Thanks very much for having us. We thought, when we were asked to do this, we thought we would, rather than do a contradiction or didactic lecture, we would go through a case, both to show some of the interesting things that are happening. There's lots happening in transplant right now, and mostly kind of give an approach of how two different experts would look at the data set. So it's really kind of getting into the way we do clinical reasoning. So specifically, we're going to walk through a case. The case doesn't matter so much. It is an interesting case, but it's more about how we approach-- how we approach different things, and really think through the clinical reasoning. We have nothing to disclose. So fairly bread and butter case. We have a 71-year-old female. I actually got a question recently, do you transplant people in their 70s? Yes, all the time. There's no absolute age limit anymore. We've done even low 80s. End stage kidney disease, from renal limited ACNA vasculitis. So when I see this, it's not uncommon that this is somebody who comes to the table with an autoimmune disease, and probably immunosuppression, because you can't get to transplant without getting immunosuppression on the way. She has hypertension and dyslipidemia, which is par for the course and very common. OK, so what other word? We don't really call things renal anymore. I guess people do, but nobody knows what renal renal is. So we're now kidney doctors and we call things kidney. So we had unrelated kidney transplant in July of last year. She's CMV high-risk, and what we mean is that as a package, as a present with the kidney, she got this EV. So she has no native immunity to that. We'll dissect this a little bit more, but it gets exposed to the virus by virtue of the transplanted organ. So her post-transplant course, she developed syph CMV viremia. At about seven months, we're seeing this. So in transplant, there are certain things you're so much at risk for-- we'll go into this-- that we think it's worthwhile giving an antibiotic for primary prophylaxis. So one of the main things we do this for is syph CMV. And in this case, because the risk is highest-- no native immunity-- we'll give patients a longer course. And what we're seeing is sometimes, rather than giving CVM during prophylaxis, breaking through that, you're seeing it later. So this is not an unusual circumstance. We see this probably every month or two. She has recurrent UTIs. Again, not unusual. It's probably the most common infection we see up here in infection. It's more common in women. It's partly related to immunosuppression. I'll dissect this a little bit later. But she's got a few cases. She's gotten antibiotics and gotten over this. She had one episode of rejection. There's different flavors of rejection. Most of what we're worried about early on is cellular, and we know this is going to be relatively mild because it was treated with steroids alone. Steroids add to her global burden immunosuppression certainly, but not as much as antibody. So this is a modest increment we'll call this. So one of the things I want to point out, which I do as a clinician, and probably some of the experts here do here is I have scripts for things. I have ideas about how things look like. So I think I know what a heart failure with a EF of 25 looks like and I know what a cirrhosis with a meld of 30 looks like. And as I get better, as I have more and more gray hair, and I have plenty now, I have more and more detailed scripts. And so when I look at data sets, I look at the patient and I compare them and their data to what I think they should be. So what is an ANCA vasculitis 71-year-old year out in transplant look like? And what do their labs look like? And what do the medications look like? And in that difference And in that difference, that's the changes. Serum sodium is 140 for Kurt's patient with meld of 30. That's too high. It's normal, but it's not right. Phosphorous is normal in a dialysis patient. Shouldn't be normal. They're always high. Serum sodium is too low. In that waiver is where a lot of the clinical information is. So she's in the clinic 4 months later. She presents with fever, and cough, and abdominal pain. And I'll say, a lot of symptoms in transplant are related to medication, so that's our first reflex-- low white counts, abdominal pain-- but the combination of fever will likely get her to the ER and likely admitted. Great. All right, well, thank you for setting that up, Alden. So we're going to be going back and forth during this case presentation. It's not one versus the other. This isn't a debate. This is a discussion of how we work as a multi-disciplinary team when taking care of these types of patients. So what I wanted to start with, echoing what Alden was talking about just a second ago, is give a conceptual framework of how we approach immunocompromised infectious diseases. And I think one of the things that we start with-- this is a common model that we think of as ID clinicians, about infectious diseases. And I think it becomes really apropos-- as I'll talk about in little bit-- about immunocompromised infectious diseases and organ transplant recipients. But if you boil it down, we consider an infectious disease to be the consequence of a lot of interacting factors-- interacting factors between the host, the environment, and the microbe. And all of these are important in the eventual consequence of infection. So we'll be talking-- because this is an immunocompromised patient, this is a solid organ transplant recipient on immunosuppressant medications about-- in the issues with the host, about their net state of immunity and immune reactivity. The environment is really important as well. And so certainly, you can think about things that interact with the environment and host, things like crowding. Or do you have-- does a host-- does a patient have exposures to soil, to water, to other things in the environment that potentially could impact and lead to infection? Importantly, we can think about the environment in the microbe interaction, so global warming, and how that can affect what occurs with microbes. And finally, microbe and patient interaction-- so we are often thinking about pathogens, and in this we'll talk about-- pathogens become a little bit more broadly defined when you talk about immunocompromised