48: Breaking Down Breakbone

James is an ID fellow at the combined Rush University Medical Center and Cook County Health ID fellowship program in Chicago. He also spends time as an attending hospitalist at Rush as well. James is a Navy veteran physician of 10 years with airspace and tropical medicine training through the U.S. Department of Defense with several deployments into tropical and subtropical areas for global health, tropical medicine and disaster relief.

Next, I will welcome our guest consultant today, Dr. Ryan Maves. Ryan is a Professor of Medicine and Anesthesiology at the Wake Forest School of Medicine in Winston-Salem, North Carolina. He is board certified in Internal Medicine, Infectious Diseases and Critical Care Medicine. He currently serves as the medical director of the Transplant ID program and a faculty intensivist at Wake. Ryan is a retired captain of the U.S.

Navy with 22 years of active duty service and prior deployment to Afghanistan. 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. Welcome to the show guys.

And so she's the one that kind of, shocking, she manages our money. And so, um, but yeah, I find all that stuff, very fascinating and infuriating, but, uh, and otherwise I, I rock climb. 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. Or fall, which I've done before. So.

Um, and now he reports that he's feeling quote unquote, "blah" uh, and some complaining of some fatigue. 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. He stayed in hotels, not hostels. And he had two new female sexual partners with 90%, he said, condom usage.

So none for foreplay or for oral sex, but for vaginal intercourse, which he had only vaginal and not oral. And so he took no prophylaxis ongoing to Thailand. He did no pre-travel clinic visit and he is not been vaccinated for the year for the flu. And he had no pre-travel vaccinations. He denies any significant medical history or surgical history. 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.

He did have two episodes of blacking out while traveling, uh, one was in Bangkok and one was in Phuket. So he was intermittent tobacco use, occasional marijuana use, no IV drug use, and he has no history of STDs. And he has no known allergies. So, uh, Ryan, what else would you like to know in this returning traveler who's coming with fever and malaise?

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. 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. Right.

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? Number one and number two causes of death and returning travelers are what? Their MIs (myocardial infarctions) and car accidents, right? Neither of which are readily prevented by DEET or vaccination, right?

And similarly among infectious causes, cosmopolitan infections, meaning influenza, meaning other respiratory viruses. Um, you know, an older folks might be a bit sicker, pneumococcus, right? Those things still need to be on our list. So. You know, we still need to remember to do that kind of standard issue febrile workup and our standard issue assessment of clinical stability. How sick are they? Do they require admission? Are they unstable? Do they walk in under their own power?

And they're having a conversation, they're satting normally on room air, all those sorts of things we need to consider. That being said, we will assume that we have set those things aside, right. We'll assume that we have addressed those. And we have a pretty good idea that, okay, this guy doesn't have any real respiratory symptoms. Um, is he tolerating PO?

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? This is an undifferentiated fever, right? Did he have much in the way of myalgia or arthralgia?

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

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. Right. It sort of tapers off, . That's not the case in Bangkok. That's not the case in Chiang Mai. But it's at least worth seeing that we can't totally exclude malaria and probably doing some evaluation for malaria is reasonable. Although it seems like that that's relatively less likely.

So the big things that I would be worried about in this gentleman would be arboviral disease, right? Because that's going to be a big thing. That's going to be largely dengue in someone returning from Thailand. Um, other arboviruses, which we can chat about. And there's some subtle differences between them, but it's very difficult to clinically distinguish between them at the bedside.

Uh and then Some bacterial infections, so leptospirosis would be a good example of something that can be fairly ubiquitous in tropical settings, in, uh, developing settings. And then just because we got to mention it is, you know, he did make some special new friends while he was in Thailand. 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. Did he pay for sex?

I really do think we need to make sure that we're screening him for acute HIV in this setting. Um, and typically that'd be with some matter of nucleic acid amplification testing, um, So what does that get us to? I think the thing that we're thinking about, the thing that we're concerned about here is probably dengue, right? But there is a differential between, uh, both dengue looking at differing degrees of severity. And there's also the things that track with dengue.

Um, so chikungunya, Zika, um, which are both less common in this part of the world. Um, and then the things that will mimic it, the things that resemble it, we mentioned influenza earlier. Leptospirosis would be another one that would be important to try to exclude. And if we can't exclude it to our satisfaction, at least consider empiric treatment for.

