During more than three decades of her career in pediatric pulmonology, Susanna McColley, MD, has seen the average life expectancy for children with cystic fibrosis advance from teenage years to age 61. In this episode, Dr. McColley details the evolution of cystic fibrosis diagnosis and treatment and discusses how she is addressing the ongoing disparities in CF research, education, and care.
Guest: Susanna McColley, MD, Attending Physician, Pulmonary Medicine; Professor of Pediatrics (Pulmonary and Sleep Medicine), Northwestern University Feinberg School of Medicine; Scientific Director for Interdisciplinary Research Partnerships, Stanley Manne Children’s Research Institute
Host: Patrick C. Seed, MD, PhD, FIDSA, Attending Physician, Infectious Disease; President & Chief Research Officer, Stanley Manne Children’s Research Institute; Children’s Research Fund Chair in Basic Science; Professor of Pediatrics (Infectious Disease) and Microbiology-Immunology, Northwestern University Feinberg School of Medicine
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Show Notes
- McColley was interested in cystic fibrosis (CF) from a young age. At the start of her career in medical school in the 1980s, the cause of CF was unknown, and clinical research programs for CF weren’t available. However, McColley continued to pursue a career in pediatric pulmonology and to study an early cellular marker of CF.
- While McColley was a fellow in 1989, the genetic cause of cystic fibrosis was discovered, spurring interest in treatments for the disease. She led some of the first clinical trials of these new CF drugs. Treatments helped increase the expected life expectancy from teens to 20s to, now, 56 years.
- In the mid-2000s, cystic fibrosis screening was recommended for all newborns, and states would determine their individual testing programs. McColley says there is significant evidence that early diagnosis of CF improves nutrition, childhood growth, and overall survival.
- McColley provides a brief history of the structural causes of disparities in CF screening. When gene variant panels for cystic fibrosis testing were first being developed, they excluded non-European variants, and CF carriers from other continents of birth such as Africa and Asia were missed. As a result, there is a lingering false bias of CF as a disease that only affects people of European ancestry and white people. This bias has also led to disparities in drug development.
- The consequences of delayed diagnosis of CF range from seizures and bleeding to death.
- McColley is leading Achieving Equity for Disease Prevention in Cystic Fibrosis, a campaign through the Centers for Disease Control and Prevention that aims to spread awareness of the disease and the importance of newborn screening.
- The diverse care team at Lurie Children’s Cystic Fibrosis Center is equipped to serve children with CF from all backgrounds in Chicago and beyond.
Transcript
[00:00:00] Patrick Seed, MD, PhD: This is In Pursuit, research perspectives from Ann & Robert H. Lurie Children's Hospital of Chicago. I am your host, Dr. Patrick Seed, president and chief research officer of Stanley Manne Children's Research Institute, one of the nation's largest freestanding pediatric research centers. Our guest today has over 30 years experience in the research, diagnosis and treatment of cystic fibrosis in children. And she's passionate about reducing healthcare disparities for children with CF. She's the scientific director for interdisciplinary research partnerships here at Manne Research Institute, an attending physician of pulmonary medicine at Lurie Children's and a professor of Pediatrics for pulmonary and sleep medicine at Northwestern University Feinberg School of Medicine. She's also currently the editor in chief of Pediatric Pulmonology. Our guest also serves as the associate clinical director for child health and the TL1 multidisciplinary training program director in child and adolescent health at NUCATS, the Northwestern University Clinical and Translational Sciences Institute. Dr. Susanna McColley, welcome to the podcast and thanks so much for joining me today.
[00:01:11] Susanna McColley, MD: Thank you very much, Pat. I'm really honored to be here and excited to talk about my passions in science.
