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Gavin: Hello, welcome to another special episode of The Lancet Voice. I'm Gavin Cleaver. 

Jessamy: And I'm Jessamy Baganal. 

Gavin: So we're talking today about something that's got a lot of media attention recently, and that's presentation of Kawasaki like syndrome in children. Jessamy, tell us a little bit, really, about what this Kawasaki like syndrome is.

Jessamy: So Kawasaki disease is a relatively new concept that was first seen in 1961, and then A case of 50 were reported by Mr. Dr. Kawasaki in 1967. It's something that we don't really understand quite why it happens. It's an immune response to infections. And patients typically present with quite striking features.

So they have a kind of strawberry tongue, a redness of their hands and feet become a bit swollen and they get rashes on them. It's a vasculitis, so it means that there's some inflammation. in the body in some of the blood vessels. 

Gavin: How badly does it affect children generally when they do get this disease?

Jessamy: In general it's a self limiting disease and what we mean by that is that, we believe that it's immune mediated, so it's the body's immune response going in overdrive almost, producing a set of symptoms and signs that can make you quite unwell or make these children's quite unwell, but at the end, it's self resolving.

And it seems to be if we are able to treat it effectively in hospital, either with something called IV immunoglobulins or other medications that are able to alter and change the immune response a little bit, then patients generally recover and do quite well. It can cause Problems with the heart and some of those complications can be long term.

It just depends on what the course is for those specific children, really. 

Gavin: Yeah, so we talked with Dr. Lorenzo Dantiga, who's the Director of General Paediatrics at a hospital in Bergamo in Italy. He's one of the authors of the new paper in The Lancet, and of course, he's been working at a hospital in one of the worst affected regions of Italy.

Jessamy: Okay, so Lorenzo, it's great to have you with us today. Perhaps you could tell us a little bit about who you are, what your role is, and where you work. 

Lorenzo: Yes, D'Antica. I'm the director of the paediatric unit and child health at the Papa Giovanni XXIII Hospital in Italy. That is a big hospital in Lombardy, northern Italy.

And the hospital is dedicated to the care of patients and children. And we have a big pediatric unit. We look after patients with any disease. And we are also a referral center for pediatric transplantation. And in this case, we obviously concentrated in in COVID 19 pandemic. 

Jessamy: And you've published this great series with us about 10 children who presented with this sort of Kawasaki like presentation over the period of COVID 19 outbreak.

Could you tell us a little bit about what Kawasaki disease is? 

Lorenzo: Yes, Kawasaki disease is classified as a vasculitis of the medium caliber arteries. It involves very often the heart. Arteries. So the coronaries, but it presents typically with high temperature for more than five days. And a rash and some other abnormalities that are quite easily visible.

For instance, abnormalities of the hands and feet such as erythema or swelling. And also, what we call mucositis, for instance, the conjunctiva is inflamed and also the mucosa of the oral cavity is inflamed. So that's the typical presentation and it has been described in Japan in 1967. 

Jessamy: I guess from a medical school point of view, we always learn about the sort of strawberry tongue picture.

Lorenzo: Yeah that's quite nice to see, yes. There is also the strawberry tank, which is not typical only of Kapowska disease, but that's, yeah, that's a sign. 

Jessamy: And as you say, it's a relatively kind of new disease in terms of our knowledge about it and understanding, first described in 1967. How did that come about, that sort of first description?

Lorenzo: This disease, for some reason, is more common in the Far East. So it was firstly seen, actually seen in 1967, but described later. And then there were a few outbreaks in those regions. They were recorded in Japan in 1979, 1992 and 1986, but very soon all pediatricians realized that this disease is diagnosed, should be diagnosed because it's present worldwide.

Jessamy: And this sort of vasculitis, that's an inflammation essentially of the sort of veins and arteries. It tends to be self resolving, is that correct? 

Lorenzo: Yes, it does. Although if you don't manage, if you don't treat these patients appropriately, it can have more complications. It is self resolving, but if it is treated, it has less complications.

