Dr. Blair Bigham:
I'm Blair Bigham.
Dr. Mojola Omole:
I'm Mojola Omole. This is the CMAJ podcast.
So, today we have a case study detailing the workup of a very rare infection. The case study title is-
Dr. Blair Bigham:
No, don't give it away, Jola.
Dr. Mojola Omole:
All right.
Dr. Blair Bigham:
We're going to keep the title a secret.
Dr. Mojola Omole:
Okay. Okay, but what did you find fascinating about this article, and why you wanted to look at it?
Dr. Blair Bigham:
Well, I am a wannabe infectious disease doctor, first of all, so I find zebras weird and wonderful and interesting. This case study I thought not only was super cool, but also super timely. During the pandemic, I stopped bothering to ask about a travel history. I think most people did, but it used to be such a routine question you'd always ask, in the last 90 days, have you been out of the country? You'd always ask that. Then we just stopped asking it because no one was traveling, and it almost sounded really dumb to say, oh, have you been outside Canada? People were like, no, we're shut down. Now, everyone is ramping up their travel, they have that revenge travel, they're traveling all over the place, and of course, March break vacationers are-
Dr. Mojola Omole:
You mean mainly, you?
Dr. Blair Bigham:
Well, me. Well, I'm sorry, weren't you recently away as well, Jola?
Dr. Mojola Omole:
I went to Florida.
Dr. Blair Bigham:
Oh, so tropical and warm. Anyways, planes are shuttling people like you back to Canada now, and I thought it would be a great opportunity to refresh our memories on how to approach fever in the return traveler. But it's not just tropical destinations from far away that should pique the interest of a doc when someone comes back with a fever. Pathogens are rewriting the map.
Dr. Mojola Omole:
I think part of that is due to the climate. We call it climate change, but let's be honest, it is a climate crisis.
Dr. Blair Bigham:
Not if you're a tick, it's like opening up new real estate opportunities for you.
Dr. Mojola Omole:
Yes, and so we are having different topology of what we know infections to be. A huge part of that is due to the climate crisis, which just reminds us that everything, so many things within medicine is interconnected to planetary health and until we address that, that would make our jobs a lot harder.
Dr. Blair Bigham:
So let's zoom in from the health of the planet to the health of this one patient who came back from travel with a fever. Let's start the investigation.
Dr. Mojola Omole:
Dr. Mara Waters is the lead author on a case of a strange infection in a return traveler. She's an infectious disease fellow at the University of Toronto, and we reached her all the way in Lima, Peru today, where she's pursuing a diploma in tropical medicine. Thanks so much for joining us, Mara.
Dr. Mara Waters:
Thanks for having me.
Dr. Mojola Omole:
So tell us about this mystery. How did this patient present to the emergency department?
Dr. Mara Waters:
So this was a woman in her 60s, and she came to the emergency department with three days of fever and pain in her ankle. So, the emergency physicians consulted orthopedics, because they were worried about septic arthritis. So she was worked up in the standard way where she had a joint aspiration to look for infections that might be within the joint. But the emergency physicians and internal medicine team astutely also elicited that she had recently traveled from India, six weeks prior to coming to the emergency department.
Dr. Blair Bigham:
She had been back for six weeks?
Dr. Mara Waters:
Yes, she'd been back for six weeks.
Dr. Blair Bigham:
Oh.
Dr. Mojola Omole:
Okay, and so they did the aspiration, and then what happened?
Dr. Mara Waters:
So the aspirate showed, it didn't show frank pus, it showed some bloody fluid and that was sent to the lab to look for standard causes of septic arthritis with bacterial culture. The most common causes of septic arthritis that we see are related to skin organisms, so sometimes you can have a scratch on your skin and then the skin bugs like staph aureus or group A Strep can get in within the joint and cause infection there. So she was also empirically started on antibiotics to cover for those, but unfortunately, she continued to have fevers and pain in her ankle. So the infectious diseases team was consulted to look for broader workup of infections that might localize to the joint, as well as other infections that can cause fever when returning from travel.
