UA-184069179-1 48: Breaking Down Breakbone - Febrile
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Episode 48

48: Breaking Down Breakbone

Drs. James Wilson and Ryan Maves break down two episodes of fever in a returning traveler

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Transcript
Sara Dong:

Hi, everyone.

Sara Dong:

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

Sara Dong:

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

Sara Dong:

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

Sara Dong:

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

Sara Dong:

My co-host today is Dr.

Sara Dong:

James Wilson.

Sara Dong:

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

Sara Dong:

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

Sara Dong:

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

Sara Dong:

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

Sara Dong:

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

Sara Dong:

Ryan Maves.

Sara Dong:

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

Sara Dong:

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

Sara Dong:

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

Sara Dong:

Ryan is a retired captain of the U.S.

Sara Dong:

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

Sara Dong:

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.

Sara Dong:

Welcome to the show guys.

James Wilson:

Thanks for having us, so excited.

Ryan Maves:

Yeah.

Ryan Maves:

Thank you so much.

Sara Dong:

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

Sara Dong:

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

Sara Dong:

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

Sara Dong:

Maybe I'll start with Ryan.

Ryan Maves:

Oh, sure.

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

And I have

Sara Dong:

I just finished it too.

Sara Dong:

Yeah.

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.

Ryan Maves:

He's 15.

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

But you understand if you've seen it, you

James Wilson:

The Bald eagle one.

James Wilson:

Sure.

Ryan Maves:

You understand why I want that now.

Ryan Maves:

So that's me.

Sara Dong:

Yeah.

Sara Dong:

Yeah.

Sara Dong:

What about you, James?

James Wilson:

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

James Wilson:

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

James Wilson:

Uh, stuff, his podcasts.

James Wilson:

They love his podcasts.

James Wilson:

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

James Wilson:

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

James Wilson:

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.

James Wilson:

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

James Wilson:

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

James Wilson:

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.

James Wilson:

Or fall, which I've done before.

James Wilson:

So.

Sara Dong:

Love it.

Sara Dong:

Love it.

Sara Dong:

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

Sara Dong:

I'm so glad you guys are here.

Sara Dong:

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

Sara Dong:

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

James Wilson:

Awesome.

James Wilson:

Thank you so much.

James Wilson:

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

James Wilson:

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

James Wilson:

He's three days post return at this time.

James Wilson:

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

James Wilson:

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

James Wilson:

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

James Wilson:

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

James Wilson:

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.

James Wilson:

He stayed in hotels, not hostels.

James Wilson:

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

James Wilson:

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

James Wilson:

And so he took no prophylaxis ongoing to Thailand.

James Wilson:

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

James Wilson:

And he had no pre-travel vaccinations.

James Wilson:

He denies any significant medical history or surgical history.

James Wilson:

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.

James Wilson:

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

James Wilson:

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

James Wilson:

And he has no known allergies.

James Wilson:

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

Ryan Maves:

Yeah.

Ryan Maves:

All right.

Ryan Maves:

Well, thank you so much.

Ryan Maves:

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

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Right.

Ryan Maves:

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?

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

Those things still need to be on our list.

Ryan Maves:

So.

Ryan Maves:

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

Ryan Maves:

How sick are they?

Ryan Maves:

Do they require admission?

Ryan Maves:

Are they unstable?

Ryan Maves:

Do they walk in under their own power?

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

We'll assume that we have addressed those.

Ryan Maves:

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

Ryan Maves:

Um, is he tolerating PO?

James Wilson:

He is tolerating PO.

Ryan Maves:

Okay.

Ryan Maves:

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

James Wilson:

It's decreased over the last day,

Ryan Maves:

Okay.

Ryan Maves:

Okay.

James Wilson:

But he's able to eat and drink.

Ryan Maves:

Okay.

Ryan Maves:

Okay.

Ryan Maves:

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

Ryan Maves:

He said some dark stools intermittently.

James Wilson:

Uh, no loose stools, no constipation.

James Wilson:

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

Ryan Maves:

Sure, sure.

Ryan Maves:

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.

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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?

Ryan Maves:

This is an undifferentiated fever, right?

Ryan Maves:

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

James Wilson:

No myalgia, just malaise, fatigue and fever.

Ryan Maves:

And any kind of a rash?

James Wilson:

Not complaining of

Ryan Maves:

Okay.

Ryan Maves:

Okay.

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

He was in largely urban areas.

Ryan Maves:

So the odds of malaria are pretty slender, right?

Ryan Maves:

Bangkok is a very modern city.

Ryan Maves:

Chiangmai is a very modern city.

Ryan Maves:

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

Ryan Maves:

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?

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Right.

Ryan Maves:

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

Ryan Maves:

That's not the case in Chiang Mai.

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

Because that's going to be a big thing.

Ryan Maves:

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

Ryan Maves:

Um, other arboviruses, which we can chat about.

Ryan Maves:

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

Ryan Maves:

Uh and then

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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.

Ryan Maves:

Did he pay for sex?

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

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.

James Wilson:

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

James Wilson:

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

James Wilson:

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

James Wilson:

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?

Ryan Maves:

Yeah.

Ryan Maves:

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.

