Episode 167: A Coronavirus Dance

Chris Dall: Hello and welcome to the Osterholm Update, a podcast on COVID-19 and other infectious diseases with Doctor Michael Osterholm. Doctor Osterholm is an internationally recognized medical detective and director of the Center for Infectious Disease Research and Policy, or CIDRAP, at the University of Minnesota. In this podcast, Doctor Osterholm draws on nearly 50 years of experience investigating infectious disease outbreaks to provide straight talk on the latest infectious disease and public health threats. I'm Chris Dall, reporter for CIDRAP news, and I'm your host for these conversations. Welcome back, everyone, to another episode of The Osterholm Update podcast. As many of our listeners know, the updated vaccines for COVID-19 have been a major topic of discussion for the last few months on this podcast. When they would become available, when people should get them, which is the best one to get, etc. we've spent time on this issue because we know that's one of the topics our listeners are interested in. But our audience may be an outlier when it comes to interest in COVID vaccines. According to a recent poll conducted by the University of Michigan in August, only 45% of Americans over the age of 50 say they're likely to get an updated COVID vaccine this season. Among respondents 75 and older, only 59% said they would get the vaccine. The backdrop for this may be that Americans simply aren't as concerned about COVID-19 as they were a few years ago. In another poll from the Foundation for Infectious Diseases, only 20% of Americans said they were concerned about COVID. What does this mean for the upcoming winter respiratory season? That will be one of the topics we'll tackle on this October 3rd episode of the podcast, after we bring you the latest data on COVID-19. We'll also bring you updates on H5N1 avian influenza and seasonal influenza. Discuss the FDA's approval of Flumist, answer an ID query on long COVID, and discuss an outbreak of Marburg virus in Rwanda and a recent UN meeting on antimicrobial resistance. And we'll bring you the latest installment of this week in public health history. But before we get started, we'll begin with Doctor Osterholm's opening comments and dedication.

Dr. Osterholm: Thanks, Chris, and welcome back to all the podcast, family members and anyone who might be attending for the first time. I hope we're able to provide you with the information you're looking for. Today, I want to do something somewhat different in terms of the opening for this podcast, and send a very personal message to many of the podcast listeners, not just a professional message. On Tuesday of this week, the University of Minnesota announced the establishment of the Michael T Osterholm Endowed Chair in Infectious Disease Research and Policy. To say the least, That is beyond my wildest dream that might ever have happened to my career. It's an honor that I take very seriously and with great humility. I've had a very fortunate career. I'm soon going on 50 years in the business, all of it here in Minnesota, and with an incredible team of people that have made it possible for me to do what I do. Well, I'm not ready to leave yet. I still have fire in the belly. I still have that belief that we can do more to make the world a better place when it comes to infectious diseases, but at the same time, the idea of planning for the future is really important. And succession planning is just one of those things. So what this chair allows us to do is to bring in someone who we believe will be able to take CIDRAP to even a whole new level after I'm retired and gone, and this position actually allows that to happen.

Dr. Osterholm: But it wouldn't have happened the position. But for you, it is amazing to me that the support for this chair came, first of all, from Christy Walton and the Alumbra Innovations Foundation. Christy is one of my heroes. She is someone who has a social conscience. That is absolutely a gift. She has done so much to make this world a better place, and her foundation made it possible for us to really leverage the kinds of support that we got from you. Many of the people here on this podcast, and that's where the second part comes in. Over 1000 donors have provided support for this chair. That just blows me away and frankly, brings tears to my eyes to even think about it. I want to say thank you to you, because many of the people who did donate to this chair are members of this podcast family. And you know what I'm talking about when I talk about podcast family. I know in our business of science. You know, you're not supposed to get into those kinds of human emotional sides of the world. You know, just the facts, ma'am. But in fact, we can't do that. You know that this podcast has always been all about the relationship between you, the audience, us here at CIDRAP and this incredible podcast team. And it has been a wonderful, beautiful experience throughout this pandemic. When I'm asked often, what were the lessons learned in this pandemic, one of the lessons I say very clearly is there is more good in people than there is other.

Dr. Osterholm: And this podcast family is a classic example of that. So I just want to start out today by saying thank you again. If when you hear about this pod new chair, I'm not leaving, I'm not going. There may be some that would like to see me do that, but you're still stuck with me. And from that perspective, to all of you who have provided support for this, Those. Thank you, thank you, thank you. To say that I'm appreciative is such an understatement. It's kind of like saying that the Grand Canyon is just a big ditch. I am very appreciative for what you've done and very humbled by it. Now with that, it's hard to make a transition to light, particularly as it's getting darker. But as all of you know, that is one of the requirements of being part of this podcast family. You have to stick through this. Okay. Well, today here in Minneapolis, Saint Paul, sunrise was at 7:14. Sunset at 6:48. That's 11 hours, 34 minutes and 20s of sunlight. We're losing sunlight at about three minutes and five seconds a day. And unfortunately, we're marching towards that December 21st date, when it will only be eight hours and 46 minutes and 10s of sunlight. But then it turns, and I'm looking forward to that already. Now, in terms of our dearest colleagues in Auckland and again, part of the podcast family I just want to share with you has now adopted the Occidental Belgian Beer House on Vulcan Lane in Auckland.

Dr. Osterholm: As I continue to get more and more pictures from individuals who stop off there when they're in New Zealand on vacation or business, and it's a wonderful thing to see that US connection via this podcast with The Occidental. It's a great place and thank you for your stories. Well, today at the Occidental sunrise is at 6:53 a.m., sunset at 7:26 p.m. that's 12 hours, 37 minutes and seven seconds of sunlight. They're gaining about two minutes and 20s a day. So the only difference here, however, is our weather in the upper Midwest at least, still remains to remarkable. With temperatures into the 80s during the day in Auckland, the lows are in the 50s, highs in the 60s with lots of rain. And let me just close with one last aspect of weather the world right now is suffering in so many ways from so many things. But what Hurricane Helene has done is simply absolutely incredible. I've had an opportunity to talk to a dear friend who has a satellite internet connection and a generator on site, and it's really critical because they are cut off from the world. The two roads that lead from their location bridges are out in both of those, and so I can only imagine how challenging it is right now. For those who are living through the aspects of Helene and our thoughts go out to you.