Dr. Mojola Omole:
So then how did you guys figure this all out?
Dr. Mara Waters:
So, lots of serologies were sent to look for different infections, but most of those were negative, or all of them were negative, and we also made sure that she didn't have malaria, important to rule out when someone comes back from a tropical location, and that was also negative.
Dr. Mojola Omole:
What type of serologies did you send?
Dr. Mara Waters:
Serologies were sent for Brucella, which is an organism not so common in India, but it can definitely cause osteoarticular manifestations in large joints, and that was negative. We also had sent Q fever and we also sent HIV, not because it causes a septic arthritis, but just because it will really change the infectious differential. But because those were unrevealing, and she continued to have fevers, she underwent a second aspiration of the joint. This time it was not only sent to look for bacteria, but also for fungi and mycobacteria.
The main concern from the infectious diseases team was that this might be tuberculosis, because tuberculosis is a really common bone and joint disease, can really commonly happen and it wouldn't happen necessarily with recent travel, but it can be acquired and have a really long latency. So, she was from India and it may have simply reactivated by a chance at this time, but we were all very surprised when the result from the bacterial culture came because we weren't expecting this organism.
Dr. Blair Bigham:
We've kept our audience in suspense long enough.
Dr. Mojola Omole:
So what-
Dr. Blair Bigham:
What did you guys find on the culture?
Dr. Mojola Omole:
Yeah, I was going to say-.
Dr. Blair Bigham:
Oh, sorry Jola, I'm just so excited. I want to know what it was.
Dr. Mojola Omole:
This is like the nerd prom.
Dr. Mara Waters:
We get very excited about very cool things. So, this bacteria is called Burkholderia pseudomallei, and it's an organism that is mainly found in tropical areas. So most commonly from Southeast Asia, particularly Thailand and Northern Australia. Darwin has been where most of the studies have been, but our patient was from India, and it really triggered us to look into the patterns of where Burkholderia pseudomallei can be found. There's lots of evidence showing that the endemicity is changing and it's common within other parts of Southeast Asia, including India, but it's also now being found in the Americas, particularly South America, but there also have been some local cases in-
Dr. Mojola Omole:
Like Peru?
Dr. Mara Waters:
It is in Peru, yes.
Dr. Mojola Omole:
Just joking.
Dr. Mara Waters:
It's here, and in the southern states in Mississippi there was a case. So yeah, it was very exciting for us to get this result. It was a bit hard to isolate, so our standard lab techniques where we take a little piece from the culture plate and look at it in this machine called MALDI, misidentified it a little bit, but because we had this, once we saw that it was Burkholderia, we were worried about this type called pseudomallei. So we sent it to reference labs like the National Microbiology Lab, where they did PCR testing to identify it properly.
Dr. Mojola Omole:
So, you said that it can be found, you told us where it can be found in the world. How is it contracted?
Dr. Mara Waters:
Yeah, so it's not very common among travelers, though it can happen, but it's contracted. It lives in the soil, especially in moist soil, and it can live there for many years. So, it's most common among farmers or people who are working barefoot in those areas, but that could potentially be travelers. You can acquire it through a couple different ways. It's most commonly inhaled, so especially when there's lots of rain, the rain almost aerosolizes the soil, and so it can be inhaled and cause pneumonia, but it can also be acquired percutaneously just through the skin and can cause local skin lesions. Also, if you're drinking water that's contaminated with soil, it can be ingested. But in all of those possible ways of transmission, it can also then get into the bloodstream and spread to other parts of the body, which is likely how her infection got to the joint.
Dr. Mojola Omole:
What are the typical symptoms that most people could present with?
Dr. Mara Waters:
The most common would be pneumonia, that's the most common manifestation. In the lung it can also locally invade and cause lung abscesses or empyema in the pleural space, but it's very much similar to TB. It can be called a great mimicker because it can really cause abscesses anywhere. So it can go to bone and joint and cause septic arthritis or osteomyelitis. It can also go to the liver and spleen and cause abscesses there. In children, interestingly, it has a preponderance to go to the parotid glands and cause parotid abscess, so almost looking like mumps. So yeah, it can really go all over, so that's why we wanted to share this case just to think in someone who's returning from travel who has an abscess and it's not responding to the typical antibiotics or an infection hasn't been isolated, just to maybe think about melioidosis, but also other travel-related infections.
