ROUGH EDITED COPY

EHDI
Malpensa ‑ 10:15 am CST Breakout Session
March 5, 2019

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Implementation and Outcomes of a New CMV Screening Protocol at Boston Children's Hospital
with  Derek Stiles and Kaitlyn Fitzpatrick 
 
   >> DEREK STILES: Good morning, everybody. Thank you very much for coming to our presentation today. And it's great to be presenting after Lurie children's. I feel like it's a great segue. Hopefully most of you were here for that presentation as well, because you'll see how it goes together. I'm the director of audiology at Boston children's hospital. With me is Kaitlyn Fitzpatrick. She's one of our audiologists. I did not have a slide showing off our facilities as nicely as Lurie childrens, but it seems similar. They have six and we have six sites. They have several audiologists and so do we. I think we are probably pretty similar in where we're coming from. Neither of us have any particular conflicts of interest apart from being employees of Boston children's hospital. 
    What Wes ear going to talk about today is basically cytomegalovirus, and some of the deficits you see with cytomegalovirus, the protocol that we developed at Boston children's hospital to identify and manage these children. And then also share with you some of the data that we've collected over the years that we've implemented this protocol. So, we've actually been doing this since 2015. So, we've got a fair amount of data about how our process is working and what's happening with these children. 
    So, cytomegalovirus is a member of the Herpesviridae family of viruses. Typically it's contracted in an adult through contact with bodily fluids. Often it's contact with a young child. Young children tend to shed this virus more readily than adults do, so it's easy to contract the virus from them. Now if it's a pregnant woman who is contracting the primary infection, there appears to be a transplacental transmission to the fetus in about one third of those mothers. Half of those will result in a symptomatic congenital CMV in the newborn. So, our estimate is around 8,000 children are affected by cCMV per year. Clearly it's in the thousands. So, congenital CMV can have many effects. Microcephaly, motor delays, seizures, loss. Often on a CT or MRI you can see calcifications in the brain matter. And of course what we're mostly focused on is hearing loss. There is some association where children who have increased levels of the CMV virus or a longer duration of the excretion of the CMV virus are more likely to develop hearing loss. And the etiology of the hearing loss in CMV is thought to be an inflammatory response.  So when the virus presents in the ear, it causes inflammation of the endolymph, which does damage to the tissues inside the ear and causes the hearing loss. 
    So as was mentioned in the previous presentation as well, there is treatment now for congenital CMV. It's not like one of these where you diagnose it and you can't do anything about it. There is something that can be done, which I think speaks to the urgency of trying to identify these children as early as possible. So, anti‑viral medications such as Valganciclovir can prevent or slow the progression of hearing and vision loss. The hallmark study by Kimberlin et al, and I call it hallmark because it's the most heavily cited, it included infants that were less than one month of age. And I want you guys to keep that in mind for the data that we're presenting today, because through our process, we're not typically identifying children that early. So, whether the results that were obtained through this study are the results that we can expect through our process, I think it's not quite clear. 
    Anyhow, in this study, the median age for treatment was 8 days of age. So, these children were identified and treated right away. In their study, they had a group of children who received Valganciclovir and a group with no treatment. And you can see the difference. In the no treatment groups, there was a greater likelihood of hearing getting worse over time. That's the red mark.  So the first two horizontal ‑‑ I'm sorry. Vertical bars are at the six month follow‑up, and the next is at the 12‑month follow‑up. So, the children who received treatment were typically more likely to demonstrate stable hearing and less likely to show a decrease in their hearing ‑‑ an increase in their hearing thresholds, a decrease in their hearing. 
    
    So what we were kind of faced with is what do we do to kind of address hearing loss in children with CMV when there's no state mandate for universal newborn CMV screening? So we had to come up with something ourselves, because our state was not stepping in with any kind of, "We're going to screen all children for CMV so we know who to flag and who to monitor." 
   >> KAITLYN FITZPATRICK: We are in awe of Illinois for implementing the mandate. It is not the case in Massachusetts. So, we are not there just yet. So, in our department, we as a team kind of came together and said what are we going to do with these children? You know? We know that CMV is an etiology that we need to be aware of, and we need to act fast. There are several hospitals who volunteer to actually do that CMV screen for children who refer, whether unilateral or bilateral refer. But from our perspective, how are we going to monitor them? How are we going to identify them if they have not been born at one of the fantastic hospitals with the resources to implement a screen? We audiologists met together and identified point people to develop and work on the guideline, do best practice research, and coordinate with our primary otolaryngologist and communicate with the folks in infectious diseases. The department is not that big, so we often communicate with them face to face, which is helpful in implementing our guideline. 
