Okay. Thank you everyone for coming. I'm going to go ahead and get us started so we stay on time with our three cases. So I'm Dr. Kelly Cockett and I am an ID critical care physician from UNMC in Omaha, Nebraska. And I'm going to introduce the session and then let our expert panelists introduce themselves. And each presenter for case presentation will introduce themselves as they come up to the stage. So this is the session, in case you weren't sure. You did what where? Evaluating the critically ill febrile traveler. And with that, I'll let you guys please introduce yourselves. My name is Stella Ogake. I'm a pulmonary and critical care physician at The Ohio State University. And I'm Mike Kavanaugh. I am an ID critical care physician and residency program director at Portsmouth Naval Hospital. Hello. My name is Angel Koz. I'm pulmonary and critical care and I work at the Cleveland Clinic. All right. And with that, I'm going to let Dr. Maves come up. I will give you one warning. We did have some ARS in here. I am not sure if it's going to work correctly. So if they come up, we may be doing something on the fly while you answer your questions. Sounds good. All right. All right. Let's go ahead and get started. All right. So we're going to talk about a case of a young man with fever and hemoptysis after travel in the Pacific. My name is Ryan Maves. I'm a professor of medicine and anesthesiology in the sections of ID and critical care at Wake Forest University. I have some disclosures, none of which are relevant to this presentation. This is our QRS for the ARS, which I am 100% confident will work without a hitch. I absolutely guarantee it. All right. Okay. So brief introduction. So this patient is a 21-year-old man who resides in California. He's an active duty sailor in the U.S. Navy. He recently deployed on board a destroyer, that on the right is a destroyer, to the Western Pacific with ports calls ashore in Vietnam and northern Australia. He then spent five days in Oahu during the transit home, where he engaged in tourist activities. Shortly after getting back, two days later, after returning to San Diego, he had the onset of sore throat and malaise. He received azithromycin in an outpatient clinic for presumptive treatment of streptococcal pharyngitis. Two days later, he continues to deteriorate and comes to the emergency department at, for a number of us in the audience and Dr. Kavan on me up here, our former hospital, presenting with a fever, chills, dyspnea, headache, hemoptysis, and a rash. He's admitted to the ward, decompensates within about six hours, is intubated and transferred to the intensive care unit for ongoing care. When we examine him, he is febrile, he is normotensive, he is tachycardic. When he first hit the door in the emergency department, he was sat in 98% on ambient air, but decompensated relatively rapidly, down to 81%. He is, at the time of our evaluation, intubated and sedated. He has conjunctival injections and shoddy cervical lymphadenopathy, bilateral RALs, and the ET tube circuit, we can see some bloody sputum. He has palpable hepatosplenomegaly, and that is actually palpable, that's not like pretend palpable, like you can actually feel his spleen. He has a petechial rash, this is not his leg, but this is what it looked like on his bilateral lower extremities. He had normal white count, thrombocytopenic at 102, CPK is elevated at 1,700, creatinine is 2.2, ALT and AST and bilirubin are somewhat elevated, but not dramatically so. Because of the fever and headache preceding, he had a lumbar puncture after intubation, which showed 32 whites, lymphocyte predominant, but with normal protein and glucose, and a negative gram stain for any bacteria. This is his chest CT, it looks a little small, I appreciate, but you can see some largely peripheral, but also some central ground glass opacification, and a relatively normal mediastinum, which is not visible on this cut. So he's admitted to the unit, cultures and molecular assays for blood sputum and CSF are sent, they are pending. He received empiric IV vancomycin, ceftriaxone, and acyclovir, kind of pointed at the possible neurologic involvement. ID was consulted, which is to say that I invited myself to see the patient. Those of you who are Balboa veterans will not be surprised by this behavior on my part. All right, how did this come to be? Patient syndrome is likely a result, so we're not going to answer this now, don't answer this on the ARS yet, we'll talk about it. Likely the result of exposure to another human's genitals, animal urine, respiratory droplets from a sick person, or a renegade autoantibody. We will now discuss. All right, so first off, I'd like to know, obviously we're going to establish the standard critical care support. The antibiotics are okay, but we're probably going to modify those in just a moment. Aside from that, is there ability to get any history from a bystander or he's tubed and we have what we have at this point? What question do you have in the history? I'd love to know sexual activity on this trip, for one. As far as labs, we may be able to tweak and see if there's an HIV risk that could tweak into a little bit of things that could affect that area of the world in terms of kind of what's happening. Water exposure, clearly, any tick exposure or any other type of Aedes mosquitoes. So what sorts of things are you thinking with that differential, Dr. Cavanagh? So a lot of different things here. So if we're talking about him being HIV positive, that sore throat pattern could have been an acute HIV during that period. It would be nice to know if what his white count is. I know we wouldn't necessarily have a CD4 yet, but you can kind of cheat a little bit and get a gauge of what the lymphocytes are if he's leukopenic. Could put him into a different pattern than if he has a completely normal white count. You could see if he has a relative immunity, sorry, a relative immunocompromised condition. The swimming, fresh water, that's the urine question. Leptospirosis could cause a vasculitis of the lungs that could be, kind of put some of these things together. Other things, the tick exposure, nothing really except for the fact that, well, two-fold, you see the petechial rash. So you have both spotted fever group and scrub typhus group. In that area of the world, there's a lot of scrub typhus there, possibility. And then with the Aedes mosquito dengue, which doesn't necessarily do this, but if you end up with a dengue pleural effusion, that could potentially do so. And he doesn't have any pleural effusions on his GSC-T, by the way. Okay. Okay. I agree. And just as a side note, he was in Southeast Asia about a month ago, right? So if incubation period plays a role into your considerations here. So a little quick