Respiratory Infections and NCDs: Evidence, Mechanisms and Clinical implications

ESWI Secretariat 0:00

Welcome to ESWI Airborne and our special spotlight series on the Interdisciplinary Disease Collaboration on Respiratory Infections and Non-Communicable Diseases, otherwise known as the IDC. This episode is the first in our series entitled Breath and Beyond, and it is made possible thanks to the kind support of AstraZeneca and Sanofi, Winthrop Industrie.

Jane Barratt 0:45

My name is Jane Barrett. In our earlier discussions, we introduced the rationale for bringing respiratory infections and non-communicable diseases into the same scientific conversation. Today we're going to go further. For a scientific audience, the harder questions are: what can we say with confidence? Where might we be over-interpreting? And what evidence is needed to embed respiratory infection prevention in NCD care? I have the great pleasure of being joined by two of our IDC co-chairs, Professor Tor Biering-Sørensen, Professor at the University of Copenhagen, whose research includes the Danish studies at the centre of today's discussion, and Dr. Marco Goeijenbier, ESWI board member and physician at Spaarne Hospital in the Netherlands, who brings a broader clinical and scientific perspective on respiratory infections and chronic diseases. So, welcome.

I'm really going to start off and ask you about what the evidence really shows? So, Tor, let me start with the Danish studies. What do the Dan Flu 2 and Dan RSV studies allow us to say with confidence? And where are we at risk of overinterpreting the results?

Tor Biering-Sørensen 2:07

So, first of all, thank you so much, Jane. It's uh great to be here together with you and Marco. Um, so the Dan Flu 2 and the Dan RSV trials were the first of its kind, you know, trials designed to assess whether vaccines lower the risk of hard endpoints like being hospitalized. Remember, you know, the first the phase three trials of vaccines are not powered for hard outcomes, they are powered to assess whether you prevent an infection. Uh, but these trials were conducted in in such a big size, a large size, that they actually had power to assess whether we also prevent hospitalization events and not only the infection or when having the infection. So that's that's you know what they would assign to. And and therefore what we can say with confidence uh based on uh reading out from these trials is that it seems as if we can prevent hospitalizations um with with uh with vaccines for an RSV vaccine specifically. We know that we can prevent uh RSV uh infection and hospitalizations uh with RSV. We also know that we can prevent hospitalizations uh that are more broad, so all-cause hospitalization uh events due to respiratory tract disease if we uh vaccinate our elderly with an RSV vaccine. And this, of course, underscores the fact that RSV is not a disease like flu or COVID that is being uh tested for as broadly since we see that we prevent uh some of the all-cause outcomes, right? The they're just not being measured. For Dan Flu 2, it was a uh high-dose flu vaccine versus a standard dose flu vaccine, um, which we compared in a randomized trial of more than 300,000 individuals. There we saw that the primary endpoint of hospitalizations for phenomena influenza wasn't actually significant, so we didn't reach our primary outcome. But we saw a very big effect on hospitalizations for flu specifically, uh, a relative risk reduction of close to 40%, which is much, much greater than what we expected, you know, when we know that that the relative risk for getting flu with a high dose versus standard dose flu vaccine from the phase three trial was only 25% lower risk of having flu. So this actually translates into a potentially greater risk of of uh preventing flu hospitalization specifically. So if we look into these uh non-communicable diseases specifically, which we discussed so much, none of the trials were actually powered for these endpoints, right? But we see that they have a much higher baseline risk. So people who are diseased, when they are being vaccinated, they have a much greater absolute risk reduction, underscoring the fact that that we can prevent many more hospitalization events uh when when when using vaccines in these specific patient populations. And I think that is what I would argue we at least can say with confidence based on the randomized evidence. Vaccines don't only prevent the infection, they also prevent the downstream hospitalization. But regarding non-accumulable diseases, it's mainly that we uh we prevent more absolute hospitalization events because they have a greater or higher baseline risk. So that would be my my interpretation uh uh and and and and you know trying not to overinterpret uh these findings from these specific trials.

