Dr Cori Cross (Host): Welcome to Peds Cast, a podcast brought to you by Children's of Alabama. I'm pediatrician Dr. Cori Cross. Today, we'll be discussing the Rare Infectious Disease Network, led by the University of Alabama at Birmingham. This group of 40 academic medical centers has cooperated closely for decades as the Collaborative Antiviral Study Group to investigate the natural history and treatment of rare congenital and perinatal infectious diseases.

Host: To dive into this topic, we are honored to have Dr. David Kimberlin here with us today. Dr. Kimberlin holds the Sergio Stagno Endowed Chair in Pediatric Infectious Diseases at the University of Alabama at Birmingham, where he is the Vice Chair for the Clinical and Translational Research and Co-director of the Division of Pediatric Infectious Diseases at the University of Alabama at Birmingham. He is also the principal investigator of the Congenital and Perinatal Infections Consortium and has received the 2022 Walter T. Hughes Distinguished Physician Award from the Pediatric Infectious Disease Society. Dr. Kimberlin, thank you for joining us today.

Dr David Kimberlin: Thank you very much for having me. I'm delighted to be here.

Host: So, tell us about the Rare Infectious Disease Network. What is the goal of this network?

Dr David Kimberlin: Well, the RDCRN, the Rare Diseases Clinical Research Network, is an NCATS NIH-funded entity that's comprised of actually 20 different consortiums. We are one of the 20, the Congenital and Perinatal Infections Consortium that you mentioned in your intro or CPIC. CPIC is one of the 20 consortiums that make up the RDCRN. And what the RDCRN's mission is, and certainly our component of it, is to try to advance the therapeutic options for patients with rare diseases.

Rare diseases are defined in the United States as being less than 200,000 total people affected across the entire country. And there's thousands of rare diseases. So if you look at the total number of rare diseases, even though they're affecting each a small number of people, about 10% of the United States population can qualify as having a rare disease. And yet, a vanishingly small percentage of them have any kind of therapeutic options. So, one of the main areas of emphasis that the NIH has put here with the RDCRN is to try to improve those percentages to get up to, you know, one in four rare diseases, for example, having a treatment option.

Host: Got it. And so because they are so rare, it's hard to have a study where you have a bunch in the same area because that just doesn't happen. So, you need to work across multiple departments to be able to get enough people to study that. Is that correct?

Dr David Kimberlin: That's exactly it. And it really makes sense. I mean, as you said in your question, it does not affect any given disease, does not affect that many people. And so, you need to go and kind of cast a broad net, if you will, and go to where a lot of different folks are in order to get enough people that have or affected by that particular disease, to be able to come onto a study and advance the field.

This is something that the predecessor to the CPIC, which had been called the Collaborative Antiviral Study Group or CASG, started back in the 1970s by Rich Whitley, who's been my mentor and friend for decades now. What they learned very early on is that if you have a rare, in our case, perinatal or congenital infection, you've got to have many, many sites that access a lot of different patients and provide care for a lot of different patients in order to be able to enroll on a systematic single protocol, research protocol and gather information from across the country, sometimes even across the world and, therefore, be able to learn enough about the disease and the diagnostics for the disease and the treatment of the disease to really advance the field and have the ultimate goal, which is to impact patients' lives.

Host: And so, tell us a little bit about how this has opened up research opportunities for you.

Dr David Kimberlin: It's been tremendous for me. I joined UAB, University of Alabama at Birmingham, in 1996 as a faculty member. I'd done a couple years of fellowship training prior to that here as well. Before that, I was in Dallas for all of my training up to that point. And so, I've been here for, you know, close to 30 years now. And it's, throughout that time, been a tremendous privilege to work with colleagues at other academic medical centers across the country and, as I said before, across the world in some of our studies, to be able to improve the lives of children and the families that take care of those children. It's really been a remarkable experience, that would not have happened had I not been in a place that had already kind of probed this, explored it, developed the framework to be able to do this kind of really important work. And I think all of us together had been able to make those advances, first and foremost, in conjunction and collaboration with the families themselves and then, in the process, to ask new questions. And those new questions are what the CPIC now is focusing on.

Host: Got it. So, Dr. Kimberlin, in the 25 years or so since you've been doing this, tell us a little bit about the studies that you've been a part of and how that research has changed patient care and outcomes.

Dr David Kimberlin: I think a couple of the bigger ones are either with neonatal herpes or congenital cytomegalovirus or CMV infection. With neonatal herpes, the CASG back in the 1980s had established that the current drug used to treat it, acyclovir, was a safer way to treat that particular infection. It's a viral infection that babies acquire during the birth process from their moms if the moms have the herpes simplex virus in the genital tract at the time. And by using acyclovir intravenously, it improved the likelihood that the baby would survive. And for those that survived, it, to some extent, improved their developmental outcomes.

During the 2000s, we did a subsequent study that was of oral acyclovir following that initial period of a few weeks of intravenous acyclovir. And what we found was that by giving oral acyclovir for six months after treatment for that acute infection, we can really improve developmental outcomes quite substantially for those babies that had their brains infected with the virus from the very beginning. And that was a really major kind of an advance that the group collaboratively together contributed to advancing the field with.