And The most important complication is the dilatation of the coronary arteries, which we call aneurysmatic dilatations that can persist through, into the adult age. And and that type of lesion can be actually a problem in adulthood. And is 

Jessamy: there a relationship then between when you treat Kawasaki's disease and whether you get these long term complications from the disease?

Lorenzo: Yes to some extent, yes, and the main treatment is quite well standardized. We actually use the American Heart Association guidelines and these involve the use of an infusion of antibodies that we call immunoglobulins and the aspirate infusion at anti inflammatory dosage and in some cases also steroids.

Jessamy: So maybe we could just talk a little bit about the case series. How did it come about? When did you first start realizing? That something unusual was happening. 

Lorenzo: Unfortunately, the Bergamo province has been affected by this virus very early on. It was actually the first area affected by the, this novel coronavirus in western countries.

Actually we, we represent a particular observatory to see the manifestations of this disease. At the beginning, we were concerned about the respiratory aspects because we knew that in adults the respiratory disease was quite tough and quite dangerous. And we were also concerned about the immunosuppressed patients because as I was saying we have many children were transplanted or on oncology treatments.

But we soon realized that all these aspects were actually not very relevant, and at some point, a little bit later, I should say, about a month after the first cases showed up, we started to see a few cases of Kawasaki disease and Dr. Verdoni, who is my colleague looking after patients with this disease and with their rheumatology disorders told me we're seeing two or three days one after the other with Kawasaki disease.

So we started focusing on that. And in actually in 20 days, we saw 10 patients. We described those 10, but I can tell you that by now they're already 20. 

Jessamy: How interesting. And this is a sort of in, in your manuscript, you say a kind of 30 fold increase on what it has been over the last five years.

Lorenzo: That's right. 

Jessamy: And in terms of our sort of understanding about what's going on here. Obviously it's a very much an evolving field and so we don't have all the answers but from your own sort of perspective and the sort of perspectives of your unit, which has now had quite, a large experience of this.

What do you think is happening? 

Lorenzo: As you can imagine, we reviewed all the past literature, both on the coronavirus the coronaviruses family and Kawasaki disease to see whether There was anything about this association in the past. So it is quite obvious to us that there is an association in these cases, but we want you also to understand whether there was anything suggesting that in the past.

We want to understand more on that. Actually, we saw that in the past the family of coronaviruses that is a very special family of viruses because they don't act directly, but they act actually triggering a very severe immune response in the host. Actually, they were involved in this disease, but some authors, some colleagues have been looking for the virus itself in patients with Kawasaki and very often the virus is already going when you look for it.

If you look at the serology, meaning the antibodies against the virus, that's probably the way to connect the two, the disease with a virus. And actually in nine sorry, 2014, a group from Japan did that and looked at serology and found that a strain of coronavirus was actually, apparently involved in some case of Kawasaki disease because many of the children with that disease were positive to the antibodies.

We believe this is a very tough strain of coronavirus. But we also want to test the hypothesis that the family of coronaviruses have been involved even in the past in this disease. 

Jessamy: Perhaps you could summarize the main findings of the study. 

Lorenzo: I think we should say that we have recorded a large number of patients presenting with the features of Kawasaki disease.

They actually all fulfilled the criteria for Kawasaki disease in a very short period of time. These patients are a little bit different or quite different from the classical type of Kawasaki disease because despite they fulfilled the criteria. They have a more severe disease, definitely. Some will be brought directly to intensive care units or to the cardiology unit because they have a very severe cardiovascular involvement.

So actually these patients can actually, can also be misdiagnosed. because then intensivists focusing on the cardiac and cardiovascular aspects might not look at other aspects that at that point are, less important. And in fact, three or four of our patients actually came directly to our intensive care.

But when we discussed those, it was clear that there were very severe cases. So I would say these are cases of severe Kawasaki disease requiring aggressive treatment. I would say most of them require adjunctive steroid treatment that occurred clearly in association with an epidemic of of the novel coronavirus.

