2020 UCSD KD Parent Symposium (Virtual Event) Q&A Session
Watch the annual Kawasaki Disease Parent Symposium hosted by the University of California San Diego, Kawasaki Disease Research Center via the link below, or scroll down to read the transcribed questions and answers asked during the Q&A sessions.
KD Parent Symposium 2020 – Transcript
Part 1 of Q & A
What about vaccinations and Kawasaki Disease? Any evidence for or against routine vaccines and their relationship to Kawasaki Disease? But more importantly, if there’s a COVID vaccine in 3-4 months, are we all okay with that vaccine in children?
There’s been no association between a vaccine and Kawasaki Disease. To clear things up, after you receive IVIG, there is a wait period for the development of live viral vaccines (e.g. the MMR and the varicella vaccines took 11 months to develop). As for the COVID-19, the current vaccine trials are only in adults, but hopefully there will eventually be pediatric trials. As a pediatric infectious disease physician, I have strong faith in the safety studies that are done here in the United States. I have 10- and 13-year-old daughters, and when it comes time for children to be vaccinated, I will just say, as a parent, that I will be there in line once the safety studies come out.
Recently, in the news, there’s some evidence that your blood type might be protective against acquiring COVID and I think also evidence that it might be protective against severe disease, and that’s blood type O. Could blood type O have any relationship to Kawasaki Disease? Could blood type affect susceptibility to Kawasaki Disease?
We’re actually studying that, and we began learning about the blood types of our patients. The IVIG preparations that we use now have a high titer of antibodies against one of the blood groups (blood group A). So, if your child is blood group A and received IVIG, it would mean that they are being given antibodies that attack their own red cells, and so, as physicians, we will observe a drop in their hemoglobin. In other words, we’re creating anemia in the patient. Luckily, they will recover from that. Nonetheless, it is unfortunate, but it comes with the preparation there’s nothing we can do about it – it is something somewhat new in the last several years, because a change in manufacturing has created this problem. Because of that, we started looking at blood types and now we’re continuing to look at the blood type of our mis-C patients and our KD patients to see if there is any relationship between IVIG resistance, aneurysms or any other outcomes in mis-C. Right now it’s just too early to tell anything for sure, and we need fairly large numbers to be able to do the statistics to have a robust data set.
Why do some children get KD and others don’t? Why does one twin get the disease and not the other twin?
Siblings share 50% of their genes (50% of their genes are identical, 50% are completely different) and so they are not clones of one another – they are not identical and even twins can be fraternal (meaning they’re really just siblings that were born and incubated at same time). Thus, it stands to reason that if you have a disease that has complex genetics (meaning that a portion of the genetics signature came from mom, a portion came from dad) and you make a new human being, you roll the genetic dice, and some children may have ended up with the full pattern which made them susceptible to the triggers of KD, which caused them to develop it eventually. It can happen that children in a family who were not alive at the time that the first child had their disease could be born with the same complex genetic pattern – this happens, although fairly rarely, and if the child is exposed to the same trigger factors, they can also develop Kawasaki Disease.
To do genetic studies to unravel a disease like KD, we’ve needed very big cohorts of patients, particularly to study the following: “Is there a genetic component to aneurysms or not?” Because aneurysms are only a small proportion, we’ve needed very large cohorts, and this really emphasizes how important international collaboration is; any one hospital would be unlikely to have had big enough numbers, but by pooling the patients from the US, from the UK, and from the rest of Europe, we’ve created a big enough group of patients to do proper genetics studies. Currently, the results of a very large and carefully done genetics study which shows that there is a very strong genetic component in who gets KD and who doesn’t. This has already been seen in previous studies, but we’ve added to it and have hopes of publishing these results in the press soon. In particular, we’ve identified that there are some genes that control who gets aneurysms or not, and this new finding will point us to new aspects of the biology to try and understand the mechanism. We hope to have these findings come out in the journals soon, because this huge collection of patients with KD and controls that we’ve used for the study is a wonderful resource for further work because we’ve only just begun to do the initial analyses and there’s going to be more coming out of the study. In conclusion, I think there’s a very strong genetic component when it comes to the development of aneurysms as well as the disease itself. But as aforementioned, it’s not all genetic – there’s also the role that an external agent, which is yet to be identified, plays in triggering KD.