Look, that's that's very impressive, Tor. I'm gonna turn to Marco now. Marco, you're on the front line. So, you know, with your with your you know clinical perspective and a broader scientific perspective, where is the respiratory infection and NCD relationship best established? And where does it remain more speculative from your put your point of view?

Marco Goeijenbier 6:05

Thank you, Jane, and always a pleasure to discuss uh these kind of topics with you and with Tor. Um and this is a this is a good question to uh to actually start with, uh, because of course we do know that from disease X uh uh you have a higher chance of of developing more severe respiratory outcome of specific respiratory infections. So we do know that that certain chronic diseases predispose to a more clinic, a severe clinical course of infections. But it's the other way around now where we where we should actually gather more and more evidence. So I think the link is real, but it's not uniform. Uh so we need to define it by pathogen, by patient group, and by clinical outcome, but also really understand uh the mechanism behind it. Um so I think now uh uh really linking uh non-communical diseases uh towards uh respiratory infections, uh the the best evidence comes, of course, from from uh the the occurrence of the increased occurrence of cardiovascular events uh uh after a couple of weeks of a respiratory infection. That link is quite clear, but we absolutely do not understand why this occurs. So is it is it the virus itself? Is it systemic inflammation? Uh is it only in specific risk patients and are we actually doing a stress test with a with a with a more severe infection? Um so I think the uh the studies that are coming out now, or the data that has been gathered the past years show that that by vaccinating you reduce reduce the the burden of these non-communical diseases on healthcare. But but why and how we don't understand yet. Um so my view is well, well, the concept is starting to get established, but the size of the effect, the pathogen-specific mechanisms, the best endpoints for prevention, those are still area areas where the science really needs to mature.

You know, it really feels as though we're sort of on the edge of some major, you know, um major um results that are going to theoretically, you know, change the way we see practice in the future. And so I I want to turn turn to you again, Tor, and talk about the Dan Flu 2 study.

Um Marco mentioned, you know, the importance of the cardiovascular outcomes, but what was the strongest cardiovascular signal and and how should a cautious scientist interpret it? Now you're both, aren't you? You're a scientist and a clinician. So, you know, with your scientist hat, um how are you interpreting this?

No, that's that's a great question, and I um I can only uh echo uh what Marco just mentioned, you know, that over the last um uh at least two decades we have seen this uh this increased risk of cardiovascular outcomes, uh also temporarily um associated with uh respiratory tract infections, and that has been mainly ischemic events that that those studies uh have been been focused on. Very interestingly, in in Danflu II and also fluunity HD, which was the combination of DanFlu and Galflu, which were two trials that were were uh conducted with the same protocol with the pre-specified intention to pool those two data sets. We saw that the greatest uh uh the or the the greatest risk uh lowering effects of a high dose flu vaccine versus a standard dose flu vaccine, which we know prevents flu and which we know are very um very useful in in preventing uh inf uh influenza infections, we saw the greatest risk reduction uh in heart failure hospitalization. Um and that was uh I think prior prior to our uh initiating the studies, not the cardiovascular outcome, which I at least expected. I had done a lot of of observation data or studies using self-control case series analysis, looking at these uh temporal associations, and that was my cardiinfarction or stroke. But it seems as if we are potentially preventing heart failure hospitalization in a greater magnitude than at least these ischemic events. And that that's very, very interesting and a new eye-opening uh experience, at least for me. And remember, I'm a cardiologist and I'm a heart failure cardiologist specifically. So I was you know extremely excited to see this 20% relative risk reduction of heart failure hospitalization, which we experienced in Danflu, in Galfu and Influnity. Um so it has opened a whole new way of thinking, and and maybe we should focus more on heart failure than the ischemic events uh when when when talking about respiratory trait uh diseases.

You know, both of you are really disgusting about the reduction in hospitalizations, and with that is the reduction on the health dollar. So these results are really benchmark in policy development also. I wish I wish our audience could see both of you because you're nodding in agreement each time one of you, you know, responds to a question.

