“Developments in Diagnosis and Treatment of Kawasaki Disease” by Jane Newburger for OPENPediatrics

a nurse in the emergency department is assessing a toddler who has kawasaki disease
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Welcome to World Shared Practice Forum. Im Dr. Jeff Burns, Chief of Critical Care at Boston Childrens Hospital and Harvard Medical School. Were very pleased to have with us today, Dr. Jane Newburger. Dr. Newburger is the Associate Chair of Cardiology. Shes also the Executive Director of the Program for Neurodevelopmental Outcomes, and the Director of the Kawasaki Program at Boston Childrens Hospital. She is also the Commonwealth Professor of Pediatrics at Harvard Medical School. Jane, welcome. Colleagues around the world undoubtedly know you for your prolific work and investigation in Kawasakis disease. And so my first question to you is, in a way, the obvious one: What should we know about the history of Kawasaki disease? And more importantly, what should we know about the presentation of Kawasaki disease? Thanks so much, Jeff. So Kawasaki disease was described in 1967 by an ordinary Japanese pediatrician named Tomisaku Kawasaki. And at the time, he thought that the illness resolved without intervention. And remember that there was no echocardiography at the time and no effective treatment. In fact, initially, people didnt even know the coronaries were involved. And since that time, theres been a rapid increase in the incidence of Kawasaki disease. So that now, most recently in Japan, the incidence is almost 300 per 100,000 children under age 4 years. And so thats 3 per 1,000– not so different from the incidence of cyanotic or critical congenital heart disease. The diagnostic criteria that Dr. Kawasaki first wrote about are exactly the same ones that we have today– fever for five days, more than 101.3 degrees, together with four out of five clinical criteria. And those are: bilateral conjunctival injection, erythema and cracking of the lips, the tongue, and erythema of pharynx– strawberry tongue– redness of the palms, swelling or edema of the fingers and toes. And then, in the second week of the disease– usually just at about 14 days– you have peeling that begins under the fingertips and then spreads down the fingers and then begins on the toes. One of the cardinal criteria for Kawasaki disease is a polymorphous exanthem, which means a rash that can look like anything– except that it is never bullous or vesicular. And then finally, about 60% of children have an enlarged cervical lymph node. And in 2004, the American Heart Association changed– made a small modification to the epidemiologic criteria, so that you could make the diagnosis of Kawasaki disease if you had fever and four out of five clinical criteria on day four of illness, rather than day five. And then secondly, you could have fewer than four clinical criteria if you had aneurysms, or enlargement of the coronaries on echo or some other modality. The average age– using hospital administrative data– the average age at presentation in Kawasaki disease is 80% of children are less than age five years. But the other 20% are older. And there is a tail, so you can even have this, rarely, in adolescence. But no matter what age you are, boys outnumber girls somewhere between about 1.3 to 1.5 to 1. And whats interesting, thats across the age spectrum. And whats interesting about it, is that that male predominance is a little more typical for infectious diseases than autoimmune diseases. So the rash in Kawasaki disease can really look like anything– all the way from morbilliform, to erythema multiforme. The only aspect of rash that almost never happens is its not vesicular or bullous. And it tends to be accentuated in the groin, even in children not in diapers. And for boys, they tend to have a little bit of meatal irritation. The eyes in Kawasaki disease are dry, red eyes. So unlike in viral illnesses where you have soupy or exudative eyes, these are dry red eyes with whats called perilimbal sparing, meaning that the area around the iris is white. And if you have a very skilled ophthalmologist who can do a slit lamp exam in an irritable toddler– so its a skill– about 85% of children in the first week will have a little bit of anterior chamber uveitis. The lips are dry and cracked. And the tongue is a strawberry tongue, just like you see in strep. So the little tiny papillae– the so-called filiform papillae– slough and they leave a denuded red tongue with prominant fungiform papillae. The node in Kawasaki disease is virtually always unilateral, only happens in 60% of kids, and if you do an ultrasound, what you see is its really actually a clump of nodes. Its not a single node. And that suggests that maybe the etiology of the disease has a respiratory portal