1 00:00:12,990 --> 00:00:14,070 Sara Dong: Hi everyone. 2 00:00:14,100 --> 00:00:18,390 Welcome to Febrile -- a cultured podcast about all things infectious disease. 3 00:00:18,450 --> 00:00:23,610 We use consult questions that dive into ID clinical reasoning, diagnostics, and anti-microbial management. 4 00:00:24,150 --> 00:00:27,510 I'm Sara Dong, your host and a Med-Peds ID fellow. 5 00:00:27,660 --> 00:00:32,205 Here on Febrile, we use patient cases to learn about high yield ID topics. 6 00:00:32,415 --> 00:00:37,215 We'll present pieces of the story of a patient's case, and then pause along the way to hear from our guest consultant. 7 00:00:37,575 --> 00:00:39,885 My co-host today is Dr. 8 00:00:39,885 --> 00:00:40,415 Kevin He. 9 00:00:40,785 --> 00:00:45,165 He is an Internal Medicine resident at Beth Israel Deaconess Medical Center in Boston. 10 00:00:45,555 --> 00:00:55,065 And if you haven't heard it already, I would definitely recommend checking out Kevin's previous episode on Cryptococcus, which is episode 17, also known as Yeastie Boys. 11 00:00:55,755 --> 00:01:05,085 Next I will introduce our guest today, Joseph Sassine is an Assistant Professor of Medicine and a Transplant ID physician at the University of Oklahoma Health Sciences Center. 12 00:01:05,385 --> 00:01:10,965 He previously completed his Internal Medicine residency at the Icahn School of Medicine at Mount Sinai and St. 13 00:01:10,965 --> 00:01:13,305 Luke's Roosevelt Hospital Center in New York City. 14 00:01:13,575 --> 00:01:20,535 This was followed by his ID fellowship at the University of Texas Health Sciences Center and MD Anderson Cancer Center in Houston. 15 00:01:21,405 --> 00:01:29,295 Today is part one of the Troll of Transplantation, where we're going to talk a little bit about CMV and solid organ transplant recipients. 16 00:01:29,355 --> 00:01:31,634 Stay tuned for part two was Dr. 17 00:01:31,634 --> 00:01:37,845 Camille Kotton that'll be coming out two weeks from this episode, thinking more about resistant and refractory CMV disease. 18 00:01:38,265 --> 00:01:39,945 All right, let's get started. 19 00:01:39,975 --> 00:01:41,115 Welcome to the show guys. 20 00:01:42,035 --> 00:01:42,544 Joseph Sassine: Thank you. 21 00:01:42,815 --> 00:01:56,554 Sara Dong: Before we dive into the case, we like to start off because as everyone's favorite cultured podcast, uh, we ask our guests, if there's a little piece of culture or something you have enjoyed recently that you would like to share with the listeners. 22 00:01:56,824 --> 00:01:57,274 Joseph Sassine: Sure. 23 00:01:57,274 --> 00:02:00,935 So first, thank you for having me and I look forward to our discussion today. 24 00:02:01,384 --> 00:02:02,285 In terms of culture. 25 00:02:02,285 --> 00:02:09,234 I'm a big opera fan and I have a soft spot for the works of Bizet and Verdi. 26 00:02:10,154 --> 00:02:22,214 During the earlier stages of the pandemic, uh, the Met Opera from New York City was streaming some of its greatest works online for free, and that was a great wellness resource at least for me. 27 00:02:22,534 --> 00:02:26,640 I think now you can access them on demand for a subscription. 28 00:02:26,679 --> 00:02:30,480 Sara Dong: Well I know nothing about opera, so I'll have to use your recommendations. 29 00:02:30,750 --> 00:02:39,869 And so today's consult question is about a seventy year old male who has had a renal transplant and comes in with abdominal pain and diarrhea. 30 00:02:40,170 --> 00:02:43,350 And so they would like us to help them evaluate for infection. 31 00:02:43,739 --> 00:02:45,690 Um, so I will throw it over to Kevin. 32 00:02:46,109 --> 00:02:47,859 Kevin He: I'll get started with our case. 33 00:02:48,250 --> 00:02:58,114 This is a 70 year old male with end stage renal disease, secondary to hypertensive nephropathy, who is status post a deceased donor renal transplant in October of 2020. 34 00:02:58,685 --> 00:03:10,445 The serologies are CMV donor positive, recipient negative as well as EBV donor indeterminate, recipient negative who is presenting with one month fatigue, abdominal pain and diarrhea. 35 00:03:11,405 --> 00:03:19,935 His PMH is also notable for a large B cell lymphoma, s/p splenectomy and gastric wedge resection seven years ago, for which he received six cycles of chemotherapy. 36 00:03:19,935 --> 00:03:23,894 It has been in remission since, as well as coronary artery disease. 37 00:03:24,975 --> 00:03:50,010 Regarding his transplant history, he underwent a deceased donor renal transplant in October 2020 with serologies pre-transplant being hepatitis B negative/ non-immune, Hepatitis A negative, Hepatitis C negative, CMV serology negative, donor CMV antibody positive, EBV negative, donor EBV indeterminate, and Toxoplasma negative, donor Toxo negative. 