Um, Marco, from a clinical perspective though, you know, what is the most convincing pathway linking respiratory infection to cardiovascular decompensation?

That's another great question. Uh so uh for me, the the most convincing pathway, it's it's not a single mechanism. Uh I tried to study it during my PhD looking into ferrets uh who got influenza, see what happened there. But it's a combination of several mechanisms all happening at the same time in a patient with limited reserve, as Thor already discussed. So during or after respiratory infection, you see systemic inflammation, uh, you get an endothelial cell response, so the inner vascular the inner layer of your vasculature will will respond. You actually move towards a pro-trombotic state. Uh at the same time, due to the underlying disease, a patient can become hypoxic, tachycardia, so heart rhythm goes up, he goes uh the patient can become febrile, and this all increases myocardial oxygen demand uh while oxygen delivery might may be reduced. So we're actually looking at this this huge stress test. And and maybe in healthy young persons uh you can pass this stress test without any major events, but in those with limited reserve or already underlying cardiac disease, it can be the the the drop that makes the bucket flood, right? So so I would describe respiratory infection as a systemic stress test. Uh healthy healthy people are okay, but people with NCDs have have much less reserve.

Look, it it's interesting about this stress test for healthy people, they may manage it. But with people that have NCDs or and in the latter half of life, you know, they're really going to struggle with that stress test.

So there's one interesting point during the the the first wave of uh of of COVID. Um so so when there was absolutely no uh predisposing immunity, you you did see uh cardiac ischemia in in relatively healthy people. So but that's because then the virus got so big. Uh so it's it's continuously uh a balance between uh the pathogen on one side and the host or the patient at the other.

It's beautiful the way that you talk about it. You know, the pathogen and the you know, it's it's this balance that you're all that the body is always trying to attain, isn't it? Um Tor, you've talked a little bit about heart failure, but I want to go back to it and and with a particular emphasis. So is the heart failure signal biologically plausible, clinically meaningful, and strong enough to shape future vaccine studies? Um what do you think from your work?

Yes, I I think you know it's you know, when when thinking about it, you know, we we've had since this association, which um uh Mar Marco also um mentioned about all of these cardiovascular outcomes, and and there's been a lot of research on this specific topic, um, where there's come up a lot of hypotheses about whether you know you're uh stabilizing uh or making a plaque unstable if you have an infection. There's been a lot of hypothet hypothesis about you know the mechanisms. I don't really understand it. Well in heart failure, I think it's probably much it's much more easy to understand. Remember, now we had the trial, we've seen the effect, so now we know that them there must be some kind of causal uh relationship between preventing flu and then preventing heart failure hospitalizations, right? Because it's from randomized evidence that we have seen these uh these results. Of course, the trials haven't been powered specifically for the heart failure endpoints, and that has to be underscore. So it is still hypothesis generating. But understanding that you know the main symptom in heart failure, that's diphnia, right? So it's it's an increase uh in the pressure uh in the lungs, in the vessels in the lungs. Where is it that this these respiratory infections they uh they infect? And I know Marco knows much more about this in detail, but it's the lungs as well, right? And and is the the thing that we see in our heart failure patients when they're hospitalized for acute heart failure, that is uh is fluid in the lungs. And infection does also make you know the lung permeability of the vessel um higher, so you also have a greater um greater um uh risk of having fluid in the lungs, right? So the heart and and these infections are actually uh leading to or um or attacking the same system and creating the perfect storm for for having fluid in the lungs, right? So I think that's at least that's been my uh my uh way of thinking that people who are already in risk of having heart failure that haven't been pushed over the border, if they get an infection, you know, the permeability of the blood vessels in the lung might get more permeable, and thereby the higher pressure that you see in the vessels that they already have uh leads to fluid in the lungs, which is the cardinal symptom in our heart failure patients. So I think uh it makes sense probably also much more than all the other theories that we've had with with the mechanisms of how a flu, R C V COVID potentially causes myocardial infarctions, uh strokes, and so on. Um but but I know that that Marco, he is a greater specialist in this than I than I am. So so that's at least been my you know um my way of thinking. But this is of course after I know the results, right? And after I this link.