The other was congenital CMV. This is also an infection that babies can be born with, although this one is acquired during the pregnancy itself, it's an in utero infection, and it affects about one in 200 live births, it's the most common congenital infection in the United States. And what we did across a number of years was build upon earlier studies of antiviral treatment of babies that are symptomatic with CMV when they're born. And we learned initially that intravenous ganciclovir, a different antiviral drug, improved their likelihood of having better hearing outcomes, but we didn't really have the opportunity to continue IV ganciclovir for long, long periods of time, weeks and weeks of time because it's a hard medication to give.

So, there was a newer drug, an oral version, called valganciclovir that we had available to us through a partnership with the pharmaceutical company that makes it. And then, to be able to do studies, NIH-funded studies, of that oral treatment option for longer periods of time. And we found that giving that drug for six months as well in babies with symptomatic congenital CMV improved their hearing outcomes even further and improved their developmental outcomes, their neurologic outcomes.

I think those are two of our bigger contributions. We've had other things as well with influenza in young babies, with enterovirus infection in young babies. So, we have other ways that we've contributed. But in terms of really changing the standard of care, I think probably CMV and neonatal HSV are our bigger accomplishments.

Host: No, it's amazing. And they're not really that rare, those two diseases. I mean, what you're talking about in the treatments and what you've been able to accomplish, I'm sure that that has affected numerous babies and their families. So, as a pediatrician, this is something that we do see. And so, it's important to be doing this work.

Dr David Kimberlin: Well, I appreciate you saying that. We certainly hope that's the case and I think it likely is. With neonatal herpes, there's a couple of thousand babies born every year in the United States who develop neonatal HSV disease. And with CMV, it's probably more in the 20,000 range, but only about 10% of them are symptomatic at birth. So, probably another 2000 or so that would be eligible for valganciclovir treatment. So when you look at 3.6 million births a year, it can seem like a small number. But a few thousand babies impacted by these really quite devastating infections is a real impact. And to be able to have the opportunity to try to make their lives better has been something that's been very rewarding for All of us.

Host: So Dr. Kimberlin, tell us how having CPIC being based out of University of Alabama at Birmingham and Children's of Alabama, how has having it centered there affected the city of Birmingham and impacted Alabama?

Dr David Kimberlin: Throughout the years that either the Collaborative Antiviral Study group, or now the Congenital and Perinatal Infections Consortium has been in existence, it's been based out of University of Alabama at Birmingham and Children's of Alabama. This is where the central unit is. Just an absolutely phenomenally talented group of colleagues that I have the privilege of working with who know all about regulatory oversight of studies, know all about how to manage sites that are enrolling on studies, know all about how to do the sub-awards and subcontracts that are necessary to provide the funding for those studies, so that the NIH dollars that come to UAB can then get passed along to the sites that are doing the work.

All of that really is just something that really has not been able to be replicated in my judgment at any other institution. And so, having that kind of skillset available at Children's of Alabama and the University of Alabama at Birmingham not only impacts, not only effects or improves the likelihood of performing a study well through CPIC, or in the older days through CASG, but it also provides a certain amount, a certain level of expertise that can influence other researchers that are here at our institution, that might have a question about doing a multi-center trial in the critical care unit, for example, or in the outpatient setting as another example. And so, being able to have this. this cadre of really, really gifted and very experienced people in the field available not only for CPIC, but also available to other people doing additional research in our area is something that I hope anyway has really had that kind of positive impact. It certainly seems to have, in terms of career development and faculty development and, I think downstream of that as well, inpatient care.

Host: No, it definitely seems as if Children's of Alabama and University of Alabama at Birmingham are at the forefront of this, and really bringing true change to the treatment of these diseases. In summary, is there anything else you'd like to share with our listeners today or some take-home message?

Dr David Kimberlin: I think I'd like to, number one, thank them for taking time to listen to this. But number two, I'd like to pull out a thread here that I hope anyway I've touched on already, but it's just really, really critical. And none of this is possible, none of it is possible, without the patients and the families of those patients who put their trust in us, and I want families to hear our gratitude. What oftentimes, when we're meeting for the first time, is just a tremendously difficult situation for them because they've just been told of a diagnosis they didn't anticipate in their baby, which is kind of the worst thing you could think of that a parent would go through. And yet, they still put their trust in us and say, "Yes, I want to work with you all," I think is something that I just really cannot express deeply enough is meaningful to me and to my colleagues that do this work. We can only imagine what these families are going through and that they see us as an opportunity hopefully to improve their own child's life, but then also that opportunity to contribute to the greater good and the impact that it has on babies that have yet to be born, is something that really is a real gift and the opportunity to walk that journey with them, at least to the extent we can, is something that I want them to hear my gratitude for.

Host: That is so well said. Thank you for that. Dr. Kimberlin, this has been a great discussion. Thank you for joining us and sharing your expertise with us today.

Dr David Kimberlin: I really appreciate the opportunity. Thank you.

Host: For more information or to refer patients to Children's of Alabama, visit childrensal.org. That concludes this episode of Children's of Alabama Peds Cast. If you found this podcast helpful, please share it on your social channels and be sure to check out the entire podcast library for other topics that might be of interest to you. Please remember to subscribe, rate and review this podcast. Thanks for listening to this episode of Peds Cast. I'm your host, Dr. Cori Cross.