Are children who had Kawasaki Disease more or less susceptible to COVID-19? And if they develop COVID-19, do you worry that they could have further heart damage for any reason from COVID if they already had some heart damage from Kawasaki Disease?
We had a meeting with our colleagues in Japan and learned of a child there who had had KD and then got typical COVID-19 disease. Even though this was a child, they developed that adult type of the disease. Mis-C has not been seen in Japan, Korea or Taiwan because of the genetic component to it– it’s not the right genetics for it. That child did not have an unusually severe disease, and right now we have no reason to think that children who have had KD have any different response to the virus than typical children.
How effective is steroid therapy as adjunct to standard treatment in terms of preventing or reducing the degree of aneurysm formation?
Steroids are used as a rescue therapy and are used for children with coronary artery aneurysms at many centers. Many of you that are families of ours (that we’ve cared for) know that we employ other anti-inflammatories instead of steroids. Nonetheless, we are currently working with the Boston Children’s Group who use steroids for children with coronary artery aneurysms to design a trial that would help us answer the question of which treatment combination is the best for treating children with coronary artery aneurysms due to Kawasaki Disease. Every center does what they are accustomed to, and our goal is to actually have a randomized study nationwide that will answer the question of whether getting steroids versus infliximab vs something else is the better answer.
UK trials on steroids:
Currently, there is a trial being performed across Europe which will compare immunoglobulin alone with immunoglobulin and steroids given right up front at the same time as the primary treatment. The idea is to check whether or not there will be a better outcome when steroids are given not as rescue therapy, but exactly at the same time as the primary treatment. There’s been a lot of debate about the design of the trial, but I think it’s now being accepted and already a large number of sites have started enrolling and the trial is going to be evolving over the next year.
KD Parent Symposium: Q&A Session 2
Is a calcium score needed for a child who had minimal heart involvement? What about an unexplained heart attack, could it have been KD?
Dr. Gordon: We use calcium scoring to determine if there has been damage to the artery resulting in aneurysms. There are several patients who had Kawasaki disease in their childhood, and we do not really know how they are doing. They were told they were fine; they are just not sure. A normal calcium score is 0. What we found is that if a child has aneurysms that are persisting, 10 years after that event there will be significant calcium in the arteries. So, it is a very inexpensive safe screening test. We have identified patients who have coronary aneurysms who were not on therapy, who should be on therapy. That is how we tend to use it. If you have aneurysms, if that is known, we do not need to do a calcium score because we already know there is an aneurysm.
Calcium in the arteries does not mean you have had a heart attack; we mostly use it as a screening test. If we did an echo test of the heart, we would look for wall motion abnormalities. If part of the heart does not squeeze properly then there has been some damage and that probably reflects a heart attack from childhood.
What is the general follow-up for a child who appears to have no residual or had no concurrent heart involvement at the time of their first disease versus a child who clearly had coronary artery involvement?
Dr. Gordon: What they do at Rady’s is take care of these children and then they become adults and its not right to go back and be with the little people. There really are two groups, and so the group that had no aneurysm, never had a problem, a-okay from the beginning, they are a-okay going forward. Sometimes we will recommend a calcium score, which totally seals the deal that everything is okay. So, there is that group which does not need, once we kind of reestablished that everything is fine, does not need a follow up and at the other extreme, children with persistent, large aneurysms need to have regular follow-ups, 6 months, 12-month follow-up, needs to on as an adult I think one of the direct oral anticoagulants and statins such as atorvastatin Lipitor, they need to have stress echoes periodically. Then there are children who have moderate aneurysms that persist. Ivan is an example of a patient who has kind of lost a follow-up for social, medical reasons and life happens to these children, and Dr Burgess, extraordinarily good at keeping track of people, but even she is not perfect. So I think there are really two groups, and there is a transition to adult care that we need to establish firmly that you are in one camp or another, are you the normal one who’s going to be fine or do we have reasons for concern and the calcium test, this is one of the major findings of the San Diego collaborative KD studies, we established that after 10 years we can find calcium that reflects aneurysms that need to be cared for, and that is a way if we don’t know the answer to the question of which group you’re in, that is a good way of helping to distinguish. What do you think Dr. Burns?
Dr. Burns: I was a co-author of the 2017 guidelines along with a large group of people, and in those guidelines, they recommend no follow-up beyond one year for patients who have had always normal echoes. That is not our practice in San Diego, we just feel as though working with these families for a more extended period helps us provide education, counselling, and reassurance to monitor every five years, to see that things are okay but that is not a national practice and we have no data to say that our way is better than anyone else’s way so there are the guidelines and then there is what we do. Mike do you want to comment on what the follow-up is for always normal echo patients in the UK?
