1 00:00:11,650 --> 00:00:12,600 Sara Dong: Hello everyone. 2 00:00:12,630 --> 00:00:16,760 Welcome to Febrile- a cultured podcast about all things infectious disease. 3 00:00:17,180 --> 00:00:22,590 We use consult questions to dive into ID clinical reasoning, diagnostics, and antimicrobial management. 4 00:00:23,010 --> 00:00:26,270 I'm Sara Dong, your host and an adult and pediatric ID fellow. 5 00:00:26,535 --> 00:00:30,945 Here on Febrile, we use patient cases and consult questions to learn about high yield ID topics. 6 00:00:31,275 --> 00:00:36,185 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 00:00:36,795 --> 00:00:42,035 I am excited to welcome you back to our Febrile series entitled Curious Congenital Conundrums. 8 00:00:42,385 --> 00:00:46,515 This is our second case, and I'm fortunate to be here with Ella and Jason. 9 00:00:46,975 --> 00:00:47,195 Dr. 10 00:00:47,555 --> 00:00:50,835 Ella Dzora is a pediatric registrar in South Yorkshire, England. 11 00:00:51,175 --> 00:00:55,555 She is an interest in infectious diseases in global health, particularly migrant health. 12 00:00:55,960 --> 00:00:57,860 Our guest discussant today is Dr. 13 00:00:57,860 --> 00:00:58,850 Jason Brophy. 14 00:00:59,240 --> 00:01:08,100 He is a pediatric ID specialist and researcher at the Children's Hospital of Eastern Ontario, and an Associate Professor of Pediatrics at the University of Ottawa. 15 00:01:08,400 --> 00:01:23,450 His research and clinical interests are pediatric HIV and congenital infections, and he also works as a pediatric HIV clinical advisor with a Clinton Health Access Initiative, supporting the uptake and optimal pediatric HIV care in west central Africa and Southeast Asia. 16 00:01:23,805 --> 00:01:25,385 Thanks so much for being here, guys. 17 00:01:25,925 --> 00:01:26,865 Ella Dzora: Thanks for having us. 18 00:01:26,865 --> 00:01:27,625 Jason Brophy: Thanks very much. 19 00:01:28,845 --> 00:01:30,105 Sara Dong: Uh, I'm so glad you're here. 20 00:01:30,605 --> 00:01:38,585 Um, before we jump into the case, I always like to do a quick pause and just see if you could share a piece of culture or something that you've enjoyed recently. 21 00:01:39,700 --> 00:01:47,200 Jason Brophy: So I have one, it's not, I didn't enjoy it recently, but I've been thinking a lot about it over the course of the pandemic. 22 00:01:47,710 --> 00:01:57,350 This book called "Polio: An American Story", which I think should be required reading for any infectious disease fellow or physician. 23 00:01:57,790 --> 00:02:08,475 Uh, it's about the history of polio in the US, years of this yearly summer pandemic or epidemics, uh, and then the race to find a vaccine. 24 00:02:08,894 --> 00:02:11,515 And then people being worried about taking the vaccine. 25 00:02:11,905 --> 00:02:16,315 It's very reminiscent of what we're going sounds, and it's really well written. 26 00:02:16,315 --> 00:02:17,425 It won a Pulitzer Prize. 27 00:02:17,445 --> 00:02:17,665 So. 28 00:02:18,054 --> 00:02:23,024 I've given it to our ID fellows as, as Christmas gifts for some time. 29 00:02:23,684 --> 00:02:24,545 Sara Dong: That's a good idea. 30 00:02:24,975 --> 00:02:41,815 Ella Dzora: I've actually just been reading a, a similar book, but, um, a bit broader called Plague's Progress, which charts, um, kind of humanities rise and fall on the background of the different plagues that have swept us through the centuries, which is very, very, very interesting as well. 31 00:02:42,675 --> 00:02:44,765 That wasn't gonna be my cultural point, but it was 32 00:02:47,025 --> 00:02:48,485 Sara Dong: You can share another one if you have. 33 00:02:48,485 --> 00:02:53,885 Ella Dzora: Well, I, I I'm actually Scottish, although I, uh, live and work in south Yorkshire at the moment in England. 34 00:02:54,385 --> 00:02:59,734 Um, but we had Burns night recently who-- Robbie Burns is our national poet. 35 00:03:00,475 --> 00:03:14,935 Um, and it was really nice for the first time in three years, to be able to get together with some other Scots and just have some tunes and some haggis and just reminisce and celebrate actually, uh, you know, being Scottish and getting together and doing that. 36 00:03:14,954 --> 00:03:17,454 So that was the first time we've done that in one, it was really lovely. 37 00:03:17,915 --> 00:03:18,205 Yeah. 38 00:03:18,705 --> 00:03:19,725 Sara Dong: Oh, that's wonderful. 39 00:03:20,245 --> 00:03:23,205 I actually had not heard of Burns night before, I will say. 40 00:03:23,455 --> 00:03:27,885 until one of my co-fellows, uh, suggested one for our fellow group. 41 00:03:28,505 --> 00:03:30,085 Um, so that's awesome. 42 00:03:30,455 --> 00:03:30,805 Great. 43 00:03:31,035 --> 00:03:34,325 Well, uh, I'm gonna throw it over you Ella, to walk us through the case. 44 00:03:34,785 --> 00:03:41,900 Ella Dzora: So our case today, Jason, you receive a consult on the ward for a 23 day old baby who's been admitted with seizures. 45 00:03:42,400 --> 00:03:49,500 The infant was flown down from the Northern Canadian territory of Nunavut two days earlier, due to clusters of generalized tonic, chronic movements. 46 00:03:50,140 --> 00:03:56,190 A CT head has been done on arrival at your hospital, and that demonstrates intracranial calcifications and ventriculomegaly. 47 00:03:56,360 --> 00:04:00,650 And, and the peds team is concerned about congenital infection as a cause of the infant seizures. 48 00:04:01,125 --> 00:04:08,704 Can you describe your initial approach in gathering additional history in this case and what you'd be looking for in physical exam to work through your differential diagnosis? 