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Sara Dong: Hi, everyone.

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Welcome to Febrile, a cultured podcast about all things infectious disease.

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We use consult questions to dive into ID clinical reasoning, diagnostics, and anti-microbial management.

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I'm Sara Dong, your host and a Med-Peds ID fellow.

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Here on Febrile, we use patient cases and chat with ID consultants to learn more about high yield ID topics.

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My co-host today is Dr.

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James Wilson.

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James is an ID fellow at the combined Rush University Medical Center and Cook County Health ID fellowship program in Chicago.

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He also spends time as an attending hospitalist at Rush as well.

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James is a Navy veteran physician of 10 years with airspace and tropical medicine training through the U.S.

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Department of Defense with several deployments into tropical and subtropical areas for global health, tropical medicine and disaster relief.

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Next, I will welcome our guest consultant today, Dr.

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Ryan Maves.

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Ryan is a Professor of Medicine and Anesthesiology at the Wake Forest School of Medicine in Winston-Salem, North Carolina.

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He is board certified in Internal Medicine, Infectious Diseases and Critical Care Medicine.

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He currently serves as the medical director of the Transplant ID program and a faculty intensivist at Wake.

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Ryan is a retired captain of the U.S.

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Navy with 22 years of active duty service and prior deployment to Afghanistan.

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His research currently focuses on the epidemiology and treatment of severe viral diseases, including SARS-CoV-2, as well as disaster responses to public health emergencies.

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Welcome to the show guys.

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James Wilson: Thanks for having us, so excited.

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Ryan Maves: Yeah.

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Thank you so much.

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Sara Dong: Um, and so before we jump into the case, I always ask the same question.

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I'm just trying to know a little sort of nonmedical thing about you.

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Can you guys share any pieces of culture or things that you've enjoyed recently?

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Maybe I'll start with Ryan.

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Ryan Maves: Oh, sure.

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Um, you know, so I am probably a giant overgrown child.

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So, um, so, so, uh, I just came off of, uh, watching Peacemaker on HBO.

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And I have

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Sara Dong: I just finished it too.

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Yeah.

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Ryan Maves: I have to say that, you know, I didn't have high expectations, but, um, one of my sons recommended I watch it.

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He's 15.

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And you know, maybe I shouldn't be in the business of taking, uh, taking TV recommendations from my 15 year old son.

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But I gotta tell ya, he's the, you know, my boy is batting a thousand because it was just such a delight.

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And I now want to go and buy myself a pet eagle, which is probably illegal, which is probably illegal.

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But you understand if you've seen it, you

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James Wilson: The Bald eagle one.

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Sure.

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Ryan Maves: You understand why I want that now.

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So that's me.

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Sara Dong: Yeah.

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Yeah.

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What about you, James?

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James Wilson: Um, I'm going to sound like I'm just trying to one up, I get this point.

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I just started going back through like a lot of Michael Lewis.

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Uh, stuff, his podcasts.

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They love his podcasts.

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And so he rereleased "Liar's Poker" unabridged audio book.

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And so I went back through that and "Big Short" and "Flash Boys" and stuff.

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So I, I know nothing about the money market or any, or how to do anything financial, which my wife is, is the business major, is  a corporate real estate person.

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And so she's the one that kind of, shocking, she manages our money.

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And so, um, but yeah, I find all that stuff, very fascinating and infuriating, but, uh, and otherwise I, I rock climb.

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That's my, like, that's my mental space where I can go and dump my brain for a while and just focus on one problem at a time.

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Or fall, which I've done before.

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So.

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Sara Dong: Love it.

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Love it.

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Um, well, you know, we have a new consult question today.

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I'm so glad you guys are here.

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We have a 35 year old who's actually just returned from Thailand with fever and malaise.

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So I'm going to hand it over to James to tell us about the case.

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James Wilson: Awesome.

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Thank you so much.

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Uh, uh, Sara, so, uh, Dr.

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Maves, a 35 year old gentlemen  who has returned from vacation to Thailand.

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He's three days post return at this time.

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So he was vacationing for two weeks in different urban areas of Thailand, Bangkok, Chiang Mai, Phuket.

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And this was all during October, uh, and he traveled in between all of them by plane.

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So as I had mentioned, he returned three days prior with fevers beginning a day prior to presentation to the office.

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Um, and now he reports that he's feeling quote unquote, "blah" uh, and some complaining of some fatigue.

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So the patient has been attributing most of this to jet lag until last night when the fever started, and really did associate with a long night out, in Bangkok before he got on the plane early morning, uh, before he returned home.

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He stayed in hotels, not hostels.

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And he had two new female sexual partners with 90%, he said, condom usage.

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So none for foreplay or for oral sex, but for vaginal intercourse, which he had only vaginal and not oral.

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And so he took no prophylaxis ongoing to Thailand.

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He did no pre-travel clinic visit and he is not been vaccinated for the year for the flu.

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And he had no pre-travel vaccinations.

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He denies any significant medical history or surgical history.

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He endorses heavy alcohol use while he was in country on his vacation, but occasionally while he is out and, you know, at home working.

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He did have two episodes of blacking out while traveling, uh, one was in Bangkok and one was in Phuket.

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So he was intermittent tobacco use, occasional marijuana use, no IV drug use, and he has no history of STDs.

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And he has no known allergies.

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So, uh, Ryan, what else would you like to know in this returning traveler who's coming with fever and malaise?

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Ryan Maves: Yeah.

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All right.

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Well, thank you so much.

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I mean, that's a, that's a great case and not an unusual case.

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Now I think one thing that we do have to just to kind of address the giant elephant in the room of course, is that I assume this took place in 2019, so we can set aside, you know, one of our more common causes of fever in a returning traveler or fever in a non returning traveler or in a non traveler, which is COVID-19.

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So setting all of that aside, um, although I do think that is useful for us to remember before we get into really discussing this case.

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Is that, in the returning traveler, I think particularly in folks traveling, um, from say Eastern Asia, south Asia, Sub-Saharan Africa and the like, there is an instinctive desire to reach for the geographically unique diseases that we don't see commonly in North America.

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Right.

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But it's worth recognizing that both in terms of morbidity and mortality, um, the most common causes of both of those things in returning travelers are relatively cosmopolitan syndromes, right?

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Number one and number two causes of death and returning travelers are what?

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Their MIs (myocardial infarctions) and car accidents, right?

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Neither of which are readily prevented by DEET or vaccination, right?

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And similarly among infectious causes, cosmopolitan infections, meaning influenza, meaning other respiratory viruses.

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Um, you know, an older folks might be a bit sicker, pneumococcus, right?

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Those things still need to be on our list.

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So.

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You know, we still need to remember to do that kind of standard issue febrile workup and our standard issue assessment of clinical stability.

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How sick are they?

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Do they require admission?

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Are they unstable?

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Do they walk in under their own power?

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And they're having a conversation, they're satting normally on room air, all those sorts of things we need to consider.

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That being said, we will assume that we have set those things aside, right.

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We'll assume that we have addressed those.

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And we have a pretty good idea that, okay, this guy doesn't have any real respiratory symptoms.

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Um, is he tolerating PO?

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James Wilson: He is tolerating PO.

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Ryan Maves: Okay.

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Maybe not much of an appetite, I would gather, but, but is able to keep food down?

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James Wilson: It's decreased over the last day,

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Ryan Maves: Okay.

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Okay.

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James Wilson: But he's able to eat and drink.

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Ryan Maves: Okay.

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Okay.

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So that's also encouraging and you said, what did you say about his stool again?

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He said some dark stools intermittently.

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James Wilson: Uh,  no loose stools, no constipation.

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Um, he had some on the day after from returning, but he had also had a, a long night out and some street food.

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Ryan Maves: Sure, sure.

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So his bowel habits aren't anything you'd particularly expect to be abnormal and it, and it is also worth noting, particularly in people returning from Southeast Asia that, you know, Campylobacter very early in its syndrome can be more of a systemic illness before the diarrhea, and occasionally the dysentery really kick in.

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And that can kind of sneak up on you a little bit.

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Um, but in the absence of any  real GI syndrome, it's hard to tag Campylobacter.

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So then we're kind of stuck looking at, okay, what are the causes of, and it's useful to give syndromes a name, right?

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This is an undifferentiated fever, right?

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Did he have much in the way of myalgia or arthralgia?

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James Wilson: No myalgia, just malaise, fatigue and fever.

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Ryan Maves: And any kind of a rash?

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James Wilson: Not complaining of

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Ryan Maves: Okay.

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Okay.

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So with, again, with an undifferentiated fever, there's kind of a list of things that we always need to consider.

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Now, Thailand is certainly endemic for malaria in certain areas.

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You know, it doesn't sound like, you know, you mentioned he traveled by air.

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He was in largely urban areas.

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So the odds of malaria are pretty slender, right?

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Bangkok is a very modern city.

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Chiangmai is a very modern city.

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These aren't places where you would expect to find malaria, and they're generally not reported.

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Sometimes when we're traveling in a tropical countries, in developing countries, the, the border between urban and rural is how should I say vague?

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I spent a number of years working in Peru and my group spent a fair bit of time in, uh, Iquitos, which is a large city in the Peruvian Amazon.

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There's a lot of endemic arboviral disease within Iquitos, and there's a lot of malaria outside of Iquitos, but there's not like a wall around Iquitos telling you you're in or out of the city.

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Right.

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It sort of tapers off, . That's not the case in Bangkok.

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That's not the case in Chiang Mai.

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But it's at least worth seeing that we can't totally exclude malaria and probably doing some evaluation for malaria is reasonable.

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Although it seems like that that's relatively less likely.

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So the big things that I would be worried about in this gentleman would be arboviral disease, right?

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Because that's going to be a big thing.

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That's going to be largely dengue in someone returning from Thailand.

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Um, other arboviruses, which we can chat about.

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And there's some subtle differences between them, but it's very difficult to clinically distinguish between them at the bedside.

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Uh and then

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Some bacterial infections, so leptospirosis would be a good example of something that can be fairly ubiquitous in tropical settings, in, uh, developing settings.

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And then just because we got to mention it is, you know, he did make some special new friends while he was in Thailand.

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And although 90%, uh, use of barrier protection is, it's not nothing, but we don't know much about the circumstances of those of those friends.

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Did he pay for sex?

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I really do think we need to make sure that we're screening him for acute HIV in this setting.

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Um, and typically that'd be with some matter of nucleic acid amplification testing, um, So what does that get us to?

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I think the thing that we're thinking about, the thing that we're concerned about here is probably dengue, right?

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But  there is a differential between, uh, both dengue looking at differing degrees of severity.

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And there's also the things that track with dengue.

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Um, so chikungunya, Zika, um, which are both less common in this part of the world.

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Um, and then the things that will mimic it, the things that resemble it, we mentioned influenza earlier.

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Leptospirosis would be another one that would be important to try to exclude.

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And if we can't exclude it to our satisfaction, at least consider empiric treatment for.

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James Wilson: So, you know, when you see him , he came in with a 99.9 for his temperature in Fahrenheit, and he was tach'ing (tachycardic) the 100s.

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Uh, but otherwise he had a normal blood pressure of 120s/80s.,  was satting well on room air.

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His exam significantly unremarkable, except for just a mild conjunctival pallor and some dry mucus membranes.

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Um, at this point, nothing else had been ordered or done.