of entry in some kids. We often do an ultrasound– or even a CT– in children who present with a very large unilateral lymph node, because we need to distinguish between an infected node with a toxin-producing bacteria versus Kawasaki. And its almost always the first. And the kids who have this, its an initial symptom together with fever. Its much less common– by the way– in young infants. So we tend to see it more in children after the first year of life. So the hands in Kawasaki disease are densely erythematous. So the palms and the soles are erythematous. You do not have a rash, but rather just a diffusely red palm or sole. The fingers, the digits, fingers and toes are swollen. This can be hard to tell in a toddler whos pudgy. But for older kids, its very obvious. And exactly two weeks almost on the nose from the first day of fever, one begins to peel the fingers right under the nailbed. They tend to kind of slough off. And the children love to peel that skin. It doesnt hurt. Once in a while, the nail itself comes off but thats rare. Fingers always before toes. And about 95% of kids have this. There are many other softer signs of Kawasaki disease. So children tend to be really irritable. Japanese investigators have done EEGs in children, and they found that some of these kids actually have delta waves. So theyre encephalopathic. If you do a lumbar puncture, there are findings that are very typical to what you see in aseptic meningitis, creates a great deal of confusion. Because most of the children who come to us have already received antibiotics. And the specter of partially treated meningitis often is rased. Hearing loss is a symptom that about one in five children has temporary sensorineural hearing loss. And it is fortunately usually transient, but very rarely– weve had two at our hospital– you can have permanent hearing loss, almost like a Cogans syndrome-like picture. Most children have a little bit of hepatitis. Once in a while, you have somebody who comes in with transaminases of 500 or 600, causing confusion. But its again, always temporary or transient. And about 3% of children have hydrops of the gallbladder. For boys, occasionally, well have orchitis. And urethritis is also common. And then, although we wont talk a lot about myocarditis, the ejection fraction of– the left ventricular ejection fraction is depressed from its normal baseline in about 85% of patients. And some actually come in with frankly, abnormal ejection fraction. Even without coronary aneurysms? Even without coronary aneurysms. It happens before the aneurysms in the first week of the disease. It can be a mode of presentation, and some children come in with whats called Kawasaki shock syndrome, where they actually, its often warm shock. They leak from their vasculature. You can have pleural effusions and ascites. And sometimes, its combined with poor function. And it comes before there are aneurysms. But these patients have a higher likelihood of developing aneurysms than children who dont have poor function early on. Arthritis and arthralgias happen in about 1/3 of children. And most of the

time, its in the digits. But occasionally, you have somebody who has large joint arthritis. When its Kawasaki disease, the arthritis is always gone in two months. Occasionally, in the differential diagnosis, you have a patient who looks just like a Kawasaki disease, but goes on to be a juvenile rheumatoid arthritis. But we dont make that diagnosis for a very long time. One of the most frightening parts of Kawasaki disease– for the office pediatrician– is that first of all, the signs and symptoms come and go. So if you have a different pediatrician in the office every day, somebody might see the node, and somebody else might see the rash and red eyes. And then, the peeling might be seen by yet another person. The other frightening thing is that if you take all children with coronary aneurysms is– we did a four center study– the four hospitals were Boston Childrens Hospital, Lurie Childrens Hospital, which is Northwestern, Childrens Hospital of Los Angeles, and University of California in San Diego. We found that 30% of children with aneurysms never had complete criteria. So they had so-called incomplete Kawasaki disease, which means you have to have a very high level of suspicion about this illness. And if you dont think of it, the hardest job is for the office pediatrician, and thats genuine. By the time they get to the cardiologist, like me, its a pretty easy job that we have. I wonder if I could turn now and ask our colleagues around the world a question. In your response, could you first please leave your city and country location? And the question is this: Where you practice, how do you approach the assessment and treatment of the child with suspected incomplete