Virus infections, blood clots and bleeding

Clare Taylor: 0:15

Welcome everybody to ESWI Airborne. This is the podcast of the European Scientific Working Group on Influenza, otherwise known as ESWI. This is your host, Clare Taylor, speaking, and you're in the right place for expertise on all things viral, as we hear directly from ESWI members, and these are the people who know the most about viruses, pandemics, vaccines and more. Now, regular ESWI Airborne listeners may remember today's guest, Marco Goeijenbier, from his contribution to another episode titled Spotlight on the Burden of Flu for People Living with Diabetes, and Marco was involved in that episode because of his role as chair of the influenza diabetes community, which aims at protecting people living with diabetes from influenza and other viral respiratory diseases like COVID-19. Marco, welcome back to ESWI Airborne and it's great to be talking with you here again.

Marco Goeijenbier: 1:18

Thank you very much, Clare. Thank you for the invitation and this introduction. I'm looking forward to talking to you again.

And Marco, you are a busy man. As I recall, your day-to-day work is in intensive care at Erasmus MC in Rotterdam and you also do research work in virology. And how are you today, Marco? Have you just come off a long shift in intensive care?

Well, Clare, to be honest, yeah, I did. So my intensive care clinical work moved from Erasmus to Haarlem and Hooftorp, now to the Spaarne Gasthuis, and I'm still working as a researcher in intensive care and Erasmus, collaborating with the Department of Virology.

Okay, great. Well, I hope you're feeling ready for it, because today we're going to be talking about virus infections and the mechanisms of thrombosis and bleeding, the pre-pandemic state of knowledge from influenza and hemorrhagic fever viruses, and what we've learned from COVID. This sounds like an awful lot to me, so let's unpack this a bit. Let's start off with what, in a nutshell, is hemorrhagic fever.

Well, Clare, so hemorrhagic fever, or more specifically viral hemorrhagic fever, is normally used to describe a syndrome that occurs after infection with specific viruses, and the syndrome is characterized in patients with high fever, multi-organ failure and potentially bleeding complications. And these bleedings can occur on any side of the body. So you can think of nasal bleedings, gastrointestinal bleedings, intrapulmonary bleedings. And this viral hemorrhagic fever often occurs in more and more tropical, exotic areas, because the viruses that cause this syndrome circulate there and they're associated with quite a high mortality. And I also, because of this very severe course of disease and blood everywhere, they appeal also a bit to imagination. So I think some of the viral hemorrhagic fevers are known to our listeners because of Hollywood productions, other TV productions and so on, because often these viruses are used in the more exciting movie world.

So what names might we recognize? Can you name some of these viruses?

Well sure so. For instance, ebola, that's one of the most virulent pathogens amongst the viral hemorrhagic fevers, because of case fatality rates that can go up to 90 percent. Depends a bit on which report, which study you read. What we learned from the the 2014 outbreak is that it differs a bit between between immortality to between 30 to 90 percent. But also, next to ebola, you have dengue fever, which is very well known from travel medicine, yellow fever, hanta virus, lasa fever virus, new world viruses, and those are all very different viruses, transmitted on a different route, some by mosquitoes, some via rodents, some human to human, but they share their common clinical presentation, which is the viral hemorrhagic fever syndrome.

Now influenza is not a hemorrhagic fever right?

No influenza isn't part of the viral hemorrhagic fever group. However, this is where it becomes very interesting, Clare, because respiratory viruses like influenza and definitely also sars-cov-2, like COVID- 19, they are associated with with coagulation complications. So the bleeding and coagulation system does respond towards the infection. However, they tend to be at the other side of the spectrum. So they do not really cause bleeding, but they cause the blood to clot too heavy. So you get actually clotting complications like thrombosis, pulmonary embolism, myocardial infarction or stroke. This is a bit the other side of the spectrum. So, no, influenza is not a hemorrhagic fever, but it is associated with complications due to the coagulation system.