Chris Dall: Mike, if you look at all the indicators tracked by the CDC, including wastewater levels, it appears that at least here in the United States, we've seen a plateau of the summer surge and COVID activity appears to be declining. At the same time, we have a new variant, yet another one, XEC, gaining traction. So what's your assessment of where we are right now with COVID and what do we know about XEC?

Dr. Osterholm: Chris, it's very clear we're in a dance right now with this coronavirus. And it's changing. We're changing and we're both trying to keep time and keep step with each other. And so let me just say that this has been one of the more challenging and in some ways from a scientific perspective, fascinating relationships between this virus, its emergence in 2019 and where we're at today. And we still have things left to learn. But having said that, fortunately it is looking like we're finally on the tail end of this recent peak. In cases. As I've mentioned before, while COVID isn't seasonal, we do see a pattern in this virus cycling as new variants emerge. While immune protection from vaccines or previous infection actually begins to wane, it is not going to be a seasonal trend that we see with influenza, but a recurring cycling based on variance and immunity. Right now, all signs are pointing towards the end of this current cycle. Wastewater concentrations, while considered high across the entire country, with the majority of states including 33 and the District of Columbia still considered high, these levels are decreasing at every region and currently at levels that were last experienced early in July. Hospitalizations have declined since the last episode two weeks ago, with 4650 Americans reported to be hospitalized in 33% of the hospitals that reported their hospitalization data for the past week.

Dr. Osterholm: Of these 4650 patients, about 12% are in an ICU. Now, if we make the same assumptions we've been making that the third of hospitals reporting their COVID hospitalizations are not categorically different than the other two thirds of hospitals in the country, then we could estimate that there are probably between 13,000 and 15,000 Americans currently hospitalized with COVID-19, which is down compared to the 14,500 to 16,500 range we estimated two weeks ago. Let me also remind you that we're just a few weeks away from hospitals being required to report their COVID-19 hospitalizations, so we won't have to make these assumptions and estimates much longer. We really can use this data as quickly as possible. I'll provide a quick update in the emergency department trend by age group that we've been keeping an eye on over the past few episodes. As a reminder, during the month of August, 0 to 11 year olds had the highest percentage of Ed visits for COVID than any other age group, peaking at nearly 5% of Ed visits in the age group testing positive for COVID-19. I think a number of these cases reflected exposures at schools, as school was beginning at that time in a number of areas in the country. During our last episode, this percentage had declined to about 2% in kids, which was still higher than the national percentage but lower than the 65 to 74 year olds and 75 years of age and older groups.

Dr. Osterholm: This recent experience was the first time we saw children with a higher rate than we actually see. For those who are in the older age groups. Now, let me comment on one aspect of what we're seeing, as I think it really is a critical issue, and that's how do we look at the impact of COVID today in terms of serious illness, hospitalizations and deaths? Well, I'm happy to report the one indicator that I think we could all agree upon is by far the worst outcome we can imagine, namely deaths. They are starting to decline, but last week, we still lost 1213 American lives to COVID, marking the seventh straight week with more than 1000 deaths and the 12th straight with more than 500. However, if we look at the age distribution of these deaths. It's very telling, both in terms of what's happening but what we need to do about it. If we look at the preliminary August deaths, which right now are much more complete than we see for September, 97.1% of all the deaths were in those 55 years of age and older. And in fact, even 90.7% were in those 65 years of age and older. If we look at the September preliminary data, we see the same thing. 96.4% of the deaths are in those 55 years of age and older.

Dr. Osterholm: And if we look at a subset of those, 90.9% of the deaths are in those 65 years of age and older. This is really an important point because we right now, I realize there are many people who have decided COVID's done we're over with it. Not just the pandemic, but the disease itself. Chris, you alluded to that in your introduction about uptake of vaccine and how we're seeing real challenges there. Well, I'm telling you right now, if we wanted to minimize the number of deaths that are occurring in this country, we have got to have an all out effort to get those, particularly 65 years of age and older, vaccinated, because as much as these vaccines are not great vaccines, they're good vaccines, but not great. We do have the data to support that. They do reduce serious illness, hospitalizations and deaths, and in particularly even in the older age populations. Yet we see many long term care facilities, many individuals in our community who are 65 years of age and older, who have not been vaccinated, and we've really got to work on this. This, to me, is just absolutely critical. Now, where do we sit in terms of what this looks like with regard to the past again? Yes, we're way beyond the pandemic as we once knew it, but losing 1200 Americans to COVID a week is still substantial, but it's down substantially from where we were in the past.

Dr. Osterholm: Think about this 25,000 deaths a week in January of 2021, 21,000 deaths a week in January of 2022. And even this past January of 24, we were at 2500 deaths. And now today we are back down to 1200. We could do much more about that. So I hope everyone who's listening to this podcast, if you haven't gotten your new dose of vaccine, it's been at least two months since your previous one. It's been 2 to 3 months since your previous illness. Then I think it's really important that you get in and get that dose of COVID vaccine as soon as possible. And let me just emphasize this vaccine situation as I've just described right now, uptake can only be described as incredibly low, with only 4.5% of the US adults reported to have received the 24 to 25 COVID-19 vaccine, which is lower than the 9.6% who have received an influenza vaccine despite it still being early for influenza vaccine, which I'll get to that topic later. So again, I want to keep emphasizing what this means and how important this is. If we want to keep people out of the hospital, if we want to reduce the number of deaths, we've got to target that older age population.

Dr. Osterholm: And I recognize that I'm in it. So let me go ahead, though, and do a quick update on the international piece. The international data is very limited, especially because the W.H.O. releases their report monthly. But what we do know is that the international picture looks pretty similar to what we're experiencing here in the US. Activity remains elevated in many countries, but has decreased in remaining relatively unchanged. Most European countries are experiencing declining COVID-19 activity, and it seems, for the most part, that the EU experienced a very similar wave or cycle as we did in the US. The most recent cycle occurred earlier in the year than it did in 2023, but levels of activity were similar in both years. And as I've already noted, the 65 plus age group was by far the most affected. One thing to note with the international picture is the rise of the variant XEC, which appeared in Berlin in June and accounted for 12% of SARS-CoV-2 lineages in the European region in September so far. This brings me to the XEC variant, which is getting quite a bit of attention right now, including here in the US. So what do we know about this XEC variant? First, we know that it's a recombinant mix of the CS.11  and the CP3.3. Next we know that it's proving to have a very substantial growth advantage over all the other circulating variants.