Ryan Maves:

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?

Ryan Maves:

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

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

It is not in Asia.

Ryan Maves:

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

Ryan Maves:

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.

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

Intellectually?

Ryan Maves:

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

Ryan Maves:

Emotionally?

Ryan Maves:

It would be hard to resist.

Ryan Maves:

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

Ryan Maves:

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.

Ryan Maves:

And so getting blood cultures would be useful for that.

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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

Ryan Maves:

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?

Ryan Maves:

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

Ryan Maves:

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..

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Those would be the big ones.

Ryan Maves:

And then I guess we need to think about pathogen specific assays, right?

Ryan Maves:

And there are a whole bunch of those.

Ryan Maves:

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?

Ryan Maves:

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

Ryan Maves:

So we have dengue is the most common one.

Ryan Maves:

And dengue is kind of interesting.

Ryan Maves:

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.

Ryan Maves:

And we just lump them as serotypes because they're clinically so similar and clearly very closely related.

Ryan Maves:

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.

Ryan Maves:

Thinking about other so dengue is one of the classic flaviviruses.

Ryan Maves:

Um, and it is widespread in urban environments throughout developing countries.

Ryan Maves:

And that's why really in this person, why we're thinking more dengue than malaria, right?

Ryan Maves:

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,

Ryan Maves:

and in assessing the febrile returning traveler.

Ryan Maves:

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?

Ryan Maves:

So malaria, rural areas, bites you at night.

Ryan Maves:

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.

Ryan Maves:

It's the tiger mosquito.

Ryan Maves:

It's a little less adapted to urban environments, but you see it in like China and Hawaii.

Ryan Maves:

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.

Ryan Maves:

So, Aedes is adapted to urban environment.

Ryan Maves:

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.

Ryan Maves:

And so malaria, rural, bites you at night.

Ryan Maves:

Aedes, urban, mosquitoes bite you in the day.

Ryan Maves:

And the, the challenge that we really have here is that, for things like malaria, right?

Ryan Maves:

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?

Ryan Maves:

We have chemoprophylaxis, I can put someone on atovaquone-proguanil or doxycycline, or in kind of select circumstances nowadays, mefloquine.

Ryan Maves:

You know, and that's very effective in combination with things like insect precautions and the like.

Ryan Maves:

For dengue, what we have is don't get bitten.

Ryan Maves:

You know, it's basically our options for prophylaxis are don't get bitten.

Ryan Maves:

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.

Ryan Maves:

But that's pretty, you know, people get a little how shall I phrase this lackadaisical about that, right?

Ryan Maves:

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.

Ryan Maves:

But, um, but I'm not perfect at it.

Ryan Maves:

I am probably just lucky on some level.

Ryan Maves:

Right.

Ryan Maves:

And it would be great if we had a widespread, highly effective dengue vaccine, but we don't like we don't right now.

Ryan Maves:

Now we do have Dengvaxia, which is an advance in public health.

Ryan Maves:

And Dengvaxia is a tetravalent, uh, dengue vaccine.

Ryan Maves:

Uh it's chimeric vaccine and is protective.

Ryan Maves:

It does reduce the risk of dengue acquisition.

Ryan Maves:

The problem is that the population who had benefits is very, very narrow, right.

Ryan Maves:

And it's basically kids and young adolescents who've had dengue before, right?

Ryan Maves:

So, you know, I'm, I'm an adult infectious disease doctor traveling and, you know, practicing in North Carolina.

Ryan Maves:

I don't have a lot of children and young adolescents with histories of prior dengue who I see.

Ryan Maves:

So Dengvaxia is not a thing that I'm likely to be able to implement in my own practice.

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.

James Wilson:

And so that.

James Wilson:

That is, that is really not the fever in the returning traveler quote unquote, that we would normally think of.

James Wilson:

And so these are usually put in to a packed and tropical and subtropical regions.

James Wilson:

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

Ryan Maves:

Yeah.

Ryan Maves:

As a standard recommendation, it's relatively a few countries use it standardly.

Ryan Maves:

It is FDA approved.

Ryan Maves:

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.

Ryan Maves:

So, you know, other flaviviruses can mimic Zika is very closely related.

Ryan Maves:

Um, Zika tends to cause relatively milder illness, uh, than dengue in the whole.

Ryan Maves:

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.

Ryan Maves:

Otherwise like if I had to pick between getting like dengue or Zika, I would totally pick Zika, right?

Ryan Maves:

Because it is generally a milder disease, right?

Ryan Maves:

Generally milder disease.

Ryan Maves:

Chikungunya, not a flavivirus, unlike the other two.

Ryan Maves:

Chikungunya tends to have more arthralgias, it tends to have less of the kind of severe manifestations.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Yellow fever is a much more severe disease, but again does not occur here.

Ryan Maves:

Again, another flavivirus, where the word flavivirus comes from.

Ryan Maves:

Flavi means yellow.

Ryan Maves:

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.

Ryan Maves:

And for disease.

Ryan Maves:

This mild, you know, you could make a case for just trying doxycycline empirically in him.

Ryan Maves:

So then the challenge comes, and this is especially in this kind of clinical setting.

