The Monster Behind the Fever: Understanding Kawasaki Disease


It is mysterious that a healthy child could suddenly develop serious heart problems, but such is the case when Kawasaki Disease (KD) has taken its toll on a child’s body.

by Mandeep Bajwa | staff writer | SQ Vol. 10 (2012-2013)

When a child develops a fever, parents usually react by simply giving medicine to reduce the fever, check under the bed for monsters, and put the child to bed. Unbeknownst to the caretakers, a monster may be hiding not under the bed but in the child’s heart.

The Monster Surfaces

For Dr. Jane Burns, Director of the Kawasaki Disease Research Center at UCSD/Rady’s Children’s Hospital, this mystery of Kawasaki Disease and strong desire to help the children affected is what has always driven her forward for the 30 years she has been working with the disease.

“The eyes cannot see what the mind does not know” is a Hindu proverb that Dr. Burns uses when talking about the history of the diagnosis of KD. In the past doctors were puzzled by the symptoms that include fever coupled with swollen, hands, feet, and lymph nodes in the neck, along with bloodshot eyes, red rashes on the skin, bleeding lips, and a strawberry tongue (Figure 1). But only recently were these telltale symptoms of Kawasaki Disease outlined and the first cases diagnosed.

Figure 1. Kawasaki Disease, discovered in Japan in 1960, is a widespread inflammation of the  body’s medium-sized blood vessels that affects mainly children under the age of fi ve. The cause is unknown. But the symptoms, which also include fever, are striking.

Figure 1. Kawasaki Disease, discovered in Japan in 1960, is a widespread inflammation of the body’s medium-sized blood vessels that affects mainly children under the age of five. The cause is unknown. But the symptoms, which also include fever, are striking. 6

Dr. Burns has been working with this disease from the very beginning of its recognition in the U.S. starting as a third year resident in 1981 at the University of Colorado School of Medicine where she witnessed the heartbreaking condition firsthand. A very ill baby was flown into Denver from Wyoming to the hospital where Dr. Burns was working. The high fever and rash was unresponsive to treatment confusing the residents and doctors. An infectious disease fellow who visited the patient with Dr. Burns suspected Kawasaki Disease and this truly mesmerized her because this was now the third time she had seen patients with this curious disease. At the time, there was no cure available for the child and after 21 days in the hospital the baby died. If a KD patient is not properly managed the possibility of damage to the arteries covering the heart rises, which may cause aneurysms putting the child at risk for complications, even heart attack and death.

When Dr. Burns was able to perform an autopsy on the child she was amazed to see beaded aneurysms dotting the little heart confirming the diagnosis of Kawasaki Disease. In a heartwarming move, the family, who had had no contact with Dr. Burns until after the death of their baby, had gone around their town collecting money and brought this money handing it to her saying, “We want you to do research on Kawasaki Disease.” That is exactly what she has done along with so much more. Dr. Burns has peered into the depths of this disease working alongside historians, filmmakers, microbiologists, cardiologists, and people from many other walks of life to try to solve the mysteries of KD.

Pathogenesis and Treatment

In Japan, 1 in 150 children will contract KD and in the United States 5000 to 6000 new cases are diagnosed each year with possibly many more cases being attributed to other diseases and missed. 4 For children in the United States and Japan, KD is the leading cause of acquired heart disease in children. When a child develops KD, the coronary arteries surrounding the heart are inflamed. The endothelial lining of the arteries recruit neutrophils from the flowing blood stream which transverse the cell layer and migrate into the vessel wall. Neutrophils recruit other cells such as T cells, which cause further inflammation in the vessel wall.1 If the disease is not recognized and the child not treated, then one in four children will develop coronary artery aneurysms. The coronary artery balloons out causing a swirling of blood cells that can form a blood clot that could result in a heart attack.

DragonCover2

Writer’s Note: Thomas Wievegg is a freelance illustrator and concept artist from Sweden. When he was approached by myself and Dr. Jane Burns about using his “Dragon on The Heart” art, he generously offered to donate the piece to Saltman Quarterly. He said, “Never would I have thought that this painting I did almost two years ago would have this ‘meaning’ and end up in an article about heart disease. It’s funny how things happen sometimes.” His donation to Saltman Quarterly adds a captivating piece of art that exemplifies the true nature of Kawasaki Disease.