Kawasaki disease? Were back now with Dr. Newburger. Dr. Newburger, you mentioned that the diagnostic criteria got changed in 2004– and in particular, that the diagnosis could be made a day earlier. Could you tell us what the reasoning behind that was? Absolutely. The reason that we wanted to clarify the diagnostic criteria was so that children didnt go untreated. By convention in Kawasaki disease, day one is the first day of fever. By day four, children will have had fever for the first day plus the additional three days. And we think that theres some advantage to being treated sooner, rather than later. So when you have complete Kawasaki disease on day four of illness, theres really no advantage– and possibly some disadvantage– to withholding treatment. We also wanted individuals to know that the likelihood of aneurysms is just as high in incomplete Kawasaki disease as in complete Kawasaki disease. We were worried that pediatricians might withhold IVIG to somebody with abnormal coronaries, simply because they didnt meet four criteria. So the revision was to be sure that children who needed treatment were able to receive it. And I suspect I speak for many of my colleagues around the world who are wondering, “Is there a biomarker out there?” Im sure people have been looking, but is there a biomarker to assist in this diagnosis? As youve pointed out, its such a difficult diagnosis. Its an extraordinarily important area of research thats ongoing in various laboratories. And the holy grail is that even if we cant find the etiology of Kawasaki disease, that at least we would have some array of biomarkers that would help us. But to date, we dont have that, you know, equivalent of an ANA for lupus. Now, I suppose the next question on all of our minds– and for as long as Ive known you when I was training as an intern, the question is: What causes Kawasakis? So thats the Nobel Prize that were all hoping to have. There are lots of factors that suggest that Kawasaki disease might be an infection or triggered by an infection. There seem to be seasonal peaks. So no matter where you live, when the weather gets cold, we seem to see more cases of Kawasakis. In the past, there have been focal wave-like like epidemics, both in Japan in particular, but also through the United States. The clinical features look tremendously like other infections, particularly, toxin-mediated diseases like toxic shock, either staph toxic shock or strep toxic shock. Excellent infectious disease specialists also find it very hard to distinguish from measles or atypical measles, except there are no Koplik spots. Theres a peak incidence in the toddler age range. It doesnt appear in adults, and its rare– although devastating– in the first three months of life, suggesting that maybe there is transplacental acquisition of immunity, and that by the time youre an adult, youre no longer susceptible. So all of those factors at least make one think that there must be an infectious component to it. If you go to infectious diseases meetings, people will have extremely vigorous discussions about whether there could be a bacterial super antigen that causes Kawasaki disease, or whether its a viral disease. Even stronger arguments come into play about whether theres a single trigger– for example, a single etiology– or whether there could be many different triggers that are infectious– or exposures– that then go down a final common pathway. The greatest argument that there could be a single etiologic agent comes from Anne Rowleys group. And Anne is at Lurie Childrens Hospital and has gathered post-mortem specimens from around the world of children with Kawasaki disease, and has compared those to post-mortems in children who died of other causes. And what she finds are these perinuclear intracytoplasmic inclusion bodies that look very much like viral particles. And they are much, much more likely to be present in Kawasaki disease specimens than in autopsies for other causes in children. Interestingly, by the time you are an adult, about 25% of us have these. And she is working very hard to kind of extract what these particles might be. But we dont know yet. Fascinating data thats epidemiologic comes out of a climatology literature, where wind patterns– tropospheric wind patterns from Mongolia or Asia in Japan, Hawaii, and San Diego– have shown almost superimposable patterns of the incidence of Kawasaki disease with peaks in the tropospheric wind patterns. Climatologists then were funded to fly a jet into the troposphere. And they gathered tropospheric dust– which was deep-sequenced at the Rockefeller, to see whether there was something in that that could be explanatory. So far all theyve found is Candida species. But we still think that there has to be something there. And many experts in the field