KD Symposium 2016 A Parent s Summary

Transcription

1 Freya's St ry Raising awareness of Kawasaki Disease KD Symposium 2016 A Parent s Summary 1

2 Contents Slide Subject 3 Introduction 4 Latest Statistics 5 A Question of Genetics 6 Genetic Susceptibility 7 What else do we know about KD? 8 Blowing in the Wind? 9 Improving Diagnosis 10 How should KD patients be followed? Kawasaki Disease into adulthood Long- term concerns/prognosis 18 Kawasaki Disease and pregnancy 19 Emerging Treatments for KD 20 Coronary Complications: Infants and Children 21 Fundraising and Awareness opportunities 2

3 Introduction The 2016 Kawasaki Disease Symposium was held in San Diego, California (US) on the 29 th October 2016, with key members of the Kawasaki Disease Research Team providing the latest updates in the world of KD. With the help of the KD Foundation, the event was streamed live across the world via Facebook, enabling thousands to benefit from the wealth of information and expertise shared at the event. The event lasted approximately 3 hours, so not all remote viewers were able to view the entire recording, and even though it continues to be available to view on the KD Foundation Facebook page, some parents may not have the luxury of time to watch and digest all of the information contained within it. I was lucky enough to be able to watch live for most of the event, and was afforded some time to sit uninterrupted to watch the recording after the event, and felt it might be useful for me to share some of the key things that I took away from the session as a parent. I hope you will find the information useful. All of the information I have included was provided by the speakers during the event, and I have replicated some of the presentation material where appropriate. The contents have been reviewed by the speakers, and permission to share has been granted by both Dr Jane Burns and Dr Adriana Tremoulet. You can watch the live recording of the event through the KD Foundation s Facebook page: Joanne McBride Mother of Freya McBride, diagnosed June

4 Latest Statistics Latest Japanese headline numbers Attack rate 302 cases per 100,000 (children <5 years of age) 14,000 new cases in Japan in 2014 Affects 1 in every 60 boys, and 1 in every 75 girls KD is more common in Japan than autism is in the US! Cases are on the increase Unlike other countries, where diagnoses increase with medical professional knowledge, in Japan it is so common that ALL medical professionals have a strong awareness of the disease and it is claimed that a diagnosis is NEVER missed As a result, increases of cases in Japan can be considered a true increase and suggests increased exposure to the (unknown) environmental agent/trigger San Diego headline numbers Population of San Diego is 3,200,000 KD attack rate is 48:100, new cases each year 1:2000 children in San Diego alone Rady Children s Hospital handle the majority of cases in Southern California and the West Coast 4

5 A Question of Genetics Evidence that KD has a genetic component Increased incidence of KD among certain ethnic/racial populations; Asian and Asian Americans In San Diego County, there is a 2.7 fold increased risk of KD for Asian people Siblings of an index KD case have a tenfold increased relative risk of KD in Japan Twofold increased likelihood of a history of KD in a parent of a child with KD (Japan) Emerging recognition of KD Pedigrees where there are multiple affected family members Key questions Why do only certain children get KD? Why do only certain KD patients get Coronary Artery Aneurysms? Studies continue to look at the DNA of patients with KD, and patients of KD with CAA. Even without treatment, only 1:4 children with KD will go onto develop coronary aneurysms Children who go onto develop CAA are considered a genetic subset of the group that are susceptible to KD What can genetics tell us? There are c.10 million variations in the genetic code that makes you different from the person standing next to you Genes work in pathways understanding those pathways can be translated to treatment in the clinic Goal is to be able to identify children at risk of CAA in the ER (A&E) to employ aggressive treatment at the offset KD is a complex genetic disease not a simple mutation of genes 5

