Alexandra Ward

Health officials in China have confirmed a case of bubonic plague in a herdsman from the Inner Mongolia district, triggering increased prevention measures throughout the region, according to the 

The man, who was diagnosed Sunday, is under isolation at a local hospital where he is receiving treatment and reported to be in stable condition.

>>> The infectious disease news you want, anytime you want. 

The city health commission has issued a Level 3 warning to last until the end of year, urging residents not to hunt, transport, or consume potentially infected animals, including marmots, and to practice good infection prevention measures.

"At present, there is a risk of a human plague epidemic spreading in this city. The public should improve its self-protection awareness and ability, and report abnormal health conditions promptly," the local health authority said, 

The confirmed case follows 2 others reported last week in Mongolia in brothers who had consumed marmot meat, 

 bacterium, bubonic plague is spread via the bites of infected fleas from small mammals.

"The lymph node then becomes inflamed, tense and painful, and is called a 'bubo,'" according to the 

. "At advanced stages of infection the inflamed lymph nodes can turn into open sores filled with puss. Human to human transmission of bubonic plague is rare. Bubonic plague can advance and spread to the lungs, which is the more severe type of plague called Pneumonic plague."

Without treatment, plague’s case-fatality ratio ranges from 30% to 100%.

Articles

Health officials in China have confirmed a case of bubonic plague in a herdsman from the Inner Mongolia district, triggering increased prevention measures throughout the region.

China Confirms Case of Bubonic Plague

Thomas File, Jr. MD, MSc, FIDSA, president of Infectious Diseases Society of America (IDSA), chair of the Infectious Disease Division, and co-director of the Antimicrobial Stewardship Program at Summa Health in Ohio, discusses IDSA’s role in the COVID-19 pandemic.

Interview transcript (modified slightly for readability):

: Hi, I’m Allie Ward, editorial director of 

. Joining me today is Dr. Thomas File, president of the Infectious Diseases Society of America, chair of the Infectious Disease Division, and co-director of the Antimicrobial Stewardship Program at Summa Health in Ohio.

Dr. File, let’s jump right in. IDSA has been at the forefront of the COVID-19 pandemic since the beginning, continuously setting and updating guidelines, as well as weighing in on some of the debate surrounding aspects of public health’s management of COVID. Can you talk a bit about IDSA’s role in this pandemic?

 Thank you Allie, for having me, and sure, I'd love to do this. As you can appreciate, all of our members and our staff have been working tirelessly almost 24/7 on this pandemic for the last 6 months really. I can remember very vividly getting an email on January 21 actually from one of our ID colleagues, who's a member of IDSA, who had just admitted at the time the first patient with COVID-19 or infection due to SARS-CoV-2 to a hospital in Washington and of course that started multiple patients that we've seen since then. But literally, since then and into February, our volunteer members of IDSA, our staff of our association have pivoted away from non-COVID activities to almost 24/7 working on COVID.

As you said, we've been working almost on all aspects. Many of our members are involved in research for antivirals, for developing vaccines. We've been working very hard in the public health sector—many of our members are public health experts&mdash;we've been working very extensively in education, educating the public, educating our colleagues. But most importantly, actually taking care of patients. We have a membership of over 12,000 infectious disease specialists and scientists and researchers and public health experts and other health professionals all involved in the care of patients with infectious diseases. Basically, we've all been working on this COVID pandemic since that time.

Now, as you mentioned, our society has done many things on our website to develop protocols, to develop policies. We've developed a variety of telebriefings to help educate the public and the media. We've developed very significant rapid guidelines for our members and for everybody else caring for these patients. We have guidelines for management and treatment, guidelines for infection control, and guidelines for diagnostic testing. And these are live guidelines. They're living documents so we're changing them and we're already updating the management and treatment guidelines as we see new information coming together. We've been had to be in significant communication with government, with policymakers, both national and the state and local level, to make sure that we're getting the best information so that our patients are being appropriately treated. We're working very closely with US Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH). We've developed a learning network with CDC. As you can see, our society has been very active. We're working very tirelessly, but that's our mission. We want to make sure that we provide the best care for our patients. We all have to collectively work to respond appropriately to this pandemic.

: In formulating guidelines, how challenging has it been to keep up with the volume of news and data regarding COVID? What advice do you have for clinicians in the field trying to keep up on the latest developments?

 Now, Allie, that's absolutely appropriate. Almost there's new information daily, and it's really important that we have accurate information and not misinformation, unfortunately, which can sometimes happen, particularly on social media and it can be disseminated so. As you're even aware, some of the studies that have been published had to be retracted because we have to just make sure that information that is being disseminated is appropriate and that it is the best for care of our patients. It's vital that we all have sources of very accurate information. Obviously, IDSA has a very active website. We have a COVID resource center there that has all kinds of information. There's a directory, whether you want to go to various guidelines or if you want to go to protocols from other institutions to see how they're handling personal protective equipment (PPE) and contingency assessment. There’re telebriefings, there’re podcasts, we have blogs on our website. So we have all kinds of sources of information that can be accessed through our website, which is 

: Last week, the US Food and Drug Administration (FDA) revoked the emergency use authorizations for hydroxychloroquine and chloroquine. IDSA put out a statement supporting the decision. Can you talk a bit about how did the organization came to its conclusion there?