So this is why we're talking about these together today, because one causes excess bleeding and the others cause clotting, and both of which are complications. And typically, how many people will develop complications like these in the course of a common viral infection?

So I think this is a very interesting question and I think if we zoom out first a bit, so looking at viruses from a coagulation perspective, you have these viruses that are associated with bleeding, the so-called hemorrhagic fever viruses we just discussed, and there it's a completely different story complication-wise because of the very severe course of infection. But then if we look at the other spectrum, so the viruses associated with thrombosis, the so-called procoagulant viruses, and these are often the respiratory viruses or chronic infections like hepatitis B and HIV, they generally lead to more clotting. However, infection generally leads to inflammation anyway, which activates the coagulation system. And if you only look at the coagulation complications, then it really really depends on the virus and how ill the person really got, the patient really got. So on average it's very difficult.

But if we just look at the studies that were performed the past years during the COVID pandemic also, that data comes from specific super subgroups.

So for instance, we have studies looking at pro coagulant complications, so thrombotic complications, clotting in the lungs in very ill COVID-19 patients on the intensive care. So in that group we know that almost 20 to 40% can develop a pulmonary embolism, so a blood clot in the lungs during COVID-19. However, if we look at the complete population worldwide, that might even be only a percent or 0.1% or 0. 01%. So because most studies focus on a subgroup, it's really really hard to say for the general populations how many patients develop complications and then what kind of complications. So normally we would say that in patients with a decreased immune response due to an underlying disease, age or medication they take, that those patients have a higher chance of developing any kind of complication. However, also healthy patients can develop pulmonary embolism, can develop a stupor infection after influenza, and so on. So it's a very interesting question but it's very hard to answer.

Okay, so we can say, for sure, that there are certain populations that are more susceptible, but that's not the whole story, is it?

No, no, no, I don't think that indeed, that's the whole story. But there definitely are certain subgroups. For instance, we know, and we discussed before, that the severe course of influenza seen in persons living with diabetes can be both explained by host factors and by the fact that they have diabetes, by the fact that they take certain medications, but also that there are specific viral factors. So both your immune system is a little hampered so you might get, early in the phase of disease, a higher viral load. However, also it seems that the virus benefits from rapid glucose level changes or at least effect of infection are more heavy in those living with diabetes. So we do know that. So specific subgroups or risk groups even a better name, I think risk groups have a higher chance of developing certain complications. But again, it depends on the virus, it depends on the risk group and it depends on the type of complication.

Do people experience these complications, many of which are quite serious, when they are actually ill, or do the complications develop afterwards?

I think that's the key question there, Clare, also to really understand what is what is happening. And again, this, this really depends on on what kind of complication we're talking about. But if we focus back on on the coagulation abnormalities or the thrombotic complications, blood clotting somewhere where it shouldn't this is more mainly during the most severe phase of the disease. So after first a period of standard flu-like systems for instance, if you listen to my voice now a little bit of a runny nose and a little cough and then seven to 10 days post-infection, you can have these pro-thrombotic complications, but those are often patients that are already in the hospital.

Bacterial super infections after influenza occur when you're actually recovering from the virus. So, for instance, some of your epithelial cells are damaged due to the viral infection and then the bacteria gets the chance to cause a super infection. So this is a little bit after the viral infection. And then you have, for instance, fungal super infections in healthy, immune, patent patients, so patients with acute immune system who can develop aspergillus pneumoniae after influenza. So again, this really depends on what complication you're talking about. But what we, for instance, didn't really know five years ago is that these, for instance, fungal superinfections, can occur in young, previously healthy patients, so someone who shortly seems to recover from a viral infection and then suddenly gets worse again. That's when you really need to take in mind that there's a super infection. And then, of course, yeah, what kind of complications are there? Are there more you, you have to do long COVID and so on? Well, we can, we can have separate podcasts, podcasts about about those subjects, I think.