In order to treat the disease, administration of intravenous immunoglobulin (IVIG), which is essentially a solution of human antibodies, acts to deregulate the inflammation through poorly understand mechanisms. After treatment, if abnormal dilation of the arteries has occurred, scarring regenerates the near normal diameter of the artery.

In those who go untreated, about 25% of these children will develop aneurysms, but if the disease is recognized within the first ten days of fever, IVIG treatment can substantially reduce the risk of aneurysms to less than 5%. 1 Even if a child recovers from KD without aneurysms, there is the chance that the damage done to the arteries over time could cause scarring and impede blood flow causing a lack of nutrition and oxygen supply to the heart, termed myocardial ischemia, which can occur decades later in adulthood.2 The narrowing could also increase the risk of heart attack.2

At the Forefront of Discovery

It all started with the Polymerase Chain Reaction (PCR) that is used to amplify a specific DNA sequence and is used in some cases for pathogen discovery. Dr. Burns was able to work with some of the creators of PCR like John Sninsky and Henry Ehrlich when the technique was still new. She used this technique to attempt to discover a pathogen associated with Kawasaki Disease but the study failed to yield an answer.

Nonetheless, the use of PCR to study KD is the first example of many to showcase how Kawasaki Disease has in many cases and continues to be the first topic of molecular study to utilize a newly discovered technique thanks to Dr. Burns unyielding desire to experiment.

She calls it “science with a purpose,” and the purpose is to help the kids.

In 1996, Burns used the study of single nucleotide polymorphisms (SNP), which were only beginning to be investigated, to identify possible genetic relationships to KD. It was known that the TNF-α cytokine was elevated in patients presenting the symptoms of Kawasaki Disease. This cytokine is a chemical messenger made by the body to promote inflammation and immune cell activation, which are known to play a role in KD. This observation led to genetic studies that located polymorphisms, which are essential changes in the genetic code of the DNA, in the promoter region of the TNF-α gene, which might cause it to be over-expressed. This in turn led to a clinical study that was the first to study the effectiveness of infliximab, which is a monoclonal antibody that binds to the TNF-α cytokine and blocks its actions. It was found that infliximab successfully eliminated the fever present in the children with KD and was helpful for children who were resistant to IVIG treatment.3

A more recent study completed by researchers in Japan in collaboration with Burns at UCSD utilized sibling pairs with KD. In this study the ITPKC pathway has a mutation that is associated with immune cell activation may be of special importance in those children who are IVIG resistant and require other treatments. It was shown that in this pathway a molecule called calcinuerin is a regulator of the gene creating IL2 that acts to increase inflammation.4 If the amount of IL2 could be decreased then the inflammation in KD patients could be reduced. The UCSD group recently reported the use of Cyclosporin A, a specific inhibitor of calcinuerin, as effective therapy for resistant KD patients.4 (Figure 2)

These two studies only touch the surface of the work Dr. Burns has done. Along with her colleagues she continues to test new techniques in hopes of gaining clinical treatment options and developing a better understanding of this mysterious disease. Burns considers herself extremely lucky to have her feet in both the science lab and the treatment of children. She calls it “science with a purpose,” and the purpose is to help the kids.

The Monster that Flies with the Wind

Figure 2

Figure 2. Calcinuerin and NFAT regulate the synthesis of IL-2, which normally causes inflammation. Cyclosporin inhibits Calcinuerin and lowers production of IL-2 thereby decreasing inflammation. This entire pathway is influenced by the ITPKC pathway, which has been found to have a mutation that causes immune cell activation and inflammation. (Courtesy of Dr. Chisato Shimizu, Burns Laboratory)8


Burns teamed up with climate scientist Daniel Cayan from Scripps Institution of Oceanography at UCSD. Burns noted that there was an increase of KD incidence in the spring and summer months and a decrease in the fall and winter months. In Dr. Burns study, medical records indicated KD occurrence in Japan, Hawaii, and San Diego occur in similar peaks from November through March. 5 In Japan it was shown that KD fluctuates in a consistent pattern throughout the Japanese archipelago.4

Working with a climate team from Barcelona headed by Xavier Rodo, analysis of satellite data suggested that there are wind patterns associated with the months of KD incidence. A northwest wind pattern sweeps from central Asia and over Japan and then travels from Japan to Hawaii eventually reaching the West Coast.5 Northwest winds are associated with the winter/spring months and with a higher incidence of KD and southeast winds are associated with lower incidence (Figure 3). This suggests that a unique agent, possibly a microbe, may travel in the winds.5