6 Genetic Susceptibility Racial/ethnic susceptibility The Asian population is over- represented as a proportion of all KD cases worldwide African- Americans are also highly represented On the Indian sub- continent, where IVIG is not available/affordable, KD is very common. It is estimated that 0.5million children are diagnosed every year What makes these ethnic groups more susceptible to Kawasaki Disease? Why are only some children affected by KD? It is proposed that an environmental trigger can reach both a genetically susceptible host and a genetically resistant host, with different outcomes A genetically susceptible host will manifest an immunologic reaction (clinical KD) and result in a genetically defined outcome (which can be modified by treatment) A genetically resistant host will be asymptomatic and develop immunity What about siblings/twins? There has been some evidence In genetically identical twins, where one twin contracted KD, and the other did not, but where an echocardiogram showed subtle signs of heart damage in the unaffected twin. As a result, when a twin is diagnosed with KD, Rady Children s Hospital recommend that the unaffected twin undergoes an echocardiogram to look for any subtle signs of Kawasaki disease Siblings have a tenfold risk of KD So what is the latest theory? It is believed that children are born with a genetic predisposition to KD, and that those children have breathed in something that triggers the disease Researchers have moved away from the theory of an infectious trigger for the disease Some researchers are considering a type of rare virus Most likely theory is that the environmental trigger is an antigen a protein or molecule that stimulates the immune system 6

7 What else do we know about Kawasaki disease? Seasonality Although cases are diagnosed sporadically throughout the year, KD is definitely a seasonal disease Peaks in San Diego, California, are seen through the Winter months (Dec/Jan/Feb) with a spike in cases in March, and then again mid- Summer These peaks are coherent across the Northern Hemisphere, but the data is not available for the Southern Hemisphere Environmental Risks There is no way to prevent Kawasaki disease Whatever the trigger is, it is something widespread in the environment Previous theories have included chemical agents (e.g. carpet cleaner) and dietary triggers (e.g. soy consumption). There has been no scientific evidence to support a chemical link, and other theories are inconclusive There is absolutely no link between childhood vaccinations and Kawasaki disease Can a child get it more than once? KD is considered an immunising event 95% of children who get KD will never get it again This means that if the research efforts can establish the cause, and who is genetically susceptible to KD, they could develop and immunisation to prevent KD altogether The risk of getting KD more than once is racially and ethnically driven in Japan, the recurrence rate has been reported as high as 10%, in the Asian population (e.g. Philippines, Korea) the rate is reported around 5%, and in the Hispanic and White population, the recurrence rate is considerably lower at around 1% What else? An overlap with some allergies is evident there is a disproportionate population of children with KD who suffer with skin conditions such as eczema and psoriasis. However, as allergies are generally more common in the Asian population where the majority of reported cases are, it is difficult to study Prof Burns confirmed that an autoimmune disease is where antibodies are made to attack the self, or where T- cells that get confused attack the self, and this is not the case with KD. Autoimmune diseases tend to remain with the patient for life, which is also not the case with KD 7

8 Blowing in the Wind? Professor Mark Thiemens is a leading authority on aerosol chemistry. He is heading up the research that is trying to understand what it might be that is potentially carried in the wind, and breathed in by children who go on to develop Kawasaki disease. What do we know? KD appeared after World War II The source region is in North East China It appears in Japan It is airborne Peaks in early Spring and Summer There is some evidence of some association with burning there is mining in the region, as well as some bio- mass burning But we don t know what it is The science bit Professor Mark Thiemens and his team are looking at the role of particles in the atmosphere in relation to Kawasaki Disease Atmospheric sampling shows that there were changes in the air mass around 1947 sampling is being carried out in the presumed region There are a series of lakes in the area where it is believed particles in the air may have been transported sampling of these lakes is taking place to ascertain what happened before and after the first incidence of KD Particles can be biologic or non- biologic. Those particles need to be measured to understand what is in them and on them 8

