Hard to diagnose, with an unknown cause, Kawasaki disease has been puzzling doctors for 150 years. Jeremy Hsu explores what we know, and still don't know, about this troubling childhood heart condition.
A child's death from scarlet fever wouldn't have raised any eyebrows during the devastating epidemics that swept Europe and North America in the 1800s. But Samuel Gee, a highly regarded physician in England, found something very strange while cutting open the corpse of a seven-year-old boy in London in 1870. Gee's autopsy findings, preserved in a single paragraph written in 1871, recorded signs of damage called aneurysms in the coronary arteries running across the surface of the boy's heart. In the affected regions, the main blood vessels that supply blood to the heart had expanded like modelling balloons because of weakened vessel walls.
Gee described the case as follows:
"The peculiarity of the following case lies in the age of the patient. William Shrosbree, aet. 7, died in Mark on October 20, 1870, in consequence of scarlatinal dropsy with inter-current pneumonia and meningitis. The pericardium was natural. The heart natural in size, and the valves healthy. The coronary arteries were dilated into aneurysms at three places, namely, at the apex of the heart a small aneurysm the size of a pea; at the base of the right ventricle, close to the tip of the right auricular appendix, and near to the mouth of one of the coronary arteries, another aneurysm of the same size; and at the back of the heart, at the base of the ventricles, and in the sulcus between the ventricles, a third aneurysm the size of a horse bean. These aneurysms contained small recent clots, quite loose. The aorta near the valves, and the aortic cusp of the mitral valve, presented specks of atheroma."
The case presented a puzzle to Gee. He commonly studied child patients while he worked at St Bartholomew's, a London hospital founded in 1123 that's often known simply as Barts. The boy's medical history of having suffered a rash over his body would not have surprised Gee, as it was typical of scarlet fever, but heart disease in such a young child was simply baffling. Whatever the cause, it was beyond Gee's Victorian-era medical knowledge.
Unable to solve the mystery, Gee did the next best thing: preserving the boy's heart in formaldehyde and creating a medical curiosity for future generations in the process. The heart would float alone in its jar for more than 100 years before its significance was recognised -- evidence of the earliest recorded case of Kawasaki disease in the world.
Alongside rheumatic heart disease, Kawasaki disease is the leading cause of acquired heart disease in young children in high-income countries. Modern medicine can treat most patients with Kawasaki if they are diagnosed early enough.
But progress has been limited, and we still do not know what causes it. There have been many theories since the disease was first medically recognisedby Japanese physician Tomisaku Kawasaki in 1967. Some researchers have pointed to an unknown virus. Others say it's a bacterial or fungal toxin. In the 1980s, the US Centres for Disease Control and Prevention suspected carpet-cleaning chemicals. Several groups have hypothesised that the disease is the result of many different agents that can trigger an overreaction of the patient's immune system.
Nobody has a satisfactory answer.
Kawasaki disease found me as a third-grader growing up in Cleveland, Ohio. An Asian-American boy with ancestral ties to Taiwan and China, I fit the typical patient profile. In the US, children of Asian descent have the highest rates of Kawasaki disease, followed by blacks, Hispanics and whites. The disease is more common among boys than girls. But as an eight-year-old, I was somewhat older than the typical patient. Most are five or under, and the average age to have Kawasaki disease is two.
A month before I fell ill, I was watching a CNN news broadcast in awe as anti-aircraft fire lit up the night skies over Baghdad. It was the start of the US-led bombardment during Operation Desert Storm in January 1991. By the time US and coalition troops had begun their main ground assault on 24 February, I no longer cared about the war half a world away. I was caught up in my own battle.
I developed the classic symptoms within a week. On Saturday, at the start of my illness, my parents took me to the doctor's office to get a throat culture to test for a bacterial infection. It came back negative. I soon became feverish. The lymph nodes on the sides of my neck became swollen. My tongue took on a strawberry appearance and my lips grew dry and cracked. The skin on my fingers and toes began peeling. My eyes took on a reddish hue. I vomited. At one point, I felt too weak to walk upstairs to the first floor of my family home. I dropped to my hands and knees and crawled instead.
Such a cascade of symptoms helped me in one way: I was too preoccupied with my misery in the present to worry about the significance of my strange illness. Knowing better, my parents hid their anxiety from me at the time. My mum channelled her energy into tirelessly calling different paediatricians and friends in search of answers.
Five days after the start of my illness, paediatricians diagnosed me with Kawasaki disease. I was admitted to Rainbow Babies & Children's Hospital on Thursday. By that time, I was complaining of aching joints and had developed a rash on my legs and ankles. My palms and feet were red and warm to the touch.
