1 00:00:12,690 --> 00:00:13,590 Sara Dong: Hi everyone. 2 00:00:13,620 --> 00:00:17,890 Welcome to Febrile, a cultured podcast about all things infectious disease. 3 00:00:17,940 --> 00:00:22,925 We use consult questions to dive into ID clinical reasoning, diagnostics and anti-microbial management. 4 00:00:23,165 --> 00:00:25,955 I am your host, Sara Dong, and I am a Med-Peds ID fellow. 5 00:00:26,045 --> 00:00:27,665 I am joined here today by Dr. 6 00:00:27,665 --> 00:00:37,575 Camille Kotton, who is the clinical director of the Transplant ID and Immunocompromised Host program at Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. 7 00:00:37,665 --> 00:00:48,350 She has previously served as chair of the ID Community of Practice of the American society of Transplantation, as well as president of the Transplant ID Section of The Transplantation Society. 8 00:00:48,379 --> 00:00:55,580 Highlights of her time as president include development of the international guidelines on CMV management after solid organ transplantation. 9 00:00:55,790 --> 00:00:56,090 Dr. 10 00:00:56,090 --> 00:01:06,050 Cotton has also authored the past three versions of the AST travel medicine guidelines and has been an author of the CDC Yellow Book chapter on immunocompromised hosts and travel for the past decade. 11 00:01:06,525 --> 00:01:14,835 Her clinical interests include vaccinations in transplant candidates and recipients, CMV, zoonoses and travel and tropical medicine and the transplant setting. 12 00:01:14,985 --> 00:01:24,125 She is also a member of this CDC Advisory Committee on Immunization Practices and has been heavily involved in national decisions regarding COVID-19 vaccines. 13 00:01:24,405 --> 00:01:25,935 Thanks for coming, Camille. 14 00:01:26,265 --> 00:01:27,405 Camille Kotton: Great to be here with you. 15 00:01:27,705 --> 00:01:29,385 Sara Dong: I'm very excited that you're here. 16 00:01:29,895 --> 00:01:40,155 Uh, before we jump in, we're doing our classic question as everyone's favorite cultured podcast, could you share some piece of culture that you've enjoyed recently? 17 00:01:41,414 --> 00:01:49,574 Camille Kotton: I have really been, I think because of Peloton, I've really been enjoying music, um, again. 18 00:01:49,574 --> 00:01:54,255 I feel I've been listening to so, so much science and medicine lately. 19 00:01:54,375 --> 00:02:00,655 I've actually, this might be a little embarrassing, but taken to listening to Jackson Brown really loud in the car on my way to work. 20 00:02:01,025 --> 00:02:02,535 And it's just awesome. 21 00:02:05,820 --> 00:02:06,570 Sara Dong: That's perfect. 22 00:02:06,570 --> 00:02:09,660 That's exactly the kind of thing I hope people will answer with. 23 00:02:09,960 --> 00:02:22,410 Today's consult question is actually building off of our last episode, where we talked about a 70 year old, uh, renal transplant patient who had abdominal pain and diarrhea related to CMV. 24 00:02:23,315 --> 00:02:34,265 And so we're going to just adjust and build off of that case, but to refresh everyone's memory and to give you, uh, insight into the case, I'm still going to give you a little bit of background. 25 00:02:34,775 --> 00:02:36,875 So this was a 70 year old male. 26 00:02:36,905 --> 00:02:47,415 He had end-stage renal disease, secondary to hypertensive nephropathy, and had a deceased donor renal transplant about a year and a half ago. 27 00:02:47,985 --> 00:02:56,605 He was CMV donor positive, recipient negative, and came in with about a month of fatigue, abdominal pain and diarrhea. 28 00:02:56,995 --> 00:03:01,825 His maintenance immunosuppression is tacrolimus and mycophenolate. 29 00:03:02,095 --> 00:03:13,765 So inpatient, he is started on IV ganciclovir, has some improvement in diarrhea and his first two viral loads for week one and week two are about the same. 30 00:03:13,975 --> 00:03:15,685 They're 6.2 log. 31 00:03:15,745 --> 00:03:17,545 And then 6.25 log. 32 00:03:17,605 --> 00:03:30,705 He is on full dose ganciclovir, and the transplant team has decreased his immunosuppression slightly, but a team member calls you and says, "I'm worried, the first viral load hasn't significantly decreased." 33 00:03:31,305 --> 00:03:43,935 and I think this is a question that we get a lot and I was hoping you could explain the timeframe and the anticipated response to antiviral therapy in cases like this of CMV disease in transplant patients. 34 00:03:44,240 --> 00:03:44,930 Camille Kotton: Sure. 35 00:03:45,050 --> 00:03:46,850 Well, this is kind of a classic case. 36 00:03:46,880 --> 00:03:57,000 I will say this is somebody at significant risk of, major, CMV disease in that they were, um, donor CMV, donor positive, recipient negative. 37 00:03:57,540 --> 00:04:02,649 Also the age of 70, um, you know, we're doing a lot more transplants and people in their 70s. 38 00:04:03,234 --> 00:04:16,164 And we've learned a lot about the immune system, certainly with COVID-19 we've learned a lot about the immune system, And we see that also with CMV that older folks, D+R- also have trouble, um, clearing CMV. 39 00:04:16,194 --> 00:04:19,784 And they seem to have worse CMV, somewhat anecdotal. 40 00:04:20,085 --> 00:04:22,935 Um, but definitely something we see clinically. 