Bob Underwood, MD (Host): Welcome to Pediatric Insights, Advances and Innovations with Children's Health, where we explore the latest in pediatric care and research. And I'm your host, Dr. Bob Underwood. Today we're discussing sleep disorders in children with cystic fibrosis with Pediatric Pulmonologist, Aarti Shakkottai. Dr. Shakkottai, thank you for joining us today.

This is really a interesting subject.

Aarti Shakkottai, MD: Thank you. It's my pleasure to be here.

Host: So I'm going to start off with, let's go back to the basics. You are the expert in Pediatric Pulmonology at Children's Health, so if you can make it understandable for the rest of us, briefly give us a refresher on cystic fibrosis and help us understand why sleep issues, particularly obstructive sleep apnea, are a concern for these particular patients.

Aarti Shakkottai, MD: Absolutely. So cystic fibrosis is a genetic disorder that affects multiple organ systems, including the upper airway and sinuses, lungs, pancreas, liver, and the gastrointestinal tract. It is caused by mutations in a specific gene called the cystic fibrosis chance membrane conductance regulator gene. And this gene is responsible for coding a protein of the same name.

And this protein is typically found on the apical surface of epithelial cells, and is responsible for transporting chloride ions across the cell surface. And basically when this protein stops functioning, there is really thick mucus that builds up and surrounds these cells. And so within the lungs, the presence of this thick mucus leads to recurrent infections, progressive inflammation that ultimately culminates in respiratory failure.

 There is also thick mucus in the upper airway and sinuses that leads to rhinosinusitis, and nasal polyps. Within the pancreas, the buildup of mucus prevents release of digestive enzymes that are essential for absorption of nutrients from the diet, and so this leads to malnutrition and vitamin deficiencies that we so typically see in our individuals with cystic fibrosis. And it is all cystic fibrosis also leads to liver disease because there's obstruction of the biliary ducts within the liver. This is all stuff that we've known for a very long time. There is now data more recently that the CFTR, which is the protein that I was talking about in CF, is expressed in other non epithelial cells. It is also expressed in areas of the central and peripheral nervous system. And so, now we are looking at not just the pulmonary or GI manifestations or even the reproductive manifestations of CF, but some of the neurologic ones as well.

And sleep issues have long been reported among individuals with cystic fibrosis. The very first article on sleep apnea or any kind of sleep derangements in CF actually came out in 1983, and from then to now, there been articles saying that people with CF have difficulty falling asleep, staying asleep, struggle with daytime sleepiness.

When they do sleep at night, their sleep is restless, they have trouble breathing, snoring, all of those things. Historically, all of these complaints or issues have been attributed to their lung disease, their sinus disease, malnutrition. And one of my earliest work on this topic, which was actually published back in 2020 while I was still at the University of Michigan, found that sleep apnea in particular, was about three times higher in both children and adults with CF compared to those without CF, and we actually did match both our individuals with CF, with those without CF for age, gender, race and body mass index or BMI; and found that even with all of that matching that those with CF had more OSA. And interestingly, this was independent of lung disease severity, and this has now gone on to be supported by a few other studies, including a meta-analysis that came out back in 2021 that found prevalence of OSA to be 65% among children with CF, including those with either preserved lung function or even just a mild lung function impairment. So this is really exciting stuff. And this is all, even prior to modulators becoming so widespread.

Host: Yeah. And that's fascinating. I think that to me, the fact that the first studies were over 40 years ago, yet we're still revealing new information about OSA in the CF patient. It really is fascinating. So, once again, you're speaking as a professor at UT Southwestern Medical Center, so help us understand, because the next subject we're going into is Highly Effective Modulator Therapy or HEMT. Help us understand what that is and then we'll start to get into how does it transform lives and work.

Aarti Shakkottai, MD: Sure. So the Highly Effective Modulator Therapies are designed to correct the malfunctioning CFTR protein. So the first of the modulators was a potentiator called ivacaftor that came out back in 2012, which is when I first got into this field. And so I still remember that very vividly.

And now we've had several more of these therapies. And so from Kalydeco, which was the first of the modulators. To Symdek or combi Symdeko, Trikafta, and now, more recently, ALYFTREK. And these modulators have two components to them. One is a potentiator, which for all of them is still ivakaftor. And then you have correctors, which depending on the drug, are a little different.

So Lumacaftor, Tezacaftor, Elexacaftor and what they do collectively is to aid in trafficking of the CFTR protein to the cell surface and improve its functionality. And so in individuals with CF, depending on the severity of their mutation, they either have very little CFTR protein that makes it to the surface of the cells, or their CFTR protein is up there, but doesn't work as well. And these modulators help correct both of those issues.

Host: And so this is transforming lives in children with CF, from both a pulmonary and a nutritional perspective.

Aarti Shakkottai, MD: Absolutely. I mean, thanks to these modulators, we now have fewer children coming into the hospital with disease exacerbations. Children with CF are gaining weight, growing. I recently saw a paper that said that the number of children and adults who are now overweight and obese is increasing.