9 Improving Diagnosis Adriana Tremoulet, Associate Director of the Kawasaki Disease Research Centre, gave an update on the latest initiatives designed to improve the speed and accuracy of diagnosis for Kawasaki Disease, adding that some of these initiatives may indeed support the diagnosis of other paediatric illnesses too. Why is a diagnostic test for KD important?! Early treatment reduces the risk of coronary artery abnormalities! Diagnosis of KD are still being missed Although not the strongest horse in the race, there is some research being validated with reference to a urine test that produces a chemical signature that can distinguish KD from other febrile illnesses Urine Test Biomarkers Analysis from a diagnostic test which looks at segments of the child s DNA and can discriminate between bacterial and viral infections in febrile children is exciting, but requires further research KD Diagnostic Test Artificial Intelligence linked to Electronic Medical records NLP effectively seeks KD related key words (e.g. fever, rash ) and will alert the clinician to a risk of KD, which will allow the medical professional to probe further into the child s condition, historical symptoms, etc Reduces the risk of misdiagnosis Natural Language Processing Mobile (Cell) Phone App A cell- phone application which will allow clinicians around the globe to enter background information and symptoms App designed to work out the probability of the child having KD Validation needed to determine viability, efficiency and accuracy The eye does not see what the mind does not know (Anonymous) 9

10 How should KD patients be followed? These guidelines are those utilised by Rady Children s Hospital in San Diego. The American Heart Association (AHA) have written revised guidelines, but these will not be available until Diagnosis and Initial Treatment Short- term follow- up 12 months post- diagnosis Exit Visit Diagnose and treat as soon as possible (it is a myth that you have to wait for 5+ days of fever) IVIG + aspirin Echo at baseline, whilst the child is in hospital Discharge once fever has been resolved for 24 hours Follow up days post- discharge from hospital If echo is normal and blood tests show resolving inflammation discontinue aspirin and follow up at one year Echocardiogram If first two echoes were normal return for echo and doctor visit every 5 years (this is due to some known issues with the heart muscle that have been found later in life). N.B. medical insurances may not pay for these visits as AHA guidelines do not recommend further follow- up after one year in these circumstances If echo is abnormal at any point from diagnosis, follow- up should be tailored to the individual patient Age years decision to be made about transition to adult care: Echo ECG Fasting lipid panel Blood pressure CT calcium score Reproductive counselling (due to increased risk of susceptibility in offspring) If all normal, discharge from care Resources: Online guide for KD parents and physicians can be found in various languages via this link:- The KD Foundation video, Kawasaki Disease: A Parents Guide, can be found on You Tube 10

11 Kawasaki Disease into Adulthood Dr Lori B. Daniels is an adult Cardiologist, and specialist in Kawasaki Disease. The following slides describe the protocols observed at Rady Children s Hospital in San Diego. Overview If your echocardiogram was always normal (and reliable) there have been no long- term abnormalities found, no long- term follow up is needed If you have abnormalities, or you do not know, long- term follow- up is needed for life by a cardiologist who is knowledgeable about KD vasculopathy Screening for Coronary Aneurysms Coronary angiogram contrast (a type of dye ) is injected into the arteries CT Calcium score looks at calcification and is widely used in adult cardiovascular care. A 35- year old uncle of a KD patient, who had KD himself at 1- year old and enrolled in the adult study, was told his arteries were normal. A CT calcium score was obtained, which returned a result of 851mm (this should be zero). A CT angiogram was performed, which showed a 7.1mm aneurysm and he was placed on Warfarin and Aspirin More about Calcium Scores CT Calcium score is recommended 10 years post diagnosis The adult study showed evidence of calcification in 166 individual patients who had sustained coronary artery aneurysms Tools to prevent complications Calcium CT for screening and detection of aneurysms (see above) Medical therapy to prevent clotting Stents for opening narrowing or blocked arteries, or bypass if necessary There are new bioresorbable stents which are placed in the artery but completely disappear after 3 years 11