Still, I was lucky. My physicians had dramatically boosted my chances of full recovery by diagnosing me within the first seven to ten days, a crucial window for treating Kawasaki disease. The hospital stuck an intravenous needle into my arm to deliver a single large dose of gamma globulin, a type of immunoglobulin, which contains antibodies derived from plasma from many blood donations.
This treatment has proved effective in preventing most patients from developing coronary artery aneurysms. This condition, where part of the coronary artery balloons, can lead to heart attacks and, very occasionally, premature death during childhood or adulthood. About 20 per cent of children with untreated Kawasaki disease will develop coronary artery aneurysms.
While intravenous immunoglobulin is the main treatment for Kawasaki disease, a small group of unfortunate patients don't respond to the standard treatment and remain at risk of developing coronary aneurysms. Other therapies have been tried but remain unproven: corticosteroids for intravenous immunoglobulin-resistant patients, tumour inhibitors such as etanercept or infliximab, or the immunosuppressant drug cyclosporin A.
Although aspirin is not normally given to under-16s, children with Kawasaki usually get aspirin to bring down the fever and ease joint pain. When I failed to swallow some aspirin tablets and spat them out into my cup of water, the nurse on the night shift was not amused. I ended up having to drink my medicine as a bitter dose of aspirin-flavoured water. But my health was on the mend.
By Friday, I was eating frozen sherbet and feeling much better. Troops of medical residents stopped by my hospital room to hear about my unusual disease from an attending physician. By Saturday morning, I was allowed to go home. In the following months, echocardiogram tests showed that my coronary arteries had become only slightly enlarged as a result of the illness, before returning to normal size.
I had survived my encounter with Kawasaki disease. But as I said, I was lucky. I fell ill at a time when more US physicians were recognising and diagnosing the disease, and when -- just as importantly -- they had learned, from Japanese colleagues, how to treat it.
I didn't fully appreciate the psychological impact of Kawasaki disease until I attended a parents' session at the Eleventh International Kawasaki Disease Symposium in Hawaii in early 2015. There I watched one young mother choked up with tears as she recounted her two-year-old son's recent experience of Kawasaki disease. "It's just so emotional," she said. "My husband and I just don't know anything."
Another mother asked for help because her hometown physicians had failed to diagnose her son before he developed coronary aneurysms. "I don't want to be left behind again," she said.
Greg Chin, one of the organisers of the parents' session, is President of the Kawasaki Disease Foundation. Chin helped create the foundation after his firstborn son came down with the disease in 1998. Luckily, his son recovered. But he knows first-hand the common anxieties for parents of children with Kawasaki disease.
"You're frustrated, you want answers, you're stressed and you're not getting a lot of sleep," Chin said. "All of a sudden you're told your child has Kawasaki disease. What is it? The chances you've heard of it are pretty slim."
Anxiety often grows as parents learn that it's an unknown disease with no definitive medical diagnosis and no known cause, he says. When parents are told that the disease could potentially cause heart damage in their young child, the stress level "goes through the roof".
Even if treatment proves successful, parents spend the following weeks checking the temperature of their child and wondering about the possibility of a relapse. The stressful period can stretch for months as follow-up echocardiograms check for any signs of coronary artery damage. In the rare worst cases, patients who develop coronary aneurysms may face a lifetime of uncertainty.
"It's a terrible situation in the current century of medicine when you have to tell parents you know what's wrong with their child, but you don't know the cause of the illness," said Anne Rowley, a physician specialising in paediatric infectious diseases at Northwestern University Feinberg School of Medicine and the Ann & Robert H Lurie Children's Hospital of Chicago. "We have a treatment but don't know how it works. The child could be left with lifelong heart disease. This is what modern medicine has to tell them."
The winds create a seasonal phenomenon known as Yellow sand, Asian dust, or variations thereof. Every spring, dust from the Gobi Desert in northern China and Mongolia enters the atmosphere and travels east to other parts of China, Japan and Korea. The dust sometimes picks up industrial pollution from China as it sweeps the land.
Today, Japan has the highest rate of Kawasaki disease in the world, and the numbers keep rising. The annual incidence for the last few years has been well above 200 per 100,000 children under the age of five, reaching 264.8 children per 100,000 in 2012(meaning that there were almost 14,000 cases that year). South Korea and Taiwan have the second- and third-highest rates of Kawasaki disease in the world.
The first cases outside of Japan were seen in Hawaii in the early 1970s. Today, it is the US state with the highest incidence of Kawasaki disease (about 50 cases per 100,000 children under five, compared with nearly 21 cases per 100,000 on the US mainland). But the large population of Japanese Americans living in Hawaii suffer from much higher rates of disease, similar to those seen in Japan itself.
Some researchers began wondering if the winds could be playing a role in the spread of Kawasaki disease. Xavier Rodó, a numerical ecologist and climatologist at the Catalan Institute of Climate Sciences in Spain, led the charge. He teamed up with Japanese and US colleagues to find out more.