 If you look at the FDA site, they indicate that their decision was based on new information, which suggested—and we agree with that&mdash; that suggests that there's really no significant benefit of these 2 drugs in patients who are infected with SARS-CoV-2 or who have COVID-19.

Literally in the last week, 2 very large studies—I'm talking about tens of thousands of patients that are enrolled in these studies…One is a recovery study that's overseen by investigators in Oxford, England. And then the SOLIDARITY study, which is overseen by the World Health Organization (WHO) both suspended or halted recruitment into studies where they were evaluating hydroxychloroquine. Why? Because in their assessment, they really did not find any benefit. And then also there was a study that was published out of University of Minnesota showing that patients who were exposed to COVID-19 and then given hydroxychloroquine really had no benefit in preventing infection. We have robust data now, which suggests that there just isn't a significant benefit at all of hydroxychloroquine. It certainly was our assessment as well at IDSA. We're going to be showing that in our updated guidelines as well, that there's just really no benefit of these 2 agents.

: News broke this week that investigators in the UK saw some success with a cheap and widely available steroid in terms of reducing mortality in patients with COVID-19. What was your reaction to that news and do you consider dexamethasone a viable treatment candidate?

 Anytime we get good news, and there's data that suggests that there's interventions that can be helpful to our patients, we certainly welcome that. Again, this is from the same adaptive study that I just mentioned, that recovery study that's overseen by investigators in Oxford, England. This is a preliminary report, we haven't seen the published data, so we have to really look at the published data. But it's the use of dexamethasone, particularly in patients who are fairly severely ill and have significant illness often requiring mechanical ventilation. And that's important because, up until now, there's been a question about what interventions can be valuable in these patients who now are to the stage where now they're on the ventilator, perhaps developing acute respiratory disease syndrome (ARDS). The fact that there's a study that suggests that there's benefit is very helpful. We still have to wait to see the peer-reviewed published data, but I'm certainly encouraged by this initial information.

: Switching gears to vaccination…Are you encouraged by some of the progress being made on vaccine development for COVID-19?

 I'm encouraged by that as well. I'm a very optimistic person, actually. At least when I hear about the progress that a variety of investigators and developers are having with their development of a specific vaccine—and there are several that are in evaluation right now different platforms for the vaccines&mdash;I'm encouraged because it looks like they're going to already be starting phase 3 studies next month. Hopefully these can be geared up and show definite benefit and be shown to be very, very safe.

What's the earliest that could be available? I don't know. I mean, people say possibly by the end of the year. I think that's very, very optimistic. But certainly, if we can get it within a year, from the standpoint of vaccine development, that is very, very quick. It's really going to be important because until we can have a vaccine and therefore have a large segment of the population receive this vaccine, therefore have herd immunity, it's going to be very difficult to control this pandemic.

: From your perspective, what has been the biggest obstacle in navigating this pandemic?

 When I think about that, there's probably several. I think right now the biggest issue is what I'm going to call, and what others have called, “COVID fatigue.” So much of the population has been in stay-at-home mode or shelter-in-place mode for a couple months. Now, the weather's nicer, communities are opening up, restrictions are reduced, and people are outside. They want to perhaps remove their masks, forget about social distancing, and that is not good. That's going to jeopardize being able to safely open up the community. I think we have to provide good guidance that says, when we're opening up, we still have to practice these good health measures, such as physical distancing, such as wearing masks, such as hand hygiene, such as disinfection. That's extremely important, or else we're going to jeopardize opening up the communities. And some states have seen a significant spike in cases as they're opening up. That's the worst that we could see if we have to lock down again, and we don't certainly want to do that. I think what I'm going to call “COVID fatigue” is a big issue and we have to try to maintain good practices and promote this to the general public.

I think other issues of concern is we still probably don't have the adequate testing that we need. Until we can have adequate, easily accessible testing, and then you can do contact tracing so we can go back into this mode of containment, so that we identify patients, we identify who's in contact with them, we can quarantine them or self-monitor them, so that we can contain further transmission. That's going to be extremely important.

From a standpoint of workforce, I'm going to say a barrier is that we just don't have enough of us. We don't have enough public health experts; we don't have enough people who actually are going to be required to do the contact-tracing. There's one study that suggests we probably need at least 300,000 in the United States to do that adequately, and we just don't have that right now so we have to ramp up. This is a potential obstacle if we're going to be able to continue to contain this pandemic as best as possible.

: Concerns over a “second wave” are mounting as we approach fall and the start of flu season. How serious could this second wave be and what can clinicians do to ensure the public is aware of this threat?

