Drs. Shilpa Vasishta and Christina Coyle navigate us through fever in a returning traveler

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Hi everyone.

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

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

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

Here on Febrile, we use patient cases and consult questions to learn about high yield ID topics.

Joining me as co-host today is Dr.

Shilpa Vasishta.

. She is a first-year ID fellow at the Icahn School of Medicine in Mount Sinai in New York with an interest in medical education.

Hi, excited to be here.

And our guests consultant today is Dr.

Christina Coyle.

Christina is a Infectious Disease physician and Professor of Medicine and Pathology at the Albert Einstein College of Medicine.

She has practiced tropical medicine for over 25 years and oversees the largest tropical medicine clinic in the Bronx at Jacobi Medical Center.

Hi, it's Christina Coyle, excited to be here.

Awesome.

And, uh, before we start the case, we always ask this one nonmedical question and we call ourselves a cultured podcast and would love it if you'd be willing to share a piece of culture that brought you happiness or joy recently,

I'll start.

Um, so what brings me joy?

I think, uh, for me, I'm passionate about ballet.

Most people know I'm obsessed with it and I've been dancing since I'm seven and I'm 60, so you can do the math.

I certainly wouldn't call it dancing now, but I'm obsessed also with, uh, ballet performances.

So it's a real passion of mine.

Dr.

Coyle, that is so awesome.

I too love ballet.

And what I was actually going to plug today is not specifically ballet, but a related art form that my son has taken interest in, which is tap dancing.

Um, I say this kind of loosely because he's only 15 months old, but he loves the movie Happy Feet, which actually features spectacular tap dancing, um, from one of arguably the world's best tap dancers Savion Glover.

Um, and my son loves to imitate it.

And so I would highly recommend it for any family that loves dance and maybe has a one-year-old boy

Excellent!

The main thing here, Sara, is that dance equal joy!

Yes.

Um, well I love these little pieces of culture, but, um, so we'll jump into today's case.

The consult question is about worsening fevers.

Uh, so Shilpa, I'll hand it over to you.

Thank you.

So we have today, a 38 year old female who's presenting to medical attention with fevers.

Her symptoms began three days ago and are accompanied by headache and nausea.

They have progressively worsened prompting her to present to the emergency department today.

She denies any associated sore throat, rhinorrhea, cough, abdominal pain, vomiting, diarrhea, or dysuria.

Her past medical history includes prediabetes within hemoglobin A1C of 6.0.

And for medications, she takes an oral contraceptive.

The patient is originally from Brazil, moved to the U S at age 25, and she recalls being hospitalized once in her early twenties for a kidney infection.

She currently lives in the Northeast with her husband and two pet cats.

She works in technology and travels approximately twice yearly for work, last to Nigeria 10 days ago.

On presentation, the patient is febrile to a maximum temperature of 103.5 degrees Fahrenheit.

She's tachycardic to a heart rate of 130, she's normotensive and saturating 99% on room air.

On exam, she is well-appearing with moist mucus membranes.

She has no jaundice or scleral actress and her neck is supple.

She is tachycardic.

However respirations are non labored and lungs are clear to auscultation.

Her abdomen is nontender.

Liver and spleen are nonpalpable and she has no rashes.

Neurologically she's alert and oriented times four with no deficits on initial lab work.

She has a white blood cell count of three, a hemoglobin of 10 and platelets of 90.

On chemistries she's hyponatremic to 128, has a metabolic acidosis with a bicarb of 16, and an elevated creatinine to 1.2.

Her transaminases are elevated to the sixties and chest x-ray demonstrates clear lungs.

What are your initial thoughts in hearing this case?

And what additional information would you like?

Okay.

So, um, we have a 38 year old, born in Brazil, but residing now in the states (USA) who now travels to Nigeria less than 10 days ago, who's complaining of a fever.

She's also complaining of a headache and, her labs are significant, as you said, for a low white count, thrombocytopenia, a bicarb on the low-ish side, a chest x-ray that's negative.

We don't hear a urine.

So we'll talk about what else we'll want, but the minute you're called as a fellow for somebody with a fever, the first thing you want to know is obviously where they traveled to and how long they've been back from the region.

Knowing the geographic area is critical to your assessment as an ID fellow.

So that's the first thing you're going to do.

I'm going to just tell you some tips and tricks.

So if you don't know anything about the region, you can go to cdc.gov and travel and look up the region there, and it will give you everything that is in that region that's infectious.

And you're thinking as the ID fellow when you get this phone call, is, what is life-threatening in this particular patient?

What is treatable, right?

And what's transmissible.

Do I need to isolate this person?

Those are the three questions that you asked yourself when you get this phone call.

And then of course, we talked about the time that they came back from their trips.

So we're looking at incubation, we're going to be focusing on the exposure history, uh, the time course, and of course the associated signs, signs, and symptoms.

And so in terms of onset of fever from the trip, I kind of break it up into less than a month and greater than a month.

And even with that, I kind of think less than two weeks because we know things like the flu have a short incubation.

COVID has a short incubation.

And then we know things like dengue, chikungunya, um, all have incubations of less than two weeks.

So if the person's already greater than two weeks out, that's making those less likely.