on some of those things. A little, little quick. A little quick on some and a little long on others. Yeah, yeah. And in terms of sexual contact, he did have protected intercourse with a heterosexual partner. He was never that, in his post-extubation course on further history, never admitted to paying for sex or to contact with commercial sex workers and no reported MSM behavior. And an HIV screening ELISA was negative. This case actually slightly predates the antigen antibody fourth-gen testing. I think just additional things that might have relevance is, is he taking any anticoagulation? Did he have any low extremity swelling from travel? Does he have any history of DVT? Any other family history that predisposes him to bleeding conditions? Yeah, so no anticoagulants. So just as a side, and just for a general perspective, being on aspirin, of course, would be acceptable. But being on, say, a Pixivan or Warfarin would preclude him from deploying at sea. And no known family history of sudden death or venous thromboembolism. Aside from the infectious, which is the top of the differential, I think we also have to probably think about non-infectious etiologies, like, I mean, he has thrombocytopenia, he has renal failure. We have to think about TTP as a potential, although that could be caused by some of these entities as well. And then just, I mean, just thinking inside the box, just thinking about the common things, like, I know he has the travel exposure, but, I mean, he has a pattern of round glass opacities on the CAT scan. It could be just a run-of-the-mill pneumonia. But I agree that the empiric coverage probably should change if we are suspecting some of these Ricketts or tick-borne diseases should need to include a tetracycline. Yeah. No, absolutely. That's great. Any questions from the crowd before I jump into the discussion so we stay on schedule? I'm going to just add one more thing. Yes, sir. Are we going to let the crowd go first? No, no, no. The other thing, too, is certain areas of the world, and it depends on what year this case was happening, are going to have a high multidrug-resistant risk. So particularly there, a lot of it has to do with the kind of excessively easy access to antibiotics. So you probably need to upgrade your ceftriaxone. Even though we, to potentially a cefepime or a ceftazidime-level meropenem, if we're thinking like meleodosis or something along those lines. Yeah. Excellent. Sir, please. I'm just curious if there were any other sick contacts in his… Just him. …that went, or in the family when he came back, anybody else? No, just him. And that's actually a great point. You know, the birthing on a destroyer for an enlisted sailor is, you know, on the low end for people in a bay, and it's usually more like 12, and he is the only one who is sick. All right. Any family history of vasculitis or any type of diseases like that? No. And the question was, was there any family history of vasculitis or other related autoimmune diseases? No. All right. All right. Okay. So, we'll do our poll now. I'm strangely excited. I really want to see how this goes. What is a renegade autoantibody? You know, like a vasculitis or something. Like an anka. Yeah, that's true. Renegade. They're like, you're not. Yeah. All right. All right. Animal urine is the winner. 7% for another human's genitals, though. Brothers and sisters never change. All right. That's a good spread. OK. So this guy has lepto. All right. So this guy has leptospirosis. So this is a Hawaii-centric talk in honor of our hosts here. So this is a zoonotic disease of global importance. There are estimated about five cases per 100,000 people per year. Exposures via infected animal urine. Mammals will shed leptospires in their urine, and then will infect other mammals, including us, via skin breaks, via mucosa, and via the conjunctiva. It's actually a fairly common portal of entry, particularly in swimmers. Rodents are the main reservoir, but dogs, pigs, and cattle also matter. There is a broad differential here. And part of the challenge in many this tropical and travel-associated diseases is that our diagnostics lag. And we have to make decisions in advance of having a formal diagnosis. So this gentleman did not actually have any particularly compelling risk factors for malaria. But a returning traveler, we have to exclude malaria through whatever pathway we have. Dengue, Zika, chikungunya, all clinically can resemble this very markedly, especially when severe. Yellow fever. There's no yellow fever in Asia. There's no yellow fever in the middle of the Pacific. So we can remove that. But the syndrome would be not unlike this. And other arboviruses as well, and we are discovering more of these on a regular basis. Typhoid, viral hemorrhagic fevers. Again, his exposure history is incompatible. In the incubation period, even if he had been in a VHF endemic area, it had been a month since he'd been there. That's on the outside for VHF. And rickettsiosis, in this lab pattern of relative leukopenia, thrombocytopenia, low-grade LFT abnormalities, is what an ID will sort of jokingly refer to as a doxycycline deficiency disease. I know it's not a good joke, but we are what we are. It's a true story, though. And this counts. And this counts. All right, so there is a high prevalence of this disease in resource-limited tropical regions. You see up to 25% zero conversion in some hyperendemic areas. And I'll show you a picture of one of them. Occupational exposures are common. Farming, agriculture, work with animals, close contact with infected animals, and then tourism. So for a lot of us, when we see lepto, it's going to be associated with people who are swimming in waterfalls, who go on river rafting. Sometimes some of these triathlete things through mud and splashing around is actually a fairly common way we'll see small leptospirosis outbreaks. Age, comorbidities, immune factors. And this is interesting, that some of the risk factors for severe disease have more to do with host HLA typing than they do with the pathogen itself. And the HLA-DQ6 is one that's been specifically associated with the risk of severe disease. So this is where the gentleman in question went swimming. That is here on this island. And this is the sign next to the trail that gets you to that swimming hole. So anyways, all right. Now lepto in Hawaii, lepto is endemic here. And those signs are there for a reason. There are about 30 confirmed cases per year, recognizing that there are a lot of things that are more common rather than less common. Severe cases are more likely to be diagnosed. Milder cases are generally undiagnosed. The true number is likely much higher than that. A lot of them, or 80% of them, are due to outdoor recreational activities, or actually taro farming, which