    So we developed a guideline. It was approved by the rest of our staff. We often go back and forth and say, you know, is there anything else that's missing? These are the things like that quality team that you guys at Lurie have implemented. We bring it out to the staff. Does everyone agree? 
    We also wanted to get trained on how to do a cheek swab, the buccal swap. And that would be our first step, and we wanted to be sure we were trained on how to do that if for some reason that nursing staff was not available that day, place, and time. We didn't want to waste any time. We wanted to collect that swab right then and there. And we needed to be trained on how to request the lab and do everything through the electronic medical record. That was implemented in 2015. What we came up with audiological is we were going to do this cheek swab test on children under 12 months of age that were being identified with any degree and any type of hearing loss at our facility. So, most of the time, those are kids who are, you know, follow‑up for the newborn hearing screening. Whether that was they referred or often times we're seeing children who are a tier 1 risk factor. They may have passed, but they are still receiving ongoing audiological monitoring. So, we decided those are the folks we're going to do the screening guideline on. If we are identifying hearing loss, even if it is related to middle ear dysfunction that we have identified today, maybe they already have a diagnosis that could potentially explain a hearing loss, we're still doing it because you can have multiple etiologies for hearing loss. We would make sure to collect a cheek swab by the nursing staff on site or the audiologists. We made sure we identify the patient, wearing gloves, communicating with the lab effectively. You have to know the specific time it was collected. The lab puts it on ice and follows through from there. 
    From there we also need to inform an attending physician and physician assistant that we did request this lab. This patient, this child is on our radar and they should be on your radar as well. Depending on the day which you have collected the swab, families will probably be informed within four days of those results. They are informed via telephone or e‑mail communication if they can't really get in touch with the family. At that time, from the physician assistant. If the results of the CMV screening was negative, they would follow up with audiology as planned. So, the PA connects the mangle audiologist and says it was negative, follow‑up as you normally would. But if it did come back as being positive, yes, sir, the audiologist is informed, the family is contacted, and infectious diseases is informed immediately. It prompts quick follow‑up similar to what Lurie Children's did. We're seeing the kids fast in infectious diseases. A repeat ABR or behavioral test as soon as possible. And you're meeting otolaryngology to make sure they're keeping tabs on what's going on. 
    Often times imaging, so MRI or CT scan would be warranted at that point in time. They will look to see if there's those brain calcifications that we're seeing. All of these things are usually being done quickly, which can be overwhelming for families, but we want to do as much as quickly as possible. So, from an audiologic standpoint, those children identified as CMV positive, we are doing hearing tests every month until a year and annual thereafter. And thereafter is pretty broad. We're still recommending follow‑up, because you can still see the late onset. For those children with hearing loss, every three months until one year of age, and then it transitions to, you know, what you would normally do for any child with hearing loss. So, oftentimes I think that would be an every six month management, but if you start to see something change, if it's not stable, you're probably seeing them sooner than every six months, you know? Maybe you enter the age of we're not going to do anything for you. And so we need to see you a little sooner to fill in blanks and make sure you're getting ear‑specific information. I think often times we are really aware of how important ear‑specific information is, especially during that first year of life. And so, if the family is really able and willing to you know, keep a child from falling asleep in the car on the way to our appointments, we're going to try and do an unsedated ABR for as long as we possibly can. We are coordinating around nap time. We are using, you know, as much of our resources as we can to try and get that child to fall asleep. And you know, if we have to book for a little bit longer to get that ear‑specific information, we're going to really try and do so. We are not thrilled about doing sedated ABRs or ABRs under anesthesia. We're trying to do that after surgery, because it muddies the water, because we're not sure if it's true hearing loss or hearing loss that is impacted by suctioning and surgery. We try to do unsedated ABR for as long as we possibly can. Families are really experts. They know how to get that kid to sleep. They have the tools that they need. 