Ryan Maves:

Like how do you diagnose it?

Ryan Maves:

Right?

Ryan Maves:

Because on some level mild dengue - it's not that big a deal.

Ryan Maves:

Right.

Ryan Maves:

And so the reasons we would want to diagnose it is (a) to give it a name, right.

Ryan Maves:

Because that can be helpful.

Ryan Maves:

And because there is a residual risk of severe disease.

Ryan Maves:

And so do at least want to do some sort of risk stratification for this, uh, for this gentleman.

Ryan Maves:

And I guess one question I it's worth asking is where was he born?

Ryan Maves:

Was he born in North America?

Ryan Maves:

Was he born in the continental US or was he born overseas?

James Wilson:

Midwest, so Chicago land.

Ryan Maves:

So, so relatively low rates of dengue in Chicago.

Ryan Maves:

So that is reassuring,

Ryan Maves:

right?

Ryan Maves:

Yeah.

Ryan Maves:

Cause I mean, I'll just anecdotally, I'll tell you that.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Not that that's perfectly predictive, but you know, we got to risk stratify these people somehow.

Ryan Maves:

All right.

Ryan Maves:

All right.

Ryan Maves:

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.

Ryan Maves:

So we have, we talked about CBCs.

Ryan Maves:

We talked about chemistry panels, blood cultures, just to be paranoid.

Ryan Maves:

And I'm an ID doctor.

Ryan Maves:

And, you know, the indication for blood cultures is like fever and having blood.

Ryan Maves:

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.

Ryan Maves:

So, you know, blood cultures, it's kind of like

James Wilson:

this may or may not be absolutely

Ryan Maves:

yeah, yeah.

Ryan Maves:

So dengue?

Ryan Maves:

Um, so with all that going around, um, how could we actually diagnose dengue?

Ryan Maves:

There's a bunch of ways we could do it.

Ryan Maves:

There are some interesting physical exam findings that we could pursue.

Ryan Maves:

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.

Ryan Maves:

You leave it on there for a few minutes, then measure.

Ryan Maves:

You look for petechiae in a, you know, it's generally a two and a half centimeter by two and a half centimeter square.

Ryan Maves:

You count them.

Ryan Maves:

And that can be predictive of capillary fragility, which can be predictive in some cases of dengue.

Ryan Maves:

It is a physical exam fun fact.

Ryan Maves:

I don't think that it necessarily contributes much to the diagnosis or the management of the case.

Ryan Maves:

That is neither sensitive nor specific finding for dengue.

Ryan Maves:

If you find it it's neat.

Ryan Maves:

If I had a fellow come up to me and say, Hey, I found this patient.

Ryan Maves:

I think they have dengue, I did this thing.

Ryan Maves:

It was positive.

Ryan Maves:

I would think, oh, that's neat.

Ryan Maves:

So, but not terribly helpful.

Ryan Maves:

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.

Ryan Maves:

James, you mentioned that they don't seem to have any obvious lesions in their eyes.

Ryan Maves:

That's helpful.

Ryan Maves:

Both for things that are also absent like jaundice or icterus um, And then we got to find some specific labs, right.

Ryan Maves:

And so probably the purists answer would be, this is kind of neat.

Ryan Maves:

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.

Ryan Maves:

But basically what it is is a three valent PCR for dengue, zika, chikungunya.

Ryan Maves:

CDC will run it.

Ryan Maves:

State and county public health departments can order it through channels, depending if they have it available.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

And that's super helpful.

Ryan Maves:

You can send off serologies for dengue, Zika, and chik[ungunya]..

Ryan Maves:

I will tell you that every positive Zika IgM, who I saw during the Zika epidemic, turned out to actually have dengue.

Ryan Maves:

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.

Ryan Maves:

I have never diagnosed a case of chikungunya.

Ryan Maves:

Um, so hard to say, I have colleagues, who've seen it a lot.

Ryan Maves:

Uh, and then dengue, you know, you can, there are a number of commercial ELISA based assays.

Ryan Maves:

Um, again, a lot of cross-reactivity with other flaviviruses.

Ryan Maves:

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.

Ryan Maves:

Uh, the kinetics of that, there is a little bit of a delay in when those start to kick in.

Ryan Maves:

And then lastly, there is actually a dipstick.

Ryan Maves:

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.

Ryan Maves:

And so all flaviviruses have these non-structural proteins -- NS1, NS3, NS5.

Ryan Maves:

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.

Ryan Maves:

Well, there's a lot of the same things present on dengue,

Ryan Maves:

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.

Ryan Maves:

That is FDA approved in the U S but I gotta say , not a lot of urgent cares have those stocked.

Sara Dong:

Yeah.

Sara Dong:

So I am just going to pause us here for a moment.

Sara Dong:

Uh, to focus on the lab testing because I think there's so much great information here.

Sara Dong:

So you've mentioned how we can establish diagnosis directly.

Sara Dong:

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.

Sara Dong:

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.

Sara Dong:

And importantly can stick around for a long time, longer than what we

Sara Dong:

often expect with IgM, but.

Sara Dong:

Uh, has the difficulty of lots of cross-reactivity.

