Join Drs. Caitlyn Vlasschaert, Hariharasudan Natarajan, Sam Kant, Jeannina Smith, and Samira Farouk as they chat about the Trolls of Transplantation region of NephMadness featuring BK virus and CMV!

Read more about the regions and cast your brackets at https://ajkdblog.org/tag/nephmadness2026/

Episodes | Consult Notes | Subscribe | Twitter | Merch | febrilepodcast@gmail.com

Febrile is produced with support from the Infectious Diseases Society of America (IDSA)

Hi everyone.

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

We dive into ID clinical reasoning, diagnostics and antimicrobial management.

I'm Sara Dong, your host.

I am super excited to have a special collab with Neph Madness today.

We have several guests joining us, so I'm gonna let them introduce themselves,

Caitlyn, maybe I'll start with you.

Hi, I'm Caitlyn Vlasschaert.

I'm a fourth year nephrology fellow at Queens University up

in Kingston, Ontario, Canada.

Hello everyone.

I'm Hari.

I'm currently a second year nephrology fellow at Mount Sinai Hospital.

I'm excited to be here today.

Hi, I'm Jeannina Smith.

I am an infectious disease specialist in transplantation.

I'm the Medical Director of Transplant Infectious Disease at the University of

Wisconsin, and I am very excited to be here to talk about one of my very favorite

subjects, the troll of transplant.

I'm Sam Kant.

I'm a transplant nephrologist at St. Vincent's University

Hospital, Dublin, which is, within the University College Dublin.

So thanks for having us, Sara.

Hi, I am Samira Farouk.

I'm a transplant nephrologist and program director of the Nephrology Fellowship

program at Mount Sinai in New York City.

Um and relevant for this, I've been part of the Neph Madness Executive

Committee for the last several years, and really thrilled to be here.

And thank you to the Febrile podcast for hosting us.

Before we jump into Neph Madness, we always ask one question.

As everyone's favorite cultured podcast, if you could share a little piece of

culture, just something fun, non-work, related that brings you happiness.

I just did a [The] Pitt marathon.

Um, and though I found it like sort of stressful, it's also sort

of relaxing to see medical cases where I don't have to respond.

Uh, so, uh, I did a, a major like four hour Pitt binge fest just

yesterday and uh, it was a good one.

Very nice.

I am a huge, uh, sports fan and will watch any sport,

particularly love women's sports.

Been watching a ton of Olympics.

It's gotten very stressful in the figure skating arena, so

taking a little bit of a break.

But any sport on TV will be my kind of go-to.

Some of the women athletes had a pretty good quote.

They said, why is it focusing so much on women's competitions?

And they said, when?

When the men get as many gold medals as the US women, perhaps

their coverage will match.

Yeah.

I'd say for me, I'm a huge classic rock fan and a lot of my travels

and sort of activities center around trying to make it to a concert.

Usually people's last concerts as they're doing a farewell tour.

I saw Fleetwood Mac's 50th anniversary concert.

Best concert ever been to, I hope they don't tour again.

So that's like I saw the last round.

So, growing up in Southern India, I am deeply passionate

about South Indian cuisine, and I believe it's the best food in the world.

I am constantly on lookout for the best South Indian restaurant in New York City.

And if you are ever in this part of the country and you need recommendations,

I will be delighted to help you out.

I will take those recommendations later.

Well thank you guys so much for joining.

It's so fun, obviously, uh, Febrile we tend to have a lot of ID

guests, so it's nice to have a mix.

We have some kidney folks with us today.

For those who aren't familiar, Samira, could you give listeners an

overview of what Neph Madness is?

And how to participate?

Yeah, definitely.

Um, so just before we get into it, I think for people that are familiar

with Neph Madness and the nephrology community, Neph Madness is a very

special, exciting time of year.

It's almost like the holidays.

And so we're really fired up getting close to it.

So it's an annual online educational initiative, which, uh, when it

was started and how it was named is, inspired by March Madness.

And so for those of you that might not know, March Madness is a US

college basketball competition where college teams are pitted against

each other in a bracket, and then at the end you have one winner.

So kind of take that bracket, replace geographic regions with nephrology

topics and replace those teams with subtopics within those regions.

And so, we ultimately have a bracket of 16 topics, and to play Neph Madness,

your job is to read our scouting reports about each of those topics,

and then complete your bracket to pick a winner for each section and then

eventually a winner for the competition.

So how do you win?

Uh, you want your bracket to match that of our Blue Ribbon panels bracket.

So that's a group of experts from around the world, patients we try

to represent as much as we can.

They actually complete their voting before the tournament begins on

March 1st, so we know what the right answer is before we start.

It's in a special locked envelope somewhere that I don't have access to.

Um, and during the month of March, the goal is to not only complete

your brackets at nephmadness.com, but also to learn about these topics,

to talk about these topics in your favorite social media platform.

Uh, many fellowship and residency programs, uh, will have sessions

where they go through these brackets.

Um, our team actually puts together a pre-made slide set that you

can use if you're interested in hosting a session at your program.

And, uh, we've also had some friendly fellowship, fellowship competition

once the bracket results get announced.

So, uh, we're here today to talk about one of the sections.

As a transplant nephrologist today is the transplant region.

And I will say that I've been a part of Neph Madness, uh, since I think 2019.

And I have been begging for these two teams to get into the tournament

and they finally let them in, mainly because of some of the exciting

things that are happening with them.

