Approaches to Biliary Atresia Care at Cincinnati Children’s - Anna Peters, MD, PhD - Racial disparities in the early diagnosis of biliary atresia

All right. Well, um, the next speaker is Doctor Anna Peters, who, like Doctor Mike is a children's lifer at this point. But, uh, Doctor Anna Peters is currently the associate medical director for liver transplant. Uh, and she has a research focus that includes the genomic characterization of the donor immune system and liver allograft prior to implantation and at the time of acute cellular rejection. Uh, in order to more completely characterize the molecular process of acute liver transplant rejection in children. But today, we talk about a completely different topic that dovetails well with Doctor Mike's, um, um, talk about the early and appropriate time diagnosis with, um, specifically focusing on racial disparities in the early diagnosis of biliary atresia. So, Doctor Peters, All right. Thank you everyone for hanging in there with us. I am the last talk before the break. Um, so I look forward to your questions and some good conversation about this topic. I have no financial disclosures, but as a disclaimer, as Alex mentioned, I'm a PhD trained immunologist and cell biologist and not an epidemiologist, but Um, this project sort of stemmed from, uh, a collective clinical experience on the wards of what we were seeing in, uh, patients with biliary atresia, and the data discussed today, uh, come from the US health system, which is complicated and, uh, fractured and, um, may not be representative of other more unified homogeneous health systems across the world. So this is a case um that sort of prompted this study, and this is an 8 week old, uh, well-appearing full-term Hispanic male. Um, I was on call and received a phone call from the emergency department at a uh referring hospital, um, where this child had been sent for evaluation of sclerolicoris. And incidentally, looking back through his records, he had had a fractionated bilirubin measured on day of life too with an elevated direct bilirubin of 1.1 that was not followed up. Uh, in the ER, although he was well appearing, he had an elevated direct bilirubin, a high GGT cholestasis, and a common bile duct that was not visualized by ultrasound. So we emergently admitted him. He had a liver biopsy consistent with large duct obstruction and had a Kasai operation performed during this index hospitalization on day of life 62. So after that target date that we just discussed of Kasai, um, less than 45 days with the best outcomes. So the objectives today, we'll talk about, um, again, reinforce the timely evaluation of newborn jaundice and how it affects biliotresia outcomes and effects of race and social determinants of health on BA diagnosis and post-Kassai outcomes. So, uh, Doctor Mike just discussed very eloquently and thoroughly that, um, the early outcomes after BA, uh, diagnosis in the 1st 2 years of life to really avoid early liver transplant is the early diagnosis, the better. So, the, um, early diagnosis early Cassai leads to better outcomes. And um in summary of that same French paper and some other papers, um, there's less than 20% success rate of uh drainage after Casai if it's performed in infants over 90 days of age. Um, we know that the bilirubin level 3 months after Kasai predicts survival with native liver at 2 years. Um, with those greater than 2 at that time point having only a 20% 3-year transplant-free survival. And as we've discussed a little bit already and we'll talk more about in the Q&A period to follow, um, is there an age that's too young for Kasai? And it doesn't seem to be the case based on published literature as long as you've ruled out other causes, and that evaluation takes time. Um, and so realistically, making a diagnosis around 30 days of age, I think is probably the best we can get at this point in time. Um, as far as the US goes, we have competing guidelines on when to screen jaundiced infants. So, the, uh, this really puts the general practitioner, um, pediatrician, family practitioner, um, nurse practitioner who's seeing these infants in a very difficult spot, finding these needles in haystacks, where in North America, we have an incident. of 1 in 20,000 live births. So the AAP says send a fraction of bilirubin in formula-fed infants if they're jaundiced at more than 2 weeks, but you can wait up to 4 weeks in a breastfed infant, whereas NASA began, our pediatric GI Society sends us, says send fraction of bilirubin in all jaundiced infants. So what is a pediatrician to do here? Um, Doctor Mike already reviewed the, um, Baylor and Texas Children's Hospital experience with neonatal screening in which they did, um, Uh, fractionated bilirubin within the newborn period and then followed all positive screening test results up 2 weeks later. And the main advantage to this is that it decreased their time to diagnosis by about 1 month, um, which when we're talking about CASA outcomes, doing that CASA between 70 days versus, you know, 40 days, that really makes a difference in the outcomes and transplant for survival for those patients. More recent study utilizing this sort of same retrospective, um, newborns, uh, period screening in Utah, in the Intermountain Health System. They, uh, did a