Jessamy: And just going a bit more into the sort of presenting symptoms. They're much more sort of gastrointestinal symptoms for these patients. I know that, this is something that we're seeing in other countries now, and certainly within the NHS there was this NHS alert put out. because there was concern that some patients were presenting with, sore tummies and being misdiagnosed, potentially worked up for appendicitis when in fact, this was a calcite like presentation.

Lorenzo: Yes, in fact, even in our series, six of ten patients had some gastrointestinal signs. The coronavirus does involve the gastrointestinal tract since the receptor the ACE2 receptor is also present in the gastrointestinal tract and also in the biliary tract. So the virus has been shown to also to be present and infected the gastrointestinal tract.

So it is quite likely that the virus itself in these patients is causing some gastrointestinal problems. And that is probably the reason why. We see these symptoms quite often in these patients. So whereas in Kawasaki, the classical Kawasaki disease, they're not very common. 

Jessamy: And this differs slightly from a letter that we published yesterday, which was Tuesday, the 6th of May, that showed a group of patients in South London who were asymptomatic and didn't have any symptoms of a kind of current infection.

What was the sort of profile of the patients in this case series? 

Lorenzo: Think we have seen all the wide, the entire spectrum of manifestations of this coronavirus in our unit, because unfortunately, as I was saying, our pro province have been widely infected by this. For sure there are patients that are as completely asymptomatic.

And actually we decided early on to test all patients admitted to the, to our unit. Even if they were admitted for other reasons and we found quite I would say 10 percent of the patients were positive at the nasopharyngeal swab. So there are definitely asymptomatic patients, there are patients with some mild respiratory disease, there are newborns and infants with a more severe picture, a viral sepsis, but they also respond very well.

And now we know that there are patients presented with this Kawasaki like disease. 

Jessamy: But particularly these Kawasaki patients, their sort of profile is not one of children with a huge amount of sort of comorbidities or immunosuppressants. They are fairly average children and it's unclear why this presentation has occurred in them.

Lorenzo: In general patients having Kawasaki disease are actually normal children, very healthy children. There is obviously some susceptibility in these patients that we don't know anything about that, but we do know that just some of children that are infected by this virus, for instance, develop Kawasaki disease.

For instance, we worked out that probably in, in our province, in our experience in about a thousand children infected, probably just one. develop cover second disease. So there was some predisposition, but at the moment we don't know much about it, but it is not new because even before we were seeing cover second disease in very healthy Children.

Jessamy: And two of the patients tested negative for SARS CoV 2 serology. What's your explanation for that? 

Lorenzo: Two of ten of these patients tested negative. They were both tested after immunoglobulin infusion and one was tested the day after immunoglobulin infusion. That might be one reason, a good reason probably.

One patient might also be not related to this infection. We cannot, you know Your kind of baseline 

Jessamy: presentation of Kawasaki disease that you made. 

Lorenzo: Yeah, it might be because usually we have one or two in this period. So we cannot exclude that one patient was classical Kawasaki related to some other condition, maybe some other infection, but one particularly I'm pretty convinced that we should have tested this patient before immunoglobulins, but you have to consider that the serology testing have become available a little bit late.

After the emergence of the epidemic. So we actually tested everybody at the same time once we had a test available. 

Jessamy: What do you see as the kind of implications for our understanding of the sort of immunological processes that are going on with SARS CoV 2 or what insights can be gained from this case series?

Lorenzo: I think this case series confirms that that SARS CoV 2 is a virus not damaging directly. but to triggering a very severe immune response in the heart. That's true even in lung disease and COVID 19 disease. We have clearly seen that injury is mediated by the heart's immune response. So actually, the best treatment is is with immunomodulators and that's also why probably immunosuppressed patients for other reasons are not affected that actually might be protected.

We also published something on that because we have many patients. So this manifestation, which is clearly an immune mediated manifestation confirms that these are very special viruses that we have to concentrate on their ability to trigger a cytokine storm what we call also a macrophage activation syndrome in the host.