[00:01:18] Patrick Seed, MD, PhD: Well, me too. I wanted to just start with a landscape view of cystic fibrosis because I think it's such a remarkable example of a disease that's really driven progressive and pioneering approaches to the improvements in more than just cystic fibrosis, really a way to contemplate how to tackle other diseases. And I think of things that are really unique and defining about it, like the very high-functioning family patient provider networks that have emerged from it, the natural history work that's both led to very organized clinical trials and also systematic reviews, right, of outcomes based on different care models that then have changed practice. Of course, you can't forget the activism for universal testing. And the whole field of precision therapeutics that owes so much to cystic fibrosis as a disease entity. So as a provider and researcher, what have you witnessed over the past couple decades in terms of the evolution of cystic fibrosis in terms of diagnosis and care?
[00:02:15] Susanna McColley, MD: When I started medical school, cystic fibrosis still had a prognosis of many childhood deaths, and the cause of it had not been discovered yet, but there was a signal in that they had discovered that there was an abnormality with chloride transport in cells. So I became very interested in this in medical school at Northwestern. And then I intentionally went through the Match program looking for programs that had strong cystic fibrosis research but also had started divisions in pediatric pulmonary medicine because that actually didn't exist as a specialty when I graduated. When I started my fellowship in pulmonology at Johns Hopkins, I wanted to do clinical research in cystic fibrosis, and I was told that I couldn't because there was no such thing. And so rather than fight, I got clinical research training in the field of sleep, which was really emerging. And I continued to do work in cystic fibrosis and did some CF research and training, but that positioned me for my current career. Now, when I was a second-year fellow at Johns Hopkins, the gene defect in cystic fibrosis was discovered, and it was a huge media coverage for this finding and a prediction that this would lead to a cure, to the extent that we had families calling in who had heard about this in the newspaper or on the radio or on the television and said, I heard there's going to be a cure. Can my child get that the next time I see you? And I have to say that that moment was my motivating moment that this discovery had to go into treatment. As you noted, there has been a lot of epidemiology that is really important for clinical trials, and in my early years, including when I started on the faculty at Northwestern and at Children's Memorial Hospital, now Ann & Robert H. Lurie Children's Hospital of Chicago, I had the opportunity to work with a large group in what's called the Epidemiological Study of Cystic Fibrosis and also with the Cystic Fibrosis Foundation registry and also did some small prospective studies. So that kind of helped me build things up and also define natural history, so that I was ready when there were opportunities to participate and ultimately lead clinical trials. Many people say CF is the greatest science story ever told. That discovery back in 1989 of the gene defect in cystic fibrosis called the cystic fibrosis transmembrane conductance regulator, that really led to more interest in new therapeutics for cystic fibrosis. And so we were able to build a clinical trials program and were then positioned to be a site when some of these amazing new therapies were being studied. The first one that was studied was called ivacaftor. It works for only about 9 percent of people with cystic fibrosis, but we were involved in the pivotal clinical trial. And, this was a placebo-controlled clinical trial. So, half the people were getting no medicine and half were getting medicine. It's the first time I ever did a clinical trial where I could actually tell, and frankly the participants could tell, that they were getting an active drug by the near-immediate change in their health. And that has really turned the tables in cystic fibrosis. And then you alluded to activism, advocacy earlier, so another thing that I had the privilege of being involved in is some conferences that took place between the Cystic Fibrosis Foundation and the Centers for Disease Control to evaluate the benefits versus risks of newborn screening for cystic fibrosis. And the evidence is really overwhelming that if you diagnose a baby in the first few weeks of life, they have not only better early nutrition but better growth throughout childhood and better survival. So, that was recommended, United States-wide in the mid-2000s. We implemented it in Illinois through 2008. And then that's something that has required studies and refinement over time. So starting with the clinical interest, becoming a clinical expert, doing the epidemiology clinical trials and now really turning more to public health is what's taken me forward, and there are always a lot more questions to answer.
[00:07:17] Patrick Seed, MD, PhD: What did the outlook look for a child who was born around the time that you sort of got into the field and were training? And what does that look like now, you know, for a child who can get all of these benefits for early diagnosis and is in the group of children who will respond to some of these most advanced therapeutics?