believe that something in that tropospheric dust is eliciting a reaction from the innate immune system. We also know that genetics are important. You would know that that has to be true simply from the fact that theres such a racial predilection for individuals of Japanese or Korean ancestry. So no matter where you live– whether its in Hawaii, the continental US, or Japan– Japanese children have an incidence that, you know, may be as high as 300 per 100,000. If we look at data that is from the United States, where racial ethnic groups are kind of grouped, Asian and Pacific Islanders have an incidence of about 33 per 100,000, compared to African-Americans of 17 per 100,000, Hispanics 11 per 100,000, and Caucasians about 9 per 100,000 by CDC data from Holman et al. It doesnt matter where you live. So, we also know that siblings have about a tenfold relative risk of having Kawasakis, that for half the cases, theyre in the same period as the index case, same acute phase. And the other half happened later. There are some twin studies that suggest a much higher incidence in identical twins. And then finally, theres emerging recognition of Kawasaki disease in successive generations. So that in Japan currently, children who have Kawasaki disease

have parents who have about a two times relative risk of having had it when they were children. Many of us send our DNA in trios to Singapore, where theres a very big registry. We tend to send ours to Singapore via San Diego. But whats interesting is that some of the polymorphisms in these pathways suggest treatment strategies. So the calcinuerin-NFAT pathway– or ITPKC pathway– contributes both to coronary artery lesions and to the likelihood that you will get Kawasaki disease. And that suggests that maybe treatment with calcineurin inhibitors would be effective. The TGF beta polymorphisms also seem to contribute to the risk of coronary lesions, suggesting maybe treatment with statins could be helpful. And then, FC gamma receptor 2A seems to contribute to disease susceptibility, which is interesting, because gamma globulin is still our most effective agent for this illness. Dr. Newburger, thats an absolutely fascinating description of what the etiology might be. But the take-home lesson– as youve stated– is that the incident rate for these high risk populations remains the same, no matter where they may move in the world. And of course, so that now leads to the question of, how do you treat this in the acute phase? So Im going to start with the goals of the acute phase. Our first goal is to reduce the acute inflammatory response. We would like to prevent aneurysms. And then, if aneurysms are already present at the time that the child presents, we want to minimize the peak size that they reach, and also prevent blood clots or thrombosis in the coronaries. The standard therapy is Intravenous Gamma Globulin, which is given at 2 grams per kilogram. We give it over about 8 to 12 hours. Thats a slower rate than we give for ITP, for example, because these children often have impaired contractility. And its important to know that the 2 grams per kilo is about like giving four liters of normal saline. I mean, its a very big solute load. We also treat with high dose aspirin, just until the child defervesces for 48 hours. And then, we give antiplatelet doses of 3 to 5 milligrams per kilogram per day. And thats once a day. The dose of aspirin historically in the US, has been 80 milligrams per kilogram per day divided in four daily doses. In Japan, they give 30 to 50 milligrams per kilogram per day. And that really is fine. Its very important to know that aspirin has no effect on your coronary aneurysms. Its solely given as an anti-inflammatory. We know that there is a dose response effect of IVIG. So if you give anywhere up to 2 grams per kilo– in a meta-analysis done by Turei and colleagues– it was shown that you have a steady reduction in the likelihood of having aneurysms by six to eight weeks later, if you give that 2 milligram per kilogram dose. And its that dose response relationship that has led to the practice, which is very common in children who have recrudescent or recurrent fever after IVIG. So either your fever never went away, or it goes away and it comes back 36 hours after cessation or the end of that first IVIG, then we often give a second dose of IVIG at that same dose of 2 grams per kilo per day. So Jane, I have to ask this– my colleagues around the world salute you for the work that youve done in really, being the one to demonstrate that gamma globulin was an effective treatment for the coronary artery aneurysms in particular. How did you come up with gamma globulin as a biologically plausible intervention in this disorder, when its so uncertain as to whats causing it? Why did you come across