49: Hats Off

Kruti is the ID staff physician and co-director of antibiotic stewardship at Cleveland Clinic Florida Indian River Hospital. She completed her ID fellowship at UT Southwestern Medical Center, her internship and residency at the University of Florida, and her med school education at Nova Southeastern University. She has a particular interest in general ID, HIV and opportunistic infections and antibiotic stewardship. Welcome to the show.

So if people listen to the last two episodes. Um, but today we're actually gonna talk about an interesting case that you saw on fellowship. And I'm not gonna give any spoilers yet, but we thought we would just start with a kind of a review and a reminder. Reemphasizing what we've talked about in some of the prior episodes. And that would be how to evaluate these patients who come in with a fever that have recently traveled somewhere.

And from a history standpoint, we talk a lot about symptoms and really the time period of those symptoms. How important that timeline and comparing it to incubation periods is, and then certainly all the other things we like to know. What did you do while you were traveling? Were you spelunking, were you swimming? Were you around animals, insects.

Um, and then we certainly talk about food and water consumption and then something that we also have emphasized is vaccinations and whether or not patients have had some sort of chemoprophylaxis provided before their trip. And so a couple of our last guests have included places. Or references that they point learners to when they're encountering these cases.

I thought I would start by asking if you had a favorite thing that you like to mention to everyone and any other sort of special pearls when approaching these patients.

And then of course, if these people did get their pre travel vaccinations or prophylaxis, cause that makes a huge difference. One of the websites that I really like is the CDC Travelers Health website. What's really great about it is if you go to that website and you actually can, can click down to exactly which country they may have traveled to.

And it tells you based on that country, kind of the risk factors of what they may be exposed to, and then the recommendations on if they need certain types of vaccinations or prophylaxis. So I think that's a great start to look for kind of exposure risk by country. And I know we will include that.

and I think another important thing is always kind of when you get a patient like this, that comes through your ER or to your hospital, and you get that call as that fellow on call that night, you should always ask yourself, does this patient need isolation? Because that's huge. And we always have to consider things like Ebola, severe respiratory viruses, diarrhea illnesses, and things that can actually be contagious to other patients.

So the way I approach this is if you don't know what this patient has yet, but it sounds contagious or it sounds like it's something severe, always when in doubt, just place them in isolation until you can see them. You know, if it's an overnight call until you see them the next morning, until you can get some more lab work back, until you can rule out a couple things. It's better to kind of are on that side of caution and put them in isolation.

and I know we already kind of talked a little bit about it, but you know, don't ever forget that you have to rule out malaria cuz malaria is an infectious disease emergency.

And then the family had started to notice generalized weakness, confusion, and then really progression to what was more of somnolence. Around this time he started to have fevers and weight loss. He did not have any other associated symptoms, such as headache, cough, dyspnea, rash, joint pain, or diarrhea. And so for a little background about the patient, he was born in Cameroon. Attended college in Nigeria and then returned to Cameroon to work as a missionary and a theological professor.

He has a pretty extensive travel history. Um, back in 2001, he had traveled to Mali, Senegal, Algeria, and Guinea, um, immigrated to the US. And then has had a couple trips since living in the US. So in 2013, he traveled to several countries, including back to Cameroon, Nigeria, South Africa, Ghana, the Central African Republic, and many other non-African countries. His last trip to Cameroon was in 2017.

Um, and then in November of 2018, he did have a trip in Ghana where he spent some time outdoors and mentions that he had an insect bite on his thigh. That was a little bit red, a little bit painful. Uh, he did have some weakness and fatigue around this time, which was similar to a prior episode of malaria. This improved though. He had been doing a little bit better, but then in May of 2019, he developed fever, night sweats, and weight loss.

Uh, he had been traveling at the time, continued traveling, visited Jerusalem in June of 2019. So about a month into these, uh, newer symptoms and he had a syncopal event requiring hospitalization, but we don't really have any other details available to us. He is back in the US as of July of 2019. And when he got back, he went to a local hospital for fever, weight loss, and this weakness. He had a CT scan of his chest, abdomen and pelvis, which showed diffuse lymphadenopathy.

And ultimately had a supraclavicular lymph node biopsy, but the results were benign, didn't show any evidence on malignancy. And so the patient was discharged home without really a clear diagnosis of what was going on. And unfortunately his symptoms progressed to the point where he was having nightly fevers. And this sort of ties us back to where we were talking earlier. He had been increasingly confused and weak.

He has stopped working completely and actually has been using a wheelchair to get around. He came to your hospital with this confusion, weakness, and now somnolence. When you meet him on exam, he is cachetic, he is febrile and tachycardic. He has no evidence of lymph adenopathy at this point. And his cardiac, respiratory, abdominal and skin exams were normal. And then on neurology exam, I mentioned he was, uh, slow to respond.

We have all this information about his travel, thankfully with a lot of details right now, and then these symptoms. So what are you thinking about at this point? How are you gonna approach this case?