patients. But it's really not just probably microbe. It's really microbiome that we have this-- we are vessels for microbes. There's 10-fold or higher greater number of bacteria with us, on us, in us, than there are human cells. And so, when we think about this, and how those impact risk for infections or risks against infection, those become important consideration. So this is what we generally think about as ID clinicians when we're seeing patients, is how are all these factors interacting with one another? And really, as I said, becomes apropos with organ transplant recipients. So in terms of risk for infections with patients who had organ transplants, there's a lot of things to consider. So of course, there is the pre-transplant history. And all of them just talked about this with this particular patient, who has anca vasculitis, and has probably seen some level of immune suppression going into the transplant. And that maybe informed where she may be now, post-transplant within the first year or so. There is also-- so those are recipient factors. There's also the host-- the donor factors. And so, you always have to keep in mind, we really have 2 patients here that we're dealing with, not just 1. The relative importance of those 2 may depend on the time after transplant. So there's intra-operative factors to think about. These are surgical patients. There are surgical complications. There are complications of hospitalization. And in addition, there's also post-transplant issues, around medications, around exposures in the environment. So all of these conspire to make us aware that timing really becomes key post-transplant. I'll talk a little bit about this later as well. The epidemiology of exposure is also very important, and again, complex in transplant recipient. So hospitalized patients who have undergone surgery-- these are going to be a patient population in general. They're going to be at risk for nosocomial pathogens, drug resistant pathogens, those things that we see all the time when we're taking care of patients on our inpatient wards. But of course, when they go home, or when they're interacting with people in the community, they're certainly not protected from community associated pathogens. So we need to consider those factors as well. And in addition, starting to get into the more zebras, the opportunistic infections of transplant patients, there are things. There are organisms that potentially do not have the potential for causing significant infections usually in immuno competent patients, have become important for transplant patients. Things like endemic fungi, environmental protozoa-- of course, there's exceptions to the rule, but certainly these patients are canaries in the coal mine in terms of risk factors for infection. Reactivated infections become important. The recipient is seen prior to their life-- prior to becoming immune suppressed. And they again are viral, bacterial, fungal, and even protozoa infections, depending on what their exposure history is. And then getting back once again to donors, there is the potential of donor transmitted infections. These are really the least common infections that we deal with on a day to day basis, but they are some of the most noteworthy and are often very difficult to diagnose. They tend to occur early after transplant, usually within the first month of transplant. And these are the cases where they sometimes land in the newspapers. When you have an unexpected donor drive infection that leads to a bad outcome, these are the things that become noteworthy and can hit the newspapers. So a common framework that you'll see, if you go to up to date, or you go to a general medicine textbook, or ID textbook, is something like this, talking about the timeline of post transplant infections. And what I want to caution you, or just advise you about, is that this is a framework. This is not set in stone. But this provides a conceptual framework, taking in the factors I just spoke about, in terms of net state of immune suppression, exposure epidemiology, and pre-transplant factors, to give a framework in terms of what we think may be at play when we're dealing with a potential host post-transplant infection. And it's important, because at some point, we need to be able to direct and narrow our differential to do appropriate therapies, because the one thing that sometimes can be a little bit concerning to providers who are taking care of these patients who have infections, is the concept of the concern that they're immune suppressed. They could be at risk for anything. And if you get into that habit of saying they can be at risk for anything, they can be at risk for everything, and not being able to narrow that differential, you are doing a lot of testing. A lot of it is probably not necessary. So we need to-- and you're, in fact, perhaps delaying diagnoses. So you have to be cognizant of that. And that's where we come into play. So early after transplant, usually within the first 4 weeks or so after transplant, that's a period of time when we're really seeing, for the most part-- well, I should say, at least, usually-- nosocomial infections, infections that are occurring around the operation of the transplant-- in this case, a kidney transplant. So those are the times where we're seeing graft issues, where there's leaks, or UTIs, or the consequences of hospitalization, like hospital associated pnuemonias or catheter infections. Hopefully we're doing all those much better, and practicing our bundles, putting on my hospital epidemiology hat. If we're doing the things that we do to prevent infection, hopefully those are reduced. But those are the periods of times that we see these. In addition, we sometimes see the residua of infection that was occurring before the transplant, recognized or unrecognized. And as I said earlier, the things that may be coming over from the donor, so recognized and unrecognized infections from the donor. The middle period of time here-- and this is, again, rule of thumb, broad stroke-- is 1 to 6 months. This is a period of time when we're seeing the biggest period of immune suppression for the patients. Immune suppression is a consequence of time and space. So these patients who have been on bolus immune suppression at the time of transplant, and then have time-- hopefully doing well