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So based on that, what would you, you know, you had mentioned something in your differential, you know, maybe like a fourth generation HIV test, um, any other labs that you would like to get up front or other diagnostics?

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Ryan Maves: Yeah.

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I mean, certainly if we're thinking arboviral infection on the list, as well as the other things we discussed, I think certainly a basic CBC and a chemistry panel is very reasonable.

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And particularly in the case of where we're suspecting an arboviral disease, it's very helpful to have a look just at the CBC, right?

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Because that is going to give us some hints, both in terms of diagnosis and in severity of illness.

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Where, for example, with more severe forms of dengue, I haven't heard anything that would make me think that at this immediate point, there can be features like hemoconcentration, like a unusually high hemoglobin can be a hint as can of course, low platelets would certainly be suggestive of it.

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Um, on the chemistry panel, you know, you don't expect to see a lot of, for example, profound transaminase elevations with most of the arboviral infections, but they do occur and that can be at least somewhat useful.

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Yellow fever is the obvious exception to that, but there is no yellow fever in, in Asia, uh, for reasons that are, I think, incompletely understood, but for whatever reason, yellow fever, just it's in Sub-Saharan Africa, it's in south America or Latin America.

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It is not in Asia.

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Um, it'll also be helpful because we do have a differential diagnosis here.

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If we saw, again, he doesn't sound that sick, but if we saw, for example, a profoundly elevated say bilirubin and relatively less elevated transaminases, that would be suggestive of leptospirosis, although certainly not diagnostic.

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So I'd getting those just to kind of flesh it out.

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And then the other things we talked about, would it be worth screening him on some level for malaria.

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Intellectually?

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I don't think it's necessary, really.

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Emotionally?

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It would be hard to resist.

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Right, but you would, you would want to maybe at least satisfy yourself that you checked, you know.

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Beyond that, blood culture certainly can be useful because one thing I neglected to mention would be typhoid and enteric fever can produce this sort of same, um, undifferentiated, febrile illness.

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And so getting blood cultures would be useful for that.

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And also just to acknowledge  that there are other diagnoses besides again, tropical diseases not seen in north America, commonly.

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Um, Group A strep bacteremia, things that can cause relatively mild disease initially, but can become very severe if missed down the road.

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He doesn't sound like he has that, but it's just a thought.

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Um, so CBC, blood cultures would be reasonable, depending on your assessment of how sick he is.

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The one thing that makes me wonder about blood cultures in him a little harder than I normally would is that he's a little tachycardic you mentioned, right?

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You know, that's not much of a dengue thing, right?

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Dengue is one of those things like typhoid, like rickettsia, is it often presents with the  Faget sign, the, uh, the disassociation between fever and tachycardia..

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Now, if you're dehydrated, if your volume down, if you're bleeding in cases of some very severe cases of dengue or other disorders like that, then certainly that's, that's not a law of nature.

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00:15:34,130 --> 00:15:41,930
That's not a law of physics that if you're tachycardic and febrile, it can't be dengue, but it's at least worth to consider that that does affect your differential a bit.

206
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Those would be the big ones.

207
00:15:43,610 --> 00:15:49,490
And then I guess we need to think about pathogen specific assays, right?

208
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And there are a whole bunch of those.

209
00:15:51,620 --> 00:16:00,050
So kind of looping back then too, you know, what we think are the most likely entities, uh, diagnosis gets to be pretty tricky here, right?

210
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Cause if we go down the list of kind of the big ticket items here for undifferentiated fevers, um, of viral origin, right?

211
00:16:08,990 --> 00:16:11,750
So we have dengue is the most common one.

212
00:16:12,650 --> 00:16:14,150
And dengue is kind of interesting.

213
00:16:14,180 --> 00:16:24,830
Well, dengue is totally interesting for a variety of reasons, but you know, you could argue that  there are four serotypes of dengue, but I think you can argue pretty effectively that there are actually four different species of virus.

214
00:16:24,830 --> 00:16:29,840
And we just lump them as serotypes because they're clinically so similar and clearly very closely related.

215
00:16:30,320 --> 00:16:44,270
And honestly, with the emergence of Zika a few years ago, you know, you can kind of make a case that Zika's like dengue five, except that there may already be another dengue five, but there's basically, four main serotypes of dengue.

216
00:16:44,290 --> 00:16:47,160
Thinking about other so dengue is one of the classic flaviviruses.

217
00:16:47,620 --> 00:16:51,730
Um, and it is widespread in urban environments throughout developing countries.

218
00:16:51,730 --> 00:16:57,400
And that's why really in this person, why we're thinking more dengue than malaria, right?

219
00:16:57,400 --> 00:17:05,360
Cause if you're, if you're looking at, kind of got to divide this up, and this is useful in both the pre-travel consultation, when we're giving advice to people before they travel overseas,

220
00:17:05,420 --> 00:17:10,010
and in assessing the febrile returning traveler.

221
00:17:10,520 --> 00:17:21,350
Malaria is a disease of rural areas, that malaria is spread by, you know, Anopheles mosquitoes, uh, that are in rural areas and they bite you at night, you know, dusk to dawn, right?

222
00:17:21,350 --> 00:17:24,140
So malaria, rural areas, bites you at night.

223
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Dengue on the other hand, so dengue is spread always by mosquitoes of the genus Aedes, usually Aedes aegypti, occasionally Aedes albopictus depending on where you are.

224
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It's the tiger mosquito.

225
00:17:36,800 --> 00:17:41,720
It's a little less adapted to urban environments, but you see it in like China and Hawaii.

226
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And maybe there's like this, like one park in Tokyo that has dengue and that's probably Aedes albopictus that's transmitting it there.

227
00:17:49,730 --> 00:17:54,250
So, Aedes is adapted to urban environment.

228
00:17:54,260 --> 00:18:05,580
So it like it nests and it lays its eggs in like pools of  rainwater that form in pots that are in, uh, like old tires lying around  and things like that.

229
00:18:05,910 --> 00:18:09,740
And so malaria, rural, bites you at night.

230
00:18:10,120 --> 00:18:13,590
Aedes, urban, mosquitoes bite you in the day.

231
00:18:14,820 --> 00:18:19,950
And the, the challenge that we really have here is that, for things like malaria, right?

232
00:18:19,950 --> 00:18:32,490
If someone's going to a malarious area, if they're going to larger Subsaharan Africa, or very rural places to Southeast Asia or India, or what have you, uh, Latin America, um, we have prophylaxis, right?

233
00:18:32,490 --> 00:18:40,620
We have chemoprophylaxis, I can put someone on atovaquone-proguanil or doxycycline, or in kind of select circumstances nowadays, mefloquine.

234
00:18:41,610 --> 00:18:46,500
You know, and that's very effective in combination with things like insect precautions and the like.

235
00:18:47,070 --> 00:18:49,720
For dengue, what we have is don't get bitten.

236
00:18:50,360 --> 00:18:54,015
You know, it's basically our options for prophylaxis are don't get bitten.

237
00:18:54,255 --> 00:19:03,945
And that means insect cautions, that means DEET, you know, somewhere in the 30 to 40%, you know, concentrations, picaridin is also a reasonable option you have.

238
00:19:04,245 --> 00:19:09,855
But that's pretty, you know, people get a little how shall I phrase this lackadaisical about that, right?

239
00:19:09,855 --> 00:19:21,765
Like I'm pretty good when I go to, when I traveled to Peru, um, about using insect repellent when I'm walking around in the Peruvian Amazon and cities in the Peruvian Amazon.

240
00:19:22,155 --> 00:19:25,575
But, um, but I'm not perfect at it.

241
00:19:25,635 --> 00:19:28,245
I am probably just lucky on some level.

242
00:19:28,245 --> 00:19:28,515
Right.

243
00:19:28,965 --> 00:19:35,115
And it would be great if we had a widespread, highly effective dengue vaccine, but we don't like we don't right now.

244
00:19:35,145 --> 00:19:38,475
Now we do have Dengvaxia, which is an advance in public health.

245
00:19:38,475 --> 00:19:43,515
And Dengvaxia is a tetravalent, uh, dengue vaccine.

246
00:19:43,575 --> 00:19:46,935
Uh it's chimeric vaccine and is protective.

247
00:19:46,935 --> 00:19:49,335
It does reduce the risk of dengue acquisition.

248
00:19:49,335 --> 00:19:53,385
The problem is that the population who had benefits is very, very narrow, right.

249
00:19:53,385 --> 00:19:58,485
And it's basically kids and young adolescents who've had dengue before, right?

250
00:19:59,205 --> 00:20:05,475
So, you know, I'm, I'm an adult infectious disease doctor traveling and, you know, practicing in North Carolina.

251
00:20:05,685 --> 00:20:10,935
I don't have a lot of children and young adolescents with histories of prior dengue who I see.

252
00:20:11,295 --> 00:20:15,825
So Dengvaxia is not a thing that I'm likely to be able to implement in my own practice.

253
00:20:16,295 --> 00:20:24,565
James Wilson: I was going to ask about this later, but since we're here, uh, with Dengvaxia, it's mostly for those living in regions is what we're saying.

254
00:20:24,565 --> 00:20:25,285
And so that.

255
00:20:26,640 --> 00:20:31,590
That is, that is really not the fever in the returning traveler quote unquote, that we would normally think of.

256
00:20:31,590 --> 00:20:35,850
And so these are usually put in to a packed and tropical and subtropical regions.

257
00:20:36,300 --> 00:20:46,530
Um, and it seems the Philippines is the only one that has that mandated Dengvaxia several years ago, uh, to be used as my understanding prior, just prior to the WHO

258
00:20:47,125 --> 00:20:47,395
Ryan Maves: Yeah.

259
00:20:47,395 --> 00:20:50,785
As a standard recommendation, it's relatively a few countries use it standardly.

260
00:20:50,785 --> 00:20:51,815
It is FDA approved.

261
00:20:51,815 --> 00:21:00,085
It, it is theoretically available in the U S but it's not a thing that we can offer to travelers as routinely as pre-exposure pre-travel preparation.

262
00:21:00,165 --> 00:21:04,365
So, you know, other flaviviruses can mimic Zika is very closely related.

263
00:21:04,455 --> 00:21:09,145
Um, Zika tends to cause relatively milder illness, uh, than dengue in the whole.

264
00:21:09,165 --> 00:21:22,830
But the thing that obviously is concerning about Zika is this sort of unique tropism for both sexual spread / sexual transmission and for its effects on neonates or not neonates, I'm sorry, fetuses and the effects on neurological development.

265
00:21:23,130 --> 00:21:29,640
Otherwise like if I had to pick between getting like dengue or Zika, I would totally pick Zika, right?

266
00:21:29,670 --> 00:21:32,700
Because it is generally a milder disease, right?

267
00:21:32,760 --> 00:21:33,510
Generally milder disease.

268
00:21:34,330 --> 00:21:37,560
Chikungunya, not a flavivirus, unlike the other two.

269
00:21:37,810 --> 00:21:43,060
Chikungunya tends to have more arthralgias, it tends to have less of the kind of severe manifestations.

270
00:21:43,150 --> 00:21:53,590
But arthralgias can last a very, very, very long time and they can be very crippling and they actually can clinically and sometimes even biochemically mimic rheumatoid arthritis.