 I think that's a great concern. There're many potential scenarios as to what's going to happen with this pandemic, but I have to think that the most common is that we're going to continue to see low level of activities, and maybe general occasional spikes as we go through the summer. But then the great concern is that when we go into the late fall or early winter, the respiratory season, we're going to see another surge. If you look at the history of pandemics, that's what's happened, I mean, even the 1918-1919, even the 2009-2010 pandemic with H1N1, it started in the late winter, early spring, but then the next winter it was even worse and so we have to be concerned about that. And then like you said, if this occurs at the same time as influenza, it could even be worse because we do know that dual infections, even dual viral infections, can be associated with greater morbidity and, unfortunately, mortality. What should we do? Well, again, we have to be prepared for that. Hopefully, we'll have some antiviral medicines that we've already mentioned. But again, we're going to have to be very, very stringent on maintaining the health measures that I've mentioned and using the masks. When people go back into colleges and businesses or whatever, we're going to have to wear the mask, we're going to have to physical distance as best as possible, and practice hand hygiene, so we're just going to have to be very aware of that and promote that as best as possible until we have that vaccine.

: What is your message to your peers and colleagues in infectious disease during this time?

 Those of us in infectious disease, we've been working tirelessly 24/7 to control this pandemic, and I'm so proud of all my friends and colleagues who are doing this and, in many cases, even putting their lives at risk, their families at risk, but they're doing this because they know that this is best for the community, this is the best for their patients. This is our mission. I'm very proud of our colleagues who are involved in this case against this pandemic. Collectively, let me just say this: If we all work together, we are going to get through this. So thank you to every one of you who are working tirelessly to manage this pandemic.

Videos

Thomas File, Jr. MD, MSc, FIDSA, president of the Infectious Diseases Society of America, weighs in on COVID vaccine development, fears of a second wave, and treatment candidates.
 

Thomas File, MD: IDSA's Role During COVID-19

 Steven Woloshin, MD, MS, co-director of the Center for Medicine and Media at The Dartmouth Institute, discusses a recently authored article in the New England Journal of Medicine describing the challenges and implications of false negative tests for SARS-CoV-2 infection.

 and joining me today is Dr. Steven Woloshin, co-director of the Center for Medicine and Media at The Dartmouth Institute and founder of the Lisa Schwartz Program for Truth in Medicine.

Dr. Woloshin and colleagues recently authored a Perspective article in the 

 describing the challenges and implications of false negative tests for SARS-CoV-2 infection.

Let’s dive right in. What prompted the 

 article on the accuracy of SARS-CoV-2 diagnostic tests?

 Sure. I missed my mother. I wanted to visit her. She would be considered at higher risk because of her age and she lives in New Jersey and I wanted to visit her and I just wondered whether I should get tested or not. In my research, I’m often looking at US Food and Drug Administration (FDA) documents, mostly about drug approvals, and so naturally I went to read about the tests that have been authorized under Emergency Use Authorization (EUA). I started looking at them and the more that I read, the less convinced I was [and] the more concerned I was about the quality of the validation studies. I figured it would be good to communicate what I learned to my colleagues and others, and also [in] talking to people there was also some confusion about how to interpret test results in general. So the article also included a bit on how to calculate probabilities using the sensitivity/specificity of the test.

: Do we have any estimates about just how common false negatives are for COVID diagnostic tests?

 We do but I think there's a lot that we don't know, and the evidence is kind of spotty. What we know is if you look at the EUA, the companies are supposed to report sensitivity and specificity; it's a part of the clinical performance of the test. The problem is, often what they're presenting is the percent agreement between a new test and some previously authorized test. And those numbers usually come out to be…positive agreements or like in the 95% range. I think the sensitivities are often at 100% level. The problem is that that's not what clinical sensitivity and clinical specificity mean.

Because when I want to know how well a test works, I certainly want to know that if I have a specimen with the virus in it, that the test will identify, it will be positive. I want to know that if I have a specimen that doesn't have this virus in it or virus particles, whatever it is you're looking for, and I test it and it will be negative. That's really critically important.

But as a clinician, I want to know if I have a patient who had COVID, and I test them, will the test be positive? And that’s really different. And the reason it's different is because, in the first case, when it has no positive and no negative specimens, I've taken out a lot of uncertainty that exists in clinical practice because when I see a patient, I have to take the sample, so it might be that long, it might be an inadequate sample. It has to be processed. It has to be transported to the lab. All that sort of stuff might cause problems. Once it gets the lab, the test itself might not function. And so with all these things, they're always opportunities for error.

The way the EUA, the percent agreement approach, works, you miss out on all that pre-analytic phase, all that stuff happens before the actual test is done. And that means that the sensitivity of the test is overestimated. Because swabs might not be done right, they might not pick up the virus or might be done at the wrong time, early on in a latent infection when the person isn’t producing a lot of virus particles, or it may be processed incorrectly, handled incorrectly, whatever. You need to account for all that stuff.

None of the EUAs that we looked at provide that kind of information. [In] published studies—some are preprints, some are actually published&mdash;there’s been an attempt to try to get at this clinical sensitivity. In our article, we cite a meta-analysis on the 5 trials, and they gave a range of false negative rates of 2% to about 30%. And most recently, just 2 weeks ago, there was an article in the 

, which looked at false negative rates by time from the time of exposure, and all the time costs of the infection. They looked at 7 studies, and they found ranges of false negative rates, they did some modeling…Sensitivity varies according to time so at the time that you’re initially exposed, there is very little virus in your body, so the false negative rate is really high. Over time, over maybe 5 days or so until symptoms start to appear, the false negative rate drops. And then by about 3-4 days after symptoms appear, the false negative rate gets to its lowest point, but still about 20%. It matters what the timing of when the sample is drawn.