41 00:04:23,355 --> 00:04:27,315 And then the fact this person, it sounds like had a month of symptoms before they came in. 42 00:04:27,735 --> 00:04:35,054 So the disease often seems to be pretty entrenched, you know, like significant and a little harder to eradicate in that setting. 43 00:04:35,595 --> 00:04:42,355 This has, this topic of the viral load monitoring has come up with each version of the CMV guidelines. 44 00:04:42,990 --> 00:04:43,799 And I have to say it. 45 00:04:43,799 --> 00:04:49,350 The first CMV guidelines meeting, I had 40 odd experts in the room from all over the world. 46 00:04:49,350 --> 00:04:50,280 And I was so excited. 47 00:04:50,280 --> 00:05:02,159 Cause I thought maybe they could explain to me why we start with a specific viral load, and then one week out, we often either see the same number or sometimes even an increase. 48 00:05:03,449 --> 00:05:05,850 Um, cause I thought they would be able to explain that to me. 49 00:05:06,309 --> 00:05:15,380 So what we called it, was actually not viral load, but CMV DNAemia is actually the term that we should use. 50 00:05:16,190 --> 00:05:18,020 And that's what we use in the guidelines. 51 00:05:18,020 --> 00:05:26,870 And it actually helps to really understand why your numbers aren't coming down because all we're measuring is DNA in the bloodstream. 52 00:05:27,170 --> 00:05:32,090 Like it doesn't reflect the live virus, dead virus, it's none of that. 53 00:05:32,090 --> 00:05:34,190 It's just the amount of DNA in the bloodstream. 54 00:05:34,220 --> 00:05:39,410 And you have to think that if you started treatment, maybe you lysed a bunch of cells. 55 00:05:39,410 --> 00:05:43,370 You know, maybe there's a bunch of more dead CMV circulating. 56 00:05:43,730 --> 00:05:48,050 So we often say that you can see a bump or at least not a fall at week one. 57 00:05:49,115 --> 00:05:58,175 But usually, what we said in the guidelines, is by week two, you should see some type of decrease in the level of CMV DNAemia. 58 00:05:59,465 --> 00:06:03,485 I have to say, I still sit, refer to it as far of a load because that's what we use colloquially. 59 00:06:03,485 --> 00:06:13,205 But when you think about CMV DNAemia, it does make sense that your DNA levels don't just plummet with initiation of therapy. 60 00:06:13,925 --> 00:06:21,465 I also think that when we use ganciclovir, we see a little longer, um, DNAemia. 61 00:06:21,485 --> 00:06:34,115 Then I've noticed that when patients are on foscarnet, it seems to be, um, tough acting foscarnet and they seem to have a more, um, rapid decrease in their DNAemia. 62 00:06:34,685 --> 00:06:44,585 Although that's not really a reason to use foscarnet because of the associated toxicities, but nonetheless, it is, um, something I've, I've sort of noticed over time. 63 00:06:45,005 --> 00:06:51,915 So then I guess I would say back to you, so then what happened by week two of intravenous ganciclovir? 64 00:06:53,560 --> 00:07:02,590 Sara Dong: So at this point, the viral load goes to right around five log and kind of stays there for two, really the next two weeks. 65 00:07:02,710 --> 00:07:08,980 And so the question of could this be resistant or refractory CMV disease comes to the forefront. 66 00:07:09,690 --> 00:07:21,780 And, you know, this case is quite general, but I wanted us to pit stop first and say, how do we define what is refractory CMV, resistant CMV? 67 00:07:22,110 --> 00:07:31,020 Because I think we have to be on the same page for the definition to be able to understand what's our threshold to test for resistance, and when do we need to change agents? 68 00:07:31,350 --> 00:07:32,970 Camille Kotton: That is a great topic. 69 00:07:33,180 --> 00:07:33,720 So, right. 70 00:07:33,720 --> 00:07:56,015 So good job sort of not bringing it up at week one because, uh, no one thinks that at week one, we're going to be making the diagnosis of resistant refractory disease, but usually by week 2, 3, 4, you know, sort of heading into that area, by which time we should have seen a response in the level of DNAemia as well as a clinical response. 71 00:07:56,085 --> 00:08:02,085 So that's where we should start to think of the clinical diagnosis of resistant/refractory disease. 72 00:08:02,114 --> 00:08:04,694 And that is actually first and foremost, a clinical disease. 73 00:08:04,694 --> 00:08:08,864 Like you, you know, you look at the patient, how have they responded to therapy? 74 00:08:08,864 --> 00:08:10,124 Are they still having diarrhea? 75 00:08:10,135 --> 00:08:12,344 Are they still having their CMV symptoms? 76 00:08:12,434 --> 00:08:19,219 Um, one and then two has their, um, DNAemia not improved over time. 77 00:08:19,310 --> 00:08:24,890 Um, or is it kind of more or less stayed stagnant and not decreased the way you hoped? 78 00:08:25,460 --> 00:08:26,690 So it's interesting. 79 00:08:26,719 --> 00:08:33,744 Um, the term resistant/refractory disease is actually I think a really nice one. 80 00:08:33,744 --> 00:08:43,885 It's something that we developed, really kind of fleshed out, in a working group called the CMV Forum, which is a variety of different CMV experts come to the table. 81 00:08:44,155 --> 00:08:55,315 And it's interesting because it's people from academics, clinical medicine, diagnostic companies, um, therapeutic companies, the FDA, the European agencies. 