This person is within the two weeks, so the differential diagnosis gets very, very large, right?

Once you go past two weeks, that becomes much less likely.

And that's very helpful for you to think about.

Once you're within a month, right?

You're always thinking about falciparum malaria.

So malaria one, two, and three.

And then once you move outside of a month, you start thinking about things like hepatitis, schistosomiasis (because we're talking about Africa right now).

So these are causes of fevers that are, are greater than a month.

Um, and then I do want to add in there, we don't see P.vivax normally from West Africa because it needs the Duffy antigen to enter and it's tends to be lacking in west Africans.

We can see from East Africa, um, and of course, most P.vivax in the United States in travelers is, is reported from Southeast Asia.

But P.vivax, because of the hypnozoites or the liver stage can be a cause of late fever and malaria.

The other thing you want to know is where the patient was born and you already told me that.

Because that's going to tell you whether or not the patient has a likelihood of being exposed to certain diseases.

And so we, um, also talked about the type of traveler people are.

So I normally ask patients, why did you go?

Did you go for fun?

Did you go for business or, are you visiting friends and family?

There is a whole literature on visiting friends and family, and they are referred to as VFR.

And so VFRs, are individuals that are returning home to their own country or a spouse's country or a parent's country, where there's a higher infectious disease risks than the country that they're currently residing in.

And so when we look at these individuals, they are less likely to have had a pre-travel assessment.

And they're more likely to come back home with a vaccine preventable illness.

So this is really important.

This individual's not a VFR, but as an ID specialist, that's something you want to really think about.

And you also want to think about it when you're caring for individuals that are migrants, because they do tend to go back home and visit their friends and family.

We talked a little bit about length of time in the country.

So you want to know how long the person's been in the country.

And obviously I ask for an itinerary.

So if the person's a short-term traveler in one city, it's not a big deal, but once somebody's somewhere for awhile, I actually make them write out their itinerary for me.

Travel history really takes quite a while.

I ask everything you can think about, obviously.

Sexual activity during the trip.

Um, the stuff you normally think about mosquitoes, right?

Exposure to animals, fresh water exposure, always in Africa, but really anywhere, but, uh, especially in Africa because of the risk of uh schisto.

Then I also ask about whether or not they used repellent and whether or not they were good at it.

It's not going to change whether or not I'm going to be worried about malaria.

It also gives me an idea of what type of a traveler they are.

I also ask if they use bed nets or if they use screens, uh, or if they stayed in a room with screens.

We always ask about food and water.

Right?

We ask about bottled water.

Everyone says they use bottled water.

Um, and so before someone goes, we always say, boil it, cook it, peel it or forget it.

The reality is that's really hard to do, uh, for an entire trip.

And so, , the more you stray from that, the more you're at risk for foodborne illnesses, such as hepatitis, , and typhoid, especially in areas with poor sanitation, so if you're in more rural areas.

Your differential diagnosis, I put it in like almost three buckets.

I do a geographicgeographic, right?.

So that helps me hone down.

Exposures.

And then the syndromic, and then I kind of put them together and I see where they intersect.

This is what makes the returning traveler with fevers so much fun because it really is like being a detective.

So you're putting all the puzzle pieces together and then I see where they intersect.

And then of course I'm rating the thing that if I don't recognize it and treat it that evening, it could cause harm.

And so I'm doing a risk assessment also on what's the most likely, or what's the thing that that's going to, um, really harm this patient if I don't make the diagnosis.

And I'm guessing that some of your risk assessment tackles pre-travel considerations, are there any tools or suggestions you have for approaching that?

I ask a lot about pre-travel.

So I'll spend a few minutes here on a website.

You can go to CDC.

Um, many of you might have actually pre-travel programs.

For those fellows that don't, there was a lovely website, and that is supported by CDCs Global TravEpiNet.

It's called GTEN.

And it's called, called "Heading Home Healthy.".

It's actually a pre-travel, but if you're seeing the patient post travel, you can put the patient in there and you put in the age of this patient and you put that they went to Nigeria and, um, any allergies or whatever else they might have asked for pregnancy and some other things.

So it's going to come up with vaccines.

And so yellow fever is going to come up, but you're going to find out that you are going to need proof of vaccination to even get in to Nigeria.

So she probably had yellow fever.

You, of course, you're going to ask are typhoid comes up, but I'm going to tell you it's pretty uncommon in Africa.

Meningo[coccus] comes up during the dry season.

So that's important.

She has a headache.

You're not sure if she took the meningo vaccine.

Hepatitis A.

You want to know whether or not she's immune or whether or not she was vaccinated.

Hepatitis B.

. Flu vaccine.

And obviously COVID vaccine right now is easy because you need to show it to, to fly.

Um, but I added it on the list for completeness.

Um, you should make sure they're up to date on their routine immunizations, just because measles outbreaks are very common, uh, throughout the world.

And it's something we have to think about, and we don't see a lot of it anymore.

And especially younger people who trained in the States normally have never even seen a case of measles.

So it's really important for us to ask about vaccination.

And then you can either, when you go on CDC or Heading Home Healthy, they will tell you about our outbreaks.