49 00:04:09,055 --> 00:04:09,345 Jason Brophy: Yeah. 50 00:04:09,345 --> 00:04:27,085 So these are very interesting consults to get our, uh, trainees very, very excited, cuz they don't come along very often, thankfully, but I think there's a broad history that you would need to consider, but the, the first thing would just be what's gone on during this pregnancy? 51 00:04:27,614 --> 00:04:37,814 What kinds of exposures has the mom had, uh, in terms of illnesses, febrile illnesses, mono like illnesses, in particular rash illnesses. 52 00:04:38,184 --> 00:04:47,084 You'd also want to know was there any, uh, any findings on her prenatal investigations such as her antenatal ultrasounds? 53 00:04:47,914 --> 00:04:56,424 And many of the congenital infections will have some typical findings on these, those antenatal fetal ultrasounds, uh, that can be telling. 54 00:04:56,525 --> 00:05:08,174 And that may or may not actually lead to findings later at the time of birth, but maybe clues that we could, uh, have recognized a congenital infection earlier during the pregnancy. 55 00:05:09,639 --> 00:05:22,580 We'd wanna know what were the findings at delivery with respect to the, the growth parameters, uh, and things like hepatosplenomegaly or rash or eye findings in particular, uh, head growth. 56 00:05:22,599 --> 00:05:39,214 So microcephaly or macrocephaly, and then you would want to know what had gone on with the baby, since birth, uh, if they were growing well, if they were having any, uh, ongoing concerns that had been bringing them to medical attention or that the parents themselves had recognized as being a concern. 57 00:05:39,554 --> 00:05:42,134 And then lastly would be a good exposure history. 58 00:05:42,154 --> 00:06:03,264 So what's gone on in the mom's life, uh, with respect to her exposures in her environment, as well as her diet and, and in particular, uh, things like food intake that we know has/is associated with, uh, specific infections, like, uh, raw undercooked meat or unpasteurized dairy products, like goats milk. 59 00:06:04,149 --> 00:06:17,399 For this, this case in particular, we know that there are some specific cultural practices or cultural habits in terms of eating, uh, with respect to raw meat that we know put, uh, patients at risk. 60 00:06:17,789 --> 00:06:27,544 Lastly, I always like to ask about travel because, um, we always think of what's local or what's local to, uh, where the person's coming from, but they may have traveled during pregnancy. 61 00:06:28,324 --> 00:06:38,534 We all remember what happened about five or six years ago with, uh, Zika, uh, and how that kind of took over the world, knowing what, well it took over the world in terms of panic. 62 00:06:39,294 --> 00:06:44,654 I don't know that we saw that many cases, uh, but having that kind of full history is really important. 63 00:06:45,484 --> 00:06:51,464 Ella Dzora: Uh, just shows how important it is to understand the cultural context that your patients are coming from for those exposures. 64 00:06:51,464 --> 00:06:51,704 Yeah. 65 00:06:52,604 --> 00:06:55,224 Um, so thankfully the baby hasn't seized since admission. 66 00:06:55,524 --> 00:06:58,854 Um, they've been loaded with phenobarbital. 67 00:06:59,004 --> 00:07:01,854 The peds neurology team is involved. 68 00:07:02,364 --> 00:07:09,054 They've done a basic panel of blood work, including a CBC, electrolytes, renal function and liver enzymes, and that's all come back as normal. 69 00:07:09,234 --> 00:07:19,154 The CRP measures 19, blood and urine cultures were taken prior to starting ampicillin, cefotaxime, acyclovir at the Northern referral center. 70 00:07:19,914 --> 00:07:21,924 They've done a blood HSV PCR. 71 00:07:22,344 --> 00:07:28,114 Um, but an LP was deferred because it was noticed that the child's head circumference was greater than the 99th centile (%ile). 72 00:07:28,244 --> 00:07:39,694 When considering congenital infections in the differential diagnosis in a sick neonate, what would your approach be to requesting diagnostic tests and what are other specialties may be required to help you with further investigations? 73 00:07:40,754 --> 00:08:09,239 Jason Brophy: So these patients, it it's very, there's a big tendency to throw the book at them, because there are so many things that it could be, uh, but a differential diagnosis in a case like this would, would take you to specific congenital infections, uh, particularly toxoplasmosis, uh, cytomegalovirus or CMV, other things like I talked about Zika virus, uh, West Nile virus is known to cause congenital infection rarely, but it's been described. 74 00:08:09,669 --> 00:08:13,239 More common things like HSV and VZV can affect the brain as well. 75 00:08:13,339 --> 00:08:17,359 So, so those are the things we would be thinking about in the infectious world. 76 00:08:17,389 --> 00:08:20,719 There's like a, a broad non-infectious differential. 77 00:08:20,939 --> 00:08:23,879 Um, but really that should be guided by your initial investigations. 78 00:08:24,579 --> 00:08:49,264 And so, uh, for a child like this, you would want to start minimally with having some, uh, head imaging to know what's going on and in terms of the baby's seizing , and in particular , noting that the, that if the head circumference is, is elevated, uh, is there, is there hydrocephalus , happening, which in itself would require further management. 79 00:08:49,444 --> 00:08:54,024 And so having, uh, having a good start with head imaging. 80 00:08:54,024 --> 00:09:12,794 And head ultrasound is a very nice, uh, modality to start with in that there's no radiation involved and it's actually very good at picking up things like ventriculomegaly and calcifications, uh, as well as other potential things like bleeds, which could be playing a role in a patient like this. 81 00:09:13,444 --> 00:09:20,344 We would also, uh, want to think about a lumbar puncture to have the information of what's going on there. 