retrospective review of all newborns over a fifteen-year period that in this health system, um, it was their practice to send fractionated bilirubin on all infants and this was data that was already there, ready to be mined. So, um, those, the, what was included in the study were almost 253,000 well babies, including 18 BA infants. And those BA infants had an elevated conjugated bilirubin above the upper limit of normal, ranging from 0.6 to 4.5 in the newborn period. And this is again more confirmation that conjugated or direct bilirubin levels are elevated in the newborn period in VA infants, which can decrease our time to screening. Um, as far as prior studies, um, before our, uh, our study, there has been a long-standing, um, knowledge that race and socio socioeconomic factors are linked to VA outcomes dating back to 1995, in which it was first described that African-American infants were on average 2.5 weeks older than white infants at the time of CASAI. Um, those infants trended toward decreased post-Kasai survival, um, transplant-free survival, and non-Hispanic white infants, um, in the Texas Children's, uh, cohort had a shorter time to specialist referral compared to Hispanic or, um, African-American infants. And in a large, um, Study looking at um hospitalization data published in 2018, those, uh, when they looked at risk factors for those patients undergoing late Kasai, so CASai after Day of Life 60, those two important risk factors were that those patients, those infants were more likely to be African-American and also be uninsured. But, uh, to date, this is sort of what we know about socioeconomic factors that insurance status and, and race play a role in how quickly these infants get to subspecialty care. The objective of our study, um, was to determine the effect of race on VA diagnosis and post-Cassa outcomes in our cohort at Cincinnati Children's and then determine the association of socioeconomic factors on VA diagnosis and post-Cassa outcomes using a measure, um, uh, Neighborhood deprivation index, which I'll talk about a little bit more of what that is, that helps quantify, um, the degree of, um, deprivation, uh, a patient might be facing in their, uh, neighborhood. Our methods were, um, this is a retrospective single-center study that relied on, um, self-reported race within the EMR. We use the patient's address at the time of the first, uh, epic encounter that we used to calculate, um, neighborhood deprivation index. This calculation failed in a couple of subjects, um, one of which because they had a foreign address and three, had a PO box that couldn't be linked to a census tract. Um, the primary outcomes for our study were time to hepatology care. So this included outpatient clinic visit, emergency department visit, or hospital admission, um, in which a pediatric hepatologist became aware of the patient. Um, the time to hepatoport and arrest to be measured in days of life, and then survival with native liver at 2 years of age. The secondary outcomes were laboratory parameters at the time of Kasai, uh, at 3 and 12 months post HPE, achievement of biliary drainage, and, um, transplant measures including, uh, age at transplant, time on the waitlist, um, which has previously been linked to, um, race and socioeconomic status. Those patients tend to have longer waiting times, PE score, and exception points at the time of transplant. This is our study population which included 145 patients with a diagnosis uh code of biliary atresia, uh, over a 10-year period. Uh, 75 were excluded, um, because they didn't have, uh, either the Kasai performed not at Cincinnati Children's at an outside hospital or we didn't have, uh, full records available, or they were referred, uh, either for liver transplant or transplant evaluation. It left us with 69 patients, the majority of whom were white, and then we grouped um the non-white patients into uh 13 Black or African-Americans, um, 3 Asians, and then, uh, 3 identified as other. When we look at uh the time to first hepatology encounter based on race, there was a statistically significant increase in the, when these patients were referred to us by about 1 month. So the median time to hepatology encounter was um 67 days in non-white infants, um, which is a month later than white infants. As such, the time to liver biopsy timing from the patient's time of birth. Um, also was statistically significantly increased. And as a result, because of this late referral and late diagnosis, the rate of Kasai offering to non-white patients was 53% versus 84% in the white cohort. And when we did logis, you know, very, uh, logistic analysis, um, the odds ratio of receiving a Kasai, um, if you were white, you were almost 5 times more likely to receive a Kasai than if you were not white. Um, next, we looked at, um, components of, um, or the effect of socioeconomic status on, um, time to referral and post-Cassa outcomes using, um, a composite measure, uh, called the Neighborhood deprivation index. And instead of just looking at insurance status, sorry, my light went off, um, or, um, Which has been used in the past. This is a composite measure of, of six areas that has been used to uh measure degree of socioeconomic distress uh in other liver disease patients, in the transplant population, and