38. A Respiratory Triple Threat

Contagious Conversations  /  Episode 38. A Respiratory Triple Threat





David Snyder: Hello and welcome to Contagious Conversations. I'm David Snyder, director of content for the CDC Foundation and host of today's conversation. Every episode, we hear from inspiring leaders and innovators who make the world healthier and safer for us all. Contagious Conversations is brought to you by the CDC Foundation, an independent nonprofit that builds partnerships to help the Centers for Disease Control and Prevention save and improve more lives.

Joining me today is Dr. Laura Evans, professor in the division of Pulmonary Critical Care and Sleep Medicine at the University of Washington. She's also medical director of Critical Care at the University of Washington Medical Center. Dr. Evans serves as the principal investigator of a severe acute respiratory infection preparedness study known as SARI Prep, supported by the CDC Foundation as a way to provide better clinical care and treatment for those with severe respiratory illness. In this episode, we discuss the recent tridemic of COVID-19, influenza and respiratory syncytial virus, often called RSV. We also explore the origins, purpose and impact of the severe acute respiratory infection-preparedness study. Welcome, Laura.

Laura Evans: Thanks so much for having me. It's a joy to be here.

David Snyder: Thank you. So, this year Americans faced simultaneous surges in COVID-19, influenza and RSV, which some described as a tridemic. Can you talk to us a bit about why this was a unique and remarkable event in public health?

Laura Evans: Well, I think it was certainly really impactful for everybody in a way that it arrived three years, or nearly three years, after the onset of the COVID pandemic. And I think it's timing of this surge of RSV, influenza and COVID is a direct response to this three years preceding of the COVID pandemic that we really saw minimal activity of both RSV and influenza in the depths of the COVID pandemic, I think largely in part to the non-pharmaceutical interventions that were so widespread: social distancing, masking. And with the relaxation of all of those sort of interventions aimed at reducing transmission of COVID, we also saw a huge resurgence of influenza and RSV and it all coincided at exactly the same time. One of the pieces of this that was especially challenging and of particular interest to me and my colleagues on the SARI Prep study was the timing of these together and the impact that these have on the healthcare system.

So, what was different about this was that all of these infections surged at the same time. It involved both adult and pediatric patients at the same time, and it had a huge impact on our healthcare delivery system in a way that was very widespread, and really, availability and capacity of the healthcare system was severely strained by this tridemic or all three of these infections surging at the same time.

David Snyder: Absolutely. I mean, you talked there about the widespread impact of these respiratory infections. When we talk about these acute respiratory infections, can you help us understand better from a kind of on-the-ground perspective how these impact the lives of those who are infected?

Laura Evans: Yeah, thanks for that question. I think that's the really critical question and why me and my colleagues are engaged in this work. So, we're particularly interested in, as you mentioned in the intro, our project is called Severe Acute Respiratory Infection Preparedness, and severe acute respiratory infection has a particular definition that's used globally, which includes basically, the requirement that somebody be hospitalized from a severe acute respiratory infection, usually a viral cause. And so definitionally, if we're talking about a population of people with an infection severe enough to be hospitalized, that's going to have both severe impacts on that patient. All of these infections can be associated with significant morbidity and mortality, and it may have significant impacts on the healthcare system, as well. Colloquially, and in society, prior to the COVID-19 pandemic, we kind of talked about flu like it was just a thing.

I remember hearing even prominent people in the news saying things like, ‘I didn't know people died of the flu.’ So, it just became this sort of phenomenon that we kind of live with on a seasonal basis, and most of us were not severely affected, but I think what we neglected in the way we approached influenza and hopefully a way that will change after the COVID-19 pandemic and with projects like SARI-Prep is remembering that seasonal influenza is a phenomenon that kills between 12,000 and 50,000 Americans annually. So, it is a large impact event every year, and it happens reproducibly.