So yeah. Look, I I think that's a very comprehensive kind of position. But I do want to actually challenge Marco a little bit more on how the science should be changing now.

Um it seems to me that, you know, the Dan studies have really pushed us to look at bi-directional relationships. And uh Marco, I just want to ask you, are we still too pathogen-centered in the way we study respiratory infections? You know, should we be moving more to a patient-centered model? And what would change scientifically? I know it's a it's a it's a broad question, but it's a question that's important.

Yeah, it's it's definitely a broad question. Um just to quickly get back to Tor, I think you're getting quite a specialist yourself there on this point here, because that's just an excellent answer. I wouldn't add anything there. Uh, but do yeah, I do think we are still quite pathogen centered. Uh quite uh for every pathogen and every vaccine available, there needs to be one specific trial. So we often design studies around whether we prevent influenza, we prevent RSV, we pre we prevent SARS-CoV-2, and that's the virological endpoint. That's important. But for many patients and especially clinicians, the real question is different. Does prevention reduce hospitalization? Does it reduce decompensation? Does it reduce exacerbation of COPD? And then when you focus on one specific pathogen and you put a lot of money and a lot of effort in it, but you forget about the others, then the patient might just as well be very, very, very well uh protected against influenza, but gets an RSV infection or uh a SARS-CoV-2 infection, and with the same uh systemic inflammatory response, the same pro-cagoline response and the same um uh uh the same outcomes. But then so so I think first the the endpoints need to become clinically very meaningful, but that that's happening now. So so the Tor is doing a great job there. Uh it's not only laboratory-confirmed infection, but it's it should focus on hospitalization. And that's that's a whole other uh subject, and we can make multiple podcasts about it, but but the the the burden on on hospital care uh is a is a big problem, especially with aging uh society. Uh so we have uh less and less people actually willing to work in healthcare, and we've got more and more patients there. So anything that that can reduce the burden on hospital uh capacity is very, very important. But then also, secondly, in these studies, population should be selected based on on vulnerability. So not only only age, age is useful, but age is very, very crude. So we move better better risk stratification, heart failure, COPD, diabetes, frailty. Um we had a lovely discussion in in Brussels with with lots of of stakeholders that are really diving into this subject. And maybe one of the most important questions is if I prevent uh uh uh uh by any means possible the different respiratory infections, so by uh by an optimized uh vaccination schedule, uh will that that person live longer without any care? Uh so so I think those are very, very important questions. But then finally, we need to get the right disciplines uh involved from the beginning. So you need cardiologists, pulmonologists, geriatrics, primary care, epidemic epidemiology, but also implementation science. Uh and this should help define the question from the start.

Yes. Look, I'm just going to come back to you again, Marco, and and ask about evidence threshold and implementation. Um because I'm really interested. Part of the meeting in Brussels, we talked about vaccination being part of NCD management. And you're a clinician at the front lines, you know, right as we speak. So, what would convince you that vaccination should be treated not only as an infection prevention, but as part of NCD management?

Yeah, well, you you made this statement earlier during this podcast that I think we're on the verge of seeing something big, and I absolutely agree there. I think we're we're getting there, but we're not there yet. Um, so what would make my life easy, because of course I'm I'm a believer, and and I think all the all the evidence is there in different boxes, and we just need to combine them, and we need to combine them and then add uh data from the giga trials that that are that are done now. Uh, but it would make my life easier convincing my my co-workers if we see consistent evidence that vaccination reduces clinically meaningful meaningful outcomes in well-defined NCD populations. That's what we need. Uh and we need it on a large scale. Uh, and then we need people to actually help us, so from a completely different field, social sciences, or how we bring this data to policymakers and how we would actually change daily clinical work.