12 Kawasaki Disease into Adulthood (continued) Follow up into adulthood, as observed by Rady Children s Hospital: No abnormalities Transient dilation Small- medium sized aneurysms in childhood Giant (>8mm)/ persistent aneurysms CT calcium score + echo If normal, reassurance and no medication Discharge from care CT calcium score + echo If normal, reassurance and no medication Discharge from care? (this needs more research to determine best practice for this patient cohort) CT calcium score if positive for calcium, CT angiogram to visualise the vessels Stress echo non invasive test to measure heart activity under stress, usually walking/running on a treadmill. If evidence for concern, invasive angiogram and possible therapeutic intervention ECG Follow with stress echo and ECG as individualised by a KD knowledgeable MD One baby aspirin (81mg) per day As for small- medium sized aneurysms with the addition of the following: Warfarin (Coumadin) or novel oral anticoagulant (NOACS) therapy (e.g. apixaban, rivaroxaban) Adult KD studies are still underway if you are a KD patient and are over 15 years of age, you can still enroll for the study adultkd@ucsd.edu for further information 12

13 Long term concerns/prognosis The information in the following slides mostly came out of the Q&A sessions at the end of the Symposium What is the long- term prognosis for giant aneurysms Require tricky management - patient should be under a specialist who has handled many cases The consultant should have a good understanding of KD, be familiar with potential complications, and know how to take care of them Children should be able to live normal, long, productive lives - medication and follow- up is vitally important 75% of children with giant CAA will require intervention in adulthood, e.g. catheter interventions or bypass Can children with aneurysms who are taking long- term aspirin still suffer a heart attack? Assuming the aneurysm is small enough not to require dual anti- platelet medication, the risk should be considered low You should ask your cardiologist how many complicated KD patients have they personally taken care of if the answer is one, you should change! Is the damage to the heart permanent? Once an aneurysm has formed, that vessel is never normal again The bulge space caused by an aneurysm fills in with scar tissue or layered blood clot that has calcified We should use the term remodel rather than normal or healed as it gives parents a false understanding The blood vessel is always abnormal, however children can live normal lives as long as they are monitored and on appropriate medication 13

14 Long term concerns/prognosis (continued) The information in the following slides mostly came out of the Q&A sessions at the end of the Symposium Does a child have KD for life? This depends on the extent of coronary artery damage as there is evidence of changes in the actual heart muscle Most kids had KD, but we should remain aware of any heart changes Echocardiogram what about the part you can t see? An echocardiogram can generally see approximately 3mm into the coronary arteries Echocardiogram in children is considered different to that in an adult and you get a good view of the arteries In children with Kawasaki disease, problems always show up in the first part of the artery you don t see issues further down the artery where there is no evidence of damage in the first section Are heart murmurs related to KD? There is no direct link between a heart murmur and KD. Some minor, common heart abnormalities are detected during echocardiogram, but there is no evidence to suggest that all abnormalities found are a direct result of Kawasaki disease. 14

15 Long term concerns/prognosis (continued) The information in the following slides mostly came out of the Q&A sessions at the end of the Symposium Any connection to cholesterol? There is no correlation between high levels of cholesterol in adulthood and patients who have had KD What about nutritional advice? Children (and adults) should be encouraged to live a heart- healthy lifestyle:limited saturated fat, no smoking, exercise, fruit and vegetables There is evidence that smoking compounds the problems related with Kawasaki disease There is no correlation between high levels of cholesterol post- KD Flu/chicken pox + aspirin Some parents are concerned about a condition called Reye s Syndrome, which has in the past been linked to children being given aspirin for the high fever typically seen with flu and/or chicken pox Reye s Syndrome is a potentially dangerous illness, however it is incredibly rare, and has only ever been connected to high doses of aspirin, and not the low anti- platelet doses administered to KD children If you are concerned, you should speak to your clinician it may be advisable to replace aspirin with another drug in some circumstances 15