We kind of pay more attention to it in the settings of, if you think back to the 2009 H1N1 pandemic, that one was a little bit more severe than our typical annual flu. But there's an opportunity here to look at something that happens on an annual basis, seasonal influenza, and learn a lot about how we manage people with that severe infection, and then, use that as well as sort of a platform to understand other severe acute respiratory viral infections as well; how to manage people, how to help more people survive or do better with this infection, but also how to manage the systems and understand the underlying biology of what causes severe illness in these patients, as well.

David Snyder: So much of what you just said, it brings up several questions. I mean, one thing that came to mind, I just was reading a study that said only about 25% of US adults are kind of worried about getting seriously ill from either flu or RSV. Given that overload of health information that we've all gotten during the COVID pandemic, what barriers do we face kind of educating people about the health risks of these respiratory infections, and how do you go about doing that when people are on kind of super-saturation mode with information?

Laura Evans: Oh, I think that's a great question and one that people far smarter than me who spend their full careers in public health are grappling with every day in their professional lives and probably their personal lives, as well. We all get asked over family gatherings of, ‘Should I get the flu shot? Should I not get the flu shot? Every time I get the flu shot, I get sick.’ The fact that most people who get influenza don't get seriously ill has given us a sense of comfort with it that negates that some people really do get very seriously ill. And again, we're talking on an average year, probably somewhere in this range of 30,000 or so people die from influenza. And I think that there's an argument here to say, ‘Yes, we need very strong vaccination campaigns,’ to that. And it's not just about me reducing my personal risk, but also that if I get the influenza vaccine, I may reduce the risks of the people around me who may be more vulnerable than me.

And so, I think there is a sort of a group protection mentality for that. So, even if I don't get it for myself, because I don't think I'm going to become seriously ill from influenza, I may get it to try to protect my elderly parents. They're much more vulnerable than I am if they get influenza. They're much more likely to be hospitalized and much more likely to die from an influenza infection than I am. So, I think there is an argument here around protecting ourselves and protecting our communities. We also just have to look at the last three years of COVID and look at how disruptive to our day-to-day lives a widespread pandemic of severe respiratory illness is and all of the associated impacts around that.

I work in the critical care unit. I work in the intensive care unit with the sickest of the sick people, but a pandemic like COVID affects every aspect of our society. Children are out of school for a period of time. We're now having emerging data about the effects on learning for children's whose schooling was interrupted by the pandemic. So, it's really beyond just the acute hospital system, as well, but impacts every aspect of our lives.

David Snyder: That word just jumped out at me so much. I think disruptive is probably the best summary at all levels of how we've been affected by COVID in these last three years now. So, to take a step back then, can you tell us a little bit about the origins of the Severe Acute Respiratory Infection Preparedness study during the COVID response? How and why did it come about specifically?

Laura Evans: Yeah. Well, I was so glad you led the introduction with asking about influenza and RSV, as well, because our research group didn't arise out of a particular interest in COVID-19. In fact, when we started working together, we didn't know about COVID-19. We didn't know that it existed. It hadn't yet happened. But we were really interested in this concept of severe acute respiratory infections and severe illness, the stress and strain on the healthcare system, as well as understanding both the clinical management of hospitalized patients with severe acute respiratory infection as well as the underpinning biology. So, why do some people get so sick and other people don't, beyond the factors that we can kind of see–age, chronic illness–but what are the other factors in the host response that may predispose somebody to getting particularly ill or even be protective against becoming very, very ill from a severe acute respiratory infection?

So, we were already kind of interested in this space, and then, we also had this aspect of being interested in, and I think this is something, hopefully we'll come back to again, is this idea of a warm base for doing this type of research and understanding the way severe acute respiratory infection can behave and understanding its biology and its impacts on the healthcare system. So, we were already very engaged in this idea that we know seasonal flu happens every year, that we are not taking advantage of the opportunities to learn about this virus, to learn about its management, to learn about its impacts, and that definitionally leaves us with¬–because we don't have this warm base of continuing work in this space–that leaves us as a society more vulnerable during epidemic and during pandemic events like this to not learn as much as we can and not respond as well as we could.