271
00:21:53,740 --> 00:22:22,260
And there's some great series done by, uh, uh, uh, James and I we're in the we're in the military together, way back when, um, done by the French military in  Pacific island, uh, the French, uh, French possessions in French Polynesia and the like, um, On the use of methotrexate to treat post chikungunya arthritis and it's reasonably effective, but it's very much like how we would treat, um, RA and probably has some overlaps in its pathogenesis.

272
00:22:23,340 --> 00:22:27,030
Yellow fever is a much more severe disease, but again does not occur here.

273
00:22:27,120 --> 00:22:30,240
Again, another flavivirus, where the word flavivirus comes from.

274
00:22:30,240 --> 00:22:31,110
Flavi means yellow.

275
00:22:32,070 --> 00:22:49,160
Um, there is of course a highly effective vaccine and the history of yellow fever and yellow fever vaccination is, you know, there are, there are books written about that, and I won't waste much time other to say, this guy doesn't have yellow fever and then lepto[spirosis], which is bacterial, but can clinically overlap a lot.

276
00:22:49,250 --> 00:22:50,390
And for disease.

277
00:22:50,390 --> 00:22:54,440
This mild, you know, you could make a case for just trying doxycycline empirically in him.

278
00:22:55,520 --> 00:23:00,320
So then the challenge comes, and this is especially in this kind of clinical setting.

279
00:23:00,320 --> 00:23:01,670
Like how do you diagnose it?

280
00:23:01,730 --> 00:23:02,030
Right?

281
00:23:02,210 --> 00:23:07,960
Because on some level mild dengue - it's not that big a deal.

282
00:23:08,020 --> 00:23:08,470
Right.

283
00:23:08,530 --> 00:23:11,980
And so the reasons we would want to diagnose it is (a) to give it a name, right.

284
00:23:11,980 --> 00:23:12,820
Because that can be helpful.

285
00:23:12,820 --> 00:23:15,700
And because there is a residual risk of severe disease.

286
00:23:16,270 --> 00:23:21,160
And so do at least want to do some sort of risk stratification for this, uh, for this gentleman.

287
00:23:21,160 --> 00:23:25,060
And I guess one question I it's worth asking is where was he born?

288
00:23:25,300 --> 00:23:26,830
Was he born in North America?

289
00:23:26,830 --> 00:23:30,430
Was he born in the continental US or was he born overseas?

290
00:23:30,925 --> 00:23:33,025
James Wilson: Midwest, so Chicago land.

291
00:23:33,370 --> 00:23:36,490
Ryan Maves: So, so relatively low rates of dengue in Chicago.

292
00:23:36,490 --> 00:23:37,570
So that is reassuring,

293
00:23:37,630 --> 00:23:37,930
right?

294
00:23:38,410 --> 00:23:38,710
Yeah.

295
00:23:38,860 --> 00:23:41,050
Cause I mean, I'll just anecdotally, I'll tell you that.

296
00:23:41,130 --> 00:24:00,590
One of my first consults as a new ID fellow, um, was a young man, 19 years old, uh, who grew up in San Diego, but was born and spent his first several years of life in the Western Pacific and traveled back to visit family, uh, you know, visit his grandparents, his aunts and uncles, and comes back with dengue hemorrhagic fever.

297
00:24:01,190 --> 00:24:08,060
Um, and so it is at least somewhat worth knowing whether or not there is some history of some prior exposure that could play a role.

298
00:24:08,330 --> 00:24:12,560
Not that that's perfectly predictive, but you know, we got to risk stratify these people somehow.

299
00:24:13,760 --> 00:24:14,330
All right.

300
00:24:14,540 --> 00:24:14,900
All right.

301
00:24:14,900 --> 00:24:22,340
So then we get to, how are we going to diagnose it and, and, and what are kind of physical examination strategies and laboratory strategy.

302
00:24:22,350 --> 00:24:23,840
So we have, we talked about CBCs.

303
00:24:23,840 --> 00:24:27,290
We talked about chemistry panels, blood cultures, just to be paranoid.

304
00:24:27,290 --> 00:24:28,640
And I'm an ID doctor.

305
00:24:28,640 --> 00:24:34,400
And, you know, the indication for blood cultures is like fever and having blood.

306
00:24:35,000 --> 00:24:59,230
So where, uh, where in, in my old place in San Diego, when, when James was, earlier in training, the residents had a meme of me going around the ICU, uh, which was me scowling in a corner and it said, indications for inpatient hIV testing, presence of blood and or genitalium.

307
00:25:01,630 --> 00:25:04,210
So, you know, blood cultures, it's kind of like

308
00:25:04,415 --> 00:25:05,945
James Wilson: this may or may not be absolutely

309
00:25:06,190 --> 00:25:07,210
Ryan Maves: yeah, yeah.

310
00:25:08,170 --> 00:25:09,040
So dengue?

311
00:25:10,060 --> 00:25:16,800
Um, so with all that going around, um, how could we actually diagnose dengue?

312
00:25:16,800 --> 00:25:18,210
There's a bunch of ways we could do it.

313
00:25:18,260 --> 00:25:21,350
There are some interesting physical exam findings that we could pursue.

314
00:25:21,500 --> 00:25:31,190
Uh, the tourniquet test is a thing you'll find in textbooks a bit where you, you know, you take a blood pressure cuff, you inflate it to, you know, halfway between systolic and diastolic.

315
00:25:31,190 --> 00:25:33,050
You leave it on there for a few minutes, then measure.

316
00:25:33,755 --> 00:25:38,975
You look for petechiae in a, you know, it's generally a two and a half centimeter by two and a half centimeter square.

317
00:25:38,975 --> 00:25:39,755
You count them.

318
00:25:39,755 --> 00:25:44,825
And that can be predictive of capillary fragility, which can be predictive in some cases of dengue.

319
00:25:45,245 --> 00:25:48,425
It is a physical exam fun fact.

320
00:25:48,455 --> 00:25:52,955
I don't think that it necessarily contributes much to the diagnosis or the management of the case.

321
00:25:52,955 --> 00:25:55,415
That is neither sensitive nor specific finding for dengue.

322
00:25:55,835 --> 00:25:56,795
If you find it it's neat.

323
00:25:57,305 --> 00:26:00,515
If I had a fellow come up to me and say, Hey, I found this patient.

324
00:26:00,515 --> 00:26:02,315
I think they have dengue, I did this thing.

325
00:26:02,315 --> 00:26:03,065
It was positive.

326
00:26:03,065 --> 00:26:04,235
I would think, oh, that's neat.

327
00:26:04,595 --> 00:26:07,175
So, but not terribly helpful.

328
00:26:07,205 --> 00:26:16,985
We do want to look for signs of hemorrhage on exam, obviously that they have any mucosal bleeding, any petechiae, anything on their hard palate or soft palate, uh, anything on their conjunctiva.

329
00:26:17,015 --> 00:26:21,325
James, you mentioned that they don't seem to have any obvious lesions in their eyes.

330
00:26:21,355 --> 00:26:22,015
That's helpful.

331
00:26:22,045 --> 00:26:30,820
Both for things that are also absent like jaundice or icterus um, And then we got to find some specific labs, right.

332
00:26:30,820 --> 00:26:34,660
And so probably the purists answer would be, this is kind of neat.

333
00:26:34,660 --> 00:26:44,110
This came out, started coming out when Zika first started being a thing is, gosh, I have to find out if this is actually like a trade name or generic name, but a Trioplex.

334
00:26:45,580 --> 00:26:49,840
But basically what it is is a three valent PCR for dengue, zika, chikungunya.

335
00:26:50,350 --> 00:26:51,490
CDC will run it.

336
00:26:51,490 --> 00:26:55,990
State and county public health departments can order it through channels, depending if they have it available.

337
00:26:56,440 --> 00:27:02,590
Uh, in the Department of Defense, we can get these run at the Walter Reed Army Institute of Research or at the Naval Medical Research Center.

338
00:27:03,040 --> 00:27:19,240
Um, so if you are military affiliated and I'll say, this is one of those things that comes up a little more for people practicing the military, um, because we have a, as we say, highly mobile population, um, So what that can be run off of blood and urine.

339
00:27:19,990 --> 00:27:29,680
Urine is probably  more sensitive, and it's probably positive longer because the period of viremia in acute dengue is relatively brief, but you can be shedding virus in your urine for a longer stretch of time.

340
00:27:30,040 --> 00:27:31,000
And that's super helpful.

341
00:27:31,480 --> 00:27:34,570
You can send off serologies for dengue, Zika, and chik[ungunya]..

342
00:27:34,870 --> 00:27:40,605
I will tell you that every positive Zika IgM, who I saw during the Zika epidemic, turned out to actually have dengue.

343
00:27:40,635 --> 00:27:47,415
So there's a lot of cross-reactivity on the flavivirus side of things, and I have never seen, or at least I should rephrase that.

344
00:27:47,415 --> 00:27:49,805
I have never diagnosed a case of chikungunya.

345
00:27:50,395 --> 00:27:54,645
Um, so hard to say, I have colleagues, who've seen it a lot.

346
00:27:55,545 --> 00:28:00,525
Uh, and then dengue, you know, you can, there are a number of commercial ELISA based assays.

347
00:28:01,065 --> 00:28:04,385
Um, again, a lot of cross-reactivity with other flaviviruses.

348
00:28:04,725 --> 00:28:12,755
So you have to take it  with a little bit of a grain of salt, um, but helpful if positive, particularly if you get convalescent titers down the road for IgG.

349
00:28:13,265 --> 00:28:16,925
Uh, the kinetics of that, there is a little bit of a delay in when those start to kick in.

350
00:28:18,455 --> 00:28:20,405
And then lastly, there is actually a dipstick.

351
00:28:20,435 --> 00:28:37,415
And I think those of us who, you know, ordered the, the rapid COVID tests that you can get mailed to you or purchased in the store, so the same manufacturer actually makes  a dengue dipstick for the, uh,  NS1 antigen, the non-structural protein one.

352
00:28:37,415 --> 00:28:42,765
And so all flaviviruses have these non-structural proteins -- NS1, NS3, NS5.

353
00:28:42,785 --> 00:28:58,175
You know, if you've taken care of Hep C, you know, hepatitis C is a flavivirus, basically, and it has a lot of the Hep C drugs target NS3 or NS5,  involved in Hep C replication.

354
00:28:59,075 --> 00:29:01,485
Well, there's a lot of the same things present on dengue,

355
00:29:01,505 --> 00:29:11,555
so NS1 one of those, and that can be detected in serum with a rapid test, very specific, not quite as sensitive as you like, but if it's positive, it's positive.

356
00:29:12,035 --> 00:29:17,915
That is FDA approved in the U S but I gotta say , not a lot of urgent cares have those stocked.

357
00:29:19,545 --> 00:29:20,025
Sara Dong: Yeah.

358
00:29:20,055 --> 00:29:23,385
So I am just going to pause us here for a moment.

359
00:29:23,685 --> 00:29:28,815
Uh, to focus on the lab testing because I think there's so much great information here.

360
00:29:29,235 --> 00:29:32,625
So you've mentioned how we can establish diagnosis directly.

361
00:29:32,835 --> 00:29:47,055
So by detecting viral components in the serums, this could be the serum non-structural protein or that NS1 antigen testing, and we have PCR, both of which should be detectable in that first week of illness.

362
00:29:47,655 --> 00:29:57,915
And then for serology, we can detect dengue IgM via ELISA, which would be positive somewhere around, you know, four to six days after onset of illness.