They soon found a consistent pattern between seasonal shifts in the winds coming out of Central Asia and fluctuations in the number of Kawasaki disease cases in Japan, Hawaii and San Diego (reported in a 2011 paper). The wind patterns even showed a possible connection with year-to-year variations in cases.
The next step involved pinpointing the geographical source of whatever was being carried on the winds. To narrow the search, Rodó and colleagues looked at the daily numbers of Kawasaki disease cases within individual Japanese cities and also focused on three major epidemics that took place in 1979, 1982 and 1986. Their results, published in 2014, pointed to a region in north-east China.
Patients seemed to develop the first signs of fever within a day of being exposed to whatever might be carried on the winds -- far too short an incubation period for most known infectious agents, including viruses. "We could see that the disease could not be an infection, because there was not enough time for the disease to progress within an individual patient," Rodó explained. "It was faster than any respiratory pathogen known today."
The timeframe between exposure and illness suggests that Kawasaki disease may be an almost immediate bodily reaction, said Rodó, triggered by something like a bacterial or fungal toxin. Past studies have indicated a genetic susceptibility to Kawasaki disease within individual families and certain ethnic populations, which suggests that a person's genetics plays a role in whether they're susceptible to the toxin or not.
Rodó and his team need to expand their findings beyond Japan, Hawaii and the US west coast, but he is optimistic. They have already used aircraft to collect samples of the air above Japan, and a preliminary sweep of the samples has found as many as 11 different species of the fungus Candida, the most common cause of fungal infections in humans. The team eventually hopes to collect air and ground samples from north-east China.
If the theory is correct, China is almost certainly not the only source of any windborne agent, says Rodó. The existence of other sources would help explain the worldwide incidence of Kawasaki disease, which varies wildly from country to country. For instance, the latest figures show that South Korea has 134 cases of Kawasaki disease per 100,000 under-fives; Australia, nine; and England, eight.
Most researchers working on Kawasaki disease don't try to propose all-encompassing theories about the cause of the disease. Instead, they focus on chipping away at the smaller unknowns in different ways.
Some researchers mimic the condition in genetically modified mice to study how immune-system responses damage the arteries; others use mice to begin examining the possible role of bacteria that live inside the gut. Genetic studies of humans have also helped identify specific immune-system signals and molecules that seem to play a role in the disease. Such research typically flies under the radar of both the media and the public.
By comparison, the windborne theory has earned an occasional flurry of media attention for Kawasaki disease over the last few years. But the truth is that it's just one of several theories about the cause. Such theories continue to spark strong disagreement among Kawasaki researchers. For instance, most researchers I spoke with have adopted wait-and-see stances on the windborne theory, ranging from cautious to sceptical.
One of the more controversial ideas to come out recently is from Michael Portman, Director of Pediatric Cardiovascular Research at the Seattle Children's Hospital. In 2012, he published a studyabout how diets rich in soy might put children at greater risk of getting Kawasaki disease. It focused on how organic compounds found in soy, called isoflavones, could affect the immune system's balance and inflammatory response.
Portman's research found some association between high rates of soy consumption and high rates of Kawasaki disease in a Hawaiian population, and similar results showed up for a survey in Seattle. But when Portman presented his theory at the Kawasaki Disease Symposium in 2015, some Japanese researchers seemed disturbed by the implications for East Asian diets. Several lined up at the microphones in the aisles to give their critiques.
"I really believe that genetics is the main factor," Portman told me. "But there is interplay between genetic susceptibility and environmental factors. And I'm not saying soy is a main factor, but I do think it's an environmental factor, because they're ingesting it."
A team of researchers in Toronto, Canada, is focusing on the idea that multiple agents are responsible. According to the hypothesis, these agents, be they infectious diseases or environmental factors, may modulate the immune response to make kids more or less tolerant to triggers. Other agents might be the triggers themselves.
"I think we're at the point where we're not going to find a single cause of Kawasaki disease," said Cedric Manlhiot, Managing Director and Lead Statistician at the Cardiovascular Data Management Centre, University of Toronto. "We have all these weak signals coming from environmental studies that show this maybe or that maybe. It's all maybe."
While many researchers have given up on the idea of a virus being the main cause of Kawasaki disease, the Chicago-based physician Anne Rowley isn't one of them. She and her colleagues believe that the patterns of Kawasaki disease cases still point most strongly to an infectious agent such as a virus.
Their hunch is that the cause is some sort of respiratory virus, which infects many people when inhaled, but causes symptoms only in people with certain genetic vulnerabilities. Children may be most vulnerable because of the fact that their immune systems are still developing and they have lost protective antibodies that are passed on from their mothers during early life.