82 00:09:20,684 --> 00:09:25,864 Um, especially if, if it's a, a child who presents with additional features like fever. 83 00:09:26,564 --> 00:09:35,374 So not to forget the, the more common things like bacterial meningitis, uh, HSV encephalitis, particularly at this baby's age. 84 00:09:36,164 --> 00:09:42,144 Uh, and then the, the less common causes of infection, things like Listeria meningitis, for example. 85 00:09:43,114 --> 00:09:48,614 Having those initial investigations, depending on what you find in your initial TORCH investigation. 86 00:09:48,794 --> 00:09:59,139 So say we do find on that initial workup with, uh, with head head ultrasound, that there is, uh, signs of calcification or hydrocephalus. 87 00:09:59,369 --> 00:10:03,939 Obviously we would go on to other imaging like MRI or, or CT scan. 88 00:10:04,079 --> 00:10:11,609 CT scan in the past would've been one of the most common investigations because it's very nice at picking up calcifications. 89 00:10:12,150 --> 00:10:20,540 But we are more conscious of radiation exposure, uh, at this young age nowadays, and we're more inclined to get an MRI. 90 00:10:20,950 --> 00:10:26,810 In a patient of this age, we, we can often bundle them and they would not require a general anesthetic. 91 00:10:27,310 --> 00:10:30,650 So these are kind of the practicalities of working up these patients. 92 00:10:31,190 --> 00:10:38,320 It's a balance between having the best investigation and having the one that you can get easily, or that has the least, uh, potential complications. 93 00:10:39,290 --> 00:10:54,720 If we were to find, calcifications in the head or hydrocephalus, uh, ventriculomegaly, then we would go down the TORCH pathway, thinking about, serologic investigations, mostly, uh, for things like toxoplasmosis, cytomegalo virus. 94 00:10:55,090 --> 00:10:57,985 And HSV, VZV, syphilis. 95 00:10:58,495 --> 00:11:04,805 And then if there were additional potential exposures, like the travel part, then you think about Zika virus. 96 00:11:05,165 --> 00:11:12,705 For CMV and Zika virus, PCR testing is often better investigation, at least if you know that there's been an exposure. 97 00:11:12,975 --> 00:11:19,215 Like if the, if the CMV IgG is positive, then you know, that mom had CMV at some point. 98 00:11:20,120 --> 00:11:28,340 And then you would want a urine or saliva PCR as the most sensitive test, uh, to have a sense of, if CMV was playing a role. 99 00:11:28,580 --> 00:11:36,580 Likewise, for, for Zika virus, we can do, uh, blood or urine PCR for Zika to know if there was a congenital Zika infection. 100 00:11:37,440 --> 00:11:43,410 Not a lot of Zika up in Nunavut, being close to the Arctic circle or in the Arctic circle. 101 00:11:43,870 --> 00:11:46,345 Um, but, um, but yeah, People travel. 102 00:11:46,565 --> 00:11:50,185 So, uh, if that was part of the history, then you would want to look at that. 103 00:11:50,965 --> 00:11:59,025 And, and I didn't mention eye exam, but eye exam is very helpful in these patients because so many of these infections have eye manifestations. 104 00:11:59,525 --> 00:12:08,895 And so, uh, things like chorioretinitis, uh, either active or healed or inactive, or scarred as well as cataracts. 105 00:12:08,895 --> 00:12:13,455 And I've seen all three in, in patients with multiple of these infections 106 00:12:14,635 --> 00:12:16,355 Ella Dzora: And Dr. 107 00:12:16,385 --> 00:12:32,835 Brophy, would you mind maybe just touching on, you mentioned about maternal serology, um, but particularly thinking about toxoplasmosis, um, maybe just run us through serology in the neonate and maybe the use of IgA, which is a bit more unusual in toxoplasmosis, maybe than in other infections. 108 00:12:33,785 --> 00:12:34,075 Jason Brophy: Yeah. 109 00:12:34,695 --> 00:12:46,590 And so, so we usually start with a Toxoplasma IgG/IgM done locally, uh, which can be done on a number of different standard serology platforms. 110 00:12:47,290 --> 00:12:49,510 And, uh, and that could be done on mom and baby. 111 00:12:49,890 --> 00:12:54,750 Uh, and that would tell you if there's been toxoplasma infection in the past for mom. 112 00:12:55,170 --> 00:12:57,550 Of course IgM doesn't pass from mom to baby. 113 00:12:57,570 --> 00:13:01,590 So if a baby had an IgM, uh, that would be very suggestive. 114 00:13:01,890 --> 00:13:06,880 And likewise, if mom had an IgM positive, then that would be very suggestive as well. 115 00:13:07,140 --> 00:13:21,590 But the problem with, with IgM is (a) it's not very sensitive or not a hundred percent sensitive in infants, uh, they don't reliably make serology responses, especially in the, in premature babies. 116 00:13:22,210 --> 00:13:25,750 Uh, that would not be the end of the story in terms of working them up. 117 00:13:25,890 --> 00:13:30,590 And the other part is if a mom has an IgM, you, you need to think about the timing. 118 00:13:31,390 --> 00:13:35,200 Because, uh, IgM can remain positive for a long period of time. 119 00:13:35,340 --> 00:13:47,080 So in a patient like this, where a baby's already born, if the mom had an IgM positive, and we know that it can stay positive for up to a year, uh, then that would be very suggestive that something happened during the pregnancy. 120 00:13:47,740 --> 00:13:53,310 But regardless, when you have this setup, you would want to go on to more definitive testing. 121 00:13:53,930 --> 00:13:57,070 For most of us that requires sending it out to a reference lab. 122 00:13:57,760 --> 00:14:09,820 The most common lab that's used is the, the laboratory in California, which provides really detailed serology, including IgA , which is a very sensitive test for toxoplasma. 