Dr. Osterholm: And that this advantage may be related to a change in the nucleocapsid protein rather than the key spike mutation, which is what we have seen in the past. We know this has been detected in 29 countries, including the US, where it has been detected in at least 27 states in the District of Columbia. At the moment, XEC accounts for only 6% of US cases of COVID-19. For context, KP 2.3 is still the dominant variant, accounting for almost 59% of cases in the past week. But I think XEC's prevalence is going to grow quickly, and it will be interesting to see how quickly it grows in the coming weeks and months. There's still a lot that we don't know about this variant and the fact that it has new mutation sites. We don't know how well our vaccines will perform against this variant, but I'm still counting on what I've said to you all along. There still will be substantial protection, particularly for those who are at highest risk of serious illness. So while I don't have a crystal ball that gives me all these answers, I think right now, yes, XEC is going to be a challenge. But the vaccines, if we use them now, we can also fight off that challenge very well. So now we'll keep an eye on XEC and we'll make sure to give you updates as time goes on.

Dr. Osterholm: What it means. The last point I want to make is really about you and what you can do about COVID right now. You can now request for free tests to be delivered to your home by going to COVID test. Org that's COVID test.org. We'll put a link in our podcast website notes as well. So if you want to get new tests that have not expired, feel free to go to that website and get them. The second thing I want to just note that the vaccines are readily available in our community. Most of you should be able to get them with no additional charge. Whether you're in a health plan, Medicare, or Medicaid. A number of states actually have reimbursement programs right now, so please don't let that also be a deterrent for you going out and seeking to get the vaccine. So let me just conclude this COVID section by saying, welcome to the dance. We're going to be talking about this virus for as long as I can imagine. But at the same time, I feel more confident now than I ever have. We can match up against this virus with what vaccines we do have, what treatments we have, and we are in a much, much better place than we were 2 to 3 years ago.

Chris Dall: So, Mike, as you noted earlier, it doesn't really feel like the beginning of cold and flu season here in Minnesota. But it is. So what is the latest on seasonal flu?

Dr. Osterholm: Well, let me just start out by saying it's really still too early to get your flu shot. I know I'm going against the grain here, swimming up Niagara Falls, whatever. But in fact, we see such limited activity right now in the flu world out there. I wouldn't want to waste that protection that my body basically pulls together following a flu vaccine that then diminishes over time. Now, I don't want that to happen now. I want that to happen later when I'm more likely to encounter the flu season. I know that many of our listeners and some members of the podcast team have been strongly encouraged by health care providers to get their flu vaccines as soon as possible, especially when they're already at a pharmacy or clinic for another appointment or a COVID booster. Yes, get your COVID booster now. And while there is good intention behind these suggestions to get your flu shot, the only people who should be getting flu vaccine at this point in the season are those with a strong reason to believe that they will not have any other opportunity to be vaccinated in the next few months. If you fit into this category, then it may be best for you to get your vaccine now. But if you believe you will have other opportunities to get vaccinated later this fall, I strongly encourage you to wait.

Dr. Osterholm: We typically don't recommend vaccination until activity has just started to pick up for the season because, as I've pointed out multiple times, the immune protection from flu vaccination only peaks for a few months. It decreases from the time you get the dose about 2 to 12% per month. So if I'm four months out from my dose of influenza vaccine, I can have as much as 40% or more of the protection I had shortly after vaccination now lost to helping me fight the flu off at that later date. So I know this is not a popular idea. I know that we have to be mindful of a rush to get vaccine and then not have available slots to get vaccinated, but I, as I've promised you all along, we will keep you posted. I do not see any indications right now that influenza activity warrants getting vaccinated. And I'll follow this carefully and closely with you. And at that point, I just want to really emphasize the fact that, again, flu vaccines are good, they're not great, but one of the ways to make them good is use them the best you can. And the way you can do that is make sure that you don't get your vaccine too early into the flu season.

Chris Dall: Mike, I understand you have some concerns about the FDA's recent approval of Flumist, which is given intranasally and can be self-administered. What's your concern?

Dr. Osterholm: Well, it's really important to emphasize the fact that Flumist is a live attenuated vaccine, meaning that it's one that's put into the nose, basically, and you spray a live attenuated virus into your mucosal surfaces. That's where you want to mount that immune response. Let me just point out that I've been burned in my career on Flumist, and what we have seen with regard to live attenuated vaccines in the past. Back in 2011 and 12, our group at CIDRAP actually published a now a quite well-known paper that looked at the actual effectiveness of flu vaccines in a way that no one had done before, trying to capture all the information we could that was addressing this ongoing, forever stated statement that, in fact, flu vaccines protect 70 to 90% of the time. Well, they don't. They often are much lower than that. 40 or 50% in a given season may actually be a good level of protection. Now, I'm still a very, very strong supporter of flu vaccination because I'll take 40 or 50% protection over zero any time, so it's still worth it to get it. But one of the things that we found when we did this particular research is that Flumist looked really good, superior to the results we saw with inactivated vaccines, the injectables. But the problem was we hadn't done enough analysis to realize that these were all studies done in young kids. And when we look at what happens over time, if I've actually developed influenza infection, I actually develop a type of immunity that may not be protecting me against getting infected, but it may very well reduce how well that vaccine take occurs with the live attenuated vaccine, meaning there's enough in the mucosal surface to, at least in a sense, minimize that live attenuated vaccine success.

Dr. Osterholm: And so when studies were done on adults, they found very different results. And these were studies that Arnold Monto and his group at the University of Michigan did. Others did, showing that in fact, in adults, live attenuated vaccine isn't necessarily that effective. Now it still has some effect. And I would say that's better than nothing at all. But if I had my choice, I would go for the inactivated virus vaccine every time. As I do now, and because of my age, I can get the higher dose. But what the FDA did is approved this vaccine for 2 to 49 year olds to be allowing for administration in the home by a family member, and that may very well work, particularly for younger kids. But I think it's going to give you an inferior response relative to what you could get with the inactivated vaccine. So I know, again, I'm running up against the current here, but to me, I don't see this as a real game changer. I, I want people to get vaccinated for flu, but I would much rather have them get the inactivated vaccine and not the live attenuated vaccine. I know this will be a point of some controversy. There'll be others saying, no, no, no, you should get the live attenuated. That's really a good vaccine. And again, as I said in kids, I think that may be true. But right now for adults, that's not the vaccine I'd want to get. So I don't see this new approval by the FDA is really furthering our efforts here. In terms of flu vaccine uptake and having the most impact we can.