other health outcomes. This is an example of how the data comes out of the algorithm, and this is a map of the city of Cincinnati, and you can see that those with the highest deprivation index, so this is measured from 0 to 1 with 1 being the maximum or most economically distressed area. This comes down to census tracts, so this bright yellow is the most highly deprived area, whereas the areas in blue are areas of uh Less economic distress. When we looked at the degree of exposure to neighborhood deprivation by race in BA infants, this was not different between white and non-white infants. Um, but, um, when we looked at those infants who received CSai, um, either, um, just straight with or without, um, those who did not receive a CSAi operation, uh, had increased, uh, deprivation index compared to those who did. Uh, and this transplant translated to transplant-free survival and that those, um, who were either transplanted by age of 2 or died, uh, had higher neighborhood deprivation index measures than those who, uh, survived to the age of 2. Once we controlled for race in a univariate analysis, the, those with high neighborhood deprivation index or the most economically distressed, um, infants. Uh, were less likely by about 50% to receive casai or to survive for 2 years with their native liver. So, uh, in summary, these infants are, uh, living in various neighborhoods of various economic backgrounds, and they're coming to us late. Um, and if they're coming to us late, they're probably coming to other transplant centers and other, uh, medical centers also late. So, um, I would advocate, and we can have more discussion about this in the chat, that we, um, Need to have uh Earlier screening and at the very least, all jaundiced infants really should have fractionated bilirubin measure by 2 weeks of age. So in summary, um, we've shown that racial and socioeconomic disparities are present in biliary atresia care. Um, recapitulating some further things, but again, showing that for the first time, these are distinct. Um, so, race and socioeconomic status individually affect referral timing and access to surgical treatment, and then socioeconomic status really, um, is, uh, affecting transplant-free survival independently of race in our patient population. And so this has led to initiatives with us trying to increase our partnership. Um, with newborn pediatric, uh, care within our region. So, uh, the pediatric Primary Care Center is Cincinnati Children's, um, group of primary care practitioners, and we did a grand rounds with them and as a result, they They have changed their practice and that any infant who gets a direct, I guess a total bilirubin measured for evaluation of jaundice, they just default automatically in the order set to send a fractionated bilirubin as well. And we're also collaborating with Health Fine and area birth hospitals to try to see how we can uh institute, um, newborn screening uh for direct bilirubin in our, in our area. And with that, I'd like to thank those who contributed to our study and particularly Julie Bond who is um a gastroenterologist uh practicing with us and some of our funding for statistics. And happy to take any questions. That was great, Anna. Um, while we're waiting for everyone to come up, I actually have a question for you regarding, um, Mandates and legislation. So, when we see major socioeconomic disparities, And we know, yes, at our organization, we can have a trigger for fractionated bilirubin. But if we start identifying areas where we know that there's something that could be done to to curb the, the disparities, has anyone ever successfully had a federal mandate to, to take that off of us begging people to do it and just saying this This needs to be a trigger, and these are the lists of triggers in your office that you have to have, and we'll start seeing a decrease in disparities. Has that ever happened? I, so as far as biliary attrition, not yet, but I think it's, it's time, and quite frankly, I think it's beyond time. Um, at least this disparity has been noticed since 1995. So nothing's changed because we haven't changed it. And so we, it's not just me, I think collectively, this is a call to advocacy and to really work with each other and to work with the federal government to figure out what exactly is needed to implement newborn screening, um, because, um, Number one, I think biliaryresia does meet the guidelines for a screenable disease in that um the incidence, even though it's rare in North America, is 1 in 20, 1 in 25,000, which is similar to CF which is included on the newborn screen. And we have an intervention that is timely and that um can really uh cost effectively uh prevent poor outcomes in these infants. So, what it gonna, is, what's it gonna take to get there? I think it's going to take collaboration between the AAP, between pediatric GI societies, if there's a surgical society, I, I'm not a surgeon, so I don't know. If, I think it's gonna take working together, um, to figure out how to do this on a national level in the United States. Um. I just, I just wonder if there's precedent in other diseases where this has, so I think for transplant, yes, um, so, particularly the kidney transplant, um, groups have advocated to, um, have immunosuppressive