Jessamy: And what are the sort of next steps for research? What is it that we need to see next to broaden out and fill out our understanding of what's going on here? 

Lorenzo: In my view if you want to understand more on etiology of Kawasaki disease, we have to start looking at immune response against viruses because as I was saying most likely this disease is due to immune response to a virus, but we should look at serology, not to for instance, PCR looking at directly to the virus.

So if you want to understand about the etiology, I think that's the way forward. In terms of the epidemic, I think there are. important issues here because once we are ending the lockdown period and we have to allow persons, including the children, to go back, for instance, back to school, we have to consider the implications of this.

Of course, this remains a rare disease, but we have to be aware. That it will present more commonly. Another issue is that related you to the immunity to the virus and the vaccine in the future. So if we can develop a vaccine, probably if this is the main cause and will remain the main cause, probably we can also prevent the development of Kawasaki related to the coronavirus.

Jessamy: That's great Lorenzo, and I guess we should just finish by saying that in fact all the outcomes of all of these children were good, and they were all discharged from hospital and to be doing well. 

Lorenzo: This is an important message I would like to give because although correctly, there are being warning around.

I think it is important to say that this remains a rare disease. As I was saying, probably it affects just one in a thousand children that got infected by the virus. And secondly, although some require intensive treatment, they respond very quickly. I think it is important to consider, to use steroids at the very beginning.

And in a few days, these patients will respond to the blood pressure would get back to normal. And at the end, all these patients, at least in our experience, went back home and they're very well. They went back to being fit and very well. 

Jessamy: That's great, Lorenzo. Thank you so much. 

Gavin: Thank you. So as we always try and stress our understanding of COVID 19 is very limited.

And Jasmine, we're talking about a disease, Kawasaki's syndrome, that we really know very little about. Being caused by a disease that we really know very little about. It's we're really in a kind of mystery zone here in terms of the causes of this particular disease. 

Jessamy: Yeah, exactly. And I think the important things to stress here is that it's still very rare for children to be affected by SARS CoV 2.

Or to get any kind of severe response to COVID 19. This is something that is an emerging problem. We didn't really get much information from this. from China. And there might be, several reasons why that is. This seems to be the sort of first case series and we're looking for more information.

So the comment authors who, who wrote a nice linked comment to this, to put it in context one of them was Russell Weitweiner, who's president of the Royal College of Pediatricians and the other is Liz Whittaker. who's leading one of the sort of UK groups to try and get a larger cohort of patients to understand what's going on here.

Gavin: It's particularly interesting, I think, especially with all the talk about reopening schools, of course, which is something that's happening in phased terms in Europe at the moment. It's it's important for us to be aware of complications like this that we, that seem to arise from COVID 19 in children.

But like you said, it's really important to stress how incredibly rare this disease is, as well as children being affected really by symptoms of COVID 19. 

Jessamy: Exactly. So I think the message still is that, we should be reassured that children, for the most part, don't get severe disease. All of the children in this particular case series.

Survived and had good outcomes, but there is obviously some potential link between having the virus and later having some kind of immune mediated quite severe response to it in children and that needs a lot more untangling and a lot more information. for us to really understand what's going on there.

And I think that's something that we're seeing, we've just published a correspondence letter from a group about a small series of children in South London who have presenting symptoms that are similar to this sort of Kawasaki like presentation. And so what we're seeing are clinicians, across the world becoming alive to this situation and We'll be, I'm sure, seeing much more many more cases and many more pieces of the puzzle as we move forward.

Gavin: Yeah, absolutely. Very really fascinating, interesting piece of research. Thanks for listening to this episode of The Lancet Voice. We'll have more episodes coming soon, and you can find our whole archive, which since the outbreak of COVID 19 has covered lots of topics to do with COVID, including advice for asthmatics, for pregnant women, for the elderly, other topics including misinformation and you can find this archive wherever you usually get your podcasts.

Thanks for listening again, and see you next time. 

Jessamy: Yeah, see you next time. Thank you. Bye.