38 00:03:50,579 --> 00:03:56,220 He was induced with basiliximab and was maintained on a regimen of tacrolimus, mycophenolate and prednisone. 39 00:03:56,470 --> 00:04:00,839 His postoperative course was complicated by delayed graft function, which eventually improved. 40 00:04:01,320 --> 00:04:07,119 His prednisone had been tapered off prior to discharge from his transplant admission, and his DSA has remained below the median range. 41 00:04:07,859 --> 00:04:18,795 He was initially given prophylaxis against PCP with Bactrim [trimethoprim-sulfamethaxazole] and CMV with valganciclovir with the anticipated duration of the latter being six months, given his high risk CMV status. 42 00:04:19,935 --> 00:04:22,914 Now, before we get back to the case, Dr. 43 00:04:22,914 --> 00:04:25,335 Sassine, we wanted to pause here to discuss this last point. 44 00:04:25,335 --> 00:04:33,125 There are two major strategies for CMV disease prevention after solid organ transplant -- antiviral prophylaxis and preemptive therapy. 45 00:04:33,835 --> 00:04:42,210 Would you be able to give us a brief overview of the difference between these approaches and how we utilize the serostatus of the donor and the recipient to help stratify the risk of infection? 46 00:04:42,990 --> 00:04:43,350 Joseph Sassine: Sure. 47 00:04:43,350 --> 00:04:52,910 So first let's, uh, remember that CMV is probably the most common infection after transplant and one of the most significant complications of transplant. 48 00:04:53,800 --> 00:05:06,780 CMV can affect the transplant recipient through it's direct lytic effects, which manifest with end organ disease directly caused by CMV, such as pneumonitis, colitis, gastritis, hepatitis, retinitis. 49 00:05:07,590 --> 00:05:24,060 As well as through its indirect effects, CMV is an immunomodulatory virus and CMV reactivations have been associated with graft rejection, graft versus host disease, and worsening immunosuppression by virtue of the virus or some of its therapies. 50 00:05:24,549 --> 00:05:28,250 Thus leading to a higher incidence of bacterial and fungal infections. 51 00:05:29,830 --> 00:05:35,865 For these reasons, it's very important to be proactive when it comes to CMV issues in this patient population. 52 00:05:35,895 --> 00:05:42,795 As you mentioned, there are two strategies that can be used and that actually are not mutually exclusive. 53 00:05:43,635 --> 00:05:57,315 The first one is prophylaxis, which is the administration of an antiviral drug to all patients who are at risk for a determined period of time after the transplant, and that duration is usually based on their risk level. 54 00:05:57,975 --> 00:06:02,935 Prophylaxis is an effective strategy in preventing direct and indirect CMV effects. 55 00:06:03,585 --> 00:06:06,975 It was proven effective in large randomized controlled trials. 56 00:06:07,575 --> 00:06:18,015 It is easy to coordinate and apply since you are following an algorithm and it has a positive impact on the indirect outcomes, such as graft loss and mortality. 57 00:06:18,765 --> 00:06:29,775 Nevertheless, with prophylaxis, you will be exposing all of your patients to the antiviral, whereas some of these patients might never develop the CMV infection or disease. 58 00:06:30,345 --> 00:06:33,255 Uh, so there's always the risk of over-treatment. 59 00:06:33,465 --> 00:06:38,475 And with that comes the risk of unnecessary toxicities and higher drug cost. 60 00:06:39,385 --> 00:06:53,145 Prophylaxis might also delay CMV specific immune reconstitution, and lastly, one should be aware of the risk of post-prophylaxis delayed-onset CMV disease, particularly in the highest risk patients. 61 00:06:54,360 --> 00:07:05,720 And the drugs currently use for prophylaxis in solid organ transplant recipients are oral valganciclovir, like your patient here, or IV ganciclovir. 62 00:07:06,390 --> 00:07:15,660 Letermovir was approved for prophylactic use and hematopoietic cell transplant recipients, but it's not yet approved for using solid organ transplantations. 63 00:07:16,455 --> 00:07:26,175 One of the trials looking into prophylaxis with letermovir in kidney transplant recipients is estimated to be completed in April 2022, so stay tuned for news on that front. 64 00:07:26,175 --> 00:07:42,804 On the other hand, preemptive therapy is based on the concept of surveillance of viremia after transplant and the administration of antiviral therapy to patients who reach a certain threshold of viremia or what we call CMV infection. 65 00:07:43,425 --> 00:07:46,465 To halt the progression of viremia and end-organ disease. 