is particularly common in native Hawaiian communities, also with fishpond fishing as well. And this has a lot to do with efforts to increase food security and food sovereignty here in the Hawaiian islands. It's biphasic illness. Most cases are pretty mild, fever, headache, and myalgia. One of the distinctive features that if you were to see a patient like this with relatively mild disease is relatively severe lumbar and calf pain, like bad lumbar and calf pain. And that is one of the more sort of, like severe myalgia is not that common in infections. Flu, lepto, a couple other things. Bartonella do that, COVID. Conjunctival subfusion is another key feature. The meningitis is actually sterile meningitis. It's just antibody mediated. There is actually a little bit of a renegade autoantibody in there. So those people who selected that, you were right. Asymptomatic seroconversion is seen in highly endemic areas. There are two forms of severe disease. Wild syndrome, which is the thing most of you have heard of, that's ecteric leptospirosis. The key for that when you see it is a disproportionate elevation of bilirubin over transaminases. So your ALT will be up a bit. It'll be 200, 300. But your bili will be 20. That disproportionate elevation is one of the key features. This is a severe multi-system disease with non-oligarchic AKI, myocarditis, and severe hepatitis. Mortality for this can be quite high, greater than 10%. What this gentleman had, unfortunately, was severe pulmonary hemorrhage syndrome. You'll notice that his LFTs were not that dramatic as bilirubin was about to. But you see immune deposition on pathology, which is actually, histopathologically, looks very much like Goodpasture syndrome with evidence of some antigen antibody complex deposition, as well as kind of chunks of dead spirochetes. It's pretty hard to isolate leptospira directly from the lungs of people with this, but a potentially very high case fatality rate. This is Belen. Belen is a district of Iquitos in Peru. This is the dry season. You'll notice a lot of these buildings are on stilts when it's the wet season. This is actually floating out in the middle of the Amazon. This is one of these hyper-endemic areas. A lot of rodents, a lot of dogs, relatively limited sanitation operations. About 25% of people seroconvert to lepto per year here. Diagnosis is hard, right? Microscopic agglutination testing is the diagnostic old standard. It's a serologic test. This is only performed at reference laboratories. It is very time-consuming and often is negative at the time of acute presentation. You can get PCR off of blood and urine. We tried in this guy. Didn't work. There are a number of screening ELISAs, but again, you have to get confirmation. And there are easily 100 potentially pathogenic serovars, which make ELISA testing relatively challenging. Ceftriaxone and ibupenicillin are roughly equivalent for treatment of severe disease. Doxy is acceptable for mild or improving disease. Adding doxy to this guy's regimen while he's being worked up, though, would be 100% appropriate. Current data do not support the use of steroids in SPHS, unlike other kind of causes of diffuse alveolar hemorrhage. Doxy and azithro might be effective for prophylaxis. And I actually kind of wonder if the person who gave him azithro in clinic for pharyngitis might have been like the hand of God and may have accidentally saved his life. So hard to know. So we sent PCR and serology. He got better fast, extubated after 48 hours, discharged in hospital day seven, prescribed doxy to complete 14 days of therapy. We did get convalescence here, which was positive for leptospira interrigans, serovar copenhagiae, which is one of the more commonly described and is well-described here on Oahu. And he ultimately made a full recovery. Thank you. Any questions? Yes, ma'am. Could you come up to the mic? Hello. My name is Julia Mohamed. I am one of the residents from internal medicine at Nazareth Hospital in Philadelphia. Welcome. I'm just interested because we had a similar case. But it was like with a prolonged stay, end up in dialysis. Anything happen with this guy in terms of renal recovery? He actually recovered pretty well. He recovered pretty well. You know, you always wonder a little bit in people who have sepsis. And this is essentially sepsis induced AKI, right? If there is, even if you see if their creatinine normalizes, is there some residual subclinical CKD that won't appear till later in life? But yeah, he actually bounced back beautifully. It's good to be 21, I think is the take-home answer. But you know, Philly, it's interesting. There have been reported cases of what we'll call urban leptospirosis in the United States. Joe Vanetz, who's currently at Yale. Joe was at UCSD for a long time and is one of the world's great leptospirologists. Joe started his career when he was finding an outbreak of lepto among commercial sex workers in alleyways in Baltimore. And there's pictures of Joe running around like trapping rats in the alleyways and finding that people living in sort of, shall we say, marginal housing situations can acquire lepto in US cities. So it does happen. I just needed to add something in regards to the case we had, because it was similar. And since it's a rare disease and it's very difficult to diagnose. I'm from Albania, where lepto is usually endemic and we have a lot of cases. And it was like, considered something out of usual to ask for a lepto testing for a patient who had almost similar. His form was more like a whale disease form with more ictus, severe renal dysfunction. And initially, we were thinking it could be a TTP case with neurological manifestations. And we asked for an ADEMTS. Which presumably is still pending and will come back to your grandchildren. It actually came back as abnormal. And I've seen in literature being mentioned. Yeah, and that's a good point, that a lot of this is immune mediated and you will find some abnormal immunologic markers that might lead us a bit astray in the workup of these folks. Thank you very much. Thank you for sharing your case. All right, thank you very much. I'll turn it over to Dr. Harris. Hi, everyone. I am Gavin Harris. I am also an infectious diseases and critical care physician coming from Emory University in Atlanta. Unlike Dr. Mabes, I have nothing to disclose. You did not. All right, so let's get started. So let's meet our patient. So we have a 61-year-old man presenting with one week of fever, intractable nausea, and vomiting. He's a returning traveler from South America to Texas, which is where he is from. And his story goes like this. So he traveled to Argentina in early September to visit his family. At the time, he spent some time in urban and rural areas. He went hiking in the foothills