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SA: Hello, and welcome to Master the MRCPCH. In this series, we tap into the expertise here at Great Ormond Street Hospital to give you an overview of a topic on the RCPCH exam curriculum. So whether you're revising for an exam or just brushing up on a need to know topic. Hopefully this podcast can give you the information that you need.
I'm Dr. Sarah Ahmed, a pediatric registrar and the current digital learning education fellow here at GOSH.
In today's episode, we will be speaking with Dr. Seilesh Kadambari, consultant and honorary associate professor at the UCL Great Ormond Street Institute of Child Health. We’re going to be talking about congenital CMV. We'll be covering aetiology and epidemiology, presentation, investigation, and management. Congenital CMV fits into the exam curriculum in the domains of both neonatology and infectious disease.
Seilesh, thank you for joining me today.
SK: Thank you, Sarah. Thank you for inviting me.
SA: So before we delve into more detail, I wanted to start by asking, what would you like people to get out of this podcast?
SK: Well, I think just awareness of congenital CMV. So it's the most common infection passed from mom to baby. So just to be aware of it, know how it presents, know how to diagnose it and ideally know how to treat it. I'm sure we'll talk about treatment later, but it's that kind of just awareness really.
SA: Fantastic. I think those are really good learning outcomes to keep in mind as we go through this talk. So let's start at the very beginning. What is congenital CMV?
SK: So congenital means mum to baby and CMV stands for cytomegalovirus. So “cyto” cell, “megalo” big and “virus”. And if you look under a microscope, it's actually a pretty big virus. One of the biggest, one of the bigger herpes viruses. And congenital CMV is an infection that in the UK about half of all adults will have. So the serial positivity rate is about 50 to 60%. And, it doesn't do anything. So in immunocompetent adults or children, we don't worry about it at all. We really only worry about it in those who are severely immunosuppressed. So at GOSH, about immunosuppressed about a third of the children we look after are severely immunosuppressed. But in congenital CMV, we’re worried about infection passed from mom to baby. And in those instances, you can have babies with severe disease secondary from congenital CMV.
So the most common form of that disease will be sensorineural hearing loss. So about 15% of all babies with CMV will have hearing loss and a small proportion, so about 10% will look very, very unwell. So 10% of babies with congenital CMV will be on the neonatal unit, and they'll be a very smart neonatal SHO who will be like, “oh, CMV! Let's test for it”. Or there'll be a consultant who's seen several cases of CMV in their career.
But they'll look like the baby will look obviously like they're unwell, they'll have a petechial rash, microcephaly, hepatitis, bone marrow suppression, seizures, cranial calcification. And so people will think about congenital CMV. That's 10 percent of all babies. 90 percent of all babies will look well, they'll be on the postnatal ward, they'll go home on day one or day two of life.
But of those 90% about 15 percent will have hearing loss, and we don't test for CMV at birth routinely, we don't screen for it. And so we miss that opportunity to detect it. And if those babies have confirmed hearing loss, through audiological investigations. But when we look at the aetiology, when audiologists or community paediatricians then do the aetiological tests, it's often months down the line when it's too late to start treatment
SA: Do we know in absolute numbers, roughly how many mums and babies are affected every year?
SK: In the UK it's probably somewhere about one in 200. So, it's pretty common. Like I said, not all of them will be symptomatic, the majority won't be symptomatic, but it's a common congenital infection.
SA: And we've spoken a little bit about presenting symptoms already, but can we go into a little bit more detail? So you mentioned rashes, seizures um, hearing loss. What else is there?
SK: So, typically the 10 percent who look very, well, so 5 percent will die from it. And it's a cause of stillbirth and miscarriage. 10 percent will look like they've got CMV. So they'll have a classic blueberry muffin rash or a petechial rash. They'll have a microcephaly, like a head circumference way below the point 4th centile. When the cranial ultrasound scan’s done, they'll have intraventricular calcification or when the MRIs done, it become more obvious. Hearing is the most common feature. So often these babies who look unwell will have hearing loss as well. And that sensorineural hearing loss, some babies can have ophthalmic disease, chorea retinitis, because it's really important for a trained paediatric ophthalmologist to do an assessment.
And then. Some of these babies also get thrombocytopenia, anaemia, neutropenia, and hepatitis due to CMV. So it's really important to carefully monitor all of those aspects of blood tests as well. That's the 10 percent who look unwell, and they'll almost always end up on a neonatal unit. But like I said, 90 percent are well. They'll never need the attention of a doctor. But of those 90%, 15 percent will have hearing loss.