66 00:07:47,235 --> 00:08:02,055 This strategy essentially tampers down many of the disadvantages of prophylaxis by targeting therapy to the patients who are at highest risk of disease, minimizing over treatment, minimizing toxicities, and minimizing the drug costs. 67 00:08:02,775 --> 00:08:12,780 However, a strategy that's purely based on preemptive therapy would miss some cases of CMV end organ disease that are not preceded by viremia. 68 00:08:12,780 --> 00:08:23,440 And most notably here, you're talking about GI disease, so colitis and gastritis, which can be seen with undetectable viremia in the peripheral blood. 69 00:08:24,580 --> 00:08:30,870 This strategy, the preemptive strategy, also relies on the availability of sensitive CMV testing. 70 00:08:31,590 --> 00:08:41,445 Uh, currently we rely on quantitative nucleic acid amplification testing, as opposed to pp65 antigenemia detection in, in older days. 71 00:08:41,445 --> 00:08:46,185 And that used to rely on the number of lymphocytes present in the peripheral blood. 72 00:08:47,835 --> 00:08:54,704 You also want your CMV test to have a quick turn around time to allow for a quick and rapid response. 73 00:08:54,704 --> 00:08:59,515 So you would want 24, 48 hours at most in terms of, uh, turnaround time. 74 00:09:00,285 --> 00:09:04,965 In real life, we actually use a mix of both, uh, prophylaxis and preemptive therapy. 75 00:09:04,965 --> 00:09:09,210 This is why I said earlier they're not necessarily mutually exclusive. 76 00:09:09,790 --> 00:09:16,200 What proportions of each strategy, uh, are used, depends on the individual patient risks. 77 00:09:16,980 --> 00:09:29,970 As a general principle, the major risk factor for CMV disease after solid organ transplant is a qualitative or quantitative deficiency in global immunity and / or in CMV specific immunity. 78 00:09:30,720 --> 00:09:38,855 To estimate the patient's risk, we usually measure pre-transplant serologies for both the donor and the recipient. 79 00:09:39,615 --> 00:09:45,115 There are certain assays that measure CMV specific cell-mediated immunity. 80 00:09:46,815 --> 00:09:54,015 The use of those assays in the pre-transplant stage is still investigational, we will come back to those a little later. 81 00:09:54,635 --> 00:10:06,720 The highest risk group when you measure serologies, is going to be the recipients who are seronegative but to receive an organ from a seropositive donor. 82 00:10:06,780 --> 00:10:09,500 And this is what we refer to as D+R-. 83 00:10:11,370 --> 00:10:14,980 The moderate risk group would be seropositive recipients, so R+. 84 00:10:16,530 --> 00:10:27,980 Within that group, those who receive an organ from a seropositive donor, so D+R+ are at higher risk compared to those who have a seronegative donor, so D-R+. 85 00:10:29,189 --> 00:10:35,750 The lowest risk group are the recipients who are seronegative and who receive an organ from a seronegative donors. 86 00:10:35,750 --> 00:10:37,729 So this is D-R-. 87 00:10:37,999 --> 00:10:42,870 Just a side note, in hematopoietic stem cell transplant, it's different. 88 00:10:43,229 --> 00:10:46,810 It's usually a recipient seropositive that's the major determinant. 89 00:10:48,400 --> 00:10:57,315 Beyond seropositivity for both the donor and the recipient, there are additional risk factors for CMV reactivation. 90 00:10:57,345 --> 00:11:16,275 These include lymphodepleting agents, such as antithymocyte globulin, alemtuzumab, quite high doses of maintenance immunosuppression, allograft rejection, especially that this is after accompanied by another round of lymphodepleting therapy, and the type of organ being transplanted. 91 00:11:16,275 --> 00:11:20,175 So lungs and small intestines are higher risk than other organs. 92 00:11:21,064 --> 00:11:28,965 The use of mTOR inhibitors, such as sirolimus and everolimus, is actually associated with a lower risk of a CMV. 93 00:11:29,735 --> 00:11:39,975 There's an interesting concept called the net state of immunosuppression, uh, which is kind of important to estimate each individual patient's risk of impact. 94 00:11:40,860 --> 00:11:45,150 There's a nice paper that addresses it in CID in 2020 by Dr. 95 00:11:45,150 --> 00:11:47,890 Jay Fishman, so I can refer to that. 96 00:11:48,690 --> 00:12:08,490 With this in mind, the AST ID COP Guidelines of 2019 recommend antiviral prophylaxis with valganciclovir, uh, usually administered at 900 mg once a day or ganciclovir as five mg/kg, ideally once a day. 97 00:12:09,390 --> 00:12:25,830 And these are doses for normal renal function, and this regimen, or one of these two agents, are recommended for high-risk D+R- patients, as well as for moderate-risk R+ patients. 98 00:12:26,760 --> 00:12:37,590 The duration of prophylaxis that is recommended varies between 3 and 12 months, depending on the level of risk of the patient, whether they high-risk versus moderate risk. 99 00:12:38,310 --> 00:12:40,730 And depending on the organ being transplanted. 