The title of the region is called Trolls of Transplantation.

So we have team number one.

It's gonna be the very scary BK virus.

And on the other side, I know that Jeannina will call, uh, CMV,

cytomegalovirus, the troll of transplant.

And, um, I think it's really exciting to have these two topics at the intersection

of not only nephrology, but also transplantation, infectious disease.

And I think they really highlight how multidisciplinary and very

complicated transplant patients can be.

So before we get into the specifics, just a quick overview.

BK is a polyoma virus that lies dormant, sleeping in the kidney.

Can cause graft damage, when it's, uh, basically reactivated and

really in very important cause of allograft loss in a high number of

our kidney transplant recipients.

Whereas CMV cytomegalovirus, which I recently learned as part of this is herpes

virus number five, um, that we can ask Jeannina why we never call it by its other

name, um, is the most common opportunistic infection in kidney transplantation.

And of course has serious, both systemic and kidney allograft consequences.

And so today we're gonna kind of unpack, uh, why these two uh, viral

bench warmers have become so dominant.

What makes them, uh, so important and of course why they're gonna, one of them I

hope is gonna win the whole tournament.

I love it.

Yeah.

I'm personally biased that I feel like I think about these every day.

So,

um, all right.

Well I am gonna hand it over to Hari and Caitlyn to walk us through

some of the background and then up and coming things as we think

about CMV and BK in transplant.

Sure, thanks.

So I can get us started.

I think it's probably important before we get into how we sort of monitor and

treat these viruses to talk a little bit about the biology because they're

quite different, the two viruses, and how we specifically, how we treat

them, I think really, relies on our understanding of what they are and,

kind of the specifics about them.

So BK, as Dr. Farouk mentioned, is a small polyomavirus.

It's about five kilobases.

So really small.

It only really encodes, uh, not much, uh, just sort of the viral capsid

protein and not much that we can target.

So when we talk about treatment, we'll see how a lot of what we do

is really just trying to allow our immune system to handle it, but

there's not much in terms of kinases, polymerases that we can target.

It, it hijacks our host immune machinery to be able to

replicate and become problematic.

And so it, lives in the uroepithelial cells and tubular

epithelial cells of the kidney.

And when it becomes activated, that viral replication causes issues

directly locally to the kidney causing kidney damage that we end up seeing

manifest, uh, if we don't treat it.

So it's quite different, as I mentioned from CMV and maybe

Hari can give us a bit about CMV.

Of course.

So, compared to BK, CMV is the large DNA virus, and in fact, in the herpes

family it has the largest genome.

And with this genome, it also expresses a lot of protein.

The most important of which is the polymerase enzyme and the kinase,

meaning that we have targets to, uh, use pharmacological therapy for.

So unlike BK, along with immunosuppression, we also

have medications that we can use to target these proteins.

Unlike BK which goes and hides in the urothelial cells.

CMV hides within the hematopoietic progenitor cells.

So when it reactivates, it's a systemic disease, it can affect any organ,

including the kidneys, and hence has a very high mortality and morbidity.

Jeannina, anything you wanted to add to that?

I think that it's really important to consider, uh, Sara knows

the, the 2026 is supposed to be the year of the host where we consider the host

pathogen interaction, and I love that both of you mentioned the importance of

considering the host's immune response.

I would actually argue that modification or reduction of immunosuppression is

the cornerstone of therapy for both.

Although it's shares it's position at the top with the

antivirals, in the case of CMV.

Okay, so maybe we can next move on to how we screen or

watch for the emergence of these viruses in our kidney transplant recipients.

So, starting with BK first.

Usually as mentioned, it's something that a lot of people

just carry without knowing it.

And your native immune system can survey for them and, and keep it under check.

But in the setting of transplant, we don't really screen to see who has

what BK serotype, uh, at baseline.

We just usually screen everyone.

And so for, I think the protocols can vary center to center, but in general, you're

screening for DNA of BK in the serum.

Usually on a monthly basis, for the first while.

And then, uh, every three months we're usually about the first two years.

But again, I think center to center variability.

Then after the first two year period, and even within that first two year period,

but especially after you're watching for, um, needing to test for cause.

So if someone has an AKI [acute kidney injury], if you've recently treated

for rejection or if you've recently increased immunosuppression, there

are certain cases where you may wanna retest for BK to make sure that that's

not at play either contributing to worsening graft function or kind of

in the process of reemerging in the setting of decreased immunosuppression.

And there's a lot of cases where you're personalizing when and if you're

gonna be screening for it as well.

So what do you do when you find BK?

It, it, again, center to center, some variability, but depending

on the viral load to some extent.

In general, if it's less than 10,000, we might repeat it to see if it's

persistent a week or two later.

But again, the focus should be on finding it and confirming

that it's truly there early.

Um, if it's above 10,000, that's fairly diagnostic of BK associated

nephropathy or very high risk.

And so in both cases we will we'll discuss the first step

is to reduce immunosuppression.

So the degree to which or what you'll do, depends to some extent

how severe you think the BK viremia is, and if you think there's already

some associated graft dysfunction.

And there's been various strategies, uh, discussed including

whether you do anti metabolite reduction or CNI reduction first.

So I think it'll be great to hear about what some of the experts do

in practice or what they've seen.

Um, and then just important to mention, I think that in certain

cases, biopsy is warranted and so especially, if there's an AKI, often in

children, they'll do biopsies as well.