363
00:29:58,305 --> 00:30:01,545
And importantly can stick around for a long time, longer than what we

364
00:30:02,085 --> 00:30:04,095
often expect with IgM, but.

365
00:30:04,635 --> 00:30:07,905
Uh, has the difficulty of lots of cross-reactivity.

366
00:30:09,285 --> 00:30:13,305
We certainly could confirm diagnosis with paired acute and convalescent results.

367
00:30:13,725 --> 00:30:25,065
Uh, but one thing I was wondering if you could mention was how we use or can use plaque reduction neutralization assays, uh, which sometimes come up for arboviruses like dengue..

368
00:30:25,248 --> 00:30:30,128
Ryan Maves: Serologic testing, there is a thing called a PRNT which is a plaque reduction neutralization test.

369
00:30:31,448 --> 00:30:45,218
It's kind of a confirmatory test, but it's also, it's a way around those flavirvirus cross reactions we talked about right now, like Zika and yellow fever and dengue gay, and sometimes Hep C will have cross-reactive antibodies.

370
00:30:45,788 --> 00:30:48,038
But, um, on ELISA I should say.

371
00:30:48,038 --> 00:30:51,788
So a PRNT is like a functional study if you will, for antibody.

372
00:30:51,798 --> 00:30:55,698
So you take  well plates that are coated with usually Vero cells.

373
00:30:56,418 --> 00:31:09,378
And these are then inoculated with both a certain amount of different virus, so dengue 1, dengue 2, dengue 3, dengue 4, as well as a patient's serum at varying dilutions.

374
00:31:09,408 --> 00:31:11,778
And what you're looking for is a viral cytopathic effect.

375
00:31:11,778 --> 00:31:27,548
And what that basically is is you look at the sheet of cells that are usually stained to blue, and you'll look for a little holes where they've seen where the virus is causing cell lysis, and then you count at what dilution of serum, you see a 50% reduction in the amount of cell lysis on those plates.

376
00:31:27,548 --> 00:31:29,188
So you just count, right?

377
00:31:29,198 --> 00:31:32,708
You're just taking a little card and you count how many of those holes are.

378
00:31:32,918 --> 00:31:41,378
And that is relatively specific for telling you which serotype, which type of dengue is responsible for that.

379
00:31:41,378 --> 00:31:48,308
So, because there's gonna be some cross-reaction between antibodies against dengue 2 having some residual activity against dengue 1, for example.

380
00:31:48,998 --> 00:32:03,468
But if you, if you do run a PRN T on it, you can say, Hey, listen, the, uh, the titer causing a PRNT reduction of 50%,  for dengue three is much higher than the titers for one, two and four.

381
00:32:03,828 --> 00:32:07,668
Well, it gives you a pretty good idea that that person is infected with dengue three.

382
00:32:08,118 --> 00:32:10,628
Now that is mostly of epidemiological interest,

383
00:32:10,938 --> 00:32:11,238
right?

384
00:32:11,238 --> 00:32:16,128
That's not necessarily a thing that affects our management of a patient at the bedside, but it is kind of neat.

385
00:32:16,548 --> 00:32:17,748
It is a cool test to run.

386
00:32:17,778 --> 00:32:24,528
If you're an institution that can run them or sometimes CDC or other agencies will run those for epidemiologic tracking purposes.

387
00:32:25,008 --> 00:32:25,788
That's kind of cool.

388
00:32:26,118 --> 00:32:29,448
It doesn't affect much of what we do at the bedside with a given patient though.

389
00:32:30,183 --> 00:32:40,693
So thinking about other things that would suggest and go beyond, obviously having some sort of micro biologic or serologic diagnosis, pancytopenia is going to be, is fairly distinctive for dengue.

390
00:32:40,913 --> 00:32:53,013
Obviously that's not the most specific sign in the world, but someone's a little bit leukopenia and it's not you know, a white count of 0.4 and a hemoglobin of five and 22 platelets or anything like that.

391
00:32:53,403 --> 00:33:02,403
But having relative leukopenia, relative lymphopenia, moderate anemia, and low platelets is going to be very predictive.

392
00:33:02,673 --> 00:33:22,243
And it was kind of interesting when there are some studies that try to tease out like what syndromes are more likely both laboratory and clinical to be dengue compared with other kind of adjacent infections, you know, an AST greater than 60, white count less than 5,000,  and absolute neutrophil count less than 3000.

393
00:33:22,483 --> 00:33:28,183
This has at least some degree of predictive value in a patient with a compatible travel history and a compatible syndrome.

394
00:33:28,183 --> 00:33:29,143
And so that can be helpful.

395
00:33:29,143 --> 00:33:32,743
Now, granted, that's also kind of true of like rickettsia.

396
00:33:33,043 --> 00:33:38,353
So we do have to be a little bit modest in that that, you know,  I don't, I've never known for sure.

397
00:33:38,353 --> 00:33:47,803
If the, like the, the concept of the doxycyclin deficiency disease is universal in, in, uh, in ID, but it looks very much like that.

398
00:33:47,803 --> 00:33:58,033
So again, we have to be at least having an element of modesty about that, that thing can look like dengue, but could potentially be something with an overlapping laboratory scenario.

399
00:33:58,573 --> 00:34:03,613
Um, you know, if you're comparing it to like chik[ungunya] for example, the chikungunya, you know, there's going to be less rash.

400
00:34:03,643 --> 00:34:04,903
There's going to be more arthralgia.

401
00:34:05,173 --> 00:34:10,813
There's going to be more, uh, conjunctivitis often in patients with chikungunya, but that is not carved in stone.

402
00:34:10,813 --> 00:34:18,763
And often the, you know, dengue's old nickname is breakbone fever, distinguishing severe myalgia from severe arthralgia is perhaps not as easy as it sounds.

403
00:34:21,428 --> 00:34:30,538
James Wilson: I would ask since we're talking about the diagnosis, um, They changed the terminology and we saying dengue and then we may discuss hemorrhagic fever

404
00:34:31,368 --> 00:34:31,978
shock syndrome.

405
00:34:31,978 --> 00:34:38,758
But that was changed in 2009, um, to, you know, dengue, dengue with warning signs and, you know,

406
00:34:39,878 --> 00:34:47,098
severe dengue I think in common lingo, at least, uh, in the hospitals I've worked at are in an American, you know, conferences or whatever.

407
00:34:47,098 --> 00:34:50,128
I still feel is thrown around or dengue hemorrhagic fever.

408
00:34:50,488 --> 00:34:53,308
Um, would you mind commenting on the change?

409
00:34:53,328 --> 00:34:54,168
Ryan Maves: No, not at all.

410
00:34:54,168 --> 00:34:59,448
So, you know, historically there was this division of dengue into kind of three flavors.

411
00:34:59,448 --> 00:35:06,468
If you will, sort of classic dengue, dengue hemorrhagic fever and dengue shock syndrome, and they exist on a continuum of severity.

412
00:35:06,498 --> 00:35:13,158
Now, part of the problem is that dengue hemorrhagic fever and dengue shock syndrome had fairly strict criteria.

413
00:35:13,158 --> 00:35:18,198
You had to  meet these definitions to have, to qualify if you will, as having them.

414
00:35:18,498 --> 00:35:26,203
Well, it turns out the people could maybe not meet DHF criteria, but we're still clearly very sick and clearly were at risk for progression.

415
00:35:26,203 --> 00:35:39,823
And so that you know, WHO and other international groups have moved away from that definition to now to say, look at what we call dengue with warning signs and then dengue, you know,  then severe dengue, right?

416
00:35:39,823 --> 00:35:44,713
And then within the spectrum of severe dengue , you can add shock, which really is just hypotension.

417
00:35:44,713 --> 00:36:00,058
And my, you know, my, my intensivist itself would say that hypotension and shock are not the same thing, but clearly they are related and clearly they overlap and clearly someone who presents with dengue and hypotension is at risk for more severe outcomes.

418
00:36:00,418 --> 00:36:00,688
Right?

419
00:36:00,688 --> 00:36:10,588
If you figure, if you figure that the mortality of dengue shock syndrome in a modern monitored hospital setting is probably about 0.1%.

420
00:36:10,768 --> 00:36:19,408
And that's just really with fluid resuscitation and close monitoring, uh, the risk of mortality of that group of patients is up to 20% in resource limited settings, right?

421
00:36:19,408 --> 00:36:21,088
So those are people who are definitely at risk of dying.

422
00:36:21,088 --> 00:36:26,668
And really the, the tragedy here is that that that group at risk are largely infants, right?

423
00:36:26,698 --> 00:36:28,828
Those are the ones who are at the greatest risk of passing.

424
00:36:28,828 --> 00:36:36,828
It is, you know, the, the graveyards of the world are not filling up with  wealthy travelers from North America, dying of dengue shock syndrome.

425
00:36:36,908 --> 00:37:04,353
The burden of morbidity and mortality is overwhelmingly, although not exclusively on, on infants, on little kids in, uh, in endemic areas, So when we kind of look at like what those features that would kind of lead us to call someone's having, uh, having severe dengue, um, you know, the, the old definition included for like dengue hemorrhagic fever.

426
00:37:04,383 --> 00:37:14,433
The big thing was this plasma leakage, this idea you had capillary leakage, uh, that would often be associated with pleural and peritoneal effusions, and often hypovolemic shock.

427
00:37:14,733 --> 00:37:15,003
Right?

428
00:37:15,003 --> 00:37:16,233
So you'd just start leaking out.

429
00:37:16,233 --> 00:37:19,653
And because of that, you'd get hemoconcentration and relatively high hematocrit.

430
00:37:20,013 --> 00:37:34,068
These are the folks who have maybe petechiae, maybe have some, maybe a little GI bleeding, but they usually don't like bleed overtly, um These people also feel lousy for a very, very, very, very long time.

431
00:37:34,488 --> 00:37:43,368
You add on top of those hemorrhagic slash capillary leakage phenomena, the existence of hypotension, then you have dengue shock syndrome, right?

432
00:37:43,728 --> 00:37:46,098
So still a useful kind of concept.

433
00:37:46,128 --> 00:37:54,758
Capillary leakage, marker of severe dengue that can manifest is with hemorrhage, that can manifest with pleural effusions ascites et cetera.

434
00:37:54,848 --> 00:37:56,048
It can manifest with frank bleeding.

435
00:37:56,048 --> 00:38:02,678
It can manifest with shock, um, but it becomes impractical because of those definitions.

436
00:38:02,678 --> 00:38:13,058
So when you look at the new scoring systems, there's dengue with warning signs, and these are people who in, when we see these folks in North America, we should really very strongly admit.

437
00:38:13,868 --> 00:38:15,578
We would almost certainly admit the majority of them.

438
00:38:15,708 --> 00:38:21,188
These are people with abdominal pain, uh, certainly anything that resembles peritoneal signs.

439
00:38:21,218 --> 00:38:22,508
Those folks need to be admitted.

440
00:38:22,688 --> 00:38:25,643
People who have overt signs of plasma leakage.

441
00:38:25,703 --> 00:38:33,893
So again, effusions, for example, if you've got a chest film and you saw pleural effusions, that would be a marker for admission, overt mucosal bleeding.

442
00:38:34,643 --> 00:38:37,973
Obviously these are people we are very likely to admit regardless.