So, we were really fortunate to get linked up with the Foundation at the beginning of the COVID-19 pandemic due to generous donors and the Foundation's work to say, ‘Hopefully, we can use this response as an opportunity to help build this warm base infrastructure so that we can learn about COVID-19 obviously, but we can also build the underpinnings of how we continue to learn from this.’ We know that COVID-19 is not the last pandemic we're going to see. It's not the only emerging virus we will deal with in our lifespans. So, how do we now build this infrastructure to be able to respond nimbly and effectively for the next threat, as well?

David Snyder: And that brings up so many points. I mean, it's not just about COVID, it's about others as well. So, maybe we can highlight a little bit, what are the main goals of the study then as you go through? What are some of the main goals you're trying to accomplish?

Laura Evans: Yeah. Thanks for that. I think there's several main goals for it. Probably the biggest overarching goal about this is exactly this concept that I just used, the phrase of a warm base. And what I mean by that is having a platform to do continuous work in the space of severe acute respiratory infection. So, not something I turn on and turn off when an epidemic arises or when a pandemic arises, but something that's always active and ready. One of the things that we learned during this study is really that building things takes time. That seems kind of obvious, right? You're like, ‘Well, of course you can't just clap your hands and have a research infrastructure ready to go,’ but there's a regulatory process that has to be followed, rightfully so. You have to have collaborations. You have to have partnerships in place. And when something arises like a public health emergency, that can happen very quickly.

And if we don't have that infrastructure built, when in the beginning throes of an emergency is not the right time to be building infrastructure. We should have that infrastructure ready to go. That's that warm base. We should have it ready to go. We should have those collaborations in place. We should have those partnerships in place. We should have those regulatory approvals in place so that then I can ramp up and scale our research response to the scale of the emergency so that we can be insured that we're learning quickly, nimbly, and pushing out what we learn to patients and their families and our communities along the way.

So, I think that's the overarching kind of goal of this study. There's a lot of specific goals of the study as well, in terms of understanding how these viruses behave, how they behave in certain patients, so again, why some patients may get more sick, some patients may get less sick, understanding the difference in, and we call that in the host response to infection. So, in order to accomplish that, we're collecting very detailed clinical information about the clinical picture of these patients from comorbidities, what other chronic conditions they may have, to their biologic response. So, we're getting multiple blood samples, urine samples, sputum samples so that we can look at the chemical response within the body, the proteomics, the transcriptomics, what happens on a cell signaling level, as well, to a response to infection.

And then the other component that I mentioned a little bit earlier, but I want to come back to emphasize, there's something really unique I think about this project. We're used to thinking about patients in isolation, that an infection happens to a patient. We treat the patient and hopefully they get better.

But one of the things that I think COVID-19 really brought to light is that patient care doesn't happen in a vacuum. It happens in a healthcare system. And so, one of the really critical pieces that I think is very unique to SARI Prep is this link to individual patient stories, individual patient clinical data, but also looking at what's happening in the healthcare system. And so, we've been collecting data on the perception of healthcare stress in the emergency department and in the intensive care units throughout this pandemic. And we'll be linking that to seeing if there's signals that when under a more stressed healthcare system that patients don't do as well or looking at factors that predict that.

David Snyder: We'll be right back with Dr. Laura Evans.

The Severe Acute Respiratory Infection Preparedness study aims to inform and improve clinical management of patients suffering from respiratory infections. To learn more about the study and for a full list of recent study publications, go to cdcfoundation.org and search respiratory infections.

And now back to our conversation with Dr. Laura Evans.

It's interesting to me that this looks not only, this study looks not only at patient health, but also stresses caused by caring for those with respiratory illnesses, medical staff, people in hospitals that we don't often hear about. I'm curious, how did you measure that level of stress?