123 00:14:10,070 --> 00:14:14,690 It provides the reference IgM ISAGA uh, which is also very helpful. 124 00:14:15,350 --> 00:14:21,255 And then you can compare mom and babies, uh, IgG, uh, titers with the dye test. 125 00:14:21,835 --> 00:14:31,845 Uh, and as we say with most infections, uh, congenital infections, if baby has a fourfold higher titer of IgG than mom, then that's very suggestive. 126 00:14:32,545 --> 00:14:41,475 Lastly, we can do PCR tests on amniotic fluid during pregnancy on placental tissue, uh, on baby CSF or blood. 127 00:14:42,055 --> 00:14:44,235 Uh, I've seen it offered on urine as well. 128 00:14:44,695 --> 00:14:45,995 And all of these are very helpful. 129 00:14:47,430 --> 00:15:04,010 If we were getting involved during the pregnancy prior to the delivery of the baby, uh, and say it was either a setup where we knew mom had an exposure or mom had a, a suggestive illness, like a, uh, mononucleosis type illness, for example, or eye disease. 130 00:15:04,460 --> 00:15:17,350 And we were thinking about toxoplasma and mom had positive, uh, serologic testing with IgG/IgM, then you can do the avidity testing on IgG, which, uh, gives us a sense for the timing of the infection. 131 00:15:17,690 --> 00:15:27,245 Uh, and if predated the pregnancy, if there was high avidity versus, um, if it was likely in the last four months of pregnancy, uh, in the case of low validity. 132 00:15:27,905 --> 00:15:29,205 And so that would be very helpful. 133 00:15:29,305 --> 00:15:32,565 And then you need to figure out what is going on with the baby. 134 00:15:33,065 --> 00:15:39,525 And so, uh, if the baby has no findings on ultrasound, then you don't know, has the infection happened yet or not? 135 00:15:40,075 --> 00:15:51,575 So having an amniocentesis at, it's recommended at, at, or after 18 weeks, ideally to tell us if there is, uh, already congenital infection or not. 136 00:15:52,025 --> 00:15:55,395 That is the recommendation when we know that a mom has had an infection of pregnancy. 137 00:15:55,645 --> 00:15:56,115 Ella Dzora: Thank you. 138 00:15:56,115 --> 00:15:56,915 That's really comprehensive. 139 00:15:56,915 --> 00:15:57,475 That's great. 140 00:15:58,610 --> 00:16:11,750 Um, so back to our case, uh, the general peds team, uh, has helped to arrange some diagnostic testing of the infant, including getting a neurosurgical consult and an urgent MRI is scheduled and that confirms severe hydrocephalus. 141 00:16:11,930 --> 00:16:15,870 And, uh, so the neurosurgical team have placed an emergency shunt. 142 00:16:16,410 --> 00:16:28,370 CSF from the shunt demonstrates an elevated protein of 1.9 g/dL, and further testing reveals a normal CBC, normal electrolytes, liver enzymes and bilirubin. 143 00:16:28,960 --> 00:16:36,270 Toxoplasma serology is positive, so the dye titer is 1:256 and the IgM is positive. 144 00:16:37,380 --> 00:16:40,490 Moms current toxoplasma serology is 1:64. 145 00:16:41,800 --> 00:16:44,750 Blood toxoplasma PCR remains pending at present. 146 00:16:44,820 --> 00:16:46,270 It's been sent to the reference lab. 147 00:16:46,810 --> 00:16:51,950 Um, and unfortunately, no maternal lesion serum samples or placenta remains for testing. 148 00:16:52,680 --> 00:17:01,490 The audiology exam is normal, uh, but ophthalmology exam, uh, reveals a large active retinal lesion, just adjacent to the fovea of the left eye. 149 00:17:01,640 --> 00:17:02,100 So, Dr. 150 00:17:02,100 --> 00:17:06,520 Brophy, can you discuss your approach, uh, to treatment of congenital toxoplasmosis? 151 00:17:06,840 --> 00:17:09,940 How do you approach treatment discussions with your patient with parents? 152 00:17:10,600 --> 00:17:20,525 Jason Brophy: The treatment of congenital toxo is a bit fraught in that, um, it's a, I usually introduce it to parents as being tough. 153 00:17:21,305 --> 00:17:32,535 Uh, it's a very long treatment course, uh, in that they're, they should be treated for one year and it requires multiple medications with side effects that require at minimum, blood work monitoring. 154 00:17:33,075 --> 00:17:50,315 And so, in a case of moderate to severe infection in a, in congenital infection, you would want to use a combination of pyrimethamine and sulfadiazine, and these are, uh, two medications that have been shown to work best for congenital infection. 155 00:17:50,875 --> 00:18:08,435 In other scenarios, uh, like in adults with reactivation disease or, uh, with toxoplasma lymphadenitis, other other forms and there are, uh, other options for treatment, including trimethoprim sulfamethoxazole, uh, clindamycin and macrolides. 156 00:18:08,895 --> 00:18:14,875 But in this setting of congenital infection, uh pyrimethamine and sulfadiazine are their recommended treatments. 157 00:18:15,265 --> 00:18:27,305 Both of them can have side effects of, of, uh, marrow suppression, pyrimethamine in particular, causing anemia, macrocytic anemia, uh, and sulfadiazine in particular causing neutropenia. 158 00:18:28,030 --> 00:18:43,540 We usually, uh, recommend in addition to these two medications, the addition of folinic acid or leucovorin three days a week, and that will help reduce the, the risk of pyrimethamine associated anemia and, and marrow suppression generally. 159 00:18:43,680 --> 00:18:56,350 Uh, but these three medications need to be monitored closely with blood work, including complete blood count, as well as liver and renal screening for proteinuria, uh, as a side effect of pyrimethamine. 160 00:18:56,700 --> 00:19:04,040 So it's recommended to do those more frequently in the first month of therapy and then, um, a monthly for the duration of the 12 months of treatment. 