Sara Dong:

We certainly could confirm diagnosis with paired acute and convalescent results.

Sara Dong:

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..

Ryan Maves:

Serologic testing, there is a thing called a PRNT which is a plaque reduction neutralization test.

Ryan Maves:

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.

Ryan Maves:

But, um, on ELISA I should say.

Ryan Maves:

So a PRNT is like a functional study if you will, for antibody.

Ryan Maves:

So you take well plates that are coated with usually Vero cells.

Ryan Maves:

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.

Ryan Maves:

And what you're looking for is a viral cytopathic effect.

Ryan Maves:

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.

Ryan Maves:

So you just count, right?

Ryan Maves:

You're just taking a little card and you count how many of those holes are.

Ryan Maves:

And that is relatively specific for telling you which serotype, which type of dengue is responsible for that.

Ryan Maves:

So, because there's gonna be some cross-reaction between antibodies against dengue 2 having some residual activity against dengue 1, for example.

Ryan Maves:

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.

Ryan Maves:

Well, it gives you a pretty good idea that that person is infected with dengue three.

Ryan Maves:

Now that is mostly of epidemiological interest,

Ryan Maves:

right?

Ryan Maves:

That's not necessarily a thing that affects our management of a patient at the bedside, but it is kind of neat.

Ryan Maves:

It is a cool test to run.

Ryan Maves:

If you're an institution that can run them or sometimes CDC or other agencies will run those for epidemiologic tracking purposes.

Ryan Maves:

That's kind of cool.

Ryan Maves:

It doesn't affect much of what we do at the bedside with a given patient though.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

But having relative leukopenia, relative lymphopenia, moderate anemia, and low platelets is going to be very predictive.

Ryan Maves:

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.

Ryan Maves:

This has at least some degree of predictive value in a patient with a compatible travel history and a compatible syndrome.

Ryan Maves:

And so that can be helpful.

Ryan Maves:

Now, granted, that's also kind of true of like rickettsia.

Ryan Maves:

So we do have to be a little bit modest in that that, you know, I don't, I've never known for sure.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

There's going to be more arthralgia.

Ryan Maves:

There's going to be more, uh, conjunctivitis often in patients with chikungunya, but that is not carved in stone.

Ryan Maves:

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.

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

James Wilson:

shock syndrome.

James Wilson:

But that was changed in 2009, um, to, you know, dengue, dengue with warning signs and, you know,

James Wilson:

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.

James Wilson:

I still feel is thrown around or dengue hemorrhagic fever.

James Wilson:

Um, would you mind commenting on the change?

Ryan Maves:

No, not at all.

Ryan Maves:

So, you know, historically there was this division of dengue into kind of three flavors.

Ryan Maves:

If you will, sort of classic dengue, dengue hemorrhagic fever and dengue shock syndrome, and they exist on a continuum of severity.

Ryan Maves:

Now, part of the problem is that dengue hemorrhagic fever and dengue shock syndrome had fairly strict criteria.

Ryan Maves:

You had to meet these definitions to have, to qualify if you will, as having them.

Ryan Maves:

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.

Ryan Maves:

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?

Ryan Maves:

And then within the spectrum of severe dengue , you can add shock, which really is just hypotension.

Ryan Maves:

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.

Ryan Maves:

Right?

Ryan Maves:

If you figure, if you figure that the mortality of dengue shock syndrome in a modern monitored hospital setting is probably about 0.1%.

Ryan Maves:

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?

Ryan Maves:

So those are people who are definitely at risk of dying.

Ryan Maves:

And really the, the tragedy here is that that that group at risk are largely infants, right?

Ryan Maves:

Those are the ones who are at the greatest risk of passing.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Right?

Ryan Maves:

So you'd just start leaking out.

Ryan Maves:

And because of that, you'd get hemoconcentration and relatively high hematocrit.

Ryan Maves:

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.

Ryan Maves:

You add on top of those hemorrhagic slash capillary leakage phenomena, the existence of hypotension, then you have dengue shock syndrome, right?

Ryan Maves:

So still a useful kind of concept.

Ryan Maves:

Capillary leakage, marker of severe dengue that can manifest is with hemorrhage, that can manifest with pleural effusions ascites et cetera.

Ryan Maves:

It can manifest with frank bleeding.

Ryan Maves:

It can manifest with shock, um, but it becomes impractical because of those definitions.

Ryan Maves:

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.

Ryan Maves:

We would almost certainly admit the majority of them.

Ryan Maves:

These are people with abdominal pain, uh, certainly anything that resembles peritoneal signs.

Ryan Maves:

Those folks need to be admitted.

Ryan Maves:

People who have overt signs of plasma leakage.

Ryan Maves:

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.

Ryan Maves:

Obviously these are people we are very likely to admit regardless.

Ryan Maves:

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.

Ryan Maves:

Um, that would be a trigger for admission.

Ryan Maves:

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.

Ryan Maves:

Be it myocardial, be it severe delirium or encephalopathy.

Ryan Maves:

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.

Ryan Maves:

. With all of this background, I think what we really need to sort out is what this gentleman's risk of severe disease is.

Ryan Maves:

The initial description sounds okay.