Laura Evans: It's a great question, and I'm really fortunate. You're just talking to me, but this is a whole big team that's behind this work. And so, I'm really lucky to have a bunch of really smart, insightful collaborators. And one in particular has made healthcare systems stress sort of the focus of his research career. What we've done is in this particular study, we've measured this stress by asking the perceptions of the people doing the work in the hospitals of how stressed is their hospital. And we're delving down into different components of this. We're saying, ‘Is your hospital stressed? Yes or no? If yes, tell us about where the areas of stress are. Is it in the emergency department? Is it in the intensive care unit?’ And then, ‘Why is that stress there?’ So, is it due to problems with staffing? Is it due to problems with accessibility of equipment, for example?

If you remember back to the beginning of the COVID-19 pandemic, we heard constant communication about the lack of availability of personal protective equipment or PPE, the lack of availability of ventilators. And what we saw in our survey responses, and this has been published recently in critical care medicine, is that the responses from our participants really changed over time. So, early in the pandemic, the source of stress and the source of shortages was really around equipment. It was predominantly focused on personal protective equipment. And so, then you go back, and you think about, ‘Oh yeah, this is actually what was showing up in the lay press, that people didn't have access to sufficient number of N95 masks.’ And then, we saw a shift as the pandemic went on, and the source of stress to the healthcare system really focused in on staffing. And it was really around the lack of availability of staffing that was the source of stress in the system.

And so, I think this getting the perceptions of people providing on the ground care, I think is really insightful to see what is the experience like on the healthcare system. We'll also be linking that to quantitative measures, so it's looking at the activity of the healthcare system. Does that respond to absolute numbers of increases in patients? Are those surrogates that we can use? Or those indicators of stress, do they match up or do they not match up? And I think that'll be a really interesting piece as we think about how to assess stress on a healthcare system going forward. I would advocate that looking at not only what happens to patients, but looking at the impact on the system is also a critical component of an effective response to a public health emergency that we need to be able to understand and measure what's going on in the system in order to have a good response to a public health emergency.

David Snyder: So interesting. The stress remained throughout, but what caused the stress was different. It just morphed as the pandemic went on. And it gets back to that word disruptive that you used earlier. Disruptive for those who are infected by it, but disruptive for those who were caring for it personally and professionally. I mean, that word just keeps coming up. To touch base on something you mentioned a little earlier too, the word infrastructure comes up a lot. You talked a little bit earlier about partnerships and regulatory approvals as part of that infrastructure. Can you give us any more examples of what emerging respiratory diseases and treatments looks like?

Laura Evans: Yeah, thanks for the question. It's something I'm obviously passionate about as is the rest of our research group with SARI Prep. And I think, to me, it comes back to this idea that you can't build a system in the setting of an emergency. You need that system to be in place. And there are many key components to that system in order to have an effective response to an emergency from a research perspective. When you get into research, you get into these very, what seemed very minute, and so how do I define something like what seems as simple as a day on the mechanical ventilator means? Do I mean a full day? Does that have to be a 24-hour period? Does any part of a day count? Or is it over a certain amount of time out of that day in order for that to count as a day on mechanical ventilation?

So, you need all of those elements worked out ahead of time so that you're not hashing out these small but really important details in the middle of an emergency. You want those. So, we would call that the case report form. So, to have all of the data variables defined, agreed upon ahead of time so that we can have those sort of ready to go in place or better yet, we're doing this on an annual basis with seasonal influenza. And so, we have this annualized data that then we can kind of ramp up in the setting of public health emergency.

I was really pleased to see that recently the White House Office of Science Technology Policy issued a request for information that I think got at this very question. So, they issued an RFI about emergency clinical research infrastructure. And I was really happy that our investigator team, SARI Prep, in conjunction with the Society of Critical Care Medicine and many other partners and led a response to this RFI, because I'm very hopeful that this message of that you have to have the system in place ahead of time is getting out and that there'll be more support for that approach. And that's one reason that I think this funding from the CDC Foundation was so vital because it helps us build this case for why the infrastructure needs to be there.