And I think one paper said a third of adults with CF are now overweight or obese, which I think is amazing considering what we've been dealing with the last so many years, which is trying to get the weight up in these individuals. So it's all thanks to these modulators and there's been data to support that these modulators help with sinus disease, with improving lung function, and improving, you know, reproductive capabilities in our individuals with CF. So really, dramatic improvements in many aspects of the disease.

Host: So you have some key findings from some recent studies regarding the prevalence of sleep apnea, obstructive sleep apnea in children who are on HEMT. How has that changed?

Aarti Shakkottai, MD: The reason I got into that study and wanted to do it is because of all the dramatic improvements that we've seen in our children with CF and since historically sleep issues have been attributed to either sinus disease or pulmonary disease, some combination of both malnutrition; I was curious to see if now with these modulators and all of those issues getting better or going away, do those sleep issues and specifically sleep apnea, go away or get better also, and what I found was really very surprising and not what we expected. And what we found, we looked at sleep studies in 49 children with CF, and we found that those who were on a modulator had four times more OSA compared to those who were not on a modulator, which was really mind blowing when we thought about it. And we went back and looked at several things including their lung function and nutritional status, specifically height, weight, and BMI.

And we looked at presence of upper airway pathology. So do they have sinus disease? Do they have large adenoids, tonsils? And none of it really was significant as a predictor of why these kids who were on modulator had more OSA. And that is something that we're still looking into at the moment, and that's some of our work that we're working on right now.

Host: But didn't the study show something about tonsilar hypertrophy as a independent risk factor?

Aarti Shakkottai, MD: Mm-hmm. It was an independent risk factor, even outside of modulator therapy. So that is something that has historically, in children without cystic fibrosis, one of the risk factors for obstructive sleep apnea is having large tonsils, large adenoids. And we knew that even from the general pediatric population, which is why in children who have sleep apnea, the first line of treatment is to have your adenoids and tonsils removed. And so what we were curious about was in the CF population historically, tonsilar hypertrophy or adenoid hypertrophy was not something that is either well reported or considered an issue. But what we found in this particular population was that, again, those that had OSA, regardless of whether they were on a modulator or not, tonsilar hypertrophy was a risk factor, which again, made sense as to kind of thinking about it broadly in children.

But it was interesting also that the modulators, despite all their benefit in the upper airway certainly didn't seem to address the tonsilar hypertrophy, so it was interesting from two angles.

Host: So now we know how important it is for physicians really to assess the upper airway pathologies for tonsilar hypertrophy and other things especially when they're taking care of patients with CF.

Aarti Shakkottai, MD: Absolutely. I mean, you'll hear me say this to my colleagues, to residents and fellows. When you are doing your history, doing your physical exam, look for those things. Look for, chronic rhinitis. Look for enlarged tonsils while you're doing your exam, and if they are present, even if you didn't ask about sleep kind of leading up to your exam, go back and ask about sleep. Go back and ask about snoring.

Host: Yeah, absolutely. So what is the standard diagnostic approach for OSA in children and when should a physician consider referring a child with CF for a sleep study?

Aarti Shakkottai, MD: The most important part of any history including a sleep history is trying to figure out what is happening at night. And because these children are sleeping, your parents are the best historians, they're trying to figure out are they snoring at night? Are they stopping breathing? Are they very restless?

Are they breathing through their nose, their mouth, what's going on there? And then on your exam trying to figure out is their nose chronically blocked? Are they mouth breathing, even in your clinic, do they have large tonsils? And if that is the case, you have a low threshold to refer for sleep study.

Because right now the gold standard for diagnosis for obstructive sleep apnea in children is an in-lab polysonography or sleep study. In adults, we have the ability to do home sleep apnea testing. Unfortunately, we're not there yet in children, and so when you have the suspicion, the best way to know for certain is to bring them in and do the sleep studyin the lab.

Host: What's one key takeaway that you would want to share with physicians who are caring for children with CF related to their sleep health?

Aarti Shakkottai, MD: I would say ask about sleep. The visits in patients with cystic fibrosis can often be really long because we're focused on so many aspects of their health, including their pulmonary health, their digestive health, their mental health, and adherence to medications and so on and so forth. But please don't ignore sleep when you're doing this history because we know that these children and adolescents suffer from poor sleep, even beyond sleep apnea.

Individuals with CF have difficulty falling asleep, staying asleep, are very restless at night. And I think identifying those things, asking about those things and seeking out treatment will help improve their health and wellbeing and quality of life and so much more.

Host: Oh, that's awesome. Thank you for sharing with us. And if people want to know more about the sleep disorders program, they can go to childrens.com/sleep and find out more about the program that you're on. Dr. Shakkottai, thank you so much for being with us today. I learned a lot, for sure.

Aarti Shakkottai, MD: Thank you. It was my pleasure.

Host: Absolutely. And thank you to our audience for listening to Pediatric Insights, Advances and Innovations with Children's Health, where we explore the latest in pediatric care and research. You can find more information at children's.com. And if you found this podcast helpful, please rate and review or share the episode and please follow Children's Health on your social channels.