Chris Dall: Mike, given the polling data I cited in the intro and the the low uptake that we're seeing so far, how do you see the upcoming winter respiratory virus season playing out?

Dr. Osterholm: Well, Chris, you know, P.T. Barnum once said, if you want to make it in the big top, do not ever get into a ring with kids or animals, okay? And I think those are very wise words. I feel the same way about making predictions about respiratory viruses in a given respiratory season. So having qualified my results. Let me just say that the CDC's new forecasting group just put out a document this past week and a half looking at what they think will be the likelihood of a respiratory season of some significance. And of course, there's qualifications. But if they look at the combined COVID, flu and RSV combination, they actually expect that hospitalization burdens will be at or lower than they were last year, which last year they were moderate. I think this is actually a probably reasonable expectation, based on what we've seen with influenza viruses in the southern hemisphere up until now. You know, they've just moved out of their winter into their spring summer. This is often a good real life model to actually anticipate what might happen in the other hemisphere as we move into their winter. Now, I've already talked about COVID-19 and the fact that, you know, we've seen this peak.

Dr. Osterholm: It is coming down right now in cases. I think this reflects the maximal infection in the community. A lot of immunity right now. The XEC variant will surely continue to challenge us. We'll have to see how that goes, but I think we probably have a few months right now of lowered susceptibility in the population because of previous infection or vaccination. So if you minimize the COVID-19 cases, you look at flu and RSV and feel like because of the past activity that we've seen in the past several years, we we don't have evidence there's going to be a big hole in protection out there, that somehow there's going to be a large number of people who have not previously been exposed. So I do agree with CDC. I think the upcoming 2024 respiratory season peak hospitalization burden will be similar to or lower than last year, which is good news because last year, while it wasn't a crisis challenge, it still did in many locations where the number of hospital beds has been so reduced on cost containment issues, it still could be a challenge. But I think we're not looking at any major hit during the upcoming winter season.

Chris Dall: Let's turn now to H5 avian influenza. We continue to see a rising number of infected dairy cattle herds in California, the nation's largest dairy producer. Also, a recent study in the journal nature found that global strategies to control mammal to mammal avian flu transmission aren't working and pose an ongoing threat to people. Mike, regarding the ongoing outbreak in dairy cattle, is this just the new normal?

Dr. Osterholm: Chris I would be happy to ascribe this as the new normal if I had any idea what normal is with this situation. This is clearly one where we're in uncharted territories. No one had imagined eight months ago that dairy cattle would be a critical source of H5N1 virus in our human experience. Now that we have it here, we're all trying to learn and understand what it means. Let me just point out that in Colorado right now, the evidence supports the fact that they have pretty much cleared most of the farms that were previously infected as now being infection free, and they're back providing milk on the market. That's a good sign that says, yes, you can manage it within a given farm. I think we're all looking forward to those data becoming publicly available with the discussion. But I commend the Colorado group for what they're doing there. We're all looking with bated breath on what's happening in California, where we now have 44 different farms that have activity, and it appears that that number is growing every week as they're doing more bulk tank testing. The question I have there, which I don't see us getting any answers from the USDA as to what's happening, is this new infections. If it is new infections, how are they occurring? Are they because we have workers or other individuals going from farm to farm, spreading the virus with them as they go from one environment to the other? Is this, in fact a potential for another spillover? I don't think that there's any evidence to support that, but you might consider that.

Dr. Osterholm: I think more likely is that for a number of these farms, they may have had activity going on for some time before it was actually detected. And once they started doing bulk tank sampling in California, in areas where they saw some farms with it, the number of positive farms just grew and grew and grew. So we'll have to wait and see. But what we don't yet understand is what is it that is going to take us to try to, in a sense, eradicate this virus out of the dairy cattle of the United States? I might add that a paper published just this past week from Canada looked at their dairy operations, and they did widespread sampling in a number of areas of Canada and dairy cattle, and found no evidence of H5N1, which actually supports the fact that the spillover and the movement of cattle that did occur was largely a US based issue, meaning we weren't seeing cattle moving around the world. So at this point, I think it's fair to say that we just have lots of questions about the cattle. Now, where we're all on somewhat bated breath, you might say, is what's happened in Missouri. As you know, there was a patient who was hospitalized for an illness other than influenza who was not seriously ill, but was cultured as part of routine surveillance activities in Missouri and turned up having H5N1 because the individual was never suspected of having influenza H5N1.

Dr. Osterholm: By the time that there was actually confirmation of that, the patient had left and gone home, and people who might have been exposed to that patient were, in fact, now out beyond the time period that they themselves would have been culture positive, meaning that it would have been too late to do throat swabs on them and see if you can find the virus. So now we're waiting on what would be serology blood tests there. We can actually look for an antibody response to H5N1, which will be very unique. And that will tell us where other people infected. Now, where I'm having a problem right now is there's so many in the media and some of my colleagues who are basically leaving the public with the sense that there have been cases of H5N1 in health care workers in Missouri and related to this original case, that they just don't have the data to support that. There were several health care workers who had contact with the patient who did have respiratory illnesses in that same time period. And the problem with that is, is that there were a number of respiratory pathogens at the time that were in the community, and that any one of these could have also caused their that individual to have symptoms of a respiratory illness. So we desperately need the blood samples from these individuals who have agreed to give it to the public health agency. But it's taking far, far too long. I hope when this thing is over, we can go back and do a hot wash.