The bottom line is that the evidence is mixed. It's maybe not the best evidence. It sounds like the best guess is that, on average, the sensitivity of the PCR test is probably in the 70% range. That's the figure that you often see, but this is one of the things that would really be great if we had better evidence, so if the test was subjected to better tests that recorded the real clinical sensitivity and specificity in the EUA document.

: In what ways can SARS-CoV-2 diagnostic tests produce inaccurate results?

The problem is if the tests were perfect, then if you tested positive you know the person is infected. If you tested negative, you know they’re not infected. That’d be great. But no test is perfect. You have to account for that in how you interpret the results. Because of the false negative rate, when you have a negative test, you may not have ruled out infection. And that matters. If the test has a really low sensitivity, it's possible…and that matters because if you tell someone they’re negative, they may think that they're clear and they can go out and do what they want. They're not infecting other people and that's not the case. Because if there are people who have false negative results, and they go out and they don't practice social distancing or wear a mask or go into high-risk environments like a nursing home or something, they may be able to transmit the disease even if they feel well. It's a real important issue. That why it's so important to get a handle on what the false negative rate really is in order to intelligently interpret negative results.

: Complicating matters is the speed with which manufacturers are creating these tests and the rate of the FDA’s Emergency Use Authorizations. How do we balance the need for quickly getting these diagnostic products to market in a pandemic situation with the quality control aspect of making sure the test are producing accurate results? I imagine there must be some level of sacrifice on quality control for the sake of speed.

 That's a great question and everyone always criticizes the FDA for being too fast and too slow and I've had a lot of sympathy for them because I think they're trying to do the best they can. In the beginning of the pandemic, there was a desperate need to get testing out there. It makes sense that the EUA allowed the companies to expedite the process. Now, when you have a whole bunch of tests out there, I think the last time I looked there was maybe 100 tests, not all PCR tests but quite a few…Now, I think maybe it makes sense to start raising the bar, and even going back to the authorized testing and asking for more clinically relevant.

: You also point out that we need a reference standard for measuring the sensitivity of SARS-CoV-2 tests in asymptomatic patients. Why is that an urgent issue?

 The first part of the question is easy. The second part is hard. It matters because there’s this idea that testing is a ticket out of this situation because, by testing, we're going to identify people who are infected, and quarantine them, and keep them away from people, from spreading the virus, particularly to people who are high risk. But because we know that there is transmission of people who have no symptoms, either they're asymptomatic—they never develop symptoms through the course of their infection&mdash;or they’re pre-symptomatic&mdash;they're tested before they have symptoms but they’re infectious&mdash;it’s crucial to know how well the tests work on people without symptoms. And none of the EUAs we looked at evaluated tests in that population, so we just don't know. You have people without symptoms who may be different than people with symptoms, the viral loads may be different, the transmission may be different, the infectivity may be different. We don’t know. And that's crucial information that we need to know. There’s a lot to know about this virus and this is a crucial thing that we need to get a handle on in order to make intelligent decisions about how to approach testing.

Steven Woloshin, MD, MS, discusses a recently authored article in the New England Journal of Medicine describing the challenges and implications of false negative tests for SARS-CoV-2 infection.

Steven Woloshin, MD, MS: Challenges of False Negative COVID-19 Tests

 Matthew F. Pullen, MD, infectious diseases and international medicine physician at the University of Minnesota and one of the investigators on the recent hydroxychloroquine prophylaxis trial, speaks with 

 about the clinical takeaways from the study, as well as what COVID-19 data will be published next.

, and joining me today is Dr. Matthew Pullen from the University of Minnesota.

He was part of the team running the first randomized clinical trial of hydroxychloroquine for the post-exposure prevention of COVID-19. The team’s results were published yesterday in the 

Dr. Pullen, we know the trial showed no significant difference in the risk of infection following exposure in those taking hydroxychloroquine and those taking placebo, but can you explain in a bit more detail about the major clinical takeaways from this study?

 This study was very specifically looking at the role of hydroxychloroquine in preventing infection in people who had recently been exposed to someone with SARS-CoV-2. We have similar protocols in health care workers who have needle sticks from patients who have HIV and hepatitis C where we provide them with specific medications very shortly after the exposure in the hopes of preventing the infection. There were some in vitro data suggesting that hydroxychloroquine might play a similar role for this infection. But what we found was that it did not prevent infection when provided within 4 days of an exposure in any of our participants. There was no statistically significant difference between the placebo group and the hydroxychloroquine group. The main takeaway would be that it's, at least for postexposure, not an effective preventative medication.

: Can you walk us through the study design and methodology? How did you select participants, and how were they dosed?

 This is a randomized, double-blind, placebo-controlled trial—kind of the gold standard for strong clinical and medical evidence. We knew we wanted to pull from a large sample size to strengthen our power and that kind of necessitated recruiting from all over the country, especially back in March when the numbers hadn't really spiked just yet in our region. Due to that, we decided to use an online system called REDCap. It's a means of capturing survey data from participants directly. We reached out to colleagues and other universities, colleagues that were clinicians in other communities. We used social media to try to bring attention to it. We got a lot of media attention early on, which was great. We made sure to always have our website address or an email address mentioned in all the media, and you guys certainly helped with that early on. We got a lot of attention from that, a lot of participants have emailed us saying they'd seen the 

. It was a unique way to run it study, but it was very cool. I’m a huge tech nerd and programmer myself, so anytime I can use technology for something like this is great.