Marco, how do you define a super infection?

So a super infection is an infection after the first infection. So, for instance, you're infected with the influenza virus inside of the lungs, inside the respiratory tract, and while you're recovering from this virus or you're still a little bit ill, a bacteria or a fungi infects also the respiratory tract because of the, for instance, the hampered barrier that's there due to the infection that caused damage by the virus.

Thanks a lot for explaining that. That cleared it up. Is it similar to how some people, but not all people get long COVID or lose their sense of smell, for example?

Yeah, well, so this, this long covid story, I think it is very interesting and there are currently many, many uh strong research groups in the world working on on long covid, also from ESWI uh, we try to uh to put attention on long covid.

As a researcher I'm definitely no, no expert there, but as a a clinician working in internal medicine, I have the idea that persistent symptoms after a severe virus infection happened already way before COVID. So also after a severe influenza infection, a severe CMV infection, you can have prolonged extra respiratory symptoms. You have your tiredness, your concentration problems, your headache. I think the fact that the group is now so big simply because so many people got COVID-19. So now is really the first time we can actually do a proper study because our cohort will be big enough. But then again, yeah, I'm very interested in common pathways and this is the same for the coagulation response. I think for many things and some people will absolutely not agree with me, but I think for many things in complication-wise, after a viral infection, it doesn't really matter which virus it is, but it matters most how much virus particles are in a specific organ.

Apart from the size of the control group, or is it for that reason only? How has the COVID pandemic provided this opportunity to better understand the complications of other common viral infections?

Yeah, so I think the SARS-CoV-2 pandemic learned us a lot, simply because of the high numbers, the many different type of patients, also patients with other underlying diseases, specific subgroup patients coming from all over the world, and the virus was everywhere. So we didn't have to do what we did for the past hundred years in medicine, that we extrapolate data from white male Western Europeans to other parts of the world, for instance, a Southeast Asian female. So COVID was everywhere and also almost every researcher became a COVID researcher and there were definitely also some positive sides of that, besides all the competition in the research field. But I think now the numbers are big enough to really understand what is happening during a viral infection in certain parts of the body and also after.

And in some way, as we're sort of referring to some of the silver linings. This was a special area for you because your doctoral thesis, which you successfully defended in 2015, was on hemostasis and viral infection. So do you continue to focus your research on that today in between your other multiple duties?

Well, that's a very good question, Clare. So, to be honest, it definitely is my favorite subject. I'd like to talk about it, I'd like to study it. However, maybe also inspired by one of my scientific heroes not sportive heroes, but definitely scientific heroes Professor Ab Osterhaus. I do lack a bit of focus, so I do a lot of different things. It's a combination of enthusiasm and a lot of energies, but there aren't many projects I actually turn down, so I do a lot of a little, or yeah, that's probably how you summarize it best. So, again, I currently most of my time I spent at the intensive care unit in the Sparne Gasthuis Hospital and I think on an intensive care where most extreme conditions happen. Patients come with the most severest form of disease. You're continuously exposed to potentially new treatments, potentially new mechanisms behind disease and because of my enthusiasm, I would like to study them all. But most of the focus is indeed on coagulation response during infection, local coagulation in the lung, especially in the most severely ill.

How has the scientific knowledge grown? What have we learned from COVID?

That's a very good question.

I think we're currently learning a lot.

First of all, there's a crazy amount of papers published, so you do need to look now a bit for a needle in a haystack.

Well, maybe that's a bit too negative, but I think, like thousands of papers have been published and you need to look for the papers that really moved our field forward so for my field, personally i strongly believe that covid learned us what a virus can do. If it gets deep enough in your respiratory tract, so deep enough in the lungs, and there's no pre-existing immunity, so the immune response will take a bit before it can actually clear viral particles. And then again, what we really learned, what we already thought a bit but was hard to prove, but the balance between a good and solid immune response in the early phase of infection, so which you need to protect the virus from getting to your lower respiratory tract of infections, or which you need to protect the virus from getting to your lower respiratory tract towards a too heavy immune response, or later in disease, where your immune response should actually calm down a bit but is damaging the lungs. I think that is something that that we really learned from the covid pandemic

and is this a high priority for research funding at the moment?