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?

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.

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. 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. It is not in Asia.

Um, it'll also be helpful because we do have a differential diagnosis here. 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. So I'd getting those just to kind of flesh it out. And then the other things we talked about, would it be worth screening him on some level for malaria. Intellectually?

I don't think it's necessary, really. Emotionally? It would be hard to resist. Right, but you would, you would want to maybe at least satisfy yourself that you checked, you know. 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. And so getting blood cultures would be useful for that.

And also just to acknowledge that there are other diagnoses besides again, tropical diseases not seen in north America, commonly. Um, Group A strep bacteremia, things that can cause relatively mild disease initially, but can become very severe if missed down the road. He doesn't sound like he has that, but it's just a thought. Um, so CBC, blood cultures would be reasonable, depending on your assessment of how sick he is.

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

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. 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. Those would be the big ones. And then I guess we need to think about pathogen specific assays, right?

And there are a whole bunch of those. 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? Cause if we go down the list of kind of the big ticket items here for undifferentiated fevers, um, of viral origin, right? So we have dengue is the most common one. And dengue is kind of interesting.

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

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. Thinking about other so dengue is one of the classic flaviviruses. Um, and it is widespread in urban environments throughout developing countries. And that's why really in this person, why we're thinking more dengue than malaria, right?

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, and in assessing the febrile returning traveler. 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? So malaria, rural areas, bites you at night.

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. It's the tiger mosquito. It's a little less adapted to urban environments, but you see it in like China and Hawaii. 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. So, Aedes is adapted to urban environment.

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. And so malaria, rural, bites you at night. Aedes, urban, mosquitoes bite you in the day. And the, the challenge that we really have here is that, for things like malaria, right?

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? We have chemoprophylaxis, I can put someone on atovaquone-proguanil or doxycycline, or in kind of select circumstances nowadays, mefloquine. You know, and that's very effective in combination with things like insect precautions and the like. For dengue, what we have is don't get bitten.

You know, it's basically our options for prophylaxis are don't get bitten. 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. But that's pretty, you know, people get a little how shall I phrase this lackadaisical about that, right?

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. But, um, but I'm not perfect at it. I am probably just lucky on some level. Right. And it would be great if we had a widespread, highly effective dengue vaccine, but we don't like we don't right now. Now we do have Dengvaxia, which is an advance in public health. And Dengvaxia is a tetravalent, uh, dengue vaccine.

Uh it's chimeric vaccine and is protective. It does reduce the risk of dengue acquisition. The problem is that the population who had benefits is very, very narrow, right. And it's basically kids and young adolescents who've had dengue before, right? So, you know, I'm, I'm an adult infectious disease doctor traveling and, you know, practicing in North Carolina. I don't have a lot of children and young adolescents with histories of prior dengue who I see.

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

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

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. Otherwise like if I had to pick between getting like dengue or Zika, I would totally pick Zika, right? Because it is generally a milder disease, right? Generally milder disease. Chikungunya, not a flavivirus, unlike the other two.

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

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.

Yellow fever is a much more severe disease, but again does not occur here. Again, another flavivirus, where the word flavivirus comes from. Flavi means yellow. 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.

And for disease. This mild, you know, you could make a case for just trying doxycycline empirically in him. So then the challenge comes, and this is especially in this kind of clinical setting. Like how do you diagnose it? Right? Because on some level mild dengue - it's not that big a deal. Right. And so the reasons we would want to diagnose it is (a) to give it a name, right. Because that can be helpful. And because there is a residual risk of severe disease.

And so do at least want to do some sort of risk stratification for this, uh, for this gentleman. And I guess one question I it's worth asking is where was he born? Was he born in North America? Was he born in the continental US or was he born overseas?

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. Not that that's perfectly predictive, but you know, we got to risk stratify these people somehow. All right. All right. 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. So we have, we talked about CBCs. We talked about chemistry panels, blood cultures, just to be paranoid.