gamma globulin? Well, I think chance favors the prepared mind. In Japan, there was a child with ITP who developed Kawasaki disease. And when he got his gamma globulin for ITP, his Kawasaki disease got better. And Dr. Furusho in Kyoto– and his colleagues– performed a small randomized trial. And that was actually the first randomized trial in children with Kawasaki disease, where children were assigned to gamma globulin or not. And that study suggested that there might be some efficacy. And we then formed a US multi-center group in which we had an open trial in which individuals knew if they got IVIG plus aspirin, versus aspirin alone. But the end point, which were the echocardiographic findings of coronary enlargement, were read blindly. So we followed Furoshos initial small study with an open label, but blinded endpoint trial that was performed across seven centers in the US. And then, that study– which compared IVIG plus aspirin to aspirin alone– was stopped early. Because of treatment efficacy, it became unethical to withhold IVIG. And we followed it with a comparison of two doses, 400 milligrams per kilogram per day over four days, versus 2 grams per kilogram as a single dose. And the 2 grams per kilogram was more effective in controlling fever, although it didnt make a huge difference in coronaries. And remember, its a devastating disease. And at the time, there was no real solid proof of good treatment. Lets turn now to our colleagues around the world and ask you a question. In your response, please first identify your city and country location. The question is this– how do you treat the child who continues to have fever and expanding coronary aneurysms, despite intravenous immunoglobulin therapy? Were back now with Dr. Jane Newburger, discussing Kawasaki disease. And since that time, are there any more efficacious therapies than gamma globulin for the prevention of coronary artery aneurysms? The first way that we use additional therapies is in so-called rescue therapies. So thats the child who initially got IVIG, but seems to be at high risk either because their fever doesnt go away, or because they are having expanding aneurysms. Nobody knows what the perfect therapy for that is. But the kinds of therapy that are used are corticosteroids– either on sort of a longer course of maybe three weeks of tapering steroids, or pulsed-dose corticosteroids. Individuals weve also used TNF-alpha blockers, particularly infliximab. And some studies ongoing with etanercept. Cyclosporine is a calcineurin inhibitor, for which there are limited data. But there is an ongoing very large trial in Japan, and we will have more information. A lot of data– both from genetics and also from seeing T cells– T8 cells– in segments of the vascular wall that make us think that cyclosporine could be an effective therapy. We have an ongoing study here in San Diego using an IL1 receptor antagonist– anakinra– but we dont yet have solid proof that this will be effective. In Asia, methotrexate is used. And occasionally, centers use plasmapheresis, but that is a very complicated technology that we havent used a lot in the US– especially because there are so many other agents. The other strategy– rather than waiting for fever to continue or to recrudesce– is to try to find high-risk patients right up front, and to treat them with more aggressive primary therapy. And you could either target the highest risk patients, or you could say “Im going to treat all patients like they might be high risk.” Because we know that even if you take a general population, that you will still have 5% of children develop aneurysms if they get IVIG alone. And the best study on primary adjunctive therapies the so-called RAISE trial that appeared in The Lancet. And this was a phase 3 randomized open-label blinded-enpoint study of children with severe Kawasaki disease using something called the Kobayashi score, which is a Japanese risk score. Doesnt work great in non-Japanese populations, but its wonderful in Japan. And 74 institutions took part in this. And what they did

was their standard treatment group was IVIG 2 grams per kilogram, plus aspirin at the dose of 30 milligrams per kilogram per day until fever was resolved. And then, 5 milligrams per kilogram per day. The experimental group included prednisolone. And these investigators gave 2 grams per kilogram per day IV prednisolone until the CRP was less than 0.5, then, they switched to oral at 2 milligrams per kilogram per day. They gave it three divided doses orally for five days. If the CRP was good, they tapered it to 1 milligram per kilogram per day for five days. And then, they halved it again. And what they found was really remarkable– that they had a highly statistically significant improvement in the incidence of coronary artery aneurysms