And so, I consider SARI Prep to be really foundational work in promoting this concept of having a warm base infrastructure for emergency clinical research. This is around severe acute respiratory infection, but you could obviously model this to any public health emergency. It doesn't have to be a viral respiratory illness. You could imagine that if you build this type of infrastructure that has some regulatory approvals, has case report forms already defined, has a procedure for biologic sampling, so getting blood specimens, whatever the sort of specimen of interest is, but that you could apply this to lots of different scenarios. You could apply this to monkeypox or whatever the next thing down the road is. And so, having this infrastructure in place gives us the possibility to have a nimble and much more effective response so that we're learning much more quickly than we have traditionally and getting those results back to clinicians at the bedside, patients in our communities.

David Snyder: So important. It really speaks to just how important that preparedness is. Like you said, middle of emergency is not the time to be building infrastructure. Has anything surprised you as you've worked on this study or what has stood out to you?

Laura Evans: I think one thing–and with the benefit of hindsight, you wonder if you should have been surprised by something–one thing that did surprise me, our study is a no more than minimal risk study. We're not doing an intervention. We're enrolling patients, collecting clinical data, it's anonymized clinical data, and doing some blood sampling and some other biological sampling. So, it's not an interventional trial, but I was a bit surprised by the reluctance of patients to participate in research, kind of link it in my mind to some of the same epidemic of misinformation and disinformation that has happened at the same time as this COVID-19 pandemic and the lack of trust in the healthcare system. And so, I was surprised by that. It was more difficult than we anticipated for a study that really has no more than minimal risk to have patients or their family members if they were not able to provide consent to provide consent for the study, that people were more suspicious of this than I anticipated.

David Snyder: So interesting. And I think we've all seen so much in the last few years and learned so much just about the impact of that misinformation and the uphill battle that it creates in getting out the correct information. So, it's interesting that you bring that up. We talked a bit about this a couple times, but I'd like to circle back on it, as well. I mean, COVID taught us a lot of things, but it taught us that pandemics can occur at any time. Life can be disrupted at any time. How specifically do you think the study can help us better prepare for the next outbreak? We talked about infrastructure. Can you think of any other ways that this study will be able to prepare us for the next, like you said, the next one that comes along?

Laura Evans: Yeah, infrastructure, obviously, I think is really key to this. And one aspect of building infrastructure that we haven't touched on yet that I do want to place a huge amount of emphasis on is that we also need to ensure that we have much more equitable access to research and participation in research. And when we don't build that ahead of time, the places that can participate in research are the ones that are already kind of the research powerhouses. And we're not getting to communities where access to research and access to clinical trials has been much more limited, and that promulgates and perpetuates the inequities that we have already in our healthcare delivery system and in our access to cutting edge research. So, I think there's a huge component here to build the case further for infrastructure, that this is a pathway towards better equity in how we provide healthcare and how we provide access to clinical research from that.

In terms of other ways that this helps get us prepared, I think there's a big component of relationship building in this, as well. So, that is another form of infrastructure in many ways. But when you have these relationships between, and I think one of the things that's been really cool about this project in particular is the nature of this collaboration between the CDC Foundation as the funding agency, between academic health partners who are many of our clinical researchers in this study through the Society of Critical Care Medicine, who are functioning as our data coordinating center and clinical coordinating center, which is the largest multi-professional, critical care society in the United States. It's a really interesting bringing together of different stakeholders in this space. And I think by beginning to build these relationships, that puts us in a much better place for learning and for responding to the next event.

David Snyder: I'm so glad you brought up that issue of equity, that is just such a critical issue now and going forward across the whole venue of public health. So, I'm really glad you brought that up. It's such an important topic. Laura, this has been such an interesting discussion. You've raise so many critical points. So, thank you so much for your insight, and thank you so much for joining us today.

Laura Evans: Oh, thanks so much for having me. It was great to talk to you.

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