And that's super important because you'll know, oh, wow, there's an outbreak of X going on in this particular region.

And so they'll warn you and you'll know going in there, there's an Ebola outbreak wherever this patient has traveled or whatever it might be.

For the most part, we're pretty good about knowing outbreaks as ID people, but it's always good to refresh ourselves.

And of course the most important thing is malaria prophylaxis.

Did this person have a pre-travel assessment and were they offered malaria prophylaxis?

That's number one.

And then number two, did they take their malaria prophylaxis?

Right.

So any breaks in malaria prophylaxis?

First of all, it's not completely, you're not going to be a hundred percent effective with malaria prophylaxis.

That's why we always tell people to use, uh, insect repellent et cetera, in addition to the, the prophylaxis.

And a lot of people aren't always compliant.

And if you think about something like doxycycline, for example, you miss one dose and you can break through.

We will do a differential, but, you know, before we even walk in the room, despite what she tells us, we're going to be thinking malaria one, two, and three.

No matter what she looks like, whether she's febrile, no matter we are going to be thinking malaria.

Malaria is the most important cause of fever amongst those individuals traveling back from Africa.

90% of cases in the US um, are acquired in Sub-Saharan Africa, and the number of cases of malaria in the US have been increasing since 1970s.

And so when you look at it, the majority of those cases are from West Africa.

So you're going in with that mindset.

I will tell you the most common reason for travel in those individuals is normally those individuals visiting friends and family.

Your main thing that you're thinking about is I need to get malaria in, or out of the picture as ID fellow when you're on the phone.

And the other thing I wanted to say to you, which I think is really important, not as that appropriate to this patient, is that many times, in up to 40% of cases, patients can present with other symptoms.

So their GI symptoms, so they can have diarrhea predominating the picture.

And the fever may not be what they complain about.

And so you can get derailed and misdiagnosed.

And so if you look, there's a couple of studies from the states, also one from my institution, uh, one in Canada that shows that there's a fair amount of misdiagnosis in these individuals.

So again, lack of fever and having other symptoms besides headache and myalgias, you must rule out malaria.

You just must, it has to be on your list.

So how do we approach these labs when we're getting this call as the ID fellow.

This patient kind of checks the boxes.

So we see a lot of malaria uh, the I'm in the Bronx and we have the largest numbers of malaria in the United States, up here in the, new York does, and then within New York, the Bronx and upper Manhattan.

So I get called a fair amount for the returning traveler from West Africa.

So once I I'm obviously thinking malaria, malaria.

So what are the questions that I'm going to ask, I'm going to start?

Or what are the things that are going to get me worried about this patient?

So we normally see thrombocytopenia, it's rare to not see thrombocytopenia.

There's sequestration in the spleen, spleen of platelets..

So we rarely don't see it.

So if I see here someone's got a platelet count of 350, that actually makes it less likely that it's malaria.

It doesn't mean it's not, I'm still gonna rule it out, but thrombocytopenia is normally the rule.

It is not prognostic of how sick the patient is.

The prognosis is really going to be on end organ and also parasitemia.

Right.

We can see any white count in malaria.

We could see a low white count.

We normally don't see high white count similarly.

So if you start seeing a white count of 25, that's gonna make malaria either less likely or dual infection.

The person might have a bacterial infection plus malaria.

Also, we're a bit worried about that bicarb of 16, and that should be something that's a red flag for us.

And the creatinine is slightly elevated.

So these things are red flags when we get called on the phone phone, we also hear that she's from Brazil.

So we're not sure if she's ever had malaria before.

There is some malaria in Brazil.

So, but it was years ago, right?

She's a long-term long time out of Brazil.

So we're assuming she's non-immune so that's also making us worried.

So this is all my malaria brain going on, but I don't want to get too focused on malaria and missed other things.

Right.

So the other things you're going to ask for are going to be urine, right?

I'm going to ask for obviously, um, a blood smear, I'm going to ask for an LDH.

I'm going to ask for a lactate.

You already have a chest x-ray and I'm going to ask for blood cultures, but what ID person isn't going to ask for blood cultures.

Um, so I think we'll stop there and hear what happened and then, based on this patient then start saying what's likely and what's not.

Yeah, sure.

Um, so a little bit of additional history, patient reports staying in an urban area of Nigeria for two weeks during her most recent period of travel.

She resided in a hotel where she ate most of her meals, uh, though did also eat food, including both cooked foods and fresh produce obtained from outdoor vendors.

Uh, she drank exclusively bottled water.

She did make one weekend trip during which she hiked in a wooded area and swam in a freshwater lake.

She does not recall any contact with animals though, does endorse mosquito bites despite use of mosquito netting.

And she was not sexually active during her travel.

She had a pre-travel consultation where she completed yellow fever vaccination, and was offered typhoid vaccination, but declined.

She was otherwise noted to be up to date on routine immunizations.

She was prescribed doxycycline, which she reports not taking consistently during her two weeks of travel.

Okay, great.

So let's go over the history that you just told me.

So I'm on the phone now.

I'm still the ID fellow on the phone.

And so she's, uh, she's a short-term traveler.

She's been there for two weeks.

she was in a hotel, but she did have some high risk behavior in terms of her eating.