Prof. Levin: Jane I think very similar to yours; the cardiologists view has been that if the echo has never abnormal, is completely normal, at follow-up they can be discharged from treatment, we have often taken the view that they should be followed for longer, particularly recognizing that the quality of echo in being confident that you have excluded problems is reliant on who did it and how careful they were and what the age of the child was. We have certainly had patients who have had echoes done by one set of cardiologists that missed things, so we tended to follow our patients like youth for longer also because there is a learning and education component to it.
Dr. Gordon: I just want to reinforce what I said about the calcium score, it is really very difficult to have 100 percent confidence in things that you did not do or did not see and don’t really know, and the beauty of the calcium score is its inexpensive, it is very low radiation, and it takes a few minutes to do and it just settles the question. So, something to consider.
Dr. Tremoulet: And to close on this topic, I just wanted to add for our patients that are out there, as your kids grow up, we just ask that you share your child’s Kawasaki story with your child so that your kids understand what happened to them. Many of our kids are 10 months or 5 years old, they do not remember any of this but we want to empower our patients and our children to understand their own medical history so they can take control of their own medical care.
Dr. Burns: I should also mention that Dr. Tremoulet and Dr. Gordon and an extended group of people are working on a document for the American Heart Association that will give some concrete guidance about how we prepare children who have important aneurysms, who require adult cardiology follow-up, howe we prepare them for that transition. That’s something that we’ve certainly experience where we’ve had patients with important medical problems, with aneurysms but this is a rough age, you are a 18 year old guy who feels great, and is not on any education, you’re sure that you don’t need any follow-up or even if you’re on medication, you decide that you don’t need those medications, and unfortunately that’s what happens, and so we’ve lost a lot of our patients through that transition period where they just don’t follow up, and of course health insurance issues and its complicated in this country.
Prof. Levin: Jane, I don’t know if its better, but the UK, as you know, has taken a line of preparing guidance on transition from children to adulthood, you and John were very helpful in contributing to that guidance and because the NHS does have joined up care, it is now mandated that children should be followed until they reach the age of being passed to adult cardiologists and there should be a formal transition with all the information and history being passe don to an adult unit that then becomes responsible and I think this has been a big step forward in providing joined up care between children and adults on a long-term basis.
Do you think there will be more sensitive methods of detecting sub-clinical damage beyond an ultrasound and a calcium score? Will there be other methods in the future or are these methods sufficient?
Dr. Burns: Well, if I can jump in, we had one publication and some papers under review by trainees in our program and visiting scholars from Japan who have worked with Cesaro Shimizu in our group to look at biomarkers, these are proteins in the blood that can give a signal about scar formation and ongoing inflammation. I think with larger studies and larger numbers of patients evaluated using these protein biomarkers, we can in fact bring some molecular data to the imaging that we currently use. So, I think there will certainly be more sophisticated ways, the PET scan that Dr. Gordon showed is a fabulous technology but its tons of radiation, and its not something that would ever be undertaken, or should be undertaken, on a routine basis for our patients, to look visually for inflammation. It works very well for that purpose, but its just too much radiation. So, I think that ass engineering improves, that kind of imaging where we can see, physically see, inflammation but with a lower radiation cost will be an advancement that will coming down the pike, but it is not here yet.
When is a good time to tell your child he had KD? He is currently two and has three large aneurysms.
Dr. Tremoulet: So, we formally discuss the transition of care to understand, if children know what they have, starting at the age of 12. With patients with aneurysms, we are seeing them much more frequently, so I think it is important as you take your child to the local Kawasaki clinic/cardiology group to discuss why your child is there at the age appropriate. And so, for a two, three, five-year-old, we are going to the heart doctor today, to check you with a disease called Kawasaki disease. As they get to be a little bit older, at school age, we bring in a heart model, show kids what their heart looks like and where there were issues. When they get to be about 12, we pull out a sheet that describes exactly how they presented, and we share pictures and ask the family if they have pictures from when their child was diagnosed and do you want to share those today in the office. So, we try to keep it age appropriate, and what we are trying to avoid is that someone go through, finish at 18, and does not even know what Kawasaki disease. So, I think it is never too early just to say we are going to the heart doctor to check out your heart for Kawasaki disease and go from there.