443
00:38:38,303 --> 00:38:55,973
A lethargy, inability to tolerate PO, severe vomiting, and then if you saw overt hemoconcentration, so you saw someone who was sick, maybe had some petechiae in their mouth, maybe had some pleural effusions, um, and then, you know, you get a hemoglobin on them and their hemoglobin is 17.

444
00:38:57,083 --> 00:38:59,753
Um, that would be a trigger for admission.

445
00:39:00,143 --> 00:39:09,983
Um, severe dengue then is going to be someone with frank plasma leakage, someone who's hypotensive, um, someone who has evidence of some other form of organ failure.

446
00:39:09,983 --> 00:39:13,553
Be it myocardial, be it severe delirium or encephalopathy.

447
00:39:14,013 --> 00:39:20,013
If someone did have overt signs of hepatitis, that's a person who you would need to admit because that person is a very high risk.

448
00:39:20,533 --> 00:39:27,023
. With all of this background, I think what we really need to sort out is what this gentleman's risk of severe disease is.

449
00:39:27,443 --> 00:39:29,003
The initial description sounds okay.

450
00:39:29,003 --> 00:39:31,253
But I think the laboratory may shed a little more light on that.

451
00:39:32,498 --> 00:39:32,798
James Wilson: Yeah.

452
00:39:32,828 --> 00:39:49,978
And so he went home with symptomatic treatment, um, and his lab work that I had ordered was a CBC, CMP, fourth gen HIV test, uh, you know, rapid flu, and an EBV swab, a Monospot, and um, you know, those results came back two days later.

453
00:39:49,978 --> 00:39:55,138
His CBC showed he had a white count of 3.1 with an ANC of 2,900.

454
00:39:55,678 --> 00:40:02,048
Uh, he had a hematocrit of 43% and his platelets were 170.

455
00:40:02,628 --> 00:40:13,748
His CMP, uh a little dehydrated is 148,  for  his sodium, 3.9 for his potassium, 111 chloride, 26 bicarb, 22 to 1.3 for BUN, Creatinine.

456
00:40:15,028 --> 00:40:22,048
for glucose with AST 65, ALT ALP at 111, total bilirubin 1.2 and an albumin at 2.8.

457
00:40:22,858 --> 00:40:24,028
I then had him come in.

458
00:40:24,028 --> 00:40:25,918
I saw him and he looked grand.

459
00:40:26,398 --> 00:40:31,158
Um, and so I repeated the labs another day later.

460
00:40:31,168 --> 00:40:36,888
So over the course of about a week and they all reverted to what his baseline was from his physical a year prior

461
00:40:36,933 --> 00:40:37,383
Ryan Maves: Excellent.

462
00:40:38,043 --> 00:40:38,373
Yeah.

463
00:40:38,373 --> 00:40:41,023
So it sounds like he had certainly some laboratory

464
00:40:41,573 --> 00:40:42,403
James Wilson: HIV EBV

465
00:40:43,073 --> 00:40:43,453
Ryan Maves: Excellent.

466
00:40:43,473 --> 00:40:48,573
So, you know, relative leukopenia that resolved spontaneously, platelets are normal.

467
00:40:48,693 --> 00:40:50,193
All of this is very reassuring.

468
00:40:50,193 --> 00:40:54,003
Small LFT abnormalities or transaminase abnormalities that are getting better.

469
00:40:54,093 --> 00:41:00,513
So, yeah, so it sounds like this gentlemen had, you know, a fairly common manifestation of what we presume is dengue.

470
00:41:00,993 --> 00:41:12,363
Um, based on the topic we're talking about today, uh, and is likely to have a very good outcome in our care for him would be purely symptomatic and supportive with a few provisos here and there.

471
00:41:14,063 --> 00:41:14,253
James Wilson: Yeah.

472
00:41:14,303 --> 00:41:20,933
I think it's important to note that the patient had defervesced more than 48 hours prior to presentation to the clinic.

473
00:41:21,027 --> 00:41:35,807
During that timeframe, when we have any patient that we're suspecting dengue fever, that two to five days post defervescence is when you were most concerned to look for dengue hemorrhagic fever, and, um, you severe sepsis.

474
00:41:36,047 --> 00:41:41,897
Um, and if they make it past that five to seven day window after the fact, then they're probably going to be in the clear.

475
00:41:42,477 --> 00:41:48,877
Ryan Maves: that is sort of the danger time when people at their maximum risk of decompensation or at least clinical worsening from severe dengue.

476
00:41:48,927 --> 00:41:50,997
So that's, that's a, that's a great point.

477
00:41:50,997 --> 00:41:55,617
And you know, and again, those, those windows of time, two to five days and so forth, right?

478
00:41:55,617 --> 00:41:57,477
That's those are not laws of nature.

479
00:41:57,477 --> 00:42:05,957
Those are not carved in stone,  but you can definitely say that if someone is a good week or more out from their acute fever, that they're probably out of danger, right?

480
00:42:06,347 --> 00:42:11,207
It's also probably a good point to mention that the incubation period for dengue at most, a couple of weeks.

481
00:42:11,687 --> 00:42:20,297
And so a traveler who is returned from a dengue endemic region more than a couple of weeks ago, it is very unlikely that dengue is necessarily the cause of their acute illness.

482
00:42:20,297 --> 00:42:33,217
There are things with longer incubation periods, of course, typhoid, malaria, and many others, but dengue, it's a fairly typical virus in its incubation period for an acute viral infection is pretty focused, you know, maybe a couple of weeks.

483
00:42:33,792 --> 00:42:36,462
James Wilson: So I, I told him Tylenol and fluids.

484
00:42:36,462 --> 00:42:44,507
And if you couldn't tolerate PO, uh, to  Um, and he was asking, he's like, I just kind of feel a little lousy.

485
00:42:44,927 --> 00:42:47,087
Um, you know, I took some Tylenol didn't help.

486
00:42:47,087 --> 00:42:52,457
Can I take Motrin or in the military, we call it a vitamin M uh, for some ibuprofen high dose.

487
00:42:52,457 --> 00:42:54,107
And I told him to change his socks.

488
00:42:54,137 --> 00:42:58,947
But the big thing was, is I told him not to take any NSAIDs.

489
00:42:59,087 --> 00:43:04,817
Um, is there, I remembered that briefly from training, but didn't couldn't remember why at the time.

490
00:43:04,922 --> 00:43:24,497
Ryan Maves: Yeah, I think the real concern with NSAIDs is we do worry about that maybe potentiating risk of bleeding and people who progressed to a more hemorrhagic type of picture and, um, I doubt very much there's any large trials of say ibuprofen versus acetaminophen in the management of mild dengue and probably a person who is totally fine.

491
00:43:24,497 --> 00:43:31,247
I suspect a lot of people are taking ibuprofen for, for undiagnosed dengue like behind our backs.

492
00:43:31,277 --> 00:43:42,697
But in general,  the purest answer and the advice that we would give, uh, is to avoid NSAIDs and instead sticking primarily to acetaminophen for, um, for symptomatic relief.

493
00:43:43,267 --> 00:43:43,597
Right.

494
00:43:45,782 --> 00:43:51,752
And then, you know, trying to maintain, reasonable volume status, eat what you can eat, avoid dehydration.

495
00:43:51,902 --> 00:43:56,162
But again, these are things just for symptomatic control and his prognosis is probably pretty good.

496
00:43:56,162 --> 00:43:58,892
Although the fact that he feels lousy is very common, right?

497
00:43:59,342 --> 00:44:17,162
Uh, one of the, one of the less pleasant features of dengue is that recovery is often somewhat prolonged, uh, that people can have a relatively mild illness, but still feel blah for several weeks afterwards, this prolonged post dengue asthenia I guess we could call it.

498
00:44:19,192 --> 00:44:19,702
James Wilson: Perfect.

499
00:44:20,212 --> 00:44:30,127
Um, so that was the first part because  he happened to repeat his q [every] six month trips to Thailand, which he had started four years prior.

500
00:44:30,577 --> 00:44:48,707
Uh, and he went back again in April, And so he came back and had been febrile for several days and his fever broke and he was still felt lousy, but he needed to come back to work as a pharmaceutical rep.

501
00:44:49,127 --> 00:44:52,337
He came back to work and just so happened to come into the clinic.

502
00:44:52,347 --> 00:44:53,607
He looked terrible.

503
00:44:54,087 --> 00:44:58,517
And so he told me that he had changed the trip that he had gone on a little bit.

504
00:44:58,517 --> 00:45:03,467
In this time he added Chiang Rai uh, to his trip, which is a little more rural.

505
00:45:03,777 --> 00:45:11,247
He'd gone to an elephant park and a tiger park, but he began having severe a headache for three days after returning.

506
00:45:11,307 --> 00:45:14,397
Uh, and he had marked retro-orbital pain on the right.

507
00:45:15,027 --> 00:45:21,357
Uh, but when he came in, he was afebrile at that time, but he just looked sunken.

508
00:45:21,837 --> 00:45:32,162
And so I took a look at him and had him sit down and he had a, what looked like a significant petechial rash on the, his right wrist.

509
00:45:32,162 --> 00:45:35,132
And I had him pull his sleeves up and it was on both sides.

510
00:45:35,942 --> 00:45:44,252
And so at that point we got blood pressures,  and he was at best 100 over 60.

511
00:45:44,562 --> 00:45:47,472
we took it several times, which gave him the tourniquet sign.

512
00:45:47,542 --> 00:45:53,582
Uh he was tachy[cardic] in the one  with mild diffuse abdominal tenderness, more so in the bilateral upper quadrants.

513
00:45:53,972 --> 00:45:58,212
Um, and he had been endorsing dark stools during the last week.

514
00:45:58,292 --> 00:46:02,882
And so  advised him that he needed to go to the local ER, which happened across the street.

515
00:46:02,932 --> 00:46:13,312
So when he made it to the ER, he was still 90/50 [blood pressure], they bolus'd liters of normal saline, he, um, but he had tachycardia at that point in the 110s, uh, despite the fluids.

516
00:46:13,312 --> 00:46:19,032
The ER obtained urine culture, UA,  blood cultures, they attempted to get a sputum culture.

517
00:46:20,082 --> 00:46:24,342
Is he had CBC, a CMP and a lactic acidosis, and these things were all cooking.

518
00:46:24,762 --> 00:46:30,732
Uh, when they page the ID attending, that was on call based on his travel history.

519
00:46:31,182 --> 00:46:36,762
So let's say that they, their question at that point was, do we get an LP given his headache?

520
00:46:37,212 --> 00:46:40,392
So that was the phone call that went to the infectious disease physician.

521
00:46:40,392 --> 00:46:43,122
And let's assume that that would be you in the setting,

522
00:46:43,482 --> 00:46:48,102
Ryan Maves: Yeah, well, I, so it's a bit of a pickle, right?

523
00:46:48,132 --> 00:46:58,602
Because in general, my answer to folks about, do I do an LP on a fever and a headache is that the time to do an LP is when you ask yourself, should I do an LP?

524
00:46:59,292 --> 00:46:59,652
Right.

525
00:47:00,072 --> 00:47:19,662
Um, now there are some features of him that makes me kind of drifts me, both kind of pro and con, one is that, you know, he's not probably the obvious risk group for meningococcal disease, but we at least need to acknowledge that someone with new and progressive petechiae and a fever and a headache that we need to, at least, you know, he doesn't live in congregate housing.