And then especially if it's a case where the individual is considered higher

immunological risks, so if they've had prior rejection or a recent DSA

positive, you may want to do, um, a biopsy because the risk of reducing

immunosuppression may be greater.

And then of course there's a lot of clinical judgment that

comes into how exactly you're, you're managing all of this.

Yeah, I'll just add to that.

Thanks, Caitlyn.

I think the screening can be very tough, uh, particularly when

you get out from the first year.

I think most transplant centers like, uh, we do at ours.

We're screening for BK virus every month and everything is protocolized.

When the patient leaves the hospital, those tests are in and basically,

you have a plan for 12 months.

I think what happens after that, it becomes a little bit more nebulous.

And I think we all have different approaches.

I feel like I modify mine a bit, uh, based on the person in front

of me, but I think I try to check it at least, once a year if I can.

And I think something that makes a BK so challenging is that is the completely

asymptomatic nature, not to kind of jump ahead to, you know, voting on

the bracket, but, but it's really silent and, you could just check it

randomly and find a very high number that you're surprised by because we

have not great ways to, to predict it.

And then, um, as you were kind of alluding to with when we do a biopsy or

not, the treatment is, is tough without any, uh, for now targeted antivirals.

Um, who can you lower immunosuppression on or not.

And we have new tools now, like, donor derived cell-free DNA, that can help

guide us a little bit more, um, as a non-invasive biomarker that can tell

us not specifically about the presence of rejection, but about kidney injury.

And so in most of the time when we talk about donor derived,

cell-free, DNA, we're talking about screening for subclinical rejection.

However, if somebody has BK nephropathy, they can also have release of that DNA.

It's, it's still injury to the kidney cells.

Um, but, if you're lowering immunosuppression, that might

be one way to, to look for the potential development of a rejection.

So the screening, I think, again, the take homes are that

there's no really, uh, rules.

Um, once we get past the first year, you can have it any time.

You know, we have a mnemonic that we use for AKI of the kidney

transplant "CRAB" and the B stands for BK and other viruses like CMV.

So BK, again, taking a stand.

Yeah.

And when we talk about prevention of CMV infection, um, I think it's most

helpful when we think of CMV as a problem of the lack of educated T cells or the

lack of the activity of those T cells.

And so, I think understanding that concept means that we don't have to

memorize all R this, D that , but instead to say, does the person have

preformed T cell immunity to CMV?

And if so, what are we doing to put a boot on the neck of those T cells?

So, I think when you think about it that way, it's really helpful.

And so we do know that if you don't treat with antivirals and someone has CMV.

If they're donor positive, recipient positive, if they've had the virus

in their body, that they have an extremely high incidence of

developing viremia, meaning you can detect the virus in their blood.

And actually further, they have an extremely high risk of developing

CMV disease, either CMV syndrome, where they feel sick, they feel

virally, they have fevers and aches.

Um, and during that they may have some transaminitis and

some cell count problems, or CMV disease where they actually have

infiltration of their tissues.

And in kidney transplant recipients, that's most likely

gonna be in the GI tract.

Um, and so we know that we have to do something to prevent that.

And prior to, the drugs that we have available now, um, this was a horrible and

hideous and deadly troll of transplant.

But when we developed drugs to help us and protocols to help us, um, manage

this infection using antivirals, the troll shrunk and became more manageable,

but it's still under the bridge.

So if you ask me my opinions about CMV prevention, I would

say that it's evolved over time.

And so, I'm an ID doctor and I like to quash those viruses, and I don't

like the idea of chronic inflammation.

And so 10 years ago, I would've told you, without a doubt, use our

best drug and use it hard and help prevent that virus from waking up and

coming out of the cave of latency.

I think that I've evolved and become softer with time towards

the virus as I understand the importance of the immune response.

And so what we've seen is that especially when someone has no preformed immunity

to CMV, giving them a little taste, um, allows them to educate their T cells

and have some protection down the road.

So in the old days when I crushed that virus and made sure that there was no

recurrence, at some point it's like, while we're talking about games, the game of

kick the can because, um, we knew patients couldn't stand antivirals forever.

It was too toxic and too expensive and too difficult.

And so what we found is that they would delay CMV but not infinitely.

As soon as you came off antivirals, there was a high risk

of post prophylaxis infection.

And what we're seeing is with some of the other preventative measures, so

universal prophylaxis can either be done nowadays with, uh, ganciclovir product,

usually valganciclovir or with letermovir.

Um, and there's preemptive monitoring.

And what that is is checking CMV frequently because we know that

viremia precedes clinical disease.

So as it turns out, we first got a whiff from liver transplant patients that the

patients may do better overall if you allow them to develop some CMV specific

immunity by using preemptive therapy.

And interestingly, um, I was also maybe a bit of a naysayer about letermovir

because it doesn't crush that virus the way that I like to crush the virus.

Um, we often have low levels of CMV viremia, a little bit of breakthrough.

And at first I thought that was a terrible, terrible idea.

But as it turns out, it gives our immune system a little shot at the virus.

And so we are seeing better development of T-cell specific immunity in that group.

Um, and there's some other advantages that we can talk about later.

But those are some ways that I can think about and approach how I prevent

CMV in my transplant recipients.

I have a, a little bit of a naive question.

So we know that for both BK and CMV, you know, the majority of adult population

has been exposed and were seropositive.