after their transplant, a month plus out-- they've had an experience of having reduced immune system and potential exposures to community pathogens, opportunistic pathogens, as well as the things that occurred early after transplant, over this period of time. And this is when we tend to see the reactivated CMV and other herpes viruses, hepatitis viruses-- BK virus is a particular concern in kidney transplant recipients-- and these types of organisms. And in fact, that's where we tend to try to direct our either preventative therapies through prophylaxis, or preemption-- monitoring for signs and symptoms of infection. So that's-- when you think about opportunistic infections, this is really the period of time when we're most concerned about that. And it's also the time that, on the general medicine service, unfortunately, you probably don't get a lot of experience with this, unless you happen to be rotating on a-- for the residents, if you're rotating on a medical service that is doing this in consultation, or on a medical transplant service. Unless the patient's in the intensive care unit-- I guess that would be the exception. So these tend to be sometimes the most interesting patients from ID standpoint. But they are complicated. And then finally, after 6 months, this is the period of time when we typically see-- if the patient's doing well-- community associated pathogens, as I was alluding to earlier. Now, that doesn't mean that the zebras can't occur. And sometimes the zebras occur because the transplants aren't going well. And they're getting treated for rejection, or they're having unusual epidemiologic exposures. Sometimes, it's just time that a patient's been on a certain level of immune suppression for their organs. And with immune senescence in a person that was 50 years old, 20 years later is 70 years old, and they have an organ and they're on a relatively high amount of immune suppression for themselves, then sometimes an opportunistic infection can be that marker that they're over immune suppressed. So like I said, this is a framework that we try to use to guide our differentials, but don't subscribe to it completely. All right, so back to Alden. OK, thank you. So let's just go through the medications, just as like-- usually the way I look at it. So as I'll explain a little bit, these are pretty standard medications. So she's on tacrolimus, which is a calceineurin inhibitor. I'll review this in a second. To me, this is a medium dose. So this is consistent with what I might expect. Prednisone's at 10, so that says low, medium dose. May be related to the rejection. CellCept, a medium dose, on typical cholesterol-- many patients with chronic kidney disease are on a larger dose of vitamin D, because they degrade it, so 2000 units would be not unusual-- and the completed valganciclovir, as we've said before. In particular, I told you she had anca vasculitis. She had both of the big guns, Cytoxan and Rituximab. Rituximab, again, a B cell agent, Cytoxan a combined agent. We worry about a lot of immunosuppression here, and also the Cytoxan exposure for bladder cancer. And her tacrolimus levels have been 5 to 7, which is medium. How much is right? Well, it's kind of like how much salt you put in your cooking. Depends on the person eating the cooking, depends on what meal you're making-- it's all based on the circumstance. This I would consider a medium amount, and not unusual. So it doesn't ring any bells for me. OK, so it brings up this topic. This is one of a couple things I want you to leave with. One is this idea. So the story I tell you is, when I was a resident in Dallas in the early 90s, it was the middle of the AIDS epidemic. We thought of people either being immunosuppressed, and they had all of these crazy infections, or you weren't. So it was kind of a binary construct. I have a sense of what this looks like, and a sense of what normal looks like. I would submit to you that's no longer appropriate. That's a spectrum. It's no surprise, right? And so a lot of what we do in transplant is setting up just how hot. I call it dialing the immunostat. Which flavor of medication? How much do I need? A kidney needs different than a heart, needs different than a pancreas. A kidney needs different in 1 month than they do in a year, then 5 years. And when they come in the hospital with a pneumonia, they need less, right? So a lot of what we do is get a sense of where is this immunostat set? And how do we set it? That is a lot of the art of transplant. So one thing to leave with is that. I wanted to briefly go-- this is not meant to be a lecture on all different kinds of immunosuppression, but just give you broad strokes. So a lot of folks, not all, are on glucocorticoids-- not so much liver, not hearts, but kidneys and pancreas transplants. Antimetabolites is kind of like the side meal. This is the ones that I might stop in the hospital if someone's pretty sick. These inhibit cell turnover, as I'll review. Calcineurin inhibitors target of Rapamycin inhibitors and co-stimulation blockade are the main meal, so I would have to really be pushed to stop them. Most commonly it's calcineurin inhibitors, most commonly tacrolimus. But as I'll show you, there's lots and lots of options now. Antibody therapy are usually short term, mostly. And as I said, some of them-- the lytic antibodies like [INAUDIBLE] will last for 6, 9, 12 months. So if somebody had rejection like she did, and got treated with this, that shadow of immunosuppression goes way out and has to be considered. Not meant to be inclusive, but there's all these new classes. So traditional immunosuppression for organ transplant is T cell mediated, because that's what early rejection is. And what's dogging us, and the reason we don't have better long term survival, is largely B cell. So if you go to a transplant meeting, most of the action and excitement is on B cell thing. So this is a short list of all the new agents that are coming online now, including proximal, middle, end, and complement inhibitors, which are going to target the B cell, and are going to also spill over in other fields where B cells are important, like rheumatology. So you're going to stay tuned for that. This is like my-- for transfer people, it's an obligate [INAUDIBLE] slide. We used to tell you in medical school, this is an obligate immunosuppression