Dr. Osterholm: I believe that the state of Missouri public health officials have been dragging their feet in a way that is just unacceptable. You know, we're still waiting for the blood samples to arrive in Atlanta for them to test them for antibody. So number one is please do not yet assume that what's happened in Missouri is evidence of transmission of H5N1 from a patient to other health care workers. You know, by the time you listen to this podcast, maybe we'll have data available that will in fact answer this specifically. My own personal view, based on dealing with this virus extensively since 2003, in the field, is that this is not an example of H5N1 spillover to other people. And I think you're going to find that no one's going to be positive for H5N1. I could be wrong, and I'll be the first to acknowledge it if I am, but I don't think that's the case. And so there was a story in the New York Times last week that I thought was over the top in leaving people with the sense that, oh, my. The H5N1 outbreak in Missouri, while it didn't say exactly that, the feeling of who they interviewed and what they said all really could lead you to believe that that was the case. So I don't believe at this point that we have an H5N1 situation. And I might add, clearly, there's no evidence of ongoing transmission, meaning that we're now into third, fourth or fifth generations of cases based on exposure to that original case.

Dr. Osterholm: We don't see any evidence of that. So there's no urgent situation confronting us. But we want clarification. Was there any H5N1 transmission that point again? Did I come back to. I don't think that's going to be the case. The one lesson I hope we're learning here is that whether it's the cattle or the humans, we have not done a good job overall of state and local health departments as the CDC, in helping to make this be a seamless investigation. Now, in the defense of public health agencies, it's been a real challenge working with agricultural agencies and farmers themselves. They have often not allowed public health to be on the farm. Cdc can only come into a state when there's an invitation. So if their absence from a location doesn't mean that they just aren't coming. They would more than be willing to come. It's a matter of if they can. So stay tuned on this one. I don't see anything right now that appears to be changing the overall picture of still seeing cattle infected multiple farms in multiple states, but no evidence right now of any serious public health challenge to humans. Again, that could change overnight. One reassortment event and a cow's udder with an H5N1 virus and a seasonal flu virus. And this could all be for naught. We could be in a whole different ball game, but right now I don't see that being the case.

Chris Dall: It's time now for our ID query. This week we received an email from longtime listener Olivia, who wrote, I would love to hear more about the post-acute outcomes associated with COVID. For many of us listeners, the bigger concerns lie in how COVID might affect us in the months and years after, be it long COVID, immunity, damage, or other organ or cancer risks. Given that infections are now nearly impossible to avoid and we're all looking into futures with potentially multiple cases a year, these long run potentialities are growing more and more relevant to the members of the podcast family. So first of all, thank you to Olivia for this email. We've not had a long COVID update in several episodes, and this is a good reminder that it's a topic of great interest to our listeners, and it's something that we promise to provide more of. So, Mike, can you give us an update on some of the latest research on long COVID?

Dr. Osterholm: Well, Chris, first of all, I want to echo what you said and thank Olivia for this very thoughtful email. I also want to note that just because we haven't had a long COVID update in a few episodes doesn't mean we find it any less important than we did a few months ago. We know you're out there, you're suffering, and we hear you. For listeners who are interested in long COVID updates between episodes, I would highly encourage you to follow the work of our CIDRAP news team. They cover smaller studies and updates than we don't always have time to include in our episodes, and they do an outstanding job translating information from complex studies into something that is quite easily digestible. With that in mind, Olivia, I want to briefly cover three long COVID studies that were recently covered by CIDRAP news. All of these CIDRAP news articles will be linked in our episode description. The first is a preprint, a study that has not yet been peer reviewed, involving nearly 3400 surveyed participants. Survey participants were polled between March 30th and September 1st of 2023, and asked about how many times they had been infected with SARS-CoV-2 and whether they experienced long COVID. The researchers found that those who had two COVID-19 infections were more than twice as likely to report experiencing long COVID, and those who had three or more COVID-19 infections were nearly four times as likely to report experiencing long COVID, compared to those who had had just one COVID infection. In other words, the researchers found that the risk of long COVID increased with reinfection.

Dr. Osterholm: Specifically, they found that the odds of experiencing fatigue and functional limitations difficulty with everyday tasks like dressing and bathing were much higher with reinfection. These results are certainly very concerning, especially now that so much of the population has been infected at least once and is at risk for reinfection. This bears additional study. The second study I want to highlight is one that looked at the long term brain impacts of severe COVID infection. The study was conducted by researchers in the UK, who compared cognitive outcomes in 351 patients who were hospitalized for COVID and nearly 3000 matched controls people who were not hospitalized due to COVID infection. Researchers assessed the participants cognitive skills, conducted blood tests, and examined brain scans sometime between 12 and 18 months after their COVID Hospitalizations. Sadly, the researchers found that the post-COVID cognitive declines in hospitalized patients looked similar to 20 years of normal aging. Participants had reduced brain volume and high levels of proteins associated with brain injury in their blood. Fortunately, the researchers did see trends towards some recovery with longer term follow up. Still, these findings are far from hopeful and are an important reminder of the complications that can occur with severe COVID infection. Finally, on a more optimistic note, the third study I want to cover is one from the ongoing NIH recovery trial looking at the efficacy of the diabetes drug metformin on preventing long COVID. These are studies that actually originated here in Minnesota at the University of Minnesota. Looking at metformin. We've previously covered that trial that I just mentioned, which found that metformin reduced the risk of long COVID by 40% in And adults who are overweight or obese but were not diabetic.

Dr. Osterholm: This new study looked at the effectiveness of metformin in preventing long COVID among adults who are type two diabetic, by comparing electronic health records from nearly 76,000 adults taking metformin for diabetes and over 13,000 adults taking other diabetes medications. They found that those taking metformin had a 13 to 21% lower rate of developing long COVID than those taking other medications to treat their diabetes. These results are really promising, particularly because metformin is a very well studied drug with strong safety profiles. I hope we continue to see research on the effects of metformin used on long COVID prevention in additional populations, assuming that the results continue to be promising, I hope that more providers consider prescribing metformin for their patients with acute COVID infections. Right now, I can tell you with certainty, if I were to have a COVID case, I'd want my Paxlovid and I'd want my metformin. And finally, as I always do in covering long COVID, I want to take a moment to say to our listeners that are struggling with this condition, or who have friends or family struggling with this condition, we are here for you. We think about long COVID every day. We may not be able to cover this issue in every episode, but please know it's always at the front of our minds and we will not stop listening to you and advocating for you. And our news team will continue to exhaustively cover the long COVID issue.

