Predicting the aneurysm risk for kids with Kawasaki disease

When Olivia Nelson was 3 years old, her parents noticed that she had a fever that wouldn’t get better. They brought her to a nearby hospital, where she spent about two weeks being screened for diseases.

As doctors tried to find a diagnosis, a lymph node on Olivia’s neck became swollen. Alarmed and wanting an answer, the Nelsons asked to transfer to Seattle Children’s. “It was very frustrating,” said Olivia’s father, Trevor Nelson. “She was in the hospital for two weeks in and out, and they still couldn’t figure out what was happening.” Soon after the family arrived at the hospital, Olivia was diagnosed with Kawasaki disease, a serious inflammatory condition affecting the eyes, lips, hands and coronary arteries, also known as mucocutaneous lymph node syndrome (MCLS). The disease affects about 7,000 children in the U.S. each year. Though the family was relieved to have a correct diagnosis, they learned Olivia had developed coronary aneurysms, the enlargement of her coronary arteries due to the persistent inflammation.

portrait of michael portman
Dr. Michael Portman, a cardiologist in Seattle Children’s Kawasaki Research Clinic and researcher at Seattle Children’s Research Institute.
Source: Seattle Children's

A new study funded by the National Institutes of Health (NIH) could improve the quality of life for children with Kawasaki disease at risk of developing coronary artery aneurysms like Olivia did. Dr. Michael Portman, a cardiologist at Seattle Children’s Heart Center Kawasaki Disease Clinic and researcher at Seattle Children’s Research Institute, hopes to find genetic biomarkers that will predict which patients will not respond to the standard treatment and thus have a higher risk of developing coronary artery problems. “Olivia will have lifelong issues related to her heart and coronary arteries,” said Portman. “It’s a shame that a 9-year-old has severe heart disease that might have been prevented had we had ways to quickly diagnose and treat her disease effectively.”

The need for early predictions

In December 2018, Portman, the principal investigator at Seattle Children’s Research Institute, along with Dr. Sadeep Shrestha, the principal investigator from the University of Alabama at Birmingham, received a grant from the National Institutes of Health for nearly $3.5 million that will fund the research through 2022. 

The study includes about 800 patients, the majority of which are Seattle Children’s patients who are already enrolled in an existing bank of DNA and clinical data. Sites in Montreal and Alabama will also participate. The researchers hypothesize that new DNA sequencing technology will provide better understanding of the disease and identify biomarkers to accurately predict children’s Kawasaki disease treatment response and potential for developing coronary aneurysms. “The most exciting thing about this study is that it gives us the opportunity to look at the whole genome, including genes that have not been looked at for Kawasaki disease before,” said Portman. “We are hoping to find genes that we can rapidly screen for when a patient comes to the hospital so that we can determine if more intensive therapy is needed.”

The current treatment for Kawasaki disease is intravenous immunoglobulin (IVIG), a medicine given through an IV that can significantly reduce the risk of certain heart problems. However, approximately 20% to 25% of patients treated with IVIG have recurrent or persistent fever and inflammation. Children who don’t respond to IVIG are at especially high risk for coronary artery aneurysms. Studies have shown that children with giant aneurysms are at lifelong risk for developing coronary artery clots or narrowing and then require additional medical treatment. Doctors are currently unable to predict whether children will respond to IVIG. To remedy this, Portman and other researchers will use the wealth of DNA and clinical data along with recently updated clinical criteria to identify rare and common variants, which determine IVIG response.

Through whole genome sequencing, which involves sequencing the entire DNA of a patient, researchers will identify genetic variations that could serve as clinical biomarkers for IVIG resistance in Kawasaki disease patients. They will compare genetic variations for children resistant to the current treatment with those who respond to it – a differentiation they have been unable to make until now. The study will also account for race, an important variant in Kawasaki disease, by examining questions such as whether IVIG resistance is greater among African-Americans. Genetic information gathered to date suggests that Kawasaki disease susceptibility and treatment response strongly depends on genetic background.

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Journey to recovery

Hopefully, through our research, we can identify patients at risk for aneurysms earlier and use more intensive therapy upfront in these patients to better treat their disease

Michael Portman

Following her diagnosis, Olivia’s condition improved, and her fever went away after blood transfusions and two rounds of IVIG. However, Olivia still has giant coronary aneurysms and will need blood-thinning medications for the rest of her life. “From there, it was just a long road to recovery, making sure she had her anticoagulant, aspirin and her asthma medications,” said Nelson. “After the diagnosis and the IVIG, she had lost about 40 percent of her hair and probably 15 pounds. It was a journey.” Today, Olivia can’t participate in activities like gym class, but she likes to ride her bike, write stories and create art. When she grows up, she wants to be a scientist.

Motivated by a desire to help not only Olivia, but other children with Kawasaki disease, the Nelsons enrolled in their first clinical trial that Portman was leading when Olivia was 3. “We signed up for a study because even if we ended up getting a placebo or if the actual drug didn’t help, it’s going to help somebody else in the long run,” said Nelson. “We decided it was the best thing to do, because we want Olivia to get the most out of life. There’s not even a hesitation when it comes to participating in research. As much as Dr. Portman has helped us, it’s the least we can do to help him.”

Now, Olivia is in a trial for a newer anti-coagulation drug that is working well for her. “With the current drug, she has almost no bruising and can eat whatever she wants,” said Nelson. Olivia’s DNA will also be analyzed as part of the NIH-funded study that Portman is working on to develop biomarkers for children who might develop aneurysms. “Olivia is an important subject for the study, because not many children have the aneurysms and the DNA for each patient with an aneurysm is very precious,” said Portman. “Hopefully, through our research, we can identify patients at risk for aneurysms earlier and use more intensive therapy upfront in these patients to better treat their disease. Olivia’s participation will definitely benefit children in the future.”

Source: Seattle Children’s Research Institute


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