It should, I think. First of all, timing is essential. No patient is the same and timing of specific treatment. So a patient comes towards the hospital and if you need to decide, am I going to attack the pathogen now? So am I going to attack the virus or the bacteria, or am I going to attack the immune system?

Personalized medicine that's where our focus should be, and I think this personalized diagnosis and treatment is a subject for many grant calls currently, and there are European and other international funding available. However, these are often huge grant proposals, often with high demands in terms of multidisciplinary partnerships, monitoring, et cetera, et cetera, and also deciding who gets the grant is often based on a number of high-impact papers in that specific subject already and previous successful grant applications. So this makes grant writing a very competitive field, and that's something that worries me a bit. I witness often that in partnership projects, you do not get the maximum result because of competition. Everybody needs to think of his own funding and his own chance of getting another grant, and that's not always the best, because there are only a couple of places on the paper for good authorship. That does not always give the best results, though.

Would you welcome more freedom in how the research funding is allocated or more flexible rules?

Absolutely, yeah, absolutely.

Let's take one of these potential complications, say blood clots or thrombosis. Can you give us a picture of how this actually happens, what the mechanism is?

So I do not know exactly, but I do really like to talk about the potential mechanism. So look at a virus particle and somebody sneezes in the room who is infected with COVID-19. You inhale this virus particle and if you're lucky, it stays in your nose. You get a little bit of a runny nose. Nothing really happens. If you have bad luck, a lot of virus particles enter your respiratory tract and it goes down and down. You get first the flu-like symptoms with your nose and your throat, but then it goes down towards the lungs and inside of the lungs. I think that that's where most of the problems really happen.

So the lung is a pro-coagulant organ. The lung really doesn't want to bleed because you have your oxygen taking out of room air towards your circulation. A little bit of blood inside of the lung would mean you drown in your own blood, so the lung is really anxious to clot. Then the virus gets in this lower part of the lungs and it infects the layer where the oxygen will actually enter the circulation, the so-called epithelial cells. And these epithelial cells get infected and during any inflammation, any infection, you get a procoagulant response. So despite that, there are all these molecules trying to fight the virus also, those molecules will make the blood a little bit thicker. And on the other side is the blood vessel, because that's where you extract the oxygen.

And in those that part of the lung, you have your endothelial cells. And the endothelial cells are a bit the master of of coagulation and they, they'll also respond to a pro-coagulant way. They'll try to defend and keep the virus out for not getting into into the body, but they do it on a way that that they get pro-coagulant. So they, they tend to clot on the side of the surface. So the small little blood vessels around the part of the lungs where your oxygen gets in, that's where clotting starts. And then, if you're very, very unlucky, you'll get like a snowball effect, because more inflammation, more coagulation and so on, and then also on other sides of the body you can start to clot.

Does this give us some clues as to how these complications could be prevented?

So again, this really depends also on the virus.

So if we go back to the beginning of our talk and we look at the viral hemorrhagic fever pathogens, you just need to make sure that you do not get infected. And for a hantavirus infection, that's a virus that's spread by rodents you need to make sure that you do not get in contact with rodent excreta. If you look at dengue, you need to make sure that you don't get stung by a mosquito. But if you look in the case of COVID, well, to prevent infection, I think we can all conclude now that that's very, very difficult or even impossible, so infection cannot be prevented. So then you need to make sure that the virus does not go to the lower part of your respiratory tract, and this can be done, for instance, by high antibody levels or high T cell response, by vaccination, early treatment, for instance with antivirals or very exciting stuff. A former colleague from Erasmus, Rory de Vries, wrote a paper about lipopeptides that can be used as post-exposure prophylaxis. So you know, you've been in contact with an infected person and you can actually use this treatment to make sure that the virus that's in your nose and in your throat does not get eliminated, does not get the chance to go down the lower respiratory tract and also we know that specific risk groups have a higher chance of these complications. So we should really focus on prevention in these risk groups.