slide. It's worth talking about a little bit. Again, I'm not trying to teach you about immunosuppression, as much as give you a sense of how complicated it is, and how we can design individual approaches to patients. So this is the T cell side again. We're traditionally T cell oriented. So if my T cell is presenting an antigen to-- I mean, an antigen itself-- presenting an antigen to the T cell, it's that 9 to 12 amino acids that's cognate. But that's not enough, right? That's the T cell receptor. That's signal 1. You have to have co-stimulation. And there's various forms of co-stimulation, each of which can now be blocked-- CD28 version, CD40 version. And then you need to turn on a cell. I tell my followers, it's like you had a soldier in a barracks. And he gets a call that there's a disturbance downtown-- god forbid, another disturbance downtown. And you need to get a military response there. If you don't get the phone call, there's no response. But just getting the call is not enough. You have to get other soldiers involved. They have to be armed. They have to get into the truck and drive out. They have to know-- so there has to be multiple steps. So a T cell has to get into the [INAUDIBLE] signal, turn on to make [INAUDIBLE] cells, memory and effector. They have to get into the bloodstream, know where to go with the right address, get into the organ, and then be able to attack-- all of which now have individual drugs that target them. So we think of signal 1-2-3, but this is the way the new immunosuppression is. So any of you in fields-- GI, internal medicine, rheumatology-- this is what's coming. You're going to be designing specific patient therapies with immunosuppression. OK, so at this point we'll go back-- I'll come back to this paradigm, this model, of infectious disease. Alden did a fantastic job of illustrating how complex immune suppression is, and how even more complex it's becoming. So as a transplant, you know I'm not a specialist. I'm sort of an enthusiast. So I'm able to take a look at that patient that Alden-- of our patient here and say, OK, they're on prednisone. We don't know what the dose, but prednisone, CellCept, MMF, mycophenolate, and tacro with levels of 5 to 7. And that, to me, at this point of this person's post-transplant, what it sounds like that's a ballpark middle level of immune suppression. But that's my gestalt, having done this. But it's really important. And this is, again, where the multidisciplinary part of this care is. That I need to have conversations, or will seek conversations with my colleagues, to say, what do you think is happening with this patient? Do you think they're over immune suppressed? Are they under immune suppressed? Where are they in terms of this immunostat rheostat. And then that becomes really important for me in constructing my differential in thinking about a patient. And then when an infection is diagnosed, to think about, how should we be modulating the immune suppression? Certainly, if a person has a life threatening infection, we have to think about reducing it, cutting it. But sometimes there is that-- and maybe some of you have heard about this, or seen about this-- you can actually be overaggressive with that. And you have the potential to risk things like immune reconstitution syndrome, if you do things too aggressively. So these become conversations with our transplant colleagues. So again, we have these host factors that we've already alluded to, that all that was highlighting in terms of regimen. I talked about earlier, about timing. All these come into the idea of the immunostat. What else can occur? What other things can we do to mitigate or prevent infections in our transplant patient? One is, of course, immunization. And so there is a significant focus that we want to do before a person receives a transplant, to protect them as best as possible before they're exposed to pathogens. So that's something that is a focus of our pre-transplant clinic and the people that work there. The environment-- there is a very important discussion that occurs with transplant education in the transplant clinics before patients have transplants. And they receive just an incredible amount of information. A lot of the process about this healthy living after transplant is directed towards these. What should you do? Should you garden? What type of travel can you do? What type of water do you drink? What occurs with your animals? Should you be the one that's taking care of the cat box? Things like that. Those are really, really important conversations that sometimes the doctors really aren't involved with, but sometimes I try to address when I see that there's an opportunity. But they are really a foundational component of transplant education. And then, finally, there's the microbe section. And we have the opportunity, through the host, to effect what are the risks of the pathogen post-transplant. And that's-- as I alluded to earlier, in that first 2 periods, the 0 to 6 month period of time-- where we can direct prophylaxis or prevention strategies directed at microbes. And so they're really across all classes of microbes: viruses, bacteria, fungi, and even protozoa. The reason I highlight CMV, in terms of viruses, is that really is the most common opportunistic infection that we see post-transplant. It's, of course, the one that we saw here. But even with effective prophylaxis, valganciclovir, effective therapeutics, it still is the most common opportunistic infection in many cases that have all been talked about earlier. It's just delayed. It's probably less, but it's still delayed. And it still has consequences in terms of patient outcomes, of organ outcomes, and a host of other things. CMV is rather unique, in that not only it causes syndromic disease, but can also-- because it's immune disregulate-- is an immune disregulator itself-- it can actually predispose patients to other types of infections. So you can see more listeriosis, for example, or more pneumocystis in these patients who have CMV disease post-transplant. Of course, it's directly infective in organs, so you could see hepatitis, and enteritis, and retinitis, and a whole host of different other manifestations of tissue invasive disease with CMV. Our patient was donor positive, recipient negative, sort of high risk. But even if you have