Chris Dall: Now for some other infectious disease news, as if Central Africa didn't have enough infectious disease issues to deal with, health authorities in Rwanda have reported the detection of 27 cases of the highly virulent Marburg virus disease, with nine confirmed deaths. So, Mike, for starters, what is Marburg and how worrisome is this outbreak?

Dr. Osterholm: Well, Chris, I'll start by answering the first part of your question. What is Marburg? Marburg virus disease is caused by a filovirus, the same family as the virus that causes Ebola. Marburg is up to 85 to 90% fatal without treatment, and the symptoms and transmission patterns are very similar to that of other hemorrhagic fevers in the same family virus. Notably, the source of this virus ultimately is the Egyptian fruit bats, which are through parts of Africa and the Middle East. These bats carry the virus, and when humans have contact with them, they can pick this virus up. Symptoms of Marburg, which include fever, diarrhea, vomiting and severe hemorrhaging or blood loss, can begin anywhere from 3 to 21 days following exposure. Once the virus is infecting a human, it can then spread through direct contact with blood or other body fluids. It's not airborne, like SARS-CoV-2 or measles. There are currently no approved vaccines or treatments for Marburg virus disease, though there are many currently in development. As you mentioned, there is currently an outbreak of Marburg virus in Rwanda. As you pointed out, with 27 confirmed cases and nine deaths, I'm sure these numbers are going to change substantially in the days ahead. The apparent lower case fatality rate of nine deaths for 27 patients should be interpreted cautiously, as these are very early case onsets, and I think a number of these patients still are very likely to die in the days ahead.

Dr. Osterholm: This is the first outbreak of Marburg that's been reported in Rwanda, though there have been outbreaks in neighboring countries in recent years. Let me just say at the outset, if there was any country where this had to emerge, Rwanda may be what you would call the best country. Nobody wants any country to have Marburg. But because Rwanda has by far one of the most sophisticated healthcare delivery systems of any African country, this really makes for a much more efficient public health response, so that is good news. The outbreak was declared this past Friday, with the first six deaths reported the following day. As is often the case with viruses like Marburg and Ebola, most or at least 70% of those affected so far have been health care workers, as they are the ones most likely to have the type of close contact with blood and other body fluids needed for an exposure to occur. This is particularly true in countries without robust medical and public health infrastructure, where access to the appropriate PPE and other infection control measures may be limited. There have been at least 300 contacts of infected individuals that have been identified in Rwanda, some who have been put into isolation facilities and others who have been instructed to quarantine at home.

Dr. Osterholm: Rwanda's health ministry has imposed a limit on funeral sizes for those who have died of Marburg virus, namely at 50 attendees, and it announced that visitors will not be permitted to health care facilities for the next 14 days to reduce the risk of disease transmission. With all this in mind, I want to address the second part of your question. How worrisome is this outbreak? Well, let me just remind everyone that Marburg, again, is very similar to Ebola. And for decades, everyone assumed Ebola would always be a small regional outbreak at most usually a very localized outbreak. Until the 2014 2016 West Africa Ebola outbreak occurred, where there there were over 29,000 cases, over 11,325 deaths. Yes. Could Marburg get that big? It could. If in fact, we see the kind of risk factors we saw in West Africa with Ebola, with the close human contact, the inability of health care systems to respond, and unfortunately, the slow response of the international community. So do I think it'll get that big? I don't think so, I hope not. I again, am encouraged by the opening salvo being in Rwanda and their ability to respond to help limit it, but I think it's clearly one where we could anticipate much larger outbreaks. And because people travel who could be infected without knowing it initially, we could see cases show up in countries around the world, just as we saw with Ebola in 2014 and 16.

Dr. Osterholm: We ended up having cases right here in the United States. So while the efforts with Ebola were successful in stopping that outbreak, it should give us pause to believe we could do the very same with this. But I think at this point, again, the idea that we invest what we can as quickly as we can to limit transmission will be very important. And finally, it goes back to something that our center has really wrestled with for some time. Back in 2017 and 18, we were responsible for putting together a vaccine development roadmap for Marburg virus vaccines, and that sat on our website, largely unused for the past several years. Uh, and it now is the time to say, boy, wouldn't it have been great if we would have had a vaccine that we could use in these kinds of settings, both in terms of outbreak response, but even vaccinating in advance of a potential Marburg outbreak. So stay tuned. We're going to hear more about this. Uh, do I believe that the world understands how critical it is right now to get this under control? They're reminded constantly by what Ebola did in 20 1416. But at this point, we still don't know which way this is going to tip.

Chris Dall: Finally, the United Nations last week held its second high level meeting on antimicrobial Microbial resistance, or Amr, and member states approved a political declaration with a wide ranging set of commitments to address the issue. Mike, do you think this could help turn the tide against what you have called a slow motion tsunami?

Dr. Osterholm: Chris, I wish I could be optimistic about this, but it's a challenge, as many of you on this podcast know, because we've discussed this issue before. Antimicrobial resistance has already had quote unquote wake up call studies that laid out much of what we saw at the high level meeting antimicrobial resistance last week in the United Nations in 2015. The British government, under the leadership of Sir Jim O'Neill, put out what would become known as the O'Neill report, which was an exhaustive review of antimicrobial resistance. What needed to be done to curb it? How we could address it. The finances were there, the kinds of estimates of what would happen if we didn't respond or there. And yet I look back on what advances were made since that time in addressing this, and in many ways, it's like climate change. It just seems to be so big, so difficult to get your arms around that many people feel like, well, yeah, it's a real problem, but what are we going to do about it? And I'm so glad that the United Nations did, at a second high level meeting on antimicrobial resistance, really tried to address this, but there wasn't really anything new. You know, we still have challenges with supply availability in many parts of the world, even here in the United States. Look what's happened with syphilis, where for those individuals who are pregnant, who can't take the basic antibiotic that is being used to treat syphilis, and they need a backup common antibiotic, but it's in such short supply they don't have it. I mean, here in Minnesota, we had 29 cases of congenital syphilis last year in our state when I was state epidemiologist back in the early 80s.