Ryan Maves:

But I think the laboratory may shed a little more light on that.

James Wilson:

Yeah.

James Wilson:

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.

James Wilson:

His CBC showed he had a white count of 3.1 with an ANC of 2,900.

James Wilson:

Uh, he had a hematocrit of 43% and his platelets were 170.

James Wilson:

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.

James Wilson:

for glucose with AST 65, ALT ALP at 111, total bilirubin 1.2 and an albumin at 2.8.

James Wilson:

I then had him come in.

James Wilson:

I saw him and he looked grand.

James Wilson:

Um, and so I repeated the labs another day later.

James Wilson:

So over the course of about a week and they all reverted to what his baseline was from his physical a year prior

Ryan Maves:

Excellent.

Ryan Maves:

Yeah.

Ryan Maves:

So it sounds like he had certainly some laboratory

James Wilson:

HIV EBV

Ryan Maves:

Excellent.

Ryan Maves:

So, you know, relative leukopenia that resolved spontaneously, platelets are normal.

Ryan Maves:

All of this is very reassuring.

Ryan Maves:

Small LFT abnormalities or transaminase abnormalities that are getting better.

Ryan Maves:

So, yeah, so it sounds like this gentlemen had, you know, a fairly common manifestation of what we presume is dengue.

Ryan Maves:

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.

James Wilson:

Yeah.

James Wilson:

I think it's important to note that the patient had defervesced more than 48 hours prior to presentation to the clinic.

James Wilson:

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.

James Wilson:

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.

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.

Ryan Maves:

So that's, that's a, that's a great point.

Ryan Maves:

And you know, and again, those, those windows of time, two to five days and so forth, right?

Ryan Maves:

That's those are not laws of nature.

Ryan Maves:

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?

Ryan Maves:

It's also probably a good point to mention that the incubation period for dengue at most, a couple of weeks.

Ryan Maves:

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.

Ryan Maves:

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.

James Wilson:

So I, I told him Tylenol and fluids.

James Wilson:

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.

James Wilson:

Um, you know, I took some Tylenol didn't help.

James Wilson:

Can I take Motrin or in the military, we call it a vitamin M uh, for some ibuprofen high dose.

James Wilson:

And I told him to change his socks.

James Wilson:

But the big thing was, is I told him not to take any NSAIDs.

James Wilson:

Um, is there, I remembered that briefly from training, but didn't couldn't remember why at the time.

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.

Ryan Maves:

I suspect a lot of people are taking ibuprofen for, for undiagnosed dengue like behind our backs.

Ryan Maves:

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.

Ryan Maves:

Right.

Ryan Maves:

And then, you know, trying to maintain, reasonable volume status, eat what you can eat, avoid dehydration.

Ryan Maves:

But again, these are things just for symptomatic control and his prognosis is probably pretty good.

Ryan Maves:

Although the fact that he feels lousy is very common, right?

Ryan Maves:

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.

James Wilson:

Perfect.

James Wilson:

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.

James Wilson:

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.

James Wilson:

He came back to work and just so happened to come into the clinic.

James Wilson:

He looked terrible.

James Wilson:

And so he told me that he had changed the trip that he had gone on a little bit.

James Wilson:

In this time he added Chiang Rai uh, to his trip, which is a little more rural.

James Wilson:

He'd gone to an elephant park and a tiger park, but he began having severe a headache for three days after returning.

James Wilson:

Uh, and he had marked retro-orbital pain on the right.

James Wilson:

Uh, but when he came in, he was afebrile at that time, but he just looked sunken.

James Wilson:

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.

James Wilson:

And I had him pull his sleeves up and it was on both sides.

James Wilson:

And so at that point we got blood pressures, and he was at best 100 over 60.

James Wilson:

we took it several times, which gave him the tourniquet sign.

James Wilson:

Uh he was tachy[cardic] in the one with mild diffuse abdominal tenderness, more so in the bilateral upper quadrants.

James Wilson:

Um, and he had been endorsing dark stools during the last week.

James Wilson:

And so advised him that he needed to go to the local ER, which happened across the street.

James Wilson:

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.

James Wilson:

The ER obtained urine culture, UA, blood cultures, they attempted to get a sputum culture.

James Wilson:

Is he had CBC, a CMP and a lactic acidosis, and these things were all cooking.

James Wilson:

Uh, when they page the ID attending, that was on call based on his travel history.

James Wilson:

So let's say that they, their question at that point was, do we get an LP given his headache?

James Wilson:

So that was the phone call that went to the infectious disease physician.

James Wilson:

And let's assume that that would be you in the setting,

Ryan Maves:

Yeah, well, I, so it's a bit of a pickle, right?

Ryan Maves:

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?

Ryan Maves:

Right.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Right.

Ryan Maves:

Um, now that being said his syndrome, and since we're on the topic, his syndrome, I think we know the answer to that.

Ryan Maves:

Um, but I, I'm certainly not going to be, uh, not going to be recorded on, uh, on Dr.

Ryan Maves:

Dong's famous podcast not not LP a man with fever and rapidly evolving

Sara Dong:

I'm glad that your response to that is the same as mine.

Sara Dong:

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.