any time during the study period, at four weeks, and also, patients requiring additional rescue therapy. Finally, they had a much lower incidence of a need for non-response to this therapy, requiring– having fever– or requiring additional therapy. The data were significant in terms of coronaries at a P-value of less than 0.001. Those data are remarkable. That same regimen has been used certainly, at our center. But its modified a little bit, because in Japan, theres no penalty for staying in the hospital. Whereas we try to get people out of the hospital a little bit faster. And so we use an oral regimen, rather than requiring it IV for any length of time. We also have tended to give our steroids twice a day, rather than three times a day– which is very hard for American families to, kind of, comply with. Our hope is that with multi-center registries, well have a much better sense. There isnt a US randomized study of steroids, but were hoping that well know a lot more about whether were doing well through observational registry-type data. So Dr. Newburger, I suspect my colleagues are wondering a question that Im wondering right now, which is, “How do you treat what you would call a high-risk patient? How do you approach that patient?” If we think that a child is at high risk for aneurysms, we give them standard therapy of IVIG 2 grams per kilo, the aspirin for anti-inflammatory, and we add prednisolone in the RAISE regimen of 2 milligrams per kilogram per day, divided in two doses. If they seem to be having continued enlargement of coronaries, we sometimes add cyclosporine. And for the children who are really increasing their aneurysm size at a prodigious rate, we even use cyclosporine at times. My colleague in San Diego, Jane Burns, will often choose infliximab rather than corticosteroids. And we have done this also in the past. We really do not know for sure whether infliximab or steroids are better. Its a rare disease. And again, we hope that well have data from registry analysis. And so that leads, of course, me to wonder and could you tell us– so what is the natural history of these coronary aneurysms? If you have Kawasaki disease, its possible that you will never develop any aneurysms. And that is the usual case in patients who were treated promptly, ideally, within the first seven days of fever, and even up to 10 days. Those children– by and large– dont have aneurysms, and they just never develop a significant amount of dilation. The second thing that can happen is you can start with a normal coronary and it dilates somewhat, but its transient. And that coronary goes back to normal. The third possibility is that you actually develop an aneurysm. And an aneurysm is like– can be like a bubble. It can look like a cigar. It can look like just a very, very large highway that goes all along the coronary. And what one has over time is that the shape of the aneurysm actually changes. So for individuals who have aneurysms, that aneurysm can clot completely and become occluded. And if it does, it may stay occluded. If it becomes– if it occludes completely suddenly and you dont have collateral blood vessels, then you may develop a myocardial infarction. Many times occluded coronaries actually recanalize slowly over time, particularly when they occur in the right coronary artery. For individuals who dont occlude, they can still have what we call layered mural thrombus, meaning that because theres stagnant flow along the edges of the aneurysm, you can just have layered clot. Or you can develop a process called luminal myofibroblastic proliferation. And these myofibroblasts multiply or proliferate in response to injury of the vessel. Its a kind of a stereotypic response that happens with vascular injury, only that same healing response that begins to bring the wall in and decrease the lumen size can also cause stenosis at either end of the aneurysm. So you may bring the overall dimension down, but at either edge, you can have tightness that develops. So Jane, whos at risk for these aneurysms? Interestingly, although boys are more likely than girls to have Kawasaki disease, even when you adjust for that, males are still more likely to get aneurysms. Children of a very young age– particularly less than six months– develop aneurysms. And we dont understand why this very young subset of kids is so prone to aneurysms. Older children are also more likely to have aneurysms. In part, its because often, physicians forget that you could be 8, 9, 10 or even 15 and have Kawasaki disease. So that they tend to be diagnosed a little bit late. If you have persistent fever, despite IVIG, every study has shown that thats a risk factor. Your labs at presentation that indicate that youre more inflamed are also risk factors. Children with Kawasaki disease at the