Dr. Osterholm: If someone had said to me, we're one day going to have 29 cases of congenital syphilis, I said, no way. That would require a complete default of the medical and public health systems. So I don't believe, but we still have supply challenges. Then we have the issue of how do we actually match up the right drug and bug, and we don't have the kind of tests today that what we call point of care tests that a clinician would know immediately at bedside what that organism is and what it's resistance to. And there surely are prototypes. There are surely technologies that could get us close to that, where we could understand we don't need to use the howitzer here. This is a BB gun kind of infection in terms of the organism and its resistance pattern. On the other hand, we don't want to treat with a BB gun when we need a howitzer to take on this case. And so we have seen very little that way. We continue to see over-the-counter drug availability for many antibiotics around the world. So when your environmental sanitation programs are desperately lacking sewers, safe water, etc., a lot of gastrointestinal illnesses, etc. end up resulting in going to the local store and getting antibiotics over the counter. Well, that also is a real challenge because that doesn't match up the bug drug combination. So, you know, I just want to close by saying there's also the issue of investing in new drugs. And we surely need to do that. There are things that are being done to help move that forward. But what is the market for those? Imagine a drug today that you make with the idea of selling it.

Dr. Osterholm: And anybody who's been watching the pharmaceutical company commercials on the TV or in print, you know, we're selling drugs, selling drugs, selling drugs. And these are drugs often that you'll need for the rest of your life. Now we have antibiotics where we say, don't use this unless you absolutely have to. And when you do use it, use as little as you can. Now what's the market incentive around that. Okay. And so from a pharmaceutical industry standpoint, what is it that would entice them to continue to want to stay in the world of anti-infectives and infectious diseases? And we see basically a major pullout of companies over the past several years in this area. They'd much rather invest in lifestyle drugs, chronic disease, drugs, etc. so I think we have a real challenge. I hope that we see some kind of actions that come out of this meeting. But as you've heard me say many times, hope is not a strategy. And I don't see what's going to be different than what we saw with the O'Neill report in 2015. So while I may be, uh, jaded and and not objective on this issue, I think my, you know, almost 50 years in the business gives me some perspective to say this is a critical issue. We need to do much more, and we're not. And, Chris, you know, I'd like to toss it back to you. You cover this topic area for CIDRAP news. You are well recognized on an international level for your reporting. What's your sense of what this is all about?

Chris Dall: Well thanks, Mike. Um, first of all, I agree with everything that you that you have said. Um, there were a few things about the UN meeting and the political declaration that was adopted that stuck out to me, and I started covering this topic in 2016, right around the time of the first UN high level meeting on this issue. So the first thing that stuck out to me was they recognized that right now there are two different issues going on with Amr. One is that in high income countries like the United States. We're seeing an increase in multidrug resistant bacterial infections. So these are the types of infections that occur in ICUs, in patients who are immune compromised or have other health issues. And the antibiotics we've been using to treat them are becoming less effective. On top of that, as you noted, the pipeline for new antibiotics is very weak for a variety of reasons. And so our treatment options are becoming limited. The other issue you have, though, is that in developing nations, the bigger issue is the lack of infection prevention control and a lack of access to antibiotics. So these are countries where you not only have a larger prevalence of bacterial infections. And that's because, as you noted, they have lack of access to clean water and sanitation. Maybe their children aren't getting the vaccines they need for preventable diseases. And on top of that, they don't have access to the right antibiotic that could treat those infections.

Chris Dall: So yes, the antibiotic might not be available in that country, or it might be too expensive, or they could go get one over the counter. But who knows if it's the right antibiotic. And if they're not getting the right antibiotic, their infection is not going to be cleared and it's only going to promote resistance. So a lot of people think that addressing those issues, promoting infection prevention and control and increasing antibiotic access could do more to help slow Amr than producing new antibiotics. So the UN now seems to recognize this. And you saw a lot of focus on infection prevention and antibiotic access in the document. So and a lot of people really thought that was important. The other issue that received a lot of attention is the infrastructure for dealing with this issue. Back in 2016, the UN called for countries to have national Amr action plans. And right now 178 countries do have those plans, but only about two thirds of them have implemented them. Only about 10% have dedicated funding. Mike, I think you'd agree that an action plan that isn't being implemented and has no funding doesn't really help anyone. So the UN is calling for all countries to implement those plans by 2030, and instead a target of $100 million in international funding to help countries that lack money with their plans. Is that going to be enough? It's hard to say, but at least there is an acknowledgment of of the problem. Finally, the last thing here the UN document did not set any targets for reducing inappropriate antibiotic use in people or food producing animals.

Chris Dall: And I think some people were really disappointed by that. So as you know, we have a big problem all over the world with people using antibiotics for things like cold symptoms and other respiratory ailments that are probably caused by viruses. There's also widespread use of antibiotics in the beef and poultry and pork industries. Both of these issues are contributing to rising rates of Amr around the world. Many groups are calling for a 20% reduction in inappropriate human antibiotic use and a 30% reduction in an inappropriate use in food animals. But the UN document steered clear of those targets. So can we get a 10% reduction in Amr deaths by 2030, which is what the UN is calling for without setting those type of targets. We'll see. I share some of your skepticism around this, Mike, because I've been covering this for eight years. We've seen a lot of reports like this. We've seen a lot of policies put out. But this is an issue like climate change. It's very challenging for people, for countries to get their arms around. It's hidden in a lot of ways, and there are a lot of issues that the world is dealing with right now. So hopefully when the UN meets in 2029 to discuss this topic again, we'll have some seen some forward progress, but that remains to be seen.

Dr. Osterholm: Thanks, Chris, for your very thoughtful comments, and I think you have laid out very nicely from your own experience covering this topic. The challenges that we have. And you know, failure is not an option here. This is about our kids and our grandkids in the world we live in. And the idea that one day we may be entering into a post-antibiotic era, that's that's a frightening thought. So I hope that the world takes this seriously, uh, as it's one of those situations where if we don't, we will ultimately one day know, uh, a kind of a post-antibiotic era consequence, and then it'll be too late.

Chris Dall: And now it's time for this week in public health history. Mike, who are we commemorating this week?