100 00:12:40,730 --> 00:12:49,410 So lung and heart-lung transplants have the longest durations, and these are the ones that will reach the 12 month. 101 00:12:49,410 --> 00:12:54,000 The guidelines also provide recommendations regarding the preemptive therapy as an option. 102 00:12:54,510 --> 00:12:59,839 If logistic support is available, they also provide instructions on monitoring intervals. 103 00:13:00,795 --> 00:13:12,135 They do not provide a specific viral load threshold to initiate therapy, but they rather recommend this threshold be assay specific, center specific, and risk specific. 104 00:13:12,285 --> 00:13:18,464 Some patients might require longer prophylaxis and/or monitoring than the recommended duration. 105 00:13:18,464 --> 00:13:26,415 So we have to keep an open mind with those numbers, but particularly if they receive further lymphodepleting therapy for the treatment of rejection. 106 00:13:26,590 --> 00:13:28,170 Kevin He: Thank you, that was a very helpful outline. 107 00:13:28,439 --> 00:13:42,030 Looking at the specifics relevant to our patient, and just for some additional context, he completed his valganciclovir after the six month duration of prophylaxis in April when he was transplanted in October of the preceding year. 108 00:13:42,510 --> 00:13:53,160 And in June, about two months afterwards, he began to have this constant generalized abdominal pain, fatigue, and for the last month, persistent, non bloody watery diarrhea. 109 00:13:54,120 --> 00:13:57,630 Now this constellation of symptoms prompted him to present to the ER. 110 00:13:58,080 --> 00:14:03,480 In the ED, he was noted to have creatinine elevated to 1.5 from baseline of 0.9 to 1.1. 111 00:14:04,160 --> 00:14:11,370 Leukocytosis to 13.8 with a total neutrophil count of around 13,000, and a total lymphocyte count of 740. 112 00:14:11,580 --> 00:14:24,510 Bicarb was 11, anion gap of 19, as well as LFTs notable for a mild transaminitis, ALT of 73 and AST of 101 and alk phos 123, and a T-bili 0.6. 113 00:14:24,740 --> 00:14:32,280 His LDH was 345 and he was a little hypoalbuminemic to 3.4 and his lactate was elevated at 2.6. 114 00:14:32,950 --> 00:14:37,020 His tacrolimus trough was drawn and it turned out to be 4.4. 115 00:14:37,930 --> 00:14:42,990 His UA was not pyuric and they did get some blood and urine cultures that are pending. 116 00:14:45,165 --> 00:14:48,105 A little bit of additional history for this patient. 117 00:14:48,105 --> 00:14:51,975 He was born and raised in Massachusetts and now lives in Boston. 118 00:14:52,275 --> 00:14:58,515 He never traveled outside North America, but has roamed around the United States, west coast, Midwest as well as Canada. 119 00:14:59,235 --> 00:15:07,305 He hasn't traveled at all since this transplant last year and is currently retired, but used to work at an office desk job. 120 00:15:07,785 --> 00:15:15,145 Previously did have a pet cat, but the cat's now staying at his children's since his transplant and he's been being diligent and avoiding raw foods. 121 00:15:15,895 --> 00:15:16,915 He's never used tobacco. 122 00:15:17,005 --> 00:15:20,185 Doesn't drink alcohol and uses no recreational drugs. 123 00:15:21,564 --> 00:15:26,875 And when you go and talk to him, he's not in distress, but a little uncomfortable when his abdomen is palpated. 124 00:15:26,875 --> 00:15:31,765 He's a little bit tender non-specifically without any signs of guarding or rebound. 125 00:15:32,515 --> 00:15:33,925 He's not fluid overloaded. 126 00:15:34,075 --> 00:15:46,735 In fact, he appears a little bit dry and a RUQ ultrasound obtained in the ED illustrates some cholelithiasis, but no hepatobiliary ductal dilatation and no signs of cholecystitis. 127 00:15:47,155 --> 00:16:03,315 Now with all of these details together, we just wanted to see what you're thinking about so far and while we certainly suspect that CMV is probably the issue here, we do want to keep an open mind about what should be on the infectious diseases differential for diarrhea in a solid organ transplant recipient. 128 00:16:03,735 --> 00:16:04,065 Joseph Sassine: Great. 129 00:16:04,065 --> 00:16:14,245 So certainly here CMV remains a concern, particularly with the entity I mentioned earlier, post-prophylaxis delayed onset CMV. 130 00:16:15,120 --> 00:16:31,640 And this usually occurs in D+R- patients in the first three to six months after completion of prophylaxis, which is in contrast with a truly late onset CMV disease that can occur years after transplantation. 