These are some very practical recommendations and also in the interest of practical recommendations well, hindsight is 20-20, they say, but based on what we know now, ;arco, how could we have dealt differently and better with the recent pandemic?

Yeah, well, so that's something I actually. Well, I think many people are thinking of a lot. During the COVID pandemic, I was really in the front line on the ICU so it's hard to zoom out and if I look back, maybe even for the policymakers it was hard to zoom out. COVID was suddenly there. We all reacted in a different manner. We all, I think, did our best. Now, looking back it's always easy, of course, looking back If we have to do it again, if we have to start over, um, I think there are some great examples in the, in the, in the world, which we could extrapolate to to the whole world, to do different countries.

I think in the UK they did really really well, uh, scientifically, with collaborating, uh including all patients in in one big cohort and and and treating them all all the same, showing us, for instance, that dexa medicine could actually work, uh, treatment that didn't work.

I would, I, what I would do differently if we can do it again, is that I think still, and well, definitely in some, some subgroups in the Netherlands or in Europe, that we again focus too much on on our own patient group, our own specific field, um, and, and that we didn't combine all the knowledge together again, maybe because of competition, uh, even though COVID was there, uh, and everybody wanted to beat covet, uh, some people also really needed the pandemic to to move forward in their, in their scientific career, and I don't think we always got the optimal result, or we didn't get the optimal result as soon or as rapid as possible because of the competition in the scientific field. Well, clinically, what we could have done better, I think it's just capacity-wise. We need to be prepared that we can easily increase our capacity beds, ventilation machines, but also out-of-hospital care, general practitioners. So healthcare is really something you should really think about how to respond in times of emergency and need to have a backup plan.

Marco thanks a lot for that, and I just want to pop in one last question, which you described yourself as working on the front lines through the pandemic Did it change you? Did it change your attitude professionally?

Yeah, yes, yes, it did. Um, to be honest, um, I think there were parts during the pandemic, um, where you uh, emotionally, uh, you turn yourself off and and I'm a emotional person, so I also need emotion in my daily care to give a patient optimal care. So I think there were parts during the pandemic where I turned into a robot and I don't think me as a robot I'm the best intensive care physician possible. However, also sometimes you need to turn off your own emotions. How did it change me? Now, after the pandemic, I think we learned a lot. We also know that we can do a lot and very sick patients can still recover. But, yeah, well, from a personal perspective, a new pandemic needs to wait a couple of years, because I don't think I'm ready for another one yet.

I sincerely wish you the best of luck with your continued work on these important areas, Marco, and you've really been a wonderful guest at ESWI Airborne today. Thank you so much.

Thank you very much, Clare. I really enjoyed talking to you.

How nice! Folks keep on tuning in to ESWI Airborne, the viral podcast series, for all the latest on viruses, hemorrhagic fevers, vaccination, influenza and more from the people working on the front lines and in ESWI, the European Scientific Working Group on Influenza. And until next time, dear listeners, stay safe.

ESWI Secretariat: 26:29

ESWI Airborne is brought to you by ESWI, the European Scientific Working Group on influenza and other acute respiratory viruses. These episodes would not be possible without the team's efforts and we would like to extend special thanks to our ESWI secretariat, our technical and Secretariat, our technical and IT teams, our arts team and our host, Clare Taylor. The podcasts are recorded virtually and we thank our guests for their participation in this inspiring series. Talks are adapted to a global audience and are intended to be educational. For any specific medical questions you may have, these should be addressed to your local general practitioner. Many thanks to our sponsoring partners and thank you for listening.

Virus infections, blood clots and bleeding

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