worldwide from being diagnosed too late to prevent coronary artery damage. If we can develop a test based on our gene signature, this could transform diagnosis and enable early treatment of children affected by the disease.”

Prevalence rates of KD are increasing among children in Asia. Japan has the highest incidence rate, with more than 16,000 new cases per year. One in every 60 boys and one in every 75 girls in Japan will develop KD during childhood.

Incidence rates in the U.S. are lower —19 to 25 cases per 100,000 children under age 5—but it is rising, at least in San Diego County. Predictive models estimate that by 2030, 1 in every 1,600 American adults will have been affected by the disease.

Citation for second study : JAMA Pediatrics. DOI: 10.1001/jamapediatrics.2018.2293

In a third study, scientists identified a gene variant for Kawasaki disease susceptibility

Gene variant identified for Kawasaki disease susceptibility

Kawasaki disease (KD) is the most common acquired heart disease in children. Untreated, roughly one-quarter of children with KD develop coronary artery aneurysms—balloon-like bulges of heart vessels—that may ultimately result in heart attacks, congestive heart failure or sudden death.

The causative agent for KD remains unknown—a windborne pathogen is suspected—but equally mysterious is why and how some children are more susceptible. Researchers at University of California San Diego School of Medicine, with colleagues at Rady Children’s Institute for Genomic Medicine and in London and Singapore, have conducted novel whole genome sequencing of a family in which two of four children were affected by KD. They have identified plausible gene variants that predispose some children to developing the disease.

The findings were recently published in the PLOS ONE.

“This is the first successful analysis of whole genome sequence from a family that revealed a new gene implicated in KD susceptibility,” said senior author Jane C. Burns, MD, professor and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego. “The finding is intriguing because this gene, a member of the Toll-like receptor family, encodes for a protein that is expressed on the cell surface and uniquely binds to proteins outside the cell that come from fungi. This may be a clue that fungal antigens could be one environmental trigger for the disease.”

Prevalence rates of KD are increasing among children in Asia, the United States and Western Europe. In Japan, the country with the highest incidence: 306 out of every 100,000 children under the age of five, with more than 14,000 new cases annually. One in every 60 boys and one in every 75 girls in Japan will develop KD during childhood.

Incidence rates in the United States are lower—9 to 19 per 100,000 children under age 5—but rising, at least in San Diego County. Predictive models estimate that by 2030, 1 in every 1,600 American adults will have been affected by the disease.

KD has a clear genetic link. It is most common in the U.S. among persons of Asian or African descent, but its genetics is complex and researchers have struggled to identify which gene variants and combinations cause some children to develop the disease. Burns and colleagues employed analysis of whole genome sequence for the first time to examine a six-member African-American family in which two children had KD, but the parents and other siblings did not.

“Despite their apparent increased susceptibility, children of African-American descent have been excluded from previous KD genetic analysis,” the authors wrote.

Key among the tools used was whole genome sequencing, a process in which the complete DNA sequence of a person’s genome is determined at a single time. The researchers also looked at genome-wide association studies, which search for genetic variation in large populations. The goal was to find, if possible, distinct gene variants that, in combination, might indicate predisposition to and higher likelihood of developing KD.

The researchers identified a variation of the toll-like receptor 6 gene, which plays a fundamental role in the immune system, that may be linked to the pro-inflammatory state during the acute stage of KD. Previous research had not identified this gene as influencing susceptibility to KD.

In addition, another variant in a gene called tumor-associated calcium signal transducer 2, which is involved in cellular calcium signaling, was highlighted. The authors said further investigation of TACSTD2 is needed.

Burns said the study, with its analytic approach and use of whole genome sequencing, represents a new method for uncovering relevant gene variants in families affected by not just KD, but many other complex genetic diseases.

“The analysis of whole genome sequence to understand disease genetics is only recently becoming a tool that is affordable and manageable due to new developments in computer science. We are excited to be learning how to harness the power of this analysis to study our children,” Burns said.

“Our next approach will be to compare the whole genome sequence from KD patients with severe heart damage to those with no damage despite no or delayed treatment. We hope this will lead us to the genetic pathways that result in damage to the coronary arteries, which in turn will suggest new therapies to target those pathways.”

Citation for third study : Jihoon Kim et al. Whole genome sequencing of an African American family highlights toll like receptor 6 variants in Kawasaki disease susceptibility, PLOS ONE. DOI: 10.1371/journal.pone.0170977.

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