131 00:16:32,380 --> 00:17:03,570 There are various efforts that can be done to prevent this, including close clinical follow up, and early treatment when symptoms occur like here, uh, or routine viral surveys after completion of prophylaxis, further prolongation of antiviral prophylaxis, but that usually comes at the expense of, uh, significant myelotoxicity, and/or immunologic monitoring at the end of prophylaxis and thereafter, usually with things like lymphocyte count, CD4 count, or CMV specific cell-mediated immunity. 132 00:17:04,020 --> 00:17:12,480 To get back to your original question, the differential diagnosis of diarrhea and solid organ transplant recipients, as you can imagine, it's very broad. 133 00:17:13,230 --> 00:17:20,130 To follow the classical scheme of infectious versus non-infectious, infections include bacteria. 134 00:17:20,190 --> 00:17:21,899 C diff is a big one. 135 00:17:22,710 --> 00:17:27,660 Campylobacter, Salmonella, Aeromonas, E.coli, bacterial overgrowth. 136 00:17:28,230 --> 00:17:34,710 Viruses, obviously such as CMV, but also the GI viruses, Norovirus, Adenovirus, and the others. 137 00:17:35,280 --> 00:17:36,540 And parasites. 138 00:17:36,889 --> 00:17:44,550 The classic Giardia and Entamoeba, but also the traditional GI opportunistic parasites. 139 00:17:44,550 --> 00:17:49,110 So Cryptosporidium, Microsporidium, Cystisospora, and Cyclospora. 140 00:17:49,889 --> 00:17:53,490 Keep in mind that these patients can have noninfectious causes of diarrhea. 141 00:17:54,705 --> 00:17:56,595 Uh, mostly medication-related. 142 00:17:56,695 --> 00:18:06,635 Immunosuppressives such as mycophenolate, tacrolimus, sirolimus, cyclosporine, and just plain other non immunosuppressive medications. 143 00:18:07,044 --> 00:18:13,885 Diarrhea can also be a manifestation of graft versus host disease or post-transplant lymphoproliferative disease. 144 00:18:14,565 --> 00:18:24,165 For the sake of time, I will not go into the timeline of infections after organ transplantation, but there's a nice comprehensive figure in again, Dr. 145 00:18:24,165 --> 00:18:32,415 Fishman's review of infections and organ transplant recipients in NEJM back in 2007, and I think that still holds up to this day. 146 00:18:33,075 --> 00:18:34,875 Kevin He: Thank you for that excellent differential. 147 00:18:35,445 --> 00:18:38,775 Now diving into the diagnosis for our patient. 148 00:18:38,955 --> 00:18:48,305 The CMV viral load was obtained and did return at 6.25 log or about 1.7 million copies/ml. 149 00:18:50,145 --> 00:18:58,604 Would you be able to give us a quick overview about CMV disease and its distinction from infection, and how do we put this case together? 150 00:18:58,604 --> 00:19:02,594 And what, if any, additional workup would you suggest at this point now that we have this information? 151 00:19:03,165 --> 00:19:03,705 Joseph Sassine: Sure. 152 00:19:03,705 --> 00:19:08,445 So I think it's always important to define the disease entities you are dealing with. 153 00:19:09,085 --> 00:19:24,510 While most of these definitions are actually designed for clinical trials, to agree on standardized definitions that would allow studies to be comparable, I think they are very useful for our daily clinical practice, uh, particularly to guide us in our diagnostic approach. 154 00:19:24,810 --> 00:19:30,810 For CMV and transplant patients, there's a landmark definitions paper that was published in CID in 2017. 155 00:19:31,929 --> 00:19:42,375 In this paper, CMV infection is defined as virus isolation, or detection of viral proteins or nucleic acids in any body fluid or tissue specimen. 156 00:19:42,825 --> 00:19:55,275 When this specimen is the blood, then the assays can measure virus in the plasma, serum, or whole blood-- we talk about viraemia, which is culturing virus from the blood. 157 00:19:55,685 --> 00:20:01,605 Antigenemia, which is detecting the pp65 antigen that's specific for CMV. 158 00:20:02,265 --> 00:20:08,415 Or DNAemia, which is detection of CMV DNA, which is the most common technique nowadays. 159 00:20:09,540 --> 00:20:25,450 CMV disease includes end organ disease caused by CMV, such as pneumonia, GI disease, hepatitis, retinitis, et cetera, as well as CMV syndrome, which is an entity that is only described in solid organ transplant. 160 00:20:25,450 --> 00:20:44,195 And that includes detection of CMV in the blood with at least two of the following-- a fever, new or increased malaise or fatigue, leukopenia and neutropenia, atypical lymphocytes (more than 5%), thrombocytopenia, elevated AST or ALT to twice the upper limit of normal. 161 00:20:44,785 --> 00:20:54,675 The AST ID Guidelines summarize those definitions, including the ones for proven and probable end organ disease in their first table in the guidelines. 162 00:20:55,054 --> 00:21:01,475 To use those definitions would make it easier to determine what diagnostic workup is needed. 