Dr. Mojola Omole:
How dangerous is this infection, since it seems to be like a bit of a mimicker like TB?
Dr. Mara Waters:
Yeah, it does cause sepsis and in some of the older data, sepsis occurs in about 20% of cases. So in Canada, likely the prognosis is still very good because we have great access to intensive care, but in places like Thailand where that access might be more limited, there is quite high mortality with this infection.
Dr. Mojola Omole:
Oh, wow.
Dr. Mara Waters:
So it can become serious, yeah.
Dr. Blair Bigham:
So if it can become... I'm an emergency doctor, so now I'm getting scared that it's not going to show up on any of my standard tests, it's not going to show up on a blood smear. How can you calm down an emerg doc now who's worried that, oh my goodness, what if I miss this? Is sepsis common or it sounds like it's often slow growing?
Dr. Mara Waters:
Yeah.
Dr. Blair Bigham:
What do emerg docs and family docs who see people at first presentation with their fever need to pick up on?
Dr. Mara Waters:
So that's a great question, and I don't want to elicit anxiety because it actually will be picked up pretty... The best test for it is to send cultures, so blood cultures and then cultures of an area with the abscess and it should grow. So why it didn't grow on the first aspirate that we did of the joint, not sure. Maybe there just wasn't enough bacteria there yet for it to grow.
Dr. Blair Bigham:
Oh, okay, okay.
Dr. Mara Waters:
You don't need to send anything special. I think the main thing is after you send the cultures, if something is growing and you don't know what it is, just call your local, friendly ID doc to help. That's I think a rule of any weird bug that you don't know what it is, but yeah, you don't need to send anything special. It was just on the backend that we got to nerd out a bit and send some extra tests.
Dr. Mojola Omole:
So because you mentioned that it has a higher mortality in places like Thailand. Is it challenging to treat or is it an access issue?
Dr. Mara Waters:
Yeah, that's also a great... It's probably a mix of both because we do need, it is resistant to some of the first, for example, we had our patient on cefazolin or Ancef, which is often a first-line agent for septic arthritis because we think it's probably from staph or strep, but Burkholderia pseudomallei is resistant to penicillins and some cephalosporins. So really, the first-line treatment is meropenem, which we wouldn't often use up front-
Dr. Blair Bigham:
Oh, wow.
Dr. Mara Waters:
... For a community-acquired infection. In other places, I don't know specifically about Thailand, but certainly access to carbapenems or broader antibiotics might be a bit more limited, but it's more difficult to treat in the sense that we need a prolonged duration of antibiotics, much longer than we normally would for septic arthritis. So for osteoarticular disease, we might treat for three or four months, if not longer. The reason for the longer duration of treatment is because there was higher rates of relapse when it was treated with shorter courses. So, that is the challenge because patients might need to be on an IV for quite a long time and need a PICC line, and we treat in combination often with Septra. So it's treatable, we have the antibiotics, but it's just a longer course.
Dr. Mojola Omole:
As an ID specialist, what was the most interesting takeaway from this for you?
Dr. Mara Waters:
The really interesting point for us when we were learning from this case was that firstly, Canada has such an amazing, diverse population with so many travelers and migrants. So it's important for us in ID to really be up to date about what infections can come from where, and to serve our population appropriately. But then what was really interesting about this was that we learned about the evolving endemicity of Burkholderia pseudomallei, because in the textbooks that we had read, India wasn't a common place. That changing endemicity, we think might be related to climate change and changes in soil from changes in climate, just given how widespread it's been noticed to be in environmental studies. So yeah, it's really interesting because geography is changing and this isn't the only infection that's being influenced by climate change. So yeah, it really does bring together the one health philosophy of thinking about where we're from and considering geography when we're making diagnoses.