Over in this case, I think the most important thing is his travel history is extremely important because he's been to so many places and you have to really think about where he's been and what could he have been exposed to. So by looking at his travel history, I think that that could definitely shorten our differential because the places that he's been to would point us to certain things. and then you also have to think about which infections are most prevalent in those countries.

So the way I kind of approach this is that, you know, this case would be a typical case of kind of fever of unknown origin. So this person has had fevers for many weeks now, has had a little bit of a workup, with no answer at this point and kind of going back to kind of what we think of when a patient comes in with fever of unknown origin, the most common causes are usually infectious, rheumatologic, or malignancy.

So, you know, you have to definitely think about all those things and roll these things out in these patients. So our initial differential here is, you know, obviously we considered rheumatologic and malignancy and we did run, um, certain autoimmune tests, ANA, things to look for lupus, Sjogrens disease, um, some other things.

And then our initial infectious differential was along the lines of tuberculosis, HIV, obviously, malaria, african trypanosomiasis, other endemic fungal infections, and then just other vector born infections, just because he had recalled that insect bite that he had in the past. So what we do at this point is, you know, we develop a differential in our mind. We say based on where he's been, these are the things he could have been exposed to. These are the things that he might have.

So where do we go next? And you always wanna start with kind of a basic initial workup. So that usually considers into fact things like basic labs. So obviously check blood counts, check kidney function, liver function, CBC, CMP. To rule out malaria, you always have to check those blood smears. And then based on kind of what symptoms they have, you wanna go a little bit further and you can consider imaging.

You know, if patients came in with respiratory symptoms, you would do a chest x-ray or a CT scan of the chest. and you always wanna kind of start there and go further. If they're having urinary symptoms, you can check a urinalysis, check a urine culture, check blood cultures, kind of start with your basic infectious workup. And then if they're having diarrhea symptoms, you can check a stool culture, stool ova parasites, if they had exposure in other countries.

And then if you are concerned about things like dengue, Zika, chikungunya then you can check viral serologies. Patients that always travel to other countries, there's always a risk of hepatitis A, you can do hepatitis testing and then also get further imaging based on their symptoms. So in this patient's case, you know, one of his main concerning symptoms was his confusion, his lethargy, his somnolence, you know, obviously we were concerned that something was going on neurologically.

So in his case, we did definitely get a CT scan, CT of the head, an MRI of the brain. And we got a lumbar puncture because, you know, we have to rule out neurological things in this patient.

And comparing the images there wasn't something that stood out as new or concerning for malignancy. And then as you mentioned, from a ID standpoint, the workup was quite broad. We had blood cultures, we had peripheral blood smears. We had, uh, MTB interferon gamma release, assay, syphilis screening, E BV and CMV blood PCR. We have urine Histoplasma antigen, endemic fungal antibody tests, so including Blasto[myces] and Coccioidio[ides] and then serum beta D-glucan and Cryptococcal antigen.

We had Ricketssia antibodies, West Nile virus testing, and a Lyme antibody. All of which, everything I just mentioned were negative. There was a HIV test that had a indeterminate HIV-2 antibody result, but confirmatory testing confirmed this as a false positive. Um, he also had a CD4 count, which was normal. We have the MRI and CT of the brain, which was normal. His LP was done, at this point, we're sort of on the second day of admission and the cerebral spinal fluid shows 638 nucleated cells.

And on that diff, a hundred percent lymphocytes. The cytology did not show any malignant cells. And then we'll sort of fast forward and already let you know that the CSF testing for arboviruses, VDRL, HSV, VZV and Enterovirus are all negative. So we've done all these tests and unfortunately we don't have a definitive answer here, but the patient continues to have some intermittent fevers.

Initially it was about daily and now is starting to space out, but still persistent, at least every couple days. And his somnolence seems to be worsening despite broad spectrum antimicrobial. So vancomycin, ceftriaxone, piperacillin-tazobactam, acyclovir and doxycyclin. So what's your next step here? What do you think we might be missing?

He was on doxycyclin for tickborne illnesses. And we thought at this point, you know, we really need to broaden our workup. So we looked at some of the not so common causes of the patient's symptoms. The main thing that we were really edging on here was his extensive travel history, you know, that did put him at risk for many infections that we don't typically see in the United States. And then kind of looking at his lumbar puncture.

This was the interesting part because it was definitely not normal. He had 638 nucleated cells with a hundred percent lymphocyte predominance. So there was definitely some inflammation there. And we were kind of wondering where to go from here because all of his CSF studies were negative. We decided at that point, you know, he was having these fevers, he's having weight loss and he's having scattered lymphadenopathy. He had negative biopsies of his lymph nodes.

So at this point we said, why don't we get a bone marrow biopsy and see what's going on there?

So here we have a final diagnosis of human African trypanosomiasis! Also known as African sleeping sickness, um, something that we definitely don't see commonly. So can you tell us about what you learned about human African trypanosomiasis with this case?