163 00:21:02,015 --> 00:21:06,875 With our case here, we do suspect CMV GI disease. 164 00:21:07,375 --> 00:21:12,705 The approach would be endoscopic examination would be necessary. 165 00:21:14,524 --> 00:21:35,909 We rely on the presence of symptoms, the presence of macroscopic mucosal lesions, documentation of CMV in the tissue either by histopathology, immunohistochemistry, culture, or DNA hybridization techniques to determine a proven or definite GI CMV disease. 166 00:21:36,629 --> 00:21:45,719 If you just have symptoms with documented CMV in the tissue, but without microscopic mucosal lesions, that would make it a probable GI CMV disease. 167 00:21:46,290 --> 00:22:02,520 Now that distinction might be more important for clinical trials rather than the clinical practice, but the definitions help you know what tests to order and that to diagnose GI CMV disease, you do need an endoscopic evaluation, both microscopic and tissue. 168 00:22:02,980 --> 00:22:08,079 Documenting CMV in the blood alone is not sufficient to diagnose the CMV GI disease. 169 00:22:08,655 --> 00:22:09,075 Kevin He: I see. 170 00:22:09,375 --> 00:22:30,885 So the patient ultimately actually after discussion between the primary team and some of the consultants did not undergo a colonoscopy or endoscopic evaluation given the degree of his viraemia and the symptoms that he was having, as well as, his CMV D+R- status prior to transplantation. 171 00:22:31,125 --> 00:22:39,864 He was initiated on induction therapy due to the high clinical suspicion for end organ disease due to the constellation of symptoms he was coming in with. 172 00:22:40,235 --> 00:22:47,025 Would you be able to teach us a little bit about these CMV treatment regimens, especially the differences between induction and maintenance therapy. 173 00:22:47,445 --> 00:22:50,385 When do you make the transition and when do you stop maintenance after that? 174 00:22:50,715 --> 00:22:53,665 Joseph Sassine: So first let's talk quickly about the available agents. 175 00:22:53,995 --> 00:23:08,500 The first line agents are ganciclovir and that would be dosed at 5 mg/kg IV every 12 hours or valganciclovir, which has 900 mg PO every 12 hours for patients with normal renal function. 176 00:23:09,010 --> 00:23:21,330 It is recommended to preferentially use IV ganciclovir for patients with severe life-threatening disease, for those with a very high viral load, and those with a questionable GI absorption. 177 00:23:22,290 --> 00:23:29,629 For mild to moderate disease, oral valganciclovir and IV ganciclovir are considered equally effective. 178 00:23:30,195 --> 00:23:34,425 There was a randomized trial establishing this non-inferiority back in 2007. 179 00:23:35,565 --> 00:23:53,425 For the patients who can not tolerate ganciclovir or valganciclovir, and that's usually because of cytopenias, or for those patients who fail to respond to these agents, and here we would be going into their refractory resistant CMV chapter, second line agents include foscarnet or cidofovir. 180 00:23:54,015 --> 00:23:58,710 These agents are reserved for the second line due to their significant nephrotoxicity. 181 00:23:59,100 --> 00:24:17,600 And just to get an idea of the nephrotoxicity with foscarnet, there's a study out of Johns Hopkins in 2016, showed that 50% of the patients who received foscarnet for refractory resistant CMV developed renal dysfunction by the end of treatment and 28% after 6 months. 182 00:24:18,510 --> 00:24:29,880 Now for these folks who failed to respond to ganciclovir or valganciclovir, a new agent maribavir was recently approved by the FDA in November 2021 with a much better safety profile. 183 00:24:29,880 --> 00:24:31,650 So that's an exciting development. 184 00:24:32,640 --> 00:24:38,040 There have been case reports using letermovir as a second line agent off-label. 185 00:24:38,820 --> 00:24:45,300 I personally would not use it in the setting of active, viral replication due to the high risk of resistance development. 186 00:24:45,435 --> 00:24:48,325 As you mentioned, there are two stages of therapy. 187 00:24:49,195 --> 00:24:50,955 They call them induction and maintenance. 188 00:24:50,955 --> 00:24:54,345 You can think of induction as the full dose therapy stage. 189 00:24:54,345 --> 00:25:00,285 Here, you administer antivirals at the full therapeutic dose, which I just mentioned. 190 00:25:01,155 --> 00:25:05,945 Maintenance is essentially a secondary prophylaxis phase to prevent early recurrence of CMV. 191 00:25:06,855 --> 00:25:11,675 There is no preset duration or blanket duration for induction therapy. 