161 00:19:05,350 --> 00:19:22,860 Uh, sulfadiazine is, uh, before you start it, you should check for a G6PD deficiency, uh, in that it's one of the G6PD triggers and, um, the medication dosing should be followed closely along with the child's weight over time. 162 00:19:24,025 --> 00:19:28,575 One significant issue that has really plagued us, over the last number of years. 163 00:19:29,035 --> 00:19:44,540 Not only in Canada, but in multiple countries around the world is, is a lack of these medications availability, uh, in particular sulfadiazine and so for example, we don't have, uh, any companies that make that product in Canada. 164 00:19:44,880 --> 00:19:52,220 So we need to go through, through our federal regulatory agencies to bring in products from other countries. 165 00:19:52,640 --> 00:19:58,620 And this is often a very difficult, uh, endeavor in that, uh, they're not made by very many companies. 166 00:19:58,810 --> 00:20:04,220 It's not a very lucrative product I think, uh, and that is part of the, the issue. 167 00:20:04,720 --> 00:20:11,260 And there's often a delay for us in terms of getting to start these medications because of these access issues. 168 00:20:11,880 --> 00:20:17,500 And it, it really, I, in my mind, this is an advocacy issue for us in pediatric infectious disease. 169 00:20:17,640 --> 00:20:25,695 In that these are, uh, medications that are the treatments of choice for this very severe infection at times. 170 00:20:25,955 --> 00:20:29,855 And, uh, we need to have secure access for our programs. 171 00:20:30,825 --> 00:20:41,715 Ella Dzora: And can I just clarify something you said earlier that if there was a suggestion that mom had, uh, exposure, you might do an amniocentesis at 18 weeks. 172 00:20:42,375 --> 00:20:46,075 If that showed a potential infection, would you start treatment at that point? 173 00:20:47,535 --> 00:20:51,835 If so, would it run for a year, from 18 weeks gestation or a year after delivery? 174 00:20:52,205 --> 00:20:52,555 Jason Brophy: Right. 175 00:20:53,055 --> 00:21:17,920 If a mom is diagnosed with acute toxo in pregnancy, uh, and that, like I said, those diagnoses can come in a variety of ways, either mom with an illness, uh, that triggered testing, um, mom with a finding on ultrasound that triggered testing, mom with a known exposure, uh, say to, cat feces, which I, I failed to mention earlier, which was the one that, the one thing that everybody knows, uh, about 176 00:21:17,950 --> 00:21:22,080 Ella Dzora: It's probably in this side of the pond is definitely the bigger exposure compared to raw meat, I think. 177 00:21:22,310 --> 00:21:22,600 Jason Brophy: Yeah. 178 00:21:22,710 --> 00:21:23,000 Yeah. 179 00:21:23,060 --> 00:21:36,830 And, and I have to say in, in the past, in patients who are local, like who haven't traveled, then the main risk factor is, uh, if they have a cat and they changed their litter before they knew they were pregnant, uh, or. 180 00:21:37,390 --> 00:21:45,090 The, the main, the main, uh, risk factor I've always found in those patients is not so much that because everybody knows you're not supposed to change cat litter when you're pregnant. 181 00:21:45,350 --> 00:21:46,770 Uh, but rather gardening. 182 00:21:46,950 --> 00:21:59,240 And so I usually tell moms, uh, that, uh, uh, your garden looks like a giant litter box to a cat so, so there's, uh, that's like the main factor that are identified in local cases. 183 00:21:59,825 --> 00:22:11,525 Uh, and those that have traveled, like to, um, to Africa in particular south America, uh, or our Northern patients, it's more often eating exposure that, that we suspect. 184 00:22:12,145 --> 00:22:31,110 Um, but yeah, I, if we do make that diagnosis in pregnancy, uh, before the amniocentesis, if there's no suggestion of an infection, uh, on the imaging, then the fetal imaging, then you would put the, start the mom on spiramycin, which is a macrolide that we know will prevent infection from passing from mom to baby. 185 00:22:31,210 --> 00:22:49,590 Cuz the risk of transmission early on, uh, is, is lower, but with more grave side effects, uh, or, uh, sequelae in the baby vs later in pregnancy, uh, we know that the transmission risk is much higher though with often less effect on the baby, if it happens on the third trimester. 186 00:22:49,590 --> 00:22:52,710 So spiramycin until your amniocentesis is complete. 187 00:22:52,710 --> 00:22:58,590 If the amniocentesis is negative, then the mom would be recommended to continue her spiramycin until delivery. 188 00:22:59,130 --> 00:23:08,950 Uh, if on the other hand, the amniocentesis suggests the fetus is infected, then the recommendation would be to switch to sulfadiazine and pyrimethamine. 189 00:23:09,660 --> 00:23:15,160 And I haven't had that scenario before where, uh, a baby did, uh, get that treatment prenatally. 190 00:23:15,500 --> 00:23:21,870 Um, but my understanding is that the fetus should be treated for a year or the newborn to be treated for a year postnatally. 191 00:23:22,330 --> 00:23:23,430 Ella Dzora: Thanks for clarifying that. 192 00:23:23,915 --> 00:23:29,215 Jason Brophy: And then the last, the last thing I didn't mention with the, the treatment is anti-inflammatory or steroid therapy. 193 00:23:29,625 --> 00:23:35,165 There are two criteria for the addition of a steroid like prednisone or prednisolone. 194 00:23:35,515 --> 00:23:44,605 Uh, one would be if there's active eye disease and the other would be, if there is a very high protein level in the, the, uh, CSF. 195 00:23:45,205 --> 00:23:50,345 Criteria would be, uh, one g/dL, um, or 10 g/L. 196 00:23:51,005 --> 00:23:51,295 Ella Dzora: Good. 197 00:23:51,295 --> 00:23:52,055 Thank you for that. 198 00:23:52,795 --> 00:24:06,135 Um, so yeah, so our baby, um, is started on pyrimethamine +sulfadiazine uh, and some prednisolone for the significant eye disease, folic acid, as you said to cover up the marrow suppression and remains really stable. 