Yeah, look, I'm not convinced that either of you will have an easier life because it seems to me that both of you are really, you know, stepping into pioneering areas. So um, I don't think you've got a chance on that. But Tor, one issue that was raised during the IDC meeting and the summit was the difficulty of obtaining grade 1A guideline recommendations. And there was quite a debate about this. From your perspective, what kind of heaven? Would be required to reach that level of recommendation, if at all. Because I know that you you had particular views.

No, but but I I I agree completely with Marco again, as you mentioned, Jane, you know, I'm just nodding every time Marco is saying something. And so I agree completely, you know. We already know that these vaccines work to prevent uh prevent the diseases they are designed to prevent. Now, through the GIGA trials that we power to show that they also prevent uh hospitalizations due to these kinds of infections, you know, then we have that additional information. But the trials that often are discussing these specific topics of non-cumulable diseases are of course not powered to show that a vaccine prevents, you know, a stroke or future myocardial infarction. And I think I think we have these amazing vaccines and and our all of the guidelines currently recommend them. But the only thing is if we want to recommend them specifically for preventing non-cumulable diseases, then of course we need the trials that show that that they prevent, you know, uh diabetes, they prevent uh or diabetes hospitalization, they prevent uh acute myocardial infarction, they prevent uh stroke. We do have some trials within some of these topics. We actually have it for myocardial infarction, we also have it for heart failure hospitalization. So some of these trials are being done. But it's just to say that at least within my field of cardiology, for the great majority of cardiovascular diseases that we have, we don't have these trials. So we can recommend them to prevent uh flu, prevent RSV, prevent COVID. We can also now say you can use uh RSV vaccines to prevent hospitation, and you can use the proof flu vaccine to prevent hospitalization due to the pathogens. But if we need the 1A recommendation, and I'm not sure we need them for any, for all of the diseases, right? Because it's it's it's a strong enough argument that we prevent, you know, and that's shown in randomized far that we prevent hospitalization due to the disease. Um but if we if we want to argue that we also prevent these other downstream events, that has become a a very big portion of what we think about when we talk about preventing respiratory infections in in non-cumulative diseases, then of course we would need trials designed to show that specific. For example, my uh web dream, so to say, is to you know design uh uh a trial to that is powered for heart freed hostilization now and I see that that's a 20% relative risk reduction potentially to gain from preventing uh a flu infection. So so so that would be amazing. So we could get get it into the guidelines saying that you know uh you should also get vaccinated because we prevent heart failure, because heart failure is also a disease of the lung, uh long heart infection, of course, just like the respiratory, and you are exaggerating the effect of our respiratory tract infection, right? But again, it's I know that I'm a radical trialist. We need the trials if you want the one A recommendation, but I don't think we need the one A recommendation for everything. You know, we have a lot of evidence that vaccines are amazing to prevent what they're designed to. The new uh the new part is just you know, all the additional stuff that we are beginning to understand that vaccines actually also prevent. And I can only underscore again that we also already know now that those who have diseases, chronic diseases, they at baseline are much much higher risk. We know that also from from all the data. So vaccinating them, you have a much greater absolute benefit because uh, you know, you prevent many more hospitalization events. What Mark also underscored this uh risk stratification, not only looking at age, you know, uh uh a 40-year-old uh with diabetes has a much, much greater risk than a healthy 65-year-old, probably. So so we are also simplifying stuff, or at least trying to simplify things where where we we we're not using the vaccines necessarily to those at greatest uh risk uh always. But yeah.

Yeah, Tor, I'm not sure that I would see you as a radical trialist, a positive disruptor, but perhaps not a radical trialist. But uh I take it.

I wouldn't mind this.

Look, I I think both both of you are uh radical in a positive way. How's that? Um, I've got one final question for you, and it it really takes us back to the importance of the interdisciplinary disease collaboration on respiratory infections and NCDs. You know, anybody listening to this podcast will have no hesitation in understanding the importance of the IDC collaboration. Um, you know, you are two of the co-chairs, and and this podcast has been rich in information that really is at the cutting edge. And I think the fact that you know you're both clinicians also speaks to how we take evidence into action. But this final question, um, and perhaps we start off with Tor. Um, what is the one scientific question IDC must answer next, Tor?