Dr. Mojola Omole:
Who would've thought that ID would become the champions of planetary health?
Dr. Mara Waters:
It's all connected, and yeah.
Dr. Mojola Omole:
It is.
Dr. Mara Waters:
We love thinking about infections from animals, which is also connected. So it's just, it's all great.
Dr. Mojola Omole:
Awesome, thank you so very much for joining us today.
Dr. Mara Waters:
Thank you so much for having me.
Dr. Mojola Omole:
Dr. Mara Waters is an infectious disease fellow at the University of Toronto and one of the authors of the CMAJ case report entitled: “Melioidosis with septic arthritis in a returned traveler.” We reached her today in Lima, Peru.
We'll be back after a short break.
Dr. Blair Bigham:
The case of melioidosis is fascinating, but it's very rare and unlikely to show up in your clinic or emergency room. But with people returning from March break and with travel back in full swing, what should physicians be on the lookout for in a traveler with a fever? Dr. Jeffrey Pernica is a specialist in infectious disease and tropical medicine at McMaster University. He's also one of my favorite human beings. I trained there and he was inspirational. He joins us from Hamilton, Ontario. Jeff, thank you so much for joining us today.
Dr. Jeffrey Pernica:
Thank you for having me. I'm sure that's not true, but anyway.
Dr. Blair Bigham:
Let's talk about melioidosis. Come on, how far down the list is that for you when someone has a fever?
Dr. Jeffrey Pernica:
Oh, I mean really far down. If this was an exam, on the ID exam, if there was a stem about somebody wandering around a moist area in Thailand, I think that's a good thing to think about because rates of melioidosis in Thailand are high. But I would say for most frontline physicians, people working in the emerg, family physicians, they are not going to be seeing a lot of cases with this particular pathogen.
Dr. Blair Bigham:
So let's zoom out then and give us a refresher here because I stopped asking, have you been out of the country in the last 90 days, as an emergency doctor during the pandemic. Remind us, what is on the top of the list?
Dr. Jeffrey Pernica:
So things that really every frontline provider should be thinking about is malaria, dengue, typhoid. So malaria is number one, by far, when you're talking about undifferentiated fever in people coming from sub-Saharan Africa, there was so much malaria there. There's malaria across a lot of the rest of the warm/tropical world, but there's so much in Africa that really that needs to be thought about. Everywhere else in the warm/tropical world that's not Africa, other causes of fever will be more common than malaria. Dengue, Zika, chikungunya, are all common mosquito transmitted infections that can cause fever and other things, whether it's rash or red eyes or whatnot.
Then, because I work in the greater Toronto and Hamilton area, and there is a lot of people that go back and forth to South Asia, I think it's worthwhile thinking about typhoid. By South Asia, I mean really India, Pakistan, Bangladesh, Bhutan, Nepal. The incidence of typhoid in this region is going to be substantially higher than most other parts of the world, although you can get typhoid in South America and in Africa as well.
Dr. Blair Bigham:
So let's do those one at a time and then let's try to come up with a general workup, for someone like me who is in the clinic or the ER and I'm not an ID doc. So let's just start with malaria. How are we going to pick up malaria? What are we looking out for?
Dr. Jeffrey Pernica:
So malaria can present with fever and 16 different other symptom combinations. To keep it simple, what I would say to any physician or any patient that's been to a malaria's area, if you get fever within three months of coming back from where you were, if you weren't taking malaria prophylaxis, you need a malaria test. Regardless of how good you look, regardless of what other symptoms you have, malaria is on the list and malaria kills people. Malaria kills people quickly.
I feel like a lot of physicians have twigged the idea thanks to people like yourselves and your colleagues, that sepsis is bad. So when people show up to the emerg looking sick, they should get antibiotics fast, but the same reflex for some strange reason, is not always there for malaria and malaria can kill you just as quickly. So honestly, you've been to an area within three months, not on prophylaxis, you need a malaria screen. For those of you who aren't sure where malaria is, the Committee to Advise on Tropical Medicine and Travel, CATMAT, which is a group of the public health agency of Canada, has freely available web-based resources telling you where malaria is in every country of the world.