SA: And if we're thinking about investigations, if you have a child that you suspect may have CMV or I think the more likely way that they come to the neonatal unit is you have a child who has got a low birth weight, and so you check for CMV. Should you be doing a urine test? A blood test a swab to check for it?
SK: Yeah, that's a great question. So, CMV has a much higher viral load in saliva and urine. Something like 10 to 5 6 higher in saliva and urine compared to blood. So, ideally, the gold standard has been for a long while to do a urine test. Actually, this is one of the few examples where you can use a bag. Because you're just looking at the CMV DNA. You don't need a clean catch sample.
But obviously urine samples, you have to wait for the urine to come. So saliva test is much easier. So saliva test is a non invasive, similar level of viral load. And most labs in the country can do saliva PCRs. The issue, the big issue with saliva tests that people just need to think about is you don't want contamination with breast milk. So the sample has to be taken one hour after a breast feed. You don't want to have a mom who's CMV seropositive, which will almost definitely be the case of a congenital infection. So you don't want to have a mom who's shedding CMV in the breast milk, and then essentially all you're testing is breast milk CMV DNA. Lots of us get caught out with that. And often when we do have a positive sample, we always retest with a second sample. So if you have a first positive urine or saliva, we always retest. And the second sample should ideally include a urine sample just to be 100 percent certain.
You can do blood tests, absolutely, to look at the CMV viral load, but blood viral loads are definitely lower than saliva and urine. The other way of testing is going back to the Guthrie card. Every baby has a newborn blood test at day five. You can go back to the Guthrie card, extract CMV DNA, and check using PCR.
There's an easy consent form that most hospitals will have, and Guthrie cards are often sent for testing at central laboratories. The issue with Guthrie card testing is that it's about 80 percent sensitive. So you'll miss 20 percent. So you can be falsely reassured if you have a negative result And you have to remember that even the best labs the absolute best labs in Europe Will have a sensitivity rate of 80 percent on Guthrie card And that's probably because of the blood viral load being much lower in blood or the viral load being much lower in blood than compared to saliva and urine.
SA: Okay. And if you're suspecting CMV, should you be testing for anything else? Are there any other differentials that you want to be ruling out?
SK: Yeah, absolutely. There's a fantastic paper by Justin Penner. So his surname is P E N N E R, and his first name is Justin. And he used to be the senior ID fellow at GOSH a few years ago, and he published a great paper in archives in 2021 called Stop, Think, SCORTCH. So S C O R T CH, rather than TORCH. And the S the first S here stands for syphilis.
And so I guess it's always important to think about other congenital infections that can present with hearing loss, intracranial calcification, choreo retinitis. And in that paper, there's a couple of fantastic tables and figures about when you think about these infections, which symptoms and signs should make you think about them, and which tests you send. And that's, yeah, from Archives of Disease and Childhood in 2021, and Justin Penner was the first author. So I think if you do have a baby who presents like this, don't forget about other congenital infections. And always important to go back to the booking bloods. Did the mom have a syphilis test?
The rates of syphilis in adults is going up certainly in high income countries, it's really going up quite exponentially. And so even though congenital syphilis is very rare, one could expect to see more cases of congenital syphilis. And of course, HSV is catastrophic, but some features of HSV can mimic CMV. It's important to think about, yeah, think about other congenital infections.
SA: Great, and I'll make sure that the paper's linked in the description below, but I've looked at it before actually, it's a really good paper if you're a paediatric SHO looking to revise for your exams, it's great. So, you've got a baby that you've confirmed has got CMV, how do you go about managing that baby?
SK: So often the management is done through a multi disciplinary team. You have, if a baby is on the neonatal unit, the management will be led by the neonatal consultant, but CMV is, it's still pretty rare. So 1 in 200, we don't screen for it. So we don't know the burden of disease. So, we would expect for any ID team, I think, in the country would expect a local paediatrician or local neonatologist to call us for advice. So, ideally we would need to get cranial ultrasound scans and an MRI head scan, so a radiologist. It's really important to get early audiological testing. That's very, very important. An ophthalmologist, because you need a trained paediatric ophthalmologist to do the eye assessment, and that should be done pretty soon as well. And all of those people play a role.
The timing of the diagnosis has to be made within the first three weeks of life. So you can confirm congenital mum to baby quite safely within the first three weeks of life. Anything after three weeks of life, you don't know if it's congenital or if it's postnatal and that the baby just picked it up from the outside world. So it's really important to make that early diagnosis. And the data, the randomized control trial data that's available only supports use of Antivirals, and the antiviral we use is ganciclovir. And the RCT data only supports giving it within the first month of life. And so once you think about CMV, you have to make the diagnosis pretty promptly, because you want to make sure you've got congenital infection, and you want to treat fairly promptly within the first month of life. So you want to do all the tests we talked about early.