82 00:08:55,825 --> 00:09:00,550 And so, everybody's sort of comes to the table and agrees on the terminology. 83 00:09:01,030 --> 00:09:07,000 And the first part of the disease should be refractory. 84 00:09:07,030 --> 00:09:14,590 And this patient has clinically refractory disease in that their level, their DNAemia hasn't fallen the way you liked. 85 00:09:14,710 --> 00:09:17,770 Um, so they have clinically refractory disease. 86 00:09:18,280 --> 00:09:21,640 And that actually encompasses a lot of people. 87 00:09:22,750 --> 00:09:33,160 It is a time where we would recommend, as in the flow chart in the CMV guidelines that we've published, um, International CMV Guidelines, third version, Transplantation, 2018. 88 00:09:33,700 --> 00:09:42,640 That we would recommend that you send resistance testing, which is sequencing of the usually UL 97 and UL 54 genes. 89 00:09:43,120 --> 00:09:51,130 And then they may find a specific gene that suggests a certain level of resistance to ganciclovir, valganciclovir. 90 00:09:52,240 --> 00:10:00,260 We don't recommend that with that initial week one high level, but then subsequently that's where we'd start to, recommend sequencing. 91 00:10:00,820 --> 00:10:09,170 The sequencing can be pricey, so we don't just send it, um, kind of willy nilly, but, um, when it's indicated it certainly can help a lot. 92 00:10:09,950 --> 00:10:14,360 And if they find a resistance gene, which, you know, I have kind of mixed success. 93 00:10:14,360 --> 00:10:24,380 Sometimes I clearly have a patient who has clinically resistant against the disease to ganciclovir , but there's no resistance gene found. 94 00:10:24,680 --> 00:10:26,180 And then sometimes they do find a gene. 95 00:10:26,510 --> 00:10:28,810 I will say CMV is quite heterogeneous. 96 00:10:29,095 --> 00:10:36,625 So that's one thing we often think of these as being very homogeneous, but there are, it obviously makes sense that it would be quite heterogeneous in the body. 97 00:10:37,045 --> 00:10:41,995 So I think sometimes we just miss the capacity to make the diagnosis of resistant disease. 98 00:10:42,925 --> 00:10:50,685 But when we do have resistance genes identified, I usually look up what the level of resistance is to ganciclovir. 99 00:10:51,235 --> 00:10:53,765 I often use the publications by Sunwen Chou. 100 00:10:53,815 --> 00:11:13,315 I look at the ratio of, um, the resistance mutation to, um, wild-type virus and see, you know, if it's a low level ganciclovir resistance situation, then I, then I would probably go on and try to use, um, higher dose ganciclovir and see if I can overcome that mutation. 101 00:11:14,095 --> 00:11:27,685 For whatever reason, I always seem to hit the jackpot and get something that's really highly resistant to ganciclovir, at which point, sometimes I try high-dose ganciclovir, as I'm waiting for the resistance testing and come back. 102 00:11:28,045 --> 00:11:30,895 But then I often don't have success with that. 103 00:11:30,895 --> 00:11:37,225 And many of my patients until now have had to go onto foscarnet for treatment. 104 00:11:37,525 --> 00:11:42,445 What you already did often, the things that we do, which is number one, reduce the immunosuppression. 105 00:11:42,875 --> 00:11:45,005 I'll ask, can we reduce any further? 106 00:11:45,005 --> 00:11:48,935 Cause that's really, CMV is really a disease of over immunosuppression. 107 00:11:49,445 --> 00:11:53,945 And so one of the ways to get rid of CMV can be, you know, significantly reducing the immunosuppression. 108 00:11:53,945 --> 00:12:01,065 Of course you don't want to lose the organ transplant or bone marrow transplant in the meantime, but that is a significant component. 109 00:12:01,155 --> 00:12:22,215 Sometimes if they have like, hypogammaglobulinemia, I'll ask, like, could we replace their immunoglobulins with either IVIg or CMV immunoglobulin, which is really just IVIg that's enhanced for CMV highly positive donors, but those are sort of the basic things I do at that, at that juncture. 110 00:12:22,215 --> 00:12:31,805 So in the scenario you're describing, send resistance testing and then contemplate-- what am I going to do as I wait for resistance testing to come back. 111 00:12:32,735 --> 00:12:42,485 If they're sick, I would often , and by sick, I mean, life-threatening disease, sight threatening disease, you know, you're really kind of worried, this person looks pretty bad. 112 00:12:43,085 --> 00:12:44,585 I would usually go with foscarnet. 113 00:12:45,035 --> 00:12:49,025 And then if you're like, well, it just seems kind of mild to moderate. 114 00:12:49,025 --> 00:12:50,945 Like not great, but not so bad. 115 00:12:51,005 --> 00:12:56,955 Then I'll try the high dose ganciclovir, and that's usually 10 mg/kg IV Q12 hours. 116 00:12:57,815 --> 00:13:03,965 We often give pretty close to that dose, but many of these people have reduced renal function, so then you can cut it back somewhat. 117 00:13:04,505 --> 00:13:11,915 I have to say, I really, I personally don't have as much success with that, but that's what we often do as we're waiting for resistance testing to come back. 118 00:13:12,515 --> 00:13:16,335 A common question we get is, oh, can't we just do all of that with valcyte. 