192 00:25:12,595 --> 00:25:25,820 In the valganciclovir trial I mentioned earlier, they limited therapy for three weeks and a significant proportion of patients still had viremia by three weeks, suggesting that these patients probably needed longer durations of antiviral therapy. 193 00:25:26,220 --> 00:25:33,690 This is why the AST ID Guidelines list three criteria that you need to meet before ending induction therapy. 194 00:25:33,690 --> 00:25:36,110 The first one is resolution of clinical symptoms. 195 00:25:37,095 --> 00:25:55,315 The second is virologic clearance below a threshold negative value, and this value is a test specific, based on weekly lab monitoring either with a quantitative nucleic acid amplification assay, or if you still use pp65 antigenemia. 196 00:25:56,115 --> 00:26:03,625 And they defined that as needing two consecutive results or a single negative, if you're using a highly sensitive assay. 197 00:26:04,274 --> 00:26:09,104 The third condition you have to meet is a minimum of two weeks of antiviral treatment. 198 00:26:09,975 --> 00:26:21,014 So once you meet those three conditions and you come, you complete full dose antiviral treatment, the guidelines state that secondary prophylaxis may be considered in certain high-risk patients. 199 00:26:21,524 --> 00:26:29,175 And here you would be using the prophylaxis doses as compared to the treatment doses, so once a day instead of twice a day for a normal renal function. 200 00:26:29,804 --> 00:26:33,465 The duration of antivirals and the stages are defined by the guidelines. 201 00:26:34,229 --> 00:26:36,510 Different centers use different approaches. 202 00:26:36,870 --> 00:26:39,570 Most of them will use something between one and three months. 203 00:26:40,350 --> 00:26:45,060 It also depends on the individual patient's situation, particularly in regards to lymphopenia. 204 00:26:45,360 --> 00:26:51,929 Some centers are starting to CMV specific cell-mediated immunity assays to guide that decision. 205 00:26:52,800 --> 00:27:00,709 There was a retrospective study published in CID in 2017, looking at secondary prophylaxis with valganciclovir. 206 00:27:01,980 --> 00:27:06,520 It showed the reduction and relapse with a hazard ratio of 0.19. 207 00:27:06,540 --> 00:27:08,250 So it was a significant reduction. 208 00:27:08,850 --> 00:27:13,230 Uh, but this was only in the first six weeks following treatment completion. 209 00:27:13,740 --> 00:27:17,820 The benefit did not extend beyond six weeks of secondary prophylaxis. 210 00:27:18,300 --> 00:27:31,335 I think this is still an area that deserves more investigations to determine the optimal approach and how to incorporate the use of CMV specific cell-mediated immunity and allow for CMV specific T-cell immune reconstitution. 211 00:27:32,355 --> 00:27:36,795 Before concluding the treatment chapter, there are a few more interventions to mention. 212 00:27:37,515 --> 00:27:42,405 A cautious reduction in immunosuppression should be considered, especially in moderate to severe disease. 213 00:27:42,735 --> 00:27:51,265 And usually that comes in collaboration with our transplant colleagues, because you want to weigh this against the risk of rejection. 214 00:27:52,125 --> 00:28:02,775 You can switch from IV ganciclovir to oral valganciclovir once there is clinical and virologic improvement, even if you have not competed, uh, full dose therapy yet. 215 00:28:03,645 --> 00:28:06,915 And as long as you don't have concerns for GI malabsorption. 216 00:28:07,995 --> 00:28:20,115 You should dose adjust ganciclovir and valganciclovir based on renal function, but you should not adjust them down if your patient develops neutropenia or leukopenia or cytopenias. 217 00:28:20,685 --> 00:28:24,315 Under dosing is actually a risk factor for resistance. 218 00:28:24,765 --> 00:28:32,715 So if you still would like to use those agents, you can support with growth factors or a switch to a second line agent. 219 00:28:33,825 --> 00:28:45,705 Intravenous immunoglobulins, uh, or CMV specific immunoglobulins may be considered for patients with life-threatening disease, for patients with CMV pneumonitis, or those who have hypogammaglobulinemia. 220 00:28:47,175 --> 00:28:47,595 Kevin He: Thank you. 221 00:28:47,655 --> 00:28:54,315 So as you've discussed, the patient was induced with intravenous ganciclovir, excuse me. 222 00:28:54,615 --> 00:28:58,515 And his diarrhea did improve within one week of ganciclovir initiation. 223 00:28:58,845 --> 00:29:06,465 His viral loads fell from 6.25 log at the outset, to 6.2, 5.3, and then 3.9. 224 00:29:06,675 --> 00:29:13,025 Eventually falling to undetectable levels by about six weeks after initiation of induction therapy. 225 00:29:13,899 --> 00:29:19,850 He was ultimately discharged home from the hospital with a peripherally inserted central catheter to continue his IV ganciclovir. 