Right?

So, um, she went to an outdoor, uh, food vendors.

So we know that she's at risk for typhoid, hepatitis A, um, and, and other GI pathogens, although we don't hear a lot of GI complaints.

She made a weekend trip where she hiked in a wooded area.

So that would pique my interest.

I'm going to talk to you about that, about tick-borne illnesses, but not as much in west Africa, more in South Africa, . Um, and then she swam in fresh water and I always ask my patient if they swim in fresh water, um, and any single body of fresh water in Sub-Saharan Africa should be considered to be, uh, infected with Schisto[somiasis]

so they're at risk for being exposed to schisto and that's your rule.

All right.

You don't have to look that one up.

Um, and of course we always worry about leptospirosis, and that's something that we can, we always have to think about as ID people, because we don't keep it on our list.

We'll forget about it.

Um, she doesn't really talk about contact with animals, so I don't have to go in that direction, but she endorsed a lot of mosquito bites.

So malaria was big, big, big.

Big big, big, um, she had a pre-con, uh, travel consultation.

She got her yellow fever vaccination.

Um, and, she wasn't compliant with her doxy or was she, I can't remember.

Did she, did she take her anymore?

Uh, she was prescribed them, um, and reports not taking them.

Okay.

So that's important.

For this, we talked about risk factors, so we just went over some of her risk factors.

And so this is where we now did geographic.

And we took her risk factors and we talked about the things within west Africa that might cause fever.

And now we then might think about syndromic.

And so for this patient, although she's got a headache, I would really put her into an undifferentiated fever.

And then I break it into malarial versus non malarial.

Um, and that's how I would approach her.

So the first thing we're going to do is rule out malaria, uh, but other things to consider as we're walking down to see her and get all her bloods.

Uh, when we think about an undifferentiated fever, we have to be really careful about not, not only thinking about tropical diseases.

So we need to think about UTI.

We need to think about respiratory infection.

She's got a negative chest x-ray so that's really unlikely.

We talked about influenza.

We talk about COVID she's not sexually active, but we always need to think about STDs, including acute HIV with an, an undifferentiated fever.

Um, and then it puts us into our tropical dengue, rickettsial infections, leptospirosis, and she's got a lot of risk factors that you went over that put her at risk for these illnesses.

Um, and then, a rash always changes things.

A rash puts us into dengue, chik[ungunya] again, acute HIV, measles, and then acute schisto[somiasis].

Um, and then within the rash, I always look for a eschar.

The patient has to take their clothes off.

Um, because a lot of times it's normally at the bite of the, in terms of Africa, the bite of the tick, in terms of uh Asia, it's a chigger.

Um, and so, you know, sometimes it's behind the knee, it's, uh, in places that if you're not really looking at the patient wholly, you might miss.

So I'm always looking for eschars, regional adenopathy, um, because a lot of times with rickettsial illnesses, the patient will only complain a fever and headache.

And if you're not looking, you'll miss an eschar.

. So then, you know, there's other syndromes in this patient right now, doesn't meet them.

So fever with jaundice.

So if I see that, I start thinking severe malaria, hemorrhagic, fevers, et cetera.

Fever with GI complaints.

And so we can supply you with a nice list of syndromic approach to fever and the traveler.

I just wanted to spend a few minutes on each thing to think about.

So dengue.

After malaria, the most common when we look at Geo Sentinel, which is a worldwide surveillance site, um, and, uh, supported by CDC.

The most common cause of fever on the traveler after malaria is dengue.

Dengue is transmitted by, um, Aedes aegypti or albopictus and, um, it's worldwide.

And it's found in Africa.

And the classic that you think about and that we see at my institution, is fever obviously, by a severe headache and patients classically tell you that it's retro orbital.

They really do tell you that.

So I actually asked them that, or a lot of times they'll supply that history and they'll have severe myalgias and arthralgias giving it the name breakbone fever.

The fever lasts about five to seven days and the rash is pretty, um, if you've ever seen it, it's a macular eruption and basically it's erythematous with small areas of normal skin.

So on a person with white skin or light skin, it's called islands of white in a sea of red.

This is harder to see in darker skinned individuals.

And that's why it's very important as an ID person to make sure that when you're looking at skin rashes, you look at rashes on people of all skin colors.

It's really important for us to recognize different rashes on different, uh, different skin colors.

Um, but that's the classic way that it's described, and the more important thing is that there's areas of sparing to the erythema.

And it's got a very short incubation.

I use 14 days as your cutoff when I first started this talk, but it can be five to 10 days so people can get ill during travel and might not even be reported.

Um, and risk factors are obviously everything that this patient has and leukopenia and thrombocytopenia like this patient are characteristic.

When you, you look at dengue, it's most common to be reported from Asia.

It is reported from Africa, but not commonly.

I'll tell you in my experience, I've definitely, um, diagnosed people with dengue from, um, Africa.

It is on my differential.

For this patient, I would probably rule out malaria first, before I even sent a dengue serology, me personally.

, but when you're talking about getting bit by mosquitoes and there's Aedes aegypti and albopictus in Africa.

So you have to think about chikungunya and Zika.