Ryan Maves:

Yeah, exactly, exactly.

Ryan Maves:

But that being said, we can take a look at some additional features.

Ryan Maves:

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.

Ryan Maves:

Right.

Ryan Maves:

So what did his hemodynamics do after that second liter?

James Wilson:

They remained the same, essentially.

Ryan Maves:

Okay.

Ryan Maves:

Okay.

Ryan Maves:

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..

Ryan Maves:

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.

Ryan Maves:

Just remember that when we think about what are the modifiable risk factors for mortality in septic shock, right?

Ryan Maves:

It's time of hypotension until time of active antibiotics on board, right.

Ryan Maves:

In addition to hemodynamic correction and so forth.

Ryan Maves:

So.

Ryan Maves:

We will set that aside because that is not our topic.

Ryan Maves:

Let us assume that has been addressed.

Ryan Maves:

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.

Ryan Maves:

So let's, let's not do that, but having addressed

James Wilson:

did zosyn or pip-tazo and Vancomyocin when he came in hypotensive and tachycardic

James Wilson:

with fevers,

Ryan Maves:

know,

James Wilson:

a history of

Ryan Maves:

you know, and of course this is a, this is a podcast for infectious disease doctors.

Ryan Maves:

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

Ryan Maves:

so it would be a good idea moving on.

Ryan Maves:

So in terms of diagnostics, what do we have any laboratory studies to help guide our thinking about this gentlemen?

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.

James Wilson:

Um, and then for his CMP, he had a AST of a 125 and then an ALT of 200

James Wilson:

at that point.

James Wilson:

And his total bilirubin was a 2.1.

James Wilson:

So at that point, so.

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.

Ryan Maves:

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.

Ryan Maves:

Then we would be worried about lassa.

Ryan Maves:

We could be worried about other causes of viral hemorrhagic fever, um, more common in other parts of the world.

Ryan Maves:

So it, although hemoconcentration in this particular setting is somewhat reassuring.

Ryan Maves:

In other settings.

Ryan Maves:

It is very unreassuring and just be, we need to all be remind ourselves that hemoconcentration is not normal, right?

Ryan Maves:

And that is a potential marker of capillary leakage, which is a hallmark of viral hemorrhagic fevers.

Ryan Maves:

In this gentleman's case.

Ryan Maves:

Um, you know, I think that sending off diagnostic tests again for dengue and for all the other stuff we did last time, right.

Ryan Maves:

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.

Ryan Maves:

And again, he's a little more rural area, you know?

Ryan Maves:

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.

Ryan Maves:

And I suppose, I think again, thinking as a, as an intensivist, more than an ID doctor right now, but still both are true.

Ryan Maves:

What is our risk tolerance in this gentleman?

Ryan Maves:

What is our tolerance for being wrong?

Ryan Maves:

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.

Ryan Maves:

Maybe not for malaria, but for other things you do, right?

Ryan Maves:

Like that person is unlikely to have significantly adverse outcome if you guess wrong the first time.

Ryan Maves:

So it comes in hypotensive, tachycardic, febrile, looks bad, unable to keep food down.

Ryan Maves:

That person, your margin for error is extremely limited.

Ryan Maves:

And so we need to make sure we're getting it right the first time.

Ryan Maves:

So although we will discuss features of severe flavivirus infections.

Ryan Maves:

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.

Ryan Maves:

So, um, is there any way we can get any kind of specific diagnostics for dengue on him?

Ryan Maves:

What's available?

James Wilson:

Okay.

James Wilson:

This was a community hospital, um, 10 bed, ICU type place.

James Wilson:

And so they didn't have much, they sent serologies and they sent the PCR, but they're all send out tests.

Ryan Maves:

Okay.

Ryan Maves:

That's fine.

Ryan Maves:

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

Sara Dong:

yeah, it's a send-off for everyone.

Sara Dong:

I feel

Ryan Maves:

Yeah.

Ryan Maves:

I mean, exactly.

Ryan Maves:

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.

Ryan Maves:

Right.

Ryan Maves:

But at least we can send it off.

Ryan Maves:

We can get the ball rolling on it.

Ryan Maves:

Um, you know, then the thing is like, didn't he just have dengue or aren't we pretty sure he just had dengue?

Ryan Maves:

So how is this happening now?

Ryan Maves:

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.

Ryan Maves:

It's the second time right.

Ryan Maves:

Now, that is an oversimplification, but the problem goes back to those four serotypes.

Ryan Maves:

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.

Ryan Maves:

You may have some cross-reactive immunity.

Ryan Maves:

Yeah.

Ryan Maves:

A couple of years or so.

Ryan Maves:

Right.

Ryan Maves:

But, um, but that immunity will wane.

Ryan Maves:

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.

Ryan Maves:

Right?

Ryan Maves:

And so this can lead to increase viraemia and more rapid viral replication and more severe disease.

Ryan Maves:

Now, this is an incomplete explanation of why this happens, right?

Ryan Maves:

This is an incomplete explanation.

Ryan Maves:

There's probably some host factors involved.

Ryan Maves:

Um, there may be, there may be some polymorphisms in mediators of innate immunity

Ryan Maves:

that's involved.