[00:07:35] Susanna McColley, MD: Well, when I was in medical school, we used a 1979 Robbins textbook of pathology, and the average life expectancy was teens but noted, optimistically, that some people were living into their twenties. Since the 1980s, with a lot of beneficial but incremental therapies, we slowly, slowly, slowly took that up over time. In 2022, the median life expectancy for someone born with cystic fibrosis is 56 years.
[00:08:12] Patrick Seed, MD, PhD: As a lot of your work now demonstrates, a sizable number of patients really have been left behind from these advances. And I wanted to ask you if you could describe that problem in general and the different facets of who's left behind and not yet benefiting fully from these decades of advancements.
[00:08:31] Susanna McColley, MD: The way I see the evolution of disparities in cystic fibrosis is a classic intersection of genetics and environment, an environment that includes people's experiences and biases in their care. So it's very interesting if you go back to the original report of cystic fibrosis from 1938, written by Dorothy Andersen, it was a case series. And she described clinical and pathological findings in children who were dying at about 5 years of age. And she noted the broad geographic and racial distribution of kids using terminology that we wouldn't necessarily use these days. When I was a resident, and finished this project when I was a fellow, I looked at the clinical course of our Black patients with cystic fibrosis who we saw at the clinic at Johns Hopkins and noted some phenotypic differences between the white population, what was otherwise a case control study. There were lots of problems with the way we put together our concepts of race and genetics that I recognize now, but during the time I was doing this study, the F508del variant, the one discovered in 1989 that is said to cause 70 percent of CF genes worldwide was estimated at that time. So we didn't do genetics in this study, because they weren't commercially available, but we did hypothesize that there might be a different gene variant distribution. So in spite of this single center study and some of the problems in our definitions, that turned out to be true for that population and many others. So if you look at genetics, the CF variants that cause disease, the distribution differs markedly by the continent of birth, which is probably the easiest way to look at that. So, what happened in CF testing is that panels were developed based on what were thought to be the most common CFTR genes or gene variants in the United States. And so for example, until very recently, the American College of Medical Genetics has recommended that people be screened for carrier status using a 23-variant panel that has genes of European origin. That same panel was adopted by a lot of states when newborn screening started. Those panels miss babies from what we would call demographically Black or African American, Hispanic, Asian, Indigenous kids. Now that's important both because you can have false negative carrier screening and because you can have false negative newborn screening and because people can use these limited European-derived panels diagnostically. There is also the issue not with the original description of cystic fibrosis but, as it went on, the United States and other commonwealth countries and Europe were doing most of the research. So as new variants were discovered, they continued to be enriched in European variants, and a language developed in the literature calling cystic fibrosis the most common fatal genetic disease in people of European origin or, even worse, white or Caucasian, and a bias was introduced through medical education and journals that made it appear that this is a European disease. But it's a disease that occurs all over the world, and there's actually some pretty good epidemiology on that in spite of the fact that it's not diagnosed and studied consistently across the globe. So when you look at a bias against diagnosis along with inadequate representation of genes, it sets up for a situation where disparities in health that occur in all disorders by race, ethnicity and social class are really amplified because the bias that CF is a white disease. And really a structural bias in testing, not who gets tests in the case of newborn screening but how they get tests, leads to false negative screening tests, both prenatally and, in my work, in newborn screening.
[00:13:19] Patrick Seed, MD, PhD: Tell me about CF newborn screening today.