199 00:24:06,875 --> 00:24:09,215 So the general peds team is considering discharge. 200 00:24:09,845 --> 00:24:13,085 What follow up would you, you recommend in that situation? 201 00:24:14,065 --> 00:24:24,125 Jason Brophy: The followup should be quite close, uh, over time, be that with the infectious disease, uh, clinic or, uh, their primary care or pediatric, uh, care. 202 00:24:24,125 --> 00:24:31,330 Sometimes we'll do a shared care model if they're, uh, far from the hospital, such as in the Arctic. 203 00:24:31,980 --> 00:24:41,410 We would recommend the regular monitoring of, for those toxicities, uh, through blood work, uh, as well as close monitoring of their weight so that we can make dose adjustments. 204 00:24:41,930 --> 00:24:46,570 I usually make a dose adjustment if, uh, there's been a 10% increase in the weight. 205 00:24:47,030 --> 00:24:53,370 Uh, so that, uh, they're never outside of the 90% of their recommended, uh, dosing. 206 00:24:54,030 --> 00:24:58,450 The steroids can be tapered, if they've been started, once the active eye disease resolves. 207 00:24:58,950 --> 00:25:03,010 I've never had to do a repeat lumbar puncture to reassess protein. 208 00:25:03,710 --> 00:25:10,970 But that would be, uh, I think it would be reasonable to, to wean the steroids after, uh, a certain period of time and, and notable improvement. 209 00:25:11,630 --> 00:25:17,010 And obviously these patients need close follow up from, from the point of view of their eye disease. 210 00:25:17,010 --> 00:25:20,650 If they have active eye disease, uh, some of them may develop cataracts. 211 00:25:20,650 --> 00:25:22,130 It may require surgical intervention. 212 00:25:22,950 --> 00:25:44,625 And then obviously neurologic and neurodevelopmental follow up, uh, so that we can identify any, uh, any problems that may arise and intervene as soon as we can with respect to therapies, speech therapy, uh, audiology, your hearing assessments would be very important as well, uh, to make sure that they can hear. 213 00:25:44,625 --> 00:25:57,850 And if hearing is an issue, uh, then making sure that they have augmentation so that we really, I usually frame it to the families that we want to, we want to give them the best shot at being the best version of themselves. 214 00:25:58,070 --> 00:26:06,090 And so, uh, many of these kids will have sequelae with respect to vision or hearing or, uh, neurologic function. 215 00:26:06,780 --> 00:26:26,395 So when we can intervene early with, um, with therapies like occupational or physiotherapies or, um, supporting their mobility with respect to gross motor dysfunction, support their vision so that they can see and learn, um, likewise support their hearing so that they can hear and learn. 216 00:26:26,815 --> 00:26:31,785 Um, then that is the best that we can do for them, and they can be the best versions of themselves. 217 00:26:32,885 --> 00:26:47,495 Ella Dzora: And can I ask, uh, we don't have potentially the, um, as big a geographical area that we're covering as you over in England, how much-- cause it's quite a big burden of treatment for these kids. 218 00:26:47,955 --> 00:26:53,095 How much would you expect of that to happen locally in the Northern territories and how much would they have to travel for? 219 00:26:53,640 --> 00:26:53,930 Jason Brophy: Yeah. 220 00:26:54,030 --> 00:26:57,930 So unfortunately I've had several of these patients over time. 221 00:26:58,340 --> 00:27:01,760 We try to be as, um, efficient as possible. 222 00:27:02,300 --> 00:27:06,080 And so, uh, I tend not to bring them back to see me alone. 223 00:27:06,200 --> 00:27:09,840 I, I prefer to have combined follow up with other specialties. 224 00:27:09,900 --> 00:27:24,660 So if the ophthalmologists or the neurosurgeons if they have, uh, shunts, uh, or the neurologists, uh, if they have neurologic complications like seizures, uh, I try to do a, a combined follow up with them. 225 00:27:24,760 --> 00:27:36,090 And so typically we would wanna see within a couple of months of discharge, minimally, uh, and then again, usually at three to four month intervals for the course, the, of the follow up. 226 00:27:36,350 --> 00:27:44,370 Um, here we're a bit lucky in that some of our specialists do traveling clinics and they go up to the Northern territories. 227 00:27:44,950 --> 00:27:48,050 So patients don't have to travel quite as far. 228 00:27:48,190 --> 00:27:53,970 So one 2-hour flight instead of two 2-hour flights uh, or three hour flights. 229 00:27:54,270 --> 00:27:57,205 Um, We try to be as practical as we can. 230 00:27:57,705 --> 00:28:01,645 And with the advent of virtual care, it's really made a big difference. 231 00:28:02,095 --> 00:28:17,965 So doing, having that shared care model where we're supporting their, their local practitioners, or, uh, say their pediatrician who flies into their community, than it does help, um, make what's a very difficult situation, a bit more bearable for the families. 232 00:28:18,945 --> 00:28:26,635 Ella Dzora: And just one more thing to clarify, cuz the eye disease can flare up, particularly adolescents and later in life. 233 00:28:26,775 --> 00:28:34,035 If the eye disease was quiet in that first year of, of life, how often would you have to follow it up or would you wait till they had symptoms? 234 00:28:34,665 --> 00:28:38,595 Jason Brophy: Yeah, so I usually defer those decisions to ophthalmologists. 235 00:28:38,875 --> 00:28:40,915 I don't like telling people what to do. 236 00:28:41,295 --> 00:28:49,540 Um, but, but generally they want to see them on a regular basis, like on, uh, I, I think if they're local, they'll see them more closely. 