226 00:29:20,280 --> 00:29:28,840 And after his CMV viral loads were undetectable two times in a row, uh, after the seven total weeks of induction, he was eventually transitioned to maintenance valganciclovir. 227 00:29:29,639 --> 00:29:33,000 He continued the maintenance valganciclovir for about another 10 weeks. 228 00:29:33,000 --> 00:29:35,280 As you said, he eventually discontinued it. 229 00:29:35,340 --> 00:29:41,950 And since then bi-weekly monitoring for CMV did not show any recurrent viremia. 230 00:29:42,090 --> 00:29:45,510 His monitoring was then discontinued after two months. 231 00:29:46,080 --> 00:29:47,400 So overall a good outcome. 232 00:29:47,910 --> 00:29:55,050 To end the episode, there is always some exciting news in the transplant ID world, and you alluded to a little bit of this earlier. 233 00:29:55,290 --> 00:29:59,709 Would you be able to tell us about the latest in CMV care or new therapies available for our patients? 234 00:30:00,129 --> 00:30:07,410 Joseph Sassine: There are some recent exciting developments in the CMV world and I think a great potential for more exciting news in the future. 235 00:30:08,505 --> 00:30:15,015 The most recent update is, as I mentioned earlier, the approval of maribavir for refractory or resistant post-transplant CMV. 236 00:30:15,375 --> 00:30:20,685 And that as a welcome option, especially in regards to its overall favorable safety profile. 237 00:30:21,225 --> 00:30:31,105 Some areas where we might hear news in the near future or where we need to better develop our understanding-- the use of letermovir in organ transplant recipients. 238 00:30:31,565 --> 00:30:34,590 I mentioned the ongoing primary prophylaxis trial. 239 00:30:34,620 --> 00:30:43,470 We also need to better understand the place of letermovir in secondary prophylaxis in, both in organ transplant and hematopoietic cell transplant. 240 00:30:43,650 --> 00:30:51,360 Uh, we also need to find the best way to incorporate the use of CMV cell-mediated immunity assays in our daily clinical practice. 241 00:30:51,750 --> 00:30:58,260 The use of adoptive immunotherapy for treatment, particularly using CMV specific cytotoxic T lymphocytes. 242 00:30:58,980 --> 00:31:03,330 This is mostly a field of investigation in hematopoietic cell transplant recipients. 243 00:31:03,900 --> 00:31:09,540 Finally, I recently came across a very interesting paper published earlier this year. 244 00:31:09,930 --> 00:31:13,350 It's more a hematopoietic cell transplant paper. 245 00:31:13,770 --> 00:31:31,875 They actually looked at circulating cell-free DNA profiling in those patients and how this can be used to inform all the major complications of a hematopoietic cell transplant, including GVHD, disease relapse, but also infections by plasma virome screening. 246 00:31:31,875 --> 00:31:35,055 So I just found this to be very cool. 247 00:31:35,565 --> 00:31:41,585 At the end, I want to have a special mention and recognition to my mentor, Dr. 248 00:31:41,795 --> 00:31:51,360 Roy Chemaly, who has taught me everything I know about CMV and, uh, and has accompanied me in developing that the interest of mine. 249 00:31:52,649 --> 00:31:55,979 Sara Dong: I've loved these, uh, shout outs to people's mentors. 250 00:31:56,129 --> 00:31:59,310 A big thank you to Kevin and Joseph for joining me today. 251 00:31:59,370 --> 00:32:03,810 We'll have also a second CMV episode that's going to come out in two weeks. 252 00:32:04,050 --> 00:32:16,370 Like the past couple of episodes, I just want to do a quick plug for our Febrile survey, which we're conducting to better understand how you use Febrile to teach and learn, but also to help us understand what to do to improve for future episodes. 253 00:32:16,399 --> 00:32:20,149 The survey is voluntary, anonymous, it should only take about 5 to 10 minutes. 254 00:32:20,210 --> 00:32:25,850 You can find the link to the survey on our Twitter page, on the website or in the description link for the episode. 255 00:32:26,030 --> 00:32:28,550 I'll just mention our usual disclaimer. 256 00:32:28,850 --> 00:32:35,990 All presented patients on this podcast are inspired by patient experiences, but cases are constructed or significantly altered and de-identified for learning purposes. 257 00:32:36,855 --> 00:32:45,915 Please don't forget to check out the website, febrilepodcast.com, to find "Consult Notes", which are written complements to the show with links to references as well as our library of ID infographics. 258 00:32:46,245 --> 00:32:50,264 Please reach out if you have any suggestions for future shows or want to be more involved with Febrile 259 00:32:50,355 --> 00:32:51,135 Thanks for listening. 260 00:32:51,165 --> 00:32:52,875 Stay safe and I'll see you next time.