We recruited from all over, and then we randomized participants either receiving 5 days of hydroxychloroquine or placebo, as long as they met enrolling criteria for the study. We mailed them the drug by FedEx overnight so, within 48 hours of enrolling, they received the package with medication and instructions. After that, we sent them follow-up surveys on days 1, 5, 7, 10, and 14, asking them about if they've received any testing and what the results were, what their symptoms have been lately, if they've had adverse effects from the reactions, and if anyone around them has been sick, so we try to get as much information as we could at every time point.

: And these were primarily health care workers or people who had been exposed virus in their home, right?

 About two-thirds of the people were health care workers, which is understandable given they're the ones seeing the most SARS-CoV-2 and being exposed to it the most. We also had a pretty decent number of people who had household exposures, people that were caring for a loved one or whose loved one was a health care worker and got sick and brought it home. [It] was interesting to see that mixture as well. After following them for 2 weeks each and reaching our target power, or target sample size rather, we performed our analysis, and that's when we were able to publish.

: Do any of the investigators hypothesize that a longer duration of post-exposure HCQ would yield a different result? 

 I would never give a concrete “no” to something like that, but I would say that the evidence is probably against it in that sense. With postexposure prophylaxis, you're really in a race against time fighting the replication speed of the virus. You want to kind of head it off at the pass and find something that will combat the virus before it reaches a large number of viral particles in the body. If you can't do that in 5 days, 10 days probably won't make too much of a difference; your body is likely clearing a good deal of that within 5 days and the prophylaxis is meant to aid in that process. Like I said, I would never say a concrete “no.” [It’s] probably worth the study, but I would think that 5 days is probably long enough to have seen an effect.

: Was your team surprised by the results?

 I think, throughout the process, most of us had kind of mixed feelings. We weren't sure how it was going to pan out, especially as some of these observational studies started coming in, some positive, some negative. With a lot of them, it's hard to really tell what to make of the data due to the inherent issues with observational studies, and then some of the issues within those studies themselves. So seeing that kind of mixed bag of results from other studies made us feel like each outcome was probably equally likely. But it was nice to get a pretty solid answer rather than something that was borderline.

: Were there any limitations to your trial?

 Yeah, certainly. Probably the main limitation is the same one that everyone's facing, [which] is the lack of testing in the United States, especially early on. We launched this study in mid-March and, at that time, even health care workers weren't able to get tested. A large portion of our population used the US case definition to decide if they were likely coronavirus or not when they were recording symptoms after taking prophylaxis. It is a limitation that we didn't have confirmed PCRs for everyone, whether negative or positive. But unfortunately, that was just the reality we were all living in and, to some extent, still are living in in a lot of areas.

Another limitation is that all of the symptoms were patient-reported. Given that it's an online study, we weren't physically seeing every person and assessing them ourselves through physical exam. There's always flaws in recall and the subjectivity of reporting symptoms so that that's a limitation as well. But both with the lack of testing and with the self-reported symptoms, feel like the randomization means that any issues are likely equally distributed in both the placebo and the treatment group so it probably didn't affect the analysis too much at all.

: Were there any adverse effects among the study population taking HCQ?

 The hydroxychloroquine group definitely reported gastrointestinal upset more, which is to be expected. Hydroxychloroquine certainly has a reputation for doing that. And we started with a loading dose the first day, so a higher dose, so certainly to be expected that there might be some nausea and diarrhea with that. Beyond that, we didn't really see that many adverse effects reported. We didn't see any serious adverse effects, no cardiac issues or anything like that, which we kind of expected that as well. Most of us in the group have a decent amount of experience both prescribing and taking this medication, mostly for malaria. We've all experienced the GI upset issues, but the cardiac issues really are more when it's in combination with other QT-prolonging medications. We were pleased to see that held up in our study as well [and] we didn't see anyone having heart issues from the medication.

: What’s next? Are there plans for future studies?

 We've wrapped up our preemptive treatment trial. We're working on the analysis and manuscript for that and hoping to submit it soon. We're wrapping up our preexposure prophylaxis trial at the end of the month, and then we'll start working on that analysis. We've also been collecting serology or dried blood spots from all of our participants that are willing and we're going to do some serology epidemiology studies on seroconversion amongst these studies, as well. We've got plenty of work to keep us busy.

: We look forward to discussing those results with you once they're available. Is there anything else you would like to add?

 I just want to say a huge, huge, huge thank you to anyone that participated in the study or helped spread the word or even just to email us with questions or showing interest in the study. We couldn't do any of this without all of those people. A lot of people emailed us apologizing for asking questions, but we love it when we get questions because sometimes it makes us really think and improve things. So, thank you to everyone who participated and reached out to us.

Matthew F. Pullen, MD, co-author of the recent hydroxychloroquine prophylaxis trial, shares the top clinical takeaways.