And I'm an ID doctor. And, you know, the indication for blood cultures is like fever and having blood. 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. So, you know, blood cultures, it's kind of like

You look for petechiae in a, you know, it's generally a two and a half centimeter by two and a half centimeter square. You count them. And that can be predictive of capillary fragility, which can be predictive in some cases of dengue. It is a physical exam fun fact. I don't think that it necessarily contributes much to the diagnosis or the management of the case. That is neither sensitive nor specific finding for dengue. If you find it it's neat.

If I had a fellow come up to me and say, Hey, I found this patient. I think they have dengue, I did this thing. It was positive. I would think, oh, that's neat. So, but not terribly helpful. 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. James, you mentioned that they don't seem to have any obvious lesions in their eyes. That's helpful.

Both for things that are also absent like jaundice or icterus um, And then we got to find some specific labs, right. And so probably the purists answer would be, this is kind of neat. 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. But basically what it is is a three valent PCR for dengue, zika, chikungunya. CDC will run it.

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

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. 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. And that's super helpful.

You can send off serologies for dengue, Zika, and chik[ungunya].. I will tell you that every positive Zika IgM, who I saw during the Zika epidemic, turned out to actually have dengue. 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. I have never diagnosed a case of chikungunya. Um, so hard to say, I have colleagues, who've seen it a lot.

Uh, and then dengue, you know, you can, there are a number of commercial ELISA based assays. Um, again, a lot of cross-reactivity with other flaviviruses. 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. Uh, the kinetics of that, there is a little bit of a delay in when those start to kick in. And then lastly, there is actually a dipstick.

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

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. Well, there's a lot of the same things present on dengue, 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. That is FDA approved in the U S but I gotta say , not a lot of urgent cares have those stocked.

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. And importantly can stick around for a long time, longer than what we often expect with IgM, but. Uh, has the difficulty of lots of cross-reactivity. We certainly could confirm diagnosis with paired acute and convalescent results.

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..

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

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

And that is relatively specific for telling you which serotype, which type of dengue is responsible for that. So, because there's gonna be some cross-reaction between antibodies against dengue 2 having some residual activity against dengue 1, for example. 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.

Well, it gives you a pretty good idea that that person is infected with dengue three. Now that is mostly of epidemiological interest, right? That's not necessarily a thing that affects our management of a patient at the bedside, but it is kind of neat. It is a cool test to run. If you're an institution that can run them or sometimes CDC or other agencies will run those for epidemiologic tracking purposes. That's kind of cool.

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

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

This has at least some degree of predictive value in a patient with a compatible travel history and a compatible syndrome. And so that can be helpful. Now, granted, that's also kind of true of like rickettsia. So we do have to be a little bit modest in that that, you know, I don't, I've never known for sure. 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.

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

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.

Um, would you mind commenting on the change?

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

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

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? So those are people who are definitely at risk of dying. And really the, the tragedy here is that that that group at risk are largely infants, right? Those are the ones who are at the greatest risk of passing.

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. 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.

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. Right? So you'd just start leaking out. And because of that, you'd get hemoconcentration and relatively high hematocrit.

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. You add on top of those hemorrhagic slash capillary leakage phenomena, the existence of hypotension, then you have dengue shock syndrome, right? So still a useful kind of concept.

Capillary leakage, marker of severe dengue that can manifest is with hemorrhage, that can manifest with pleural effusions ascites et cetera. It can manifest with frank bleeding. It can manifest with shock, um, but it becomes impractical because of those definitions. 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.

We would almost certainly admit the majority of them. These are people with abdominal pain, uh, certainly anything that resembles peritoneal signs. Those folks need to be admitted. People who have overt signs of plasma leakage. 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. Obviously these are people we are very likely to admit regardless.

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. Um, that would be a trigger for admission. 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.

Be it myocardial, be it severe delirium or encephalopathy. 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. . With all of this background, I think what we really need to sort out is what this gentleman's risk of severe disease is. The initial description sounds okay. But I think the laboratory may shed a little more light on that.

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. for glucose with AST 65, ALT ALP at 111, total bilirubin 1.2 and an albumin at 2.8. I then had him come in. I saw him and he looked grand. Um, and so I repeated the labs another day later. So over the course of about a week and they all reverted to what his baseline was from his physical a year prior

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.

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

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.