119 00:13:16,745 --> 00:13:20,825 But I think once you have resistant, you're suspicious of, resistant refractory disease. 120 00:13:20,825 --> 00:13:23,775 That's a good time to go with intravenous ganciclovir. 121 00:13:23,795 --> 00:13:25,955 You know exactly the dose being delivered. 122 00:13:26,105 --> 00:13:30,425 You mentioned this person has diarrhea, maybe they have malabsorption, maybe there's something else going on. 123 00:13:30,785 --> 00:13:35,375 So that's a good time to go with intravenous therapy if you are worried about resistant refractory disease. 124 00:13:35,705 --> 00:13:37,925 Sara Dong: And you've kind of touched on this as you go. 125 00:13:38,765 --> 00:13:53,405 What are the key factors that you think the ID fellows and trainees need to think about when they're sort of weighing, in that early phase -- do we think that this is a patient that more likely is going to have refractory or resistant infection versus not? 126 00:13:53,615 --> 00:13:55,325 Camille Kotton: Yeah, that's a good question. 127 00:13:55,395 --> 00:13:59,240 So, you know, who gets resistant refractory disease? 128 00:13:59,240 --> 00:14:02,960 So it is people on more significant immunosuppression. 129 00:14:03,470 --> 00:14:07,430 So maybe there they are, what we call high immunologic risk. 130 00:14:07,430 --> 00:14:10,830 Like maybe they're highly sensitized, kidney transplant recipients. 131 00:14:11,480 --> 00:14:20,840 Maybe they had like an ANCA vasculitis and went into transplant already getting like rituximab and immunosuppression in the background and then got even more immunosuppression. 132 00:14:20,840 --> 00:14:23,620 And you're already thinking like, oh, this is risky. 133 00:14:24,100 --> 00:14:30,670 If they went into transplant on Bactrim prophylaxis, that's probably a marker of somebody who's going to have problems on the other side. 134 00:14:30,970 --> 00:14:33,370 Um, you know, they went in on immunosuppression. 135 00:14:33,470 --> 00:14:42,440 The D+R- population is almost exclusively, CMV donor positive, recipient negative population, is almost exclusively where we see resistant virus develop. 136 00:14:42,830 --> 00:14:46,220 That's about 20% of transplants in the United States. 137 00:14:47,390 --> 00:15:25,035 And then, so this patient, you, you mentioned the D+R- and the age also, um, I've had a variety of older folks develop resistant, refractory disease, and it's hard because then, you know, we'd been turning to foscarnet or, um, for a few years, we were enrolling in the maribavir trial, which was a phase two, or then phase three trial, looking at maribavir for resistant/ refractory disease and comparing it with standard of care, which was either high dose ganciclovir, foscarnet or cidofovir, you know, whatever investigator, um, choice was picked. 138 00:15:26,055 --> 00:15:35,250 And I did have several patients in the maribavir arm, it's not a blinded trial in that they're either getting pills or intravenous therapy, so no blinding there. 139 00:15:35,740 --> 00:15:39,160 I had people who did really, really well with, um, maribavir. 140 00:15:40,150 --> 00:15:49,210 Sara Dong: And then my last pit stop before we go on is, you know, you've mentioned some of the genetic testing or the resistance testing we're sending. 141 00:15:49,660 --> 00:15:54,200 Can you give sort of a high-level overview of what that test is looking at? 142 00:15:54,440 --> 00:15:58,310 Camille Kotton: So there are just a couple of commercial laboratories in the US. 143 00:15:58,790 --> 00:16:05,150 Um, and if people are listening to this outside of the United States, I know that resistance testing can be hard to come by. 144 00:16:05,730 --> 00:16:16,695 Some of the commercial labs in the United States will accept specimens from abroad, but that's just a little more challenging for the shipping and all of that, but it's not something that's readily available. 145 00:16:16,695 --> 00:16:21,025 It's only done at a very small number of commercial labs. 146 00:16:21,355 --> 00:16:24,805 And then basically they take the virus and they sequence it. 147 00:16:24,865 --> 00:16:29,335 And then they're looking for the UL 97 and UL 54 genes. 148 00:16:29,695 --> 00:16:35,725 Over 90% of initial mutations will be, with ganciclovir, will be in the UL 97 gene. 149 00:16:36,395 --> 00:16:46,140 And then subsequently, um, some of these people actually go on and accumulate additional mutations, and those can be in the UL 54 gene. 150 00:16:47,040 --> 00:16:56,320 And we are even doing additional sequencing, looking for maribavir resistance and then letermovir resistance now that we have both of those. 151 00:16:56,720 --> 00:17:07,780 But the most common one and some programs for cost-savings just sequence UL 97 initially, because that's where you'll see the vast majority of resistance genes for ganciclovir. 152 00:17:08,490 --> 00:17:08,770 Sara Dong: Yeah. 153 00:17:09,745 --> 00:17:13,795 So our patient ends up having a UL 97 mutation. 154 00:17:14,395 --> 00:17:18,745 And what do you think on adjusting therapy for this patient? 155 00:17:19,585 --> 00:17:23,815 Camille Kotton: Yeah, so I look at the mutation and it's a little tricky to figure out. 156 00:17:23,815 --> 00:17:34,875 They don't actually spell out in the information they send to you, you know, like the ratio of mutant wild-type and what the likelihood of ganciclovir success would be. 157 00:17:34,875 --> 00:17:46,335 So then I usually look it up in the Sunwen Chou papers, which I save in Dropbox and, um, do a lot of Ctrl+F there. 