Dr. Burns: That is right but there is the other extreme where we make children into fragile children and I think that is really to be avoided. So, I think good information, but not overanxious care is a fine line for a parent. Obviously, children who have aneurysms, who are anticoagulant medication, who have some restrictions about participation in sports because of the anticoagulation medication largely, you want to encourage as normal a lifestyle possible given the limitations of the medications and perhaps their heart functions. But we really want to avoid making them into fragile children.
Ivan Montano: My personal experience, I can tell that I was 5-7 years old and I was taking this baby aspiring every night, and I just knew I had something that was making me take that baby aspirin, but I could not really understand what Kawasaki was then until I became a young adult at the age of 16-17 that I was starting to understand what Kawasaki was and what was the reason of me taking this medication. I believe it is about how often you go to the doctor; it is about who is your doctor that is explaining this problem to you. It depends on the kid and depends on the doctor in my personal experience. It is on you, the patient, as well to want to understand this disease.
How can fish oil therapy be used with respect to Kawasaki Disease?
Dr. Gordon: There is no data or scientific evidence for or against the use of fish oil, there is evidence in adult cardiovascular literature that fish oil is or can be a good thing for vascular health. I don’t recommend it but I think that it is probably likely to help, there are highly prepared versions of it that have been studied formally in adults, for example Vasipa is the trade name of one of these, that is effective in preventing heart attacks in adults with coronary artery disease. This is an area for future study, it probably has something to do with inhibiting inflammation. We have got several candidates that we use in say, our diabetic adults who have serious vascular diseases, with respect to Kawasaki we are hampered by the fact that the numbers are very small, it is difficult to do clinical trials that actually answer a question like this. In adult cardiology and coronary disease, we have an abundance of patients and a lot of money involved so we do the studies. And then it’s like with direct oral anticoagulants, there was no evidence that we should be using them but it was logical based on our adult experience that this was just a much better way to anticoagulated our patients and we have taken a leap of faith in my practice and it works. I can’t prove it other than my anecdotal experience so fish oil would be an approach that could be studied.
Why don’t we check for aneurysms in extremities?
Dr. Gordon: I do not know that we have seen aneurysms in the extremities if we don’t see them in the heart. They are much less frequent; I think it would be testing that is just not necessary. So, we start with the heart, this is where we see the aneurysms. I have not heard of a patient who had an aneurysm, an axillary or arm aneurysm or a femoral aneurysm, who did not have giant aneurysms in the heart. We do not go there because it’s really not necessary.
Could children with a history of KD be more susceptible to COVID or to MIS-C if they got COVID?
Prof. Levin: With the numbers of children in high burden countries who have now COVID coming up to round about 20 percent of childhood population, you would have expected that if there was going to be a signal that children with Kawasaki had either worse COVID or a reactivation, we would have seen it by now. Because COVID has been common in the child population in Italy, Spain, UK, New York for long enough, and it’s been an issue where there has been a lot of heightened parental anxiety and medical anxiety, I think we would know if there was going to be a signal that children with Kawasaki were more at risk either of bad COVID or of COVID-provoking Kawasaki, so I think not.
Dr. Burns: I absolutely agree with Prof. Levin that we haven’t seen a signal yet. I also think that if we ponder the likely scenario that both MIS-C and Kawasaki have a complex genetic substrate. So, these diseases are relatively rare in the population and they usually only occur in only one child within a kinship, although we do have siblings and relatives affected in complex degrees. But in general, I think it’s going to turn out, and of course we don’t have any hard genetic data about MIS-C yet, but I suspect that it’s going to be a complex genetic disease that creates susceptibility, and that SARS-COV-2 was the trigger just like for Kawasaki patients, they have complex genetics, and they have some other trigger, not SARS-COV-2, that triggers Kawasaki Disease. And here in the US, the study funded by the NIH, which is just getting launched, in which we will be participating here in San Diego, called the music study, is going to be whole genome sequencing on all children with MIS-C who are enrolled in the study across 21 sites in the US and all this data will immediately be placed on a server to be publicly available. If there is anything good can come out of this pandemic, the idea that large-scale data sharing that is funded by our government needs to happen and data cannot be siload or kept private for one’s own career, publications, etc. and it needs to be widely shared and rapidly shared. I think professor Levin brought this up before, that this has been the nature of our collaboration, but that is not always the rule but that will be happening in the United States and of course, Mike’s team and my team are excited to work on these rapidly growing databases of genetic sequence data form MIS-C patients and do the comparisons that Mike’s team is perfectly poised to do because of all the genetic work that we’ve done collaboratively on Kawasaki disease and now we’ll really be able to compare the two disease at the genetic level.