16 Long term concerns/prognosis (continued) The information in the following slides mostly came out of the Q&A sessions at the end of the Symposium Why is there such variation for treatment and follow- up? The standard treatment for Kawasaki disease is intravenous immunoglobulin (IVIG) and aspirin after that there is site to site variation in treatment It is standard to perform a baseline echocardiogram, follow- up with a further echo 2-3 weeks later and then a year after diagnosis Frequency of subsequent echocardiograms is then dependent on the severity of the illness how ill the child was, what coronary artery damage is present, and if the fever is persistent and further medical therapy is needed How does IVIG work? Dr Burns enrolled the first patient onto the IVIG trial in 1984 It worked, so no- one has never really questioned why! Because it is not available in some countries, or is too expensive, it is important to figure out how it works so that it can be replaced with something more globally accessible A portion of IVIG molecule serves to boost the natural processes in the body for down- regulating/controlling inflammation there is potential to make that part of the IVIG in a laboratory to use as a more accessible alternative 16

17 Long term concerns/prognosis (continued) The information in the following slides mostly came out of the Q&A sessions at the end of the Symposium Behavioural problems post- KD There is nothing specific about KD that should lead to behavioural problems post- diagnosis It should be noted that this is a vulnerable population (generally 2 years of age) Any child suffering a severe illness and/or prolonged hospitalisation is likely to have some kind of emotional response You should get help from a counsellor, therapist or other professionals trained to help families to deal with recovery after severe illness Patients and families can suffer from post- traumatic stress disorder (PTSD) It is possible that parents focus too much on the child and over- emphasize concern for the child s future, which translates into anxiety which can pass onto the child N.B there is a small UK study that suggests a potential link between KD and behavioural problems, although the sample size is too small to be considered conclusive and further research is required. The article is entitled Behaviour sequelae following acute Kawasaki disease ( bmcpediatr.biomedcentral.com/articles/ / ) Other long- term concerns? Where there were no cardiac issues, they are not recognising any health signals from the adult KD study, or any problems in any organ system, including the cardiac system (assuming a normal echo and CT calcium score) 17

18 Kawasaki Disease and Pregnancy As the KD population ages, new information is coming to light in terms of adult-specific situations, such as pregnancy. There is a paper entitled, Pregnancy in women with a history of Kawasaki disease : management and outcomes, which both Dr Lori Daniels, and Professor Jane Burns collaborated on. Data Study carried out on 21 pregnancies in 10 post- KD women 4 of those women had coronary artery aneurysms 2 of the 21 pregnancies subsequently developed KD Recommendations during Pregnancy Management by team that includes a cardiologist and maternal- fetal medicine specialist (particularly for women who sustained CAA) Normal labour and vaginal delivery is possible, with adjustments of medication (e.g. blood thinners) Counselling regarding the genetic risk of KD in offspring Women with no aneurysms/abnormalities with a normal calcium score 10 years post- diagnosis do not need specific follow up during pregnancy 18