526
00:47:19,662 --> 00:47:34,892
He hasn't returned from an area like say that, uh, the meningococcal endemic regions of Sub-Saharan Africa, uh, where he has returned from the Hajj where we would expect a higher risk for meningococcal disease.

527
00:47:35,342 --> 00:47:46,052
Um, but you know, if you ask me, I mean, if his platelet count is acceptable and he's not anticoagulated and it is on your differential, then the answer is yes.

528
00:47:46,202 --> 00:47:46,652
Right.

529
00:47:46,952 --> 00:47:52,412
Um, now that being said his syndrome, and since we're on the topic, his syndrome, I think we know the answer to that.

530
00:47:52,652 --> 00:47:58,112
Um, but I, I'm certainly not going to be, uh, not going to be recorded on, uh, on Dr.

531
00:47:58,112 --> 00:48:02,232
Dong's famous podcast not not LP a man with fever and rapidly evolving

532
00:48:02,322 --> 00:48:05,132
Sara Dong: I'm glad that your response to that is the same as mine.

533
00:48:05,132 --> 00:48:10,922
If you ask the question, then it's going to be really hard to get an ID doc to say, no, you don't need that LP.

534
00:48:11,352 --> 00:48:13,212
Ryan Maves: Yeah, exactly, exactly.

535
00:48:13,242 --> 00:48:16,392
But that being said, we can take a look at some additional features.

536
00:48:16,392 --> 00:48:26,682
So the big concern for this gentleman obviously is that, you know, he's presenting with persistent hypertension, uh, not responding completely, although his MAP is probably greater than 65.

537
00:48:26,682 --> 00:48:27,012
Right.

538
00:48:27,042 --> 00:48:30,442
So what did his hemodynamics do after that second liter?

539
00:48:32,402 --> 00:48:34,142
James Wilson: They remained the same, essentially.

540
00:48:34,192 --> 00:48:34,582
Ryan Maves: Okay.

541
00:48:34,852 --> 00:48:35,272
Okay.

542
00:48:36,262 --> 00:48:56,362
So, you know, this gets us into one of these pickles where we're having to deal with, you know, what it sounds like we're thinking this is a severe dengue based on his, shall we say recurrent exposures, but still needing to acknowledge the fact that these cosmopolitan types of infections still exist, um, that he could still just be bacteremic..

543
00:48:56,382 --> 00:49:06,022
He could still just be septic and that I would be, you know, deeply reluctant to not recommend blood cultures, empiric antibiotics, and so forth.

544
00:49:06,022 --> 00:49:11,242
Just remember that when we think about what are the modifiable risk factors for mortality in septic shock, right?

545
00:49:11,242 --> 00:49:15,322
It's time of hypotension until time of active antibiotics on board, right.

546
00:49:15,322 --> 00:49:18,202
In addition to hemodynamic correction and so forth.

547
00:49:18,232 --> 00:49:18,532
So.

548
00:49:19,732 --> 00:49:21,982
We will set that aside because that is not our topic.

549
00:49:22,162 --> 00:49:24,022
Let us assume that has been addressed.

550
00:49:24,442 --> 00:49:32,872
Um, not always a great assumption to have, and I know that we accidentally randomized people to the natural history arm of the septic shock trial on occasion.

551
00:49:33,202 --> 00:49:37,402
So let's, let's not do that, but having addressed

552
00:49:37,582 --> 00:49:44,242
James Wilson: did zosyn or pip-tazo and Vancomyocin when he came in hypotensive and tachycardic

553
00:49:44,812 --> 00:49:45,622
with fevers,

554
00:49:45,682 --> 00:49:45,982
Ryan Maves: know,

555
00:49:46,522 --> 00:49:47,062
James Wilson: a history of

556
00:49:47,272 --> 00:49:50,782
Ryan Maves: you know, and of course this is a, this is a podcast for infectious disease doctors.

557
00:49:50,782 --> 00:50:01,972
And I know we all kind of joke about that as the decerebrate choice, the antibiotic selection, um, that being said, that's probably not the most unreasonable thing, although if you're thinking fever and headache, that probably something that penetrates the CNS better than pip-tazo

558
00:50:02,032 --> 00:50:04,252
so it would be a good idea moving on.

559
00:50:04,672 --> 00:50:10,222
So in terms of diagnostics, what do we have any laboratory studies to help guide our thinking about this gentlemen?

560
00:50:10,855 --> 00:50:28,295
James Wilson: So,  his labs, that ended up coming back about an hour later, uh, his white count was two, his ANC was 1300 and  his hemoglobin was 16, and his platelets was, 65 at that point.

561
00:50:29,135 --> 00:50:40,215
Um,  and then for his CMP, he had a AST of a 125 and then an ALT of 200

562
00:50:40,995 --> 00:50:41,955
at that point.

563
00:50:42,285 --> 00:50:44,445
And  his total bilirubin was a 2.1.

564
00:50:45,195 --> 00:50:46,335
So at that point, so.

565
00:50:46,610 --> 00:50:57,890
Ryan Maves: You know of those labs, the most reassuring thing there is actually, even though there's know significant derangements all up and down is that hemoconcentration right, because that's a fairly distinctive feature.

566
00:50:57,890 --> 00:51:09,230
Now, if, if we were seeing that in a person with a different travel .History and without this prior history of presumptive, dengue, of course, let's say this person had come back from west Africa and had pharyngitis along with a lot of the same features.

567
00:51:09,530 --> 00:51:11,100
Then we would be worried about lassa.

568
00:51:11,210 --> 00:51:17,060
We could be worried about other causes of viral hemorrhagic fever, um, more common in other parts of the world.

569
00:51:17,060 --> 00:51:22,490
So it, although hemoconcentration in this particular setting is somewhat reassuring.

570
00:51:22,580 --> 00:51:23,390
In other settings.

571
00:51:23,390 --> 00:51:30,500
It is very unreassuring and just be, we need to all be remind ourselves that hemoconcentration is not normal, right?

572
00:51:30,500 --> 00:51:35,390
And that is a potential marker of capillary leakage, which is a hallmark of viral hemorrhagic fevers.

573
00:51:36,230 --> 00:51:37,130
In this gentleman's case.

574
00:51:38,785 --> 00:51:45,625
Um, you know, I think that sending off diagnostic tests again for dengue and for all the other stuff we did last time, right.

575
00:51:45,625 --> 00:52:05,965
We still need, you know, bad luck can happen multiple times just because he, you know, didn't get acute HIV, just because he didn't get acute hepatitis B last time, doesn't mean he can't get it this time, especially if, you know, if his sexual exposures and other exposures are relatively comparable.

576
00:52:06,295 --> 00:52:09,475
And again, he's a little more rural area, you know?

577
00:52:10,280 --> 00:52:17,390
Uh, high hematocrit is not a feature of malaria typically, but I, again, think we need to go down that pathway, especially given his greater severity of illness.

578
00:52:17,510 --> 00:52:23,810
And I suppose, I think again, thinking as a, as an intensivist, more than an ID doctor right now, but still both are true.

579
00:52:24,170 --> 00:52:26,780
What is our risk tolerance in this gentleman?

580
00:52:26,780 --> 00:52:29,330
What is our tolerance for being wrong?

581
00:52:29,720 --> 00:52:39,650
A hemodynamically stable patient who walks in under his or her own power sits down to clinic is able to eat, is able to drink, has good follow-up, you have a different margin for error for that patient.

582
00:52:39,890 --> 00:52:43,070
Maybe not for malaria, but for other things you do, right?

583
00:52:43,070 --> 00:52:48,470
Like that person is unlikely to have significantly adverse outcome if you guess wrong the first time.

584
00:52:49,010 --> 00:52:53,720
So it comes in hypotensive, tachycardic, febrile, looks bad, unable to keep food down.

585
00:52:53,900 --> 00:52:56,390
That person, your margin for error is extremely limited.

586
00:52:56,840 --> 00:52:59,240
And so we need to make sure we're getting it right the first time.

587
00:52:59,240 --> 00:53:03,800
So although we will discuss features of severe flavivirus infections.

588
00:53:03,800 --> 00:53:16,430
We also need to acknowledge the remainder of this differential diagnosis, which as aforementioned, probably includes a lumbar puncture along with blood culture and it's potentially with empiric antibacterial drugs and so forth.

589
00:53:17,600 --> 00:53:24,890
So, um, is there any way we can get any kind of specific diagnostics for dengue on him?

590
00:53:24,920 --> 00:53:25,700
What's available?

591
00:53:30,155 --> 00:53:30,485
James Wilson: Okay.

592
00:53:30,535 --> 00:53:34,045
This was a community hospital, um, 10 bed, ICU type place.

593
00:53:34,045 --> 00:53:38,985
And so they didn't have much, they sent serologies and they sent the PCR, but they're all send out tests.

594
00:53:39,010 --> 00:53:39,310
Ryan Maves: Okay.

595
00:53:39,310 --> 00:53:39,790
That's fine.

596
00:53:39,820 --> 00:53:47,800
Well, there's an, and, and there is nowhere, I don't know, maybe your, for working at Emory and you're across the street from CDC, you can get dengue turnaround

597
00:53:47,800 --> 00:53:49,360
Sara Dong: yeah, it's a send-off for everyone.

598
00:53:49,360 --> 00:53:49,690
I feel

599
00:53:49,810 --> 00:53:50,260
Ryan Maves: Yeah.

600
00:53:50,290 --> 00:53:51,280
I mean, exactly.

601
00:53:51,280 --> 00:53:57,430
If you can like walk across the street, then maybe your turnaround is very fast, but I think in the overwhelming majority of situations, it's going to be a send-out.

602
00:53:57,670 --> 00:53:58,000
Right.

603
00:53:58,230 --> 00:53:59,550
But at least we can send it off.

604
00:53:59,550 --> 00:54:00,960
We can get the ball rolling on it.

605
00:54:01,380 --> 00:54:09,070
Um, you know, then the thing is like, didn't he just have dengue or aren't we pretty sure he just had dengue?

606
00:54:09,130 --> 00:54:10,740
So how is this happening now?

607
00:54:11,460 --> 00:54:17,820
And so, you know, I, I remember, uh, when I was a junior fellow, I was told, you know, it's not the first time you get dengue that kills you.

608
00:54:17,820 --> 00:54:18,990
It's the second time right.

609
00:54:19,320 --> 00:54:24,690
Now, that is an oversimplification, but the problem goes back to those four serotypes.

610
00:54:25,390 --> 00:54:40,990
The simplified version is that if you are infected with, say dengue three, you likely have at least nearly lifelong sterile immunity to dengue three, your immunity to den gues one, two, and four though is relatively short-lived.

611
00:54:40,990 --> 00:54:42,720
You may have some cross-reactive immunity.

612
00:54:43,545 --> 00:54:43,695
Yeah.

613
00:54:43,725 --> 00:54:44,685
A couple of years or so.

614
00:54:45,615 --> 00:54:45,975
Right.

615
00:54:46,365 --> 00:54:51,075
But, um, but that immunity will wane.

616
00:54:51,345 --> 00:55:13,065
And one of the things that happens is that we see this waning cross-reactivity that can actually potentiate increased severity infection that this, uh, this process called antibody dependent enhancement where, um, where mononuclear cells, dendritic cells, and like will take up dengue more efficiently with a partially incompletely, uh, neutralizing antibody.

617
00:55:13,545 --> 00:55:13,845
Right?