medications covered by, uh, Medicare, Medicaid for a certain time period after transplant because prior to their advocacy, a patient would get a kidney transplant, they get medications covered for a year. And then they'd be like, oops, I can't have my immunosuppressive medications any longer. That's changed because of that transplant group's advocacy with the government. Um, so I think that there's a precedent there as well. Um, we do have a poll question, uh, that people are participating in from Doctor Peters. What factors are associated with late, uh, Kasai, meaning a Kasai done, um, past 60 days of life. So our options are black race, lack of health insurance, or both. And so while we catch up with everybody, um, Doctor Akinmbi, um, who we know very well here in Cincinnati, has a couple of questions and points for you, Doctor Peters, to respond to. Doctor Kimby writes, um, babies are screened routinely with transcutaneous, uh, bilirubinometry, which does not give any indication for elevation of direct fraction. Um, are we, are you advocating going back to our old practice of obtaining fractionated billies on all babies, and then to follow that, um, 4 million babies are delivered in the US annually. What do you think the number needed to treat for universal newborn screening would be? Mm, OK. So, first question. I think, yes. I think we could potentially do it from a dry blood spot um with the 24 hour universal newborn screen, skin testings done that way. Uh, we'd have to look into, you know, what that would be, right? Uh, so the, the two studies that I talked about, the, the one from Texas Children's and the one from Utah, you know, every lab measures even direct bilirubin. Differently. So we'd have to come, this is, this is big, right? We'd have to come to a consensus about how we're going to measure what the cutoff is going to be and then who's gonna follow up on those results. So I think that has been sort of where the field is right now as far as trying to move this forward. Um, as far as number needed to treat for newborn screening, um, I don't know that we know that answer to this degree yet. And, so to get to that answer, I think we're gonna probably need more uh multi-center studies other than just the Texas Children's Experience, which had a very diverse population. Um, and the Utah experience, which was, um, greater than 90% white infants in that screening population. So I think we need to potentially have some more data from different larger health systems that are using vaccinated bilirubin. Um, before we're able to really calculate that, uh, you know, I can point out on the bilirubin screening, I think the Harperva Group also with the, with the Canadians, uh, published that it would cost $473,000 for every year gained to do a direct. Bilirubbin. So I think the cost of screening with the direct bilirubin is still sort of a problem there. Um, but, you know, the, the numbers are there. Uh, it is, it is suitable. The question is whether integrating it in the newborn screen, dry blood spot, you know, what are creative ways of doing it. In addition, uh, in Japan, they developed the percutane, uh, device to detect the direct moving. Um, they're getting the patent soon, so there is probably like a long term, maybe they need to recap it, depending on different skin color, but the, we can expect there is some sort of device will develop in the near future. Alex, and, um, and I'm just gonna put you on the spot a little bit in the sense of this. So what's for screening, you know, what's the benefit or the cost benefit for screening for all of the other, uh, uh, um, uh, neonatal disease processes, you know, you know, what's the cost of screening that is now standard? And, you know, what was the basis for those screening processes to be put in place? Cause the frequency of those, many of those conditions, um, are, are quite low. That's a great question. What do you think about that? Um, no, it predated our existence. We've been trying to look, I mean, looking at biliary treasure, we've been trying to look at our own data, um, to be able to get the cost differential of our own, looking at, you know, what, what are the, what is the opportunity cost? What are we losing by, you know, what. This is one of the things that for biliary treats it takes a lot of effort and cost upfront for delayed cost and, you know, both, both in clinical outcomes for patients but also in healthcare spending down the line. And so those numbers have been traditionally difficult for, for us to get at and we've tried. Um, but I think that also you can broaden that into context for all cholestatic liver disease, right? So I think it was very clear in the heart ofvat study that they identified biliary resia, but they also identified other things, and that's where I think the genetic testing and all those other things, you know, we've seen that. Baby, we've seen babies and we've seen young children who have a delayed diagnosis of PIC and they've been just absolutely excoriated. And so I think from itching and from and having jaundice, and so I think that there is opportunity not only for biliary to but also for, for beyond that. I, I was gonna say, Anna, I think that you brought up a really good point and that's the follow-up of, you