So for CMV, is it because immunocompetent people are not becoming viremic, that they

don't have any sort of T-cell response or how, how can there be IgG but...

So, yeah, so I, it's not quite the same.

So almost everybody has BK and JC virus, and we know that though it

says in the nineties, it's the high nineties by the time of adulthood,

people have had this virus.

CMV, like most of the herpes viruses, has to do with our human human interaction.

So there is no other place to get the human herpes viruses.

Those are from close contact with other human beings.

And so it does have some correlation with risk behavior, and I think this

is something many of my recipients find very interesting in that, um,

a transplant recipient or potential recipient has a much lower risk of having

had prior CMV than does an organ donor.

And some of this has to do with comfort with risk behavior.

So our recipients may have been chronically ill and careful and

avoiding contact in the ways that we get human herpes viruses, so

close contact with bodily fluids.

Um, whereas our donors may be more comfortable with risks in life, that

may lead them to be more likely to be organ donors, but it also may lead

them to have more human herpes viruses.

So we do know that donors have a much higher rate of positivity.

So I think that's one of the reasons.

Certainly we know that there are different serovars and that, for example, an

organ recipient may have some preformed immunity and still get a different

CMV and still may get acutely ill.

Or it may be more.

And I think this is what I think is that our T-cell immune suppression is

powerful enough that we're not allowing that preformed immunity to come back.

But those are the patients I worry a little bit less about in the long run.

So again, once we've taken our boot off its neck and it's not quite

holding down that those T cells quite as strongly that person's preformed

immunity can come back and help.

But those that had never made immunity in the first place, there's these gentle

baby steps of showing it CMV, but not letting CMV absolutely clobber them.

Um, seems like it's gonna be helpful.

Wow, that is a really fascinating, that was not

the answer I was, uh, expecting.

Um, Hari, thinking about what we discussed so far about CMV, anything

that was particularly interesting as you were learning about this section,

as you prepared the scouting report.

So as I was preparing this section, one thing

that was new to me was the preemptive approach because at our center,

we, uh, do universal prophylaxis.

And, as Dr. Smith was mentioning, one thing that is striking was like

allowing the body to be exposed to the CMV virus and antigen to

build his own immune response.

That is completely shut down by using valganciclovir.

And I was just wondering what the downside would be of using preemptive therapy.

And then I realized that like, you know, weekly screening, uh, timely

following up of resource and like, you know, initiating the treatment at the

right time, these might be challenging.

So I think it's just very institution dependent if you have the resources

available, I think preemptive treatment will be a very good option as well.

Do we know if there's a, has anyone ever asked patients

what they, what they prefer, from just patient quality of life standpoint,

preemptive versus a universal?

I mean, I certainly think there are some patients that

hate taking medicine every day.

I think that some of this has to do with the population and how spread out it is.

Um, I come from the University of Wisconsin where we are one of the

largest transplant centers in the country, and we have a catchment, not

only all over the country, but all over the world, including some of the

pretty rural areas of the Midwest.

So I find that I would worry very much about the ability to get a lab reliably.

We have lots of snowstorms and difficulties get a lab reliably that I

need to respond to because the danger, and it is not a small one, is if a patient

is lost to follow up that viral load can sometimes shoot through the roof and you

need to be able to respond to it nimbly.

And if you're not able, um, one of my colleagues who was the medical

director of transplant infectious disease at Northwestern, I always

felt he was very spoiled because in many cases that's a big city.

He might have the similar number of patients, but they were all within a much

more tight area, um, to the hospital.

So they were able to get away with things so that I couldn't, when half my patients

were in rural areas of the Midwest.

Yeah, and I can share, we have a nice graphic, there's a chart in the

AST ID Community of Practice guidelines that has the like compare and contrast.

Hari, like you were mentioning, of prophylaxis versus preemptive therapy.

And I think the other thing to just say is I don't think it's always black and white.

I think a lot of centers have a hybrid approach

Mm-hmm.

where they do have someone on prophylaxis for whichever

agreed upon period of time, probably based on their sero status risk.

And then have some sort of preemptive monitoring after that.

And so I think, just like you said, comparing, you know, for that individual

patient, what's gonna be harder?

Is it gonna be getting those labs or, um, is it an issue with

toxicities from the meds and so on.

I went to a really fascinating, a few American

transplant congresses ago.

They had a whole debate, I think it was an hour, just about this topic.

And maybe for next Neph Madness, I can get them to give CMV an entire region

and then we can just do more of this.

Um, all

You.

Alright BK has been lying, BK has been lying dormant.

Uh, so Caitlyn, tell us about why BK has no, uh, really enemies right now

and no antivirals that have worked.

Yeah, I think it's just strategically very, very

small and it doesn't have really any targets on its surface or any viral

proteins that it uses to replicate.

So as some of the agents that we've talked about for CMV, they target some of the

polymerases, the kinases, whereas BK, they're starting to develop monoclonal

antibodies from what I understand, to the sole viral capsid protein.

But there's not much else that can actually be targeted.

So other than boosting t-cell immunity through reducing

some of the immunosuppression, there's not much that we can do.

I will say that in some of the future, uh, kind of therapy section that we cover.

There's some exciting, I think, new data on specifically posoleucel, which

is, uh, giving patients off the shelf T-cells that target not only, uh, BK but

also five other viruses including CMV.

And so I was wondering, I don't have any practical experience with this.