Chikungunya has a short incubation and here arthralgias are the prominent symptoms

. 70% of patients are going to complain of arthralgia.

And if you've ever seen somebody with chikungunya, which means bent over, they really are bent over.

This patient has no rheumatologic symptoms.

I don't think I would even send a chikungunya serology.

, Skin manifestations are also reported in chikungunyah, but we don't share that in this patient.

I'm going to spend two seconds on Zika.

You can look it up and see where Zika outbreaks are occurring.

Again, it's transmitted by the same mosquitoes as dengue and chikungunya.

The illness tends to be mild and even asymptomatic in many individuals.

And here there's a pruritic rash and patients can have arthritis,

and conjunctivitis.

Um, and so headaches and orbital pain are also reported, but there's no outbreak currently going on in Nigeria and we hear nothing really to support Zika.

So I would think that would be unlikely.

Let's spend some time on typhoid fever cause this individual ate off of roadside stands.

And so for me, we're going to do blood cultures and that's how we'll establish a diagnosis.

But for me, this wouldn't be high on my differential.

Definitely doing the blood cultures, but normally in, patients present, they've normally traveled to Southeast Asia.

They've normally had prolonged fever for greater than seven days.

They normally have chills, but they're not having rigors.

So they tend to come in a little bit later . And, um, it's, caused by Salmonella enterica serotype typhi or para typhi.

Um, incubation can be up to three weeks, early as five days.

So about 80% of cases in the United States, , diagnosed with, , typhoid, uh, individuals diagnosed with typhoid have traveled to Southeast Asia and the majority of individuals present with abdominal pain, fevers, and chills.

There is a rash, it's very hard to see, it's a salmon colored macules, rose spots.

Um, and I really check my patients carefully.

For the majority of patients in our institution are normally from, um, Bangladesh.

So I really really check and we see it mostly in children that haven't gotten vaccinated before they've left.

So there's, there's some clues.

So this makes, um, typhoid fever a little bit less likely, it's an acute fever, um, that's number one, if the patients from Africa, so that makes it a little bit less likely, although she does have risk factors.

So it's still on the list still in the running.

Let's spend two seconds on rickettsia because it comes up on the list.

So I think for Africa, you need to know about, um, African tick typhus, which is caused by Rickettsia africae.

It is most common in South Africa.

It's really not well described in west Africa, but I do think you need to know about it.

the vector is an, a tick, an Amblyomma species and it's a tick of large ruminants and wildlife.

And it's a very aggressive feeder on humans.

And that's important.

At the site of inoculation, you can get an escahar and you can have regional lymphadnopothy.

Although the patient can actually present with just really headache and fever.

And if you don't look, you'll miss the eschar.

And as I said, you know, many times patients have a number of eschars if you look closely.

Um, and it's normally in people who have been camping, hiking, such as this patient traveling.

It's very common or in safari or in grassy areas, walking in grassy areas.

Again, because they're from west Africa, it makes it less likely.

Lab wise,

they have leukopenia and thrombocytopenia, a low bicarb would.

Go against it.

Right?

You don't look systemically ill, you respond promptly to doxycycline.

You make the diagnosis, you establish it by clinical picture and serology.

So normally we just treat presumptively and they really respond quite rapidly.

Rickettsia conorii or Mediterranean tick typhus, although it's circulating, it's not a common cause of rickettsial diseases in Africa.

So the one that I would know as a, as a fellow would be, um, African tick typhus or Rickettsia africae.

Okay.

So it's really important.

The epi here doesn't support it.

We heard that the patient is not sexually active, but do not forget to ask about a sexual history or blood exposures.

So things like, um, uh, basically body piercing, people get tattoos, people have accidents and they sometimes don't tell you about it.

Minor accidents where somebody actually stitches them, uh, in rural areas with needles.

And you don't know if the needle has been cleaned, so you really need to dig down a bloodborne exposures.

And obviously I don't need to tell this audience about acute HIV and how it can present.

Um, and so then we heard about freshwater, so let's talk about leptospirosis.

And so there's lots of emerging data on people that do go rafting or kayaking.

And coming back with leptospirosis.

So we as ID people need to keep it on our radar.

The incubation is two to 26 days, but it's an average of 10 days.

So this patient, um, is within that.

Although I don't know when they were in fresh water.

The clinical course is variable, but early on, patients can come in with fever, rigors, myalgias, and headaches.

A lot like this patient and conjunctival suffusion is characteristic, but often overlooked.

I need to talk about acute schisto because we don't talk about it enough.

It occurs four to eight weeks after exposure.

So this would be on the very early side, if it was just schistosomiasis.

And I think it's too early for acute schisto because if you do the math, she's back 10 days.

So she'd be right on the cusp.

It's important.

It's a cause of a fever and normally individuals complain of a rash.

Now, not everybody is symptomatic, but those individuals with fever, commonly have urticaria.

And they normally have profound eosinophilia.

So they can have non-specific symptoms.

Two thirds of individual will actually have a cough and they'll have an abnormal chest x-ray, which will be reticulonodular.

And so it's really important for you to think about this in your patients that return with eosinophilia and a fever . So, um, that's acute schisto and the one thing I want to say to you about schisto is eggs normally are only present in 25% of individuals in the urine or stool depending on the species.