158 00:17:46,395 --> 00:17:55,245 Um, although he has a really nice section in the CMV guidelines where he describes a lot of the mutations, but not necessarily like the level of resistance conveyed. 159 00:17:55,785 --> 00:18:05,925 Um, and depending on the mutation that we find, if it's, you know, pretty highly resistant to ganciclovir that's usually, I would just switch to foscarnet. 160 00:18:06,735 --> 00:18:14,910 Um, I will say that in December the FDA approved maribavir for use in resistant/ refractory disease. 161 00:18:15,510 --> 00:18:18,120 So I haven't actually used it yet. 162 00:18:18,220 --> 00:18:23,020 We are really fortunate in that we don't actually have such high rates of resistant/ refractory disease. 163 00:18:23,620 --> 00:18:33,700 If I take a step back, one of the big ways to avoid getting resistant, refractory disease is always dosing ganciclovir correctly, the valcyte prophylaxis correctly. 164 00:18:34,245 --> 00:18:49,945 And where I've heard of programs that have rates of 10 and 20% resistant/ refractory disease, it's usually because they haven't, uh, dosed ganciclovir or valcyte, um, post-transplant usually valcyte these days, valganciclovir, rather than intravenous ganciclovir. 165 00:18:50,015 --> 00:18:54,735 And when they underdose valganciclovir, that's where you get resistance mutations. 166 00:18:55,075 --> 00:18:59,005 So first and foremost, dose the prophylaxis correctly. 167 00:18:59,065 --> 00:18:59,755 That is key. 168 00:18:59,785 --> 00:19:01,255 I always say that's the Cardinal sin. 169 00:19:01,855 --> 00:19:05,095 Some people cut the dose in half when they have leukopenia. 170 00:19:05,185 --> 00:19:07,525 Well, they're not doing anybody any favors. 171 00:19:08,005 --> 00:19:11,275 In that that really increases the risk of resistant/ refractory disease. 172 00:19:11,275 --> 00:19:18,885 I always say, if you need to, if you have really bad leukopenia with valganciclovir post-transplant, hold the drug. 173 00:19:19,360 --> 00:19:25,060 I would personally give like acyclovir or famvir, valacyclovir for disseminated zoster prophylaxis. 174 00:19:25,360 --> 00:19:33,300 And then I would just do weekly monitoring for CMV, what we call preemptive therapy and just monitor weekly for 12 to 16 weeks. 175 00:19:33,300 --> 00:19:38,220 And if they do develop CMV, treat, but, um, Yeah. 176 00:19:38,280 --> 00:19:45,600 Um, so first and foremost, always dose your drugs correctly upfront, and you won't get to this problem situation. 177 00:19:46,260 --> 00:20:06,630 Sara Dong: I'm glad you brought that up because I was hoping we would circle back at some point if I could remember, about making sure we have appropriately dosed medication, both for prophylaxis, and you know, a lot of these patients have renal worsening, renal dysfunction because of whatever their end organ disease, so making sure that we, as the ID team keep on top of the dosing. 178 00:20:06,930 --> 00:20:07,380 Camille Kotton: Right. 179 00:20:07,780 --> 00:20:12,620 It can be really challenging in this population to know what their renal function is. 180 00:20:12,680 --> 00:20:21,515 And, um, I hate to admit that I was listening to another podcast, um, of course, there's only this podcast, right, to listen to? 181 00:20:24,065 --> 00:20:25,895 But you know, it's not like every day. 182 00:20:25,895 --> 00:20:33,005 So I was listening to an Annals of Internal Medicine and they were going on and on about calculating the GFR. 183 00:20:33,860 --> 00:20:36,740 Cystatin C can be an inflammatory marker. 184 00:20:36,740 --> 00:20:56,310 And I was thinking, boy, this is why I have so much trouble as an infectious disease specialist to figure out the GFR, but you know, for not so much in pediatrics, but especially like some of our , kind of chronically ill adults, many lose a lot of muscle mass, you know, waiting for liver transplant, heart transplant, whatever it might be. 185 00:20:56,730 --> 00:20:58,500 They lose a lot of muscle mass. 186 00:20:58,500 --> 00:21:01,950 They, some can have like quite low GFR. 187 00:21:02,880 --> 00:21:04,980 But their creatinine might be like one. 188 00:21:05,280 --> 00:21:10,980 So you think like, oh, the Creatinine is one, you know, their GFR 70, we're good. 189 00:21:11,130 --> 00:21:13,890 But actually there's a lot of other factors that go into that. 190 00:21:13,890 --> 00:21:16,470 So it's really hard to figure out their true kidney function. 191 00:21:17,070 --> 00:21:29,580 I always say the best, best, best way to prevent resistant/ refractory disease is dosing the Valcyte correctly, valganciclovir, ganciclovir correctly, either for prophylaxis or for treatment. 192 00:21:29,580 --> 00:21:36,570 And I go, there's a table in the CMV guidelines, and I always say this table needs to be like followed perfectly. 193 00:21:36,600 --> 00:21:38,280 And if you do, you stay out of the woods. 194 00:21:38,580 --> 00:21:48,310 So what I was saying before, we see maybe one to two cases of resistant/ refractory disease per year at Mass General, fortunately. 