, we were telling them about this patient and saying, you know, we don't know what's going on, and they spent a lot of time being very thorough. So if it wasn't for the extensive evaluation they did, we may have never made this diagnosis. Human African trypanosomiasis is known as African sleeping sickness. And it's an infectious disease that's endemic to Sub-Saharan Africa. It's caused by the parasite Trypanosoma brucei, which is transmitted by a tsetse fly, which is the Glossina genus.

And most people that are exposed to the tsetse fly and to the disease usually live in rural areas and they depend on agriculture, fishing and animal husbandry and hunting. So there are two forms of the disease that are caused by a different subspecies. You have T.brucei gambiense, which is endemic to West and Central Africa. And this is usually kind of a slowly progressive disease. This is the one that's most prevalent, about 95% of cases.

These patients can be infected for kind of many months or years without any major signs of symptoms. And then when they finally have symptoms, they're usually pretty far advanced with CNS findings. So that's when you talk about things like the lethargy, the somnolence, um, all those neurological issues. And then you have T.brucei rhodesiense, which is, is endemic in Eastern and Southern Africa. This is more of an acute illness that kind of comes on over a span of weeks.

So, you know, when you're thinking about this, you have to really distinguish between the two, because the way they present is extremely different. And the most important thing about this is that this disease is considered fatal if it's left untreated. The disease usually goes through kind of two different stages. You have a hemo lymphatic stage, which is when it's in the blood followed by a meningoencephalitic stage when they actually cross the blood brain barrier.

And then once the parasites go into the blood brain barrier, you get these typical neurological symptoms like our patient had, which consists of things like mental confusion, abnormal behavior, tremors, weakness, issues with speech, they can even have seizures. And then eventually this does progress to somnolence , which is what happened to our patient.

So transmission is usually through the tsetse fly bite, but it can also be including things like mechanical transmission, accidental in the lab, and also sexual contact. Our patient had an extensive travel history. He had been ill for several months, but at that time, you know, human African trypanosomiasis was considered unlikely just because it's, it's pretty rare for us to see it here, but he did report travel to only urban areas in both Ghana and Cameroon.

So that was another thing that, where we thought, you know, he was in only in these urban areas and this is usually more prevalent in the rural areas. So that's why we didn't really think that it was possible. And you know, there's been a lot of reports saying that in those urban areas, HAT maybe eliminated. What was really interesting in this case is because it was such a complex travel history and there was so much involved. We did report this case to the WHO.

And the patient reported travel to only urban areas in Ghana and Cameroon. But we were told that the distinction between the urban and the rural areas in Mamfe, Cameroon, which is where he, where went, was kind of blurred and there has been recorded transmission in the periurban areas. So we were told that it was possible that he may have acquired this infection when he was in Mamfe, Cameroon, where, you know, even though he was in an, um, an urban area, He may have still caught it there.

What's really interesting here is that this is a very, very rare diagnosis in returning travelers. There's something called a Geosentinel Surveillance Network, which kind of monitors returning travelers and Trypanosoma brucei gambiense, human African trypanosomiasis, is very rare. There was only a single case reported amongst over 42,000 ill returning travelers between 2007 and 2011. So that tells you that this is not something that we see very often.

Are there other diagnostics that we could have used if we were highly suspicious of this?

Serological and PCR tests are unfortunately not available in the United States, but they can be performed at several reference labs outside the US. So we actually did have to send our samples to a couple of reference labs, not in the United States to confirm our diagnosis because although we did visualize the parasite on smear, we did wanna confirm it before we started appropriate treatment.

There's, there's a couple different ways that you can look at it, but usually have a multidisciplinary approach to get it done.

And we actually followed the WHO guidelines for treatment of severe disease with nifurtimox-eflornithine. And what was interesting is this was actually the first time that that combination therapy N E CT was used for treatment of meningoencephalitc stage of T brucei gambiense HAT in the United States. So we had to coordinate with the CDC and we used an investigational new drug application to obtain those medications and to give it to our patient.

And, you know, I think last time we had spoken with him during a couple follow ups, he was back to working and pretty much back to his baseline. So just amazing how quickly he got better after getting the medication. And I just wanted to also put out there that I really appreciated all the work of my co-authors, who were really, you know, instrumental in every part of this case.

Um, all of the faculty at UT Southwestern, you know, even though not everybody was able to be published on the case, we had so many people that we were running this case by people that were giving us advice, helping us with testing, just people to bounce ideas off of. And they were all just amazing in helping us with this. And then obviously also thank the CDC and the WHO who were all integral in diagnosis and treating this patient.

And, you know, what's important is in then the last 20 years, there's been a lot of concerted efforts diagnosed, treat and eliminate this. And the World Health Organization has actually targeted the interruption of transmission of this by 2030.

Um, that was one of the things that we did where, you know, when we hit a couple roadblocks or we just didn't know where to go with this, you know, we talked to other people in our group, we, you know, called people and other departments, utilized the people around you. If you don't have an answer yet, keep looking because you will find one as ID doctors. I know we always keep looking, but I think that's the most important thing. Yeah. And always kind of keep an open mind and keep reading.

Um, and I think that's kind of the most important stuff here.