And so the way we make that diagnosis is basically clinical and we treat presumptively while we're waiting for the serology to come back.

Um, by the way CDC recommends anybody that's been in freshwater in Sub-Saharan Africa should be screened for schisto because not everybody is symptomatic and you can have a wayward pair of worms that find their way into Batson's plexus and shoot eggs off into your spine and your brain.

So even though you're not going to get hepatosplenic disease or hematuria , it's really more about, um, those complications.

So that's just an FYI.

Um, and then of course, fever associated with hemorrhage.

You're going to look up and see whether or not there are any of the hemorrhagic fever.

If there's outbreaks, in Nigeria and you're always going to keep, you're going to keep them on your list, because again, we talked about the fact that that's a public health issue, and so these patients may need to be isolated and anybody that cares for them, um, may need to be protected.

And so that's an important thing to always keep on our list.

So what would I do next blood cultures, a UA, a flu swab or respiratory panel?

COVID I might repeat it.

HIV tests, we talked about, , pregnancy tests.

, why would I do that?

Because I'd be worried about malaria and those individuals that are pregnant are more likely to have severe malaria and it changes the way I approach them.

And then of course I would do a peripheral blood smear and I would do, um, a rapid diagnostic test for malaria.

And remember your rapid diagnostic is great for falciparum, but not as great for the other malaria.

And the most other important thing is it may miss low parasitemias and, and you don't get a percentage parasitemia.

So there are only good to say, yeah, this patient's got malaria.

And so that's important because the patient has a low bicarb is not immune.

You might jump on this patient a little bit differently.

Um, I'd ask for an LDH, a lactate.

I'd make sure I got a bilirubin.

Would I get the serologies, dengue??

I probably wouldn't, me personally, I would probably rule out my malaria, get the blood cultures that night.

So I can get a malaria smear pretty quickly.

And I, am actually very good at reading smears myself.

So of course, when we see a patient we're seeing a smear within the next 15 minutes, not everybody has access to that.

So a lot of times patients with headaches, you have to worry about, CNS infections.

And sometimes people get CT scans and LPs.

And I think that depends on how the patient looks.

Great.

Um, so we do obtain some further workup, um, and admission urinalysis and urine pregnancy tests are negative as are COVID and flu swabs.

Blood culture, as well as serologies for HIV and viral hepatitis are in process and a peripheral blood smear obtained overnight at your advising reveals normal sized red blood cells, some containing ring forms.

So the patient's blood smear is followed by thin smear on which an average of 10 to 12 ring forms are noted per high power field.

Dr.

Coyle, how would you interpret these findings and how would you characterize or classify this patient's illness?

Great.

This is the most important thing that we do as ID clinicians is we interpret the blood smear.

And so when we're looking at a blood smear, the first thing we do is we look at the size of the red cells.

And so we heard that these were normal RBC.

So when we're talking about normal size RBCs, it's moving us towards falciparum and malariae.

I'm going to leave knowlesi out of this, just because it, it occurs in Malaysia and it's not even part of the epi here.

When we talk about enlarged, red cells that are, those are the forms of malaria that, in fact, younger red cells.

And so that's your vivax and your ovale.

All right.

And so that's the way you think about.

You're hearing only rings.

And so these rings are normally when someone, especially from the lab says rings, what they mean is that it looks like the signet ring, like a diamond ring or sometimes like headphones.

And so that's the chromatin and the ring itself is the very thin cytoplasm and the diamond on the signet ring is the chromatin dot.

And so, uh, when we only see that, and they're not enlarged, it's really pushing us to falcip[arum]..

If it turns out it's malariae.

So be it.

But they tend to have very low parasitemia, malariae.

They actually infect senescent red cells.

And we're hearing a lot of red cells infected here.

So this is really pushing us towards falciparum.

The other thing is that we only see rings in this patient.

And so what that's telling us that cytoplasm from that signet ring, right, that, that blue part of the ring is going to actually enlarge over time.

And it has two ways that it can go.

It can develop into what we call a blood schizont, which is what I always say, a blue bag full of merozoites.

Um, and when that ruptures, you're going to get fever or schizogony, and each of those merozoites will then infect another red cell.

So for malaria, it's about 10 merozoites.

So for every infected schizont, you're going to get 10 to 13 red cells infected after that schizogony.

, and then of course there's gametocytes and the gametocytes do go in the periphery.

And we know in falciparum they look like banana shaped.

So that's going to get picked up by a mosquito.

That causes no symptoms.

It just tells you that the person's been infected for at least two weeks.

So those later stages that you normally, will occur in the life cycle in falciparum are sequestered.

So when you see a parasitemia of like say 3%, they could have a fever and schizogony.

And the next eight hours that parasitemia, especially in a non-immune host, can increased quite a lot.

Um, I've seen 2% in the morning in non-immune hosts and 20% in the evenings.

So what you're seeing on a blood smear, isn't representing exactly what's going on in the patient.

And there could be a sequestered biomass that you're not accounting for.

And that's why getting a blood smear and parasitemia on falciparum, you should definitely, you're taking everything into consideration, right?