for several days, felt completely well during the trip, ate local food, slept in various structures while he was hiking, including shelters, tents, and the like. Then returned home to Texas after about three weeks, but approximately three days after arrival, began to have some nonspecific symptoms, went to urgent care, was tested for the usual things, was negative, and was sent home for continued supportive care. However, he got worse, had continued fevers, nausea, abdominal pain, and also developed a mild truncal rash. Has a little bit of hypertension and hyperlipidemia, not really any other relevant medical history nor social history as well. He does live in Austin, Texas, and he supervises various sites for which he has to travel to. So after this time, he arrived in the emergency room. His vitals were a bit tachycardic, a little bit on the low side for his blood pressure, mildly tachypneic, a bit of hypoxia as well, and he was febrile. He looked quite ill at the time, was reporting significant nausea and abdominal pain, and his exam was notable for some dry mucous membranes, diminished breath sounds, diffusely tender abdomen, and a petechial rash specifically on his trunk and on his neck. Initial labs are as follows. A bit of a leukocytosis with a neutrophilic predominance. He had some anemia as well as thrombocytopenia. As you can see, he has some electrolyte abnormalities as well as an AKI, some LFT elevations as well, and this was his initial chest X-ray. So he continued, unfortunately, to have worsening respiratory distress. They retested him for the usual things that were negative. They took blood cultures, started on some antibiotics. He was admitted to the hospital. His CT chest was done on day two of admission, which showed bilateral lower lobe ground-glass opacities, and then he interestingly developed significant blurred vision and periorbital edema, along with worsening RAILs on day three. At that time, these were his labs. So he had a worsening leukocytosis, a worsening thrombocytopenia, AKI, among other things. He became unstable, was transferred to the ICU, intubated, and then placed on high-dose steroids after they saw this chest X-ray. So unfortunately, Dr. Maves used up our quota for a working ARS question for this talk. But I'm gonna pause here and let our panelists discuss the case as well. I just realized how much we like the part where the professors get to talk at the end because we breathe. Now we'll get back to business. I'm gonna start with if we can have a few questions on exposures. So kind of the usual suspect, sick contacts. Big one here would be animal exposures, but we'll stay with water. I can't expect you to give me two leptos in a row, but who knows? Sure. And where in Argentina specifically? And you said some rural, but did he go up towards the Amazon or more lower? So a bit more lower towards Aconcagua in the foothills of the mountains there. He did not have known animal exposures. And he did have several sick contacts who had similar gastrointestinal symptoms. Several sick contacts. And then the location, was he eating with family, visiting friends and relatives type of situation off the local or? Yes, so he was eating local food, visiting with family and relatives who also lived there. Did he take any prophylaxis, like malaria prophylaxis when he went there? And also did he get any vaccinations like yellow fever vaccination? Great question. So a question about prophylaxis and vaccinations. So he did have yellow fever vaccination. He did not take malaria prophylaxis. Was the yellow fever vaccines long enough before his? Yes, they were appropriately timed. Great question. Vaccinations were appropriately timed. All right. So just a few thoughts on this. When I see the white count, it actually threw me off of what I was initially thinking. I was thinking low white count with platelets, low being more viral rickettsial, but the high eating off the local economy, eating like with, makes me think possibly something enteric. So I think of like a typhoid or something along those lines, salmonella enterica typhi, because that would cause the high white. Be kind of weird for that pattern. I mean, that's almost like, again, not a perfect fitting thing, but the animal exposure in this hemisphere, Hanta could cause a Hanta pulmonary syndrome, which could give you that like serious ARDS type of pattern, probably more likely gonna be, again, a low white count than a high with that. I know I'm talking all over the place here. The northern part of Argentina is really the only part that's malarial. So it doesn't sound like he was up by the Amazon. So that would be a little less likely. Dengue is always a player and that could be a dengue x-ray, dengue thrombocytopenia, but really weird to see that type of a white count unless he had a secondary infection from something bacterial on top of it. I mean, could he have gotten dengue and now making up stuff a little bit, but could he have gotten dengue and then with the kind of the sloughing got a secondary bacterial infection, but not a lot purely fits that high white count with this. Like I say, enteric fever, typhoid, fits a lot of it, but doesn't really fit that. Yeah, the first thing that came to my mind when I was seeing in the previous x-ray, I saw there was some hint of an effusion that made me think mostly of dengue and then with all the history of GI stuff, that typhoid fever, which is fairly common. Any exposure to eating unpasteurized milk? Great question. Question about eating unpasteurized milk, the answer is no. Okay, because that's also a risk factor for brucella, which can present sometimes in a similar fashion as typhoid fever. Then thinking outside the infectious pathologies, I mean, this could be a pulmonary renal syndrome with thrombocytopenia, again, TTP, also there in the differential. I mean, it could be an autoimmune thrombocytopenia, but then this wouldn't fit unless it's a superimposed infection or a superimposed diffused alveolar hemorrhage. And again, vasculitis could definitely fit a picture like this. So, ankyl vasculitis, microscopic polyangiitis especially, or any of the other ones. Yeah, the other thing I was thinking about, like with the enteric symptoms, like was one of the entero-toxigenic, or entero-invasive, or enterohemorrhagic E. coli, because sometimes patients can have like just GI symptoms causing sepsis, which leads to ARDS, rather than like an exposure into your lungs that causes ARDS. So, I wonder if that might be going on, yeah. Very good point. And then going back to yours about brucella, is Q fever, coxiella, which you don't necessarily have to ingest. A lot more of that is from the aerosolization of kind of the animal exposure, which, if they're in a rural area, that could cause the