    So that's what we're trying to do for them. So, our data. So, we were trying to track this data from the minute we've implemented that guideline, so 2015 until 2018. And for the children between birth and 12 months of age, we had almost 2,000 patients and around 10% of them had hearing loss. So, 70% of those kids were actually screened for cytomegalovirus virus, and most of them, 93% of them came back negative. Which is I think consistent with what the research is finding. But 5% of them were positive for CMV, and that is through our ability to complete the cheek swab. Great. We're doing good work. But what we found is that of those patients that we've identified, notice the age at which we completed the swab. This is being done as age 31 days to 163 days, so way beyond that 21‑day mark, the Kimberlin steady, we're way beyond that mark for implementing treatment. In terms of their degree of hearing loss, is it unilateral? Is it bilateral? We really didn't find any significant changes in their hearing levels other than folks who had middle ear dysfunction and maybe the degree of hearing loss change because of that. But in terms of permanent hearing levels, we weren't really finding anything that fluctuated. Now a majority of these children did actually undergo treatment with Valganciclovir. Our ID department is keen on going forward with implementing treatment. The minimum would be six months' time for the Valganciclovir treatment. But it was only recommended to the folks they felt had congenital CMV. And their means of really identifying that is by way of hey, did they actually pass that newborn hearing screening? If they did, they felt it was CMV of unknown timing. So, we keep a close eye on them, yes. But they weren't necessarily implementing the Valganciclovir treatment for those folks. We did have false positives. In our department, we do that buccal swab. They have to go to infectious diseases if it came back possible and do additional diagnostic testing through urine or blood. Those folks handle that side of things, but we're still the first step. And of course those folks who had permanent hearing loss that would warrant intervention, yes, early intervention, but also hearing aids or cochlear implant treatment, we were hopeful to see them regularly and ensure that they are getting treatment. And we, of course, have lots of follow‑up. That's a thing, unfortunately. But most of our children were being identified. 
    What we did find, however, is that a bunch of our kids during that two‑year window were actually being identified before they got in the door, which is outstanding. We found it's been a community effort in our state where there's no legislation. Many times mothers are being diagnosed in ‑‑ during their ongoing pregnancy care. Was the child measuring tinier than they would expect? Maybe they would check for CMV at that time? Did they present with cold symptoms that presented? Maybe they were being tested at that point in time. And the eight to ten hospitals often would implement that ‑‑ either a CMV screening swab or diagnostic test, and they would go ahead and do that if a child referred on the newborn hearing screening. And often those kids are seeing infectious disease immediately, which is great. So, these are, I think what's of note, this included all of the children that we were seeing in our department. And often times in utero, six hours of life, two days of life, three days of life, that's when they're being swabbed or screened for CMV. So, those folks really do a better job because they get them earlier than we have been able in our facility. 
   >> DEREK STILES: So, in essence, what we were finding with our protocol is that we were not preventing any child from acquiring hearing loss. By definition, our process depends on a child showing a hearing loss on their hearing evaluation to get the CMV swab. So, it is possible that there are children out there who have normal hearing who have CMV, even who may be coming through our clinic and we're not testing them because our protocol is based on children having hearing loss. But, our process possibly prevented progression of hearing loss, and of course there's really not any way to know for sure, because you can't, you know, bring the kid back in time and then not give them Valganciclovir and see if their hearing loss would have gotten worse. But we do see that all of the children in our cohort basically had stable hearing thresholds. So, I think that does possibly give us some hope that the treatment is doing something in terms of prevention of hearing loss. A lot of the children already had hearing loss in the severe to profound range, so there wasn't much progression that was left to go at that point. 
    So in managing these children, these families are establishing care with several specialty programs. So, obviously with audiology, infectious disease for medical treatment. Also, they're making relationships with neurology, ophthalmology and otolaryngology. They are all being enrolled in early intervention because of the presence of hearing loss. But you know, we're anticipating that early intervention is treating and monitoring children with the CMV diagnosis differently than children with sensorineural hearing loss. 
    We have had some challenges associated with this process. We have challenges with the acquisition of the CMV swab. So, sometimes parents will refuse. They will decline to have the swab, which is their right. There have been questions of insurance coverage for the swab. Is it necessary? Will the insurance cover it? We do have a letter of medical necessity we can print out to cover the claims. The swab is less than $40, so it's not too much of a, you know, a hit. But it's still, you know, it's nicer if insurance pays for it. And then sometimes the audiologist just doesn't collect the swab. They might just forget, or it might be that there's a presumption that the etiology is not related to CMV. So, sometimes we see that with kids that might have middle ear dysfunction, abnormal tempenometry or show microtia. As Kaitlyn said earlier, you can have both. The incidence will be the same for those kids as the general population, so that does not mean you should not do the swab. 