You're taking the immunity into consideration and you're knowing that in eight hours, this might be different.

That's why you're looking at your end organ, your brain, right.

You're looking at your kidneys.

You're looking at the blood pressure.

You're looking at pulmonary, you're looking at all of these things and of course you're looking at acidosis.

Right.

And so these are all the things that you're looking at because you know that parasitemia although, once it's greater than 4% in some, in a non-endemic region,

so somebody that isn't being exposed all the time, right.

It's going to be severe malaria.

You're also going to be worried about somebody with 3.5%, 2%.

They're going to make you worried if they're non-immune and they've got end organ damage, and they don't look well, they just don't look well.

So these are the things that we're thinking about when we're looking at this blood smear.

And this is the reason why you only see early forms in P.falciparum, as opposed to be P.vivax and P.ovale, where you're going to see the later stages, you're going to see the schizonts in there and they're going to be enlarge and there's something called Schuffner dots that, you know, you're not going to see in the middle of the night, your parasitologist is going to pick up.

Um, and so that's the way that you're going to look at this smear.

And so then you're going to calculate out the parasitemia and to be frank, I personally always say to my residents, because we're normally there in the middle of the night, this never happens during the day.

Right.

So I normally say let's go up to hematology lab and sit there and look at the smear with the hematologist because they basically have done a smear and we're not going to wait until the morning and I kind of ballpark it.

So all you do is you basically look at the number of parasitized, the total RBCs you're doing per field.

I kind of, I, you know, it's a gross, but I normally somewhere within a couple of percentages and then the number of parasitized RBC.

So I do number of parasitized RBCs in the number of total RBCs per field.

And I do an average.

So if there's a lot, sometimes I only need to look at five fields.

Um, if, if there's not, then I look at five to 10 fields and then I average them out.

Of course, I multiply it by a hundred and I get around about percentage because I need to know how sick this patient is.

And I need to have an idea if we're talking a high parasitemia.

So we're talking that this person has a parasitemia, of greater than 4%.

So we're worried.

So high parastiemia in the absence of signs of severity is associated with an increased mortality in a non-immune individual, and I'm going to add or waning immunity.

So those individuals that I see that have been out of the endemic region for years and years and years, right?

Um, the, basically the low parasitemia, , doesn't reflect a high sequestered biomass and shouldn't reassure you.

So you have to be on top of this patient and make sure that you're getting a smear eight hours later.

So if they look sick and they have a low parasitemia and not low, low, like less than one, but not 4%.

I'm still very worried about them.

Patients can look well and if they're not treated properly, umand promptly, um, they can deteriorate very, very, uh, rapidly.

So treatment of malaria is an emergency.

It's an absolute emergency and deciding whether or not we, we want to do IV or oral is really critical for us as ID people, because we only have a window the same way we do in gram negative sepsis.

I can just, uh, provide, uh, uh, some of that, the data that you referenced there for our patient.

Uh, so the patient is, uh, as you described, diagnosed with severe Plasmodium falciparum malaria, based on confirmed parasitemia on smear with initial 2% burden and severe features, including acute anemia, metabolic acidosis, and acute kidney injury.

A repeat peripheral blood smear is obtained eight hours later and reveals an increase in parasite burden to 15%.

She remains well appearing.

What are your management recommendations for this patient?

First of all, so I think that's such a great example of how somebody like this really had a sequestered bio-mass when she first had a smear.

That initial bicarb of 16, the elevated creatinine a bit trickier.

I think, um, you have to remember that patients come in severely dehydrated with malaria.

So a lot of times we can't say anything until we hydrate them.

So I tend not to say anything until they're hydrated.

So for us, the most important thing, um, is now we've got a high parasitemia, and we've got a low bicarb and we've got a non-immune host.

So for us, she needs criteria for severe disease.

If she had had mild disease, we could have used oral, but she didn't.

And, and I just want to remind you that anywhere in Sub-Saharan Africa is considered chloroquine resistant.

So you only have three choices in non-severe disease and that's artemether / lumefantrine, which would be your number one choice.

Atovaquone proguanil, which you could use (Malarone) in non-severe disease or quinine plus doxycycline or in pregnant women, quinine plus clindamycin.

If you don't have the other two available.

So this patient meets criteria for severe disease.

So I would, especially as a fellow, I would call a lifeline.

And so your lifeline will be CDC.

And so in the middle of the night, it's always worth calling CDC.

And, um, you can either get artesunate from them or it's commercially available right now.

I just wanted to spend two seconds on severe disease in adults.

So when you look at most of your disease that you get taught in medical school, you get taught about children.

And so in Africa, the burden of disease of malaria is really seen in children under the age of five years.

And so for those individuals, we see cerebral malaria and there's a literature on this.

Um, and then acidosis.

And of course we see severe, uh, malaria anemia.

As we start moving to adulthood, and we start looking at the data coming out of Asia, where, um, malaria is not holo endemic.

So you get a lot of adults with severe disease.

We actually see yes, cerebral malaria in those individuals, um, and it acts a bit different than kids, but we see non-cardiogenic pulmonary edema more, kidney failure more, um, and so we have to be on the lookout for this as when we see an adult with malaria, I already mentioned that in pregnancy, especially the third trimester -mester uh, malaria can be more severe.