pre-existing immunity, or you develop immunity post-transplant during a CMV infection, you are at risk for CMV recurrence. Again, just depending on what the level of that rheostat is for CMV. And then finally, one thing in terms of immune senescence that I-- or the immunologic effect that I wanted to mention, but I forgot. It also predisposes you to cancer. And probably the most common cancer that it predisposes you is EBV associated PTLD. So the immune disregulation occurs because CMV reactivation can lead to EBV, either transplanted from the donor or the endogenous EBV that a patient has. Those patients can develop transformative events with those-- with EBV, and can develop polyclonal or even monoclonal EBV. So again, our prophylaxis strategies are directed towards that, valganciclovir for viruses for patients for CMV, and other herpes family viruses for people that are at risk. And then, I will belabor this, but bactrim TMP sulfa is our go to prophylactic agents for pneumocystis. It's incredibly effective for that. And it also buys you prophylaxis for toxoplasma, particularly an issue for heart transplant recipients, but we've also seen it in kidney transplant recipients. And at least in some measure, gives maybe some UTI prophylaxis, although we don't direct prophylaxis for urinary tract infections. So we're going to go back to the case now. So in terms of this patient that we have, she had influenza vaccination annually prior to transplant. And going into transplant, she'd been vaccinated for pertussis through Tdap. So she's hepatitis B immune going into the transplant. Pneumococcal vaccination that was adequate, and had been demonstrated to have measles, mumps, and rubella immunity prior to transplant. In terms of prophylaxis, she received the typical regimen that we would give for a kidney transplant recipient. She received nystatin and for 4 weeks. That's a sort of enriched period of time for corticosteroid associated thrush and other yeast infections. So she got nystatin for 4 weeks. She got bactrim actually at this point, is now about 11 months after transplant. She's still on bactrim, prophylaxis, and as we talked about, received valganciclovir, both prophylaxis and then treatment. Back to you, Alden. OK, thank you. So she comes in. Her exam is pretty normal. She is normal tensive, nontoxic. Her allograft, which remember is in kidneys, is a heterotopic organ. So as I'll show you, the kidney goes down in the pelvis, was non tender. Kidneys don't have nerves, though, remember. The transplanted kidney-- chest x-ray was normal. One thing and one word of caution with physical exam, if you find fever, or redness, or soreness, or other traditional [INAUDIBLE] kinds of findings, they're there. But immunosuppression mutes them. So the more immunosuppression you are-- classic examples is a bone marrow transplant-- the less you'll have fever. You can have a very sick person with a burst abdomen or abscess, that has no fever and no tenderness. So be careful about the sensitivity. Similarly with the urinalysis, she has some white cells. Kidney transplant patients don't have to have white cells to have an infection, because they may not mount an inflammatory response. So be careful. It's not very sensitive. And a word here, creatinine went from 0.7 to 1.2, just because I have to pitch it. So 0.7 was not surprising for her. It's a pretty normal, or near normal, creatinine. 0.7 to 1.2 is a significant jump in creatinine. Even though 1.2 is normal, it's not steady state. You've lost almost half of your function. I joke-- we usually do this calculation instead of an EGFR, which is estimated GFR, which is based on muscle mass determinants by race and gender. When we look at an actual patient, I call that my NGFR which is nephrologist GFR. Which is-- I actually look at them and guess what their muscle mass is. So this is for somebody who's 71, who's had past anca vasculitis. 1.2 is a significant increase, and white count of 3 is low. So she's admitted. She-- very often in transplants, as I'll explain to you why-- gets an ultrasound. She's got punctate stones, which makes me worry about [INAUDIBLE] for infection-- for urinary tract infections. In the case of transplants, we look at Dopplers to make sure of their flow, because you have a surgical anastomosis into the iliac vessel. So it's something we think a lot about when the creatinine goes up. Not so much at this point. Post [INAUDIBLE] residuals-- I hope I convince you-- major thing. So not in regular nephrology, but in transplant nephrology, we're very, very sensitive to urodynamic things. This is one of the things that we do differently. And I have to encourage the fellows to think about differently, because as I'll show you, it makes up a lot of the risk. And her urine culture, in this case, turned out to have klebsiella oxytoca, which is sensitive to fluoroquinolones and not to some other agents. So this is the second big lesson. One is the complexity of immunosuppression and getting the immunostat just right, although there's never a perfect thing. The second is that the heterotopic anatomy of transplant changes a lot of things. So let's start with the ultrasound. So ultrasound reminds you how much blood flow through the kidney, and also reminds you that unlike hearts, kidneys actually look like kidney beans. They actually look like they should. But this is a pretty normal looking ultrasound. The transplant, which I think is a key point here-- again, it's heterotopic. I tell patients it's like a pistol in a holster. Most of it goes down in the pelvis, and they're attached to the iliac vessels of their legs. Note a few things. One is the vessels are short, and have a surgical anastomosis. That may be in the side, like a living donor, or may come with a patch. These transplanted kidneys no longer have nerves. So if you have a kidney stone, you don't present to the ER with pain. You present with no urine output. So when you have pain, that means that the nerve fibers around the kidney-- it's so inflamed, that the pocket it's sitting in its spurts. The ureter is short. This is really key. And there is no valve here. So things that happen in the bladder-- infection and urinary retention-- are reflected into the kidney very quickly. So UTIs in native kidneys don't really very often cause AKI. You'd be awfully sick for that to