237 00:28:49,890 --> 00:28:51,820 They'll follow 'em up more frequently. 238 00:28:52,080 --> 00:28:58,100 Uh, but I think minimally on a yearly basis, especially when they're young and maybe can't verbalize their complaints. 239 00:28:58,600 --> 00:29:07,020 But yeah, the expectation with congenital infection is that, there's definitely a risk for future reactivation of eye disease. 240 00:29:07,360 --> 00:29:18,245 And that that risk is higher if, uh, they haven't been treated, like if the congenital infection wasn't diagnosed at the time, then it's very high risk of, of reactivation over their lifetime. 241 00:29:18,695 --> 00:29:24,665 That varies according to the geography or serotype or subtype of, of, toxo. 242 00:29:25,355 --> 00:29:31,855 Uh, the South American versions tending to be more aggressive, uh, than the, than the European versions. 243 00:29:32,315 --> 00:29:36,575 Um, don't think we understand that as well for our Arctic versions. 244 00:29:36,995 --> 00:29:40,255 Um, but, um, the, that follow up over time should. 245 00:29:40,535 --> 00:29:41,255 Should be there. 246 00:29:41,275 --> 00:29:46,015 And, and typically the, the bigger risk would be re reactivation usually in adolescents. 247 00:29:46,155 --> 00:29:46,575 Ella Dzora: Thanks. 248 00:29:47,595 --> 00:29:56,695 Um, so our neonate has done really well and the parents are shown how to crush and dissolve the medications for administration and infectious diseases follow up is arranged. 249 00:29:57,145 --> 00:30:02,045 Mom's really keen to, to return to her home community as she has three older children at home. 250 00:30:02,465 --> 00:30:06,965 And she's quite overwhelmed being so far away from home and alone and away from her family. 251 00:30:08,005 --> 00:30:18,625 So infectious diseases, neurology, ophthalmology, audiology, and neurosurgery follow up is arranged and interim telehealth communication, as you suggested, is arranged to assess the progress. 252 00:30:19,710 --> 00:30:28,470 Follow up drug toxicity blood work is arranged locally and at telehealth follow up three weeks later, mom asks whether or not this infection could have been prevented. 253 00:30:28,730 --> 00:30:29,950 Jason Brophy: So that's a very good question. 254 00:30:30,530 --> 00:30:36,510 We know that some jurisdictions of the world, uh, have prenatal testing that's routine for all. 255 00:30:36,880 --> 00:30:54,480 So that it's most commonly known in France, owing to their culinary proclivities, um, but in my experience, we, in, in Ottawa, we have a lot of, a lot of migrants from, uh, Francophone Africa as well as, uh, places like Morocco and Lebanon. 256 00:30:55,180 --> 00:31:07,630 Uh, and it's interesting where most of those places have toxoplasma screening practices, very similar to France because they were influenced by French through colonization over time. 257 00:31:08,280 --> 00:31:14,460 In those, in those, uh, environments or jurisdictions, toxoplasma screening in pregnancy is routine. 258 00:31:14,920 --> 00:31:23,200 Uh, and what tends to happen is you have a toxoplasma test during, uh, your initial intake into prenatal care. 259 00:31:23,730 --> 00:31:29,670 If you're seropositive with an IgG positive and an IgM negative, then you'd be clear, in the clear. 260 00:31:30,050 --> 00:31:45,270 If your IgG negative, then you'll be recommended to have, uh, repeat follow up over time and ideally a good counseling around what would be the things to do during pregnancy to reduce your risk, uh, primary infection during the pregnancy. 261 00:31:46,050 --> 00:31:58,840 So, interestingly we, because we've had had, uh, several cases, uh, in Nunavut over the last few years, we're actively in the process of introducing a prenatal, uh, screening program up there. 262 00:31:59,425 --> 00:32:00,925 The population is very small. 263 00:32:00,985 --> 00:32:09,365 The number of births per year is something around 500 to 800, uh, depending on how much of the territory you're including. 264 00:32:09,945 --> 00:32:20,125 But we have a high number of cases, uh, and it makes sense because there's increasing research showing that it it's not, it's not cat exposure up there. 265 00:32:20,125 --> 00:32:28,430 There are no cats in the Arctic, uh, region, um, or well, I guess there are probably some domestic ones, uh, but there are no wild ones. 266 00:32:28,690 --> 00:32:53,950 But we know that, uh, a number of animals that are consumed including marine mammals, like beluga and walrus and seal, well as, uh, ungulates like caribou, uh, and there's some findings from local researchers that show that, uh, some fish have, uh, evidence of, toxo uh, char and salmon and then Arctic goose as well apparently have toxo. 267 00:32:54,030 --> 00:33:03,979 So, uh, it just tells you that, um, We need to do a, a better job of counseling in pregnancy, uh, because serology's only gonna tell you if there's a problem. 268 00:33:04,590 --> 00:33:07,990 Primary prevention would be much better than secondary prevention. 269 00:33:08,250 --> 00:33:23,580 And so, yeah, as you said, if we do identify, uh, some, a woman with a primary infection of pregnancy then would use the medication approach of spiramycin, uh, and then if, uh, fetal infection confirmed sulfadiazine/pyrimethamine. 270 00:33:24,320 --> 00:33:37,620 And then, like I mentioned, the, the counseling part of, of when the mom's infection happens, uh, really dictates the risk of infection to the fetus with a lower risk of infection in first trimester. 271 00:33:38,255 --> 00:33:47,755 But if that infection does happen, uh, then a very high risk of serious congenital anomalies, like brain and eye disease. 