Yeah, that's uh a great question, Jane, and and also hard. It's good that I also have Marco by my side so he also can pitch in. But um, but I think um the the first thing is just you know following what we just discussed, you know, if if uh uh first of all, bringing all the bright people together in ITC, you know, listening to each other, uh learning from the different specialities, and then also figuring out where is it we need, where is it needed to be implemented. And it and I think the big uh thing that Mark also mentioned, the implementation gap. Often we have a lot of knowledge, and for vaccines and for these vaccines, we actually have a lot, lot of information. So and understanding the implementation gap and where it's needed, where more science is needed is is a very big thing. And when doing this science, you know, trying to do it randomized if any way possible. And I think that has been a learning point, at least for me, that within vaccines we can actually do quite innovative large-scale trials. So if we need it, then let's move ahead and push for our randomized controlled experiments showing that it actually matters when we talk about causal relationships and not just uh associations. And and then I'll give the floor to Marco.

I I think that that's an amazing start. And then to add on there, the challenge is not not only proving efficacy, but it's then embedding prevention into your route in NCD care. And if you're taking it back to clinical implementation, which of course is a very, very important discussion point, uh, we I want to see that vaccination can be embedded in the car uh care pathways, for instance, in in heart failure, in COPD, in diabetes. Um I think uh as we are at at the beginning of something big, as we already mentioned a couple of times, I think what what would convince the rest is not a single perfect study, but it's a coherent evidence package. We need the biological plausibility, consistent clinical outcome data, and and then eventually, and maybe the biggest challenge, feasibility and routine care.

Look, thank you very much. And and just to make the point that the ESWI IDC is has a unique position in the world when it comes to evidence and clinical practice and policy. And so today's discussion has taken us well beyond the claim that respiratory infections and NCDs are connected. The harder task, which has been discussed today by Tor and Marco, is to define the strength of that connection, the mechanisms behind it, and the outcomes that matter, as well as the level of evidence needed to change clinical practice. And that's why we served up, you know, some challenging questions to these uh scientists and clinicians. The Danish studies are so very important, critical in fact, because they have moved the field toward clinically meaningful endpoints. But as you can hear from these radical trialists, you know, we need to go further forward. They've also raised important questions about interpretation, generalizability, and implementation. And this is exactly where IDC has a role to play. Now, at this intersection, IDC is not simply raising awareness. That's that's part of its job, but it's certainly not its job. It is there to sharpen the science, challenge assumptions, and help identify what evidence is needed for respiratory infection prevention to become part of NCD care. And what I found most important attending the summit in Brussels was the opportunity to agree and to disagree, you know, to really debate some of the important endpoints. My sincere thanks to Dr. Goeijenbier and Biering- Sørensen for joining this discussion. And thank you very much for listening.

Thank you very much.

Thank you, Jane.

ESWI Secretariat 31:30

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 I would like to extend special thanks to our ESWI Secretariat, our technical and IT teams, our arts team, and our host. The podcasts are recorded virtually, and we thank our guests for their participation in this inspiring and educational series. Talks are adapted to a global audience and are intended as recommendations and guiding principles. 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.

Respiratory Infections and NCDs: Evidence, Mechanisms and Clinical implications

Why Link Infections And NCDs

What The Danish Trials Prove

Where The Evidence Turns Speculative

The Surprising Heart Failure Signal

Infection As A Whole Body Stress Test

From Pathogen Focus To Patient Focus

Evidence Thresholds And Guideline Debates

IDC Priorities And Closing Takeaways

Respiratory Infections and NCDs: Evidence, Mechanisms and Clinical implications

Why Link Infections And NCDs

What The Danish Trials Prove

Where The Evidence Turns Speculative

The Surprising Heart Failure Signal

Infection As A Whole Body Stress Test

From Pathogen Focus To Patient Focus

Evidence Thresholds And Guideline Debates

IDC Priorities And Closing Takeaways

More info?

Interdisciplinary Disease Collaboration (IDC) “Breath & Beyond”