Dr. Blair Bigham:
What's the best test for malaria? I've identified maybe you're from somewhere with malaria, I don't have time to Google a map, but I'm just going to order the test because I'm an emerg doc and that's what I do. What's the best way to make sure that I don't miss malaria?
Dr. Jeffrey Pernica:
So I think that you will not have the choice at most hospitals that we're talking about.
Dr. Blair Bigham:
Okay.
Dr. Jeffrey Pernica:
So most hospitals in Canada are going to do a lateral flow assay, a rapid diagnostic test. Everybody knows what these look like now because COVID, it's the same deal, but with blood for malaria. It's not as sensitive as the stuff that we learned about in medical school. It's not as sensitive as a thick smear, but a thick smear requires a skilled operator and because we don't have that much malaria in Canada, there's not that many labs that have those people. So just about every hospital will do a rapid antigen test first.
Some hospitals actually will have LAMP assay. So LAMP is another kind of molecular assay similar to PCR but not PCR. There was one approved assay, and the good thing about the LAMP assay is that it's more sensitive than a rapid diagnostic test, which means that you only have to do one to rule out malaria in a traveler, in contrast to these other tests that we've all grown up with, where you really need to get multiple negatives to be sure that person is negative.
Dr. Blair Bigham:
Let's turn to dengue and other viruses like Zika and chikungunya. What are we looking at there, in terms of where it's coming from and what to order to rule in or rule out those diseases?
Dr. Jeffrey Pernica:
Those come up a lot. Okay, just because living in Eastern Canada, there are a lot of people vacationing in areas where there's tons of dengue, Zika, chikungunya, because all of these viruses basically are propagated by the same kind of mosquitoes and they're all found in similar areas and you can find those all over the Caribbean. All over the Caribbean, all over Central America, all over South America, and those places are close to Eastern Canada. So really, they are high on the list of things causing fever, rash, malaise in the average traveler.
So malaria mosquitoes tend to bite more at dusk and dawn, so if you're more careful with your insect repellent and long sleeves during those times, you can mitigate your risk, even separate from malaria prophylaxis, still important. The thing about dengue, Zika, chikungunya, is that those mosquitoes bite during the day, they bite in cities. Generally, when people are going to hot locations for vacations, they don't love wearing a whole bunch of long sleeves. So it's easy or easier to acquire those kinds of infections.
Dr. Blair Bigham:
Should I really be sending all three serologies? Am I doing IgM, IgG for all of those? Or if I miss them, is it that big of a deal? What's my threshold for sending off a whole bunch of tests that aren't going to come back on my shift?
Dr. Jeffrey Pernica:
So that is a good question, and I think what I would say is that whether serologies get sent and whether PCRs get sent, is dependent on how sick the person is and the particularities of the travel. So the one good thing about these infections is that they're all short incubation infections. So if you came back more than two weeks before you got your fever, you do not have any of these things and I wouldn't send any testing at all. This is why I think it's unrealistic to expect frontline providers to memorize everything about travel medicine. It's easy for me because this is all I talk about all day long, I don't have to know how to do operations or fix heart attacks or anything. But what providers can do is when they are seeing the patient, get details about exactly where they went and what they did and exactly when they came back, because that information will greatly assist in the generation of an appropriate differential and figure out what tests are actually needed.
Dr. Mojola Omole:
Got you. Okay, last one, typhoid.
Dr. Jeffrey Pernica:
Yeah, so typhoid. Dengue, Zika, chikungunya has this really tight incubation, malaria has this great test that you can get right away. Typhoid is really common... Or by really, one in 3000. So super common in South Asia, but common enough, and yet diagnostic testing is limited because the best, relatively easily accessible test, a blood culture, is going to be around 50% sensitive. The doctor books say that bone marrow aspirate culture is a lot better, but nobody gets that. Typhoid can present with variable incubations, and there's a whole number of different symptoms that people can present with. So it's not as... Basically, I think about typhoid when you have somebody coming back from South Asia with a prolonged febrile illness, and all of the other tests don't seem to show anything. Especially if there are vague abdominal symptoms, cytopenias, and rash, but really, it should be a consideration for anybody coming back from South Asia with a prolonged fever NYD.