Ryan Maves:

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.

Ryan Maves:

Not that I don't know.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Um, well that mutation has affects in nature too.

Ryan Maves:

And one of the effects of that mutation is people who have it probably get more severe flavivirus disease, uh, more severe flavivirus infections.

Ryan Maves:

So, um, now this doesn't explain off the top of your head, like getting a second flavivirus infection.

Ryan Maves:

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.

Ryan Maves:

Right?

Ryan Maves:

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.

Ryan Maves:

Now, severe dengue does not happen in most hetero typic dengue infections.

Ryan Maves:

Uh, it happens only a minority of cases.

Ryan Maves:

It is not a complete and nor does it explain every case of severe dengue, right?

Ryan Maves:

There are these other host factors and things that play a role, but it is an interesting kind of model.

Ryan Maves:

And I will say, cause this is 2022 in recording this, that there are some coronaviruses that exhibit antibody dependent enhancement.

Ryan Maves:

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.

Ryan Maves:

I mentioned that because my cat is sitting in my lap and I'm thinking about it right now.

Ryan Maves:

Okay.

Ryan Maves:

And she is very comfortable.

Ryan Maves:

And to the best of my ability to tell does not have feline, uh, peritonitis virus infections.

Ryan Maves:

Although for reasons I won't get into you, I do have to give her a cyclosporine for later on.

Ryan Maves:

Um,

James Wilson:

Oh man.

Ryan Maves:

yeah.

Ryan Maves:

Yeah.

Ryan Maves:

My cats, my cats, liver transplant.

Ryan Maves:

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?

Ryan Maves:

That seems like that is probably the thing that drove his severity of disease.

Ryan Maves:

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?

Ryan Maves:

Because relatively recent, you know, different geographic regions, their dengue serotypes will shift kind of gradually over time.

Ryan Maves:

But he went to a new place, had the opportunity for a new exposure.

Ryan Maves:

And I think that explains kind of his deal.

Ryan Maves:

Right?

Ryan Maves:

So then we got to figure out is what we're going to do for it.

Ryan Maves:

And our choices are kind of limited.

James Wilson:

That was going to be my next step from, from two points, right?

James Wilson:

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.

James Wilson:

And so it sounds like he'd be going to the ICU.

James Wilson:

And so then it's a tag team with the ICU and the idea's already on board.

James Wilson:

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.

James Wilson:

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.

James Wilson:

Um, and then he did acyclovir of your, at that point, uh, as well, just because, you know, because,

James Wilson:

and, uh, exactly.

James Wilson:

Uh, and so those things were continued and Flagyl was added for whatever reason.

James Wilson:

And, and, uh, so the, those two perspectives though, you know, the TNF alpha, we are not actually doing, those are mostly animal studies.

James Wilson:

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.

James Wilson:

Certainly in this patient may be up front.

James Wilson:

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

James Wilson:

in these

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?

Ryan Maves:

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.

Ryan Maves:

Given the volumes of fluid, I'd probably personally use LR, but I don't have a ton of data to back that up.

Ryan Maves:

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.

Ryan Maves:

The only colloid in widespread clinical use and really the best one to use would be albumin.

Ryan Maves:

Could you use albumin with a clear conscience?

Ryan Maves:

Yeah.

Ryan Maves:

Um, it's more expensive.

Ryan Maves:

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.

Ryan Maves:

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

Ryan Maves:

in third spacing we see in sepsis.

Ryan Maves:

That's, you know, that is not to the best of my knowledge.

Ryan Maves:

Formally studied.

Ryan Maves:

You need detail in dengue per se.

Ryan Maves:

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.

Ryan Maves:

There isn't there, the same outcomes are the same, right.

Ryan Maves:

And, and that's fine.

Ryan Maves:

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.

Ryan Maves:

Um, you know, you mentioned TNF alpha and inhibition.

Ryan Maves:

This is, again, this is an animal model thing.

Ryan Maves:

It's actually pretty hard to make animal models for dengue.

Ryan Maves:

Like it's pretty easy to infect animals with dengue.

Ryan Maves:

Uh, when I was working in Peru, we had rodent models.

Ryan Maves:

We had a non-human primate models.

Ryan Maves:

They can get infected, they can get viremic, but they don't get that sick.

Ryan Maves:

Um, so, uh, a, an animal model of severe dengue is challenging.

Ryan Maves:

There are some, uh, rodent models where they can see like, um, worsening, uh, not even worse than it really is a word.

Ryan Maves:

Um, erythroderma basically.

Ryan Maves:

They, they, you know, are erythroderma and that is a surrogate marker.

Ryan Maves:

Um, but yeah, so TNF alpha inhibition.

Ryan Maves:

We're not going to be starting everyone on Remicade to treat, uh, uh, DHF right now.

Ryan Maves:

Antivirals, you mentioned that it is a flavivirus and we are right now in a golden age of flavirvirus therapeutics because of hepatitis C.

Ryan Maves:

Uh, there is nothing that is currently, you know, anywhere near marketing right now, but there's some early data.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

So hopefully those will continue to progress and make some, make some progress there.

Ryan Maves:

And then steroids, right?