I was just wondering where we're at with that clinically and do we see

this being a promising future therapy that, you know, in five, 10 years

that a lot of people will be on?

Or where do we see this going?

I guess I'd like to hear from what a lot of the experts think on this.

Yeah, I think it's a challenge because those,

they have short half lives.

They have to be used pretty much right away.

When I first heard about this, I was very, very concerned to be honest

about graft versus host disease.

'cause the other part, uh, other hat I wear is not just solid organ

transplant, but liquid transplant as well.

And, and that's certainly a devastating complication that I have

seen with solid organ transplant.

But thank goodness, not very often compared to the other patient

population that I care for.

And so I was assured that these cells don't persist or replicate in the body.

That made me feel better in terms of risk for development

of graft versus host disease.

But it also makes you feel worse when you realize they won't last a long time.

So they work in the very short run, at least the current iterations.

Um, but they won't, um, be a good solution over time, because they would

require frequent infusion of the cells.

Um, we had a protocol, and I have used this for patients when we

had severe and refractory CMV.

And I have to say that, um, I wanna give a shout out to another

MVP of the team, which is our transplant and ID pharmacists.

So at University of Wisconsin, we have the first in the world, an antiviral

stewardship service that assists our solid organ transplant programs and they

assess the immunosuppression, the CMV status, the CMV medications, and then

if there's breakthrough viremia, assists the transplant teams in modification

of immune suppression as well as antiviral selection and monitoring.

And so we are for sure the spoiled brats as clinicians and our patients

have done tremendously wonderful since the institution of this service.

So thank goodness we went from having multiple patients who experienced what

I think is the, the real tragedy in CMV, which is drug resistance, with

ganciclovir resistant severe disease, to having almost none every year.

Um, and I going to give a lot of the credit to those MVP colleagues.

Um, so I, as we've moved to having some new agents in the

armamentarium, I feel less inclined to think that the T-cell infusion

is gonna be the long-term solution.

I think it's still gonna be reserved for really severe cases, but, I think

we've learned a lot about CMV and how it interacts with the immune system.

And I think that with our current drugs that are available, it will continue to

be like, not something that every patient gets but used only in special cases.

Sara, what do you think?

Yeah, I've only used it in those settings for

refractory stem cell cases.

I don't actually think , I've necessarily had one for a

solid organ transplant patient.

But yeah, I have nothing additional to add.

I, the only thing I was gonna say is I was muted, but I had an audible gasp

at the thought of having an antiviral stewardship team, and that sounds amazing.

Yeah, it's pretty great.

Shout out to all the amazing pharmacists.

They're the best.

So.

Um, I have another, uh, maybe, uh, naive question.

So we have six viruses for kind of the price of one with the posoleucel.

What is the reason for that?

Is it because it's easier to train them on six at a time?

Or why?

Why do they do it that way?

Do we, do we know?

Yeah, I mean, I think that, um, I always talk to my

learners, I always say, you know, you gotta look, if you see one sexually

transmitted infection or pregnancy, you get those infections the same way.

So you always have to think about all of them.

And I think, again, when we're really thinking about the host, it's important to

remember that none of these opportunistic infections occur in isolation.

They occur because the host immune response is depressed.

And so, it's long been lore that CMV is associated with

other opportunistic infections.

And our group did show that that is in fact the case.

And so I think it's important to remember that, many of these infections, BK and

CMV especially, are actually markers.

They're markers that the immune response has been depressed.

And so I think that that would be a reason why a more pluripotent, uh,

T-cell would be valuable because you're not just at risk for BK

because of your depressed immunity.

You're not just at risk for CMV, you're at risk for EBV and many

other different infections chronic norovirus , um, other real scourges

for our, our transplant patients.

And so thinking of it in that setting, I always say kind of

considering the whole patient.

Um, I just discovered, so my, my oldest child is about to take his driver's

test that they don't require parallel parking training anymore to pass the

driver's test in Wisconsin at least.

But this, um, is a powerful marker of failure in my life, uh, is

to learn how to parallel park.

I'll still choose not to if I have any choice, but I think of getting

that sweet spot of immunosuppression exactly like parallel parking.

If you do it right, you slide right into that spot and everything's good.

But if you do it wrong, you're hitting the back bumper.

You're hitting the front bumper.

And so I think of the front bumper as rejection.

You have not enough immune suppression and that back bumper

is opportunistic infection.

Um, and so CMV is really hitting the bumper hard, so is BK to tell us that

we've over immunosuppressed that patient.

So I think on occasion it feels like for some of my patients, boy, that that

parking spot is so narrow, it's almost impossible to slide them in without, um,

getting the, uh, bumpers on either side.

All right.

Maybe let's move from posoleucel to, uh, therapies that we actually use.

Um, Hari you wanna tell us a little bit about the current state of CMV treatment?

Of course.

Uh, so before we get to the treatment, I think it's important

to understand the difference between CMV infection and CMV disease.

CME infection is defined as CMV replication, which is identified by

using CMV PCR or antigenemia tests.

CME disease, on the other hand, is CMV replication with associated symptoms.

It could be fever, thrombocytopenia, leukopenia, or it could also

be tissue invasive disease.

And, uh, the treatment of which is determined by how severe the disease is

at presentation, we either have an option to do oral valganciclovir or ganciclovir.

There has been studies showing that the oral treatment is

as good as the IV treatment.