imaging. Absolutely, great. Any questions from the audience? I don't know how it is. Thank you, it makes a lot of sense. I'll ask a question real quick. Steve Simpson, University of Kansas. I don't think you gave a differential on the white count, if I'm not mistaken, but I'm curious to know. I'm sorry, say that again. I said, I don't believe I saw a differential on the white count. So, we had a neutrophilic predominance, that's all it was given out. Neutrophil predominance accompanied by either atypical lymphocytes or immunoblasts. Are you asking me? I'm asking you, unless that's what's coming up. Right, so no, so there were significant immunoblasts with the differential, yes. Great question. All right, so any other specific test you all would want to send? You're in Legionella. Legionella, okay. Dengue, Zika, Chikungunya, and even though we kind of said it's not really malarial area, absolutely take malaria off the table. I agree, dengue, malaria, and then for the enterobacteria that we discussed, and then also the RITP and TDP. All right, fantastic. So, let's keep going in the interest of time. So, additionally, tests at the time were sent. Lyme or leukiosis malaria was negative. Dengue serology was negative. They also sent acute EBV, CMV, HIV, hepatitis screens. They were all negative. Blood cultures also remained negative. And then, a very astute person, it was already mentioned, though, sent antivirus serologies on day eight of admission, and these ended up becoming positive. So, this is actually a case of hantavirus pulmonary syndrome, a bit of an atypical case, as Dr. Cavanaugh already discussed. I'm gonna talk about three things. So, a brief overview first of hantaviruses. So, these are viruses that are of the order bunyaviridae, which also include things like arena viruses, such as loss of fever, narrow viruses of Crimean-Congo hemorrhagic fever, families that cause hemorrhagic fevers. They are tri-segmental RNA envelope viruses, and this is important in our infection prevention measures and also how we treat them. There's two main classes. There are new world hantaviruses, which we have in the Americas. They cause hantavirus pulmonary syndrome. We also have old world hantaviruses, which are mostly found in Europe and Asia, and they cause hemorrhagic fever with renal syndrome. Oh, and I should say, too, there are about 20 known species of hantaviruses as of yet, but that number continues to grow. In the United States, the most common vector you can see up on the screen is the deer mouse. This was responsible for the 1993 Four Corners outbreak of hantavirus. This virus, or all hantaviruses, are typically airborne, and so the transmission is via inhalation through exposure to rodent bodily fluids, urine, excreta, saliva, over a significant period of time. So, for our patient who stayed in shelters when he was hiking, it is presumed that he had significant exposure through this route. But we also have the Andes virus in South America, and this is a very important hantavirus. This is the causative agent that really causes most episodes of hantavirus outbreaks in South America, specifically Patagonia. There's been over 1,200 cases that have been confirmed in Argentina alone. Vectors and reservoirs are likely the same, but it has a very high mortality rate of almost 50%, and it's the only known hantavirus to possess the ability to transmit person to person. And this comes during the prodromal phase, so during that very nonspecific phase. So, for our patient who had exposure to contacts with also gastrointestinal symptoms, it is presumed that he may also have acquired it through those means. We have a clinical case definition that's defined by the CDC, as you can see on the screen. Bilateral diffuse interstitial edema resembling ARDS is very common. Mostly these are in previously healthy persons. So, hantavirus pulmonary syndrome is the most severe manifestation of hantavirus disease. Of the 20 species, about half of them are known to cause this disease. Synnombre virus and also Andes virus are the two most common accomplices here. So, the prodromal phase, as you can see, nonspecific symptoms. Andes virus can also present with conjunctivitis, facial erythema, petechiae, which is not common amongst any other hantaviruses that we know of. The hantavirus pulmonary syndrome is also known as hantavirus cardiopulmonary syndrome because there is a cardiopulmonary phase that can last for about a week or more, which is associated with ARDS and can rapidly progress into multiple forms of shock. There's also a convalescent phase if people make it here. And this can also be extremely rapid as well. This is the time course that has since been described. As you can see, thrombocytopenia really runs throughout the entire course as the significant elevations in AST and LDH. Some pearls. It's very challenging to diagnose. There is a diagnostic triad, and I'm so happy that one of our audience members asked this question too. So, immunoblasts are very characteristic when we get a differential for hantavirus pulmonary syndrome. Thrombocytopenia is very common, but its presence alone does not distinguish who may or may not develop severe disease. But there also is a left shift. There's no FDA-approved test for it. Serologies are often commonly used because they're mostly accessible. PCR is possible. Not every place can do it. And it is a nationally reportable illness. How do we manage it? Well, good supportive critical care, honestly, and the ability to identify, isolate, and inform the appropriate authorities. So, droplet and contact precautions, preferably in an airborne isolation room. As I mentioned, good supportive critical care. And then ECMO has been described quite frequently, especially in cases of Andy's virus, about hantavirus pulmonary syndrome. It's mostly VA ECMO for those who have decreased cardiac output and indices. Even with the use of ECMO, about 50% of patients will succumb, unfortunately. Do we have targeted therapies for it? Not really. We're working on it, though. Ribavirin, which interrupts RNA metabolism, has been shown to be effective against old-world hantaviruses. It's also been used against Andy's virus and Sin Nombre virus in vitro. But these are very small studies. There's talk about using it as post-exposure prophylaxis, as well. We do have monoclonal antibodies, which may be most important against just about all viral hemorrhagic fevers. And what's interesting here is that, for the ARDS picture, steroids have not yet been proven to be effective. But this is a very small study, as you can see, 60 patients, and this is considered the, quote, gold standard study that was done. But it showed no difference in mortality. What about vaccines, preventatives? Well, what's interesting is we're not