To hunt down the possible culprit, Rowley and colleagues created synthetic antibodies based on the genetic sequences of antibodies found in the inflamed arteries of children with Kawasaki disease. They then showed that the synthetic antibodies would attach themselves to tissue samples taken from the lungs of children who had died from the disease -- possible evidence that a virus had infected them through their airways.
But identifying any potential virus remains difficult, because nobody has succeeded in fully replicating the disease in animal models or in cultured tissue, which means that researchers can't just generate affected material in their labs for study. Instead, Rowley and her colleagues must manually track down cases of deaths caused by Kawasaki disease and ask for post-mortem samples. The idea of taking deeper tissue samples from living patients is out of the question, said Rowley, who wouldn't dream of putting a young child through such a procedure.
Despite the shortage of samples, Rowley's group has managed to build a collection of heart specimensfrom more than 40 patients -- some from autopsy, some from children who have received new transplanted hearts. The collection gives a sobering reality check of how extreme the consequences of Kawasaki disease can be.
In all likelihood, Kawasaki disease existed before Tomisaku Kawasaki saw his first patient in 1961. So why did it emerge as a distinct, recognisable condition only then? At the time, common diseases with similar symptoms -- such as measles -- were vanishing from the general population in Japan. Kawasaki told Shulman that this probably helped him and other Japanese physicians recognise a growing number of cases of Kawasaki disease. This process was accelerated in 1971, when Japan licensed its first measles vaccines, and in 1978, when the official immunisation programme for all young children began.
The oldest known survivors of Kawasaki disease are now in their 50s. Nobody knows exactly what, if any, effects the disease has on life expectancy, but current evidence suggest that patients can expect to live normal lives if they haven't suffered a large aneurysm. To help in the effort, as a survivor, I'm planning to participate in an adult Kawasaki disease survey being conducted at the University of California, San Diego.
There's no doubt that figuring out the cause of Kawasaki disease could help in the development of more effective treatments. But Jane Burns, Director of the Kawasaki Disease Research Center at the University of California, San Diego, believes that solving the mystery will do more than just help the thousands of patients who suffer from the disease each year. It could radically change our scientific understanding of the way that human disease can develop.
Having seen her first cases of Kawasaki disease in 1978, Burns has been studying the possible cause of the disease for the past 30 years. Most recently, she has helped chase the windborne theory. "My hunch is that it's not just going to be about the new virus or the new bacteria we didn't know about," she said. "It's going to be a new story of how disease can be created in a subset of genetically susceptible people… a story of some new paradigm for triggering the body's inflammation machinery."
Kawasaki disease remains especially challenging to study because it's a disease that affects relatively few patients. But at the 2015 symposium, there was a growing sense of international cooperation in collecting and sharing patient data on the disease. Organised registries containing such data have sprung up everywhere from North America to Europe, and a new one encompassing all of the Americas seemed to be in the process of forming as the symposium drew to a close. "We have to band together to do this science," Burns told the researchers from across the world. "This is big science -- it requires big data."
Unexpectedly, the collection of hearts in Chicago is shedding light on the life -- and death -- of one young boy who died 145 years ago. Stanford Shulman, a paediatrician at Northwestern University and the Ann and Robert H Lurie Children's Hospital in Chicago, stumbled across Samuel Gee's lone paragraph about the mysterious case of the London boy while poking through some files in the 1970s. In the early 1990s, while stopping over in London during a sabbatical, Shulman made an appointment at the Barts Pathology Museum. He enlisted the help of his wife and the Chief Registrar in Pathology at Barts to find the jar containing the boy's heart.
With the promise of receiving samples of the boy's coronary arteries, Shulman returned to Chicago. When these arrived, he took photos of the microscopic details and passed them to Jan Marc Orenstein, a pathologist at the George Washington University School of Medicine in Washington, DC. Orenstein compared images of the boy's sample with those of the hearts from the Chicago collection. Everything fitted.
"We can't conclude with 100 per cent certainty that this child had Kawasaki disease," Shulman said. "But it's extremely likely he died from it, 100 years before Dr Kawasaki's initial report of the same disease."
Half a century after Kawasaki first recognised the illness that now bears his name, much has changed. More physicians know to suspect the disease in children with telltale symptoms that don't respond to antibiotics or medicines to reduce fever. Hopefully that means more healthy survivors, such as me, and fewer young kids' organs in jars.
But the hunt continues for the ever-elusive cause of a disease that has quietly taken its toll on children's hearts and parents' minds. So too does the search for the original heart specimen, which is currently lost somewhere in the depths of the museum at Barts.
While the story of Kawasaki disease began decades ago -- when a young boy's heart was committed to a glass specimen jar filled with formaldehyde -- the ending is still being written. What more might we know by the time the heart is discovered again?
This article first appeared on Mosaic and is republished under Creative Commons licence.