happen. It may happen once in a while. In transplant patients, you don't even have to have pyuria and you may have an AKI from a urinary tract infection, because it so quickly becomes pileup. The second thing is a little bit of urinary retention-- 250, 200, 300 CCs-- can cause you to slow down your urine output. So you immediately-- urine output-- it reflects pressure back in it. So you can have a guy with a little BPH, who comes in for elective knee surgery, gets put on percocet, and his BPH now is urina-- instead of holding 100 CCs, now holds 300 CCs, and you'll get an AKI. Not really happening, classically, in normal transplant, so very, very important to think about urine flow and blood flow to this heterotopic organ. A lot of the disease is explained by that. OK, so urinary tract infections in transplant patients-- again very, very common. More common in females, more common-- but it happens at all times. They're a little different than the regular population, so we're much more likely to treat them. This anatomy, as I hope I convinced you, makes the difference in terms of risk, and how they present, and how sensitive a urinalysis is. The signs of clinical infection may not be there. You may have graft tenderness. You may have fever. You may have none of those things. When patients come into the ER with an AKI, they get a urine culture whether or not their urinalysis-- so we don't just do a reflex. They're risk-- rich for drug resistant pathogens because of their exposure and history. And I would argue that you have to look at the urodynamic parameters. OK, moving along with our case. So our patient, who again, to remind everybody, presented with fever, abdominal complaints, and some shortness of breath, and was diagnosed with a UTI-- her symptoms continued, despite fluids and a course of ciprofloxacin. She presented complaining of generalized weakness, worsening abdominal pain, nausea, maybe a couple episodes of vomiting, and dyspnea. Again, her stools were intermittently loose, maybe diarrhea-- diarrheal, but not consistent. On review of systems again, fevers, cough, there was a small amount of blood-tinged sputum that occurred, but that wasn't her major complaint. Instance where ID clinicians and I did this whole preamble about environment, her social history, I'll review here. She lives in rural Virginia, near Roanoke, with her husband. They are on well water and she admits to drinking well water, which is counseled against. She has no animal contacts, no travel, no sick contacts, no gardening-- I didn't include it here-- no tick exposures or other insect exposures that she acknowledged. She also has no known TB exposures, and she is quantiferon gold negative at the time of transplant. On exam, she has a temperature of 38.9 Celsius. She's tachypneic and has some expiratory wheezing, is on room air, she has a distended abdomen with diffuse lower abdominal tenderness, but not specific tenderness or redness, or other findings over the graft. Sometimes with pyelo with a transplant patient, you can actually feel that the graft is rather boggy. So she did not have that. Labs-- her white count was 2.0, and the differential is provided 62 S, 20 L, 6 monos, and 12 eos. So elevated eosinophils, but not an absolute eosinophil count. That was 240. Her creatinine has come down after her course of cipro. It's now 1.0. She had normal LFTs and normal amylase and lipase. And her U/A is checked and is negative. In terms of micro that we have back at this time, she has a negative C. diff PCR, a consideration after being both immunocompromised, being hospital experienced, and being on cipro. She had a negative community GI panel, 2 sets of blood cultures that were negative, a negative serum-CMV viral load, and then finally, negative RVP respiratory virus panel. And if I remember right, she presented in May or June. So a couple of points about her micro testing I want to emphasize-- the first is the interesting thing that's new over the last 5, maybe 10 years now-- is syndromic testing. I'm very interested in the concepts of ordering-- the idea of diagnostic stewardship, and ordering tests appropriately for patients. I find syndromic testing to have some warts, but in these cases, in patients who are immunocompromised, that have a large differential, I think they have a clear utility. That we don't have to cherry pick, and say, which of the GI pathogens could her little bit of diarrhea, loose stool fit into well? In terms of respiratory viruses, should we be thinking about RSV in this patient off season, or something like that? So I think that those are important. But they do still have the caveats of large panel testing. They're very expensive, particularly if they're performed as an outpatient. And we can get results that sometimes are a little bit questionable. What's-- e. coli, is that a pathogen for transplant patients? Probably not, but we get those results and we're called about that. And the second thing is CMV viral load testing. So that really is now-- not now, this has really been the last couple of decades-- CMV viral testing is really the test of choice for diagnosis of CMV. Again, she had CMV disease earlier. There have been other options in the past. Antigen testing is still talked about in the literature somewhat. I don't know of any centers that do that anymore for target specific antigen that's produced by the CMV virus, BP 65. So no longer performed. But what used to be performed, until I think about 2 months ago, was shell vial culture testing. So shell vial would be a test that you would see as an option. But there are problems with both sensitivity and specificity with shell vial culture. So while shell vial culture is a way to grow CMV faster than what were traditional culture techniques for viruses, you can sometimes-- it's not as sensitive as PCR testing. It takes a longer time than PCR testing. And then finally, there can be issues with sensitivity. It may not be adequately sensitive in some body fluids, in some circumstances. And sometimes you actually shed virus without actually having disease, so there's issues with specificity. So our laboratory doesn't even perform that anymore. We just do PCR testing. After they adopted PCR testing of other body fluids, like [INAUDIBLE] fluid in addition to serum. So those are the 2 points. And then in terms of