Hydroxychloroquine as Postexposure Prophylaxis for COVID-19: Clinical Takeaways

 Sarah Jorgensen, PharmD, MPH, BCPS, BCIDP, AAHIVP, provides a deep dive on the pharmacology and biochemistry of remdesivir.

. Joining me today is Dr. Sarah Jorgensen, an antimicrobial stewardship pharmacist with Sinai Health System in Toronto. Dr. Jorgensen, thanks so much for taking the time to speak with 

 today. What was your day-to-day like prior to COVID and what is it like now in the middle of the pandemic?

Sarah Jorgensen, PharmD, MPH, BCPS, BCIDP, AAHIVP:

 Like most people working in hospitals, everything has sort of shifted focus to preparing for and then dealing with COVID. Like most people, Zoom calls and meetings have become part of my daily routine. I'm unfortunately still that person that talks for 5 minutes with a muted microphone, so hopefully I'll get the proper Zoom etiquette before this is all over.

 of the pharmacology of remdesivir. What is it about the biochemistry and pharmacokinetics of this antiviral that make it an attractive therapeutic option for COVID-19?

 Yes, it's a really kind of neat molecule. It's called a monophosphoramidate nucleoside analogue prodrug. What it does is it competes with our endogenous nucleotides to get incorporated into the viral RNA. It was originally developed in response to the Ebola outbreak back in 2014, but was found to have really good activity, at least in vitro, against a broad range of coronaviruses, including SARS-CoV-2. For nucleotide analogues to be active, they have to get triphosphoralated, so that's adding 3 phosphate groups and adding that first phosphate group is what really slows things down. Remdesivir actually has a phosphoramidate group, which is sort of like a mask phosphate group, so that it hides until it penetrates into the cell, and then it gets unmasked and can quickly add those 2 more phosphate groups so it kind of has a jumpstart on being active and then it's good to go.

Another thing with nucleotide analogues against coronaviruses in general is that they've really been hindered by a viral enzyme called [exoribonuclease]…This enzyme goes along and it proofreads the growing RNA chain and takes out errors, which includes those analogues and so remdesivir is actually partly able to evade this enzyme. It does this through 2 mechanisms. First, it gets incorporated into the RNA chain really quickly, actually more efficiently than even our own endogenous nucleotides. And then the other reason is, when it does get incorporated, 3 more of our endogenous nucleotides get incorporated after it, and those serve to protect it from the from the enzyme that wants to splice it out. That's why we think, at least in vitro, that it seems to be pretty potent and evade a lot of these things that have hindered previous nucleoside analogues.

 I think we're learning about that really quickly. In the phase 1 studies and in also some of the Ebola studies and then [with] the compassionate use…One thing that we saw kind of consistently were these elevations in transaminase enzymes even in healthy volunteers, but it doesn't seem to have panned out in the 2 [randomized controlled trials RCTs] that that we've seen so far. They were underpowered really to detect serious liver abnormalities, but that has been reassuring that we're not seeing major problems at least so far with that regard.

 That's still an open book. It has been found to occur in in vitro studies, but we still don't really have anything in humans yet. I think we know from chronic viral infections that we tend to need cocktails of drugs to prevent resistance development. This is really the first drug that has shown any meaningful benefit for an acute viral pneumonia, so it's really unknown territory in terms of how we need to be using these [and] whether it's okay to do monotherapy or combination therapy [and] how quickly resistance can develop.

 Before the ACTT-1 study, the data was really hard to interpret. We had that compassionate use report in 

, the 61 patients but no control arm. And then the study in China by Wang and colleagues came out but had to stop early so it didn't reach its target enrollment and kind of left us with inconclusive results. So it was great to see the ACTT study finally come out. I think this was a really solid study. To enroll over 1000 patients from I think it was 60 sites globally in just a couple of months in the middle of a pandemic is really a pretty tremendous accomplishment. As I said before, this is the first time that we've actually seen a drug provide meaningful benefit for viral pneumonia. The odds were kind of stacked against it to start with. That said, , the benefit was pretty modest and the outcome, although it does seem very objective, there is still some subjectivity in deciding on oxygenation and when to discharge patients.

It was really a shame that it was stopped early. They had enrolled all of the patients, and a couple more weeks and we would have perhaps had more conclusive results around the mortality. I think at this point, we see that it hastens time to recovery. But without the full data, we don't know if it is helping patients recover who wouldn't have otherwise recovered or if it is just accelerating time to recovery in those who really would have anyway, which is valuable, especially in overstretched health care systems, but it would have been really nice to have the full results be able to be analyzed.

This is one study, too. I think to really be more sure about its efficacy, we do need to see it replicated, but fortunately there're many other RCTs still going on, so [I’m] looking forward to those and also the second arm of the ACTT study adding baricitinib.

That should be really interesting to see how that plays out because we know that in more severe patients, it seems like it's more of the hyperimmune response that is underlying a lot of the acute organ failure that we're seeing so maybe adding one of those on could provide some benefit. Although it's still a tricky balance because exactly when to add it and not cause problems with hindering viral clearances and stuff, too.

: What is the most important thing you think clinicians need to know about this drug?