Air samples were collected in the upper troposphere and they contained numerous bacterial and fungal organisms that could possibly cause KD. Although clinical samples collected from KD patients have not revealed a consistent organism, a comparison between DNA of organisms collected in air samples could be crosschecked with immune response of KD patients to point to the agent. 5 If these wind patterns are shown to carry the vector of KD transmission, it will be the first time that a human pathogen has been recognized to travel thousands of miles over an ocean without the help of man-made machine.6

Figure 4 High Res

Figure 3. Graph shows analysis of the wind vector over Japan (blue) and number of KD cases (red). The number of KD cases in Japan is slowly rising, for unknown reasons, but is strongly correlated with the average velocity of winds coming from the northwest-the direction of central Asia. 6

Looking Forward

Kawasaki Disease is a relatively unknown disease to many parents and its symptoms mirror many other common childhood conditions such as scarlet fever or viral infections. Dr. Burns is an active community educator about KD through the annual Kawasaki Disease Parent Symposium hosted each year at UCSD. This program allows parents to become aware of the telltale symptoms of the disease and also outlines the newest research and advances made in relation to Kawasaki Disease.

Dr. Burns believes this program is a way of giving back to the parents who have allowed their children to participate in various research studies, which is critical to furthering their understanding of this mysterious disease. She has also worked on documentaries about KD and the response by healthcare professionals in places such as India in hopes to further educate doctors around the world about the treatment of KD.

This mysterious affliction continues to befuddle doctors with many cases being misdiagnosed and overlooked. Dr. Burns and her colleagues research dives into the unknown and continually tries to uncover the monster hiding in the heart may it be viral, bacterial, or an environmental toxin.

Dr. Burns says she feels extremely grateful to have worked with and continue to work with some of the brightest minds in science and she continues to rope creative minds in with the mystery of KD. With all of the effort that she and some many of her colleagues devote to this disease, it seems that the light is about to uncover the monster that has evaded them for so long.

WRITTEN BY MANDEEP BAJWA. Mandeep Singh Bajwa is a Human Biology major from Earl Warren College. He will graduate in 2014.

References

  1. Newburger, J. W., M. Takahashi, M. A. Gerber, M. H. Gewitz, L. Y. Tani, J. C. Burns, S. T. Shulman, A. F. Bolger, P. Ferrieri, R. S. Baltimore, W. R. Wilson, L. M. Baddour, M. E. Levison, T. J. Pallasch, D. A. Falace, K. A. Taubert and E. Committee on Rheumatic Fever, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, A.erican Heart Association (2004). “Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association.” Pediatrics 114(6): 1708-1733.
  2. Daniels, L. B., M. S. Tjajadi, H. H. Walford, S. Jimenez-Fernandez, V. Trofimenko, D. B. Fick, H. A. Phan, P. E. Linz, K. Nayak, A. M. Kahn, J. C. Burns and J. B. Gordon (2012). “Prevalence of Kawasaki disease in young adults with suspected myocardial ischemia.” Circulation 125(20): 2447-2453.
  3. Burns, J. C., et al. “Infliximab Treatment of Intravenous Immunoglobulin-Resistant Kawasaki Disease.” J Pediatr 153.6 (2008): 833-8. Print.
  4.  Onouchi, Y., et al. “Itpkc Functional Polymorphism Associated with Kawasaki Disease Susceptibility and Formation of Coronary Artery Aneurysms.” Nat Genet 40.1 (2008): 35-42. Print.
  5. Burns, J. C., D. R. Cayan, G. Tong, E. V. Bainto, C. L. Turner, H. Shike, T. Kawasaki, Y. Nakamura, M. Yashiro and H. Yanagawa (2005). “Seasonality and temporal clustering of Kawasaki syndrome.” Epidemiology 16(2): 220-225.
  6. Frazer, Jennifer. “Infectious Disease: Blowing In The Wind.” Nature 5 Apr. 2012: 21-23. Print.
  7. Rodó, X., J. Ballester, D. Cayan, M. E. Melish, Y. Nakamura, R. Uehara and J. C. Burns (2011). “Association of Kawasaki disease with tropospheric wind patterns.” Sci Rep 1: 152.
  8. Kawasaki Disease Research Center UCSD