time of presentation are anemic. So the average hematocrit is two standard deviations below the mean for age, actually suggests that the bone marrow gets shut off its a normocytic normochromic anemia. But the more anemic you are, the higher the risk of aneurysms. Low platelet count is a risk factor at presentation, because activated platelets stick to an activated endothelium. Lower albumin, higher band count, higher CMP, lower sodium, all the laboratory parameters of worse vasculitis have been found to be risk factors. If you have enlarged coronary arteries at baseline, theyre more likely to get bigger with time. And then, some genetic factors are likely to be at play. But I would say that we have not yet– we dont yet have a test or a chip that can tell us your genotype at-risk in the way that wed love to use for a laboratory test. And how do you treat the clotting? Well, when you have a giant aneurysm, its like blood in a test tube. I mean, its stagnant. And clotting is one of our biggest challenges in Kawasaki disease. Often, we see clots by echocardiography. And then, when we see it, we do more advanced tests– either a catheterization, or a CT scan, what you can see in this picture is a still frame of an angiogram that was done because we saw a clot in Kawasaki disease. And you can see this right coronary is chock full of clot in a completely asymptomatic patient. We also sometimes see clot just incidentally on CT scans. And if you have just enough clot to make the coronary smaller but it doesnt block anything, it might even be a good thing. Id like to turn now and ask a question to our colleagues around the world. In your response, could you first please identify your city and country location? And the question is this: In your practice, what strategies do you employ to prevent thrombosis in patients with Kawasaki disease and large or giant coronary aneurysms? Were back now with Dr. Jane Newburger. We are very vigilant with our medications about preventing

for children with small aneurysms defined as less than 4 millimeters, or a Z-score less than 5, we treat just with aspirin. For children who have large or giant aneurysms– so the definition of giant is more than 8 millimeters, and large is a Z-score, meaning body surface area-adjusted dimension, greater than 10 but less than an absolute of 8 millimeters. Children with large or giant are treated the same way, and they all get anticoagulation plus aspirin. Then, in the middle– so children who have a Z-score between 5 and 10, so theyre sort of intermediate sized aneurysms– we often treat with dual antiplatelet therapy, meaning aspirin plus clopidogrel. But there are no evidence-based data to support it, its just by consensus. Most experts in the field use it. So if we see a clot, we do very, very close surveillance. In children with giant aneurysms, we tend to echo them twice a week in the, kind of, subacute phase, until they really have been very stable. And we look for thrombosis. And unlike in adults, we actually can see clots in the coronaries. We get beautiful pictures– like in this picture– where you can see a thrombus in the left anterior descending coronary artery. And we give thrombolytic therapy, usually with TPA. And in the image that you see here, this clot has disappeared by 24 hours later. The thrombus burden for Kawasakis is way beyond what one usually sees in the ordinary adult who has a plaque rupture. I mean, this is major league thrombus. And if its very old, its much harder to dissolve. Jane, I had a parent ask me in the last month if their child who had Kawasakis is at risk for having an aneurysm. And he was astute enough to ask me, “Is he going to have a brain aneurysm?” Children with giant aneurysms can have aneurysms in other vascular beds. Most often, its brachial, subclavian, femoral. Rarely, you can get an abdominal artery like a mesenteric. Its very, very rare to get carotid or basilar aneurysms. And its unheard of to get intraparenchymal arteries. You do not get an aneurysm in the brain or inside any other organ, either. So Jane, whats the natural history of these aneurysms? How long do they last? Are they at risk for the rest of their lives? So if you take all aneurysmal segments– so all different sizes– and you say, “What happens over time?” About 1/2 to as many as 80% of aneurysmal segments will remodel to a normal internal lumen dimension. So if you take an angiogram, for example– or a CT angiogram– the artery might look normal, although the walls will be thickened. If you havent regressed to normal dimension by two years later, you usually dont have any further diminution in size. Part of that is that the walls become calcified. And you almost never have remodeling or regression of a significant degree after about two years. On the other hand, the