195 00:21:48,940 --> 00:21:58,240 So luckily we avoid it, but lately people that have come in have been in the, uh, phase three maribavir versus, um, investigator initiated treatment trials. 196 00:21:59,080 --> 00:22:06,010 Now we do have this option of having maribavir, which you know, is pretty game-changing. 197 00:22:06,070 --> 00:22:07,360 Sara Dong: Um, that's exciting. 198 00:22:07,450 --> 00:22:09,310 Camille Kotton: It is really exciting to have something new. 199 00:22:09,310 --> 00:22:13,690 I mean, we've had several new anti CMV treatments come out. 200 00:22:13,740 --> 00:22:16,950 Letermovir for prophylaxis in bone marrow transplant patients. 201 00:22:17,340 --> 00:22:18,660 Not a therapeutic drug. 202 00:22:18,690 --> 00:22:22,050 It's a prophylactic drug, has a really low barrier to resistance. 203 00:22:22,510 --> 00:22:26,790 It takes just a few viral replication cycles to develop resistance to letermovir. 204 00:22:27,610 --> 00:22:32,210 So, um, It's great to have maribavir. 205 00:22:32,230 --> 00:22:34,060 It's an oral treatment. 206 00:22:34,750 --> 00:22:43,750 Until now I was putting people in the hospital usually for two to three weeks on intravenous foscarnet with like labs twice a day, heavy, heavy. 207 00:22:44,530 --> 00:22:45,630 It's so tough. 208 00:22:46,750 --> 00:22:49,675 And you know, when you tell the patient what's going to happen. 209 00:22:49,675 --> 00:23:05,895 Like, you know, you're gonna be here for two to three weeks, you're going to get your Mag [magnesium] and your Phos [phosphorus] and your K [potassium] repleted all the time and we're going to give it to you oral and IV and it's just, oh, and it's really kind of like a metabolic madness. 210 00:23:05,895 --> 00:23:16,410 And then it's always a shame to be giving it to someone who's at a kidney transplant and then they have nephrotoxicity and you're kind of like wondering what you're doing and that you're potentially harming the kidney. 211 00:23:16,800 --> 00:23:20,280 Although I will say that, so I never get outpatient foscarnet. 212 00:23:20,310 --> 00:23:21,480 I just don't do it. 213 00:23:21,480 --> 00:23:23,310 I don't feel that it's safe enough. 214 00:23:24,120 --> 00:23:37,860 But inpatient I've had a really good experience giving foscarnet with respect to toxicity, heavy, heavy, heavy monitoring, following, you know, labs like twice a day until they're really in some kind of steady state, but it often is twice a day for two to three weeks. 215 00:23:38,640 --> 00:23:42,495 Um, I've had a really good success but it's obviously a nightmare for the patient. 216 00:23:42,825 --> 00:23:47,595 So all of a sudden we have a drug where basically, you know, go take these pills twice a day. 217 00:23:47,625 --> 00:23:49,125 I'll see in clinic next week. 218 00:23:50,025 --> 00:23:52,215 As long as they're clinically well, and can go home on. 219 00:23:52,215 --> 00:23:53,715 Complete game changer, right? 220 00:23:54,015 --> 00:23:54,315 Sara Dong: Yeah. 221 00:23:54,615 --> 00:23:54,915 Yeah. 222 00:23:55,825 --> 00:24:02,845 I think as my other question, let's say this patient had a UL 54 and a UL 97. 223 00:24:03,775 --> 00:24:07,265 Maybe they have a foscarnet mutation. 224 00:24:07,475 --> 00:24:09,860 You know, how, how do we tackle that? 225 00:24:10,550 --> 00:24:11,900 Obviously not a quick answer. 226 00:24:12,920 --> 00:24:13,520 Camille Kotton: Yeah. 227 00:24:13,520 --> 00:24:21,050 Well, and especially the more they get exposed to, uh, the more mutations they accumulate over time. 228 00:24:21,050 --> 00:24:26,450 And we do have these devastating cases where they accumulate multiple mutations. 229 00:24:26,450 --> 00:24:29,300 It's usually people who are profoundly immunocompromised. 230 00:24:29,870 --> 00:24:39,530 We do see, I would say, every year I have like one or two cases of people who have just really, really, really refractory CMV. 231 00:24:40,340 --> 00:24:43,370 They have like a decent absolute lymphocyte count. 232 00:24:43,370 --> 00:24:45,500 They're not on that much immunosuppression. 233 00:24:45,890 --> 00:24:49,610 And for the life of me, I cannot clear their CMV and it just keeps coming back. 234 00:24:49,610 --> 00:24:50,630 So there are those people. 235 00:24:51,500 --> 00:24:59,290 They, there are genetic factors that, um, we don't test for in a clinical scenario, but have been identified in research settings. 236 00:24:59,350 --> 00:25:07,780 Um, and other issues such that some people really just keep having CMV and those are the people that get, that accumulate a bunch of mutations. 237 00:25:07,810 --> 00:25:09,940 And some of them actually even pass away. 238 00:25:09,940 --> 00:25:17,380 It's been pretty, pretty rare in recent times, but some people actually do pass away from like fully resistant CMV. 239 00:25:18,640 --> 00:25:23,620 That's why it's important to manage them really, really, really well from the get go. 240 00:25:23,620 --> 00:25:27,190 And I think really careful fastidious management. 241 00:25:27,250 --> 00:25:47,245 That's why I'm proud of the CMV guidelines that we wrote in that, it kind of, is like if you kind of follow the rules and do really good management and really careful testing and whatnot, usually you don't end up in a pickle, but by the time when you do end up in a pickle, often it's hard to kind of crawl out of that mess. 242 00:25:47,695 --> 00:25:48,415 Sara Dong: Yeah, I agree. 