618
00:55:13,845 --> 00:55:18,285
And so this can lead to increase viraemia and  more rapid viral replication and more severe disease.

619
00:55:18,705 --> 00:55:22,395
Now, this is an incomplete explanation of why this happens, right?

620
00:55:22,395 --> 00:55:23,835
This is an incomplete explanation.

621
00:55:23,865 --> 00:55:25,935
There's probably some host factors involved.

622
00:55:26,475 --> 00:55:33,135
Um, there may be, there may be some polymorphisms in mediators of innate immunity

623
00:55:33,615 --> 00:55:34,455
that's involved.

624
00:55:34,485 --> 00:55:46,020
There is a sort of interesting thing for, you know, for ID doctors, of course, The CCR five co-receptor, uh, which we think of as a therapeutic target for HIV.

625
00:55:46,050 --> 00:55:47,280
Not that I don't know.

626
00:55:47,310 --> 00:56:01,710
I mean, I haven't given maraviroc for years, but it is a therapeutic target for HIV and the CCR five Delta 32 mutation, which when present, when you have two copies of that, you are relatively resistant and, or immune to HIV.

627
00:56:01,710 --> 00:56:11,070
And I've just read in the paper that we had recently, a third person cured of HIV by stem cell transplant with  CCR5 delta 32 homozygous donor.

628
00:56:11,850 --> 00:56:16,560
Um, well that mutation has affects in nature too.

629
00:56:16,560 --> 00:56:23,490
And one of the effects of that mutation is people who have it probably get more severe flavivirus disease, uh, more severe flavivirus infections.

630
00:56:23,940 --> 00:56:31,920
So, um, now this doesn't explain off the top of your head, like getting a second flavivirus infection.

631
00:56:31,920 --> 00:56:49,035
I said earlier that severe dengue is more likely in infants well, this explains that in part, because maternal antibodies can mediate, cross reacting, um, you know, incompletely cross-reactive antibody responses to primary dengue infections in neonates.

632
00:56:49,065 --> 00:56:49,365
Right?

633
00:56:49,365 --> 00:57:01,665
So a two month old who gets infected with dengue one and they also have some amount of dengue three antibody from the mother, um, could get severe dengue as result of that.

634
00:57:02,025 --> 00:57:06,705
Now, severe dengue does not happen in most hetero typic dengue infections.

635
00:57:07,185 --> 00:57:08,955
Uh, it happens only a minority of cases.

636
00:57:08,955 --> 00:57:13,785
It is not a complete and nor does it explain every case of severe dengue, right?

637
00:57:13,785 --> 00:57:17,925
There are these other host factors and things that play a role, but it is an interesting kind of model.

638
00:57:17,925 --> 00:57:25,125
And I will say, cause this is 2022 in recording this, that there are some coronaviruses that exhibit antibody dependent enhancement.

639
00:57:25,485 --> 00:57:36,105
Um, actually the, uh, the feline infectious peritonitis virus, um, which is a Corona virus, uh, has, antibody dependent enhancement as part of its pathogenesis.

640
00:57:36,345 --> 00:57:39,585
I mentioned that because my cat is sitting in my lap and I'm thinking about it right now.

641
00:57:45,765 --> 00:57:45,945
Okay.

642
00:57:46,065 --> 00:57:47,295
And she is very comfortable.

643
00:57:47,295 --> 00:57:53,115
And to the best of my ability to tell does not have feline, uh, peritonitis virus infections.

644
00:57:56,335 --> 00:58:00,025
Although for reasons I won't get into you, I do have to give her a cyclosporine for later on.

645
00:58:00,685 --> 00:58:01,285
Um,

646
00:58:01,725 --> 00:58:02,235
James Wilson: Oh man.

647
00:58:02,335 --> 00:58:02,695
Ryan Maves: yeah.

648
00:58:02,725 --> 00:58:02,995
Yeah.

649
00:58:03,265 --> 00:58:05,245
My cats, my cats, liver transplant.

650
00:58:05,485 --> 00:58:17,575
No, no, it's not that, uh, it's not that, um, anyway, so this immunopotentiation though, this is a thing, and it seems like in this patient, that explains what happened to him, right?

651
00:58:17,575 --> 00:58:21,445
That seems like that is probably the thing that drove his severity of disease.

652
00:58:22,075 --> 00:58:34,495
Um, and certainly in returning traveler to explain a bit, uh, you know, Thailand has multiple circulating serotypes of dengue and it's not implausible, especially cause he went to a new place, right?

653
00:58:34,735 --> 00:58:41,455
Because relatively recent, you know, different geographic regions, their dengue serotypes will shift kind of gradually over time.

654
00:58:41,815 --> 00:58:45,415
But he went to a new place, had the opportunity for a new exposure.

655
00:58:45,715 --> 00:58:48,445
And I think that explains kind of his deal.

656
00:58:48,505 --> 00:58:48,865
Right?

657
00:58:49,615 --> 00:58:51,385
So then we got to figure out is what we're going to do for it.

658
00:58:53,145 --> 00:58:55,565
And our choices are kind of limited.

659
00:58:55,875 --> 00:59:00,645
James Wilson: That was going to be my next step  from, from two points, right?

660
00:59:00,645 --> 00:59:15,615
The primary team, uh, likely the recommendation in the setting of tachycardia and hypotension and the old nomenclature of severe sepsis versus septic shock is, you know, but he has not responded exactly to the fluids.

661
00:59:15,615 --> 00:59:17,145
And so it sounds like he'd be going to the ICU.

662
00:59:17,145 --> 00:59:20,535
And so then it's a tag team with the ICU and the idea's already on board.

663
00:59:20,865 --> 00:59:32,045
From the two perspectives, the ID perspective, um, there are some studies on TNF alpha inhibition, and there are some studies on antiviral medications that have been tried.

664
00:59:32,315 --> 00:59:43,295
In this patient who was switched by the ID physician to essentially bacterial meningitis, uh, coverage, ceftriaxone, vancomycin, and ampicillin even despite his age, he still did the amp because of the travel.

665
00:59:43,655 --> 00:59:50,825
Um, and then he did acyclovir of your, at that point, uh, as well, just because, you know, because,

666
00:59:50,885 --> 00:59:53,165
and, uh, exactly.

667
00:59:53,525 --> 00:59:58,985
Uh, and so those things were continued and Flagyl was added for whatever reason.

668
00:59:58,985 --> 01:00:07,265
And, and, uh, so the, those two perspectives though, you know, the TNF alpha, we are not actually doing, those are mostly animal studies.

669
01:00:07,485 --> 01:00:16,185
Um, and so there's no movement to use infliximab on everyone that comes in, uh, but the antiviral, um, medications, it seems that since.

670
01:00:18,290 --> 01:00:20,130
Certainly in this patient may be up front.

671
01:00:20,130 --> 01:00:30,000
We don't have enough data to use an HCV targeting med because it is a similar flavivirus, but is there any other consideration for something targeting

672
01:00:30,660 --> 01:00:30,930
in these

673
01:00:31,185 --> 01:00:39,025
Ryan Maves: I mean, you hit the, the key thing, the key features are hemodynamic support, and that is going to be largely isotonic crystalloid resuscitation, right?

674
01:00:39,025 --> 01:00:51,355
Like not half normal, not, you know, D5-Water it's going to be principally volume, isotonic crystalloids normal saline or LR, depending on your, your local preferences.

675
01:00:51,685 --> 01:00:56,485
Given the volumes of fluid, I'd probably personally use LR, but I don't have a ton of data to back that up.

676
01:00:57,085 --> 01:01:07,135
Um, so the big question is in which volume, which mode of volume resuscitation you use are gonna come down to like, do we use colloid or crystalloid right.

677
01:01:07,135 --> 01:01:11,515
The only colloid in widespread clinical use and really the best one to use would be albumin.

678
01:01:12,085 --> 01:01:14,005
Could you use albumin with a clear conscience?

679
01:01:14,125 --> 01:01:14,425
Yeah.

680
01:01:15,760 --> 01:01:17,680
Um, it's more expensive.

681
01:01:17,710 --> 01:01:40,690
There's this sort of theoretical idea of, um, albumin containing fluids, restoring capillary integrity, essentially by kind of, uh, plugging the holes in the, uh, the endothelial glycocalyx, it's the same word as we think of for bacterial glycocalyx when you're talking about, um, you know, adherence to prosthetic devices and prosthetic infections, but it's a completely different concept.

682
01:01:40,690 --> 01:02:01,390
You can think of that as sort of the thing that makes, uh, the endothelial glycocalyx has a layer of, you know, heparin, opioids and glycosaminoglycans, and sort of the thing that makes Starling forces work keeps intravascular intravascular keeps extra vascular, extra vascular, and at least in the sepsis literature, there is this idea that albumin may help restore the integrity of that and reduce some of the capillary leakage

683
01:02:01,390 --> 01:02:02,950
in third spacing we see in sepsis.

684
01:02:03,430 --> 01:02:07,030
That's, you know, that is not to the best of my knowledge.

685
01:02:07,090 --> 01:02:08,080
Formally studied.

686
01:02:08,080 --> 01:02:09,940
You need detail in dengue per se.

687
01:02:10,930 --> 01:02:21,865
Um, but what is studied in detail in dengue is from a clinician a clinician standpoint, is there any benefit to albumin containing fluids over just, you know, LR.

688
01:02:22,225 --> 01:02:26,515
There isn't there, the same outcomes are the same, right.

689
01:02:27,085 --> 01:02:28,585
And, and that's fine.

690
01:02:28,585 --> 01:02:39,145
And actually from a standpoint of a disease that overwhelmingly affects people in resource limited settings, that's good news quite frankly if there was a massive improvement of the albumin, that could be very challenging to scale.

691
01:02:39,835 --> 01:02:43,195
Um, you know, you mentioned TNF alpha and inhibition.

692
01:02:43,195 --> 01:02:44,845
This is, again, this is an animal model thing.

693
01:02:44,875 --> 01:02:47,245
It's actually pretty hard to make animal models for dengue.

694
01:02:47,695 --> 01:02:50,675
Like it's pretty easy to infect animals with dengue.

695
01:02:51,055 --> 01:02:53,545
Uh, when I was working in Peru, we had rodent models.

696
01:02:53,545 --> 01:02:55,525
We had a non-human primate models.

697
01:02:55,735 --> 01:02:59,155
They can get infected, they can get viremic, but they don't get that sick.

698
01:02:59,815 --> 01:03:04,195
Um, so, uh, a, an animal model of severe dengue is challenging.

699
01:03:04,195 --> 01:03:11,605
There are some, uh, rodent models where they can see like, um, worsening, uh, not even worse than it really is a word.

700
01:03:11,995 --> 01:03:13,945
Um, erythroderma basically.

701
01:03:14,695 --> 01:03:18,505
They, they, you know, are erythroderma and that is a surrogate marker.

702
01:03:18,805 --> 01:03:21,325
Um, but yeah, so TNF alpha inhibition.

703
01:03:21,325 --> 01:03:26,095
We're not going to be starting everyone on Remicade to treat, uh, uh, DHF right now.

704
01:03:26,485 --> 01:03:33,805
Antivirals, you mentioned that it is a flavivirus and we are right now in a golden age of flavirvirus therapeutics because of hepatitis C.

705
01:03:34,255 --> 01:03:39,535
Uh, there is nothing that is currently, you know, anywhere near marketing right now, but there's some early data.