MIS-C in Europe and Asia
Prof. Levin: I think as far as the European populations, there is a striking excess of African American people suffering from MIS-C and also South Indian, although this is less strong. And this is in contrast to the general Kawasaki epidemiology. Clearly it could have a number of different reasons other than ethnic and genetic because the African origin population also is more disadvantaged socially and economically in many of the UK cities and in Europe so there could be issues of crowding and overexposure. We don’t yet know if it is genetics related to ethnicity or increased incidence related to social circumstance. But it is a big clue and it is different from Kawasaki Disease and its seen across from European data from Italy, France, Spain, that in all those countries.
Dr. Burns: The USA data mirrors that, but it’s also important to point out that MIS-C has not been seen in Japan, Korea, and Taiwan where we have close working relationships. Now China I can’t speak to because I don’t know, but in the countries where we work closely with people really involved in pediatric infectious disease and Kawasaki Disease, they have not seen the case despite the fact that there is Kawasaki Disease.
Dr. Tremoulet: Latin America has been sorely hit by COVID-19 and MIS-C. We are just launching now a study to collect data on these patients with Dr. Yao and Dr. Ivankovich who are helping me to lead to really understand MIS-C since Latinos around the globe, children of Latin descent, have really been affected by MIS-C. So that speaks once again to genetic predisposition and we hope that and know that Latin America will teach us a lot about what’s happening worldwide and predispositions.
Does anyone observe BCG activation at the site of original inoculation in MIS-C patients?
Dr. Levin: I can only comment from the UK side and say that we haven’t seen it, and BCG has an interesting history in the UK because it used to be given universally in children at adolescent, then at birth, then depending at ethnic background. So people who came from high risk ethnicities particularly Asia, the Indian subcontinent, and Africa were offered it at birth. So there are a lot of children have recently had BCG within the past year in the Kawasaki age group, but they’re very few that have recently had a BCG in the MIS-C age group and we have not seen BCG reactivation and that may because simply because it’s so long they would have had their BCG vaccination.
Dr. Tremoulet: Our KD families outside of the US will know that it’s a sign of the BCG area of the vaccine can reactivate and can be one of the signs that clinicians use to diagnose Kawasaki Disease acutely in children. We’re actually going to prospectively collecting these data in our Latin American cohort but so far it doesn’t appear that the BCG reactivation happens with MIS-C as it happens in Kawasaki Disease.
As we are seeing an increase in the US broadly of COVID-19 and presumably will see more children as well, can you comment as Kawasaki experts, are you having trouble telling the two conditions apart or not?
Dr. Levin: I can have a guess but not a certainty. I think the thing that has the clearest help has been age and the children who’ve come in largely with MIS-C have tended to be older children and teenagers and not the typical under 5 with KD. Having said that we have children from older groups who look just like KD and who look pretty much indistinguishable from the older children with KD that we do see from time to time. Antibody testing has become more widely available and more accurate and virtually all our patients are not antibody positive but not all of them. Having said that by the 2nd wave that we’re experiencing 20% of the childhood population is antibody positive so by next year it’s not going to be terribly useful to find antibody positive. So antibody testing is not going to be of great help in pointing you to definitely being KD or not. So at the moment its age the very high shock is unusually for KD but there is an overlap and I think we are hopeful that when we’ve got data on gene expression we will find that there’s a different signature for MIS-C than for typical KD that may help us make a test that distinguishes the 2. So I think that will certainly be the hope that the molecular testing that will be better than we are clinically.
Dr. Burns: So the group at Imperial and the group at USCD have submitted a grant together and if the NIH is listening please fund us because I think we’re uniquely posed to try to get at his answer and to use the molecular techniques both of our group share great skill with as well as collaborating with other science groups looking at the T cell epitopes looking at the more sophisticated antibody measurements. There will ultimately be a molecular diagnosis but yesterday I admitted two patients to the hospital one of whom I’m sure has MIS-C but was antibody negative and had clinical features of KD and the other patient had 5/5 clinical criteria for KD but was 10 and antibody positive. When the antibody testing is there at this point in time it’s useful but we have also been doing serial antibody testing on MIS-C patients who come back to clinic and the antibody – and it could be the problem with the sensitivity, but the antibodies have no longer been measurable 3 months after the disease. So I don’t know how confusing it will be and the waning of the antibodies after natural infection is a little bit of a concern for this future success of a vaccine.