And if I were a patient, I would obviously choose to oral option, but

we still do use IV for severe disease or high CMV viral load at presentation.

So this is our first drawing option, both oral valganciclovir and ganciclovir.

These work after being activated by the kinase on the DNA polymerase.

If the patient continues to have high viral load or rising viral

load or worsening tissue invasive disease after two weeks of treatment,

we call it refractory disease.

And if the refractory disease is associated with resistance, then we

call it as a resistant CMV disease.

And for the treatment of refractory and resistant disease, we have a

new kid on the block, maribavir.

It has been shown to be as effective as foscarnet, which basically, as you

all know, is, uh, very nephrotoxic.

We don't like to use it unless we have to definitely use it, and we still use it in

case of extremely severe disease, in which case we prefer foscarnet over maribavir.

And so Jeannina of the, um, new therapies, do you feel they weigh

in compared to what we have already?

So without question, ganciclovir and valganciclovir are still

the GOAT, when it comes to treating these infections, they're extremely potent.

They're extremely effective, but they do have adverse effects.

So I think there's, there's a couple things that I would kind of

reinforce, uh, about those agents.

One is that when you're treating CMV, I just told you earlier that I've gotten

much more comfortable with the idea of giving the patient a whiff of CMV virus.

When you're treating CMV infection or disease, you cannot

show that virus your cards.

You have to be very, very mindful that you are hitting that virus with the

optimum dosing of those agents because the development of ganciclovir resistant

CMV is challenging in the best case.

So, one of the things that we encounter is people adjusting, um, too aggressively

down because of variable renal function.

I don't advocate for that.

I don't advocate for adjusting down your dose because you have cytopenias.

So you may get cytopenias.

They actually may reverse with treatment with ganciclovir because

they're caused actually by the virus.

But the last thing you wanna do in the setting of disease

is to under dose your GOAT.

So you wanna make sure that you're supporting them with GCSF if necessary.

Um, but you're not gonna decrease those doses.

When we have had refractory disease, I think having maribavir

available has been pretty amazing.

It is more effective than the very, very toxic foscarnet.

One of the things that I would highlight, however, is you got

maybe one shot, uh, and maybe not.

In those trials there was 28% development of resistance to your maribavir.

So you wanna be really cautious to protect that and to not use it

when the viral load is too high.

I think those are cases where you're definitely gonna still see failure.

We had hoped that maybe at doing adjunctive therapy, using more than

one antiviral, like we do for our hyper mutable RNA viruses would be helpful.

But in our group, we did not show that to be the case.

So I'm not saying that you couldn't try it, but it wasn't

effective when we trialed that.

So I think maribavir is a fabulous new drug to have in the armamentarium.

Think about the viral load.

Again, the viral load tells you how much replication is going on, and every time

there's replication going on, there's the chance for mutation every day.

So, the lower the viral load, the less chance for a mutation, the safer

it is to use a drug like maribavir.

That's even further for letermovir, which is why we use it for prophylaxis.

As it turns out, that has a small, very low barrier to resistance.

And so even very low viral loads will break through with resistance.

So I, I think the, the goal should always be to never develop a drug

resistant CMV, because once that happens, it's really hard for the patient.

But I am glad that we have options like we do now.

Thanks.

And, uh, this is a question for both teams, BK and CMV, what are your

thoughts about IV immunoglobulin for either, is there a role for them?

My students will tell you what I say.

I call it witchcraft.

We do it sometimes, but it's not really that different than waving

a chicken foot over the patient.

I will say one thing that I like about it when we use, uh, IV immunoglobulin

is that at least for antibody mediated rejection, there's some prevention

when we're using immunoglobulin.

And so as I'm begging the transplant nephrologist to drop that anti

metabolite off and perhaps reduce the immunosuppression further than

that, um, I think it makes us all a little more comfortable that we

have a little protection on board.

But I don't think that antibody or B cell is the major feature

of immunity to CMV or frankly BK.

And so I don't see it being reasonable that those would have a big role.

Sara, do you like 'em or do you, do you use them?

Um, I agree.

I think sometimes we use them just because.

I mean, I think for patients that you are suspicious or maybe they have hypogam for

other reasons, like looking at their IgG

Absolutely.

and repleting them.

To me, those make the most sense.

But I, I agree.

I think there are times where we're using them, a little more

sort of willy-nilly than that.

So.

They're, they're wishful thinking.

Caitlin, did you find anything to support use of IVIG in

patients with BK viremia, BK nephropathy?

Um, not much.

Uh, I think we included one link to something that

I,

had found, but honestly not much.

I kind of set you up for that.

I heard the papers kind of rustling.

There's very little, and, you know, I think that sometimes, people just can't

resist themselves and, you know, we've lowered all the immunosuppression.

They're on barely anything and we have nothing else.

So let's just give some IVIG.

Um, and I, and I think, you know, most of the time we see no, you

know, quote harm, but we actually did recently, in our center see a patient

that we think developed a TMA from IVIG, which has been, uh, reported.

So I think, uh, very few things are completely without any potential harm.

Yeah.

Yeah, I've for sure, um, seen patients get meningitis from

IVIG that was given in this setting and aseptic, but it certainly affected

their, how they felt and it's sad.

Um, so Sam is our expert for the BK team.

Sam, can you give us your take on what do you think is the current state of

BK treatment and how do you predict our new therapies are going to change

how we are able to deal with BK?