Dr. Mojola Omole:
We also now know that we've been seen more cases of measles. Is there anything else that we don't really think about that is typically uncommon in certain places where people travel, that we should have on our radar, people coming back from trips, things like measles or diphtheria?
Dr. Jeffrey Pernica:
Oh God, I am not expecting to see many cases of diphtheria. Measles on the other hand, measles is totally possible just because it's like the most infectious pathogen in the world. We were already worried about seropositivity before COVID happened, and then COVID made everything worse. So I think a lot of people are very appropriately concerned about measles.
I mean, I think measles is going to be a problem. In contrast to many of the other medical problems I think we all face on a regular basis, the question of what to do about measles has a very simple and cheap answer. It's get all these unvaccinated people caught up with their vaccines. But I think we are going to be talking about measles more commonly for the foreseeable future because even if we can fix the problem in the greater Toronto area or Ontario or Canada, there are still many jurisdictions across the world where not only is anti-vax sentiment higher, but the resources are not there to be able to address under-vaccination as well as we can here.
I am sidestepping your question entirely. What other things, because you asked me, what other things do you need to think about? I think the best thing that you can do is, I think that local providers need to make sure that they are aware of all the communications from the local public health unit because I think that the local public health unit will translate the most important things for all of the physicians that are working there. That has happened to us for things like measles and invasive group A Strep, and all of these other infectious pathogens that changed the landscape for people working on the front lines.
Dr. Blair Bigham:
Awesome, this has been a blast. Thank you so much.
Dr. Jeffrey Pernica:
Oh, you're very kind. Sorry for the long rambling answers.
Dr. Mojola Omole:
No, it wasn't, it was great, thank you.
Dr. Blair Bigham:
No, no, that's okay. I'm totally nerding out here.
Dr. Jeffrey Pernica is a specialist in infectious disease and tropical medicine, and he joins us from Hamilton.
Dr. Mojola Omole:
From the Hammer.
Dr. Blair Bigham:
The Hammer.
Dr. Jeffrey Pernica:
Awesome. Love it.
Dr. Mojola Omole:
So Blair, this must have been...throughout the interview, you were very excited.
Dr. Blair Bigham:
Yeah, this is super cool. So not only is Burkholderia, which causes melioidosis, we should have asked how those two words came together. But not only is it rare and interesting, it also just was a great opportunity to have Dr. Pernica come in and just blow our minds about what we really need to be looking for. That's far more common than melioidosis, and maybe far more deadly, but this was just, I think, fascinating.
Dr. Mojola Omole:
For sure. For me, it's really important to just highlight the fact that we need to start thinking differently when a person is coming back from travel and that we have to, as you said before, go back to asking about the travel history because as climate crisis is happening, we have different presentations for different pathogens. So this was just a really good refresher regarding that.
Dr. Blair Bigham:
It lets me off the hook, I don't have to memorize all the maps because whether it's from climate change or from just migration patterns, these bugs are moving around. So instead of just saying, oh no, that location doesn't have X, Y, and Z, just get into the habit of either taking the time to pull it up on a map, go to the CDC website or another website that you trust, or just give your ID doc a call. Yes, it's probably annoying to bug them, but maybe they will find it just cool as me and Mara and Jeff.
That's it for this very cool episode of the CMAJ podcast. If you like what you heard, please give us a five-star rating wherever you get your podcasts, and share it with your networks, your colleagues, your friends, your kids, anybody who might be interested.
The CMAJ Podcast is produced for CMAJ by PodCraft Productions. Many thanks to our very cool producer Neil, even though he doesn't know who Carmen Sandiego is. Thank you so much for listening. I'm Blair Bigham.
Dr. Mojola Omole:
I'm Mojola Omole, and make sure you listen to this podcast on your next vacation. See you next time, until then, be well.