Does anyone have any concern about the vaccine and the child’s response to the vaccine being a hyper inflammatory response in some subset of genetically predisposed hyperreactive children to produce a MIS-C type of illness?
Dr. Levin: It’s a difficult question because we are all desperately need of a vaccine but our current guess to what MIS-C is that is it a disease in some way related to a different antibody or T cell response to the COVID-19 virus. And if a small proportion of children perhaps genetically predisposed can respond differently to the virus when they see it, there is a chance that they may respond differently to the vaccine which contain proteins from the virus. And I think this concern, I hope I’m wrong, it really is the reason that good research has to be done to tease out the reason for Mis-C because a vaccine may do the same thing. It’s a real worry and we shouldn’t shy away that there is a possibility and we need to do the research before we give the vaccine to huger numbers of children.
Dr. Burns: I will also bring up the specter of adult MIS-C and I don’t know if this is something making the round so much in the UK but certainly in the US there is a number of publications and if you think about this condition as a genetic predisposition that you are born with and Sars-Cov-2 happens to be your trigger, one could imagine you could be at any age and have never seen Sars-Cov-2 before and now you see it and you’re the genetically unfortunate person who is going to respond with a MIS-C type reaction. But the safety of the vaccine will be established for national trials that are going to be very highly scrutinized and we certainly want it to be safe.
And adults will be the group that is studied first right before the vaccine is given to children, for lots of reasons including the fact that children have much milder disease and aren’t as high risk as adults. So I think we have some time to figure all this out.
Her question is her kid was diagnosed with KD at 10 months. He was diagnosed with coronary ecstasia. Her question is children with this problem, what kind of life cares s should be taken and what cardiovascular recommendations would you recommend.
Dr. Tremoulet: Our current recommendation and the American heart association is lifelong followup in the majority of cases. So if your children has had coronary artery aneurysms they need to be followed until they reach adult age and proper transition to an adult cardiologists.
CT calcium score and when it is appropriate
Dr. Tremoulet: Our adult study demonstrates that children need to have had at least a decade pass so we are doing CT calcium in children with coronary artery issues or if we’re not sure what your KD follow-up has been, we are recommending CT calcium score in late teenage years before they leave our care. As Dr. Gordon pointed out, for children who have been followed well and no long-term coronary artery damage you don’t need long term followup but if you do we recommend long term followup.
What’s the update on the blowing in the wind research.
Dr. Burns: So I’m sorry out climate team is not participating in this year’s symposium but they’ll be back next year I promise. So I think the most important thing that we’ve achieved this year is the final analysis and not publication although in preprint form of a paper, an analysis for the data here in SD followed up with an analysis of data from 9 different locations including New Zealand, Japan, Washington DC, Denver, etc. The conclusion of our data from our climate team who uses statistical techniques that are not common in biomedical science, they have analyzed clustering of cases and what I will call sub-phenotypes meaning detailed characteristics of the patients because in our database of over 100 KD patients we’ve recorded all the different aspects of initial clinical presentation and those parents will know that some of the children came in with a big lymph node, some had peeling of fingertips or toes in convalescent phase when you came back to the clinic, and some didn’t have that and in the same vein with lab data with children with liver enzymes and some children who had very high inflammatory markers and those who didn’t. So there is a statistical analysis showing that clusters of people with similar characteristics happen and the conclusion from that is there are different triggers that expose a group of children who have particular genetic susceptibility so there’s shared genetics across all children who get KD and then there are probably some very specific features in genetic background that cause you and cluster of children living in your same town to all react to exposure that happens, ex. Coronavirus, fungus body part, these are questions that are unanswered and Levin’s group at Imperial is doing some amazing work with throat swabs from all of our patients that we’ve sent to London and of course from our own patients where where they’re looking at the sequence of all living things and subtracting for the human but they’re looking at the foreign sequences, the nucleic acid that’s in the mouth and if we take those group of patients and cluster them we may be on the verge of some really important insights.