sure if vaccines have a place here, honestly, because at the time of presentation, most patients have a very robust antibody response, which is why serologies are so effective in diagnosis. There are a few vaccines that exist in China and South Korea for old-world hantaviruses, but they are very expensive and they cause significant reactions. So that is really it. Any questions? All right, well, thank you. I'm gonna turn it back over to Dr. Cockett. All right, so moving on with our cases, I introduced myself at the beginning. I am your third cleanup crew case of an ID critical care doc presenting another case for you guys. And we are gonna start with this. So we have a 52-year-old Northern Australian-born woman on an extended visit to family in the U.S. who has presented to a local critical access hospital, because I'm echoing on what shows up in an ICU when I see critical access hospital patients transferred to our center. And she presented with progressive fever, night sweats, and a 25-pound weight loss and cough. She reports she started coughing and having some intermittent fevers and some night sweats about three months ago, but she was actually attributing a lot of her symptoms with the fevers and night sweats to menopause. So really didn't think much of it, didn't really think a lot about the cough, so had not sought any care thus far. She has a past medical history significant for type two diabetes, chronic kidney disease stage three, and hypertension, all attributed to late diagnosis of diabetes. Her only medications actually at this point are metformin and lisinopril. Social history, rare alcohol use. She has a history of tobacco use as outlined there, but did quit five years ago. She is an indigenous Australian in a monogamous relationship with her husband, has two healthy adult children, and is currently staying with one whom she's visiting in the U.S. She has worked as a public health nurse and participates in contact tracing, but has no known direct exposures in which she was not in PPE during any contact tracing. Her hobbies include hiking, gardening in her backyard, and in a community garden, and traveling with her family, and she's traveled extensively on various commercial tourism trips throughout the world. Her vital signs on presentation, she is febrile to 101.2 Fahrenheit. Her heart rate is 117, blood pressure is 110 over 69, and respiratory rate 28. Her body mass index is 12. On exam, she appears frail and cachectic, but otherwise alert and appropriate. She's tachycardic with no other abnormalities on cardiac exam. She's tachypneic and does appear in some moderate respiratory distress during the interview, and had some decreased breath sounds on the upper right lung field. She had no other noted pertinent exam findings in this initial hospitalization. She was admitted to the ICU because of her respiratory status and appearing more toxic looking because of that for monitoring in this critical access hospital. Labs, hemoglobin is 8.7, CRP 25, sodium 130, albumin 2.4. Blood cultures are drawn and pending. No sputum culture due to nonproductive cough. They do have access to chest x-ray, but not to CT scan in this facility, and this is the image that is sent over. And the call comes in from the hospital saying, we need help, we need pulmonary, we need ID, and we don't know what to do. We should transfer. And I'm gonna end my case there and hand it over to our lovely panelists on your thoughts. Okay, I'll go first this time. So first thing that comes to my mind with the risk exposure at work and the presentation and the x-rays, tuberculosis, then along the same lines, things that could look like that could be, I mean, no cardiac or athenomyosis, any history of poor dentition or any history of immunosuppression that we know of. No immunosuppression known outside of diabetes, which is reasonably well-controlled per her report on metformin, and no other dental complaints or nothing noted on exam. Any history of smoking? Yes, I can go back to that slide for you right here. Two packs per day for 15 years, quit 15 years ago. I'm sorry, five years ago. Because also a lung mass that has superimposed and has an abscess, which we cannot potentially appreciate here, could give similar symptoms and look like that. And then from the non-infectious things, I mean, cavitary lung disease that could present like this is Wagoner's as well, though it's not typical, but also lung cancer with a superimposed infection. So those will be my initial thoughts. Yeah, I agree. What came to mind was TB, cancer, and then something that I read as I was preparing for this that's common in Australia, something called myeloidosis, which is caused by baculoviria pseudomyelitis. So, but I think patients are sicker than they are, so I wonder if that could be it. The other thing I was thinking about is, I mean, even though, I mean, she does contact tracing and she says no exposure, but there's a possibility that she had exposure and then other things could be like non-TB mycobacteria. And then she does gardening, so I wonder what she gets exposed to as she does gardening in this area. So the timeframe is the interesting thing on the travel here. She's been here a long time. So I'd say, look for standard American things first, which I'm sure you did, which would be a standard respiratory viral panel. With the hyponatremia, I would look for Legionella, your standard things. But I fully agree with the myeloidosis piece. So Vietnam, South and Southeast Asia, as well as Northern Australia are classic for it. And why that one fits here is because of the reactivation piece. The fact that you've been gone for a few months, different than a shorter incubation period. They used to call this the, I'm gonna misname it, but it was like the Vietnam time bomb. And it was American soldiers came back and a lot of them got sick in a much different, like later timeframe where they just reactivated. So the reactivation would fit that TB absolutely, non-tuberculous mycobacterium and then non-infectious things too. Other questions or thoughts from the audience? She was ultimately screened and was a negative for HIV. I will tell you for patients such as this coming from critical access hospitals and transfer, they have very few of these tests available. So all the broad testing comes upon arrival to the higher level facilities, but ultimately those things done a negative, yes. She's lost about 25 pounds in the last three months. So she was thin to start. Mm-hmm, yep. Yep, they had gone through tuberculosis screening in the past and she had not been noted to be positive in the past. It's a great question though with what we're discussing. Mm-hmm. No, other than just her feeling tired, she's not had any cognitive things that she or her family members