Ryan Maves:

Anytime anyone's got fever and shocks and one wants to throw steroids out at.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Um, but, uh, steroids for there are, have been trials of steroids for severe dengue gay, and it just doesn't work.

Ryan Maves:

It just doesn't work.

Ryan Maves:

It does not have that doesn't improve any patient centered endpoint.

Ryan Maves:

Um, and so I would not recommend using that as well.

Ryan Maves:

So it's largely fluids and human dynamics support.

Ryan Maves:

We don't give a lot of blood products for this.

Ryan Maves:

Uh, we generally try to avoid giving platelets for anything other than overt hemorrhage.

Ryan Maves:

Um, you know, meaning like if you're starting to have.

Ryan Maves:

And your platelet count is 10.

Ryan Maves:

Okay.

Ryan Maves:

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.

Ryan Maves:

You're just kind of fueling the fire there in that case.

Ryan Maves:

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%.

Ryan Maves:

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.

Ryan Maves:

It may just be fluids, maybe a little bit of blood products, depending on the situation you find yourself in.

James Wilson:

Yeah.

James Wilson:

And thank you for that.

James Wilson:

He did well over a course of time in the hospital and made his way home.

James Wilson:

You know, it was just supportive care, as, as you mentioned.

James Wilson:

to kind Of, I guess, tie it all back to the beginning.

James Wilson:

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.

James Wilson:

It's mostly in patients uh, that are traveling who've had exposure before.

James Wilson:

Endemic patients are the ones that get the most severe dengue, more frequently in the younger ages.

James Wilson:

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.

James Wilson:

Um, and so this has becoming a consideration in the United States and Florida and Texas, mostly.

James Wilson:

Uh, and so it seems that it's diurnal.

James Wilson:

Um, and so it's mostly DEET, permethrin, drainage of the pools and ponds that you had mentioned.

James Wilson:

Um, but we're, we're not walking around with bed nets outside during the day.

James Wilson:

And so,

Ryan Maves:

generally, it's not practical, you know, bed nets, serve as an important, a key part of malaria prevention.

Ryan Maves:

But of course that's for your sleeping.

Ryan Maves:

And again, the Aedes aegypti and Aedes albopictus mosquitoes are diurnal mosquitoes.

Ryan Maves:

These are daytime mosquitoes.

Ryan Maves:

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.

Ryan Maves:

Um, It is worth noting that DEET can kind of dissolve the stretchy part of your socks.

Ryan Maves:

So just, uh, just be careful with that.

Ryan Maves:

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.

Ryan Maves:

I'm so sorry, apple watch.

Ryan Maves:

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.

Ryan Maves:

So be careful.

Ryan Maves:

Um, it is a solvent, um, very safe, obviously for the skin, keep it away from your eyes, keep it away from your mouth.

Ryan Maves:

If you're traveling with children, help them apply it themselves.

Ryan Maves:

Uh, we talked about the vaccine.

Ryan Maves:

It is just for the great majority of listeners of this podcast.

Ryan Maves:

It's not a vaccine that's going to be of much use to them right now.

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

Um, the danger is that you could inadvertently provoke severe dengue with your vaccine.

Ryan Maves:

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.

Ryan Maves:

And I was very lucky early in my career that dengue vaccines, one of the first things I worked on.

Ryan Maves:

And so I learned a ton about vaccinology, about how vaccines work, about a vaccine development from it.

Ryan Maves:

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.

Ryan Maves:

Uh, in terms of, um, you know, you talked about local emergence in North America.

Ryan Maves:

I mean, there's always been some dengue here, right?

Ryan Maves:

I mean, right after the revolutionary war, there was a massive yellow fever outbreak in Philadelphia.

Ryan Maves:

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.

Ryan Maves:

Um, and there is a certain amount of dengue in parts of Texas as it is.

Ryan Maves:

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.

Ryan Maves:

And then when we say Florida, we're really talking like, kind of the Caribbean parts of Florida, right?

Ryan Maves:

So we're talking to Miami, we're talking the Keys, Key West, and the like but there is.

Ryan Maves:

I apologize.

Ryan Maves:

That's my dog.

Ryan Maves:

He's

Ryan Maves:

very excited right now.

Ryan Maves:

Um, but there is a certain amount of endemic, uh, dengue in North America.

Ryan Maves:

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?

Ryan Maves:

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.

Ryan Maves:

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.

Ryan Maves:

And it's probably broadly true of lots of, um, arthropod borne infections.

Ryan Maves:

Um, but it is a thing we have to be worried about.

Ryan Maves:

We do have to be concerned about.

Ryan Maves:

And so hopefully we'll, uh, hopefully we'll dodge that bullet, but time will tell.

Sara Dong:

All right.

Sara Dong:

Thank you again to James and Ryan for joining Febrile and I guess I should add Ryan's dog!

Sara Dong:

If you missed it, you can check out our last episode for more discussion on fever and returning traveler with Shilpa and Christina.

Sara Dong:

In addition, there'll be more to come on this topic with our next episode and case.

Sara Dong:

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.

Sara Dong:

Please reach out if you have any suggestions for future shows or want to be more involved with Febrile.

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