19 Emerging Treatments for KD Dr Adriana Tremoulet discussed the concept of z scores as a more consistent and appropriate measure of heart damage sustained. The idea being that children inevitably grow up, and as a result their arteries grow with them. Z scores normalise what is measured based on the height and weight of the child. The move towards z scores provides a universal language for assessing the risk of damage to the coronary arteries, and making appropriate decisions for medical therapy and intervention. Once diagnosed with coronary artery abnormalities, there is no treatment to stop progression of aneurysms. It is important to understand the genetics to be able to predict CAA susceptibility and more aggressively treat that population at diagnosis. Standard Treatment IVIG Resistance Atorvastatin KD Study Anikinra Study Intravenous immunoglobulin (IVIG) Aspirin IVIG reduces the risk of CAA from 25% to 5% In some cases, fever will persist after a dose of IVIG. When this happens, the risk of CAA goes up from 5% (expected after IVIG) to 15% Tumor Necrosis Factor Alpha (TNFa) is a molecule made by the body that promotes inflammation as part of the body s immune response TNFa effectively throws fuel on the fire Infliximab (or Remicade) decreases inflammation by inhibiting TNFa Infliximab was shown to reduce days of fever by 1 day and influenced a change in z score from baseline in the left anterior descending artery It is a drug tolerated in both children and infants At Rady Children s Infliximab is given to children with KD related CAA at first echo There is a study about to commence to compare the outcomes of using a second dose of IVIG versus Infliximab There is a paper published in The Lancet that covers this research: Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double- blind, placebo controlled trial The benefits of statins, a drug currently in use for treatment of other conditions are that they are anti- inflammatory, antioxidant and are known to prevent vessel damage and promote vessel healing RCH have enrolled 23 patients in this study Patients are aged between 2-17 years, with a z score of >2.5 or aneurismal coronary arteries Currently working on pharmacology data, but have finished collating safety data and determining maximum tolerated doses The body s immune cells create an emergency signal (known as IL- 1) set off by an immune response which is believed to be instrumental in CAA formation Some mouse models where a vasculitis was introduced, have shown it is possible to block the IL- 1 inflammatory protein Anikinra is a drug which blocks IL- 1 RCH have a trial underway for patients aged 8 months to 17 years of age with a z score >3 (although Anikinra is suitable from birth) Involves a subcutaneous injection daily for 2-3 weeks, which can be repeated if necessary 19

20 Coronary Complications: Infants and Children Dr Tremoulet also shared the below graphic which compares the outcomes for children less than 6 months old with older children, where treatment is given within 10 days of illness. The data shows that infants are at a remarkably higher risk of developing CAA even when treatment is provided in a timely manner. This makes the infant population a focus for developing aggressive treatments to prevent coronary involvement. <6 months, n=76 5% 13% 36% 46% >6 months, n=545 5% 19% 76% Normal CA CA Dilation Normal CA CA Dilation Aneurysm Giant Aneurysm Aneurysm Giant Aneurysm Even with proper treatment, the rate of aneurysm and giant aneurysm formation is significantly greater in the infant population 20

21 Fundraising and Awareness Opportunities Amy Weeks is the Senior Director of Philanthropy at Rady Children s Hospital Foundation she shared an update on the Macklin Foundation Challenge Grant, and gave some insight into some upcoming initiatives. Macklin Foundation Challenge Grant A grant from the Macklin Foundation will see all gifts to Rady Children s Hospital for KD research matched, dollar- for- dollar, up to $2.5million To read more about this challenge, or to make a donation: $1.5million has already been raised, so there is still $1million to go! KDF More than words Challenge Launched on the 1 st November 2016 Goal to raise $26,000 for KDF initiatives by KD Awareness Day (26 th January 2017) A global effort donate directly to the cause, or sign up as a fundraiser kawasaki- disease- foundations- more- than- words- challenge/ fundraiser/kdfmorethanwords UK Charity COSMIC Children of St Mary s Intensive Care - associated with Imperial College, London Ring- fenced funds for the KD Research Collaboration, which contribute to the MF Challenge Grant Virgin Money Giving campaign or you can send donations directly to the COSMIC offices in London, with a covering letter specifying that the money is for the Kawasaki Disease Research Fund The Chan- Zuckerberg Initiative Facebook Founder, Mark Zuckerberg, and Priscilla Chan, created the CZI on the 1 st December 2015 The initiative, among other things, has pledged $3billion dollars to rid the world of disease by the end of this century Dr Tomisaku Kawasaki has written to the CZI petitioning for consideration for funding into KD research, but had not yet received a reply at the time of publishing this presentation Although Kawasaki Disease research has not currently been selected for a CZI funding award, they have recently publicised information about the recipients which you can read more about here: With the right resources, we can solve Kawasaki disease Prof Jane Burns, KD Parent Symposium