706
01:03:39,535 --> 01:03:46,285
And I think obviously this has been able to be built on the really built on the back of successful antiviral rollouts for hepatitis C.

707
01:03:46,285 --> 01:03:55,945
And of course, although it's a very different virus we've had of course success with some, uh, at least with some, uh, antiviral therapies for COVID-19.

708
01:03:55,945 --> 01:04:00,055
So hopefully those will continue to progress and make some, make some progress there.

709
01:04:00,295 --> 01:04:01,255
And then steroids, right?

710
01:04:01,255 --> 01:04:04,225
Anytime anyone's got fever and shocks and one wants to throw steroids out at.

711
01:04:06,140 --> 01:04:13,850
I am recorded on tape somewhere saying, uh, in, uh, February of 2020 that I thought steroids for COVID were going to be a bad idea.

712
01:04:14,240 --> 01:04:30,380
Um, I, uh, I, I think I like to tell that story as a, as a case of showing how science is flexible, that science adapts to new data that we change our minds when we are confronted with new information, I of course changed my mind about that.

713
01:04:30,920 --> 01:04:38,750
Um, but, uh, steroids for there are, have been trials of steroids for severe dengue gay, and it just doesn't work.

714
01:04:38,810 --> 01:04:39,590
It just doesn't work.

715
01:04:39,590 --> 01:04:42,590
It does not have that doesn't improve any patient centered endpoint.

716
01:04:43,280 --> 01:04:46,220
Um, and so I would not recommend using that as well.

717
01:04:46,220 --> 01:04:49,190
So it's largely fluids and human dynamics support.

718
01:04:49,190 --> 01:04:51,230
We don't give a lot of blood products for this.

719
01:04:51,290 --> 01:04:55,280
Uh, we generally try to avoid giving platelets for anything other than overt hemorrhage.

720
01:04:55,940 --> 01:04:58,910
Um, you know, meaning like if you're starting to have.

721
01:04:59,965 --> 01:05:01,975
And your platelet count is 10.

722
01:05:02,035 --> 01:05:02,395
Okay.

723
01:05:02,395 --> 01:05:16,885
I even, I would probably give platelets for that, but even for petechiae um, very low platelet counts in the non bleeding patient, it, it would take a lot to provoke platelet transfusion, and I would generally try to shy away from it.

724
01:05:16,915 --> 01:05:19,405
You're just kind of fueling the fire there in that case.

725
01:05:20,305 --> 01:05:32,065
Um, generally these folks do very well with just supportive care and again, the mortality of severe dengue and dengue shock syndrome in a resource rich environment is about 0.1%.

726
01:05:32,095 --> 01:05:39,415
It's very low and likely this relatively young man will have a very good outcome with just supportive care, which may be hemodynamic support.

727
01:05:39,415 --> 01:05:44,305
It may just be fluids, maybe a little bit of blood products, depending on the situation you find yourself in.

728
01:05:46,260 --> 01:05:46,500
James Wilson: Yeah.

729
01:05:46,620 --> 01:05:47,790
And thank you for that.

730
01:05:47,790 --> 01:05:50,950
He did well over a course of time in the hospital and made his way home.

731
01:05:52,415 --> 01:05:54,425
You know, it was just supportive care, as, as you mentioned.

732
01:05:55,445 --> 01:05:57,635
to kind Of, I guess, tie it all back to the beginning.

733
01:05:57,635 --> 01:06:09,215
We talked about the vaccine, um, and to save Sara from us, talking for too long, uh, the travel locations and risks, you know, in prevention, we've kind of talked about it's more urban than rural.

734
01:06:09,485 --> 01:06:14,395
It's mostly in patients uh, that are traveling who've had exposure before.

735
01:06:14,555 --> 01:06:19,085
Endemic patients are the ones that get the most severe dengue, more frequently in the younger ages.

736
01:06:19,575 --> 01:06:30,915
But there has been a reemergence in the United States and in Florida in 2020, they had 40 travelers with it and then they had 71 transmission cases secondary to that and Southern Florida.

737
01:06:31,395 --> 01:06:37,095
Um, and so this has becoming a consideration in the United States and Florida and Texas, mostly.

738
01:06:37,665 --> 01:06:39,975
Uh, and so it seems that it's diurnal.

739
01:06:40,065 --> 01:06:44,985
Um, and so it's mostly DEET, permethrin, drainage of the pools and ponds that you had mentioned.

740
01:06:45,375 --> 01:06:50,325
Um, but we're, we're not walking around with bed nets outside during the day.

741
01:06:50,325 --> 01:06:50,985
And so,

742
01:06:51,030 --> 01:06:55,920
Ryan Maves: generally, it's not practical, you know, bed nets, serve as an important, a key part of malaria prevention.

743
01:06:55,950 --> 01:06:57,390
But of course that's for your sleeping.

744
01:06:57,390 --> 01:07:02,850
And again, the Aedes aegypti and Aedes albopictus mosquitoes are diurnal mosquitoes.

745
01:07:02,850 --> 01:07:03,980
These are daytime mosquitoes.

746
01:07:03,980 --> 01:07:24,440
So bed nets are not going to help, but in particularly in, in a highly endemic area, you know, DEET or picardin and based repellents for your skin, and then,  adjunctively, you could use permethrin treatment of clothing, typically one treatment with permethrin should cover your clothing for, you know, for the, for the duration for many washings, for the duration of your travel.

747
01:07:24,920 --> 01:07:30,445
Um, It is worth noting that DEET can kind of dissolve the stretchy part of your socks.

748
01:07:30,955 --> 01:07:33,295
So just, uh, just be careful with that.

749
01:07:33,505 --> 01:07:41,455
I also discovered that DEET dissolves the little, uh, the glue on the back of your iPhone that holds the battery in place, not iPhone.

750
01:07:41,455 --> 01:07:42,955
I'm so sorry, apple watch.

751
01:07:43,345 --> 01:07:54,085
Um, this is not a formal endorsement of the products of Apple corporation, but, um, but I will say I had two, uh, that happened to me when I came back from the Amazon, once that my watch fell apart.

752
01:07:54,625 --> 01:07:55,375
So be careful.

753
01:07:58,315 --> 01:08:05,665
Um, it is a solvent, um, very safe, obviously for the skin,  keep it away from your eyes, keep it away from your mouth.

754
01:08:05,665 --> 01:08:08,065
If you're traveling with children, help them apply it themselves.

755
01:08:08,575 --> 01:08:10,315
Uh, we talked about the vaccine.

756
01:08:10,315 --> 01:08:13,645
It is just for the great majority of listeners of this podcast.

757
01:08:13,645 --> 01:08:16,435
It's not a vaccine that's going to be of much use to them right now.

758
01:08:16,975 --> 01:08:32,245
Uh, there is always a lot of interest in trying to make a broader and safer vaccine, but you know, when you talk about the severe dengue and the antibody dependent enhancement, you see the problem with the dengue vaccine, right, is you got to make a vaccine that causes lat long lasting and uniform protection against all four serotypes.

759
01:08:32,245 --> 01:08:44,955
And if you have waning effectiveness against just one serotype and we all have seen, of course from COVID that the duration of protection and the duration of antibody titers against a given strain serotype variant of a virus can be variable.

760
01:08:45,375 --> 01:08:50,205
Um, the danger is that you could inadvertently provoke severe dengue with your vaccine.

761
01:08:50,595 --> 01:08:59,200
Uh, No th that hasn't actually been seen much in, in dengue vaccine trials and this, but this is the challenge that we have to overcome in vaccinology.

762
01:08:59,200 --> 01:09:04,300
And I was very lucky early in my career that dengue vaccines, one of the first things I worked on.

763
01:09:04,300 --> 01:09:10,900
And so I learned a ton about vaccinology, about how vaccines work, about a vaccine development from it.

764
01:09:10,900 --> 01:09:21,520
And, and it is really a much like in the old days where a Osler would say that to learn syphilis is to learn medicine, um, to learn dengue, to learn vaccinology.

765
01:09:21,665 --> 01:09:27,035
Uh, in terms of, um, you know, you talked about local emergence in North America.

766
01:09:27,095 --> 01:09:29,465
I mean, there's always been some dengue here, right?

767
01:09:29,465 --> 01:09:35,195
I mean, right after the revolutionary war, there was a massive yellow fever outbreak in Philadelphia.

768
01:09:35,495 --> 01:09:46,835
I believe the, uh, the gentleman after whom your institution is named, Benjamin Rush, was famous for, uh, for caring for patients during said yellow fever outbreak.

769
01:09:47,345 --> 01:09:50,915
Um, and there is a certain amount of dengue in parts of Texas as it is.

770
01:09:51,015 --> 01:09:58,855
Areas near the Texas Mexico border, because again, the Rio Grande is not a forcefield, mosquitoes and people can move across the border pretty easily.

771
01:09:59,215 --> 01:10:03,715
And then when we say Florida, we're really talking like, kind of the Caribbean parts of Florida, right?

772
01:10:03,715 --> 01:10:08,605
So we're talking to Miami, we're talking the Keys, Key West, and the like but there is.

773
01:10:09,660 --> 01:10:10,380
I apologize.

774
01:10:10,380 --> 01:10:11,100
That's my dog.

775
01:10:11,340 --> 01:10:11,520
He's

776
01:10:11,520 --> 01:10:12,450
very excited right now.

777
01:10:13,050 --> 01:10:18,570
Um, but there is a certain amount of endemic, uh, dengue in North America.

778
01:10:18,630 --> 01:10:31,950
And certainly depending on the direction that, uh, climate change takes, that zone may increase now might not increase as much as we think it does because we have competent vectors in North America already, right?

779
01:10:32,090 --> 01:10:40,500
Aedes albopictus already lives in North America, and a lot of the things that prevent widespread transmission of dengue are not, are related to vector control.

780
01:10:41,070 --> 01:10:52,020
Um, so, and some of these things are very simple, like indoor air conditioning, for example, uh, plays a big role in preventing further dengue propagation throughout the United States.

781
01:10:52,020 --> 01:10:57,000
And it's probably broadly true of lots of, um, arthropod borne infections.

782
01:10:57,630 --> 01:10:59,970
Um, but it is a thing we have to be worried about.

783
01:10:59,970 --> 01:11:01,200
We do have to be concerned about.

784
01:11:01,350 --> 01:11:05,280
And so hopefully we'll, uh, hopefully we'll dodge that bullet, but time will tell.

785
01:11:06,968 --> 01:11:07,778
Sara Dong: All right.

786
01:11:07,868 --> 01:11:12,968
Thank you again to James and Ryan for joining Febrile and I guess I should add Ryan's dog!

787
01:11:13,018 --> 01:11:18,958
If you missed it, you can check out our last episode for more discussion on fever and returning traveler with Shilpa and Christina.

788
01:11:19,438 --> 01:11:23,998
In addition, there'll be more to come on this topic with our next episode and case.

789
01:11:24,358 --> 01:11:34,918
Don't forget to check out the website, febrile podcast.com, to find the Consult Notes, which are written complements of the show with links to references, our library of ID infographics, and a link to our merch store.

790
01:11:35,538 --> 01:11:39,588
Please reach out if you have any suggestions for future shows or want to be more involved with Febrile.

791
01:11:39,918 --> 01:11:42,498
Thanks for listening, stay safe and we'll see you next time