that she's living with while visiting here have noticed. And no headache or other symptoms from that specific or ocular symptoms. Is there something in particular? To be honest. I'm from Australia. Oh, yeah, I love this. Excellent, all right. I was in Territory for a year when I was an intern. I'd say malleodosis would be the cause of this lady. She's diabetic. She's probably been exposed to the wet season in her backyard, sort of gardening. So I think chronic malleodosis would be number one or TB clinically. Thank you. No, and maybe you can answer the question because I will be honest, the BCG vaccine was not something in the history that came up. To be honest, I'm not aware of that, but I can't speak to it in full knowledge. So there's an interesting discussion happening up here. I just want to share their discussion with you guys. So one of the things we were just talking about is, so BCG doesn't necessarily prevent you from getting TB. BCG prevents you from getting TB meningitis, and BCG prevents you from dying from TB. Or it doesn't prevent you, but it decreases your mortality risk and your risk of TB meningitis, but not necessarily that you can't get pulmonary TB. And you can know just by looking at the arm. Usually you can see the scar there. There was also a little conversation up here about the BMI question. So maybe, I know since that was a question that was raised or a comment at least from the audience, thoughts on her BMI of 12? Yeah, I mean, it seems rather low, but it seems like she potentially had, was, I mean, low weight to begin with, which may be something even more chronic, so. And that makes me wonder if she's immunosuppressed to begin with. So does she have, is she malnourished? Does she have just like severe protein color malnutrition, which makes her immunosuppressed? And I'm going to, I'm sorry, I'm clicking on, only because I want to make sure we have time. But yes, the malnourishment, those questions. So thinking about it. So absolutely, meliodosis is what we're talking about here today. And I want to touch on a few things about this, and I'm not going to go back to the case for some very specific reasons as we go through this education part that we're finishing up with. So facultative oxidase positive gram-negative bacillus, Burkholderia pseudomallei, which was brought up. Now, this is really important if you think about being an oxidase positive gram-negative bacillus in a facility that may or may not have molecular testing for identification of bacteria. It may also be important even if they do, and I will touch on that further. This is an environmental pathogen that is really very widely spread in soil and fresh water. And unfortunately, frequently, it's been very ethnically defined in board questions. So often, this idea of rice paddies, some of the gardening landscaping, but really in endemic areas. And again, as was just noted, particularly in wet season or severe weather, also where there's a lot of water and earth disruption. Contracted in multiple ways. So this can be inoculation, inhalation, or ingestion, but it is rare for human-to-human transmission. So you do not tend to see outbreaks in the classic sense of people-to-people, but it could be exposure transmission where you have an outbreak where everyone is exposed at the same time. Key risk factors were also highlighted. With diabetes, chronic kidney disease really coming out in the literature as being very significant components. Chronic lung disease, this woman had never had PFTs, but didn't have any obvious blubs or anything on CT to necessarily say she had underlying COPD. Heavy alcohol use, also a significant concern. And interestingly, in the literature, there has been some back and forth on whether or not this is actually truly worse in immunosuppressed patients. So still not enough data to really define that consistently and with the clarity all the time that we might like. Now, I talked about the fact that this has been on board exams and many of the, at least American study guides, really giving very distinct areas of the world, Southeast Asia, Northern Australia, and then not as much. So this is a 2019 map showing some case presentations and impact of that. What I will tell you is in 2022, the Gulf Coast of the United States was found to be endemic with melioidosis. So at this point, it does not really matter where you are from. And if you actually look at the data and the calls to action, it is considered a extraordinarily high global burden disease neglected to the point that it is neglected from the WHO neglected diseases list of global burden, despite the fact that there are way more people impacted by this than many of the diseases on that neglected list. So this is something that could show up anywhere at any time and might be very hard to recognize if we still have kind of premature closure on where these diseases can be acquired. So this was one of the outbreaks also that came up. There's actually another patient that I believe was from Georgia that this was updated with. So there was a non-travel associated outbreak related to aromatherapy sprays that were originally from India and then were used in the United States with multiple patients, including patients who died from this outbreak. So again, how is something created? Where is it from? And understanding the fastidious nature of something that can live in water of something that can live in wet plant, earth, environmental things, and the sterility of those. Also really important that in many areas of the world, this is really considered a great mimicker. It can look like anything. So this can absolutely present with acute meliodosis, with catastrophic septic shock, with all of the multi-organ failure that you would expect of any other gram-negative bacteria causing a bacteremia. However, you also have this latent focus of infection, which can reactivate much like TB, much like other endemic fungal infections like histoplasmosis, and you can see it present years later. You also can have a more chronic component of infection, which really is a little bit more fitting for what this patient presented with, in which you have the weeks to more likely months of slow decline with a cavitary lung lesion, which can certainly look like many of the things we talked about, including cancer, tuberculosis. And I think this is really important to understand because of the broad spectrum of disease that meliodosis can present with that any of us could see and perhaps not recognize appropriately. And why do I say we can't recognize it appropriately? So it's really key that you stay suspicious if a patient is not improving. It does grow well on most culture media, which is why I did not give you culture data in this case to start with, but it's often