 I think knowing that, at this point, it doesn't seem to be a panacea for the illness, especially since we didn't see a huge benefit in those most severely ill patients, so we don't know if this is just because those groups were smaller or if [we] need something more powerful or different mechanism at that point.

I think being really vigilant and monitoring for any safety signals…[there are] still not a whole lot of patients that have been exposed to it yet so that's still kind of an evolving field.

: Your work focuses on antimicrobial stewardship. What sort opportunities to practice stewardship have you observed in this climate of COVID?

 It’s really been information-gathering and providing education. There's just a ton of data and studies coming out all the time and preprints have kind of waded into the forefront for the first time so it's really fishing through that and picking out what can help inform practice and what's good science.

In terms of stewardship, I think it has been kind of tough because when patients present with acute respiratory infection, you don't know at the time whether it's bacterial or viral. And so a lot of patients still are getting empiric antibiotics and it's knowing when and if you can peel those off.

The whole patient population for us has kind of changed too, because a lot of elective procedures have been postponed. We see a lot of usually chemo patients, so some of their treatment has been postponed too so infections in those patients are not as prevalent, but we're, of course, picking up instead a lot of COVID patients.

: Is there anything else that you would like to add?

 Just to stay tuned for what's coming up and I think there's a lot of exciting work going on and just the speed of the randomized controlled trials they're getting up is pretty amazing. So that should be exciting. I know that we're starting up several at our hospital as well so it'll be interesting to see how those play out too.

Sarah Jorgensen, PharmD, MPH, BCPS, BCIDP, AAHIVP, provides a deep dive on the pharmacology and biochemistry of remdesivir.

Reviewing the Pharmacology and Biochemistry of Remdesivir for COVID

 Kelly Cawcutt, MD, MS, professor of infectious diseases and critical care at the University of Nebraska Medical Center, and a 

 Editorial Advisory Board member, shares her thoughts on COVID's impact on health care, as well as why it's so important for clinicians to take breaks.

: Hi, I’m Allie Ward, editorial director of Contagion and joining me today we have a member of our Editorial Advisory Board, Dr. Kelly Cawcutt, who serves as professor of medicine in infectious diseases and critical care at the University of Nebraska Medical Center.

Dr. Cawcutt, thank you so much for joining me today. I want to start off and talk about how you are doing. What has your day-to-day been like the last couple months?

 Thank you so much for having me. How am I doing? I think I'm doing about as well as any of us can be. It's been really busy for everyone in medicine and, frankly, even outside of that, with schools closing and so many changes to our everyday functioning. But I've been busy spending my last several weeks doing a mix of infection control, in which we're really working on writing all of our policies. As we continue to move through this pandemic, with testing and procedures and how you reopen the hospital for more and more care. I’ve done a lot of education, which has been great trying to really help other hospitals, other groups understand what COVID-19 looks like and our infection control components, and then just some basic treatment-related discussions. Finally, I've been working in the COVID unit myself. So I've spent some time in our COVID ICU I as one of the intensivists, and I'm actually headed back there next week.

: You just finished a week in the COVID ICU. What can you share about what you’ve observed regarding the clinical characteristics of COVID-19 at this stage?

 I think some of the pieces that are just really striking… As an intensivist, we would see patients who would have severe hypoxemia and acute respiratory distress syndrome (ARDS) in the past, and we've have people on ventilators in the intensive care unit, but our average length of stay, in general in a medical ICU, is really only a couple of days historically. With our COVID-19 patients—and this has been seen in many other institutions&mdash;we see substantial lung injury with severe hypoxemia and much longer durations of stay in the hospital, and many more patients requiring ventilatory support compared to what we normally would have used in the hospital settings, which we can all reflect on that as we think of all the prior shortages. We heard in Italy and early on in New York about running out of ventilators or ICU-level beds. That's the kind of impact that we're still seeing as we are stretched a little thin with patients coming into the hospital.

: What sort of challenges are you encountering on the COVID wards?

 I think there're a lot of challenges still in making sure that we have great education to our frontline health care workers on the risks related to infection control, making sure everyone really understands how to use [personal protective equipment] appropriately. It's so critical on how we don and doff and we've seen some literature that shows some of the highest risk factors for getting COVID as a health care worker actually come down to whether or not you're doing good hand hygiene in that process. One of the classic things we've always worked on an infection control and always struggle to get full compliance to is one of the biggest things we see as an ongoing risk in health care in general right now.

I think there's a lot of drive to provide treatment for these patients with medications. And as you know, we have a lot of data that's evolving, but outside of remdesivir, which has just published preliminary data in the 

 showing a shorter duration of illness, we really haven't had great evidence-based medical treatments beyond supportive care as we would have in the past for any other patient with severe ARDS. Just that drive to have something to give these patients to treat to figure out how to do it safely and maintain that because we really don't have a clear end in sight for when we're not going to have these patients.

Something that has been echoing more so recently in the literature is really the visible disparity of groups that are affected and some of the hotspots, so seeing a lot of socioeconomic disparity in who is presenting to the hospital with severe illness and that's something that I think we are all struggling with how to assist and prevent disease spread in areas where there does appear to be higher risk. That's been a big deal in the Midwest with meatpacking plants.

: What concerns come into play regarding the use and rationing of remdesivir for COVID-19?