[00:13:21] Susanna McColley, MD: So the first step in a newborn screening test is measurement of an enzyme that's released from an inflamed pancreas. When that is above a threshold, gene variants are tested. In most state programs, if you have one gene variant, you're called a positive screen and you get evaluated. If you have zero gene variants detected, you won't be evaluated. If you have two, it's generally assumed that you will have cystic fibrosis. This is a recessive disease, so a child has to inherit one defective gene from each parent. When babies have only one variant, nine out of 10 times they are going to be a carrier. But this often gets interpreted as, oh you're probably just a carrier, you can wait. The exact cause of any given child having a delayed diagnosis is not knowable when you use epidemiologic data. But what we can say is that children who are from minoritized backgrounds in the United States are first seen at a CF center significantly later, and that we have more false negative tests. So the benefits of newborn screening are much more likely to be realized by babies who are white and not Hispanic than by babies from other – and again, I have to be careful with my definitions – these are demographic categories. But the disparity is strong. Now, since we started newborn screening, the age at which kids are first seen has actually gone down in all populations. But the gap between white, non-Hispanic kids and kids who are Black or African American, Hispanic, Asian, Indigenous, it's the same. So as there's improvement, there is still the same level of disparity. And that can affect long-term health outcomes.
[00:15:25] Patrick Seed, MD, PhD: So what does happen when there is delayed diagnosis? What are the main consequences to that?
[00:15:29] Susanna McColley, MD: So there are two types of consequences, really. So people with cystic fibrosis have this elevated chloride in their sweat. That's been the diagnostic test since the 1950s. When you lose a lot of salt in your sweat, you can become salt-depleted. For babies who have a high surface area to their body weight, they can lose so much salt from their blood that they can have seizures, cardiac rhythm disturbances and death. Another catastrophic effect is that, because kids with cystic fibrosis don't absorb fat and, therefore, fat-soluble vitamins well, they can present with bleeding. For members of the audience who don't know this, vitamin K is a fat-soluble vitamin, and it's important for blood clotting. Vitamin A deficiency can cause catastrophic consequences to the eye that needs emergency surgery. And then one of the things we found in our contemporary research is that babies who are diagnosed late, late being an average of six to seven weeks, they're much, much more likely to be hospitalized for a pulmonary reason, what we call a pulmonary exacerbation, which can be life-threatening in the first year of life. The other longer-term influences really go back to the epidemiology, where we have known for a long time that your nutritional status, so this is both your height and weight percentiles, where you're on the growth charts, during preschool years have a strong influence on your lung function in later years. Lung disease is the major cause of death in cystic fibrosis. And this is not surprising, you know, malnourished kids for any reason can have more pulmonary consequences and more pneumonia and things like that, but it's very striking finding. And then, we also know that your height and weight during preschool actually predict whether or not you'll live to be an adult. We would anticipate that the influence on how early you're diagnosed would be strong. We recently published a paper on this. And the kids who were diagnosed earlier had better nutrition, better weight percentile in the first year. And there was a deficit in height in the later-diagnosed kids up to 5 years of age. We didn't have enough data to go further because we started looking at the year that CF newborn screening was implemented throughout the country, which was 2010. But remember that height at age 5, that weight in early life, those can have consequences on later lung function and how long people live. So this is an important finding and a reason that we're really pushing for earlier and more equitable diagnosis of all babies with cystic fibrosis.
[00:18:34] Patrick Seed, MD, PhD: I'm sure that the solution to this disparity problem is complex, because it's a complex problem, but clearly, a lot of it is around awareness, so I really wanted to ask you to tell me something about your awareness campaign through the CDC on the Chronic Disease Prevention program, Achieving Equity for Disease Prevention in Cystic Fibrosis.