    There are challenges after acquisition, so we do want to be considerate of the parent's potential stress level associated with the screening. If it does show a positive result, that there might be some guilt attached that it was something transmitted from the mother to the child. We also have the challenges of false positives. Thankfully they're few and far between, but it is a moment of what's happening right now. And challenges related to loss with follow‑up, which can obviously happen with anything. We are seeing more and more hospitals sign on for elective screening. And as you can see from the earlier table that is leading to earlier diagnosis and earlier treatment. So, that's a better point in time to do the swab than to wait until they come to the diagnostic center. However, this would still be an even better if all children were swabbed at birth and didn't have to rely on a hearing test to instigate that swabbing. Asymptomatic infants will still be missed through this process that we've set up, and late onset hearing losses or losses undetectible at newborn screening such as slight or some mild losses that can get through newborn hearing screening, those kids won't be checked. So, we can still miss those kids. And later on, if we come in and find the hearing loss, we could still do the swab, but we won't necessarily know was it congenital or acquired CMV? And that has different implications. So, in summary, almost all our challenges would be solved if we had universal CMV newborn screening, but we don't so this is what we're doing. 
    We are happy to answer questions. We did bring copies of our protocol if any of you are interested in taking that. Thank you very much for your time in listening today. 
   [ Applause ]   . 
   >> I will get back there. Who was the front? 
   >> I was just curious. This is probably a lame question, but do you run into problems with audiologists doing the swab as a scope or practices issue with your board? Is that cool? 
   >> DEREK STILES: We have not gotten any problems with that. We're not really diagnosing it. We're just doing a technique and sending it to a lab, and then it's being transferred. 
   >> And we don't review the results. 
   >> Can you give me an example of what that conversation looks like? I'm doing a hearing test and I'm going to swab your kid's mouth? 
   >> Yeah. We have identified a hearing loss, and we do that whole spiel. And they often lead it. What could cause this? Why? Why? And it's like you know what? That is a good question, and today I cannot tell you the answer to that. You're going to meet with the otolaryngologist and we will work together to see if we can find out why. But one thing we can do today is collect this cheek swab. It can give us a little information about if this could be a reason why your child might have hearing loss. So, if it's okay with you, we'd like to go ahead and do that. It doesn't hurt the child. It just takes 15 seconds of rubbing in the cheek and we'll have an answer in about four days. Most of the families have been really ‑‑ they want ‑‑ it's hard, because they want that diagnosis because then they do Googling and see that there's treatment. So, that can be hard to kind of say we actually, we need to do a whole battery of tests to see why your child might have hearing loss. But yeah. 
   >> I want to applaud you guys for doing something outside of legislation. I'm the parent sponsor of the Illinois law here. It's hard and a burden for parents to do that. So, the medical community doing that, I applaud you guys for doing that. My question is challenges with ID and not getting that conclusive congenital CMV through the swab at the time of birth or earlier. I know you mentioned in your later slides that they're trying to adopt that. Is there anything that you guys are doing to maybe modify those guidelines that you were working off of to maybe make it an earlier stage swab after newborn hearing screening has failed? 
   >> DEREK STILES: I think we're doing it like as early as we can, because there this is the first real point of contact that they come to our clinic. Being taken on by the birth hospital is going to be the earliest, the next earlier stage, I think. 
   >> KAITLYN FITZPATRICK: And the Massachusetts department of public health, they are champions in so many ways. And they're spearheading trying to get the folks from CMV foundation kind of in on the conversation. And they have been talking. So, like, it is in the works, I think, hopefully in the next ‑‑ I feel like decade is fair with legislation. 
   [ Laughter ] 
    Like extremely generous. But I think once that ‑‑ once those folks are in on the table, that we're making change, hopefully. And maybe it won't be a swab. Maybe they're taking what is already being collected and doing the screening from there. It's just hard when kids are ‑‑ we're seeing them at four months of age, and we're checking for congenital CMV, you know? The kid has been in day care for three months. And there are siblings at home that are smooching them. And so there's so many different ways that it can be transmitted. So, it's hard to definitively say. And often times they're going off of the brain calcifications and saying okay, it's probable, but the Valganciclovir treatment isn't easy. You know? You have to go in for labs every two weeks. And for families who don't have means of getting to their PCP every two weeks, that may not be realistic for those kids. So, yeah. I think having the universal screen would be really really helpful. 
   >> Okay. I'm sorry. I know everyone has wonderful questions. We are out of time. If you don't mind asking Kaitlyn and Derek out in the hallway so our next presenters can come in. Thank you all for coming. If you would leave your evaluation forms on the table, I will collect them. 
    [ End of realtime stenographic captioning ]