imaging, she had a clear chest X-ray. Her abdominal CT that was non contrast showed diffuse intestinal wall thickening, ascending-- the stretch from her ascending colon to her jejunum. In addition, the lower cuts of her chest CT showed septal thickening, with some patchy ground glass infiltrates at what was visualized of her lung bases. So a diagnostic procedure was performed. And I'm not going to play guess what this is. This is not the Newman Journal. But I did want to emphasize something that is foundational. And that's Sutton's Law, that I think probably most people here are familiar with. Attributed to Willie Sutton, although in his biography, he actually said that he actually never said this-- that this was a newspaperman in Philadelphia that wanted to make good copy. But basically, he's alleged to have said, when asked why he robbed banks, he said that that's where the money is. So he didn't say that, but it really is a good truism. So in our patient, what would we target? What would we go after in this person, that has some fevers, has respiratory complaints, but also has GI issues? And if we painted a picture, right, her GI issues were the most significant. So application of Sutton's Law, conduct those tests that would confirm or refute what it is either the most likely, or potentially the most serious, life threatening condition first. So you really want to target what's most likely or most life threatening. In this case, a colonoscopy was performed. That seemed to be what her major complaints were. And so this was what was seen on colon biopsy. I won't use the highlighter, because I don't think it works well. We'll just say-- we'll delve into it a little bit. You can see in this mucosal biopsy, this colonic biopsy, there's a lot of cellular [INAUDIBLE]. There's a lot of blue here. If you go in a little bit farther, you can actually start to see not only the blue, but there's a little bit of some red/pink pink staining. So it looks like some eosinophils. And if we go in a little bit further, you see this sort of tubular structure in the biopsy. So we were sort of suspicious of this. I won't go into reason why. But we performed this test, which is not a clinical microbiology test. This was done in my laboratory, so I hope the [INAUDIBLE] police are not out. But we obtained a sample of her stool, spread it onto this blood agar plate, and as you can see, there is this growth where the stool culture was smeared. In addition, you see these tracks of bacteria that are going from this plate. And if you zoom in here, you can actually conceptualize that these are serpiginous trails of bacteria that were dragged across the plate by a strongyloides. So the other nematodes can do this, but this is really classic for strongy. These agar plates are actually probably the most sensitive. They're arguably-- there's maybe one other competitor in terms of diagnosis of-- sensitivity for diagnosis of strongy, but they are a risk. These worms can crawl off the plate and infect you as a laboratorian. So it's not performed in laboratories, unless you want to-- at least here, you have to send it out to the Mayo Clinic. But we did it on the sly here. Interestingly, she was strongy antibody positive here, at this time, at admission. And she had been negative before. Now, strongy is one of those infections that usually comes from the donor, or usually it comes from-- the recipient has been exposed to in the past. Let's say they're exposed to strongy as a child. And they have chronic infection. So it usually is an infection that occurs when people get bolus immune suppression after transplant. And then rarely, it can occur as a consequence of the donor organ coming over that has strongy in it. And for the most part, if it's recipient derived, we think-- in almost all cases of important literature, it occurs within the first 3 months. Donor derived strongy really occurs quickly, usually within that 1 month time frame I talked about earlier. To talk about the roundworm a little bit more, it's non segmented, like all other nematodes-- the elongated, cylindrical organism that's sort of a tubular-- it's a tube within a tube-- a digestive tract surrounded by other cells that are involved in its metabolism. They're really small, 1 to 2 millimeters in length. So they're barely visible on a plate if you're looking at them, but for the most part, are difficult to see. And they are both males and females. And unlike other geohelminths-- soil dwelling worms-- they can complete their entire life cycle within humans. So this is that slide that I saved you from, where they actually go through the skin. Walking barefoot outside, they go through your skin, go into your circulatory system, in through your lungs. Then you swallow them, or perhaps directly penetrate into your intestinal tract, and there they molt into an adult form. So they're filariforms. They become rhabditiforms. The rhabditiforms can go through your intestinal tract or your perianal region and do the whole thing again, because they undergo asexual reproduction within the human host. So that can be chronic infection in the setting of getting corticosteroids, or other immune suppression. You can have that accelerated. So people can develop hyper infectious syndromes, where they go through their circulation, and cause pneumonitis or pneumonia. In fact, that's probably what was happening with her cough and her wheezing. And we sort of proved it was-- I'll show in a second. And it can even go to other areas of body, all right? So strongy has a worldwide distribution. There is estimated to be 30,000,000 to 100,000,000 people that have strongy. And that occurs in the tropics, sub tropics, and even in temperate locations. So in the United States, that really is Appalachia. The seroprevalence studies are pretty historic now-- from the 60s to the 90s in the United States, the seroprevalence-- adjusted rate of seroprevalence of 0.4 to 4%. What it is now, we really don't know. This is also enriched in lower socioeconomic classes. So with more indoor plumbing and things like that, the anticipation is that this rate is lower. The factors that influence this include salinity, sanitation-- as I talked about earlier-- soil conditions, climate, and human behavior. Risk factors, again, is immune suppression, particularly corticosteroids, but other agents. And