stenosis at either end of the aneurysm can continue inexorably– so in a linear fashion over decades. And if you take large or giant aneuryms, by about 15 to 20 years later, at least one study has estimated that you may have as much as 95% stenosis at either end of the aneurysm. For small aneurysms, thats very uncommon. And for medium ones– particularly medium ones that regress to normal– if you do an intravascular ultrasound youll see that the wall is very thickened. And you still can get stenosis at either end. So if its more than 6 millimeters, you still can get stenotic elements. If you look at the survival, the worst case group are the giant aneurysms. And most studies have suggested that your survival 20 years out to 30 years out is about 88% to 90%, which means that we lose 10% of those children. Although almost certainly– since you have to go back that many years, almost certainly, we would do better today. Fortunately, we have all kinds of therapies that we can give now. And so we know that we can do both bypass operations, and stents, and transcatheter procedures. So whereas the survival of the child might be 90%, the cardiac event-free survival of children with giant aneurysms is more like 36%, if you take all children. Those who have aneurysms only on one side versus giant aneurysms both in the right and left system do better. So youre better off with disease only in one side. But we have lots and lots of therapies that we offer children today. And I think those therapies are only going to get better with time. Dr. Newburger, that is a terrific explanation of the natural history. And of course, it leads to the concern: Do these children present with ischemic heart disease, and if so, how do you recognize it in a child? Its very difficult in young children. If you look at myocardial infarctions in general– as shown in a survey in Japan done by Dr. Kato– about 40% of the time, the diagnosis is not made at the time of the myocardial infarction. Its discovered incidentally. Its not surprising, because babies dont talk, they cry a lot. I even had a child who was thought to have a left ear infection, even was clutching his left ear. And the pediatrician gave him antibiotics, even though the ear looked normal. So its a very difficult diagnosis to make. Young children tend to vomit, maybe be a little bit pale, and cry a lot. Older children will complain of chest pain. Most of the risk of myocardial infarction happens in the two years after diagnosis. And after that point– although there is a continuing risk– its a much, much lower risk. The highest risk of myocardial infarction is in those first three months after aneurysms, when youre still very hypercoagulable, and, you know, your endothelial surfaces are still extremely raw. Again, we tell patients to be vigilant. We describe to the patients themselves what signs and symptoms should cause them to go to an emergency room. And the pediatrician– in turn– should have a very low threshold for seeing children with giant aneurysms, especially– especially in that first year or two, even if theyre having vomiting and they look bad. And after that point, you can be a little more relaxed. And what happens to the children who dont have this high-risk profile, giant aneurysms? What is their outcome? So for children who never have aneurysms, who never had dilation, the outlook is very, very bright. We do not find any difference in their standardized mortality ratio from normal children in Japan. Moreover, a study in adults with Kawasaki disease– done by Andy Khan– looked at calcium scores in adults, and found that there was no coronary artery calcification in individuals who never had aneurysms, even when they were into adulthood. And calcification of the coronaries is a very sensitive test for coronary damage. So we believe that those children– as they grow up– really, at best we can tell now, should be very, very normal. For the children in between– those between large or giant aneurysms and no aneurysms– we believe that they should have lifelong care. They should always have a friend whos a cardiologist. And exactly how we tailor the follow-up depends on how severe the coronary aneurysms were. But they may have an additional risk through their lifetime of having premature coronary disease. Well, Dr. Jane Newburger, this has been an absolutely fascinating overview of Kawasakis disease. And I know I speak for my colleagues around the world when I say, thank you for your contribution in helping us at least have a treatment for Kawasaki disease. And thank you for sharing with us today your knowledge. Thank you very much. Its been a pleasure.

Cardiac Critical Care, Kawasaki Disease, Tomisaku Kawasaki, IVIG, AHA, World Shared Practice Forum, Japan
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