know, we've had patients, and there are patients who have a direct bilirubin screen or who have identified. Um, but somewhere along the way in the healthcare system, it has either been missed or hasn't been followed, or there, there hasn't been that communication piece. And I didn't know if you had any insight into kind of, you know, within the paradigms of, of what we're working with, how, how we can work that, how health systems can work within their own kind of referral patterns within their own networks, um, for, for kids to be able to get these babies to, uh, like to the centers faster and earlier. So I think Having your center or your pediatric hepatologist or whoever manages biliary atresia and does this upfront screening, um, having their contact information, I think is probably the, the most cost-effective way to do it. I can't think of a systematic way that would apply to all health systems across the United States. Um, I do know that at Children's, at Cincinnati Children's, you can reach one of us on call 24 hours a day with questions within a 2 to 5 minute response period. So that's a free resource that any physician can, can utilize. It's called physician's Priority Link, and that's probably the best, most expeditious way within the Cincinnati, you know, region, even far to get advice on, on specific patients. OK, and can I ask one last question? Doctor Akimbi in an earlier with in one of the earlier sessions went back to the old fashioned tried and true stool card. Would that be possible that when you get, when your baby gets his or her final check, well baby check before they're discharged from the hospital. Could we integrate that education? Would that be cheaper? Would that be easier? I know, obviously, you know, all the deprivation index probably also predicts not paying attention to the stool card or losing the, you know, something, but is that a, is there a way to Even publicize it, you know, like put out ads on we get into, you know. Yeah, that's a great point. And, you know, Alex, Mike already pointed out, you know, this meta-analysis of different screening techniques and the stool color card was very, very effective in the Far East. And those systems, I would like to point out, are very different from what we're operating with in the United States in that, you know, we have a large population of children who are and families who are uninsured. Um, we don't have a centralized healthcare system. Um, we don't have centralized insurance for every child. So I think the utilization of that in a fractured, you know, siloed system like we have is going to be less effective. But are there ways locally within your own health system to try to implement that and see? That's where we get into like, if we at Cincinnati Children's only see 5 to 10 biliary atresia patients a year, how are we gonna actually measure how those efforts Decrease our referral time. Does that make sense with only 5 or 10 patients per year. So, I, I think the stool color card is nice, but practically, I don't know how we could implement it nationwide and actually show a difference. And I would also add to it that It wasn't as powerful in reducing the time to Kai to what we now would say is what we are aiming for less than 45 days. They reduced it to from 70 to 60 days. So, the direct bilirubin was very powerful in making it really a significant difference. So, I would say, you know, rolling out these, these things that they are. Everything is an effort. I would probably go with something, um. Uh, measurable, uh, you know, whether it is direct bilirubin or it's, uh, um, sulfurated, uh, urinary bile, bile acids, or, you know, you know, there, there may be different ways to be a little bit more specific on biliardresia. Uh, as I said, MMP 7 on the dry blood spots so that you don't pick up all the other cholestatic liver diseases which may not be a problem ever. Um, so that, I think, but I, I would go with something measurable. Uh, one last comment from Doctor Akindi. Parents are taught in China and Taiwan to upload a photo of their baby's stool to a website. Um, where their stool is evaluated by, uh, probably an AI system, but I get that, you know, you'd always find those holes in it. I'm sure, you know, do patients have access to durable internet or, you know, ways to send these photos, but all, all hopeful, you know, ideas to, to mitigate such a, can what can be a catastrophic disease. So I'd like to point out, I'd like to point out that Doctor Akinbi was one of my attendings on my NICU rotation. Back in the day. So we're full circle and we should talk more. Um, I'm not done with this problem yet. Greg, I think you're muted. Amy, I'm sorry, Amy's going to touch on this because for our post-op cassa, we actually ask the families to send pictures at least a couple of times a week. Sometimes some of the families will send them daily. So we see a lot of pictures of stool and diapers, um, and it is a mechanism for us to try to optimize their recovery trajectory. A, I would be useful for that too. Um, well, thank you all. Thank you for another great session, Ana, and the panel. Um, we're gonna take a 15-minute break here, so we'll restart, we'll try to restart promptly here at, um, 1:15 10:15 Eastern time. So, Coffee, bio. See you in a few.