Dr. Osterholm: Well, as I think most of the listeners now know by this time, I love this section of the podcast, uh, because I think celebrating the victories in public health are really a reminder of just the power of this particular profession. We're going pretty far back this week, more than 300 years to October 4th, 1716. This marks the birth date of James Lind. Doctor Lind was born and raised in Scotland, and took coursework at what is now known as the Royal College of Surgeons at the age of 15. He began an apprenticeship as a surgeon and joined the Navy as a surgeon's mate when he was 23. You can certainly imagine the wide range of injury and diseases aboard these ships in the mid 1700s. According to records, one British expedition sent to raid Spain's holdings in the Pacific and led to the death of 1300 out of 2000 men to illness alone. An ailment known as scurvy was ravaging sailors with weakness, bleeding gums, aching joints, poor wound healing and potentially death. No one seemed to know what was causing this horrible illness, but guesses included the damp conditions aboard the salty sea air. Excessive exercise or poor digestion. Like many diseases in centuries past, there were also a variety of treatments that were purported to help captain Cook, the infamous explorer swore by a mixture of sauerkraut and malt.

Dr. Osterholm: Others use an elixir of vivitrol containing sulfuric acid. Of course, bloodletting was also proposed as a solution. It wasn't until James Lind began his work on board that a more methodical approach was taken. Doctor Lind created what we now recognize as one of the first clinical trials. He randomized a group of sailors with scurvy to receive different treatments and test how long it took to recover. By the end of the first week, the sailors who had received two oranges and one lemon per day were well enough to nurse the other sailors back to health. Alongside Lind, it was clear that this intervention had worked. It still took time for Lind's results to spread, but soon citrus fruit juices became a daily part of the sailor's diet. It wasn't until 1928, almost 200 years later, that scientists would identify that vitamin C deficiency was the culprit for scurvy and that citrus fruit was able to overcome the condition. However, Lind's contributions to medicine is undeniable in how we continue to use randomized clinical trials today. So thank you, Doctor Lind, for this invaluable scientific tool and your legacy in naval medicine. And may all of us remember the power of epidemiology and the epidemiologic methods that we use.

Chris Dall: So, Mike, what are your take home messages for today?

Dr. Osterholm: Well, you know, you can almost assume that 1 or 2 of them are going to involve the issue of COVID, and this is an urgent one. Please, please, particularly for those of you who are over age 65, avail yourself to the vaccine. If it's been at least two months since your last dose or since you've been previously infected. I'd love to see us drive those numbers of serious illness, hospitalizations and deaths down. And this is surely one important tool. Number two, I still believe it's too early to get your flu vaccine. If you've gotten it, you gotten it, go with it. But for those that have not gotten it, continue to follow us here. We will keep track of what flu activity is looking like. And as soon as we begin to see the potential for increasing cases, we'll let you know if you go in within the next days to week after that time, you still have plenty of protection within the next week or two after that with your vaccine. So you'll be covered and you will have a prolonged period of coverage well into even the beginning of the new year.

Dr. Osterholm: And finally, the H5N1 public health response is a challenge. You know, I can only say that when I look at the criticism that we as a country are focused on China and their response to the Wuhan COVID situation. I have to ask myself, who are we to be critical of them when our own responses still are sorely lacking? And I think this has been the case. I don't put it into any one bucket and say that's the culprit. The antagonism between the agricultural industry and public health surely was a challenge. The inability for CDC to go into a state without an invitation by the state to work on this. In the case of Missouri, I believe the slowness of the response has been a sure challenge. So we need to learn from this, though, and I hope that somehow, somewhere we're able to do a review or what we call a hot wash, to actually learn not to blame, but to learn and say, how could we have done this better? And what would we have done? And so if we do that, I think it'll be an incredibly valuable lesson.

Chris Dall: And what is your closing song for today, Mike?

Dr. Osterholm: Well, in keeping with the dedication, which I dedicated to all those on the podcast who have been so kind and supportive of our work at CIDRAP, this podcast family to me has been invaluable. I think back on getting through the pandemic and without any question each and every time it comes back in part to having been able to participate with you on the podcast, to hear from you, to learn from you, to understand from you. And I just I can never say it enough times. Thank you. Thank you. So this song that we've picked this week is one by Natalie Merchant, one of my favorite American singer songwriters. And the title of it is Kind and Generous. It was released as the first single from her second studio album, Ophelia. Back in 1998, it became a radio hit in North America, peaking at number 18 on the US Billboard. It's a special song in the message that it shares with us. Here it is kind and generous by Natalie Merchant. You've been so kind and generous. I don't know how you keep on giving. For your kindness. I'm in debt to you for your selflessness, my admiration for everything you've done. I know I'm bound. I'm bound to thank you for it. You've been so kind and generous. I don't know how you keep on giving. For your kindness. I'm in debt to you. And I never could have come this far without you. For everything you've done.

Dr. Osterholm: You know I'm bound. I'm bound to thank you for it. Oh, I want to thank you for so many gifts you gave with love and tenderness. I want to thank you. I want to thank you for your generosity, the love and the honesty that you gave me. I want to thank you, show my gratitude, my love, and my respect for you. I want to thank you. Oh, I want to thank you. And with that, thank you, thank you, thank you, thank you, thank you. I want to thank you. I want to thank you. I want to thank you, Natalie Merchant. I just want to thank you all again for being with us. And I want to say again one more time how much we appreciate your support with this. I would just say, hold on. We got a lot of public health issues emerging. Uh, the challenges we have are many, but I don't ever have to wonder why I do my job and why I stay at my job. You know, I've got these grandchildren that to me, that's more than enough reason every day to get up and take on the dragons of the infectious disease world. So I hope you have a good couple of weeks. Uh. Stay safe, be kind. If there's anything that I can urge you to do. Please be kind. Right now, the world needs that more than I could ever imagine. Be safe. Be kind. Thank you.

Chris Dall: Thanks for listening to the latest episode of the Osterholm update. If you enjoy the podcast, please subscribe, rate and review wherever you get your podcasts, and be sure to keep up with the latest infectious disease news by visiting our website CIDRAP.umn.edu. This podcast is supported in part by you, our listeners. If you would like to donate, please go to CIDRAP.umn.edu/support. The Osterholm Update is produced by Sydney Redepenning and Elise Holmes. Our researchers are Cory Anderson, Angela Ulrich, Meredith Arpey, Clare Stoddart, and Leah Moat.