It's not like meningococcal disease. You don't need to like, you know, treat in the next few minutes. You can take a step back, speak to your colleagues. And the other thing is, you should speak to your colleagues. You should be encouraged to because it's difficult to know which babies to treat. You should treat and you should recommend treatment if the baby's symptomatic and has obvious features or symptom disease or obvious hearing loss or obvious calcification.
But if the baby's got mild disease, very, very mild disease then it's a much harder decision and the efficacy to treat is based on one random control trial which took 10 years to recruit then publish and had 100 babies in it. So it's a very small study and that was published in 2015 in the New England Journal of Medicine. Massive effort but hard work to do the study and so that's why decision making to start treatment should always be done in the MDT, and always, and it's always good practice to speak to your colleagues about that.
And more importantly than the colleagues is to speak to the family. And these decisions to speak to the family are often done on several occasions. Lots of questions are encouraged. And when these babies are seen in clinic, we often bring them back from to clinic one, twice, three times before we start treatment, just so the family can understand. What CMV is, what the treatment entails, and what the efficacy and safety risks are, and the long term prognosis.
And I think that's the decision making between starting, in terms of starting treatment. Have you definitely got congenital CMV? Have you got samples within the first three weeks life? And have you done investigations that demonstrate disease? And if so, can you start treatment promptly within the first month of life? And do you have support from the family, which is the most important thing, and your colleagues? And, yeah, that's, that's easier said than done, because the nature of this infection is that we don't screen for it, so often we pick it up quite late, way, way after the first month of life, so it becomes a bit harder. Will you start treatment on a baby who's three months or six months or a year of age? And it's a much harder decision then, because it's out of the confines of, of any data to support that.
SA: Does the treatment come with side effects? Is that why you're having lots of conversations before you start it? Or is it more that it's just quite a commitment to starting it?
SA: Yeah, all of those things. So the study, the randomized control trial was published by the David Kimberlin. So he's the first author and he has dedicated his life to congenital CMV and neonatal HSV. Quite impressive, incredibly impressive person. With a huge group in Alabama. So they're based in Alabama and there's a big antiviral network in the United States. And we at GOSH, along with seven or eight different hospitals in the UK, collaborate really closely with David and his network. In that randomized control trial, they showed that six months of oral valgancyclovir had, some improved hearing in two thirds of babies. But in a third of babies, there was no change in hearing outcomes. So it's not an entirely efficacious drug. It doesn't work 100 percent of the time.
And a fifth of babies, so 20%, got neutropenia where the drug had to be temporarily stopped or, you know, monitored at least. So it's not an entirely safe drug either. So you have to go through that with the family in a lot of detail. And of course the families have got no, they've never heard of CMV before. So CMV awareness amongst the general population is extremely low and CMV awareness amongst healthcare professionals is pretty low too. So you're starting from scratch and you're telling the family that they've got a child with a congenital infection, which potentially could cause lifelong morbidity, but we want to crack on and possibly start to do these tests and start treatment.
So inevitably there'll be lots of really, really important questions that need to be answered. Lots of guarding about. The benefit of treatment, you know, it is beneficial, but, there's a modest benefit and it's certainly not 100 percent safe. So we monitor these babies very closely and the families will ask a huge range of extremely important, really relevant questions, which we just go through very carefully and sometimes there's no data to support those answers, which is why we, we want give as much open and honest information as we can.
*trumpet sounds*
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SA: And it's quite a multidisciplinary team approach, isn't it, to managing? I know the CNSs are really important within your team.
SK: Yeah, the CNSs are fundamental. So when we see these babies, we if we start the treatment, we review them pretty much every month. The CNSs tend to lead care. So they would make sure there's enough oral valve cancer at home It's being administered. The blood tests are being done appropriately. The results are being chased.
There's so many different teams involved So, you know ophthalmology, audiology, general pediatrics, us, allied healthcare professionals, dietitians, speech language, etc, etc. So our CNS team really tried to join all those dots together, which is a very tough job.
One group that I haven't mentioned, which we may mention later, but I want to just talk about now is CMV Action. So CMV Action are the parent support group, and they're fantastic. They have a brilliant website. So anyone who listens to this just can Google “CMV Action”, and the website's very user friendly. It's a small, very small group of volunteers who have had family members or children affected by CMV, and they have a really easy to use information sheet, which we give to families. And the support group, if contacted by family, are very proactive and will provide lots of holistic support to the family. And they're, they're pretty important as well.