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. Right. And then, you know, trying to maintain, reasonable volume status, eat what you can eat, avoid dehydration. But again, these are things just for symptomatic control and his prognosis is probably pretty good. Although the fact that he feels lousy is very common, right?

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.

And so he told me that he had changed the trip that he had gone on a little bit. In this time he added Chiang Rai uh, to his trip, which is a little more rural. He'd gone to an elephant park and a tiger park, but he began having severe a headache for three days after returning. Uh, and he had marked retro-orbital pain on the right. Uh, but when he came in, he was afebrile at that time, but he just looked sunken.

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. And I had him pull his sleeves up and it was on both sides. And so at that point we got blood pressures, and he was at best 100 over 60. we took it several times, which gave him the tourniquet sign. Uh he was tachy[cardic] in the one with mild diffuse abdominal tenderness, more so in the bilateral upper quadrants.

Um, and he had been endorsing dark stools during the last week. And so advised him that he needed to go to the local ER, which happened across the street. 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. The ER obtained urine culture, UA, blood cultures, they attempted to get a sputum culture.

Is he had CBC, a CMP and a lactic acidosis, and these things were all cooking. Uh, when they page the ID attending, that was on call based on his travel history. So let's say that they, their question at that point was, do we get an LP given his headache? So that was the phone call that went to the infectious disease physician. And let's assume that that would be you in the setting,

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.

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

Um, but I, I'm certainly not going to be, uh, not going to be recorded on, uh, on Dr. Dong's famous podcast not not LP a man with fever and rapidly evolving

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. Just remember that when we think about what are the modifiable risk factors for mortality in septic shock, right? It's time of hypotension until time of active antibiotics on board, right. In addition to hemodynamic correction and so forth. So. We will set that aside because that is not our topic. Let us assume that has been addressed.

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

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

Then we would be worried about lassa. We could be worried about other causes of viral hemorrhagic fever, um, more common in other parts of the world. So it, although hemoconcentration in this particular setting is somewhat reassuring. In other settings. It is very unreassuring and just be, we need to all be remind ourselves that hemoconcentration is not normal, right? And that is a potential marker of capillary leakage, which is a hallmark of viral hemorrhagic fevers. In this gentleman's case.

Um, you know, I think that sending off diagnostic tests again for dengue and for all the other stuff we did last time, right. 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. And again, he's a little more rural area, you know?

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. And I suppose, I think again, thinking as a, as an intensivist, more than an ID doctor right now, but still both are true. What is our risk tolerance in this gentleman? What is our tolerance for being wrong?

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. Maybe not for malaria, but for other things you do, right? Like that person is unlikely to have significantly adverse outcome if you guess wrong the first time. So it comes in hypotensive, tachycardic, febrile, looks bad, unable to keep food down.

That person, your margin for error is extremely limited. And so we need to make sure we're getting it right the first time. So although we will discuss features of severe flavivirus infections. 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.

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

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. It's the second time right. Now, that is an oversimplification, but the problem goes back to those four serotypes. 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.

You may have some cross-reactive immunity. Yeah. A couple of years or so. Right. But, um, but that immunity will wane. 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. Right?

And so this can lead to increase viraemia and more rapid viral replication and more severe disease. Now, this is an incomplete explanation of why this happens, right? This is an incomplete explanation. There's probably some host factors involved. Um, there may be, there may be some polymorphisms in mediators of innate immunity that's involved.

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. Not that I don't know. 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.

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. Um, well that mutation has affects in nature too. And one of the effects of that mutation is people who have it probably get more severe flavivirus disease, uh, more severe flavivirus infections. So, um, now this doesn't explain off the top of your head, like getting a second flavivirus infection.

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. Right? 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.

Now, severe dengue does not happen in most hetero typic dengue infections. Uh, it happens only a minority of cases. It is not a complete and nor does it explain every case of severe dengue, right? There are these other host factors and things that play a role, but it is an interesting kind of model. And I will say, cause this is 2022 in recording this, that there are some coronaviruses that exhibit antibody dependent enhancement.

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. I mentioned that because my cat is sitting in my lap and I'm thinking about it right now. Okay. And she is very comfortable. And to the best of my ability to tell does not have feline, uh, peritonitis virus infections. Although for reasons I won't get into you, I do have to give her a cyclosporine for later on. Um,

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? Because relatively recent, you know, different geographic regions, their dengue serotypes will shift kind of gradually over time. But he went to a new place, had the opportunity for a new exposure. And I think that explains kind of his deal. Right?