[00:18:55] Susanna McColley, MD: This Centers for Disease Control and Prevention chronic illness awareness grant was a new mechanism when we applied. It's expanding the approach to chronic illness, and I think this is really important because we think about chronic illness prevention and public health, we go into those very valuable things, like tobacco smoking prevention and control, lifestyle influences on hypertension, obesity and heart disease. This expansion program recognized that rare disease is a major cause of death in the United States of America. We know it's a very major cause of death in children, right? A leading cause of death in children. So this opportunity came around before many of these papers were published . We were getting these data and recognizing the limitations of scientific publishing and conferences and thinking about, How do we get to the people who really need this information? So that can be primary care doctors, that can be public health departments who may not recognize how many babies may be missed in their states since these newborn screening programs are conducted by states. And then, the general public. We proposed in this grant that cystic fibrosis in the era of newborn screening and when more people are eligible for highly effective therapies, that cystic fibrosis disease is preventable. If you have a genetic disorder, you have the genetic disorder, but that we could delay and even prevent disease onset. Our strategies were to really work on education of primary care providers and public health officials who make decisions in newborn screening programs to show these disparities. We had a variety of educational efforts. We are working on holding a series of collaborative meetings between cystic fibrosis programs and public health officials, pairing up people in the same state, some of whom we knew from other research, worked closely together, and some who did not. And then, we are working currently on a public awareness program. We actually had to do a little bit of research in order to figure out what the knowledge and experiences are, so we did some survey studies where we surveyed both general population parents and parents of children with cystic fibrosis on their knowledge and experience. We were surprised to find how many parents, and these are parents whose kids are no older than 13, many didn't remember their kid having newborn screening. Most didn't know that cystic fibrosis was tested for on newborn screening. And there were big gaps in knowledge of cystic fibrosis based on demographic, but in this case, self-reported race and ethnicity. So those things serve the basis of a public awareness campaign that we are generating right now that we hope to get out through various media sources. Parents with cystic fibrosis generally reported satisfaction with the process, but what they also reported is that many of their children were seen well after the families were first notified of the positive newborn screening test and that many families felt that there was a long delay with a definitive diagnosis and that they didn't get enough disease education. So these are all actionable and we're hoping to take this forward, not just in designing a public awareness campaign but to iterate back into future educational activities.
[00:23:09] Patrick Seed, MD, PhD: Fantastic. How are parts of this, to you, a Chicago story? How is sort of Chicago and the proximity of Lurie Children's and our Center for Cystic Fibrosis influencing what you've done?
[00:23:23] Susanna McColley, MD: Of course, one of the reasons that being in Chicago and at Lurie Children's is so terrific is that we do serve a very diverse community. Chicago is, undoubtedly, still one of the most segregated cities in the United States, but nevertheless, our hospital serves kids from all over, not just the city but the state and beyond. And so we have a very diverse CF population. We particularly have a large Hispanic population, and we've known for many years that Hispanic people with CF have much worse outcomes. I mean, this has been known for 25 years. And it's not a soft worse outcome. It's life expectancy. So the experience, the clinical observations and the families, and particularly the families who we work with have been a driving force in this and also given us the opportunity to really ask questions and refine our approaches. The environment at Lurie Children's is so collaborative, and the survey work and upcoming focus groups are being run by our colleagues at Smith Child Health Outcomes Research and Evaluation Center. They've been so helpful. I know what I want to know, but I don't know how to construct a survey. I know what I want a focus group to be like, but I don't know how to set one up, and so this has been an invaluable collaboration for me. I would also say that the diversity of the staff that we're able to attract here, I'm very grateful to the National Organization for African Americans with Cystic Fibrosis, who really helped put together a lot of the ideas for the surveys of materials and to really be a great collaborator. And then I also just want to note that one of the issues with distribution of gene variants is that many of these wonder drugs that I've worked on extensively don't work for many of the CFTR variants that are seen more frequently in people who have other than European ancestry. And so that's another big challenge for us going forward is to be sure that we have highly effective medicines for everyone .
[00:25:59] Patrick Seed, MD, PhD: Totally agree. I think there's a big future for the next steps of precision therapeutics for this group that's currently not getting the benefits of the drugs and therapies that have been developed so far. Susanna, I really want to thank you for your time today, your expertise and the history you have in cystic fibrosis clinical practice and research is really marvelous. It's been fantastic to talk to you today.
[00:26:22] Susanna McColley, MD: Thank you. I'm delighted to talk to you too, Pat, and really appreciate this time.
[00:26:27] Patrick Seed, MD, PhD: For more information on Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital of Chicago, visit our website, Research.LurieChildrens.org.