then HTLV-1 is another thing. So HTLV-1 skews your TH-1, TH-2 access, and makes people more susceptible to this. And then finally, these patients who present the classic board questions is going to be a person from an endemic region. Let's say from Mexico, who comes in, gets corticosteroids because of some medical condition, ends up in the intensive care unit with unexplained gram negative sepsis, maybe with multiple gram negative organisms. Chris Arnold-- just this morning, we talked about a patient that had enterococcal [INAUDIBLE] I believe meningitis. And non neurosurgical patients sort of presents with a rather unusual bug to cause community associated meningitis. So those are the types of patients to be thinking about with this. So, a couple brief videos that demonstrate these guys in action. So these worms were isolated from that blood agar plate, and put onto a plate that we use to visualize worms. Let's see if I can click it correctly. So again, if you took a look at the plate itself, these guys would be like little threads. You could barely see they would be moving. And if you were to take a look at this a little more defined, or a little bit of a higher magnification, you could see some of the structures that I alluded to earlier. And this is from her sputum. So this is actually collected two days after we started ivermectin, the treatment, from her. And so this can be a shock to our pulmonologist too. Oh shoot-- see these patients-- [INAUDIBLE] [LAUGHTER] All right, so I think that's it. So they can crawl-- this has got larva currents. They crawl in your skin. And you see them move around, up and down. So I'm going to take a last-- 1 minute, just to trumpet a few things in transplants. So it hopefully convinced you that transplant's complicated and interesting, and really requires a multidisciplinary approach. I think as a model for where health care is going, is where transplant is now. Just to toot our own horn, for UVA, last year we did 143 kidney or pancreas transplants, our biggest year ever in 50 years. We have up to 1,000 people we're evaluating this year alone. We have 600 people who are listed, another 600 in evaluation. So more than 1,000 people in the hopper to get transplanted. So I think what you'll see is, no matter what field you're in in UVA, you're going to start seeing these patients. We're at about 280 solid organ transplants this year, hoping to hit 500 in 5 years. That's one of the bigger ones in the country. Couple things that we're doing that differentiate us from other places. We're doing a lot of multi organ. We just started our heart kidney program. We do a lot of liver kidneys, pancreas kidney, of course. We're doing kidney transplants in lots of different higher risk populations. We do them now in compensated cirrhosis-- not all cirrhotic, sometimes we do double. But we'll push that envelope. In compensated heart failure, and particularly in pulmonary hypertension, we have a specific protocol for pulmonary hypertension in patients who've been turned down in other programs. We participate in paired donor exchange. So when your brother wants to give you his blood type B kidney, but you need an A, and someone else else's sister has the A, we do a national swap, which is interesting and cool. We do pediatric en-bloc kidneys in now very tiny babies. So the kidneys remain attached to the aorta, and the aorta's transplanted. So you get two tiny baby kidneys, as some of my team now knows, which grow into bigger kidneys over time. And your creatinine comes down over time. We do 2-for-1 kidneys. We've been importing these from [INAUDIBLE] country where other people don't use them. So you get two pistols and two holsters for a kidney that may be older, that no one wants to take. We'll take both of them and do a double transplant. I've had good outcomes with those. We are now one of the leading robotic surgery programs in the country for transplant. This is largely from our new director, Dr. Overholser. We do living-- all of the nephrectomies for living donors are done robotically. We do extremely obese patient. There is no BMI which we will not transplant. That doesn't mean it's not factored, but even within 51-- we'll go up to do 50s. We're the only one in Virginia to do that. And there are a lot of takers, turns out. You can imagine. We do a simultaneous kidney pancreas transplant. We're one of 2 places in the world that I know that does that, with robot. We are active participant in Hope in Action. That is, we do HIV positive to HIV positive transplants, as part of a national consortium study. Very exciting for us. Coming soon, stay tuned. This is soon-- I just had this meeting yesterday-- hopefully January. We're going to start putting-- purposely put hepatitis C kidney donors into hepatitis C negative people, infecting them and then treating them, to get them better access to organs. The liver transplant team's already done this successfully. So we're moving there quickly. We just heard word this morning we're going to turn on the islet cell program. It's ready to go. So islets alone-- we have been working with our liquid transplant colleagues to do allo-BMTs in combination with transplant with low dose radiation, so that you'd be tolerant. So you get part of the bone marrow from the donor, as well as the transplant, which we also use to treat diseases like sickle cell. So you get a 2-for-1 deal with bone marrow transplant. And we're really working on having one of the advanced perfusion centers, so that you can take organs-- lungs, kidneys-- perfuse them with warm-- refusing to improve their outcome and to diminish reperfusion injury. So a lot of exciting stuff. Come play in the sandbox with us. We'd be happy to have you. Thank you. [APPLAUSE] I thinks we'll move on to the next talk. I'll take any pressing questions. Awesome, well, thanks you guys again so much. [INAUDIBLE] All right. So we'll get to department updates on time. So it is an exciting week throughout both the residency program and a lot of the subspecialty divisions, as this was fellowship match week. So he does-- it was about 5 years ago. We actually bent it a little bit for the case-- All right, we've still got a mic on out there, so-- If it gets reported, just came out at-- At least those voices were out there, and not in my head, so all right. [INAUDIBLE] So all right.