243 00:25:49,645 --> 00:25:59,575 And then I think there is a section in the guidelines on this, but the other question I was going to ask is using CMV specific immune monitoring. 244 00:25:59,575 --> 00:26:00,805 Are you using that? 245 00:26:00,805 --> 00:26:01,945 How are you using that? 246 00:26:02,275 --> 00:26:02,905 Camille Kotton: Yes. 247 00:26:02,995 --> 00:26:06,805 Um, so that's a great question and a sort of a hot topic. 248 00:26:06,905 --> 00:26:09,575 So there are a couple of tests out there. 249 00:26:09,575 --> 00:26:14,015 There's the QuantiFERON- CMV, which is sort of like QuantiFERON TB. 250 00:26:14,545 --> 00:26:17,945 Um looking for, uh, you know, a T-cell response to CMV. 251 00:26:18,615 --> 00:26:24,225 So that's not commercially available, but has been used in multiple research settings. 252 00:26:24,225 --> 00:26:39,490 And it's really does, look, does look sort of promising, um, especially in CMV positive folks, um, determining either the length of prophylaxis or their risk of recurrent disease after the end of treatment. 253 00:26:40,000 --> 00:26:46,000 Although, like I said, in the beginning, we never really worry that much about the seropositive folks to begin with. 254 00:26:46,000 --> 00:26:58,640 So the fact that we now have a new diagnostic toy, sort of isn't really all that useful, cause it hasn't, hasn't been shown to really be helpful in the D+R- population. 255 00:26:59,720 --> 00:27:04,730 There's another similar test called T-SPOT CMV which is like the T-SPOT TB. 256 00:27:05,240 --> 00:27:10,690 Um, and I actually helped lead the largest trial in kidney transplant recipients. 257 00:27:11,080 --> 00:27:19,420 And really what we wanted is to find for, especially for the D+R- population, how long do we need to give prophylaxis for? 258 00:27:19,450 --> 00:27:29,125 Like, can we just get three months, six months, nine months, you know, is there a way of looking at the end of prophylaxis and saying, okay, you're all done. 259 00:27:29,155 --> 00:27:30,595 You're not going to get CMV. 260 00:27:30,775 --> 00:27:34,525 We're going to stop your prophylaxis, you know, month five, month eight, whatever it was. 261 00:27:35,305 --> 00:27:41,455 But it's kind of a catch 22 because we're trying to use this immune monitoring tool for people who are not immune. 262 00:27:42,565 --> 00:27:44,845 So it, it didn't work out. 263 00:27:44,935 --> 00:27:55,325 It did work really well for the seropositive population so that we could know the optimal duration of prophylaxis for them, but we already knew that they were going to be pretty okay anyway. 264 00:27:55,385 --> 00:28:02,195 So, I'm sort of like, why do we spend additional money on them when they weren't really the problem ones? 265 00:28:02,195 --> 00:28:05,725 So unfortunately those two have not worked out so well for the D+R-. 266 00:28:07,125 --> 00:28:12,655 , Viracor has, um, a CMV specific, uh, test. 267 00:28:13,665 --> 00:28:18,955 But interestingly I think there's only one publication that's a really mixed population. 268 00:28:18,955 --> 00:28:22,315 And basically we don't have published data on its use. 269 00:28:22,855 --> 00:28:24,085 It is commercially available. 270 00:28:24,085 --> 00:28:25,285 I know many people send it. 271 00:28:25,735 --> 00:28:33,955 I often say like, what's the utility in sending it because often they have like highly resistant/ refractory disease or recurrent CMV. 272 00:28:33,985 --> 00:28:42,760 And I say, I'm kind of, I was brought up sort of old school, um, and we were taught to not send tests that are expensive unless you absolutely need them. 273 00:28:42,760 --> 00:28:46,060 But I would say like, Well, what do you think that patient's going to have? 274 00:28:46,060 --> 00:28:53,510 And they're like, well, they're going to have not much immune response to CMV and I'm like, yeah, we knew, we knew that, like we knew that. 275 00:28:53,510 --> 00:28:59,610 So, um, I think we need a lot more data on the testing that's being done at Viracor. 276 00:28:59,660 --> 00:29:03,740 We're not actually allowed to send it through my hospital because of the lack of data. 277 00:29:03,770 --> 00:29:12,250 Um, And so they don't want to pay for something for which we don't have really a known clinical outcome or that it's not really clinically useful. 278 00:29:12,640 --> 00:29:19,420 Um, and as I mentioned, it's pretty expensive, so yeah, I sort of, that's the like, you know, mystique of CMV. 279 00:29:19,420 --> 00:29:27,550 If we could have things that would predict the risk of infection/ recurrent infection with these diagnostics, that would be wonderful. 280 00:29:27,610 --> 00:29:32,855 Maybe five to 10 years ago, I was really optimistic and now less optimistic. 281 00:29:32,885 --> 00:29:36,545 One thing that would be great as if we had a good CMV vaccine. 282 00:29:37,265 --> 00:29:48,875 Maybe then we could use an immune monitoring test so that we could know, like with vaccines, with or without prophylaxis, I mean, hopefully the vaccine so good we wouldn't need prophylaxis. 283 00:29:48,875 --> 00:29:49,745 That would be awesome. 284 00:29:50,255 --> 00:29:56,895 But if, if we did have the capacity to say, maybe do a hybrid approach, maybe those tests would be useful in that setting. 