 That's a really good question, and I think there're a few things that are really interesting about this. One is we're still under an emergency use authorization, and really FEMA has been given the capacity to distribute medication. It's a little unclear how that allocation is being done in full. We have received some for the state of Nebraska and the state really put a committee together to try and decide how to distribute that. There are variations based on how many patients you might have in a given hospital with COVID so there could be disparities where you see larger centers with more patients versus our acute critical access hospitals that may not have medication depending on how that is spread out. There're also the variations of institutions who have the clinical trials ongoing so the remdesivir studies are still ongoing with adaptive components right now happening. If you're at an institution that has the trials, there may be a different level of access to remdesivir based on if you are eligible and opt to enroll in a trial, versus having to get the medication under that EUA authorization. Unfortunately, there's a lot of potential for disparity regionally throughout the country and through different populations based on academic centers versus non-academic centers. I also think it's difficult because we know, even if we just look at the allocations that we have available here, there's not enough remdesivir to treat everyone who would qualify. Then it really may come down to each institution deciding how to ethically disperse medication and that's going to be a very difficult decision-making process that I suspect will not be standardized as you look from hospital to hospital.

: Many states are in some phase of re-opening right now. What are the risks of reopening too soon?

 I think the risk is what we saw happening in Wuhan and what we've seen happen in South Korea and other areas where as you reopen—and the risk may be there regardless of when you reopen, for clarity, because we have not gotten rid of this virus&mdash;especially if reopening is matched with a kind of sense of security in the public that masking isn't as important, physical distancing from people isn't as important, hand hygiene isn't as important…We certainly run a risk of a second surge of infection. By no means did any of our communities see that everyone became infected with this. In these other communities like Wuhan and South Korea that led the way early, they have seen a resurgence of infection with second surges coming through as they reopen. I think that's something we have to be cautious of as we are reopening in states, that reopening does not come without risk, it likely does not come without more patients developing infection and coming into the hospital. We know that if we aren't cautious with it, we may, in fact, still have a peak that could surpass certain health care systems. That, to me, is the biggest risk&mdash;that we make this big initiative to flatten the curve and now that we're reopening, everyone assumes the curve’s flat, but they forget that it only stays flat if we maintain those policies as best we can while we reopen.

: What do you see as the long-term effects of COVID-19 on the health care system?

 I think this will have in many ways revolutionized health care. It also, I think, really highlighted the fragility of health care as we know it. We've seen fragility with access to equipment, access to PPE. We've seen limitations of medications when they're being used at high levels more than historical precedent, or lack of capacity to manufacture. If one area is particularly struck with an infection, or other natural disaster, we may not have the supplies we need. I think looking at diversification of where medical supplies come from and how we research those will be one piece of this puzzle moving forward. But then honestly, it's moments like this. Not everywhere was really embracing telehealth and telemedicine and doing video conferencing. Medicine has, in many ways historically, fallen behind the business realms as far as adoption of certain technologies for so many reasons, including patient privacy and just capacity to execute appropriately. I think the use of technology that we've had almost forced upon us due to wanting to provide as much social distancing as possible is something that's going to be carried forward in medical centers in ways that was unprecedented pre-COVID. So I think that's going to be a huge shift.

I suspect as we carry this forward, the general infection control recognition and management and biopreparedness planning will really have a much more aggressive stance in health care centers across the world, and levels of education and awareness for all of our frontline health care workers regarding how critical it is to be prepared and to know how to do this every time, every shift, no matter where you are.

: What is the single most important thing that you feel clinicians like yourself need to keep in mind during this time?  

 I think that's a great question that I probably would have given varying answers to week-by-week, but coming into the weeks we've been at this, right now, I think health care workers really need to pause and remember that we need to take breaks, we need to rest. We cannot work unendingly whether it's at the patient bedside, whether it's writing policies, doing research, teaching. We can do this as a sprint the first few weeks and almost months that we have, but we are transitioning into a marathon phase and it's not sustainable without rest. It can't be sustainable without the risk of burnout or people becoming ill, or being so tired that they make mistakes in PPE donning and doffing and put themselves or others at risk. I think really recognizing the need to take breaks, to take time off. I know innumerable people around the country have revoked vacation. I did that much of the spring, and now it's really a scenario where we really have to do that. It's best for our brains, it's best for our mental and physical health. And, ultimately, if we maintain our health, that's what helps us translate that to the health of our patients, and the health of our colleagues, and the health of the country overall as we try to bring this system back up better than it was before.

: Very well said. Dr. Cawcutt, is there anything else that you'd like to add?

 One thing would be to just again, thank everybody who's watching and working so hard and tirelessly to really fight COVID-19, to do the best that we can, to provide the highest standard of care in the safest place possible for as long as we possibly can. It is a tireless job, as I just mentioned, but it is something that I want to express my gratitude to everybody who's looking and listening, because I don't think we express the gratitude for the work being done enough. And sometimes that goes a long way, so thank you so much for the opportunity to do the interview today, but also thank you to everyone for the work you're doing.

Kelly Cawcutt, MD, MS, shares her thoughts on COVID's impact on health care, as well as why it's so important for clinicians to take breaks.

Alexandra Ward

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