Well.

Know, to be honest.

Um, I always look at BK as, you know, one of those things that tells you that you're

actually immunosuppressing a lot more.

You know, I, you know, trainees always ask me, how, how do we

really make sure that we're actually immunosuppressing well or less?

It's a nice surrogate, I feel in many ways.

And then once you have it, you kind of know you need to kind of really pull back.

Of course, it's very obvious, but I think the steps in which people go about it can

be very diverse, but the best evidence is pull back on the anti-metabolites

and then kind of take it from there.

I, I think we've had a good discussion on IVIG.

You know, I think that's probably the best that's out there if you, if your

immunosuppression reduction isn't working.

I think there's another, a lot of studies from France that, you know, they've

actually looked at neutralizing antibodies that IVIG actually contains, because, you

know, you're exposed to it as a child.

Where I think 90% of, um, children would be seropositive at some

point, based on many studies.

But coming to the future, I do think there's promise anyway.

Now they're developing, um, you know, whether it's various viruses

that actually act against, uh, BK.

But I think it's about just keeping it simple, you know, I mean, making

sure you reduce the immunosuppression at the right time and above all,

have good surveillance, you know, um, we really get enthralled by new

therapies when, uh, simplicity might be the best form of sophistication.

Yeah, KISS.

Keep it simple, stupid.

That's the, maybe the punchline for both of these teams

There you go.

As we kind of wrap up or get close to the end here,

thinking about how do we surveil how immunosuppressed somebody is, would

love to hear anybody's thoughts on something I'm really excited to be able

to use in practice, torque teno virus.

What do we think about torque teno virus?

I'll jump in.

To be honest, it's promising for sure, uh, but I don't think we've studied

it enough to really come forward and say, this is what it is, I think.

You know, they've employed using it in, in guiding immunosuppression as you state,

but you know, what are the outcomes?

You know, is does this really help?

To, to, to really, um, you know, what, how often would you check it?

And how would it perform in different immunosuppression regimes?

I think so many unanswered questions.

Again, I think, uh, our good old BK, is, is enough I feel on that front, you know.

Why forget the, the, the old and gold, you know.

All right, so another Neph madness, BK versus, uh, TTV.

We'll see, uh, how it goes.

Um, ID, uh, experts.

Are you excited about TTV?

Are you just like Sam, not as excited.

I.

I say I'll believe it when I see it.

I was always taught that when you see a lot of new, uh, articles saying

that this is the new way to diagnose ventilator associated pneumonia, this

is gonna be the new way to hit the sweet spot for immunosuppression.

That probably means we haven't gotten there yet.

So we get the data, that'll be great.

I love the idea of my patients being optimally.

Im immunosuppressed.

Maybe it's like from our discussion early, the car commercial where

the car parallel parks itself.

That'd be super, um, but, I think I'll believe it when I see it.

What about you, Sara?

Yeah, I agree.

I, I don't know that we know quite how to use it yet.

I think we're a little bit closer to hopefully knowing how to use

CMV specific immunity assays.

I will fully admit, I still think there's more to learn there on

exactly how we can use that to decide you know, prophylaxis and, and who

Yeah,

take off or not.

But I think that's something I've tried to bring into my practice, at

least for more challenging cases as one other piece of data to try and

help make a specific plan when those typical, you know, algorithms don't,

don't help you manage things like CMV.

So hopeful that feels sooner on the, on the timeline as far as

incorporating into everyday practice.

I agree.

All right.

Maybe before we get to our final votes, anything else y'all wanna

share about any of these two teams that we haven't highlighted?

One thing that we haven't talked about is the origin of the names, uh, which

I think both are, fairly interesting.

Uh, BK named for the Sudanese patient from whom it was isolated

in the UK and cytomegalovirus, cyto for cell, mega for big.

So referring to those big owl eyes that we see on histopathology.

I would like to point out that the JC virus, the other polyoma

virus, was named from a patient at the Madison VA Hospital, John Cunningham.

So, uh, I feel like a little, uh, special link to those polyoma viruses.

I would also like to point out.

Google it.

It's always interesting, which person thinks owl's eyes is in their particular

purview because the hematologists love to think about their Hodgkin's owl's eyes,

whereas an ID doctor, I have a particular partiality to CMV megaloblastic cells.

We have a similar issue with the Maltese cross.

Also a hematology

Oh yes.

Fabrys.

problem.

Yeah.

We have that in ID too though, 'cause that's Babesia for us.

Yeah, for us it's the fatty oval body when you polarize

it in patients that have lipiduria, and, um, nephrotic syndrome.

all right.

Very cool.

So, most important question, how are you feeling at your bracket?

I think people are maybe a little bit biased, but we'll see.

Um, so we'll just maybe go around the horn here and, uh, tell us who you're

voting for in this bracket and why you think they are the better team.

Um, so maybe, uh, we'll start with Sara because,

Oh, no.

the least skin in the game here.

Um, I mean, I have to vote CMV here.

I don't, I don't know if it's just as an ID doctor.

I, I think about, talk about, see CMV every day, and there's just so many new

things I feel like we're on the cusp of really understanding in the coming years.

So that's, that's my pick.

All right, Sam.

Um, I think, I think you know the answer to that

for me, it's BK of course.

Um, you know, as much as I have to say CMV is, um, definitely a, I have a

little more interesting when it comes to management, a little more because

you have more things to treat it with.