272 00:33:48,295 --> 00:33:54,875 Uh, whereas if the primary infection happens later in the pregnancy, then the risk of transmission is quite high. 273 00:33:55,415 --> 00:34:03,265 Um, but the risk of, uh, disease or obvious, uh, clinical sequelae in the child is lower. 274 00:34:03,445 --> 00:34:07,585 That's presuming that you'll make the diagnosis and treat the child once they're, once they're born. 275 00:34:08,120 --> 00:34:17,200 Ella Dzora: I think the CDC website gives prevalence in 14 to 44 year old women as 9%, but that's across the states. 276 00:34:17,200 --> 00:34:22,515 Presumably there's hugely wide regional variation within that as you've highlighted. 277 00:34:22,905 --> 00:34:23,195 Jason Brophy: Yeah. 278 00:34:23,295 --> 00:34:34,285 I think we know, uh, at least in, in certain parts of the world, like, um, central Africa, uh, those rates can be like 50, 60, 70, even 80% reported. 279 00:34:34,655 --> 00:34:42,165 I think it really varies around the world and according to cultural practices around food and what you do or don't do while you're pregnant. 280 00:34:42,840 --> 00:34:43,690 Ella Dzora: That was really thorough. 281 00:34:43,690 --> 00:34:44,410 Thank you very much. 282 00:34:44,670 --> 00:34:56,945 To end, I just wanted to ask if there's any other kind of important points that you've not already highlighted that you'd like to just bring to our attention about congenital toxoplasmosis or other congenital infections in general. 283 00:34:57,575 --> 00:34:59,465 Jason Brophy: Yeah, I it's interesting. 284 00:34:59,545 --> 00:35:06,205 I find that there's such a, a wide range of parents, um, level of concern, right? 285 00:35:06,205 --> 00:35:06,945 It ranges. 286 00:35:08,185 --> 00:35:08,875 It's all natural. 287 00:35:09,375 --> 00:35:18,475 I'm not gonna worry about anything to, uh, like a high level of anxiety, uh, and not knowing, uh, what, or if you can do anything during pregnancy. 288 00:35:19,625 --> 00:35:21,995 It's, it's good to be, uh, rational. 289 00:35:22,575 --> 00:35:29,065 Uh, and I think it's good to provide, uh, good prenatal counseling around high yield things. 290 00:35:29,525 --> 00:35:43,025 And so with toxo, uh, it's around primary prevention strategies, like don't, don't take in, uh, raw or rare meats, avoid unpasteurized dairy products, like goats milk. 291 00:35:43,525 --> 00:35:49,495 If you do garden, then please wear gloves and wash your hands while after you've done. 292 00:35:49,555 --> 00:35:57,795 So, um, and if you have a cat, uh, consign your partner to, to that, in the pregnancy 293 00:35:58,375 --> 00:35:59,435 Ella Dzora: and, and ongoing. 294 00:35:59,745 --> 00:36:00,035 Sara Dong: Yeah. 295 00:36:01,325 --> 00:36:02,195 Jason Brophy: Thank you very much. 296 00:36:02,735 --> 00:36:22,975 Um, but then other other things like, uh, I didn't touch much on congenital CMV, but, uh, in my mind, that's one area that we don't talk about nearly enough in pregnancy and that, uh, literally almost every child with congenital CNV I've ever seen, uh, has a two year old sibling at home who's in daycare. 297 00:36:23,595 --> 00:36:30,975 And so we know who to target our primary prevention strategies towards, and I don't think we're doing it. 298 00:36:31,075 --> 00:36:41,525 And when we look at the other types of, um, infections that we screen for, or counsel around during pregnancy, uh, they're much lower prevalence than CMV. 299 00:36:42,025 --> 00:36:47,040 And, uh, I think we need to do a better job on, on that particular congenital affection. 300 00:36:47,550 --> 00:36:56,800 Here in Ontario, we've introduced a, an enhanced hearing screening program that includes CMV testing for every child born in the province. 301 00:36:57,380 --> 00:37:05,710 And so we've identified, um, like a tenfold or even higher numbers of infants with congenital CMV over time. 302 00:37:05,710 --> 00:37:06,150 Ella Dzora: That's huge. 303 00:37:06,370 --> 00:37:11,750 Jason Brophy: And, and just like, just like with this case where the mom asked, um, why didn't I hear about this? 304 00:37:11,770 --> 00:37:13,630 Or, or what could have been during the pregnancy? 305 00:37:14,010 --> 00:37:22,865 That's what every mom asks me, like, except for except for moms who are healthcare workers or microbiologists. 306 00:37:23,165 --> 00:37:29,605 No one else has ever heard of CMV uh, unless you've had, you've been touched by it in your own household already. 307 00:37:30,065 --> 00:37:35,645 And so I think we need to do a better job of, of talking about these things, uh, and making it routine. 308 00:37:36,395 --> 00:37:39,435 Sara Dong: Well, thank you guys, both so much for being here today. 309 00:37:39,755 --> 00:37:41,835 I learned a ton and had a lot of fun. 310 00:37:42,205 --> 00:37:43,555 Ella Dzora: Thank you so much for having me. 311 00:37:44,335 --> 00:37:44,555 Jason Brophy: Yes. 312 00:37:44,555 --> 00:37:44,915 Thanks. 313 00:37:45,395 --> 00:37:45,885 I appreciate it. 314 00:37:46,260 --> 00:37:50,610 Sara Dong: Thanks to Ella and Jason for this great discussion on congenital toxo. 315 00:37:50,860 --> 00:37:54,360 Please stay tuned for the rest of our Curious Congenital Conundrum series. 316 00:37:54,860 --> 00:38:01,640 You can find the introduction and case one in our previous episodes and be on the lookout for our third and fourth cases coming up next. 317 00:38:02,500 --> 00:38:11,610 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. 318 00:38:12,550 --> 00:38:27,880 If you are new to febrile or haven't checked it out, I encourage you to take a peek at our website febrilepodcast.com to find Consult Notes, which are written complements to the show where there are links to references as well as our library of ID infographics that you can use to learn and teach others about ID. 319 00:38:27,900 --> 00:38:30,600 Thanks for listening, stay safe and I'll see you next time.