SA: Yeah, it's really great that you've got that very supportive team around the family as they're going through quite a difficult time right at the beginning of their child's life as well.
SK: Yeah.
SA: So there's, there's one drug that we've spoken about. Are there any new treatments on the horizon or any new research that's being done into congenital CMV?
SK: Well, there have been three randomized control trials. The first looked at intravenous ganciclovir. The second looked at oral valganciclovir given an infant less than one month, and the thirdly, the oral valganciclovir could be given in infants between one month and four years of age. All three of those trials were done serially, they weren't done simultaneously.
And each one took exactly ten years by the time the guy in Alabama thought about it, to publication. So that's 30 years and three randomized control trials with about just over maybe 100 or 130 babies or children actually getting active drug. So it's incredibly difficult to do these trials, extremely difficult. There are no, for congenital CMV, there are no new antivirals that I'm aware of that are being trailed in either phase two or phase three.
I think the big development in CMV is vaccination. That's always been a big to eliminate CMV. And the first vaccine trial was published, I think, in 1981, so over 40 years ago, and yet there's no vaccine in the pipeline. Until now, and Moderna have got a really exciting candidate, which is an mRNA vaccine, which they're trailing in phase 3 trials in women of childbearing age. So that's a really exciting development. It's still many years away from licensure, there's still many unknowns about the vaccine. That's a really exciting avenue.
SA: Yeah, something to keep an eye on and watch out for. So CMV, congenital CMV is a, is a lifelong condition. What, are there any long term consequences or morbidity associated with it?
SK: Yeah. So, I mean, we talked about sensorineural hearing loss. So that's a, that's a huge, the most common clinical feature and the most severely affected babies will need cochlear implants. And there's a huge burden on the family. And on education and wider society due to just CMV related hearing loss about 5 to 10 percent of babies who are severely affected can get cerebral palsy as well due to CMV. And so looking after babies with CMV related cerebral palsy is also extremely challenging for the family, but it's also placed a huge financial burden on society.
There's a paper published a couple of years ago showing that using the most conservative estimates every year in the UK, it costs about 700 to 750 million pounds to look after people with CMV. It's hugely expensive using the most conservative estimates because of all the wider teams and therapies that are involved. So hearing loss, cerebral palsy and neuro disability, essentially. So seizures or seizure disorders are all. The more common end of long term morbidity due to CMV.
SA: Can we end with some quickfire questions? So firstly, are there any classic exam questions that could pop up about CMV?
SK: Classic exam questions. So yes, how, how did it present? So maybe you know, blueberry muffin rash, true, false. They might ask about true treatment duration, I guess. So do you give one month, six months? 12 months, the rest of your life? And the answer is six months. And I guess, do you, can you, like, how quickly do you have to start it? Can you start it, start it within one hour, one month, one year, 10 years, but ideally we should start to be in the first month of life.
SA: Fantastic. And we've already mentioned some of them, but are there any useful resources that you would recommend?
SK: Yeah, so definitely the CMV Action, the website is brilliant. Justin's paper, the SCORTCH paper. Not to big myself up, but we wrote a 15 minute, I think a nice paper, which has been used pretty widely. It's a paper we published in Archives a few years ago in 2016 which was those 15 minute consultation papers, so it's pretty straightforward pretty basic, but it just tells you the trigger points for an SHO to think about when to test for CMV, how do you test for CMV and how do you treat for it? So it's a quite a nice user friendly guide I think and that was in 2016
SA: Great. I'll have everything linked in the description so people can find it. And finally, what are your three takeaway learning points?
SK: To think about it definitely so, in your day to day practice, you know, when you're on the neonatal unit or doing community paediatrics, think about it always respect the MDT. So the MDT are, like, really important. If you're not too sure, speak to a colleague and we often, within our team at GOSH, we often speak amongst our team about patients with baby listing MDT. And we often discuss CMV babies with units all across the UK and they contact us because then it's not easy to it's not an easy illness to look after. And finally, think about the family. They're the most important people. It's an extremely difficult diagnosis to comprehend, not least because you're starting from zero. The awareness is so little. And you just have to really make sure that the family are on board. And that you answer all the questions and there is no rush in starting treatment.
SA: Fantastic. Thank you so much for a really good comprehensive, but very accessible introduction to congenital CMV.
SK: Thank you for the invite. Thanks very much.
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