So I always get a pregnancy test on my patients.

And so this patient, , we would definitely give artesunate.

There would be no doubt that we would give artesunate.

One minute on artesunate.

In the United States, uh, IV quinidine used to be available.

But as of two years ago, um, it's no longer available.

Worldwide, artesunate is felt to be the drug of choice for, , severe disease.

Um, it's well tolerated, but the more important piece to artesunate, there were two landmark trials looking at artesunate vs IV quinidine in severe malaria and IV artesunate was superior.

And that is because it works on killing those young circulating ring stage parasites that you saw on the blood smear, which quinidine doesn't.

So there's more rapid killing and so more rapid activity.

Um, and that's important because we're going to talk about a side effect of artesunate that you have to worry about in this particular patient.

I just want to say one other thing.

I want to talk about dehydration.

These patients are very dehydrated, so as ID person, we don't normally do, um, management of fluids.

This is the one situation where I really get involved because they're hypovolemic and if you over hydrate them or really give them too much fluid, too quickly,

some people feel you can get these leaky capillaries and that you're more likely to get a non cardiogenic pulmonary edema.

So what I normally tell my, uh, house staff and my emergency room and my ICU is to basically hydrate them and bring them to euvolemia.

And at that point match their I's and O's, and I think most people feel that.

And obviously I tell them about this non-cardiogenic pulmonary edema.

And the other thing is you can get hypoglycemia, especially in somebody with poor oral intake.

So I'm always just, I just always remember that if there's a change in mental status and I make sure that we give them some glucose.

So those are some things that I do when I'm managing patients.

And then the last thing is, is that patients vomit a lot.

And so it's very important if you've chosen to go oral, which we're not doing with this patient that you watch, because some patients actually have to get IV artesunate, especially pregnant patients, because they're not tolerating orals.

So even though they don't meet criteria for severe disease.

Great.

Um, so this patient does receive IV therapy with artesunate, uh, 2.4 milligrams per kilogram, dosed Q 12 hours.

A repeat peripheral smear after the third dose demonstrates persistent 4% parasitemia, therefore therapy has continued for an additional 48 hours with daily smears until her parasite burden drops to less than 1%.

She's then transitioned to oral artemether and lumefantrine to be continued for an additional three days after discharge.

Uh, what further followup will she need upon discharge?

And how would you counsel this patient on preventive measures for future travel?

For this case, what CDC recommends is that once you started artesunate, the way to think about it is that once they're at 1% or less, you're kind of treating them as uncomplicated malaria.

That's the way to think about it.

So the most important thing in a patient like this is that, um, in non-immune travelers, there's something called delayed onset hemolysis or post artesunate delayed onset hemolysis.

And you can almost assume, and I don't know if this patient had it, you can almost assume that patients with high parasitemia are going to get it.

And the reason why is it's due to that, that clearance of the young ring stages that we talked about.

And so it rapidly kills them, but the dead parasite becomes what's called pyknotic.

And so it circulates for a while, and then it gets taken out of circulation late.

And so we started seeing delayed hemolysis due to that.

And so we'll see it in non-immune travelers with high parasitemia.

This patient is at huge risk.

So the two things that I do is yes, I see them at two weeks and I check, I normally see patients a week after, myself personally, and make sure that their labs, everything looks normal.

I educate them on symptoms of anemia.

Um, because sometimes they'll just become short of breath.

So I want to let them know to call me immediately and the way to treat it normally is to actually transfuse them.

And, uh, and then we check them at two weeks.

So the most important thing is also to educate them about that.

And this is a patient that you also want to reinforce malaria prophylaxis the next time she goes.

Um, and so for her, there are three choices of, , malaria prophylaxis and she has doxycycline, which is daily.

And then there is Malarone and that is, also daily.

The difference between doxy and Malarone is that, um, doxy just has more breakthroughs if you miss doses and also for women.

Um, there's the risk of getting, uh, vaginal candidiasis.

So I always send people with Fluconazole and of course it makes you more sun sensitive.

So you really need to emphasize sunscreen no matter what in all individuals.

And, um, and then you can get a pill esophagitis.

Some people who take it just love it and their adherent.

So it's a great drug for them.

Malarone is really well tolerated, but for longer trips can be quite expensive.

And that leaves us then with mefloquine which is weekly and great for longer trips, but important because it has a black box warning for it's CNS side effects.

It's super important before you give mefloquine and the dosing we use for treatment, we tend not to use Mefloquine because of its side effect profile for treatment.

So you're going to really emphasize to her that when she goes, she needs to listen to our pre-travel advice.

Um, great that she sought it out, but she's got to listen to it.

And, um, I think that's what I would say.

Thank you to Shilpa and Christina for joining us today and talking through this awesome case.

We are planning to have several more episodes related to fever in the summer or fever in a returning traveler.

So stay tuned for those.

Uh, don't forget to check out the website febrilepodcast.com, where you can find the Consult Notes, which are written summaries from the show with links to references, our library of ID infographics and a link to our merch store.

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Thanks for listening, stay safe.