So then we got to figure out is what we're going to do for it. And our choices are kind of limited.

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

Uh, and so those things were continued and Flagyl was added for whatever reason. And, and, uh, so the, those two perspectives though, you know, the TNF alpha, we are not actually doing, those are mostly animal studies. 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. Certainly in this patient may be up front.

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 in these

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. The only colloid in widespread clinical use and really the best one to use would be albumin. Could you use albumin with a clear conscience? Yeah. Um, it's more expensive.

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.

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 in third spacing we see in sepsis.

That's, you know, that is not to the best of my knowledge. Formally studied. You need detail in dengue per se. 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. There isn't there, the same outcomes are the same, right. And, and that's fine.

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. Um, you know, you mentioned TNF alpha and inhibition. This is, again, this is an animal model thing. It's actually pretty hard to make animal models for dengue. Like it's pretty easy to infect animals with dengue. Uh, when I was working in Peru, we had rodent models.

We had a non-human primate models. They can get infected, they can get viremic, but they don't get that sick. Um, so, uh, a, an animal model of severe dengue is challenging. There are some, uh, rodent models where they can see like, um, worsening, uh, not even worse than it really is a word. Um, erythroderma basically. They, they, you know, are erythroderma and that is a surrogate marker. Um, but yeah, so TNF alpha inhibition.

We're not going to be starting everyone on Remicade to treat, uh, uh, DHF right now. Antivirals, you mentioned that it is a flavivirus and we are right now in a golden age of flavirvirus therapeutics because of hepatitis C. Uh, there is nothing that is currently, you know, anywhere near marketing right now, but there's some early data.

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. 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. So hopefully those will continue to progress and make some, make some progress there. And then steroids, right? Anytime anyone's got fever and shocks and one wants to throw steroids out at.

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

It just doesn't work. It does not have that doesn't improve any patient centered endpoint. Um, and so I would not recommend using that as well. So it's largely fluids and human dynamics support. We don't give a lot of blood products for this. Uh, we generally try to avoid giving platelets for anything other than overt hemorrhage. Um, you know, meaning like if you're starting to have. And your platelet count is 10.

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

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

Endemic patients are the ones that get the most severe dengue, more frequently in the younger ages. 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. Um, and so this has becoming a consideration in the United States and Florida and Texas, mostly. Uh, and so it seems that it's diurnal.

Um, and so it's mostly DEET, permethrin, drainage of the pools and ponds that you had mentioned. Um, but we're, we're not walking around with bed nets outside during the day. And so,

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

So just, uh, just be careful with that. 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. I'm so sorry, apple watch. 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. So be careful.

Um, it is a solvent, um, very safe, obviously for the skin, keep it away from your eyes, keep it away from your mouth. If you're traveling with children, help them apply it themselves. Uh, we talked about the vaccine. It is just for the great majority of listeners of this podcast. It's not a vaccine that's going to be of much use to them right now.

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.

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

And I was very lucky early in my career that dengue vaccines, one of the first things I worked on. And so I learned a ton about vaccinology, about how vaccines work, about a vaccine development from it. 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. Uh, in terms of, um, you know, you talked about local emergence in North America. I mean, there's always been some dengue here, right?

I mean, right after the revolutionary war, there was a massive yellow fever outbreak in Philadelphia. 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. Um, and there is a certain amount of dengue in parts of Texas as it is. 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.

And then when we say Florida, we're really talking like, kind of the Caribbean parts of Florida, right? So we're talking to Miami, we're talking the Keys, Key West, and the like but there is. I apologize. That's my dog. He's very excited right now. Um, but there is a certain amount of endemic, uh, dengue in North America.

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? 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.

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. And it's probably broadly true of lots of, um, arthropod borne infections. Um, but it is a thing we have to be worried about. We do have to be concerned about. And so hopefully we'll, uh, hopefully we'll dodge that bullet, but time will tell.

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. Please reach out if you have any suggestions for future shows or want to be more involved with Febrile. Thanks for listening, stay safe and we'll see you next time