misidentified. And it is misidentified as a Pseudomonas species. It could be misidentified as another Burkholderia, Acinetobacter, Sphingomonas, and actually multiple others. And in some labs, if you only rely on the gram stain, this has been considered normal flora and falls up under the sputum culture as normal flora only. So you could completely miss a positive culture appropriate for this. It has also failed high level detection, such as use of MALDI-TOF, where it has been misidentified. And this really matters based on how you choose to treat your patient. So one of the keys, if you do get a gram negative bacteria and it is a Pseudomonas or it is a Sphingomonas and it looks really drug resistant and you haven't asked travel history questions or water environmental exposure questions, it is something that should actually make you pause, especially if there are several cases and it really does not match your organizational antibiogram. And if you don't know what your organizational antibiogram is from the ID critical care side, man, we really want you to, because this is one of the key clinical things that you might get if the lab can't identify it correctly. So this is my ARS question that didn't work. All right, so I want everybody to know this because it's really important if a case shows up, right? So what is the drug of choice for initial therapy in this patient? I'm gonna give you a moment and I'm not gonna make anybody raise their hands. Don't worry, let the panic settle, but I am gonna make these guys answer of what you would give first. And then we'll talk about the answers. I was thinking Ceptazidine and Bromeliropinin. Okay. I agree with that. I agree with that order also, Ceptaz first. Bromeliropinin. Okay. Ceptazidine it is. So when you look at the literature, there have been a variety of combination therapies that have been used in comparison to Ceptazidine. There's also been Ceptazdoxycycline, assessment of aminoglycosides, which many of us rely on, and then of course the use of Miripenem. So when do you use Ceptazidine versus Miripenem? Because technically both are correct, but there's a reason you pick one first. So if you have a patient who is not in septic shock and who does not have CNS components, neurologic manifestations that you are concerned about, you tend to start with Ceptazidine. One, it's clinically effective and really has been considered for the most part the drug of choice. And two, because we want you to all be good stewards of antibiotics and not use more than you need to prevent further resistance in the long term. So what happens after you give Ceptazidine? Well, really important, you should call ID. If you get this, this is not a seven to 14 day run like other gram-negative bacteria. This is a long haul treatment for cure. So this is usually, now again, lacking great clinical trial data on duration of therapy. 14 days up front is generally what's used. Now this is just bread and butter idea of using 14 days and we may be able to do less, but we don't have a study that says it yet. So everybody tends to do 14 days of Ceptazidine outside of that septic shock CNS infection. If you have those other two, Meropenem. Some advocate if you use Meropenem to start, you deescalate to Ceptazidine once you are out of the septic shock standpoint. That does not have great data, but is a clinical judgment decision. After that 14 days, then you move to oral therapy with Bactrim, which is usually at least three to six months in duration. And it is based on the TMP dose. And I will tell you, this is a high dose. This is a dose that might make you just a little uncomfortable when you dose it. So you do need to make sure that you know what the dose is. Two double strengths twice a day may not be enough and for most patients. Our patients BMI might've gotten close, but still probably not enough based on our weight. So key points. This is a rapidly growing global spread when you start to look at the most recent data over the last three years, but we are grossly under evidenced in how far the spread really is and how high really the endemic nature of this is in many places, including here in the US and our Gulf Coast and other areas. It is clearly travel exposure, even if the travel is a purchase and a commodity and not the person, which becomes an interesting issue. It is listed as a potential agent for bioterrorism, easily misidentified, as I mentioned. So you have to have that high level of suspicion. We need to recognize that it's kind of like a great mimicker. We talk about syphilis being the great mimicker, but melioidosis really is also. Active, chronic, and latent forms. It can make it extremely hard to recognize unless you know it exists and think of it. And then again, longer treatment than you would normally consider, including that second phase with Bactrim. And with that, keeping us on time, any last thoughts from panelists or anyone else on this case? Otherwise I will get us closed. Yeah. So this was actually, I will be completely transparent. I have seen melioidosis. This one was an adapted case of it for this course. In the case that we had, it was actually identified by our microbiologic lab correctly using both the oxidase testing and molecular testing, and they did recognize what it was correctly. We did not have a misidentification in our case. The one, the initial case that I had was blood sample. This patient could have had positive blood cultures given the fevers that were arising, but also the same thing could have happened in sputum, and the misidentification occurs on both. And so important to note too, on a BCID panel or rapid PCR panel, it could theoretically still be identified because those loci are so similar. It could show up as a pseudomonas in those scenarios. Other questions? I'm sorry, what? From the ID side, I would desensitize the patient and make an attempt at desensitization, and that is what's recommended in the literature. And if they don't desensitize, then it becomes a question of, do you extend IV therapy a lot longer, or can we try some other less evidenced medications? Doxycycline has been used. If I had to do it and I couldn't give back to them, I'll be really honest, if they were really sick, I would extend their IV therapy upfront probably longer before I would go to a treatment like doxycycline just because of the lack of clarity of evidence of that. But we successfully desensitized so many patients at this point that I would feel pretty confident we would be able to do that. All right, thank you to our panelists, our speakers, and everyone for hanging out with us for the last hour. Thank you.

fever

chills

dyspnea

rash

ground glass opacification

hepatosplenomegaly

leptospirosis

hantavirus pulmonary syndrome

melioidosis

travel history