Um, but you know, I, as I said, you know, it's, it's such a good surrogate for how

well you're doing with immunosuppression.

Um, and above all, you know, I think, um, if you catch it early, you really, you

really make sure that patient outcomes and graft outcomes are excellent.

But then, we can really treat it well.

You know, once you get a really good handle on it.

CMV, if you don't have a good handle on it, can really, really, um, go through

it, but I think why I feel more aff affinity towards BK if that, if I could

use that term, is, um, I mean I think I've really enjoyed, uh, in, in transplant

nephrology from the start and probably my mentors that I've had, uh, have really

pushed me in that direction, you know, and I, so it's, I think it's an ode to

my mentors rather than anything else.

Um, that's why I think I choose BK as well.

All right, Jeannina, you're up.

I mean, on.

Of course.

I think so.

CMV is the most common opportunistic infection after transplant.

It's tremendously impactful.

We've had a bevy of new drugs available in our armamentarium.

We have improved outcomes for hundreds of thousands, if

not millions of our patients.

Uh, I think without question, one has to give the love to our favorite,

least favorite herpes virus.

CMV.

Strong words.

Uh, Caitlyn, you can see how you can fight that.

Yeah.

So I mean, it's a tough call for me.

I feel some amount of allegiance to BK, um, having contributed

a bit more to that section.

But I, I do think ultimately that's probably gonna be my pick mainly

because it's, I see it in some ways as sort of the nephrologist virus.

Like we're sort of the only ones that really see it and then treat it

and then, you know, think about it.

Whereas CMV again, devastating, lots more morbidity, mortality, I think in general,

associate not just thinking about graft loss, but it, it feels something special

that we sort of hold and, and watch for.

So I, I like that side of it.

Yeah, it is Neph Madness in the end, you know, so we, we take ownership,

we take ownership for what we look after.

So that's BK, you know, come on.

The bracket is devolving a little bit.

Yes, yes.

You know, I mean, uh, I know I've, I have a lot of, I've, I've, I, I

have to say, I have a lot of love and respect for ID physicians, so I do.

That's why I do like CMV quite a bit, but yes, let's, let's own what we have.

You know, it's BK

Hari, go ahead.

So, um, my vote would be for CMV.

Uh, as Dr. Smith mentioned, the most commonest opportunistic infection.

And something I found really fascinating or something that I learned during

this whole process of writing was that CMV is not just infection,

it's an, it's immunomodulatory.

It has impact on the graft outcomes, and interestingly also increases the

risk for other opportunistic infections, like aspergillus and pneumocystis.

Uh, so it has major transplant outcomes and it is preventable.

And we also have options for treatment.

So that would be my pick for, uh, this year's winner for Neph Madness.

I am gonna put in my vote, if I'm, uh, I think, uh, I guess I'm

the tiebreaker kind of, or maybe not.

Um, I'm picking this not because nephrology versus ID.

Um, I'm gonna vote for BK.

Um, the reason is that it is such a Achilles heel in many ways for

our kidney transplant recipients.

And, um, it's so challenging to tell patients that they're

losing their allograft for this completely silent virus.

That is I just learned, uh, today that is so tiny.

I didn't realize that it was so small.

Um, and sometimes, we do the biopsy.

We know there's BK viremia, we're almost hoping to find something else because

we've lowered the immunosuppression and there's nothing but just rip roaring

BK related interstitial nephritis.

And we have nothing to do, uh, but maybe kinda reach for IVIG.

And this vote is for, for hope, hopeful for better treatments for BK, for patients

in whom immunosuppression doesn't work.

Um, and then once we, uh, eradicate BK, I'm happy to focus my attention to CMV.

Excellent.

Well, I am so excited to see how the bracket ends up, how this region does.

There are a few practical things that we talked about today that I'll summarize,

but I'd love to just first emphasize how these infections really highlight how

transplant teams are multidisciplinary.

I can of course speak from my experiences.

You know, I love working together, ID, nephrology, we mentioned our

pharmacy colleagues and really the entire transplant team.

So, thinking through a few takeaways.

First, screening early and acting early.

You know, both BK and CMV tend to give you a window of warning before damage

happens, sometimes irreversible damage.

And so what you do in that window really matters.

Next, we know that reduction in immunosuppression really remains

the cornerstone, and no matter how sophisticated our diagnostics

or therapeutics become, restoring immunity is still the foundation

of care for these patients.

Next, we talked a little bit about how CMV and BK really live

in different therapeutic worlds.

CMV has a toolbox of effective antivirals, which are continuing to

expand, but BK, at least for now, really just fundamentally requires immune

restoration rather than antivirals.

And finally, biomarkers and immune-based therapies are hopefully

where the field may be heading.

They won't replace our clinical judgment, but they may help us move from making,

more sort of blunt adjustments and proceed to more personalized care.

So get out there, submit your own and group brackets for Neph Madness 2026.

The brackets are open now and submissions will close on March 31st.

Thanks again to our excellent guides and authors, Hari and

as well as Jeannina, and Sam.

You can check out the website, febrile podcast.com, where we keep the Consult

Notes, which are written supplements of the episodes with links to references,

our library of ID infographics, and a link to our merch store.

Febrile is produced with support from the Infectious Diseases

Society of America, IDSA.

Please reach out if you have any suggestions for future shows or

wanna be more involved with Febrile.

Thanks for listening.

Stay safe and I see you next time.