285 00:29:58,395 --> 00:30:06,665 Moderna is starting, um, trials of CMV vaccines, uh, mRNA CMV vaccines in women of childbearing age. 286 00:30:07,505 --> 00:30:15,035 And so I'm waiting in the wings and hopefully, they will do a similar study in transplant recipients eventually. 287 00:30:16,265 --> 00:30:16,985 Sara Dong: That's exciting. 288 00:30:17,285 --> 00:30:28,685 I mean, that's a great segue, you know, I was going to end by asking you, what do you think is the most exciting thing that you're sort of on the lookout for, for CMV and transplant? 289 00:30:29,135 --> 00:30:35,645 I think there's a ton of exciting things I feel like are constantly coming out, but anything in particular you want to highlight? 290 00:30:35,825 --> 00:30:36,065 Camille Kotton: Yeah. 291 00:30:36,065 --> 00:30:46,235 Well, um, I guess so we've looked for CMV vaccines for over 50 years, both for the congenital CMV space, as well as for immunosuppressed patients. 292 00:30:46,775 --> 00:30:55,680 So I guess I'm cautiously optimistic that may be Moderna and others may have novel approaches to CMV vaccine development. 293 00:30:55,710 --> 00:30:57,330 Unfortunately, it's been a lot harder. 294 00:30:57,330 --> 00:31:02,250 We had a nice review with Stanley Plotkin recently of all the various approaches that were underway. 295 00:31:02,760 --> 00:31:07,470 Um, City of Hope has an interesting, uh, vaccine largely for the stem cell population. 296 00:31:07,930 --> 00:31:11,740 But there's sort of nothing that looks like, you know, huge on the horizon. 297 00:31:11,770 --> 00:31:14,410 Um, but that, that would be wonderful. 298 00:31:14,710 --> 00:31:23,020 I do want to mention there's some interesting stuff going on with CMV specific T-cells that are out there. 299 00:31:23,030 --> 00:31:28,130 That's largely for like really refractory disease, but that's kind of interesting. 300 00:31:28,220 --> 00:31:39,160 Um, and now that we finally have multiple therapeutic options, it'll be interesting to see if we might be able to come up with some cocktail approaches to decrease the risk of antiviral resistance development. 301 00:31:39,810 --> 00:31:52,460 So that's something that's sort of in the future, but you do, you do wonder if combinations of various antivirals might help the specific patients or maybe with specific cases of resistant/ refractory disease. 302 00:31:53,180 --> 00:31:54,900 Sara Dong: Well, thank you so much for coming. 303 00:31:55,290 --> 00:31:56,550 Any closing thoughts? 304 00:31:56,550 --> 00:32:09,180 I'll leave it open one more time, but we covered a lot of topics that are both in the guidelines, but also thinking about these sort of that edge of what what's next and what we do in these complicated patients. 305 00:32:09,450 --> 00:32:09,990 Camille Kotton: Yeah. 306 00:32:10,050 --> 00:32:20,425 I think it's, it's a, it's a challenging field and I think it requires sort of a real understanding of a lot of different factors, which is kind of what we love in ID, right? 307 00:32:21,265 --> 00:32:24,925 And sort of reading the tea leaves and, and careful interpretation. 308 00:32:25,405 --> 00:32:31,045 I've certainly had the good fortune of working with, um, international experts on guideline development. 309 00:32:31,045 --> 00:32:33,265 And I've learned a tremendous amount from them. 310 00:32:33,705 --> 00:32:42,955 I'm happy to have emails and discussion and discuss cases, and I can introduce people to the right people to talk to if needed or whatever. 311 00:32:42,955 --> 00:32:43,855 Cause it does take. 312 00:32:44,695 --> 00:32:55,050 It it's more challenging than one than one might think it should be, especially maybe not 98% of the cases, but maybe like a lot of things in ID that, to those 2% of cases that are hard for us. 313 00:32:55,430 --> 00:32:59,650 And then, you know, certainly feel welcome to call on your CMV friends, uh, for additional help. 314 00:33:01,140 --> 00:33:07,230 Sara Dong: Thanks to Camille for joining Febrile today and coming up next is a series about congenital infections. 315 00:33:07,260 --> 00:33:09,660 And I cannot wait for you to hear these. 316 00:33:09,660 --> 00:33:10,740 They're awesome. 317 00:33:11,190 --> 00:33:14,460 So another plug for the Febrile survey, if you haven't filled it out yet. 318 00:33:14,490 --> 00:33:17,810 I have a survey to better understand how you use Febrile to teach and learn. 319 00:33:18,200 --> 00:33:21,830 So the survey is voluntary, anonymous, and should only take about five minutes. 320 00:33:21,830 --> 00:33:28,580 You can find the link to the survey on our Twitter page, in the description link for the episode, or on the website. 321 00:33:28,910 --> 00:33:38,060 Our usual disclaimer, all presented patients on this podcast are inspired by patient experiences, but cases are constructed or significantly altered and de-identified for learning purposes. 322 00:33:38,450 --> 00:33:47,695 Don't forget to check out the website, febrile podcast.com to find our consult notes with links to references from the episode as well as our library of ID infographics. 323 00:33:48,115 --> 00:33:48,955 Thanks for listening. 324 00:33:48,955 --> 00:33:50,845 Stay safe and we'll see you next week.